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CHEMICAL HAZARDS
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ISBN 0-471-26883-6
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CONTENTS
v
vi CONTENTS
INTRODUCTION:
TOXICOLOGICAL CONCEPTS
TOXICOLOGICAL CONCEPTSSETTING
EXPOSURE LIMITS
Nick H. Proctor, Ph.D.
3
4 TOXICOLOGICAL CONCEPTS
The following terms of measurement are ducting airways between the nasopharynx and
commonly used in toxicological testing and in alveoli. They are lined with ciliated epithelium
industrial hygiene practice: and coated with a thin layer of mucus secreted
primarily by goblet cells in the upper airways
ppm: Parts of vapor or gas per million parts and primarily by Clara cells at the bronchiolar
of air by volume level. This mucous covering terminates at the
lm covering the alveolar membrane. The
mg/m3: Milligrams of a substance per cubic
surface of the airways serves as a mucociliary
meter of air
escalator, moving particles up to the oral cavity,
mg/l: Milligrams of a substance per liter where they are swallowed and excreted or
of air expectorated.
The ciliated cells are most vulnerable to
damage. The most frequent degenerative
changes in these cells are loss of cilia, necrosis,
TOXICOLOGICAL CONCEPTS
and sloughing of cells into the airway lumen.
Necrosis and desquamation of nonciliated and
secretory cells are less frequently observed.
Routes of Entry of Chemicals into
After acute mild insult the nonciliated cells
the Body
proliferate and the epithelium regenerates to
normal. In the airways, nonciliated basal cells
In the occupational setting, inhalation is the
are the main proliferating population. In the
most important route of entry of chemical
bronchioles, the Clara cell is the main precur-
agents into the body, followed by contact with
sor cell for regeneration. Because of the deli-
skin and subsequent cutaneous absorption.
cate nature of the respiratory tract epithelium
Although the gastrointestinal tract is a poten-
and the close proximity of subepithelial blood
tial site of absorption, the ingestion of signi-
vessels, an inammatory response occurs to all
cant amounts of chemicals is rare in the
but the mildest form of injury. Many lesions are
occupational setting.
therefore diagnosed as rhinitis, tracheitis, and
bronchiolitis and qualied as acute, subacute,
Inhalation
and chronic depending on the stage of the
The respiratory tract is exposed to chemi- response.
cals in the inspired air. The two main factors If the insult persists, hyperplasia (cell pro-
that determine the tissue responses to chemi- liferation) proceeds and leads to an abnormal
cals are the functional anatomy of the respira- epithelium. Injury produced by chronic expo-
tory tract and the physicochemical nature of sure to irritants such as SO2, NO2, O3,
the material.13 formaldehyde, and tobacco smoke includes
The respiratory tract may be divided into undifferentiated basal cells (hyperplasia), squa-
three major regions: the nasopharyngeal (upper mous metaplasia, and goblet cell metaplasia. In
airways), the tracheobronchial tree (lower practice, many irritants produce responses
airways), and the pulmonary (alveoli). between mild and severe, and various combi-
The nasopharynx begins with the anterior nations of degeneration, inammation, and
nares and extends down to the larynx. The proliferation may be observed.
nasal passages are lined with vascular mucous The lower respiratory tract (pulmonary
epithelium composed of ciliated epithelium region or alveolar ducts and sacs) is the area
and scattered mucous glands. The nasopharynx where gas exchange occurs. Alveolar sacs, clus-
lters out large inhaled particles and is where ters of two or more alveoli, branch from alve-
the relative humidity is increased and the tem- olar ducts. It is generally considered that there
perature of the air is moderated. is a total of approximately 300 million alveoli
The airways (trachea, bronchi, and bron- in the lungs of adult humans.4 The total alveo-
chioles or tracheobronchial tree) serve as con- lar surface area in the lungs of adult humans is
Toxicological ConceptsSetting Exposure Limits 5
The epidermis consists of several types of The skin and its associated lm of lipid and
cells. The epidermal cell type apposed to the sweat may act as an effective barrier that
dermis is the stratum germinativum (basal cell the substance cannot penetrate
layer), over which are the stratum spinosum,
stratum granulosum, stratum ludicum, and the The substance may react with the skin
outermost layer or stratum corneum. The basal surface and cause primary irritation (acids,
cell layer consists of one layer of columnar alkalies, many organic solvents)
epithelial cells. On division, the basal cells
are pushed up and become the stratum spin- The substance may penetrate the skin and
osum, which consists of several layers of cells. cause allergic contact dermatitis
As these cells approach the surface of the (formaldehyde, nickel, phthalic anhydride)
skin they become larger and form the stratum
granulosum. The agent may penetrate the skin, enter
At this point the nuclei are broken up, the blood, and act systemically (aniline,
resulting in the death of the cell. The next parathion)
layer, stratum ludicum, is ill dened except in
areas of thick skin, and is said to contain To pass into the skin, the substance must
eleidin, a transformation product of the kera- enter through one or more of the following
tohyalin present in the stratum granulosum. routes: the epidermal cells, the sweat glands,
In the outermost layer, the stratum the sebaceous glands, or the hair follicles. The
corneum, the eleidin has been converted into pathway through the stratum corneum and the
keratin, which represents the ultimate fate of epidermal cells is the main avenue of penetra-
the epidermal cell. Keratin, continuously tion, as this tissue constitutes the majority of
sloughed off or worn away, is replaced by the the surface area of the skin.
cells beneath it. The time required for a basal The stratum corneum plays a critical role
cell to migrate from the stratum germinativum in determining cutaneous permeability.
to the outer part of the stratum corneum is esti- Absorption is faster through skin that is
mated at 2628 days. abraded or inamed. Chemicals that are not
The dermis is a thick brous network of normally considered hazardous may be dan-
collagen and elastin and is composed of two gerous to individuals suffering from active
layers. The outer, thinner layer is the papillary inammatory dermatoses.
layer, which has prominent papillae that merge The skin not only is a barrier to restrict
with the thick reticular layer. The papillae are diffusion of chemicals into the body, it is also
well supplied with blood by the capillaries that an organ that can metabolize a variety of topi-
are prominent in them, which serves the basal cally applied substances before they become
cell layer in the dermis with nutrients. systemically available.14 The skin has many of
The dermis contains several types of cells, the same enzymes as the liver. The activities of
including broblasts, fat cells, macrophages, several cutaneous enzymes in whole skin
histiocytes, mast cells, and cells associated with homogenates have been measured and com-
the blood vessels and nerves of the skin. The pared to hepatic activity in the mouse.15 The
predominant cell is the broblast, which is activities of the enzymes in the whole skin
associated with biosynthesis of the brous pro- homogenates were typically 26% of the
teins and ground substances such as hyaluronic hepatic values. However, there is evidence that
acid, chondroitin sulfates, and mucopolysac- the enzymes are present primarily in the epi-
charides. dermis. Because the epidermis makes up only
The appendages of skin are hair follicles, 23% of the total skin, the real activities may
sebaceous glands, eccrine and apocrine sweat range from 80% to 240% of those in the liver.
glands, hair, nails, and arrector pili muscles. Enzyme systems present include a cytochrome
When a substance contacts the skin, P-450 system and a mixed-function oxidase
various actions are possible: system.
8 THE STANDARDS SETTING PROCESS
sures in this range. An averaging period start-up Permissible Exposure Limits (PEL)
other than 15 minutes may be recommended for all workers covered by the Act.
when this is warranted by observed biological
effects.
Threshold Limit Value-Ceiling (TLV-C): The REFERENCES
concentration that should not be exceeded
during any part of the working exposure. 1. Glaister JR: Principles of Toxicological Pathology,
In the absence of a STEL, excursions in pp 6274. Philadelphia, PA, Taylor &
worker exposure levels may exceed three times Francis, 1986
the TLV-TWA for no more than a total of 30 2. West JB: Respiratory PhysiologyThe Essen-
tials. Baltimore, MD, Williams & Wilkins,
minutes during a workday, and under no cir-
1985
cumstances should they exceed ve times the
3. Gordon T, Amdur MO: Responses of the res-
TLV-TWA, provided that the TLV-TWA is piratory system to toxic agents. In Amdur
not exceeded. MO, Doull J, Klaasen CD (eds): Casarett and
Skin Notation. Substances on the list fol- Doulls Toxicology, 4th ed, pp 383406. New
lowed by the designation Skin refer to the York, Pergamon Press, 1991
potential signicant contribution to the overall 4. Charnock EL, Doershuk CF: Development
exposure by the skin route, including mucous aspects of the human lung. Pediatr Clin North
membranes and the eyes, either by contact with Am 20:275292, 1973
vapors or, of probable greater signicance, by 5. Weibel ER: Morphometry of the Human Lung.
direct skin contact with the substance. New York, Academic Press, 1963
6. Salem H: Principles of inhalation toxicology.
TLVs are revised by the ACGIH annually
In Salem H (ed): Inhalation Toxicology, pp
as new information becomes available. Each
134. New York, Marcel Dekker, 1987.
year, additional substances of interest are added 7. Raabe OG: Deposition and clearance of
to the TLV list. Certain compounds that are inhaled particles. In Gee JBL, Morgan
proven or suspected carcinogens in humans WKC, Brooks SM (eds): Occupational Lung
such as benzidine, 4-aminodiphenyl, and 4- Disease, pp 138. New York, Raven Press,
nitrodiphenyl have no TLV value, and human 1984
exposure to these agents should be avoided. 8. Raabe OG et al: Regional deposition of
Note: For a detailed discussion of carcinogenic inhaled monodisperse coarse and ne parti-
risks to humans, the publications of the IARC cles in small laboratory animals. Ann Occup
should be consulted.17 Hyg 32, Suppl 1:5363, 1988
9. American Conference of Governmental
Industrial Hygienists (ACGIH): 19941995
Threshold Limit Values and Biological Exposure
OSHA Standards Indices, p 45. Cincinnati, OH, ACGIH, 1994
10. Kennedy GK Jr :Inhalation toxicology. In
The rst occupational safety and health stan- Hayes AW: Principles and Methods of Toxicol-
dards were set when, with only minor changes, ogy, 2d ed, pp 361382. New York, Raven
the 1968 ACGIH list of nearly 400 TLVs, as Press, 1989
well as certain standards of the American 11. Hesterberg TW, Hart GA: Comparison
National Standards Institute (ANSI), were of human exposures to berglass with
incorporated into the WalshHealey Public those used in a recent rat chronic inhalation
Contracts Act. They thereby became limits of study. Regul Toxicol Pharmacol 20:S35S47,
1994
exposure for employees of federal government
12. NIOSH (National Institute for Occupational
contractors.
Safety and Health): NIOSH Manual of Ana-
Subsequently, under the authority of the lytical Methods, Method 7400, Revision 3.
Occupational Safety and Health Act of 1970, Washington, DC, US Government Printing
these same 1968 TLVs and ANSI standards Ofce, 1989
were promulgated by the Occupational Safety 13. Rongue EL: Skin structure, function, and
and Health Administration (OSHA) as the biochemistry. In: Marzulli FN, Maibach HI
10 REFERENCES
(eds) Dermatotoxicology, 3rd ed, pp 170. New 16. American Conference of Governmental
York, Hemisphere 1987 Industrial Hygienists (ACGIH): 1994
14. Noonan PK, Wester RC: Cutaneous bio- 1995 Threshold Limit Values for Chemical Sub-
transformations. In: Marzulli FN, Maibach stances and Physical Agents and Biological
HI (eds) Dermatotoxicology, 3rd ed, pp 7194. Exposure Limits. Cincinnati, OH, ACGIH,
New York, Hemisphere, 1987 1994
15. Pohl R, Philpot R, Fouts J: Cytochrome P- 17. IARC Monographs on the Evaluation of Car-
450 content and mixed-function oxidase cinogenic Risks to Humans, Vols 183. Lyon,
activity in microsomes isolated from mouse France, International Agency for Research on
skin. Drug Metab Dispos 4:442450, 1976 Cancer, 19722002.
Part
II
13
14 ACETAMIDE
5. Kane LE, Dombroske R, Alaire Y: Evaluation Uses. Cryoscopy; organic synthesis; general
of sensory irritation from some common solvent; lacquers; explosives, soldering ux;
industrial solvents. Am Ind Hyg Assoc J wetting agent; plasticizer
41:451455, 1980
6. Egle JL Jr: Effects of inhaled acetaldehyde
and propionaldehyde on blood pressure and Exposure. Ingestion; inhalation; skin absorp-
heart rate. Toxicol Appl Pharmacol 23:131135, tion
1972
7. Kruysse A, Feron VJ, Til HP: Repeated expo-
sure to acetaldehyde vapor. Studies in Syrian Toxicology. Acetamide is a mucous mem-
golden hamsters. Arch Environ Health brane irritant, a liver toxin, and a carcinogen in
30:449452, 1975 animals.
8. IARC Monographs on the Evaluation of the Car- There are no data regarding the toxicity of
cinogenic Risk of Chemicals to Humans, Vol 71, acetamide to humans.
Re-evaluation of some organic chemicals, In animals, acetamide was stated to be a
hydrazine and hydrogen peroxide, pp mild irritant to skin and eyes, although exper-
319335. Lyon, International Agency for imental details were not available. Oral admin-
Research on Cancer, 1999
istration of acetamide to rodents produced
9. Feron VJ, Kruysse A, Woutersen RA:
Respiratory tract tumors in hamsters exposed lethality with doses of 17 g/kg.1 In another
to acetaldehyde vapor alone or simultane- report, single oral dose LD50 values for male
ously to benzo(a)pyrene or diethylni- rats and male mice were 10.3 and 10.1 g/kg,
trosamine. Eur J Cancer Clin Oncol 18:1331, respectively.2 Minor changes in liver histology
1982 occur after acute exposures in rats.1
10. Woutersen RA, Appleman LM, et al: Inhala- Oral doses of 0.3 g/kg acetamide adminis-
tion toxicity of acetaldehyde in rats. III. Car- tered on days 6 through 18 of gestation pro-
cinogenicity study. Toxicology 41(2):213231, duced no toxicity or terata in rabbits. No
1986 maternal toxicity was seen at 1 g/kg, although
11. Woutersen RA, Feron VJ: Inhalation toxicity one rabbit aborted; fetal numbers and body
of acetaldehyde in rats. IV. Progression and
weights were lowered, with no terata. At 3 g/kg,
regression of nasal lesions after discontinua-
tion of exposure. Toxicology 47:295305, 1987 maternal toxicity was encountered, fetal
12. Heck H: Mechanisms of aldehyde toxicity: numbers and weights were reduced, the
Structure activity studies. CIIT Activities number of dead implants was elevated, and
5(10):106, 1985 cleft palate was seen.1 No reproductive, embry-
13. World Health Organization: Environmental otoxic, or teratogenic effects were observed in
Health Criteria 167 Acetaldehyde, 129pp. rats.1
International Programme on Chemical Acetamide produced benign and malignant
Safety (IPCS), Geneva, 1995 liver tumors in rats after oral administration. In
male mice, an increased incidence of malignant
lymphomas also was observed.2
Acetamide was mutagenic in Escherichia coli
and Salmonella typhimurium; this effect was
independent of dose. Acetamide produced
ACETAMIDE morphological transformation in Syrian
CAS: 60-35-5 hamster embryo cells in the absence of meta-
bolic activation. However, acetamide did not
CH3CONH2 induce reversions in several Salmonella
typhimurium strains.1
The IARC has determined that there is
Synonyms: Acetic acid amide; ethanamide sufcient evidence of carcinogenicity for
acetamide in experimental animals and that it
Physical Form. Deliquescent crystals is possibly carcinogenic to humans.3
ACETIC ACID 15
ACGIH has not established a threshold throat, with pharyngeal edema and chronic
limit value for acetamide. bronchitis.1 Unacclimatized humans experi-
ence extreme eye and nasal irritation at con-
centrations in excess of 25 ppm; conjunctivitis
REFERENCES from concentrations below 10 ppm has been
reported.1
1. Kennedy GL, Jr: Biological effects on In one case report a 37-year-old male
acetamide, formamide, and their monomethyl maintenance tter was accidentally exposed to
and dimethyl derivatives. CRC Crit Rev Toxicol a large cloud of hot acetic acid while discon-
17:129182, 1986
necting a pressurized pump.2 The patient suf-
2. IARC Monographs on the Evaluation of the Car-
fered rst-degree burns on the hands and face
cinogenic Risk of Chemicals to Man, Vol 7, Some
anti-thyroid and related substances, nitrofu- and developed progressive dyspnea. At 3
rans and industrial chemicals, pp 197200. months there were persistent extensive crack-
Lyon, International Agency for Research on les in the basal area of the lungs, widespread
Cancer, 1974 bronchial inammatory changes, and diffuse
3. IARC Monographs on the Evaluation of the moderate interstitial pneumonitis that
Carcinogenic Risk of Chemicals to Humans, Vol promptly improved after treatment with corti-
71, Re-evaluation of some organic chemicals, costeroids and bronchodilators.
hydrazine and hydrogen peroxide. pp In a study of ve workers exposed for 712
12111221. Lyon, International Agency for years to concentrations of 80200 ppm at
Research on Cancer, 1999
peaks, the principal ndings were blackening
and hyperkeratosis of the skin of the hands,
conjunctivitis (but no corneal damage), bron-
chitis and pharyngitis, and erosion of the
exposed teeth (incisors and canines).3 Digestive
ACETIC ACID disorders with pyrosis and constipation have
CAS: 64-19-7 also been reported at unspecied prolonged
exposures.4
CH3COOH Chronic exposure to fumes of heated
glacial acetic acid in a canning factory has been
associated with a late airway response resulting
Synonyms: Ethanoic acid; ethylic acid; in chronic inammation and severe bronchial
methane carboxylic acid; vinegar (46% solu- asthma. Inhalation challenge induced a late
tion in water) asthmatic response, conrming sensitization.5
A study of cancer mortality among 1359
Physical Form. Liquid workers involved in the production of acetic
acid and acetic anhydride found that mortality
Uses. Production of cellulose and vinyl from all causes decreased but mortality from
acetate; dyeing; pharmaceuticals and food prostate cancer was signicantly increased,
processing based on six deaths. Measurements of acetic
acid levels were not made for most of the study
Exposure. Inhalation period, but recent monitoring found exposures
ranging between 0.1 and 1.2 ppm.6
Toxicology. Acetic acid vapor is a severe irri- Glacial (100%) acetic acid caused severe
tant of the eyes, mucous membranes, and skin; injury when applied to the eyes of rabbits; in
chronic exposure may cause bronchitis and humans it has caused permanent corneal opaci-
cracking and darkening of exposed skin. cation.7 A splash of vinegar (410% acetic acid
Exposure to 50 ppm or more is intolerable solution) in the human eye causes immediate
to most persons and results in intensive pain and conjunctival hyperemia, sometimes
lacrimation and irritation of the eyes, nose, and with injury of the corneal epithelium.7
16 ACETIC ANHYDRIDE
Exposure. Inhalation
REFERENCES
Toxicology. Acetic anhydride vapor is a
1. AIHA Hygienic Guide Series: Acetic Acid. Akron, severe irritant of the eyes, mucous membranes,
OH, American Industrial Hygiene Associa- and skin.
tion, 1978 Humans exposed to undetermined but
2. Rajan KG, Davies BH: Reversible airways
high vapor concentrations complained imme-
obstruction and interstitial pneumonitis due to
acetic acid. Br J Ind Med 46:6768, 1989
diately of severe conjunctival and nasopharyn-
3. Guest D et al: Aliphatic carboxylic acids. In geal irritation, harsh cough, and dyspnea.1
Clayton GD, Clayton FE (eds): Pattys Indus- Workers exposed to vapors from a boiling
trial Hygiene and Toxicology, 3rd ed, rev, Vol 2C, mixture complained of severe eye irritation and
Toxicology, pp 49094911. New York, Wiley- lacrimation.1 The immediate effect of exposure
Interscience, 1982 to vapor concentrations above 5 ppm is acute
4. Hazard Data Bank: Sheet No 64, Acetic Acid. irritation of the eyes and upper respiratory
The Safety Practioner, pp 1112, April 1985 tract; inhalation of high vapor concentrations
5. Kivity S, Fireman E, Lerman Y: Late asthmatic may produce ulceration of the nasal mucosa
response to inhaled glacial acetic acid. Thorax and, in some instances, bronchospasm.2
49(7):7278, 1994
Delayed deaths due to acetic anhydride expo-
6. Whorton MD, Amsel J, Mandel J: Cohort
mortality study of prostrate cancer among
sure have been reported. In one case, a worker
chemical workers. Am J Ind Med 33(3): sustained burns to 35% of his body after the
293296, 1998 explosion of a drum of acetic anhydride; death
7. Grant WM: Toxicology of the Eye, 2nd ed, pp occurred after 67 days from progressive lung
8082, Springeld, IL, Charles C. Thomas, damage that included pneumothoraces and
1974 bronchopulmonary stulae.3 Autopsy revealed
8. Morita T, Takeda K, Okumura K: Evaluation extensive brous adhesions within the pleural
of clastogenicity of formic acid, acetic acid and cavity.
lactic acid on cultured mammalian cells. Mutat Both the liquid and the vapor can cause
Res 240(3):195202, 1990 severe damage to the human eye; this is char-
acterized by immediate burning, followed some
hours later by an increasing severity of reaction
with corneal and conjunctival edema.1 Intersti-
tial corneal opacity may develop over a period
ACETONE 17
Topical application of 1 ml of acetone for Acetone may be weakly genotoxic, but the
90 minutes produced reversible skin damage to majority of assays were negative.7 It was not
humans.8 tumorigenic in skin painting studies in mice.
Acetone is metabolized mainly in the liver The 2003 ACGIH threshold limit value-
by three separate pathways, leading to the time-weighted average (TLV-TWA) for
production of glucose with the subsequent acetone is 750 ppm (1780 mg/m3) with a
liberation of carbon dioxide.7 None of the short-term excursion level of 1000 ppm
intermediate metabolites appears to be toxic, (2380 mg/m3).
with the possible exception of formate. Acetone
and acetone-derived carbon dioxide are
excreted in expired air and have little tendency REFERENCES
to accumulate in the body. 1. National Institute for Occupational Safety
High concentrations of acetone were and Health, US Department of Health, Edu-
required to produce death in animals; the 4- cation and Welfare: Criteria for a Recom-
hour inhalation LC50 value is 32,000 ppm for mended Standard . . . Occupational Exposure to
rats.9 Administered in the drinking water Ketones. DHEW (NIOSH) 78173. Wash-
for 13 weeks, the minimal toxic doses were ington, DC, US Government Printing
20,000 ppm for male rats and mice and Ofce, 1978
50,000 ppm for female mice.10 The kidney, 2. Nelson KW, Ege JF Jr, Ross M, et al: Sensory
hematopoietic system, and testis were target response to certain industrial solvent vapors.
organs in male rats, and the liver was the target Am Ind Hyg Assoc J 25:282285, 1943
3. DiVincenzo GO, Yanno FJ, Astill BD: Expo-
organ for mice.
sure of man and dog to low concentrations
In animal studies acetone has been found
of acetone vapor. Am Ind Hyg Assoc J
to potentiate the toxicity of other solvents by 34:329336, 1973
altering their metabolism through induction of 4. Raleigh RL, McGee WA: Effects of short,
microsomal enzymes, particularly cytochrome high-concentration exposures to acetone as
P-450. Reported effects include: enhancement determined by observation in the work area.
of the ethanol-induced loss of righting reex in J Occup Med 14:607610, 1972
mice by reduction of the elimination rate of 5. Ross DS: Short communicationsacute
ethanol; increased hepatotoxicity of com- acetone intoxication involving eight male
pounds such as carbon tetrachloride and workers. Ann Occup Hyg. 16:7375, 1973
trichloroethylene in the rat; potentiation of 6. Dick RB, Setzer JV, Taylor BT, et al:
Neurobehavioral effects of short duration
acrylonitrile toxicity by altering the rate at
exposures to acetone and methyl ethyl
which it is metabolized to cyanide; and poten-
ketone. Br J Ind Med 46:111121, 1989
tiation of the neurotoxicity of n-hexane by 7. Agency for Toxic Substances and Disease
altering the toxicokinetics of its 2,4-hexane- Registry (ATSDR): Toxicological Prole for
dione metabolite.1114 Because occupationally Acetone. pp 1243. Atlanta, GA, US Depart-
exposed workers are most often exposed to a ment of Health and Human Services, Public
mixture of solvents, use of the rule of additiv- Health Service, 1994
ity may underestimate the effect of combined 8. Lupulescu AP, Birmingham DJ: Effect of
exposures.15 protective agent against lipid-solvent-
Signicant developmental toxicity as induced damagesultrastructural and scan-
determined by increased incidences of resorp- ning electron microscopical study of human
epidermis. Arch Environ Health 31:3336,
tions occurred in mice at levels of 6600 ppm,
1976
which also caused maternal toxicity.16
9. World Health Organization: Environmental
Depressed sperm motility and epididymal Health Criteria, 207, Acetone. 159 pp. Inter-
weight and elevated evidence of abnormal national Programme on Chemical Safety
sperm were observed in male rats receiving (IPCS), Geneva, 1998
50,000 ppm acetone in their drinking water for 10. National Toxicology Program: Toxicity Studies
13 weeks.10 of Acetone in F344/N Rats and B6C3F1 Mice
ACETONITRILE 19
(Drinking Water Studies). Toxicity report centrations it can cause convulsions, coma, and
series 3, pp 138, 1991 death.
11. Cunningham J, Sharkawi M, Plaa G: Phar- Of 15 painters exposed to the vapor of a
macological and metabolic interactions mixture containing 3040% acetonitrile for 2
between ethanol and methyl n-butyl ketone, consecutive workdays, 10 developed symptoms
methyl isobutyl ketone, methyl ethyl ketone,
ranging in severity from nausea, headache, and
or acetone in mice. Fundam Appl Toxicol
13:102109, 1989 lassitude among the lesser exposed to vomiting,
12. Charbonneau M, Perreault F, Greselin E, et respiratory depression, extreme weakness, and
al: Assessment of the minimal effective dose stupor in the more heavily exposed. Five cases
of acetone for potentiation of the hepatoxic- required hospitalization and one died; this
ity induced by trichloroethylene-carbon worker experienced the onset of chest pain 4
tetrachloride mixtures. Fundam Appl Toxicol hours after leaving the job on the second day
10:431438, 1988 of exposure, followed shortly by massive
13. Freeman JJ, Hayes EP: Microsomal metabo- hematemesis, convulsions, shock. and coma,
lism of acetonitrile to cyanide: Effects of with death occurring 14 hours after cessation
acetone and other compounds. Biochem Phar- of exposure.1 At autopsy, cyanide ion concen-
macol 37:11531160, 1988
trations (in mg%) were: blood 796, urine 215,
14. Ladefofoged O, Perbellini L: Acetone
induced changes in the toxicokinetics of 2,5- kidney 204, spleen 318, and lung 128; cyanide
hexanedione in rabbits. Scand J Work Environ ion was not detected in the liver.1
Health 12:627629, 1987 Two human subjects inhaled 160 ppm for
15. Noraberg J, Arlien-Soborg P: Neurotoxic 4 hours; one of them experienced a slight
interactions of industrially used ketones. ushing of the face 2 hours later and a slight
Neurotoxicology 21(3):409418, 2000 feeling of bronchial tightness 5 hours later.
16. Mast TJ, Rommereim RL, Weigel RJ, et al: A week before this, the same two subjects
Developmental toxicity study of acetone had inhaled 80 ppm with no effects.2 Blood
in mice and rats. Teratology 39(5): 468A, cyanide and urine thiocyanate levels did not
1989 correlate with exposure and, therefore, are not
reliable indicators of brief exposure to low
concentrations.
In male rats the LC50 was 7500 ppm for a
single 8-hour exposure; there was prostration
ACETONITRILE followed by convulsive seizures; at autopsy
CAS: 75-05-8 there was pulmonary hemorrhage.2 Rats
exposed 6 hours/day, 5 days/week for 4 weeks
CH3CN to concentrations greater than 600 ppm had
respiratory and ocular irritation and anemia.3
In another study rats repeatedly exposed to
Synonyms: Methyl cyanide; cyanomethane; 665 ppm for 7 hours daily developed pul-
ethanenitrile monary inammation, and there were minor
changes in the liver and kidneys in some
Physical Form. Colorless volatile liquid with animals.2
sweetish odor All mice and some rats receiving 1600 ppm
by inhalation 6 hours/day for up to 13 weeks
Uses. Chemical intermediate; solvent; died.4 Clinical ndings included hypoactivity,
extractant for animal and vegetable oils abnormal posture, and, in rats, clonic convul-
sions. Male mice administered 400 ppm and
Exposure. Inhalation; skin absorption females given 200 ppm, also for 13 weeks, had
focal epithelial hyperplasia and ulceration of
Toxicology. Acetonitrile causes headache, the forestomach.
dizziness, and nausea; at extremely high con- In chronic studies, mice exposed 6
20 2-ACETYLAMINOFLUORENE
hours/day, 5 days/week for 2 years to concen- 2. Pozzani UC, Carpenter CP, Palm PE, et al:
trations of up to 200 ppm had no increases An investigation of the mammalian toxicity of
in the incidences of neoplasms.4 High-dose acetonitrile. J Occup Med 1:634642, 1959
females had a signicantly increased incidence 3. Roloff V, Short R, Ribelin W, et al: Com-
of squamous hyperplasia of the epithelium of the parison of subchronic inhalation toxicity of
ve aliphatic nitriles in rats. Toxicologist 5:30,
forestomach. In male rats receiving up to 400
1985
ppm for the same duration there was a slight 4. National Toxicology Program: NTP Techni-
increase in the combined incidence of hepato- cal Report on the Toxicology and Carcinogenesis
cellular adenoma and carcinoma. There were no Studies of Acetonitrile (CAS No. 75-05-8) in
exposure-related liver lesions in female rats. F344/N Rats and B6C3F1 Mice (Inhalation
Acetonitrile was not mutagenic in Salmo- Studies). NTP TR 447, NIH Pub No. 96-
nella typhimurium assays, with or without meta- 3363, US Department of Health and Human
bolic activation.4 Positive results were obtained Services, Public Health Service, National
in a micronucleus assay, and weakly positive Institutes of Health, 1996
responses for sister chromatid exchanges and 5. Saillenfait AM, Bonnet P, Guenier JP, et al:
chromosomal aberrations occurred in Chinese Relative developmental toxicities of inhaled
aliphatic mononitriles in rats. Fundam Appl
hamster ovary cells.4
Toxicol 20:365375, 1993
No malformations related to acetonitrile 6. Berteau PE, Levinskas GJ, Rodwell DE:
exposure were observed in the offspring of Teratogenic evaluation of aliphatic nitriles in
rats orally exposed at maternally toxic levels.5,6 rats. Toxicologist 2:118, 1982
Inhalation of 5000 or 8000 ppm for 60 minutes 7. Willhite CC: Developmental toxicology of
by pregnant hamsters on day 8 of gestation was acetonitrile in the syrian golden hamster.
associated with production of severe axial Teratology 27:313325, 1983
skeletal disorders; maternal toxicity including 8. Grant WM: Toxicology of the Eye, 3rd ed, p 52.
irritation, respiratory difculty, lethargy, ataxia, Springeld, IL, Charles C. Thomas, 1986
hypothermia, and increased mortality was 9. Union Carbide Corporation: Toxicology
noted.7 At lower doses there were no signs of Studies, Acetonitrile. New York, Union
Carbide Corporation, 1965
maternal toxicity and offspring were normal.7
10. National Institute for Occupational Safety
In the rabbit eye, a drop of the liquid and Health, US Department of Health,
caused supercial injury.8 The liquid on the Education, and Welfare: Criteria for a Recom-
belly of a rabbit caused a faint erythema of mended Standard . . . Occupational Exposure to
short duration.9 The toxic effects of acetonitrile Nitriles. DHEW (NIOSH) Pub 78212, pp
are attributed to the metabolic release of 155. Washington, DC, US Government
cyanide via hepatic metabolism; cyanide in turn Printing Ofce, 1978
acts by inhibiting cytochrome oxidase and thus
impairs cellular respiration.10 Evidence of the
cyanide effect is supported by the reported
effectiveness of specic cyanide antidotes in 2-ACETYLAMINOFLUORENE
acetonitrile poisonings.10 CAS: 53-96-3
The 2003 ACGIH threshold limit
value-time-weighted average (TLV-TWA) C15H13NO
for acetonitrile is 40 ppm (67 mg/m3) with
a short-term excursion level of 60 ppm
(101 mg/m3). Synonyms: N-2-uorenylacetamide; 2-
acetaminouorene; N-
acetylaminophenanthrene; AAF
REFERENCES
Physical Form. Light tan crystals
1. Amdur ML: Accidental group exposure to
acetonitrile. J Occup Med 1:627633, 1959 Uses. As a laboratory reagent for research
2-ACETYLAMINOFLUORENE 21
purposes (specically, a positive control for car- hamsters, and rabbits at sites of local applica-
cinogenicity and mutagenicity studies) tion.5 Recent toxicological studies suggest that
both initiating (genotoxic) as well as promot-
Exposure. Inhalation ing properties (nongenotoxic interference with
mitochondrial respiration and oxidative phos-
Toxicology. 2-Acetylaminouorene (AAF) is phorylation) of AAF contribute to the forma-
a potent carcinogen in dogs, hamsters, and rats. tion of tumors in animals.6
There is no toxicity information on AAF is classied as a cytotoxic teratogen.1
humans.1 Because of demonstrated carcinogenicity in
Four of ve dogs developed tumors of the animals, contact by all routes should be
liver and urinary bladder after ingestion of avoided. In recent years this compound has
0.61.2 g AAF/kg diet for up to 91 months.2 been used only in laboratories as a model of
Animals developing tumors received a total of tumorigenic activity in animals.7 It is of little
90198 g AAF, whereas the animal with no occupational health importance.
tumor formation ingested 45 g; another group The ACGIH has not established a thresh-
of four dogs receiving 3237 g over 2.25 years old limit value for AAF.
did not develop tumors.2 The extent of tumor
formation was directly related to the amount of
AAF consumed, being most marked in those REFERENCES
animals that received nearly 200 g during the
feeding period.2 Liver tumors of varied types 1. Doull J, Klaasen CD, Amdur MO (eds): Toxi-
were observed. Multiple papillomas were pro- cology. The Basic Science of Poisons, 2nd ed, p 163.
duced in the urinary bladder, and in one dog New York, Macmillan 1980
2. Morris HP and Eyestone WH: Tumors of the
there was invasion of the submucosa and
liver and urinary bladder of the dog after
muscle by the tumor cells.
ingestion of 2-acetylaminouorene. J Natl
Intratracheal administration of 515 mg Cancer Inst 13:11391165, 1953
AAF one to two times per week for 17 months 3. Oyasu R, Kitajima T, Hoop ML, et al: Induc-
in hamsters (total dose 1100 mg) caused tion of bladder cancer in hamsters by
bladder tumors in 10 of 23 animals; all tumors repeated intratracheal administrations of
were transitional cell carcinomas with or 2-acetylaminouorene. J Natl Cancer Inst 50:
without focal squamous cell carcinomas.3 503506, 1973
In rats, AAF had no demonstrable acute 4. Wilson RH, Deeds F, Cox AJ Jr: The
toxicity in quantities up to 50 mg/kg subcuta- toxicity and carcinogenic activity of 2-
neously and 1 g/kg gastrically; however, AAF acetaminouorene. Cancer Res 1:595608,
1941
was very toxic when administered in the diet.4
5. Miller EC, Miller JA, Enomoto M: The com-
Incorporation of 0.031% AAF or higher for at
parative carcinogenicities of 1-acetylaminou-
least 95 days led to epithelial hyperplasia of the orene and its N-hydroxy metabolite in mice,
bladder, renal pelvis, liver, pancreas, and lung; hamsters, and guinea pigs. Cancer Res
19 of 39 rats developed malignant tumors, 16 24:20182031, 1964
of which were carcinomas.4 6. Neumann HG, Bitsch A, Kloon PC: The dual
Animal studies have indicated that N- role of 2-acetylaminouorene in hepatocar-
hydroxy-2-acetylaminouorene (N-hydroxy- cinogenesis: specic targets for initiation and
AAF) is a proximate carcinogenic metabolite of promotion. Mutat Res 376:169176, 1997
AAF.5 AAF is not carcinogenic in the guinea 7. Benya TJ, Cornish HH: Aromatic nitro
pig, and no N-hydroxylation of AAF has been and amino compounds. In Clayton GD and
Clayton FE (eds): Pattys Industrial Hygiene and
detected in vivo or in vitro in this species;
Toxicology 4th ed, Vol II, part B Toxicology, pp
however, administration of N-hydroxy-AAF
968970. New York, John Wiley and Sons,
causes tumors in guinea pigs.5 In addition, N- 1994
hydroxy-AAF has proved to be a carcinogen of
much greater potency than AAF in rats, mice,
22 ACETYLENE TETRABROMIDE
genic to bacteria and to induce sister chromatid trosamine. J Toxicol Environ Health 3:
exchanges in vitro.16 379394, 1977
The 2003 threshold limit value-time- 13. Lijinsky W, Reuber MD: Chronic carcino-
weighted average (TLV-TWA) is 0.1 ppm genesis studies of acrolein and related
(0.23 mg/m3) with a short-term excursion level compounds. Toxicol Ind Health 3:337345,
1987
of 0.3 ppm (0.69 mg/m3).
14. Parent RA, Caravello HE, Long JE: Two-
year toxicity and carcinogenicity study of
acrolein in rats. J Appl Toxicol 12:131139,
1992
REFERENCES
15. Parent RA, Caravello HE, Balmer MF, et al:
One-year toxicity of orally administered
1. Beauchamp RO Jr, Andjelkovich DA,
acrolein to the Beagle dog. J Appl Toxicol 12:
Kligerman AD, et al: A critical review of the
311316, 1992
literature on acrolein toxicity. Crit Rev Toxicol
16. IARC Monographs on the Evaluation of the
14:309380, 1985
Carcinogenic Risks to Humans, Vol 63, Dry
2. Henderson Y, Haggard HW: Noxious Gases,
cleaning, some chlorinated solvents and other
p 138. New York, Reinhold Publishing, 1943
industrial chemicals, pp 33772. Lyon, Inter-
3. Prentiss AM: Chemicals in War. A Treatise of
national Agency for Research on Cancer,
Chemical Warfare, pp 139140. New York,
1995
McGraw-Hill, 1937
4. Agency for Toxic Substances and Disease
Registry (ASTDR): Toxicological Prole for
Acrolein, US Department of Health and
Human Services, Public Health Service, TP-
9001, pp 145, 1990
5. Grant WM: Toxicology of the Eye, 3rd ed, pp ACRYLAMIDE
4950. Springeld, IL, Charles C. Thomas, CAS: 79-06-1
1986
6. Kutzman RS et al: Changes in rat lung C3H5NO
structure and composition as a result of
subchronic exposure to acrolein. Toxicology
34:139151, 1985 Synonyms: Acrylic amide; propenamide;
7. Astry CL, Jakab GJ: The effects of acrolein ethylenecarboxamide; vinyl amide
exposure on pulmonary antibacterial
defenses. Toxicol Appl Pharmacol 67:4954,
Physical Form. White crystalline powder
1983
8. Li L, Holian A: Acrolein: a respiratory toxin
that suppresses pulmonary host defense. Rev Uses. In the production of polyacrylamides,
Environ Health 13(1-2):99108, 1998 which are used in water and waste treat-
9. Slott VL, Hales BF: Teratogenicity and ment, paper and pulp processing, cosmetic
embryolethality of acrolein and structurally additives, and textile processing; in adhesives
related compounds in rats. Teratology and grouts; as cross-linking agents in vinyl
32:6572, 1985 polymers
10. Parent RA, Caravello HE, Christian MS,
et al: Developmental toxicity of acrolein in Exposure. Inhalation; skin absorption;
New Zealand White rabbits. Fundam Appl ingestion
Toxicol 20:248256, 1993
11. Parent RA, Caravello HE, Hoberman AM:
Toxicology. Acrylamide causes central-
Reproductive study of acrolein on two gen-
erations of rats. Fundam Appl Toxicol peripheral axonopathy; in laboratory animals it
19:228237, 1992 is carcinogenic and causes male reproductive
12. Feron VJ, Kruysse A: Effects of exposure to toxicity.
acrolein vapor in hamsters simultaneously A variety of signs and symptoms have been
treated with benzo(a)pyrene or diethylni- described in cases of acrylamide poisoning sug-
ACRYLAMIDE 25
gesting involvement of the central, peripheral, Teratogenic effects were not observed in
and autonomic nervous systems.1 Effects on the the offspring of rats given up to 50 mg/kg diet
central nervous system are characterized by for 2 weeks before mating and for 19 days
abnormal fatigue, memory difculties, and during gestation.1 In mice, high doses pro-
dizziness. With severe poisoning, confusion, duced decreased sperm count and an increase
disorientation, and hallucinations occur. in abnormal sperm morphology.6
Truncal ataxia, nystagmus, and slurred speech Acrylamide produced dominant lethal
have also been observed. Peripheral neuropa- reproductive effects in males as evidenced by
thy symptoms can include muscular weakness, reduced numbers of live pups and increased
paresthesia, numbness in hands, feet, lower resorptions at exposure levels (30 ppm in drink-
legs, and lower arms, unsteadiness, and dif- ing water) below those that caused neurotoxic-
culties in walking and standing. Clinical signs ity.7 In another report, acrylamide caused a
are loss of peripheral tendon reexes, impair- dose-dependent increase in the frequency of
ment of vibration sense, and muscular wasting morphologic abnormalities in preimplantation
in the extremities. Nerve biopsy shows loss of embryos (single-cell eggs, growth retardation,
large-diameter nerve bers as well as regener- and blastomere lysis) after paternal treatment
ating bers. Autonomic nervous system (1050 mg/kg, for 5 days).8 These more recent
involvement is indicated by excessive sweating, ndings indicate a potential risk to the off-
peripheral vasodilation, and difculties in mic- spring of men exposed to acrylamide.
turation and defecation. A statistically signicant increase in
Central nervous system effects predomi- mesothelioma of the scrotal cavity was
nate in acute exposures at massive doses, observed in rats given drinking water formu-
whereas peripheral neuropathy is more lated to provide 0.5 mg/kg body weight/day for
common with lower doses.1,2 After cessation of 2 years; in females there were signicant
exposure to acrylamide, most cases recover, increases in the number of neoplasms of the
although the course of improvement can central nervous system, thyroid, mammary
extend over months to years and depends on gland, oral cavity, clitoral gland, and uterus.9
the severity of exposure.1,2 Because peripheral Acrylamide has also been reported to act as
neurons can regenerate and central axons a skin tumor initiator in mice by three expo-
cannot, severely affected individuals may still sure routes and to increase the yield of lung
experience residual ataxia, distal weakness, adenomas in another strain of mice.10
reex loss, or sensory disturbance. In a human mortality study of 371 workers
Because most cases of human poisoning no increase in total malignant neoplasms or any
have included skin absorption, the dose- specic cancers attributable to acrylamide
response relationship has not been determined. exposure were found.11 Exposure levels reached
On the skin acrylamide causes local irritation 1.0 mg/m3 before 1957 and were between 0.1
characterized by blistering and desquamation and 0.6 mg/m3 after 1970. However, this study
of the palms and soles combined with blueness was of such a limited sample size that only large
of the hands and feet.1 excesses could have been detected.
For a number of species the oral LD50 was A much larger cohort of 8854 men, 2293
approximately 150180 mg/kg body weight. In of whom were exposed to acrylamide, from
cats a total cumulative dose of 70130 mg/kg 1925 to 1983 was examined for mortality.12
was characterized by delayed onset of ataxia.3 This cohort consisted of four chemical plant
Cats fed 10 mg/kg diet/day developed denite populations. No statistically signicant excess
hind limb weakness after 26 days; at 3 mg/kg/ of all-cause or cause-specic mortality was
day there was twitching in the hindquarters found among acrylamide workers. Analysis by
after 26 days and signs of hind limb weakness acrylamide exposure levels showed no trend of
after 68 days.4 The underlying lesion involves increased risk of mortality from several cancer
distal retrograde degeneration of long and sites. Although the authors concluded that the
large-diameter axons.5 results do not support the hypothesis that acry-
26 ACRYLAMIDE
lamide is a human carcinogen, this view was 3. Kuperman AS: Effects of acrylamide on the
challenged on the basis that the comparison central nervous system of the cat. J Pharma-
group included individuals from one of the col Exp Ther 123:180192, 1958
four plants who had a small but signicant 4. McCollister DD et al: Toxicology of acry-
excess of lung cancer (standardized mortality lamide. Toxicol Appl Pharmacol 6:172181, 1964
5. Miller MS, Spencer PS: The mechanisms of
ratio = 1.32), which had been attributed by the
acrylamide axonopathy. Annu Rev Pharmacol
authors to another occupational exposure in Toxicol 25:643666, 1985
the production of muriatic acid.13 The most 6. Sakamoto J, Hashimoto K: Reproductive
recent update of this cohort through 1994 cor- toxicity of acrylamide and related compounds
roborated the original ndings showing little in miceeffects on fertility and sperm mor-
evidence for a causal relation between exposure phology. Arch Toxicol 59:201205, 1986
to acrylamide and cancer mortality.14 Although 7. Chapin RE, Fail PA, George JD, et al: The
an increase in pancreatic cancer was noted, reproductive and neural toxicities of acry-
there was no consistent exposure-response lamide and three analogues in Swiss mice,
relationship. evaluated using the continuous breeding pro-
The IARC has determined that there is tocol. Fund Appl Toxicol 27(1):924, 1995
8. Holland N, Ahlborn T, Turteltaub K, et al:
sufcient evidence in experimental animals for
Acrylamide causes preimplantation abnor-
the carcinogenicity of acrylamide and inade- malities in embryos and induces chromatin-
quate evidence for carcinogenicity to humans. adducts in male germ cells of mice. Reprod
Overall it is considered probably carcinogenic Toxicol 13(3):16778, 1999
to humans.15 9. Johnson KA, Gorzinski SJ, Bodner KM, et al:
Acrylamide is genotoxic in a number of test Chronic toxicity and oncogenicity study on
systems.15 It induces gene mutation, structural acrylamide incorporated in the drinking
chromosomal aberrations, sister chromatid water of Fischer 344 rats. Toxicol Appl Phar-
exchange, and cell transformation. Further- macol 85:154168, 1986
more, acrylamide forms covalent adducts with 10. Bull RJ, Robinson M, Laurie RD, et al: Car-
DNA in rodents and covalent adducts with cinogenic effect of acrylamide in sencar and
A/J nice. Cancer Res 44:107111, 1984
hemoglobin in humans. Hemoglobin adducts
11. Sobel W, Bond GG, Parsons TW, et al:
have been used for biomonitoring of acry- Acrylamide cohort mortality study. Br J Ind
lamide. Studies indicate that the adducts Med 43:785788, 1986
are useful predictors of acrylamide-induced 12. Collins JJ et al: Mortality patterns among
peripheral neuropathy.16 workers exposed to acrylamide. J Occup Med
The 2003 ACGIH threshold limit value- 31:614617, 1989
time-weighted average (TLV-TWA) for acry- 13. Hogan KA, Scott CLS: Mortality patterns
lamide is 0.03 mg/m3 with a notation for skin and acrylamide exposure (letters). J Occup
absorption and an A3, conrmed animal car- Med 32:947949, 1990
cinogen with unknown relevance to humans 14. Marsh GM, Lucas LJ, Youk AO, et al: Mor-
designation. tality patterns among workers exposed to
acrylamide: 1994 follow up. Occup Environ
Med 56:181190, 1999
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Carcinogenic Risks to Humans, Vol 60, Some
1. The International Programme on Chemical industrial chemicals, pp 389429. Lyon,
Safety: Environmental Health Criteria 49 Acry- International Agency for Research on
lamide, pp 1121. World Health Organiza- Cancer, 1994
tion, Geneva, 1985 16. Calleman CJ, Wu Y, He F, et al: Relation-
2. Smith EA, Oehme FW: Acrylamide and poly- ships between biomarkers of exposure and
acrylamide: a review of production, use, envi- neurological effects in a group of workers
ronmental fate and neurotoxicity. Rev Environ exposed to acrylamide. Toxicol Appl Pharmacol
Health 9:215228, 1991 126:361371, 1994
ACRYLIC ACID 27
Prolonged skin contact with the liquid cally signicant excess was for prostate cancer
results in both systemic toxicity and the for- (5 obs. vs. 1.9 exp.).12 An excess number of lung
mation of large vesicles after a latent period of cancer cases remained (10 obs. vs. 7.2 exp.) but
several hours.1 The affected skin may resemble was not as marked.12,13 A study of 1774 workers,
a second-degree thermal burn. potentially exposed to acrylonitrile and fol-
Administration of 65 mg/kg/day by gavage lowed for 32 years, reported no signicant
to rats on days 6 to 15 of gestation produced excess of all-site or site-specic cancer mortal-
signicant maternal toxicity and an increased ity rates.14 Other epidemiological studies
incidence of malformation in the offspring.3 reported excess cancer deaths but lacked statis-
Inhalation of 80 ppm 6 hours/day by the dams tical signicance because of small cohort size,
resulted in a signicant increase of fetal low exposures, and insufcient follow-up
malformations including short tail, missing times.
vertebrae, short trunk, omphalocele, and The IARC has determined that there is
hemivertebra; maternal toxicity consisted of sufcient evidence of carcinogenicity of acry-
decreased weight gain.3 Oral administration of lonitrile in animals and that it is probably car-
10 mg/kg/day for 60 days to male mice induced cinogenic to humans.15
histopathologic changes in the testis and In vitro genotoxic studies have given posi-
reduced sperm counts compared with controls. tive results for gene mutations, chromosomal
These changes were not observed at a dosage aberrations, DNA damage, and cell transfor-
level of 1 mg/kg/day.4 A recent review of repro- mation in the presence of metabolic activation;
ductive and developmental toxicity data sug- in vivo assays have generally been negative.16
gested that acrylonitrile does not produce clear The 2003 ACGIH threshold limit value-
adverse effects on fertility, reproduction or time-weighted average (TLV-TWA) for
development at doses below those causing acrylonitrile is 2 ppm (4.3 mg/m3) with an A3-
parental toxicity.5 conrmed animal carcinogen with unknown
In a number of chronic bioassays in rats, relevance to humans designation and a notation
administration of acrylonitrile by gavage, by for skin absorption.
inhalation, and in the drinking water produced
tumors of the mammary gland, the gastroin-
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CNS.68 Administration of 500 ppm in drinking
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for 104 weeks caused increased incidences of by gavage or by inhalation. Food Cosmet
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5. Kapp RW Jr, Tyl RW, Harris SB, et al: A
and followed for 10 or more years there was a
weight-of-evidence review of acrylonitrile
greater than expected incidence of lung cancer
reproductive and developmental toxicity. Tox-
(8 obs. vs. 4.4 exp.).11 A trend toward increased icologist 36(1):260, 1997
risks of cancer of all sites was also observed with 6. Maltoni C, Ciliberti A, Di Maio V: Carcino-
increased duration of exposure and with higher genicity bioassays on rats of acrylonitrile
severity of exposure. However, in a follow-up administered by inhalation and ingestion.
of this cohort through 1983 the only statisti- Med Lav 68:401411, 1977
30 ALDRIN
erythema may be observed from skin contact, ductive system including decreased sperm
but dermatitis associated with aldrin is count and degeneration of germ cells.
unusual.5 Decreased fertility has been noted in some, but
In animal studies aldrin induced an not all, studies after oral exposure.7
increased incidence of hepatocellular carci- The 2003 ACGIH threshold limit value-
noma at two dietary doses in male mice; the time-weighted average (TLV-TWA) for
tumors showed a signicant dose-response aldrin is 0.25 mg/m3 with a notation for skin
trend and were statistically signicant at the absorption.
high dose.6 Follicular cell tumors of the thyroid
and adrenal cortical cell adenomas were
increased in female rats in the low-dose
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ical studies of workers employed in the manu- 1964
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study of a cohort having mixed exposure to plants. Arch Environ Health 10:441448, 1965
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from cancer versus 12 expected. The workers Arch Ind Hyg Occup Med 4:560566, 1951
4. Brown VKH, Hunter CG, Richardson A: A
had been exposed to the pesticides for a mean
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1982, with exposure to a number of pesticides Wilkins, 1982
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attributable to occupational exposures.10 Simi- and Dieldrin for possible Carcinogenicity. NCI
larly, a 23-year follow-up of 570 aldrin- and Carcinogenesis Technical Report Series No
dieldrin-exposed workers found no increase in 21, Washington, DC, DHEW Pub No
overall mortality rates or mortality from liver (NIH) 78-821, 1978
cancer.11 7. Agency for Toxic Substances and Disease
Registry (ATSDR): Toxicological Prole for
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Aldrin/Dieldrin. US Department of Health
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and Human Services, Public Health Service,
react directly with the DNA molecule.7 pp 1303, 2003
Accumulating evidence suggests that aldrin 8. Stevenson DE, Walborg EF Jr, North DW,
is not a likely human carcinogen and that it et al: Monograph: Reassessment of human
acts as a species-specic hepatocarcinogen in cancer risk of aldrin-dieldrin. Toxicol Lett
mice through nongenotoxic mechanisms.7,8 109(3):123186, 1999
Single high doses of aldrin (50 mg/kg) 9. Ribbens PH: Mortality study of industrial
administered orally to hamsters during the workers exposed to aldrin, dieldrin and
period of organogenesis caused a high inci- endrin. Int Arch Occup Environ Health 56:
dence of fetal deaths, congenital anomalies, and 7579, 1985
10. Amoateng-Adjepong Y, Sathiakumar N,
growth retardation.12 No information on the
Delzell E, et al: Mortality among workers at
health status of maternal animals was provided,
a pesticide manufacturing plant. J Occup Med
but this dose is in the range of reported LD50 37(4):471478, 1995
values. Decreased postnatal survival has been 11. de Jong G, Swaen GMH, Slangen JJM:
observed in laboratory animals after in utero Mortality of workers exposed to dieldrin and
exposure.7 Intraperitoneal injection of aldrin aldrin: a retrospective cohort study. Occup
has caused adverse effects on the male repro- Environ Med 54(10):702707, 1997
32 ALLYL ALCOHOL
12. Ottolenghi AD, Haseman JK, Suggs F: Ter- autopsy, ndings were focal necrosis of the liver
atogenic effects of aldrin, dieldrin, and endrin and necrosis of the convoluted tubules of the
in hamsters and mice. Teratology 9:1116, kidneys.3
1974 Allyl alcohol was not carcinogenic in
limited oral studies in rats and hamsters. It was
mutagenic in bacterial assays and in mam-
malian cells in culture.4
The warning properties are thought to be
ALLYL ALCOHOL adequate to prevent voluntary exposure to
CAS: 107-18-6 acutely dangerous concentrations but inade-
quate for chronic exposure.
C3H6O The 2003 ACGIH threshold limit value-
time-weighted average (TLV-TWA) for allyl
alcohol is 2 ppm (4.8 mg/m3) with a short-term
Synonyms: 2-Propen-1-ol; 1-propenol-3; vinyl excursion limit of 4 ppm (9.5 mg/m3) and a
carbinol notation for skin absorption.
The 2003 ACGIH threshold limit value- 11. US Environmental Protection Agencys
time-weighted average (TLV-TWA) for allyl Integrated Risk Information System
chloride is 1 ppm (3 mg/m3) with a short-term (IRIS) on Allyl Chloride (107-05-1) at
excursion limit of 2 ppm (6 mg/m3). http://www.epa.gov/ngispgm3/iris. March
2000
12. IARC Monographs on the Evaluation of the
Carcinogenic Risk of Chemicals to Humans, Vol
71, Reevaluation of some organic chemicals,
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hydrazine and hydrogen peroxide, pp
12311240. Lyon, International Agency for
1. National Institute for Occupational Safety
Research on Cancer, 1999
and Health, US Department of Health,
Education, and Welfare: Criteria for a Recom-
mended Standard . . . Occupational Exposure to
Allyl Chloride. DHEW (NIOSH) Pub No 76-
204, pp 1938. Washington, DC, US Gov-
ernment Printing Ofce, 1976 ALLYL GLYCIDYL ETHER
2. He F, Zhang SL: Effects of allyl chloride on CAS: 106-92-3
occupationally exposed subjects: Scand J
Work Environ Health 11 (Suppl 4):4345, C6H10O2
1985
3. Adams EM et al: The acute vapor toxicity of
allyl chloride. J Ind Hyg Toxicol 22:7986, Synonyms: AGE; allyl 2, 3-epoxypropyl ether
1940
4. Torkelson TR, Rowe VK: Halogenated
Physical Form. Liquid
aliphatic hydrocarbons. In Clayton GD and
Clayton FE (eds): Pattys Industrial Hygiene
and Toxicology, Vol 2B, Toxicology, pp Uses. Reactive diluent in epoxy resin
35683572. New York, Wiley-Interscience, systems; stabilizer of chlorinated compounds;
1981 manufacture of rubber
5. Torkelson TR, Wolf MA, Oyen F, Rowe VK:
Vapor toxicity of allyl chloride as determined Exposure. Inhalation; skin absorption
on laboratory animals. Am Ind Hyg Assoc J
20:217223, 1959 Toxicology. Allyl glycidyl ether (AGE)
6. He F, Lu B, Zhang S, et al: Chronic allyl causes skin, eye, and upper respiratory tract
chloride poisoning. An epidemiology clinical,
irritation and contact dermatitis; high concen-
toxicological and neuropathological study. G
trations cause pulmonary edema and narcosis,
Ital Med Lav 7:515, 1985
7. Nagano M, Yamamoto H, Harada K, et al: whereas chronic exposures induce nasal lesions
Comparative study of modication and in animals.
degradation of neurolament proteins in rats Workers exposed to the vapor and/or
subchronically treated with allyl chloride, liquid complained of dermatitis with itching,
acrylamide or 2, 5-hexanedione. Environ Res swelling, and blister formation.1 Skin sensitiza-
63:229240, 1993 tion has occurred; cross sensitization probably
8. John JA, Gushow TS, Ayres JA, et al: Tera- can occur with other epoxy agents.2
tologic evaluation of inhaled epichlorohydrin Three workers applying an epoxy-based
and allyl chloride in rats and rabbits. Fundam waterproong paint containing glycidyl ether
Appl Toxicol 3:437442, 1983
inside an underground water tank died in the
9. Zhao M: Testicular toxicity of allyl chloride.
tank of asphyxia. Constituents of epoxy resin
Fukuoka Acta Medica 88(3):4955, 1997
10. National Cancer Institute: Carcinogenesis will displace oxygen in a conned space and
Technical Report Series. Bioassay of Allyl Chloride may have an independent narcotic effect
for Possible Carcinogenicity. DHEW (NIH) on exposed workers. Strict precautionary
Pub No 78-1323, p 53. Washington, DC, US measures are recommended under these
Government Printing Ofce, 1978 conditions.3
ALLYL PROPYL DISULFIDE 35
In rats, the LC50 for 8 hours was 670 ppm; The 2003 ACGIH threshold limit value-
effects were lacrimation, nasal discharge, time-weighted average (TLV-TWA) for allyl
dyspnea, and narcosis.1 In rats repeatedly glycidyl ether is 1 ppm (4.7 mg/m3).
exposed to 600 ppm for 8 hours daily, effects
were pronounced irritation of the eyes and
respiratory tract; more than half of the rats REFERENCES
developed corneal opacity; at necropsy, after
25 exposures, pulmonary ndings were 1. Hine CH et al: The toxicology of glycidol and
inammation, bronchiectasis, and bronchop- some glycidyl ethers. AMA Arch Ind Health
neumonia.1 13:250264, 1956
2. ACGIH: Allyl glycidyl ether (AGE). Documen-
Inhalation of 7 ppm for 6 hours/day caused
tation of the Threshold Limit Values and Biologi-
necrosis and complete erosion of nasal mucosa
cal Exposure Indices, 7th ed, pp 4. Cincinnati,
after 4 days; squamous metaplasia of the respi- OH, American Congress of Governmental
ratory epithelium and focal erosion of the Industrial Hygienists (ACGIH), 2001
olfactory epithelium with evidence of regener- 3. Centers for Disease Control: Occupational
ation of some epithelial surface occurred in fatalities associated with exposure to epoxy
mice after 914 days at this exposure level.4 resin paint in an underground tankMakati,
Rats and mice exposed to concentrations as low Philippines. MMWR 39:373380, June 8, 1990
as 4 ppm for 13 weeks had squamous metapla- 4. Gagnaire F, Zissn D, Bonnet P, et al: Nasal and
sia, hyperplasia, and inammation of the nasal pulmonary toxicity of allyl glycidyl ether in
mucosa.5 mice. Toxicol Lett 39:139145, 1987
5. National Toxicology Program. Toxicology and
Chronic 24-month inhalation exposure to
Carcinogenesis Studies of Allyl Glycidyl Ether
5 or 10 ppm AGE induced nasal lesions in rats
(CAS No. 106-92-3) in Osborne Mendel Rats and
and mice.6 Inammation, degeneration, regen- B6C3F1 Mice (Inhalation Studies). Technical
eration, metaplasia, hyperplasia, and neoplasia Report No. 376. Public Health Service,
were observed in the nasal mucosa. Although National Institutes of Health. NIH Pub.
the incidence of primary nasal tumors was not No. 90-2831, Research Triangle Park, NC,
statistically signicant compared with the inci- 1990
dence in concurrent controls, the relative rarity 6. Renne RA, Brown HR, Jokinen MP: Mor-
of primary nasal tumors occurring sponta- phology of nasal lesions induced in Osborne-
neously and the presence of other nonneoplas- Mendel rats and B6C3F1 mice by chronic
tic lesions suggests that the tumors observed inhalation of allyl glycidyl ether. Toxicol Pathol
20:416425, 1992
may be related to AGE exposure. It was con-
cluded that there was some evidence of car-
cinogenicity of inhaled AGE for male mice,
equivocal evidence of carcinogenicity for
female mice and male rats, and no evidence of
carcinogenicity for female rats.5 ALLYL PROPYL DISULFIDE
AGE was mutagenic in some strains of CAS: 2179-59-1
bacteria with or without metabolic activation.
It also induced sister chromatid exchanges and C6H12S2
chromosomal aberrations in cultured cells.5
Percutaneous absorption has been docu-
mented in rabbits.2 The liquid dropped into the Synonyms: Disulde, allyl propyl; onion oil
eye of a rabbit caused severe but reversible con-
junctivitis, iritis, and corneal opacity.1 Cyto- Physical Form. Pale yellow oil
toxic effects on rat bone marrow cells, with
reduction in leukocyte counts, and testicular Source. Onions
degeneration were observed after intramuscu-
lar injections at 400 mg/kg/day. Exposure. Inhalation
36 ALUMINUM
It has been suggested that the explanation increased risk of developing encephalopathy or
of pulmonary disease among powder workers dialysis dementia.5 The disease is character-
in other countries may lie in the duration of ized by altered speech, personality changes,
exposure, the size of the particles, the density seizures, and motor dysfunction. Symptoms
of the dust, and especially the fact that all have been reversed when aluminum exposures
reported cases have been associated with expo- were lowered.
sure to a submicron-sized aluminum pyrotech- A possible association between aluminum
nic ake (powder), which has been lubricated ingestion and Alzheimer disease, which has
with a nonpolar aliphatic oil rather than the clinical and histopathologic features distinct
usually employed stearic acid.2,4 from dialysis encephalopathy, has also been
Evidence of the relatively benign nature of proposed. Alzheimer disease is pathologically
aluminum dust in measured concentrations lies characterized by the formation of neurobril-
in the 27-year experience of administration of lary tangles and senile plaques; these tangles in
freshly milled metal particles to workers the cerebral cortex and hippocampus have been
exposed to silica as a suggested means of reported to contain aluminum. It is not known
inhibiting the development of silicosis. Inhala- whether aluminum is a causal agent or whether
tion of aluminum powder of particle size of the neurodegenerative disease just allows more
1.2 m (96%), over 10- or 20-minute periods aluminum to accumulate in the brain. It has
several times weekly, resulted in no adverse been noted that Alzheimer disease may largely
health effects among thousands of workers over be a genetic disorder.5
several years. One study suggested a possible link of
The etiologic role of aluminum in neuro- aluminum in public water supplies with the
logical disorders has been of increasing inter- occurrence of Alzheimer disease in 88 county
est in recent years. Subtle neurological effects districts of England and Wales.10 In districts in
(altered performance on neurobehavioral tests which the mean aluminum concentration in
and increased reporting of subjective symp- water exceeded 0.11 mg/l, rates were 1.5 times
toms) have been detected in workers exposed higher than in districts in which the mean
to large amounts of aluminum dusts in levels were less than 0.01 mg/l. The results
factories.5 have been challenged on the basis of study
Several mortality studies of aluminum design and on the interpretation of the relative
reduction plant workers, in which the study signicance of the dose of aluminum from
cohorts totaled nearly 28,000 long-term water as a fraction of total dietary intake.11
employees, recorded no excess deaths due to Ingested aluminum is poorly absorbed, and
organic brain disorders of dementia type, and there appears to be no retention of aluminum
an analysis of the occupational mortality expe- from nutritional sources in individuals with
rience of nearly 430,000 men who died in normal kidneys. Dusts of metallic aluminum
Washington state during the years 1950 and aluminum oxide are not signicantly
through 1979 showed no excess deaths from absorbed systemically, although fume from
this cause among the 1238 former aluminum welding aluminum is absorbed through the
workers included in the study.68 However, lungs, producing a rise in aluminum levels in
three cases of a progressive neurological disor- plasma and urine.12
der, characterized by incoordination, intention Aluminum does not appear to be a poten-
tremor, and cognitive decit, in workers at an tial carcinogen. It has not been shown to be
aluminum reduction plant have been reported, carcinogenic in human epidemiological studies
and the investigators postulated that they may or in animal studies after oral or inhalation
have been related to occupational exposure to exposure.
aluminum in some form.9 Aerosols of the soluble salts of aluminum,
People on renal dialysis who have received such as the chloride and sulfate, are irritants of
high doses of aluminum in medications and in little occupational importance. Although the
dialysate uid for a number of years are at aluminum alkyls may also be irritants, there is
38 ALUMINUM OXIDES
inadequate toxicity information on these com- Aluminum and Alzheimers disease. Lancet
pounds. 4:267269, 1989
The 2003 ACGIH threshold limit value- 12. Mussi I, Calzaferri G, Buratti M, et al:
time-weighted average (TLV-TWA) for alu- Behavior of plasma and urinary aluminum
minum is 10 mg/m3 for the metal dust, 5 mg/m3 level in occupationally exposed subjects.
Int Arch Occup Environ Health 54:155161,
for pyro powders and welding fumes, as Al,
1984
and 2 mg/m3 for the soluble salts and alkyls,
as Al.
REFERENCES
ALUMINUM OXIDES
1. Mitchell J: Pulmonary brosis in an alu- Chemical Compound: Aluminum oxide (Al2O3)
minum worker. Br J Ind Med 16:123125, Mineral Name: Corundum
1959 Synonym: a-Alumina
2. Mitchell J, Manning GB, Molyneux M, Lane CAS: 1344-28-1
RE: Pulmonary brosis in workers exposed to
nely powdered aluminum. Br J Ind Med Chemical Compound: Aluminum oxyhydroxide
18:1020, 1961 (AlO2H)
3. Gross P, Harley RA Jr, deTreville RTP: Mineral Name: Boehmite, Diaspore
Pulmonary reaction to metallic aluminum Synonym: Alumina monohydrate
powders. Arch Environ Health 26:277236,
CAS: 24623-77-6
1973
4. Dinman BD: Aluminum in the lung: The
pyropowder conundrum. J Occup Med Chemical Compound: Alumina trihydroxide
29:869876, 1987 (Al(OH)3)
5. Agency for Toxic Substances and Disease Mineral Name: Gibbsite, bayerite, nordstrandite
Registry (ASTDR): Toxicological Prole for Synonym: Alumina trihydrate, aluminum
Aluminum, pp 1352. US Department of hydroxide
Health and Human Services, Public Health CAS: 21645-51-2
Service, 1999
6. Gibbs GW: Mortality experience in eastern
Canada. In Hughes JP (ed): Health Protection Uses. Production of aluminum; synthetic
in Primary Aluminium Production, Vol 2,
abrasives; refractory material
pp 5669. London, International Primary
Aluminium Institute, 1981
7. Rockette HE, Arena VC: Mortality studies of Exposure. Inhalation
aluminum reduction plant workers: Potroom
and carbon department. J Occup Med Toxicology. The aluminas are considered to
25:549557, 1983 be nuisance dusts; their role in brogenic lung
8. Milham S: Occupational Mortality in Washing- disease remains unclear.
ton State, 19501979. DHHS (NIOSH) Pub Assessment of the toxicity of aluminas has
No 83116, p 38. Washington, DC, US Gov- been complicated by the chemical and physical
ernment Printing Ofce, 1983 variants of the compounds and inconsistencies
9. Longstreth WT, Rosenstock L, Heyer NJ: in the nomenclature used to describe them.1
Neurologic disorder in three aluminum
The group of compounds referred to as alumi-
smelter workers. Arch Intern Med
nas is composed of various structural forms of
145:19721975, 1985
10. Martyn CN, Osmond C, Edwardson JA, aluminum oxide, trihydroxide, and oxyhydrox-
et al: Geographical relationship between ide.2 As these aluminas are heated, dehydration
Alzheimers disease and aluminium in drink- occurs, producing a variety of transitional
ing water. Lancet 1:5962, 1989 forms; temperatures between 200 and 500C
11. Schupf N, Silverman W, Zigman WB, et al: result in low-temperature-range transitional
ALUMINUM OXIDES 39
effects.79 p-Aminophenol has shown variable 9. Elder RL: Final report on the safety assess-
results in a wide variety of genotoxic assays.3 ment of p-aminophenol, m-aminophenol
Studies of the teratogenic effects of and o-aminophenol. J Am Coll Toxicol
p-aminophenol indicated both positive and 7(3):279333, 1988
negative effects depending on the route of 10. Rutkowski JV, Fermn VH: Comparison of
the teratogenic effects of isomeric forms of
administration. Hamsters given intravenous or
aminophenol in the Syrian Golden Hamster.
intraperitoneal injections of p-aminophenol at Toxicol Appl Pharmacol 63:264, 1982
100250 mg/kg showed signicant increases in 11. Burnett C et al: Teratology and percutaneous
malformed fetuses and resorptions in a dose- toxicity studies on hair dyes. Toxicol Environ
dependent manner.10 However, oral studies Health 1:1027, 1976
using hamsters and topical application of hair
dyes containing p-aminophenol on rats showed
no teratogenic effects.11
The ACGIH has not assigned a threshold
limit value to p-aminophenol. 2-AMINOPYRIDINE
CAS: 504-29-0
(NH2)C5H4N
REFERENCES
severe, pounding headache, nausea, ushing of Toxicology. Amitrole has low acute toxicity;
the extremities, and elevated blood pressure, in experimental animal studies subchronic
but he recovered fully within 24 hours. exposures were associated with changes in the
The LD50 in mice by intraperitoneal injec- thyroid and chronic exposures were
tion was 35 mg/kg; lethal doses in animals also carcinogenic.
produced excitement, tremors, convulsions Intentional ingestion of a mixture that con-
and tetany.1 Fatal doses were readily absorbed tained 20 mg/kg amitrole did not cause any
through the skin. A 0.2 M aqueous solution signs of intoxication.1 In one reported case
dropped in a rabbits eye was only mildly study, inhalation of a large amount of amitrole-
irritating.2 containing herbicide was associated with acute
2-Aminopyridine was not mutagenic in toxic reaction of the lungs.2 Lung injury was
a variety of Salmonella tester strains with or thought to be secondary to direct toxic damage
without metabolic activation.3 to the alveolar lining cells. The remarkable lack
The 2003 ACGIH threshold limit value- of any other reports describing pulmonary tox-
time-weighted average (TLV-TWA) for icity of this herbicide was noted, in addition to
aminopyridine is 0.5 ppm (1.9 mg/m3). the presence of other chemicals in the herbi-
cide solution.
The LD50 values in animal studies are
REFERENCES high, indicating very low acute toxicity but
varying considerably according to species.3
1. Reinhardt CF, Brittelli MR: Heterocyclic The oral LD50 in mice was 11,000 mg/kg,
and miscellaneous nitrogen compounds. In whereas 4000 mg/kg was fatal to sheep. No
Clayton GD, Clayton FE (eds): Pattys Indus- detectable signs of toxicity were noted in rats
trial Hygiene and Toxicology, 3rd ed, rev, Vol 2,
at 4080 mg/kg.4 Poisoning in animals is char-
pp 27312832. New York, Wiley-Interscience,
acterized by increased intestinal peristalsis, pul-
1981
2. Grant WM: Toxicology of the Eye, 3rd ed, p 383. monary edema, and hemorrhages in various
Springeld, IL, Charles C. Thomas, 1986 organs.3
3. Zeiger E, Anderson B, Haworth S, et al: At a level of 1000 ppm in the diet of rats,
Salmonella mutagenicity tests: III. Results signicant enlargement of the thyroid could be
from the testing of 255 chemicals. Environ Mol detected as early as 3 days.5 At a dietary level
Mutagen 9(Suppl 9):1110, 1987 of 60 or 120 ppm, there was enlargement of the
thyroid within 2 weeks.6 Morphologic changes
were noted in the thyroid of rats fed 10 or
50 mg/kg amitrole for 1113 weeks.7 Amitrole
is thought to interfere with the formation of
AMITROLE thyroxine by inhibiting the peroxidase-
CAS: 61-82-5 dependent iodide oxidation in the thyroid.1
Suppression of thyroid function leads to
C2H4N4 further stimulation by the pituitary, with result-
ant hyperplasia and tumor formation.
Like other antithyroid compounds, or like
Synonyms: Aminotriazole; Amitrole-T; Amizol; diets that are low in iodine, continuous expo-
Azolan; 3-amino-1,2,4-triazole; ATA; Cytrol; sure for long periods produces adenomatous
Weedazol changes in the thyroid glands of rats.3 Male
and female rats fed diets containing 10 or
Physical Form. White crystalline powder 100 mg/kg amitrole for life had marked
increases in the incidence of thyroid tumors in
Uses. Herbicide the high-dose group: benign thyroid tumors in
males (45/75 high dose; 5/75 controls) and
Exposure. Inhalation; ingestion females (44/75 high dose; 7/74 controls); for
44 AMITROLE
malignant thyroid tumors, the incidence was No effect on offspring growth or viability
18/75 high dose versus 3/75 for controls in was observed in rats given up to 100 mg/kg in
males, and females had 28/75 versus none in the diet for two generations; litter size and
controls.8 (The high-dose female group also weight, as well as postnatal viability, were
had an increased incidence of benign pituitary reduced in the offspring of breeding pairs
tumors.) Early studies, although limited, also exposed to 500 mg/kg in the diet.3
found increased incidence of thyroid tumors in Amitrole was not genotoxic in bacterial
rats chronically fed amitrole.3,9 assays and cultured mammalian cells or in
In mice, thyroid and liver tumors were rodents exposed in vivo; it did induce transfor-
produced after oral administration. Mice mation of Syrian hamster embryo cells in
administered 1000 mg/kg amitrole by gavage vitro.1
for 4 weeks, followed by diets containing 2192 The 2003 ACGIH threshold limit value-
mg/kg for up to 60 weeks, had an incidence of time-weighted average (TLV-TWA) for amit-
64/72 for thyroid tumors and 67/72 for liver role is 0.2 mg/m3.
tumors.10 Among 55 male mice, 9 hepatocellu-
lar adenomas and 11 hepatocellular carcinomas
were observed after a continuous diet of REFERENCES
500 mg/kg for 90 weeks; among the 49 females,
there were 5 hepatocellular adenomas and 4 1. IARC Monographs on the Evaluation of the
hepatocellular carcinomas. The untreated con- Carcinogenic Risk of Chemicals to Humans, Vol
trols had one hepatocellular adenoma and no 79, Some thyrotropic agents, pp 381410.
Lyon, International Agency for Research on
carcinomas in the males and females com-
Cancer, 2001
bined.11 There was no indication of a carcino-
2. Balkisson R, Murray D, Hoffstein V: Alveo-
genic effect in mice (or hamsters) fed up to lar damage due to inhalation of amitrole-
100 mg/kg for life.8 No skin tumor was containing herbicide. Chest 101:11741176,
observed after weekly topical applications of up 1992
to 10 mg amitrole for life.9 3. Hayes WJ Jr: Pesticides Studies in Man, pp
Very few human data are available to assess 564566. Williams and Wilkins, 1982
the long-term effects of amitrole. In a small- 4. Gaines TB, Kimbrough RD, Linder RE: The
cohort study of Swedish railroad workers, there toxicity of amitrole in the rat. Toxicol Appl
was a statistically signicant excess of all Pharmacol 26:118129, 1973
cancers among those exposed to both amitrole 5. Mayberry WE: Antithyroid effects of 3-
amino-1,2,4-triazole. Proc Soc Exp Biol Med
and chlorophenoxy herbicides (6 deaths vs.
129:551556, 1968
2.9 expected) but not among those exposed
6. Jukes TH, Shaffer CB: Antithyroid effects of
primarily to amitrole (5 deaths vs. 3.3 aminotriazole. Science 132:296297, 1960
expected).12 7. Fregly MJ: Effect of aminotriazole on thyroid
The IARC has determined that there is function the rat. Toxicol Appl Pharmacol 13:
sufcient evidence for the carcinogenicity of 271286, 1968
amitrole to experimental animals and inade- 8. Steinhoff D, Weber H, Mohr U, et al: Eval-
quate evidence for carcinogenicity to humans.1 uation of amitrole (aminotriazole) for poten-
It was noted that amitrole produces thyroid tial carcinogenicity in orally dosed rats, mice,
tumors in rodents by a nongenotoxic mecha- and golden hamsters. Toxicol Appl Pharmacol
nism that involves interference with the func- 69:161169, 1983
9. Hodge HC, Maynard EA, Downs WL, et al:
tioning of the thyroid peroxidase, resulting in
Tests on mice for evaluating carcinogenicity.
a reduction in circulating thyroid hormone
Toxicol Appl Pharmacol 9:583596, 1966
concentration and an increase secretion of 10. Innes JRM, Ulland BM, Valerio MG, et al:
thyroid-stimulating hormone.1 Amitrole would Bioassay of pesticides and industrial chemi-
not be expected to produce thyroid cancer in cals for tumorgenicity in mice; a preliminary
humans exposed to concentrations that do not note. J Natl Cancer Inst 42:11011114,
alter thyroid hormone homeostasis. 1969
AMMONIA 45
11. Vesselinovitch SD: Perinatal hepatocarcino- irritation; at 72 ppm several reported the same
genesis. Biol Res Pregnancy Perinatol 4:2225, symptoms; at 50 ppm two subjects reported
1983 nasal dryness; and at 32 ppm only one reported
12. Axelson O, Sundell L, Andersson K, et al: nasal dryness.2 Surveys of workers have gener-
Herbicide exposure and tumor mortality. ally found that the maximum concentration
An updated epidemiologic investigation on
not resulting in signicant complaints is
Swedish railroad workers. Scand J Work
Environ Health 6:7379, 1980 2025 ppm.2
Tolerance to usually irritating concentra-
tions of ammonia may be acquired by adapta-
tion, a phenomenon frequently observed
among workers who become inured to the
effects of exposure; no data are available on
AMMONIA concentrations that are irritating to workers
CAS: 7664-41-7 who are regularly exposed to ammonia and who
presumably have a higher irritation threshold.
NH3 Cytogenetic evaluation of workers exposed
to ammonia showed increased frequency of
chromosome aberrations and sister chromatid
Synonym: Ammonia gas exchanges.5
In animal studies, pigs exposed at 25, 50,
Physical Form. Colorless gas and 100 ppm continuously for 6 days exhibited
lethargy and a concentration-related depres-
Uses. Fertilizer; refrigeration; petroleum sion of body weight gain.6 Concentrations
rening; blue printing machines; manufacture greater than 50 ppm altered the pulmonary vas-
of fertilizers, nitric acid, explosives, plastics, cular response to endotoxins.
and other chemicals Liquid anhydrous ammonia in contact
with the eyes may cause serious injury to the
Exposure. Inhalation cornea and deeper structures and sometimes
blindness; on the skin it causes rst- and
Toxicology. Ammonia is a severe irritant of second-degree burns that are often severe and,
the eyes, respiratory tract, and skin. if extensive, may be fatal. Vapor concentrations
Exposure to and inhalation of concentra- of 10,000 ppm are mildly irritating to the moist
tions of 25006500 ppm, as might result from skin, whereas 30,000 ppm or greater causes a
accidents with liquid anhydrous ammonia, stinging sensation and may produce skin burns
cause severe corneal irritation, dyspnea, bron- and vesiculation.2 With skin and mucous mem-
chospasm, chest pain, and pulmonary edema brane contact, burns are of three types: cryo-
that may be fatal. Upper airway obstruction genic (from the liquid ammonia), thermal
due to laryngeal/pharyngeal edema and (from the exothermic dissociation of ammo-
desquamation of mucous membranes may nium hydroxide), and chemical (alkaline).3
occur early in the course and require endotra- The 2003 ACGIH threshold limit value-
cheal intubation or tracheostomy.13 Case time-weighted average (TLV-TWA for
reports have documented chronic airway ammonia is 25 ppm (17 mg/m3) with a short-
hyperreactivity and asthma, with associated term excursion limit of 35 ppm (24 mg/m3).
obstructive pulmonary function changes after
massive ammonia exposures.3,4
In a human experimental study that REFERENCES
exposed 10 subjects to various vapor concen-
trations for 5 minutes, 134 ppm caused irrita- 1. Department of Labor: Exposure to ammonia,
tion of the eyes, nose, and throat in most proposed standard. Fed Reg 40:5468454693,
subjects and one person complained of chest 1975
46 AMMONIUM CHLORIDE FUME
2. National Institute for Occupational Safety and making tins. He was using a ux containing
Health, US Department of Health, Education ammonium chloride and zinc chloride. A work-
and Welfare: Criteria for a Recommended related deterioration in mean daily peak expi-
Standard . . . Occupational Exposure to Ammonia. ratory ow was noted that improved when the
(NIOSH) Pub No 74-136. Washington, DC, man was away from work. The second case
US Government Printing Ofce, 1974
involved an 18-year-old man who had cough,
3. Arwood R, Hammond J, Ward G: Ammonia
inhalation. J Trauma 25:444447, 1985 wheeze, chest tightness, and sneezing while
4. Flury K, Dines D, Rodarto J, Rodgers R: working in a small rm that made and repaired
Airway obstruction due to inhalation of car and truck radiators. Symptoms developed 1
ammonia. Mayo Clinic Proc 58:389393, 1983 year after he started work at the shop. He also
5. Yadav JS and Kaushik VK: Genotoxic effect of was using a ux containing ammonium chlo-
ammonia exposure on workers in a fertilizer ride and zinc chloride.
factory. Ind J Exp Biol 35(5):487492, 1997 The fume (concentrations unspecied) is
6. Gustin P, Urbain B, Prouvost JF, et al: Effects reported to cause irritation of the eyes, nose,
of atmospheric ammonia on pulmonary hemo- throat, lungs, and skin.2 No reports are avail-
dynamics and vascular permeability in pigs: able from animal studies on the toxic effects of
interaction with endotoxins. Toxicol Appl Phar-
fume inhalation. Administered into rabbit eyes,
macol 125:1726, 1994
the liquid caused mild to severe irritation.
The 2003 threshold limit value-time-
weighted average (TLV-TWA) is 10 mg/m3
with a short-term excursion level of 20 mg/m3.
Exposure. Inhalation
Physical Form. White powder 12 days caused mild decrease in body weights
and increases in serum enzyme activities indi-
Uses. Polymerization of uorinated mono- cating hepatic effects. The effects were more
mers; surfactant obvious in males than females, and all ndings
resolved during a 42-day recovery period.
Exposure. Inhalation In a teratology study, rats were exposed
from days 6 through 15 of gestation by inhala-
Toxicology. Ammonium peruorooctanoate tion 6 hours/day to levels of 0. 0.1, 10, and
is an hepatotoxin in rats; there are no reports 25 mg/m3 and by gavage at 100 mg/kg/day in
of adverse effects in humans. corn oil.8 Maternal deaths occurred in the
In workers exposed to airborne levels up to groups given the highest level by each route,
7.6 mg/m3, blood levels of organic uoride and overt toxicity in dams was evident at
were higher than background but there were 10 mg/m3. A teratogenic response was not
no adverse health effects attributable to the demonstrated.
exposure.1 Rats fed diets containing 30 or 300 ppm
In rats ammonium peruorooctanoate ammonium peruorooctanoate for 2 years had
induced hepatomegaly that was more pro- increased liver weights with occasional necro-
nounced in the male than in the female.25 Male sis and an apparent dose-dependent increase in
rats are thought to be more sensitive to the Leydig cell adenomas, but there was no
toxic effects of ammonium peruorooctanoate evidence of an increased incidence of hepato-
because of their slower excretion rate. The cellular carcinoma.9 In a follow-up study in
rapid excretion by female rats is due to active male mice, 300 ppm in the diet for 2 years
renal tubular secretion, which is considered to caused increases in liver, Leydig cell, and pan-
be hormonally controlled by estradiol and creatic acinar cell tumors that may have been
testosterone levels. The hepatomegaly was associated with the peroxisome-proliferating
hypertrophic rather than hyperplastic and capabilities of the compound. Ammonium
involved proliferation of peroxisomes. peruorooctanoate also produced sustained
The LC50 for 4 hours in male rats was 980 increases in serum estradiol concentrations.10
mg/m3; this exposure caused an increase in liver The 2003 ACGIH threshold limit value-
size and corneal opacity that diminished over time-weighted average (TLV-TWA) for
time in survivors.6 Exposure of male rats to ammonium peruorooctanoate is 0.01 mg/m3
8 mg/m3 6 hours/day for 10 of 12 days with an A3 animal carcinogen designation and
produced reversible liver weight changes, a notation for skin absorption.
reversible increases in serum enzyme activities,
and liver necrosis. No ocular changes occurred.
No observable effects occurred at 1 mg/m3. REFERENCES
In a 90-day oral study in rhesus monkeys
at levels ranging from 3 to 100 mg/kg/day, the 1. Ubel FA, Sorenson SD, Roach DE: Health
gastrointestinal tract and reticuloendothelial status of plant workers exposed to uoro-
system were the sites of toxic effects at 30 and chemicals-a preliminary report. Am Ind Hyg
100 mg/kg/day.2 Histopathologic effects were Assoc J 41:584589, 1980
seen in the gastrointestinal tract, spleen, lymph 2. Grifth FD, Long JE: Animal toxicity studies
nodes, and bone marrow. Unlike rats, sex- with ammonium peruorooctanoate. Am Ind
Hyg Assoc J 41:576583, 1980
related differences were not evident in the
3. Kawashima Y, Uy-Yu N, Kozuka H:
monkeys. No tissue changes were observed at
Sex-related difference in the inductions by
3 or 10 mg/kg/day. peruorooctanoic acid of peroxisomal b-
Dermal application of 500 mg for 24 hours oxidation, microsomal 1-acylglycerophos-
to rabbit skin produced mild skin irritation.7 phocholine acyltransferase and cytosolic
The dermal LD50 was 4300 mg/kg. Dermal long-chain acyl-CoA hydrolase in rat liver.
application of 200 mg/kg/day to rats for 10 of Biochem J 261:595600, 1989
48 AMMONIUM SULFAMATE
NH4SO3NH2 CH3COOC5H11
causes narcosis in animals, and it is expected safety assessment of amyl acetate and isoamyl
that severe exposure would produce the same acetate. J Am Coll Toxicol 7(16):705719, 1988
effect in humans. 4. Smyth Jr JF, Carpenter CP, West CS, et al:
Several grades of technical amyl acetate are Range nding toxicity data: List VI. Am Ind
known; isoamyl acetate is the major component Hyg Assoc J 23:95107, 1962
5. Bowen SE, Balster RL: A comparison of the
of some grades, whereas n-amyl acetate pre-
acute behavioral effects of inhaled amyl, ethyl,
dominates in others.1 and butyl acetate in mice. Fundam Appl Toxicol
In humans exposure to amyl acetate vapor 35:18996, 1997
for 35 minutes at 200 ppm caused mild eye 6. Grant WM: Toxicology of the Eye, 3rd ed, pp
and nose irritation and severe throat irritation; 9798. Springeld, IL, Charles C. Thomas,
at 100 ppm slight throat discomfort has been 1986
reported.2
Inhalation of excessive concentrations may
also cause headache, fatigue, excessive saliva-
tion, oppression in the chest and occasional
vague nervousness.3
Air saturated with 5200 ppm of technical sec-AMYL ACETATE
amyl acetate (n-amyl acetate the principal com- CAS: 626-38-0
ponent) was fatal to 6 of 6 rats in 8 hours but
caused no deaths in 4 hours.4 C7H14O2
Male mice exposed for 20 minutes to up
to 4000 ppm showed changes in posture,
decreased arousal, increased tonic/clonic Synonyms: a-Methyl butyl acetate; 2-pentyl
movements, disturbances in gait, delayed right- acetate; banana oil
ing reexes, and increased sensorimotor reac-
tivity.5 On removal from exposure recovery was Physical Form. Liquid
rapid.
In standardized testing on rabbit eyes, Uses. Manufacture of lacquers, articial
amyl acetate was graded as only slightly injuri- leather, photographic lm, articial glass, cel-
ous.6 No evidence of delayed contact hyper- luloid, articial silk, and furniture polish
sensitivity due to 20% amyl acetate was
observed in repeat-insult skin patch tests of 211 Exposure. Inhalation
human subjects.3
Amyl acetates may be recognized at con- Toxicology. sec-Amyl acetate is an irritant of
centrations of 7 ppm by the fruitlike odor the eyes, mucous membranes, and skin; high
characteristic of esters; the mean olfactory concentrations cause narcosis in animals, and
detection threshold is 0.2 ppm.1,3 severe exposure is expected to produce the
The 2003 ACGIH threshold limit value- same effect in humans.
time-weighted average (TLV-TWA) for n- In humans, exposure to 500010,000 ppm
amyl acetate is 100 ppm (532 mg/m3). for short periods of time caused irritation of the
eyes and nasal passages.1 Exposure to 1000 ppm
for 1 hour is expected to produce serious toxic
effects.
REFERENCES In guinea pigs, 2000 ppm for 13.5 hours
produced no abnormal signs except irritation
1. Hygienic Guide Series: Amyl Acetate. Am Ind
Hyg Assoc J 26:199202, 1965 of the eyes and nose; at 5000 ppm, there was
2. Nelson KW, Ege Jr JF, Ross M, et al: Sensory lacrimation after 5 minutes, incoordination in
response to certain industrial solvent vapors. J 90 minutes, and narcosis within 9 hours, from
Ind Hyg Toxicol 25:2825, 1943 which animals recovered. A concentration of
3. Cosmet Ingredient Rev: Final report on the 10,000 ppm was fatal after 5 hours.1
50 ANILINE
rats dosed with aniline hydrochloride during The 2003 ACGIH threshold limit value-
gestation.8 Signs of maternal toxicity included time-weighted average (TLV-TWA) for aniline
methemoglobinemia, increased relative spleen is 2 ppm (7.6 mg/m3) with a notation for skin
weight, decreased red blood cell count, and absorption and an A3 animal carcinogen with
hematologic changes indicative of increased unknown relevance to humans designation.
hematopoietic activity. Transient signs of toxi-
city were observed postnatally in the offspring
through day 30. In a more recent report, sub-
cutaneous treatment of Wistar rats with aniline REFERENCES
hydrochloride on day 15 of gestation at doses
1. Henderson Y, Haggard HW: Noxious Gases,
ranging from 260 to 650 mg/kg caused a dose-
2nd ed. New York, Reinhold Publishing,
dependent increase in the frequency of cleft
1943
palate in the fetuses that paralleled the increase 2. Benya TJ, Cornish HH: Aromatic nitro and
in methemoglobin (maternal hypoxia) in amino compounds. In Clayton GD, Clayton
dams.9 FE (eds): Pattys Industrial Hygiene and Toxi-
Aniline hydrochloride was not carcino- cology, 4th ed, Vol II B, Toxicology, pp 949953,
genic to mice when administered orally.10 In 982984. New York, Wiley-Interscience,
one experiment it produced brosarcomas, sar- 1994
comas, and hemangiosarcomas of the spleen 3. MCA: Chemical Safety Data Sheet, SD-21,
and body cavities in rats fed diets containing Nitrobenzene, pp 56, 1214. Washington, DC,
3000 or 6000 mg/kg for 103 weeks. MCA, Inc, 1967
4. Linch AL: Biological monitoring for indus-
The high risk of bladder cancer observed
trial exposure to cyanogenic aromatic nitro
originally in workers in the aniline dye indus-
and amino compounds. Am Ind Hyg Assoc
try has been attributed to exposure to chemi- 35:426432, 1974
cals other than aniline.10 Studies showing 5. Hazard Data Sheet: Aniline. Sheet Number
signicant increase in bladder cancers, such as 78, pp 4445. The Safety Practitioner, June 3,
the one of 1749 rubber antioxidant workers 1986
that found 13 cases of bladder cancer vs. 3.61 6. Kearney TE et al: Chemically induced
expected involved signicant exposure to methemoglobinemia from aniline poisoning.
chemicals such as o-toluidine or contaminants West J Med 140:282286, 1984
that are considered to be more potent carcino- 7. MCA: Chemical Safety Data Sheet SD-17,
gens based on animal and human studies.11,12 Aniline, pp 45, 1214. Washington, DC, MCA,
Inc, 1967
Epidemiological studies of workers exposed to
8. Price CJ, et al: Teratologic and postnatal eval-
aniline but to no other known bladder carcino-
uation of aniline hydrochloride in the Fischer
gen have shown little evidence of increased 344 rat. Toxicol Appl Pharmacol 77:465489,
risk; one study showed one death from bladder 1985
cancer vs. 0.83 expected in a population of 1223 9. Matsumoto K, Ooshima Y, Kusanagi T: Cleft
men producing or using aniline.10 Nonetheless, palate induced by aniline hydrochloride in rat
NIOSH has released an alert for aniline rec- fetuses. Teratology 57(3):33A34A, 1998
ommending that exposures be reduced to the 10. IARC Monographs on the Evaluation of the
lowest possible levels.13 Carcinogenic Risk of Chemicals to Humans.
In genotoxic assays in vivo treatment Suppl 7, Overall evaluations of carcinogenic-
induced sister chromatid exchanges in the bone ity: An updating of IARC Monographs
Volumes 1 to 42, pp 99. Lyon, International
marrow of mice, and DNA strand breakage was
Agency for Research on Cancer, 1987
induced in the liver and kidney of rats.10 In vitro
11. Ward E, Carpenter A, Markowitz S, et al:
aniline was not mutagenic to bacteria and did Excess number of bladder cancers in workers
not cause DNA damage.10 exposed to ortho-toluidine and aniline. J Natl
The IARC has determined that evidence Cancer Inst 83:501506, 1991
for carcinogenicity is limited in animals and 12. Sellers C, Markowitz S: Reevaluating the
inadequate in humans.10 carcinogenicity of ortho-toluidine: a new
52 ANISIDINE
conclusion and its implications. Reg Toxicol isomers subacute effects included hematologic
Pharmacol 16:301317, 1992 changes, anemia, and nephrotoxicity.
13. National Institute for Occupational Safety A signicant increase in transitional cell
and Health (NIOSH): Preventing bladder carcinomas of the urinary bladder was found in
cancer from exposure to o-toluidine and mice and rats fed diets containing 5000 mg/kg
aniline. Am Ind Hyg Assoc J 52:A260A262,
o-anisidine hydrochloride for 103 weeks.3
1991
The IARC has determined that there is
sufcient evidence for the carcinogenicity of o-
anisidine in experimental animals and that it is
possibly carcinogenic to humans.2 Available
data were inadequate to evaluate the carcino-
ANISIDINE genicity of p-anisidine.2
CAS: 29191-52-4 (o-anisidine: 90-04-0, The 2003 ACGIH threshold limit
p-Anisidine: 104-94-9) value-time-weighted average (TLV-TWA)
for the o- and p-isomers of anisidine is 0.1 ppm
NH2C6H4OCH3 (0.5 mg/m3).
Physical Form. o-Anisidine is a yellowish 1. Pacseri I, Magos L, Batskor IA: Threshold and
liquid that darkens on exposure to air; p- toxic limits of some amino and nitro com-
anisidine is a white solid. pounds. AMA Arch Ind Health 18:18, 1958
2. IARC Monographs on the Evaluation of the
Carcinogenic Risk of Chemicals to Humans, Vol
Uses. In the preparation of azo dyes; corro-
73, Some chemicals that cause tumors of
sion inhibitor; chemical intermediate the kidney or urinary bladder in rodents, and
some other substances, pp 4958. Lyon, Inter-
Exposure. Inhalation; skin absorption national Agency for Research on Cancer,
1999
Toxicology. Anisidine, o-and p-isomers, 3. National Cancer Institute: Bioassay of o-
causes anoxia due to the formation of methe- Anisidine Hydrochloride for Possible Carcinogenic-
moglobin. o-Anisidine was carcinogenic in ity, TR-89. DHEW (NIH) Pub No 78-1339.
experimental animals. Washington, DC, US Government Printing
Workers exposed to 0.4 ppm for 3.5 Ofce, 1978
hours/day for 6 months did not develop
anemia, but there were some cases of headache
and vertigo that may have been related to the
increased levels of methemoglobin and sulfhe-
moglobin; erythrocytic inclusions (Heinz ANTIMONY (and Compounds)
bodies) were observed and absorption through CAS: 7440-36-0
the skin may have been a contributing factor.1
Anisidine is a mild skin sensitizer, and local Sb
contact may cause dermatitis.
Mice exposed 2 hours/day at 26 ppm for
a year developed anemia and reticulocytosis. Compounds: Antimony trioxide; antimony
The oral LD50 of o-anisidine is reported to trisulde; antimony trichloride; antimony pen-
be 2000 mg/kg in rats, 1400 mg/kg in mice, and toxide; antimony pentasulde; antimony pen-
870 mg/kg in rabbits. The oral LD50 of p- tachloride
anisidine is 1400 mg/kg in rats, 1300 mg/kg
in mice, and 2900 mg/kg in rabbits.2 For both Physical form. Silvery-white soft metal
ANTIMONY (and Compounds) 53
Uses. Constituent of alloys with other abrasive wheel workers exposed to antimony
metals (tin, lead, copper); suldes used in trisulde for 824 months.6 At air concentra-
compounding of rubber and manufacture of tions averaging over 3.0 mg/m3, 37 of 75
pyrotechnics; trioxide used as a re retardant in workers had electrocardiogram changes and 38
plastics, rubbers, textiles, and paints; chlorides had abnormalities in blood pressure. The lack
used as coloring agents and as catalysts; uo- of electrocardiographic changes in the oxide
rides used in organic synthesis and pottery exposures would seem to indicate a special
manufacture effect of the sulde.
A mortality study of 1014 men employed
Exposure. Inhalation between 1937 and 1971 in a Texas antimony
smelter found increased mortality from lung
Toxicology. Antimony is an irritant of the cancer (standardized mortality ratio 1.39) and
mucous membranes, eyes, and skin; heavy a positive trend in mortality with increasing
exposure to antimony trioxide and pentoxide is duration of exposure.7 The data also suggested
associated with pulmonary injury; antimony some increased mortality from nonmalignant
trisulde is considered cardiotoxic. Antimony respiratory heart disease in these workers.
trioxide is carcinogenic in experimental Female rats exposed to 4.2 and 3.2 mg/m3
animals. antimony trioxide 6 hours/day, 5 days/week, for
Contact of antimony compounds with the 1 year had lung tumors after an additional year
skin causes papules and pustules around sweat of observation.8 Similar ndings were reported
and sebaceous glands.1 in another study involving heavier exposures;
Antimony poisoning was reported in 69 of 27% of female rats exposed to 45 mg/m3 anti-
78 smelter workers during a 5-month period mony trioxide for 1 year and 25% of females
when antimony concentrations of breathing exposed to 38 mg/m3 antimony ore (mainly
zone samples in the smelter building averaged antimony trisulde) developed lung neo-
10.0711.81 mg/m3 of air (range 0.9270.7 mg/ plasms.9 No lung tumors were seen in the male
m3); dermatitis and rhinitis were reported most rats exposed to either compound or in controls.
frequently, but other symptoms included irrita- On the basis of these studies the IARC has
tion of eyes, sore throat, headache, pain or determined that there is sufcient evidence for
tightness in chest, shortness of breath, metallic the carcinogenicity of antimony trioxide in
taste, nausea, vomiting, diarrhea, weight loss, animals and limited evidence for the carcino-
and dysosmia.2 genicity of antimony trisulde.10
Symptomless radiographic lung changes A subsequent chronic inhalation study in
resembling the simple pneumoconiosis of coal rats using lower exposure levels found no evi-
workers were found in 44 of 262 men exposed dence of carcinogenicity.11 A dose-related
to antimony oxide concentrations of 0.5 increase in cataracts and microscopic changes
37 mg/m3.1,3 In another roentgenographic study in the lungs were the primary effects noted
of 51 workers exposed 9 or more years to anti- from 12 months of exposure at 0.06, 0.51, or
mony oxides, there were numerous small opac- 4.5 mg/m3 followed by a 12-month recovery
ities densely distributed in the middle and period.
lower lung elds.4 There were no characteris- In a report from Russia, an increase in the
tic pulmonary function abnormalities, but number of spontaneous abortions was reported
chronic cough was a common symptom. Brief in women exposed to antimony in the work-
exposures to antimony trichloride, approxi- place12,13 Exposure levels were not available.
mately 73 mg Sb/m3, caused gastrointestinal No effects were observed in the offspring of
symptoms as well as irritation of the skin and rats given low levels of antimony trichloride in
respiratory tract; urinary antimony ranged up the drinking water.
to 5 mg/l.5 Both positive and negative results have
Six sudden deaths and two deaths due to been reported in in vitro genotoxic assays of
chronic heart disease occurred among 125 antimony and compounds.13,14 Antimony triox-
54 ANTU (a-NAPHTHYLTHIOUREA)
ide was not genotoxic in vivo in the mouse bone 12. National Institute for Occupational Safety
marrow micronucleus assay or the rat liver and Health, US Department of Health,
DNA repair assay.14 Education and Welfare: Criteria for a Recom-
The 2003 ACGIH threshold limit value- mended Standard . . . Occupational Exposure
time-weighted average (TLV-TWA) for anti- to Antimony, DHEW (NIOSH) 78-216.
Washington, DC, US Government Printing
mony and compounds is 0.5 mg/m3 as Sb;
Ofce, 1978
antimony trioxide production is given an A2- 13. Agency for Toxic Substances and Disease
suspected human carcinogen designation with Registry (ATSDR): Toxicological Prole for
no assigned TLV. Antimony. US Department of Health and
Human Services, Public Health Service, TP-
91/02, pp 135, 1992
14. Elliott BM, Mackay JM, Clay P, et al: An
REFERENCES
assessment of the genetic toxicology of anti-
mony trioxide. Mutat Res 415(12):10917,
1. McCallum RI: The work of an occupational
1998
hygiene service in environmental control.
Ann Occup Hyg 6:5564, 1963
2. Renes LE: Antimony poisoning in industry.
AMA Arch Ind Hyg Occup Med 7:99108,
1953
3. McCallum RI: Detection of antimony in ANTU (a-NAPHTHYLTHIOUREA)
process workers lungs by x-radiation. Trans CAS: 86-88-4
Soc Occup Med 17:134138, 1967
4. Potkonjak V, Pavlovich M: Antimoniosis: A
C11H10N2S
particular form of pneumoconiosis I. Etiol-
ogy, clinical and x-ray ndings. Int Arch Occup
Environ Health 51:199207, 1983
5. Taylor PJ: Acute intoxication from antimony Synonyms: a-Naphthylthiourea; a-naphthyl-
trichloride. Br J Ind Med 23:318321, 1966 thiocarbamide
6. Brieger H, Semisch CW, Stasney J, Piatnek
DA: Industrial antimony poisoning. Ind Med Physical Form. Blue to gray powder
Surg 23:521523, 1954
7. Schnorr TM, Steenland K, Thun MJ, et al: Uses. Rodenticide
Mortality in a cohort of antimony smelter
workers. Am J Ind Med 27(5):75970, 1995
Exposure. Inhalation; ingestion
8. Department of Labor: Antimony metal; anti-
mony trioxide; and antimony sulde response
to the interagency testing committee. Fed Reg Toxicology. ANTU dust causes pulmonary
48:717724, 1983 edema and pleural effusion in animals.
9. Groth DH, Stettler LE, Burg JR, et al: Car- ANTU is probably not toxic to humans
cinogenic effects of antimony trioxide and except in large amounts; the lethal dose by
antimony ore concentrate in rats. J Toxicol ingestion is estimated to be approximately
Environ Health 18:607626, 1986 4 g/kg.1 In a case of human intoxication by
10. IARC Monographs on the Evaluation of ANTU, 80 g of a rat poison containing 30%
Carcinogenic Risks to Humans, Vol 47, Some ANTU was ingested along with a considerable
organic solvents, resin monomers and related amount of ethanol; signs attributable to ANTU
compounds, pigments and occupational
were prompt vomiting, dyspnea, cyanosis, and
exposures in paint manufacture and painting,
coarse pulmonary rales; no pleural effusion
pp 291304, Lyon, International Agency for
Research on Cancer, 1989 occurred, and the pulmonary signs gradually
11. Newton PE, Bolte HF, Daly IW, et al: cleared.1
Subchronic and chronic inhalation toxicity of Oral administration to rats of 35 mg/kg
antimony trioxide in the rat. Fundam Appl was fatal to 60% of the animals; effects were
Toxicol 22:561576, 1994 labored respiration and muscular weakness;
ARSENIC (and Compounds) 55
autopsy revealed pleural and pericardial effu- 4. IARC Monographs on the Evaluation of the Car-
sion as well as mild liver damage.2 Tachyphy- cinogenic Risk of Chemicals to Humans. Suppl 7,
laxis or tolerance to the acute toxicity of Overall evaluations of carcinogenicity: An
ANTU has been observed after repeated updating of IARC Monographs Volumes 142.
administrations; intraperitoneal injection of pp 2634. Lyon, International Agency for
Research on Cancer, 1987
2.5 mg/kg produced moderate pulmonary
5. Scott AM, Powell GM, Upshall DG, et al: Pul-
edema and large pleural effusions, but two monary toxicity of thioureas in the rat. Environ
additional 2.5 mg/kg doses at 2-day intervals Health Perspect 85:4350, 1990
caused lesser degrees of edema and minimal
pleural uid.3 Daily doses of 200 mg/kg (20%
of the median lethal dose) in rabbits were
cumulative, causing death in 56 days without
pleural effusions.2
ANTU was not carcinogenic in rodent ARSENIC (and Compounds)
feeding studies.4 Cases of bladder tumors CAS: 7440-38-2
among rat catchers exposed to ANTU have
been attributed to b-naphthylamine, a manu- As
facturing impurity of ANTU. In bacterial
assays ANTU induced mutations.
Studies on the mechanism of thiourea tox- Synonyms and Compounds: Grey arsenic;
icity have shown that thioureas have a high metallic arsenic; arsenic trichloride; arsenic tri-
degree of specicity for pulmonary endothelial oxide; arsenic salts
cells and that thioureas require metabolic acti-
vation before toxic effects are manifested.5 Physical Form. Metallic arsenic is a steel
Reduced glutathione levels have been associ- gray brittle metal; arsenic trichloride is an oily
ated with increased toxicity, but there is no evi- liquid; arsenic trioxide is a crystalline solid
dence to suggest that the appearance of edema
coincides with a decrease in glutathione. Fur- Uses/Sources. In wood preservatives; metal-
thermore, the induction of tolerance or resist- lurgy for hardening copper, lead, alloys;
ance is not correlated with an increase in pigment production; manufacture of certain
glutathione levels in rats.5 types of glass; insecticides and fungicides,
The 2003 threshold limit value-time- rodent poison; a by-product in the smelting of
weighted average (TLV-TWA) for ANTU is copper ores; dopant material in semiconductor
0.3 mg/m3. manufacture
1. Gosselin RE, Smith, RP, Hodge HC: Clinical Toxicology. Arsenic compounds are irritants
Toxicology of Commercial Products, 5th ed, of the skin, mucous membranes, and eyes; gas-
Section III, pp 4042. Baltimore, MD, trointestinal effects, peripheral neuropathy,
Williams & Wilkins, 1984 vascular lesions, skin diseases, and various
2. McClosky WT, Smith MI: Studies on the cancers are reported risks of exposure to
pharmacologic action and the pathology of
arsenic compounds.
alphanaphthylthiourea (ANTU). I. Pharma-
The degree of toxicity of arsenic is depend-
cology. Public Health Rep 60:11011113,
1945 ent on the form, either inorganic or organic,
3. Sobonya RE, Kleinerman J: Recurrent pul- and the oxidation state of the arsenical.1 Inor-
monary edema induced by alpha naphthyl ganic arsenicals are generally more toxic than
thiourea. Am Rev Respir Dis 108:926932, organic, and the trivalent forms are more toxic
1973 than the pentavalent.
56 ARSENIC (and Compounds)
Acute arsenic poisoning is rare in the occu- Several studies have suggested an associa-
pational setting and results primarily from tion between inorganic arsenic exposure and
ingestion of contaminated food and drink.2 increased risk of developmental effects (low
Initial symptoms include burning lips, con- birth weight and congenital malformations).8
striction of the throat, and dysphagia followed In a recent report, adverse pregnancy
by excruciating abdominal pain, severe nausea, outcomes including spontaneous abortion,
projectile vomiting, and profuse diarrhea.3 stillbirth, and preterm birth weights were sig-
Other toxic effects on the liver, blood-forming nicantly higher in a group of women chroni-
organs, the central and peripheral nervous cally exposed to arsenic through drinking
systems, and the cardiovascular system may water.9 Studies in animals support the view that
appear.4 Convulsions, coma, and death follow arsenic is a developmental toxicant causing
within 24 hours in severe cases.3 Levels of reduced birth weight, a variety of fetal malf-
exposure associated with acute arsenic toxicity ormations, and increased fetal mortality.
vary with the valency form of the element; However, in all cases, the doses required to
trivalent arsenic compounds are the most toxic, cause these effects resulted in signicant mater-
presumably because of their avid binding to nal toxicity.8
sulfhydryl groups. For arsenic trioxide the In a large number of studies, exposure to
reported estimated lethal dose ranges from 70 inorganic arsenic compounds in drugs, food,
to 300 mg.3,4 and water as well as in an occupational setting
Acute inhalation exposures have resulted in have been causally associated with the develop-
irritation of the upper respiratory tract, even ment of cancer, primarily of the skin and
leading to nasal perforations.4 Occupational lungs.14 An excess mortality in respiratory
exposure to arsenic compounds results in cancer has been found among smelter workers
hyperpigmentation of the skin and hyperker- and workers engaged in the production and use
atoses of palmar and plantar surfaces, as of arsenical pesticides. It should be noted,
well as dermatitis of both primary irritation however, that in a number of these studies,
and sensitization types.1 Impairment of levels of exposure are uncertain and there is
peripheral circulation and Raynaud phenome- simultaneous exposure to other agents. In a
non have been reported with long-term follow-up of 8045 smelter workers, those with
exposure.5 the highest estimated exposure and the longest
Chronic arsenic intoxication by ingestion follow-up had a ninefold increase in respiratory
is characterized by weakness, anorexia, gas- cancer mortality.10
trointestinal disturbances, impairment of cog- Another large retrospective cohort study
nitive function, peripheral neuropathy, and followed 3916 smelter workers and reported an
skin disorders. Noncirrhotic portal hyperten- overall standardized mortality ratio of 372.11
sion, splenomegaly, and bone marrow depres- Lung cancer mortality was related to intensity
sion may occur.6 Arsenic-contaminated of exposure but not to duration. Histologic
drinking water in Taiwan has been one of the types of lung carcinomas were similar to those
factors associated with blackfoot disease, a seen in smokers.
progressive loss of circulation in the ngers and Information on the association of arsenic
toes that leads to gangrene.1 with skin cancer has primarily involved nonoc-
Arsenic trichloride is a vesicant and can cupational populations exposed to contami-
cause severe damage to the respiratory system nated drinking water.4 Ingestion of arsenic has
on inhalation; it is rapidly absorbed through also been associated with lung, liver, bladder,
the skin, and a fatal case after a spill on the skin and kidney cancers. Dose-response data for
has been reported.7 The vapor of arsenic these cancers are available from epidemiologi-
trichloride is highly irritating to the eyes. Some cal studies of a Taiwanese population exposed
organic arsenicals, such as arsanilates, have a for 45 years to high levels of arsenic in the
selective effect on the optic nerve and can cause drinking water and involving more than 7000
blindness. cases of arsenical disease. For water arsenic
ARSENIC (and Compounds) 57
concentrations of 170, 470, and 800 mg/l, the 3. Winship KA: Toxicity of inorganic arsenic
corresponding mortality rate ratios for bladder salts. Adv Drug React Ac Pois Rev 3:129160,
cancer were 5.1, 12.1, and 28.7 for men and 1984
11.9, 25.1, and 65.4 for women and for kidney 4. EPA: Health Assessment Document for Inorganic
cancer were 4.9, 11.9, and 19.6 for men and 4.0, Arsenic. Final Report. Research Triangle Park,
NC, US Environmental Protection Agency,
13.9, and 37.0 for women.12 An epidemiologi-
March 1984
cal study of lung cancer has shown a linear cor- 5. Lagerkrist BA, Linderholm H, Nordberg
relation between the standard mortality ratio of GF: Arsenic and Raynauds phenomenon. Int
lung cancer and the concentration of arsenic Arch Occup Environ Health 60:361364, 1988
found in the urine. 6. Hall AH: Chronic arsenic poisoning. Toxicol
Chronic ingestion of trivalent arsenic in Lett 128(13):6972, 2002
medicinal preparations was also associated with 7. Hygienic Guide Series: Arsenic and its com-
an increased incidence of hyperkeratosis and pounds (except arsine). Am Ind Hyg Assoc J
skin cancer.4 25:610613, 1964
There is limited evidence of carcinogenic- 8. Agency for Toxic Substances and Disease
ity in experimental animals. However, in one Registry (ATSDR): Toxicological Prole for
Arsenic. pp 428. US Department of Health
report arsenic administered for 2 years in the
and Human Services, Public Health Service,
drinking water of female mice was associated 2000
with an increased incidence in tumors involv- 9. Ahmad SA, Sayed MH, Barua S, et al:
ing lung, liver, gastrointestinal tract, and skin.1 Arsenic in drinking water and pregnancy
In genotoxic assays inorganic arsenicals outcomes. Environ Health Perspect
are either inactive or weak mutagens but are 109(6):62931, 2001
able to produce chromosomal effects including 10. Lee-Feldstein A: Cumulative exposure to
aberrations and sister chromatid exchange in arsenic and its relationship to respiratory
most test systems.8 Studies of exposed human cancer among copper smelter employees. J
have detected higher incidences of chromoso- Occup Med 28:296302, 1986
mal aberrations in peripheral lymphocytes and 11. Jarup L, Pershagen G, Wall S: Cumulative
arsenic exposure and lung cancer in smelter
increases in the frequency of micronuclei in the
workers: a dose-response study. Am J Ind Med
oral mucosa cells, urothelial cells, and periph- 15:3141, 1989
eral blood lymphocytes.8,13 12. Smith A, Hopenhayn-Rich C, Bates MN, et
Regarding cancer, potential mechanisms al: Cancer risks from arsenic in drinking
include genotoxicity, altered DNA methyla- water. Environ Health Perspect 97:259267,
tion, oxidative stress, altered cell proliferation, 1992
cocarcinogenesis, and tumor promotion.14 13. Basu A, Mahata J Roy AK, et al: Enhanced
The 2003 ACGIH threshold limit value- frequency of micronuclei in individuals
time-weighted average (TLV-TWA) for exposed to arsenic through drinking water
arsenic, elemental, and inorganic compounds in West Bengal, India. Mutat Res
(except arsine) as As is 0.01 mg/m3 with an A1- 516(12):2940, 2002
14. Hughes MF: Arsenic toxicity and potential
conrmed human carcinogen designation.
mechanisms of action. Toxicol Lett
133(1):116, 2002
REFERENCES
whereas a single exposure to 0.5 ppm caused no ison of clinical indices of exposure. Fundam
effects on the hematopoietic system.11 Appl Toxicol 14:776787, 1990
Arsine, at concentrations that induced 12. Morrissey RE, Fowler BA, Harris MW, et al:
maternal toxicity in rats and mice, did not affect Arsine: absence of developmental toxicity in
end points of developmental toxicity.12 rats and mice. Fundam Appl Toxicol 15:
350356, 1990
Arsine is nonirritating with a garlic-like
odor. Warning properties of exposure to haz-
ardous concentrations are inadequate.1
The 2003 ACGIH threshold limit value-
time-weighted average (TLV-TWA) for arsine
is 0.05 ppm (0.16 mg/m3). ASBESTOS
CAS: 1332-21-4
and the physical and chemical properties of the were 99 excess deaths (above that expected on
asbestos ber.2 In general, the grade of pul- the basis of the US white male population) for
monary brosis relates to the ber burden three types of malignanciesbronchogenic
carried by the lungs.3 Fiber morphology is also (63), gastrointestinal (26), and all other sites
important. Alveolar macrophages, which nor- combined (10).1
mally phagocytize foreign bodies deposited in Mesothelioma, a relatively rare and rapidly
the lungs, seek to engulf the asbestos bers and fatal neoplasm seen chiey in crocidolite
remove them. The macrophages are unable to workers, may occur without radiological evi-
remove long bers in this manner, which dence of asbestosis at exposure levels lower
results in an ongoing focal inammatory than those required for prevention of radiolog-
response. Ultimately, epithelial cells are ically evident asbestosis.1 Mesothelioma can
replaced by brous tissue, resulting in a pro- occur after a short intensive exposure; cases in
gressive loss of lung compliance and respira- children under 19 years of age indicate that
tory function. Occasionally, asbestosis may the latent time period for development may be
develop fully in 79 years and may cause death shorter than rst estimated, although the
as early as 13 years after rst exposure. Usually, disease may occur after a very limited exposure
however, pneumoconiosis becomes evident 2030 years earlier.
2040 years after the rst exposure to asbestos. Fiber characteristics, including durability,
Once established, asbestosis progresses even harshness, surface chemistry, and dimensions
after exposure has ceased.1 Increased risk of appear to play a role in the carcinogenic
ischemic heart disease has also been associated process. Width and length of bers are impor-
with asbestosis because of impaired lung tant parameters in determining the carcino-
function.4 genic potential of various asbestos forms,
The pleura may also be affected by where a ber is dened as a particle with a
asbestos. Often there is thickening of the vis- length-to-width ratio of at least 3 : 1 and a
ceral pleura from extension of the parenchymal length of 5 mm or more. In animal studies,
inammation. The parietal pleura may show bers longer than 8 mm and narrower than 0.25
patches of severe thickening, particularly over mm were more closely linked to pleural tumors
the diaphragm and the lower portions of the irrespective of ber type.6 In general, bers
chest wall, resulting in the so-called pleural with widths greater than 1 mm are not impli-
hyaline plaques. These may be seen by X ray, cated in the occurrence of lung cancer or
especially if calcied. The health signicance of mesothelioma.7
pleural abnormalities is not precisely dened, Cigarette smoke is strongly implicated as a
but many investigators consider the pleural cocarcinogen among asbestos workers.8 The
plaques to be essentially benign.5 In some cases, incidence of lung carcinoma among nonsmok-
however, pleural thickening can lead to ing asbestos workers is not signicantly greater
decreased ventilatory capacity with severe con- than that of non-asbestos workers, whereas
sequences. Signs of lung brosis and increased asbestos workers who smoke have a much
mortality associated with asbestosis or nonma- higher incidence. Cigarette-smoking asbestos
lignant respiratory disease have been reported workers have approximately 15 times the risk
in occupationally exposed workers with cumu- of developing lung cancer compared with non-
lative exposures as low as 1570 f-yr/ml for smoking asbestos workers.9
signs of lung brosis and 321271 f-yr/ml for Asbestos has caused a variety of chromo-
asbestosis-associated mortality.5 somal aberrations both in vivo and in vitro.5
Bronchogenic carcinoma and mesothe- No obvious developmental effects were
lioma of the pleura and peritoneum are causally observed in animals exposed to high levels of
associated with asbestos exposure; excesses of asbestos during gestation.4
cancer of the stomach, colon, and rectum have The 2003 ACGIH threshold limit value-
also been observed.5 Among 632 asbestos time-weighted average (TLV-TWA) for all
workers observed from 1943 to 1967, there forms of asbestos is 0.1 ber/cc (for bers
ASPHALT FUMES 61
REFERENCES
1. National Institute for Occupational Safety and Synonyms: Asphaltic bitumen; asphaltum;
Health, US Department of Health, Education, petroleum asphalt; bitumen
and Welfare: Criteria for a Recommended
Standard . . . Occupational Exposure to Asbestos. Physical Form. Brownish-black viscous
DHEW (HSM) 72-10267. Washington, DC, liquid or solid composed essentially of hydro-
US Government Printing Ofce, 1972 carbons; residue from the evaporation of the
2. Parkes WR: Occupational Lung Disorders, 2nd
lighter hydrocarbons from petroleum
ed, p 255. London, Butterworths, 1982
3. Becklake MR: Pneumoconioses. In Murray JF,
Nadel JA: Textbook of Respiratory Medicine, Vol Uses/Sources. Asphalt fumes arise from
2, p 1577. Philadelphia, PA, WB Saunders, asphalt used for road construction, roong, and
1988 coating of construction materials and in asso-
4. Sanden A, Jarvholm B, Larsson S, et al: The ciation with the production of asphalt from
importance of lung function, nonmalignant petroleum; in asphalt-based paints
diseases associated with asbestos, and symp-
toms as predictors of ischaemic heart disease Exposure. Inhalation; skin contact
in shipyard workers exposed to asbestos. Br J
Ind Med 50:785790, 1993
5. Agency for Toxic Substances and Disease Toxicology. Acute exposure to asphalt fumes
Registry (ATSDR): Toxicological Prole for causes irritative effects. Certain extracts of
Asbestos. US Department of Health and asphalt have caused a carcinogenic skin
Human Services, Public Health Service, pp response in experimental animals.
141, 1999 The chemical composition of vapors and
6. Stanton MF, Layard M, Tegeris A, et al: fumes from asphalt products is variable and
Relation of particle dimension to carcino- depends on the crude petroleum source, type
genicity in amphibole asbestoses and other of asphalt, temperature, and extent of mixing.1
brous minerals. J Natl Cancer Inst 57:965 Therefore, the adverse effects from asphalt
975, 1981
may also vary considerably depending on the
7. Wylie AG, Bailey KF, Kelse JW, et al: The
importance of width in asbestos ber carcino-
source of exposure.
genicity and its implications for public policy. After acute exposure, subjective symptoms
Am Ind Hyg Assoc J 54:239252, 1993 including abnormal fatigue, reduced appetite,
8. Selikoff IJ, Hammond EC, Churg J: Asbestos and throat and eye irritation have been
exposure, smoking and neoplasia. JAMA 204: reported.2 Skin irritation, pruritus, and occa-
106112, 1968 sionally rashes have also been described in
9. Selikoff IJ, Lee DHK: Asbestos and Disease, p asphalt workers. In a study of road repair and
327. New York, Academic Press, 1978 construction workers symptoms increased with
increasing concentration of asphalt fumes and
with increasing asphalt temperature. In
another report of female workers in a com-
mercial lighting factory there was a causal asso-
ciation between exposure to asphalt fumes,
irritative symptoms (nausea, headache, fatigue,
skin rashes, and eye, nose and throat irritation),
and macrothrombocytosis (enlarged platelets),
which reversed with a reduction of exposure.3
62 ASPHALT FUMES
Although a causal relationship cannot be of crude oils, and the asphalts were far less
established, recent studies have suggested an mutagenic than coal tar fumes.9
association between asphalt fume exposure and NIOSH has determined that some workers
acute lower respiratory tract symptoms includ- exposed to asphalt fume are at an elevated risk
ing coughing, wheezing, and shortness of for lung cancer; however, it is uncertain
breath.1 whether this excess is related to asphalt or other
Epidemiological studies have reported carcinogens in the workplace.1
varying results. A meta-analysis of studies The 2003 ACGIH threshold limit value-
involving pavers and highway workers exposed time-weighted average (TLV-TWA) for
to asphalt did not nd overall evidence for lung asphalt fumes is 5 mg/m3.
cancer among pavers.4 In contrast, studies of
roofers have generally demonstrated an excess
number of lung cancer cases.1 The conicting REFERENCES
evidence in epidemiological studies reects the
difculties in establishing the exact nature of 1. Butler MA, Burr G, Dankovic D, et al: Hazard
the material to which the workers are exposed Review. Health Effects of OCCUPATIONAL
and in ensuring that the exposure is to asphalt exposure to Asphalt. US Department of Health
alone. Cohorts of workers such as roofers are and Human Services, Public Health Service,
often also exposed during their careers to Centers for Disease Control Prevention, Dec
asbestos and coal tar pitches, which are 2000
generally considered to be more potent 2. Norseth T, Waage J, Dale I: Acute effects and
exposure to organic compounds in road main-
carcinogens.1,5
tenance workers exposed to asphalt. Am J Ind
A few studies have reported an association
Med 20:737744, 1991
between bladder and renal cancers and occu- 3. Chase RM, Liss GM, Cole DC, et al: Toxic
pations having the potential for exposures to health effects including reversible macro-
asphalt.1 In an historical cohort study of 1320 thrombocytosis in workers exposed to asphalt
workers in the asphalt industry, there was a fumes. Am J Ind Med 25:279289, 1994
signicant increase in brain cancer [standard- 4. Partanen T, Boffetta P.: Cancer risk in asphalt
ized mortality ratio (SMR) 500] but not in workers and roofers: review and meta-analysis
respiratory, bladder, or gastrointestinal cancer.6 of epidemiologic studies. Am J Ind Med 26(6):
Of 679 Danish men who were heavily exposed 72140, 1994
to asphalt, signicant increases occurred in 5. IARC Monographs on the Evaluation of Car-
cinogenic Risks to Humans. Suppl 7, Overall
the incidences of cancer of the mouth (SMR
evaluations of carcinogenicity: An updating
1111), esophagus (698), rectum (318), and lung
of IARC Monographs Volumes 142, pp.
(344).7 133134. Lyon, International Agency for
A subsequent mortality study of this same Research on Cancer, 1987
cohort found signicant increases for death due 6. Hansen ES: Cancer mortality in the asphalt
to lung cancer.8 (Mortality from noncarcino- industry: a ten year follow up of an occupa-
genic respiratory diseases including bronchitis, tional cohort. Br J Ind Med 46:582585,
emphysema, and asthma also occurred in 1989
excess.) 7. Hansen ES: Cancer incidence in an occupa-
In mice skin-painting studies, skin tumors tional cohort exposed to bitumen fumes. Scand
were produced by steam-rened petroleum J Work Environ Health 15:101105, 1989
8. Hansen ES: Mortality of mastic asphalt
bitumens, an air-rened bitumen in toluene,
workers. Scand J Work Environ Health 17:
two cracking residue bitumens, and a pooled
2024, 1991
mixture of steam- and air-blown petroleum 9. Macado ML, Beatty PW, Fetzer JC, et al:
bitumens.5 In contrast, standard roong petro- Evaluation of the relationship between PAH
leum asphalts produced no tumors. content and mutagenic activity of fumes from
There was a vefold range in mutagenicity roong and paving asphalts and coal tar pitch.
in fumes from asphalts derived from a variety Fundam Appl Toxicol 21:492499, 1993
ATRAZINE 63
pesticides, pp 441465, Lyon, International blood cell and plasma cholinesterases; concen-
Agency for Research on Cancer, 1991 trations of 0.195 and 1.24 mg/m3 were without
effect.3
Prolonged dietary exposure of rats (13
weeks) produced biochemical and neurobehav-
ioral evidence of cholinergic toxicity with
neurobehavioral effects evident only when
AZINPHOS-METHYL there was more than 20% inhibition of
CAS: 86-50-0 cholinesterase activity.4 Rats fed azinophos-
methyl for 2 years at rates of 50 ppm and later
C10H12N3O3PS2 100 ppm had normal growth rates, but plasma,
red blood cell and brain cholinesterase activi-
ties were depressed in the females.5 Dietary
Synonyms: O,O-dimethyl-S-(4-oxo-1,2,3- levels of 5 ppm were without effect, and no
benzotriazin-3(4H)-yl methyl phosphoroth- tumorigenic activity was noted at any dosage
ioate; Guthion; Methyl Guthion; Gusathion level. Dogs receiving 300 ppm in their feed had
tremors, weakness, lethargy, and some weight
Physical Form. White crystalline solid loss; 5 ppm administered in the feed for 2 years
was without effect on cholinesterase levels. In
Uses. Acaricide; insecticide a chronic feed study there was suggestive evi-
dence of carcinogenicity in male rats based on
Exposure. Inhalation; skin absorption; neoplasms of the thyroid and pancreatic islets;
ingestion azinphos-methyl was not carcinogenic in
female rats or mice of either sex.6
Toxicology. Azinphos-methyl is an indirect No selective developmental effects were
inhibitor of cholinesterase. observed in rats or mice administered up to 5
Dosages given to volunteers for approx- mg/kg/day during gestation.7 In another report
imately 30 days ranged from 4.0 to 20 mg/ there was no effect on fetal cholinesterase even
person/day and did not produce clinical at doses that caused signicant inhibition of
effects or a signicant change in cholinesterase maternal cholinesterase in rats administered
levels. In a study of eight workers engaged in azinphos-methyl by oral gavage on gestation
the formulation of a Guthion wettable powder days 615; clinical effects in dams were associ-
and exposed to concentrations up to 9.6 mg/m3, ated with cholinesterase inhibition greater than
the lowest activity of cholinesterase in 20%. Despite maternal toxicity no embryotox-
blood serum was 78% of the value before icity was observed.8
exposure; there were no signs or symptoms of The 2003 ACGIH threshold limit value-
illness.2 time-weighted average (TLV-TWA) for azin-
It is expected that severe exposure would phos-methyl is 0.2 mg/m3 with a notation for
produce a broad spectrum of clinical effects skin absorption.
indicative of massive overstimulation of the
cholinergic system including headache, weak-
ness, dizziness, blurred vision, respiratory dif-
culty, paralysis, convulsions, and coma. REFERENCES
In animals azinophos-methyl has an acute
1. Hayes WJ Jr: Organic phosphorus pesticides.
oral toxicity similar to that of parathion,
In Pesticides Studied in Man, pp 358359.
although the acute dermal toxicity is less than Baltimore, MD, Williams & Wilkins, 1982
that of parathion.1 2. Jegier Z: Exposure to Guthion during spray-
Rats that inhaled azinphos-methyl at ing and formulating. Arch Environ Health
4.72 mg/m3, 6 hours/day, 5 days/week for 12 8:565569, 1964
weeks showed signicant depression of red 3. Kimmerle G: Subchronic inhalation toxicity of
BARIUM (and Compounds) 65
azinophos-methyl in rats. Arch Toxicol 35: gastrointestinal, hepatic, and renal systems in
8389, 1976 humans and animals.
4. Sheets LP, Hamilton BF, Sangha GK, et al: The toxicity of barium compounds de-
Subchronic neurotoxicity screening studies pends on their solubility, with the more soluble
with six organophosphate insecticides: an forms being more toxic than the relatively
assessment of behavior and morphology rela-
insoluble forms, which are inefcient sources
tive to cholinesterase inhibition. Fundam Appl
Toxicol 35(1):10119, 1997 of Ba2+ ions.1
5. Worden AN, Wheldon GH, Noel PRB, et al: Inhalation of insoluble barium-containing
Toxicity of Gusathion for the rat and dog. dusts may produce a benign pneumoconiosis,
Toxicol Appl Pharmacol 24:405412, 1973 termed baritosis.2 The condition is without
6. NCI: Bioassay of technical-grade azinphosmethyl clinical signicance. Characteristic X-ray
for possible carcinogenicity. Technical Report changes are those of small, extremely dense
Series No 069, DHEW Pub No. (NIH) 78 circumscribed nodules evenly distributed
1319, pp. 123, 1978 throughout the lung elds reecting the
7. Short RD, Minor JL, Lee CC, et al: Develop- radiopacity of the barium dust. Exposure of
mental toxicity of Guthion in rats and mice. workers to concentrations ranging to 92 mg/m3
Arch Toxicol 43:177186, 1980
of barium sulfate caused no abnormal signs or
8. Astroff AB and Young AD.: The relationship
between maternal and fetal effects following symptoms including no interference with lung
maternal organophosphate exposure during function or liability to develop pulmonary or
gestation in the rat. Toxicol Ind Health 14(6): bronchial infection.3 Ingestion of insoluble
86989, 1998 barium compounds also presents no problems
to health, barium sulfate being widely used as
a contrast agent in radiography.4
Barium ion is a muscle poison causing
stimulation and then paralysis. Initial symp-
toms are gastrointestinal, including nausea,
BARIUM (and Compounds) vomiting, colic, and diarrhea, followed by
CAS: 7440-39-3 myocardial and general muscular stimulation
with tingling in the extremities.2 Severe cases
Ba continue to loss of tendon reexes, general
muscular paralysis, and death from respiratory
arrest or ventricular brillation. Threshold of
Compounds: Solublebarium nitrate, barium a toxic dose in humans is reported to be about
sulde, barium chloride, barium hydroxide, 0.20.5 g Ba absorbed from the gut; the lethal
barium acetate; insolublebarium sulfate dose is 34 g Ba.
In animal studies, rats receiving 110 mg
Physical Form. Elemental barium is a silver barium/kg body weight in the drinking water
white metal; many of the compounds are white as barium chloride dihydrate for 15 days had
powders or crystals. no clinical ndings of toxicity. In female mice
administered 85 mg/kg/day and in male mice
Uses. Catalyst for organic reactions; lubri- given 70 mg/kg/day in the drinking water, for
cating oil additive; rat poison; manufacture of the same time period, there was no histopatho-
paper electrodes; in reworks; in electroplat- logic evidence of toxicity, although relative
ing; in medicine as a radiopaque substance for liver weights of the dosed animals were signif-
X-ray diagnosis icantly greater than those of controls.5 In 13-
week studies in mice, liver weights were lower
Exposure. Inhalation; ingestion than controls at doses above 100 mg/kg/day; at
doses of 450 mg/kg/day and 495 mg/kg/day in
Toxicology. Certain compounds of barium males and females, respectively, there was
are toxic to the cardiovascular, respiratory, multifocal to diffuse nephropathy charac-
66 BAUXITE
1. Agency for Toxic Substances and Disease Reg- Uses. Ore for production of alumina; adsor-
istry (ATSDR): Toxicological Prole for Barium. bent in oil rening
US Department of Health and Human Ser-
vices, Public Health Service, pp 1138, TP- Exposure. Inhalation
91/03, 1992
2. Reeves AL: Barium. In Friberg L et al. (eds):
Toxicology. Bauxite can be considered to be
Handbook on the Toxicology of Metals, pp
321328. New York, Elsevier North-Holland, a nuisance particulate; long experience with
1979 mining and rening of bauxite has not revealed
3. ACGIH: Barium sulfate. Documentation of the signicant adverse health effects.
threshold limit values and biological exposure Nuisance particulates have little adverse
indices, 7th ed, p 2. Cincinnati, OH, American effect on lungs and do not produce signicant
BENOMYL 67
organic disease or toxic effect when exposures 2. Bellot SM, Schade Van Westrum JAFM,
are kept under reasonable control.1 However, Wagenvoort CA, et al: Deposition of bauxite
when inhaled in excessive amounts all dusts dust and pulmonary brosis. Path Res Pract
may be expected to evoke some cellular 179:225229, 1984
response. According to ACGIH, the lung tissue 3. Beach JR, de Klerk NH, Fritschi L, et al:
Respiratory symptoms and lung function in
reaction caused by inhalation of nuisance
bauxite miners. Int Arch Occup Environ Health
particulates has the following characteristics: 74(7):489494, 2001
1) The architecture of the air spaces remains 4. Hatch TF: Summary. In Vorwald, A.J. (ed):
intact. 2) Collagen (scar tissue) is not formed Pneumoconiosis, Beryllium, Bauxite Fumes, pp
to a signicant extent. 3) The tissue reaction is 498501. New York, Harper & Brothers, 1950
potentially reversible. 5. Shaver CG, Riddel AR: Lung changes associ-
In one case report of a 70-year-old worker ated with the manufacture of alumina abra-
exclusively exposed to the dust of raw bauxite, sives. J Ind Hyg Toxicol 29:145157, 1947
deposits of bauxite were found in the lungs in
areas of mild pulmonary brosis.2 There were
no clinical symptoms, and it is not clear
whether the brosis was a response to the
bauxite or whether the bauxite accumulated in
preexisting brotic areas. BENOMYL
No serious adverse effects on respiratory CAS: 17804-35-2
health as determined by self-reported symp-
toms and spirometry were found in current C14H18N4O3
employees at three bauxite mines in Australia.3
The nuisance dust aspect of bauxite is in
sharp contrast to the limited industrial situa- Synonyms: Methyl 1-(butylcarbamoyl)-2-ben-
tion where lung injury was reported in Cana- zidimidazolecarbamate; Benlate; Benex
dian workers, who in the 1940s engaged in the
manufacture of alumina abrasives in the virtual Physical Form. White to tan crystalline
absence of fume control.4,5 Fusing of bauxite at solid
2000C gave rise to a fume composed of freshly
formed particles of amorphous silica and alu- Uses. Fungicide; ascaracide
minum oxide. Despite the poor choice of the
termbauxite fume pneumoconiosissome- Exposure. Inhalation; skin contact
times used to describe the disease, scientic
opinion favors the silica component as the Toxicology. Benomyl causes dermatitis and
probable toxic agent. It should be emphasized dermal sensitization; in experimental animals it
that bauxite from some sources may contain is a reproductive toxin and teratogen.
small amounts of silica. Contact dermatitis has been reported in
The 2003 ACGIH threshold limit Japanese women who worked in a greenhouse
value-time-weighted average (TLV-TWA) for where benomyl had been used.1 Eruptions on
bauxite is 10 mg/m3. the backs of the hands and on the forearms
consisted of redness and edema. Cases of
dermal sensitization have also been reported.2
In animal studies benomyl has low acute
REFERENCES
toxicity.2 The oral LD50 for rats was greater
1. ACGIH: Nuisance particulates. Documentation than 10 g/kg, and the dermal LD50 in rabbits
of TLVs and BEIs, 6th ed, pp 11661167. was also greater than 10 g/kg.3 There was mild
Cincinnati, OH, American Conference of Gov- irritation when benomyl was placed on the skin
ernment Industrial Hygienists (ACGIH), 1991 of the rabbit or in the rabbit eye.
68 BENZ[a]ANTHRACENE
In a 90-day inhalation study, equal groups The 2003 ACGIH threshold limit
of male and female rats were exposed nose- value-time-weighted average (TLV-TWA) for
only 6 hours/day, 5 days/week, to levels of 0, benomyl is 0.84 ppm (10 mg/m3).
10, 50, or 200 mg/m3.4 At 45 days half the
animals were killed and necropsied. Degenera-
tion of the olfactory epithelium was observed REFERENCES
in all the males and 8 of 10 females at the
highest dose level. Two of 10 males at the 1. Savitt LE: Contact dermatitis due to be-
50 mg/m3 level had less severe olfactory degen- nomyl insecticide. Arch Dermatol 105:926
eration. After 90 days of exposure, the remain- 927, 1972
2. WHO working group: Environmental Health
der of the animals were killed and ndings were
Criteria. Benomyl. Vol 148:1320, 1993
essentially the same as seen at the end of 45
3. EI du Pont de Nemours & Co, Inc: Technical
days. No other effects were observed. In a Data Sheet, June 1974
follow-up to this study, it was determined that 4. Warheit DB, Kelly DP, Carakostas MC,
the olfactory epithelial damage reported after Singer AW: A 90-day inhalation toxicity study
inhalation exposure was specic to the route of with benomyl in rats. Fundam Appl Toxicol 12:
exposure because the nasal cavity was not a 333345, 1989
target after dietary administration of benomyl.5 5. Hurtt ME, Mebus CA, Bogdanffy MS:
Rats fed diets containing 0, 5000, 10,000, or Investigation of the effects of benomyl on rat
15,000 ppm benomyl for 32 days only had tox- nasal mucosa. Fundam Appl Toxicol 21:253255,
icity in the form of decreased body weight gain 1993
6. Von Burg R: Toxicology update: Benomyl. J
and food consumption at the two highest dose
Appl Toxicol 13:377381, 1993
levels.
7. Ellis WG, Semple JL, Hoogenboom JR,
In another study mice were given diets Kavlock RJ, Zeman FJ: Benomyl-induced
containing 0, 500, 1500, 5000, or 7500 ppm craniocerebral anomalies in fetuses of ade-
benomyl for 2 years. An oncogenic response quately nourished and protein-deprived rats.
was reported in the livers of male mice dosed Teratog Carcinog Mutagen 8:377391, 1988
at 500 and 1500 ppm but not in the 5000- to 8. Linder RE, Rehnberg LF, Strader LF, Diggs
7500-ppm group; an increase in nonmalignant JP: Evaluation of reproductive parameters in
liver tumors was observed in all female treat- adult male Wistar rats after subchronic expo-
ment groups.6 At this time there does not sure (gavage) to benomyl. J Toxicol Environ
appear to be any conclusive evidence that Health 25:285298, 1988
benomyl is carcinogenic.
In a teratology study, female rats were
administered 62.5 mg/kg beginning at day 6 of
gestation.7 Fetuses examined at day 16 or day
20 showed a high incidence of craniocerebral BENZ[a]ANTHRACENE
anomalies including hydrocephalus. In another CAS: 56-55-3
study, male rats were gavaged daily with 0, 1,
5, 15, or 45 mg/kg/day.8 After 7679 days the C18H12
animals were evaluated for reproductive end-
points. At the highest dose level minimal to
moderate changes were observed including Synonyms: BA; benzanthracene; 1,2-
decreased testis weight and sperm production. benz(a)anthracene; benzo(a)anthracene; 2,3-
At 62 days the males had been mated with benzophenanthrene; naphthanthracene;
females and reproductive performance was not tetraphene
affected.
Benomyl was genotoxic, causing chromo- Physical Form. Solid; often associated with
some aberrations in vitro and in vivo, but it does or adsorbed onto ultrane airborne particulate
not directly act with DNA.2 matter
BENZENE 69
Uses. Intermediate in the production of of vision, and dyspnea on exertion; the mucous
styrene, phenol, cyclohexane, and other membranes and skin may appear pale, and a
organic chemicals; manufacture of detergents, hemorrhagic tendency may result in petechiae,
pesticides, solvents, and paint removers; found easy bruising, epistaxis, bleeding from the
in gasoline gums, or menorrhagia.6 The most serious
cases of aplastic anemia succumb within 3
Exposure. Inhalation; skin absorption months of diagnosis because of infection or
hemorrhage.7
Toxicology. Acute benzene exposure causes The mechanism of benzene-induced
central nervous system depression; chronic toxicity appears to involve the concerted action
exposure causes bone marrow depression of several benzene metabolites.1,8 Benzene is
leading to aplastic anemia and is also associated metabolized, primarily in the liver, to a variety
with an increased incidence of leukemia. of hydroxylated and opened-ring products that
Human exposure to very high concentra- are transported to the bone marrow, where sec-
tions, approximately 20,000 ppm, is fatal in ondary metabolism occurs. Metabolites may
510 minutes.13 Concentrations of 7500 ppm induce toxicity both by covalent binding to
are dangerous to life within 30 minutes. Con- cellular macromolecules and by inducing
vulsive movements and paralysis followed by oxidative damage. Metabolites may also inhibit
unconsciousness follow severe exposures. Brief stromal cells, which are necessary to support
exposure to concentrations in excess of 3000 growth of differentiating and maturing marrow
ppm is irritating to the eyes and respiratory cells.1
tract; continued exposure may cause euphoria, Numerous case reports and epidemiologi-
nausea, a staggering gait, and coma. Inhala- cal studies suggest a leukemogenic action of
tion of lower concentrations (250500 ppm) benzene in humansthe leukemia tending to
produces vertigo, drowsiness, headache, and be acute and myeloblastic in type, often fol-
nausea, whereas 25 ppm for 8 hours is without lowing aplastic changes in the bone marrow.
clinical effect. Acute myelocytic leukemia may be preceded by
The most signicant toxic effect of myelodysplastic syndrome, a preleukemic state
benzene exposure is injury to the bone marrow. characterized by abnormal marrow architec-
Chronic exposure to low concentrations may ture, inadequate hematopoiesis, and many cells
produce reversible decreases in blood cell with chromosome damage.4 Benzene may also
numbers.4 Long-term exposures to higher con- induce chronic types of leukemia.9
centrations lead to the onset of irreversible One study indicated a vefold excess of
bone marrow depression. Clinically, an initial all leukemias and a tenfold excess of myelo-
increase followed by a decrease in erythrocytes, monocytic leukemia among benzene-exposed
leukocytes, or platelets is observed, with workers as compared with the US Caucasian
progression to anemia, leukopenia, and/or male population.10 Among shoemakers chroni-
thrombocytopenia, respectively.3 If pancytope- cally exposed to benzene, the annual incidence
nia (i.e., the depression of all three cell types) of leukemia was 13.5 per 100,000, whereas the
occurs and is accompanied by bone marrow incidence in the general population was 6 per
necrosis, the syndrome is termed aplastic 100,000.11 Four cases of acute leukemia were
anemia. The hypocellularity varies greatly reported in shoemakers exposed to concentra-
from conditions in which the marrow is com- tions of benzene up to 210 ppm for 614 years;
pletely devoid of recognizable hematopoietic two of the four had aplastic anemia before
precursors to those in which the precusors of leukemia; three of the four cases of leukemia
only one cell line are absent or arrested in their were of the acute myeloblastic type; the fourth
development.5 Typical symptoms may include patient developed thrombocythemia in the
light-headedness, headache, loss of appetite, second year after an episode of aplastic anemia,
and abdominal discomfort. With more severe and acute monocytic leukemia developed
intoxication, there may be weakness, blurring later.12
BENZENE 71
tive of exposure to approximately 25 ppm of benzene exposure. Ann NY Acad Sci 271:
benzene in air.32 143151, 1976
Direct contact with the liquid may cause 10. Infante PF, Rinksy RA, Wagoner JK, Young
erythema and vesiculation; prolonged or RJ: Leukemia Among Workers Exposed to
repeated contact has been associated with the Benzene. National Institute for Occupational
Safety and Health (NIOSH), US Depart-
development of a dry, scaly dermatitis or with
ment of Health, Education and Welfare.
secondary infections.3 Some skin absorption Washington, DC, US Government Printing
can occur with lengthy exposure to solvents Ofce, April 26, 1977
containing benzene and may contribute more 11. Aksoy M et al: Leukemia in shoe-workers
to toxicity than originally believed, but the exposed chronically to benzene. Blood
dermal route is considered only a minor source 44:837841, 1974
of exposure for the general population.33 12. Aksoy M, Dincol K, Erden S, Dincol G:
The 2003 ACGIH threshold limit Acute leukemia due to chronic exposure to
value-time-weighted average (TLV-TWA) for benzene. Am J Med 52:160165, 1972
benzene is 0.5 ppm (1.6 mg/m3) with a TLV 13. Yin SN et al: Leukaemia in benzene workers:
STEL of 2.5 ppm (8 mg/m3) and an A1- A retrospective cohort study. Br J Ind Med 44:
124128, 1987
conrmed human carcinogen designation and
14. Rinsky RA et al: Leukemia in benzene
a notation for skin absorption. workers. Am J Ind Med 2:217245, 1981
15. Bond GG et al: An update of mortality
among chemical workers exposed to benzene.
REFERENCES Br J Ind Med 43:685691, 1986
16. Aksoy M: Malignancies due to occupational
1. World Health Organization: Environmental exposure to benzene. Am J Ind Med 7:
Health Criteria 150: Benzene, 156pp. Interna- 395402, 1985
tional Programme on Chemical Safety 17. IARC Monographs on the Evaluation of the Car-
(IPCS), Geneva, 1993 cinogenic Risk of Chemicals to Humans, Vol 29,
2. Gerarde HW: Toxicology and Biochemistry of Some industrial chemicals and dyestuffs,
Aromatic Hydrocarbons, pp 97108. New York, pp 93148. Lyon, International Agency for
Elsevier, 1960 Research on Cancer, May 1982
3. Department of Labor: Occupational Expo- 18. Marcus WL: Chemical of current interest
sure to Benzene. Fed Reg 42:2251622529, benzene. Toxicol Ind Health 3:205266, 1987
1977 19. Rinsky RA et al: Benzene and leukemia. An
4. Snyder R: Overview of the toxicology of epidemiologic risk assessment. N Engl J Med
benzene. J Toxicol Environ Health A 61: 316:10441050, 1987
339346, 2000 20. Paustenbach DJ, Price PS, Ollison W, et al:
5. Goldstein BD: Hematotoxicity in humans. In Reevaluation of benzene exposure for the
Laskin S, Goldstein BD: Benzene toxicity. A pliolm (rubberworker) cohort (19361976).
critical evaluation. J Toxicol Environ Health J Toxicol Environ Health 36:177231, 1992
Suppl 2:69105, 1977 21. Paxton MB, Chinchilli VM, Brett SM, et al:
6. Committee on Toxicology of the National Leukemia risk associated with benzene expo-
Research Council: Health Effects of Benzene sure in the pliolm cohort. II. Risk estimates.
a Review. US Department of Commerce, Risk Analysis 14:155161, 1994
National Technical Information Service PB- 22. Crump KS: Risk of benzene-induced
254 388, pp 123. Washington, DC, National leukemia: a sensitivity analysis of the pliolm
Academy of Sciences, 1976 cohort with additional follow-up and new
7. Rappaport JM, Nathan DG: Acquired aplas- exposure estimates. J Toxicol Environ Health
tic anemias: Pathophysiology and treatment. 42:219242, 1994
Adv Intern Med 27:547590, 1982 23. Occupational Safety and Health Administra-
8. Snyder R, Hedli CC: An overview of ben- tion: Occupational exposure to benzene;
zene metabolism. Environ Health Perspect nal rule, 29 CFR Part 1910. Fed Reg
104(Suppl 6):11651171, 1996 52(176):34460, 1987
9. Vigliani EC: Leukemia associated with 24. Snyder CA et al: The inhalation toxicology of
BENZIDINE 73
bladder and kidney. The observed mortality and unscheduled DNA repair synthesis.1 It has
rate for cancer of the bladder was 78 per also tested positive in a wide variety of in vitro
100,000 in the cohort, compared with 4.4 per genotoxic assays.1
100,000 expected for men of the same age. Of The IARC has determined that there is
42 bladder and kidney neoplasms, 16 were sufcient evidence for carcinogenicity of ben-
attributed to benzidine exposure and 18 were zidine to humans.9
attributed to combined exposure. The ACGIH has classied benzidine as
During a 17-year period, 83 workers in a an A1-conrmed human carcinogen with no
benzidine department were examined cysto- assigned threshold limit value and a notation
scopically; 34 workers had congestive lesions, 3 for skin absorption.
had pedunculated papillomas, 4 had sessile
tumors, and carcinoma was found in 13 of the
workers.5 REFERENCES
The onset of occupational bladder tumors
is insidious, and, occasionally, the disease may 1. Agency for Toxic Substances and Disease Reg-
be in an advanced stage before any signs or istry (ATSDR): Toxicological Prole for Benzi-
symptoms appear. In general, however, benzi- dine, 201pp. US Department of Health
and Human Services, Public Health Service,
dine exposure may produce a variety of lesions
2001
in the urinary bladder such as hyperemia,
2. Zavon MR, Hoegg U, Bingham E: Benzidine
inammation, and papillomas that precede exposure as a cause of bladder tumors. Arch
malignancy.6 The presence of blood in the Environ Health 27:17, 1973
urine or pain on urination may indicate such 3. Meigs JW, Marrett LD, Ulrich FU, et al:
lesions. Detection of premalignant or malig- Bladder tumor incidence among workers
nant changes may be possible through cysto- exposed to benzidine: a thirty year follow-up.
scopic examination, cytological evaluation of J Natl Cancer Inst 76:18, 1986
bladder epithelial cells shed in urine, and 4. Mancuso TF, El-Attar AA: Cohort study of
screening for occult blood.6 Recurrences are workers exposed to b-naphthylamine and ben-
frequent, and tumors may recur as papillomas zidine. J Occup Med 9:277285, 1967
5. Barsotti M, Vigliani EC: Bladder lesions from
or carcinomas irrespective of the nature of the
aromatic amines. AMA Arch Ind Hyg Occup
original lesion.7
Med 5:234241, 1952
Susceptibility to bladder cancer in humans 6. IARC Monographs on the Evaluation of the Car-
has been linked to the slow acetylator pheno- cinogenic Risk of Chemicals to Humans, Vol 29,
type of the polymorphic NAT2 N-acetyltrans- Some industrial chemicals and dyestuffs, pp
ferase gene.1 In a study from China, a 25-fold 149183. Lyon, International Agency for
increase in bladder cancer incidence and a Research on Cancer, 1982
17-fold increase in bladder cancer mortality 7. Scott TS, Williams MHC: The control of
were determined in 1972 benzidine-exposed industrial bladder tumours. Br J Ind Med 14:
workers.8 In the Asian population the slow 150163, 1957
acetylator phenotype occurs signicantly less 8. Bi W, Hayes RB, Feng P, et al: Mortality and
incidence of bladder cancer in benzidine-
often than in Caucasian populations, but an
exposed workers in China. Am J Ind Med 21:
association between those who contracted
481489, 1992
bladder cancer and phenotype has yet to be 9. IARC Monographs on the Evaluation of Carcino-
determined for this group. Other, more recent genic Risks to Human Overall Evaluations of
data have suggested that the acetylation rate Carcinogenicity, Suppl 7, An Updating of IARC
may not be an important risk factor for devel- Monographs Volumes 1 to 42, pp 123125.
oping bladder cancer.1 Lyon, International Agency for Research on
Benzidine exposure has been associated Cancer, 1987
with chromosomal aberrations and polyploidy
in the circulating peripheral lymphocytes of
workers, micronucleus induction in rodents,
BENZOIC ACID 75
Toxicology. Benzoic acid is an irritant of the 6. World Health Organization: Concise Interna-
eyes and respiratory system. tional Chemical Assessment Document (CICAD)
Although specic dose levels and durations Benzoic Acid and Sodium Benzoate, No. 26,
are not available, it is assumed that exposure 38pp. International Programme on Chemical
to the dust may be irritating to the nose and Safety, 2000
eyes.1 At elevated temperatures, fumes may
cause irritation of the eyes, respiratory system,
and skin.
The systemic toxicity of benzoic acid is
BENZO[a]PYRENE
low. Extremely large oral doses are expected to
CAS: 50-32-8
produce gastric pain, nausea, and vomiting.2 In
one case a 67-kg man ingested a single dose of
C20H12
50 mg without ill effects. In other cases daily
intake of 46 mg caused slight gastric irrita-
tion.3 After ingestion, benzoic acid is conju-
Synonyms: B[a]P; BP; 3,4-benzopyrene; 3,4-
gated with glycine and excreted as hippuric acid
benzpyrene
in the urine. However, no quantitative rela-
tionship exists between benzoic acid intake and
Physical Form. Yellow crystals
the hippuric acid excreted.
The oral LD50 in cats and dogs is 2 mg/kg.2
Sources. B[a]P is a major component of
When benzoic acid is injected in rats, tremors,
polynuclear aromatic hydrocarbons, also
convulsions, and death occur.
known as polycyclic aromatic hydrocarbons,
On human skin, intermittent exposure to
and is usually bound to small particulate matter
22 mg for 3 days caused moderate irritation.4
present in urban air, industrial and natural
Benzoic acid does not appear to be a skin sen-
combustion emissions, and cigarette smoke.
sitizer.5 In the eyes of rabbits, 100 mg was
severely irritating.4
Exposure. Inhalation
Benzoic acid was not genotoxic in bacter-
ial assays or in in vitro mammalian assays.6
Toxicology. Benzo[a] pyrene (B[a]P) causes
The ACGIH has not established a thresh-
hematologic and immunologic effects; it is car-
old limit value for benzoic acid.
cinogenic to experimental animals.
Systemic effects from B[a]P exposure have
REFERENCES
not been reported in humans.
1. Weiss G (ed): Hazardous Chemicals Data Book, Intermediate-duration oral exposure of
p. 147. Park Ridge, NJ, Noyes Data Co., 1980 mice has caused death due to adverse hemato-
2. Gosselin RE, Smith RP, Hodge HC: Clinical logic effects including aplastic anemia and pan-
Toxicology of Commercial Products, 5th ed, p II- cytopenia.1 B[a]P has been shown to markedly
203. Baltimore, MD, Williams and Wilkins, inhibit the immune system, especially T-cell-
1984 dependent antibody production by lympho-
3. Gilman AG, Goodman LS, Rall TW, et al: cytes exposed either in vivo or in vitro. It may
Goodman and Gilmans The Pharmacological also induce autoimmune responses.
Basis of Therapeutics, 7th ed, p 961. New York, B[a]P has been carcinogenic in all animal
Macmillan, 1985
species tested to date, including mouse, rat,
4. Material Data Safety Sheet No. 402. Benzoic
hamster, rabbit, guinea pig, duck, newt, dog,
Acid. Schenectady, NY, Genium Pub, February
1987 monkey, and sh.2 Intratracheal instillation and
5. Anonymous: Final report on the safety assess- inhalation studies in a number of species have
ment of benzyl alcohol, benzoic acid, and resulted in elevated incidences of respiratory
sodium benzoate. Int J Toxicol 20(suppl 3): tract and upper digestive tract tumors, and
2350, 2001 intraperitoneal and subcutaneous injections
BENZO[a]PYRENE 77
have caused increases in the number of injec- Polycyclic Aromatic Hydrocarbons (PAHs)
tion site tumors.3 B[a]P is both an initiator and (update), 458pp. US Department of Health
a complete carcinogen in mouse skin; increased and Human Services, Public Health Service,
incidences of distant site tumors have also been 1995
reported in animals as a consequence of dermal 2. IARC Monographs on the Evaluation of the
Carcinogenic Risk of Chemicals to Humans, Vol
B[a]P exposure.
3, Certain polycyclic aromatic hydrocarbons
Mice fed 0, 5, 25, or 100 ppm B[a]P for up and heterocyclic compounds, pp 91136.
to 2 years had signicant dose-related increases Lyon, International Agency for Research on
in forestomach, esophageal, and tongue papil- Cancer, 1973
lomas or carcinomas.4 3. US EPA: Drinking Water Criteria Document
B[a]P is metabolized to approximately 20 for PAH. Prepared by the Ofce of Health
primary and secondary oxidized metabolites and Environmental Assessment, Environ-
and to a variety of conjugates.5 The most po- mental Criteria and Assessment Ofce,
tent carcinogenic metabolite is 7,8-dihydroxy- Cincinnati, OH, for the Ofce of Water
9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene. Regulations and Standards, Washington,
This ultimate carcinogen binds predominantly DC, 1991
4. Culp SJ, Gaylor DW, Sheldon WG, et al: A
to guanine bases in DNA to form covalent
comparison of the tumors induced by coal tar
adducts. and benzo(a)pyrene in a 2-year bioassay. Car-
B[a]P metabolites have been shown to cinogenesis 19(1):117124, 1998
bind to DNA in cultured human hepatocytes 5. Pelkonen O and Nebert DW: Metabolism of
and in human bladder and tracheobronchial polycyclic aromatic hydrocarbons: Etiologic
explants.6,7 The metabolites identied were role in carcinogenesis. Pharmacol Rev 34:
identical to those produced in other species and 189222, 1982
differed only in the relative percentages of for- 6. Monteith DK, Novoting A, Michalopoulos
mation.7 Human tissues were most active in G, Stron SC: Metabolism of benzo[a]pyrene
metabolizing B[a]P and exhibited at least a in primary cultures of human hepatocytes:
threefold higher covalent binding of metabo- Dose-response over a four-log range. Car-
cinogenesis 8:983988, 1987
lites to DNA than hamsters, dogs, monkeys, or
7. Daniel FB, Schut HAJ, Sandwisch DW, et al:
rats. In addition, B[a]P has been tested exten- Interspecies comparisons of benzo[a]pyrene
sively in several bacterial and mammalian cell metabolism and DNA-adduct formation in
systems and has been chosen as a positive cultured human and animal bladder and
control for the validation of some of these tracheobronchial tissues. Cancer Res 43:4723
systems.8 4729, 1983
The IARC considers that there is suf- 8. Agency for Toxic Substances and Disease
cient evidence that B[a]P is carcinogenic to Registry (ATSDR): Toxicological Prole for
experimental animals.9 Benzo[a]pyrene. ATSDR/TP-88/05, pp 4853.
Developmental toxicity and impaired Atlanta, GA, Public Health Service, Centers
reproductive capacity were seen in two oral for Disease Control, 1990
9. IARC Monographs on the Evaluation of the Car-
studies in mice.10,11 The lowest observed
cinogenic Risk of Chemicals to Humans, Vol 32,
adverse effect level was 10 mg/kg/day from day Polynuclear aromatic compounds, Part 1,
7 to day 16 of gestation.11 chemical, environmental and experimental
Benzo[a]pyrene is designated an A2-sus- data, pp 211224. Lyon, International
pected human carcinogen by ACGIH and has Agency for Research on Cancer, December
no assigned threshold limit value. 1983
10. Mackenzie KM, Angevine DM: Infertility in
mice exposed in utero to benzo[a]pyrene. Biol
REFERENCES Reprod 24:183191, 1981
11. Legraverend C, Guenther TM, Nebert DW:
1. Agency for Toxic Substances and Disease Importance of the route of administration
Registry (ATSDR): Toxicological Prole for for genetic differences in benzo[a]pyrene-
78 BENZOTRICHLORIDE
induced in utero toxicity and teratogenicity. manufacturing workers who were potentially
Teratology 29:3547, 1984 exposed to benzotrichloride.3
Squamous cell carcinomas of the skin were
produced in three studies after skin application
of benzotrichloride to mice.1,4 Lung carcino-
mas, pulmonary adenomas, and lymphomas
were also observed. Intraperitoneal injection
BENZOTRICHLORIDE of benzotrichloride produced a signicant
CAS: 98-07-7 increase in the lung tumor response in strain
A/J mice within 24 weeks.5 Administration by
C7H5Cl3 gastric intubation of doses ranging from 2.0 to
0.0315 ml/mouse, twice a week for 25 weeks,
to female ICR mice produced forestomach
Synonyms: Benzenyl chloride; benzoic tumors (squamous cell carcinoma and papil-
trichloride; benzylidyne chloride; benzyl loma), lung tumors (adenocarcinoma and
trichloride; phenylchloroform; toluene trichlo- adenoma), and tumors of the hematopoietic
ride; trichlorotoluene; (trichloromethyl)- system (thymic lymphosarcoma and lymphatic
benzene leukemia), with dose-related response by 18
months.6 It was concluded that the target organ
Physical Form. Clear, oily liquid of benzotrichloride carcinogenesis in mice is
the local tissue that is primarily exposed and the
Uses. Chemical intermediate primarily in lung and hematopoietic tissue when adminis-
benzoyl chloride production; dye intermediate tered systemically.
Benzotrichloride is mutagenic in bacterial
Exposure. Inhalation; skin absorption assays.7
The IARC has determined that combined
Toxicology. Benzotrichloride is an irritant exposures to a-chlorinated toluenes (which
and a suspected human carcinogen. include benzotrichloride) are probably carcino-
The liquid has been reported to be highly genic to humans.7 There is sufcient evidence
irritating to the skin and mucous membranes in that benzotrichloride is carcinogenic in exper-
humans.1 imental animals.
In rats benzotrichloride was lethal after The ACGIH has established a ceiling
a 4-hour exposure at 1000 mg/m3 (125 ppm). threshold limit value (TLV-C) of 0.1 ppm
The oral LD50 in rats was 6 g/kg. The 2-hour (0.8 mg/m3) for occupational exposure to ben-
LC50 was 150 mg/m3 (19 ppm) in rats and zotrichloride with a skin notation and an A2
60 mg/m3 (8 ppm) in mice. Toxic effects suspected human carcinogen designation.
included central nervous system excitation,
irritation of the eyes and upper respiratory
tract, and slowed respiration. Hyperemia of the REFERENCES
extremities was also observed. Motor automa-
tism and twitching of peripheral muscles were 1. IARC Monographs on the Evaluation of Carcino-
seen at 1000 mg/m3 (125 ppm) in mice and genic Risk to Humans, Vol 29, Some industrial
rats, respectively. Leukopenia, mild anemia, chemicals and dyestuffs, pp 7380. Lyon,
International Agency for Research on Cancer,
and decreases in renal function occurred in
1982
rats after continuous inhalation exposure at
2. NIOSH: Registry of Toxic Effects of Chemical
100 mg/m3 (12.5 ppm) for 1 month.1 Substances, pp 2691011. Washington, DC,
There are no data clearly relating exposure National Institute for Occupational Safety and
to benzotrichloride to cancer in humans. Health, 1990
However, an excess of respiratory cancer (6 3. Sorahan T, Waterhouse JAH, Coke MA, et al:
cases total) was reported in benzoyl chloride A mortality study of workers in a factory
BENZOYL PEROXIDE 79
manufacturing chlorinated toluenes. Ann remain on the skin it may produce inamma-
Occup Hyg 27:17382, 1983 tion.3 No systemic effects have been reported
4. Fukuda K, Matsushita H, Sakabe H, et al: Car- in humans. The major hazards of benzoyl per-
cinogenicity of benzyl chloride, benzal chlo- oxide are res and explosions, which have
ride, benzotrichloride and benzoyl chloride in caused serious injuries and death.4
mice by skin application. Gann 72:
Rats exposed at an atmospheric concen-
655664, 1981
5. Stoner GD, You M, Morgan MA, et al: Lung tration of 24.3 mg/l of 78% benzoyl peroxide
tumor induction in strain A mice with ben- showed the following signs during a 4-hour
zotrichloride. Cancer Lett 33:16773, 1986 exposure period: eye squint, difculty in
6. Fukuda K, Matsushita H, Takemoto K, et al: breathing, salivation, lacrimation, erythema,
Carcinogenicity of benzotrichloride adminis- and an increase followed by a decrease in motor
tered to mice by gastric intubation. Ind Health activity.4 All rats appeared normal at 24 and 48
31:127131, 1993 hours after exposure.
7. IARC Monographs on the evaluation of the car- Benzoyl peroxide has been tested for car-
cinogenic risk of chemicals to humans, Vol 71, cinogenicity in mice and rats by administration
Re-evaluation of some organic chemicals, in the diet and by subcutaneous injection and
hydrazine and hydrogen peroxide, pp 45377.
in mice by skin application.5 Although no sig-
Lyon, International Agency for Research on
Cancer, 1999 nicant increases in tumor incidences were
found, the IARC has determined that all of the
studies were inadequate for a complete evalua-
tion of carcinogenicity in animals. Two studies
indicated that benzoyl peroxide may act as a
cancer promoter on mouse skin.6,7
BENZOYL PEROXIDE Among a small factory population, two
CAS: 94-36-0 cases of lung cancer were found in men prima-
rily involved in the production of benzoyl per-
(C6H5CO)2O2 oxide, but they were also exposed to benzoyl
chloride and benzotrichloride.8 Benzoyl perox-
ide exposure was associated with a greater fre-
Synonyms: Benzoyl superoxide; dibenzoyl quency of malignant melanoma in one of two
peroxide; lucidol; oxylite case control studies; it was not associated with
basal cell carcinomas of the skin in another
Physical Form. Granular, white solid study.9 The IARC has determined that there
is limited evidence for the carcinogenicity of
Uses. Bleaching our and edible oils; addi- benzoyl peroxide in experimental animals and
tive in self-curing of plastics that it is not classiable as to its carcinogenic-
ity to humans.
Exposure. Inhalation It was not mutagenic in bacterial assays and
does not cause chromosomal damage in cul-
Toxicology. Benzoyl peroxide is an irritant tured mammalian cells.9
of mucous membranes and causes both primary The 2003 ACGIH threshold limit
irritation and sensitization dermatitis. value-time-weighted average (TLV-TWA) for
Exposure of workers to levels of benzoyl peroxide is 5 mg/m3.
12.2 mg/m3 and higher has caused pronounced
irritation of the nose and throat.1
Application to the face as lotion for acne REFERENCES
treatment in two persons caused facial ery-
thema and edema; patch tests with benzoyl 1. ACGIH: Benzoyl Peroxide. Documentation of
peroxide were positive.2 In contact with the the TLVs and BEIs, 6th ed, p 123124. Cin-
eyes it may produce irritation, and if allowed to cinnati, OH, American Conference of Gov-
80 BENZYL CHLORIDE
Benzyl chloride was not teratogenic in 10. IARC Monographs on the Evaluation of the
rats orally administered 100 mg/kg on days Carcinogenic Risk of Chemicals to Humans, Vol
615 of gestation; slight fetoxicity in the form 71, Re-evaluation of some organic chemi-
of reduced fetal length was observed at this cals, hydrazine and hydrogen peroxide, pp
level.11 45377. Lyon, International Agency for
Research on Cancer, 1999
Benzyl chloride caused genetic mutations
11. Skowronski G, Abdel-Rahman MS: Teratox-
and chromosome-damaging effects in a wide icity of benzyl chloride in the rat. J Toxicol
variety of in vitro assays; it was not mutagenic Environ Health 17:5156, 1986
in vivo in the mouse micronucleus assay.10
The 2003 ACGIH threshold limit value-
time-weighted average (TLV-TWA) for benzyl
chloride is 1 ppm (5.2 mg/m3).
cases with acute beryllium pneumonitis, recov- with an eruption of erythematous, papular, or
ery occurs within 16 months; however, fatali- papulovesicular nature; the eruption usually
ties due to pulmonary edema or to spontaneous subsides within 2 weeks after cessation of expo-
pneumothorax have been reported. The human sure.1 Implantation of beryllium or its com-
threshold of an injurious concentration by pounds beneath the skin may cause necrosis of
inhalation is approximately 30 mg Be/m3 for adjacent tissue and formation of an ulcer;
the high-red oxide, 13 mg Be/m3 for the implantation of comparatively insoluble com-
low-red oxide, and 0.10.5 mg Be/m3 for the pounds may produce a localized granuloma, as
sulfate.2 has occurred from lacerations with old uores-
Beryllium disease is regarded as chronic if cent tubes containing the phosphor.3 Healing
it persists for a year or more and is usually due of ulcers and granulomas requires the surgical
to granulomas in the lungs.1,4 The onset of removal of the beryllium substance.3 Con-
berylliosis may be insidious, with only slight junctivitis may accompany contact dermatitis
cough and fatigue that can occur as early as resulting from exposure to soluble beryllium
1 year or as late as 25 years after exposure.2 compounds; angioneurotic edema may be
Progressive pulmonary insufciency, anorexia, striking.1,3
weight loss, weakness, chest pain, and constant Beryllium metal, beryllium-aluminum
hacking cough characterize the advanced alloy, beryl ore, beryllium chloride, beryllium
disease. Cyanosis and clubbing of ngers uoride, beryllium hydroxide, beryllium sul-
may be seen in approximately one-third of fate, and beryllium oxide all produce lung
cases, and cor pulmonale is another frequent tumors in rats exposed by inhalation or intra-
sequela.2 tracheally.7 The oxide and the sulfate produce
Early X rays show a ne, diffuse granular- lung tumors in monkeys after intrabronchial
ity in the lungs, a diffuse reticular pattern is implantation or inhalation. A number of
observed in the second stage, and nally, in the compounds produce osteosarcomas in rabbits
third stage, distinct nodules appear.5 after their intravenous or intramedullary
There are many similarities between beryl- administration.7
liosis and sarcoidosis, but in sarcoidosis the sys- Although a number of epidemiological
temic effects are much more pronounced.6 studies have reported an increased risk of
An immunologic basis for chronic lung cancer among occupationally exposed
beryllium disease has been postulated and a beryllium workers, deciencies in the studies
hypersensitivity phenomenon demonstrated.4,6 limit any unequivocal conclusion.79 Specic
Consistent with the concept of chronic beryl- criticisms concern the lack of consideration
liosis as a hypersensitivity pulmonary reaction of latent effects, of smoking history, and of
are the following: Persons with berylliosis also exposure to other potential carcinogens and
show delayed cutaneous hypersensitivity reac- the underestimation of expected lung cancer
tions to beryllium compounds; their peripheral deaths in comparison populations.10,11
blood lymphocytes undergo blast transforma- A subsequent study that accounted for
tion and release of macrophage inhibition smoking, included females, and extended the
factor after exposure to beryllium in vitro; latency period has strengthened the evidence of
helper/suppressor T-cell ratios are depressed; carcinogenicity in humans.12 A cohort mortal-
and there is lack of a dose-response relation- ity study of 689 patients with beryllium disease,
ship in chronic beryllium cases.2,4 Hypersensi- as determined by a case registry, found a lung
tization may lead to berylliosis in people with cancer standardized mortality ratio (SMR) of
relatively low exposures, whereas nonsensitized 2.00 based on 28 observed lung cancer deaths.13
individuals with higher exposures may have no The lung cancer excess was more pronounced
effects. in individuals with a history of acute forms of
Skin contact with soluble beryllium salts beryllium disease than among those with
may produce either primary irritation or sensi- chronic disease. Patients with a history of acute
tization dermatitis characterized by pruritis beryllium disease and lung cancer were found
BIPHENYL 83
Physical Form. Colorless to yellow solid tumors.5 It has been suggested that the forma-
tion of bladder tumors in male rats may be
Uses. Heat transfer agent; fungistat for citrus linked to the regenerative hyperplasia of the
fruits; in organic synthesis urinary epithelium caused by damage from the
calculi that are only formed at high levels of
Exposure. Inhalation; skin absorption exposure; the sex- and species specicity of
bladder tumor development may not be rele-
Toxicology. Biphenyl is an irritant of the vant to humans.5
eyes and mucous membranes and may exert a Biphenyl was not mutagenic in bacterial
toxic action on the central and peripheral assays but was positive in vitro in mammalian
nervous systems. cell systems in the presence of metabolic
In a study of 33 workers in one plant with activation.5
prolonged exposure to concentrations ranging The 2003 ACGIH threshold limit value-
up to 123 mg/m3, the most common complaints time-weighted average (TLV-TWA) is 0.2 ppm
were headache, gastrointestinal symptoms (1.3 mg/m3).
(diffuse pain, nausea, indigestion), numbness
and aching of limbs, and general fatigue.1
Neurophysiologic examination of 22 of these REFERENCES
workers showed that 19 had changes consistent
with central and/or peripheral nervous system 1. Hakkinen I, Silatanen E, Hernberg S, et al:
damage. In one fatal case in this plant, expo- Diphenyl poisoning in fruit paper production.
sure was high for 11 years, symptoms were as Arch Environ Health 26:7074, 1973
2. Sappalainen AM, Hakkinen I: Electrophysio-
just described, and, at autopsy, there was wide-
logical ndings in diphenyl poisoning. J Neurol
spread liver necrosis with some cirrhotic areas,
Neurosurg Psychiatry 38:248252, 1975
nephrotic changes, heart muscle degeneration, 3. Sandmeyer EE: Aromatic hydrocarbons. In
and edematous brain tissue.1 Clayton GD, Clayton FE (eds): Pattys Indus-
In a follow-up study, 10 of 24 workers trial Hygiene and Toxicology, 3rd ed, rev. Vol 2B,
showed electroencephalographic abnormalities Toxicology, pp 33253330. New York, Wiley-
that persisted 1 and 2 years after the initial Interscience, 1981
investigation; 9 workers had electromyo- 4. Deichmann WB, Kitzmiller KV, Dierker
graphic abnormalities that also persisted.2 M, Witherup S: Observations on the effects
Irritation to the eyes and mucous mem- of diphenyl, o- and p-amino-diphenyl, o-
branes has been reported in humans exposed at and p-nitrodiphenyl and dihydroxyoctachlor-
odiphenyl upon experimental animals. J Ind
34 ppm.3
Hyg Toxicol 29:13, 1947
Exposure of rats to biphenyl dust impreg-
5. World Health Organization: Concise Interna-
nated in diatomaceous earth at a concentration tional Chemical Assessment Document (CICAD) 6
of 300 mg/m3 for 7 hours/day, for 64 days Biphenyl, 31pp. International Programme on
caused irritation of the nasal mucosa, bron- Chemical Safety (IPCS), Geneva, 2000
chopulmonary lesions, and slight injury to the
liver and kidneys.4
Biphenyl in the diet of rodents caused
hematologic alterations including decreased
hemoglobin concentration.5 Rats administered BISMUTH TELLURIDE
diets with greater than 2500 mg biphenyl/kg CAS: 1304-82-1
have shown effects on the urinary system
including the formation of calculi and hyper- Bi2Te3
plasia and desquamation; males typically show
greater effects than females.5 In chronic
feeding studies an increase in bladder tumors Synonym: Dibismuth tritelluride
was seen in male rats, and female mice have
shown slight increases in the incidences of liver Physical form. Gray solid
BISPHENOL A 85
Exposure. Inhalation
BISPHENOL A
Toxicology. Bismuth telluride, either alone CAS: 80-05-7
or doped with selenium sulde, is apparently of
very low toxicity. OHC6H4C(CH3)2C6H4OH
In limited industrial experimental work
with bismuth telluride under controlled con-
ditions (vacuum hoods), no adverse health Synonyms: BPA; 4,4-1-methylethylidene)-
effects were encountered other than tellurium bisphenol; 4,4-isopropylidenediphenol;
breath.1 2,2-bis(4-hydroxyphenyl)propane; p,p-
In a multispecies study, dogs, rabbits, and dihydroxydiphenylpropane; diphenylol-
rats were exposed to 15 mg/m3 of bismuth propane; 4,4-isopropylidenediphenol
telluride doped with stannous telluride for
6 hours/day, 5 days/week, for one year.1 Small Physical Form. Crystals or akes; dust
granulomatous lesions without brosis oc-
curred in the lungs of dogs at 6 months. In Uses. A high-production-volume chemical
dogs autopsied 4 months after an 8 month used in manufacture of epoxy-phenolic resins
exposure the lesions had regressed, indicating (protective linings for food and beverage
a reversible process. Rabbits showed a similar cans); monomer for polycarbonate resins (used
reaction but with a decreased number of pul- in food contact materials such as returnable
monary macrophages, no brous tissue activity, beverage bottles, infant feeding bottles, plates,
and no cellular or brous tissue reaction and mugs); antioxidant in PVC plastics;
around the dust deposits in the lymph nodes. inhibitor of end polymerization in PVC
The rats exhibited no brosis and no lymph plastics
node reactions. The pulmonary lesions seen in
the study were present in all three exposed Exposure. Inhalation; skin absorption
species but were interpreted as mild and
reversible and not of serious physiologic Toxicology. Bisphenol A causes photosensi-
consequence. tivity and slight skin and eye irritation.
In a similar 11-month study in which Persistent photosensitivity developed in
animals were exposed to undoped bismuth tel- eight men after occupational exposure to hot
luride dust of 0.04-mm diameter at 15 mg/m3, epoxy resin fumes.2 The condition was limited
no adverse responses of any type were observed to sites contacted by the resin. Small doses of
other than the pulmonary responses to the ultraviolet-A light evoked abnormal reactions
inhalation of an inert dust. consisting of erythema, edema, and papules in
The 2003 ACGIH threshold limit value- the clinically involved skin. Positive pho-
time-weighted average (TLV-TWA) is 10 mg/ topatch tests were observed to epoxy resin
m3 for undoped and 5 mg/m3 for doped in four subjects and to bisphenol A in all sub-
bismuth telluride. jects. Another study showed that bisphenol A
can be released during the thermal decomposi-
tion of epoxy resin in the temperature range of
REFERENCE 250350C.3 Photosensitizing activity was
explained by the formation of free radicals
1. Stokinger HE: The metals. In Clayton GD, during exposure to ultraviolet-B radiation of
Clayton, FE (eds): Pattys Industrial Hygiene and bisphenol A vapor, to form a semiquinone
Toxicology, 3rd ed, rev, Vol 2A, Toxicology, pp derivative of bisphenol A.4
86 BISPHENOL A
Bisphenol A causes slight skin and eye irri- 2. Allen H, Kaidbey K: Persistent photosensi-
tation.5 It did not cause contact allergy in a tivity following occupational exposure to
guinea pig maximization test.6 Furthermore, epoxy resin. Arch Dermatol 115:1307, 1979
no cross-reactions were detected when animals 3. Peltonen K, et al: Determination of the pres-
sensitized to the diglycidyl ether of bisphenol ence of Bisphenol A and the absence of digly-
cidyl ether of Bisphenol A in the thermal
A were tested with bisphenol A.
degradation products of epoxy power paint.
Studies of effects of bisphenol A on repro- Am Ind Hyg Assoc J 47:399, 1986
duction showed no evidence of reduction in the 4. Peltonen K, et al: Free radicals from pho-
fertility of rats and mice.7,8 In studies on the todecomposition of Bisphenol A. Photochem
offspring, at doses that were maternally toxic, Photobiol 43:481, 1986
no fetotoxic effects occurred in rats and no ter- 5. Dow Chemical Co. OECD SIDS Dossier on
atogenic effects occurred in mice or rats. A Bisphenol A. Dow Europe AA, Horgen,
more recent three-generation reproductive Switzerland, March 14, 1994
toxicity study in rats provided no evidence that 6. Thorgeirsson A, Fregert S: Allergenicity of
low doses of bisphenol A (in the mg/kg body epoxy resins in the guinea pig. Acta Derm
weight range) can adversely affect reproduc- Venereol 57:253, 1977
7. NTP (National Toxicology Program): Bisphe-
tive function.9 Test doses ranged from 0.001
nol A: Reproduction and Fertility Assessment in
to 500 mg/kg/day in the diet. No-observed- CD-1 Mice When Administered in the Feed.
adverse-effect levels were 5 mg/kg/day for Report NTP-85192; NTIS/OTS PB86
adult systemic toxicity and 50 mg/kg/day for 103207 1985
reproductive and developmental toxicity. 8. NTP (National Toxicology Program): Terato-
Androgenic or antiandrogenic activity was not logic Evaluation of Bisphenol A (CAS No.
detected at any dose level, whereas estrogenic 80057) Administered to CD(R) Rats on Ges-
effects were observed only at the top dose, and tational Days 6 Through 15. Report NTP-
then only in the presence of signicant sys- 85089; NTIS/OTS pb85205102, 1985
temic maternal toxicity. 9. Tyl W, et al: Three generation reproduc-
A 2-year feeding study with mice and rats tive toxicity study of dietary bisphenol A in
CD Sprague-Dawley rats. Toxicol Sci 68:121,
yielded no evidence of carcinogenic effects.10
2002
Recent extensive reviews have concluded that 10. NTP (National Toxicology Program): Car-
bisphenol A is nongenotoxic in vivo.11,12 cinogenic Bioassay of Bisphenol A (CAS No.
In in vitro studies, weak estrogenic effects 80057) in F344 Rats and B6C3F1 Mice (Feed
of bisphenol A were found in cell line MCF7, Study). Technical Report No. 215; NTIS/ITS
which was established from human breast OB821184060, 115pp, 1982
cancer cells, and in studies with cytosol prepa- 11. European Union Health and Consumer Pro-
rations from isolated uteri.13 In MCF7 cells, the tection Directorate-General: Opinion of the
estrogenic effects were seen at 15 ng/ml and Scientic Committee on Food on Bisphenol A.
were manifested as in increase in cell prolifer- SCF/CS/PM/3936 Final, 22 p, 3 May 2002
ation and the induction of progesterone re- 12. Dutch Expert Committee on Occupational
Standards. Bisphenol A and its Diglycidylether:
ceptors. Bisphenol A was 10005000 times less
Health Based Recommended Occupational Expo-
potent than estradiol-17. sure Limits. No. 1996/02WGD, Rijswijk, The
Netherlands, 12 September 1996
13. Brotons JA, et al: Xenestrogens released from
lacquer coatings in food cans. Environ Health
REFERENCES
Perspect 103:608, 1995
1. Greim H (ed): Occupational Toxicants, Vol 13,
critical data evaluation for MAK values and
classication of carcinogens, Commission for
the investigation of health hazards of chemi-
cal compounds in the work area, Bisphenol A,
p 49. New York, VCH, 1999
BORON, TETRA, SODIUM SALTS 87
B2O3 REFERENCES
tional Health and Safety, Vol I, pp 204205. Delayed mortality after bromine exposure has
New York, McGraw-Hill, 1974 been associated with peribronchiolar abscesses
3. NIOSH: Occupational safety and health guide- and is thought to be due to deep tissue pene-
lines for chemical hazards-Supplement III-OHG. tration and damage caused by the relatively
Boron triuoride, pp 18. National Institute soluble bromine.4
for Occupational Safety and Health, Cincin-
A mild degree of spermatogenic suppres-
nati, OH, 1992
4. Rusch GM, Hoffman GM, McConnell RF, et sion and impaired reproductive performance
al: Inhalation toxicity studies with boron tri- was reported in a follow-up study of eight
uoride. Toxicol Appl Pharmacol 83:6978, 1986 men accidentally exposed to bromine vapor.5
5. Torkelson TR, Sadek SE, Rowe VK: The The men were exposed between 50 and 240
toxicity of boron triuoride when inhaled by minutes to unknown concentrations after a
laboratory animals. Am Ind Hyg Assoc J 22: spill. Clinical manifestations including respira-
263270, 1961 tory distress and chemical skin burns were
noted at the time of the incident. Because of
the small number in the cohort, a condent
cause-result linkage cannot be established for
bromine exposure and reproductive effects.
BROMINE The liquid or concentrated vapor in
CAS: 7726-95-6 contact with the eye will cause severe and
painful burns.6 Liquid bromine spilled on the
Br2 skin causes a mild, cooling sensation on rst
contact, followed by a burning sensation. If
bromine is not removed from the skin imme-
Synonyms: None diately, deep surface burns result; a brown dis-
coloration appears, leading to the development
Physical Form. Dark reddish-brown, of deep-seated ulcers, which heal slowly.
fuming, volatile liquid Exposure to excess bromine in pool water
(8.2 mg/ml) was thought to be responsible for
Uses. In the synthesis of antiknock com- irritative skin rashes; eye, nose, and throat
pounds for gasoline; in the production of fumi- irritation; bronchospasm; reduced exercise
gants, re retardants, sanitation preparations, tolerance; fatigue; headache; gastrointestinal
and chemical warfare gas disturbances; and myalgias in 17 adolescents.7
Several had persistent or recurrent symptoms
Exposure. Inhalation lasting weeks to months after exposure. Oral,
inhalation, and dermal absorption may all have
Toxicology. Bromine is a severe irritant of occurred under the exposure conditions.
the eyes, mucous membranes, lungs and skin. Nearly 50% of mice exposed at 240 ppm
In humans, 10 ppm is intolerable, causing for 2 hours died within 30 days; at 750 ppm, a
severe irritation of the upper respiratory tract; 7-minute exposure was lethal to 40% during
lacrimation occurs at levels below 1 ppm.1 the same follow-up period.8
Symptoms and signs in humans also include The 2003 ACGIH threshold limit value-
dizziness, headache, epistaxis, and cough, fol- time-weighted average (TLV-TWA) for
lowed some hours later by abdominal pain, bromine is 0.1 ppm (0.66 mg/m3) with a short-
diarrhea, and sometimes, a measleslike erup- term excursion limit of 0.2 ppm (1.3 mg/m3).
tion on the face, trunk, and extremities.2 Expo-
sure at 4060 ppm is thought to cause
pneumonitis and pulmonary edema within a REFERENCES
short time, and 1000 ppm may be rapidly fatal
because of choking caused by edema of the 1. Hygienic Guide Series: Bromine. Akron, OH,
glottis and because of pulmonary edema.3 American Industrial Hygiene Association, 1978.
BROMODICHLOROMETHANE 91
2. Stokinger HE: The halogens and the non- eyes is expected to cause severe burns; inhala-
metals boron and silicon. In Clayton GD, tion may cause lung injury, and lower concen-
Clayton FE (eds): Pattys Industrial Hygiene and trations may cause watering of the eyes and
Toxicology, 3rd ed, rev, Vol 2B, Toxicology, pp difculty in breathing.1
29652968. New York, Wiley-Interscience, Exposure of animals to 500 ppm caused
1981
immediate gasping, swelling of eyelids, corneal
3. Henderson Y, Haggard HW: Noxious Gases.
New York, Reinhold, 1943 opacity, lacrimation, and excessive salivation.2
4. Kraut A, Lilis R: Chemical pneumonitis due to Levels of 100 ppm produced the same effects
exposure to bromine compounds. Chest after 3 minutes; 50 ppm for 30 minutes caused
94:208210, 1988 deaths. Chronic exposure above 3 ppm pro-
5. Potashnik G, Carel R, Belmaker I, et al: duced severe nephrosis, marked toxic hepato-
Spermatogenesis and reproductive perform- sis, and severe respiratory difculty in some of
ance following human accidental exposure the exposed animals.
to bromine vapor. Reprod Toxicol 6:171174, The 2003 ACGIH threshold limit value-
1992 time-weighted average (TLV-TWA) is 0.1 ppm
6. MCA, Inc.: Chemical Safety Data Sheet SD-49, (0.72 mg/m3).
Bromine, pp 5, 1618. Washington, DC, MCA,
Inc, 1968
7. Woolf A, Shannon M: Reactive airways dys-
function and systemic complaints after mass REFERENCES
exposure to bromine. Environ Health Perspect
107(6):507509, 1999 1. ACGIH: Bromine pentauoride. Documenta-
8. Bitron MD, Aharonson EF: Delayed mortality tion of the TLVs and BEIs, 6th ed, pp 152
of mice following inhalation of acute doses of 153. Cincinnati, OH, American Conference
CH2O, SO2, Cl2 and Br2. Am Ind Hyg Assoc J of Governmental Industrial Hygienists
39:129138, 1978 (ACGIH), 1991
2. ACGIH: Bromine pentauoride. Documenta-
tion of the TLVs and BEIs, 5th ed, p 66.
Cincinnati, OH, American Conference of
Governmental Industrial Hygienists
(ACGIH), 1986
BROMINE PENTAFLUORIDE
CAS: 7789-30-2
BrF5
BROMODICHLOROMETHANE
CAS: 75-27-4
Synonyms: Bromine uoride
CHBrCl2
Physical Form. Pale yellow liquid at tem-
peratures below 40.3C; pungent, corrosive gas
at temperatures above 40.3C. Synonyms: Dichlorobromomethane; mono-
bromodichloromethane; dichloromonobro-
Uses. Oxidizer in rocket propellant systems; momethane
uorinating agent
Physical Form. Colorless liquid
Exposure. Inhalation
Uses. As a chemical intermediate for organic
Toxicology. Bromine pentauoride is an synthesis and as a laboratory reagent; formerly
extremely reactive oxidizer and is an irritant of used as a solvent and ame retardant.
the eyes, mucous membranes, and lungs. Currently, the major source of bro-
Contact of the vapor or liquid with skin or modichloromethane in the environment is
92 BROMODICHLOROMETHANE
from its formation as a by-product during chlo- and in another study liver tumors occurred
rination of water. in females exposed to 150 mg/kg/day for
180 weeks.3,6
Exposure. Ingestion; inhalation; skin The IARC has determined that there
absorption is sufcient evidence for the carcinogenicity
of bromodichloromethane in experimental
Toxicology. Bromodichloromethane is a animals and that it is possibly carcinogenic to
central nervous system depressant and causes humans.7
damage to the liver and kidneys; it is carcino- In genotoxic assays bromodichloro-
genic in experimental animals. methane produced positive and negative
No studies are available regarding health results. It caused sister chromatid exchange
effects of bromodichloromethane in humans. in human lymphocytes but not in Chinese
The LD50 for a single gavage dose in both hamster cells; chromosomal aberrations were
mice and rats has ranged from 450 to 970 mg/ observed in two of three studies; it induced
kg.13 Clinical signs associated with these expo- mutations in some bacterial assays.7
sures include piloerection, sedation, accid Bromodichloromethane was fetotoxic at
muscle tone, ataxia, and prostration; enlarge- doses that also caused signicant maternal tox-
ment and congestion of the liver and kidneys icity in a number of animal studies. However,
were observed at autopsy.3 recent studies have shown dramatic species
Subchronic exposure to bromodichloro- differences in sensitivity to bromodichloro-
methane in the range of 100300 mg/kg/day methane. After treatment on gestation day
has caused hepatic injury in mice and rats char- 10, F344 rats had a 62% incidence of full litter
acterized by increased liver weight, pale discol- resorptions at 75 mg/kg/day, whereas Sprague-
oration, increased levels of hepatic enzymes, Dawley rats had 0% incidence of full litter
and focal areas of inammation or degen- resorptions at the same dose. Timing of the
eration.4,5 Mild effects, including slightly treatment with bromodichloromethane was
increased liver weights and microscopic also critical in causing resorptions in the
changes, have been noted at doses as low as F344 rats (75% incidence of full litter resorp-
4050 mg/kg/day for 2 weeks.4 tions with treatment on gestation days 6
Damage to the kidneys has also been 10 and 0% incidence when dosed on days
reported at doses similar to those that affect the 1115).8 Two epidemiological studies have
liver. Increased renal weights were observed also noted a relationship between high levels
in rats receiving 200 mg/kg/day for 10 days, of bromodichloromethane in the drinking
and increased blood urea nitrogen has been water and an increased risk of spontaneous
reported in mice dosed with 250 mg/kg/day for abortion.9,10
2 weeks.4,5 The ACGIH has not established a thresh-
Chronic oral studies in mice and rats show old limit value for bromodichloromethane.
clear evidence that bromodichloromethane is
carcinogenic. Male mice administered 50 mg/
kg/day by gavage 5 days/week for 2 years had REFERENCES
an increased incidence of renal carcinoma;
hepatic tumors were observed in female mice 1. Chu I, Villeneuve DC, Secours VE, et al:
similarly dosed with 75 or 150 mg/kg/day.3 Toxicity of trihalomethanes: I The acute and
subacute toxicity of chloroform, bromodi-
Tumors of the large intestine (intestinal carci-
chloromethane, chlorodibromomethane and
noma) occurred in rats at incidences of 13/50
bromoform in rats. J Environ Sci Health
and 45/50 in males exposed to 50 or 100 mg/ B17:205224, 1982
kg/day, 5 days/week for 2 years, respectively; 2. Bowman FJ, Borzelleca JF, Munson AE: The
12 of 47 females were affected at the higher toxicity of some halomethanes in mice. Toxicol
dose. Kidney tumors were observed in both Appl Pharmacol 44:213215, 1978
male and female rats exposed to 100 mg/kg/day, 3. National Toxicology Program: Toxicology and
BROMOFORM 93
increase in tumor incidence was observed in Service, National Institutes of Health, NIH
mice similarly treated with 100 mg/kg/day.3 Pub No 88-2805, 1988
The IARC has determined that there is 4. Munson AE, Sain LE, Sanders VM, et al:
limited evidence for the carcinogenicity of Toxicology of organic drinking water con-
bromoform in experimental animals and that it taminants: trichloromethane, bromodichloro-
methane, dibromochloromethane, and
is not classiable as to its carcinogenicity to
tribromomethane. Environ Health Perspect
humans.6 46:117126, 1982
Bromoform has shown positive and nega- 5. Condie LW, Smallwood CL, Laurie RD:
tive results in a variety of in vitro genotoxic Comparative renal and hepatotoxicity of
assays. In vivo it did not induce micronuclei in halomethanes: Bromodichloromethane, bro-
mouse bone marrow and did not cause moform, chloroform, dibromochloromethane
unscheduled DNA synthesis in rat liver.7 and methylene chloride. Drug Chem Toxicol 6:
An increased incidence of minor skeletal 563578, 1983
variations occurred in the offspring of rats 6. IARC Monographs on the Evaluation of Carcino-
dosed at 100 or 200 mg/kg/day on days 615 of genic Risks to Humans, Vol 71, Re-evaluation
gestation.8 No adverse effect on fertility was of some Organic Chemicals, Hydrazine and
Hydrogen Peroxide, pp 13091316. Lyon,
found in either the parental or F1 generation of
International Agency for Research on Cancer,
mice treated for 18 weeks at doses up to 1999
200 mg/kg/day in a continuous breeding 7. Stocker KJ, Statham J, Howard WR, et al:
reproductive study; a decrease in neonatal (F1) Assessment of the potential in vivo genotoxic-
survival was noted in the high-dose group.6 ity of three trihalomethanes: chlorodibro-
The undiluted liquid was moderately irri- momethane, bromodichloromethane and
tating to rabbit eyes, but healing was complete bromoform. Mutagenesis 12(3):169173, 1997
in 12 days. Repeated skin contact caused mod- 8. Ruddick JA, Villeneuve DC, Chu I, et al:
erate irritation to rabbit skin.9 A teratological assessment of four tri-
The 2003 ACGIH threshold limit value- halomethanes in the rat. Environ Sci Health
time-weighted average (TLV-TWA) for bro- B18:333349, 1983
9. Torkelson TR, Rowe VK: Halogenated
moform is 0.5 ppm (5.2 mg/m3) with a notation
aliphatic hydrocarbons. In Clayton GD,
for skin absorption. Clayton FE (eds): Pattys Industrial Hygiene and
Toxicology, 3rd ed, rev, Vol 2B, Toxicology,
pp 34693470. New York, Wiley-Interscience,
1981
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1. von Oettingen WF: The Halogenated Aliphatic,
Olenic, Cyclic, Aromatic, and Aliphatic-Aromatic
Hydrocarbons Including the Halogenated Insecti-
cides, Their Toxicity and Potential Dangers. US 1,3-BUTADIENE
Public Health Service Pub No 414, pp 6567. CAS: 106-99-0
Washington, DC, US Government Printing
Ofce, 1955 C4H6
2. Agency for Toxic Substances and Disease
Registry (ATSDR): Toxicological Prole for Bro-
moform and Chlorodibromomethane. US Depart- Synonyms: Butadiene; biethylene; divinyl; ery-
ment of Health and Human Services, Public
threne; vinylethylene
Health Service, TP-90-05, p 121, 1990
3. National Toxicology Program: Toxicology and
Carcinogenesis Studies of Tribromomethane (Bro- Physical Form. Colorless gas
moform) (CAS No. 75-25-2) in F344/N Rats
and B6C3F1 Mice (Gavage Studies). Technical Uses. Manufacture of synthetic rubber, espe-
report series no. 350. US Department of cially styrene-butadiene, polybutadiene, and
Health and Human Services, Public Health neoprene rubbers
1,3-BUTADIENE 95
butane and propane and is used as a home fuel; sitized the heart to ventricular brillation
in organic synthesis; as a solvent; as a refriger- induced by epinephrine.7
ant and aerosol propellant; as a food additive Dermal penetration of butane is not
expected to any large extent, as skin contact
Exposure. Inhalation would be transient because of volatility.8 n-
Butane did not cause respiratory or eye irrita-
Toxicology. n-Butane is a central nervous tion in rabbits, but it was mildly to moderately
system depressant at high concentrations. irritating to the skin.9 Liqueed butane may
n-Butane may act primarily by depriving cause frostbite when applied directly to the
victims of oxygen.1 Initial effects include exci- skin.8
tation, euphoria, blurred vision, slurred speech, The high odor threshold does not provide
nausea, vomiting, and increased salivation. adequate warning of overexposure.2
With increasing exposure there is confusion, The 2003 ACGIH threshold limit value-
perceptual distortion, hallucinations, delusions, time-weighted average for n-butane is 800 ppm
tinnitus, and ataxia. With large doses central (1900 mg/m3), which was established because
nervous system depression, coma, and death of explosivity hazards rather than toxicological
(resulting from anoxia, vagal inhibition of the concerns.
heart, respiratory depression, or cardiac
arrhythmias) may occur.1
In six men and women, a 10-minute expo-
sure to butane gas at 10,000 ppm resulted in REFERENCES
drowsiness.2
1. International Programme Chemical Safety:
Voluntary inhalation of butane has led to
Butane. Poisons Information Monograph 945.
numerous deaths. Possible mechanisms for the International Programme Chemical Safety,
cause of death included the central respiratory www.inchem.org, 1998
and circulatory sequelae of the anesthetic prop- 2. Patty FA, Yant WP: Odor intensity and Symp-
erties of butane, laryngeal edema, chemical toms Produced by Commercial Propane, Butane,
pneumonia, and the combined effects of Pentane, Hexane and Heptane Vapors. US
cardiac toxicity and increased sympathetic Bureau of Mines Report of Investigation No
activity.3 2979, pp 110, 1929
In animal studies, the 4-hour LC50 in 3. Anderson HR, Dick B, MacNair RS, et al:
rats was 278,000 ppm and the 2-hour LC50 in An investigation of 140 deaths associated
with volatile substance abuse in the United
mice was 287,000.4 Early studies reported
Kingdom (19711981). Hum Toxicol 1:207
similar values with 270,000 ppm for 2 hours,
221, 1982
causing death in 40% of exposed mice, and 4. Shugaev BB: Concentrations of hydrocarbons
310,000 ppm for 2 hours, causing 60% mortal- in tissues as a measure of toxicity. Arch Environ
ity.5 In dogs, lethality was observed at concen- Health 18:878882, 1969
trations of 200,000250,000 ppm; anesthesia 5. Stoughton RW, Lamson PD: The relative
and relaxation preceded death. In animal anesthetic activity of the butanes and the
studies, there was only a small margin of safety pentanes. J Pharmacol Exp Ther 58:7477,
between anesthetic and lethal concentrations. 1936
Several studies have indicated that n- 6. Aviado DM, Zakheri S, Watanabe T: Non-
butane sensitizes the myocardium to epineph- Fluorinated Propellants and Solvents for Aerosols,
pp 4981. Cleveland, OH, CRC Press,
rine-induced cardiac arrhythmias. In
1977
anesthetized dogs, 5000 ppm caused hemody-
7. Chenoweth MB: Ventricular brillation
namic changes such as decreases in cardiac induced by hydrocarbons and epinephrine. J
output, left ventricular pressure, and stroke Ind Hyg Toxicol 28:151158, 1946
volume, myocardial contractility, and aortic 8. Low LK, Meeks JR, Mackerer CR: n-Butane.
pressure.6 Exposure of dogs to 120% butane In R Snyder (ed): Ethel Brownings Toxicity and
for periods of 2 minutes to 2 hours hypersen- Metabolism of Industrial Solvents, 2nd ed, Vol 1,
98 n-BUTYL ACETATE
Hydrocarbons, pp 267272. New York, ity and changes to the functional observational
Elsevier Science Pub, 1987 battery including changes in posture, decreased
9. Moore AF: Final report on the safety assess- arousal, increased tonic/clonic movements, dis-
ment of isobutane, isopentane, n-butane, and turbances in gait, delayed righting reexes,
propane. J Am Coll Toxicol 1:127142, 1982 and increased sensorimotor reactivity in mice.5
Repeated exposure of rats at 3000 ppm 6 hours/
day for 65 days resulted in transient signs of
sedation but no evidence of cumulative neuro-
toxicity based on the functional observational
n-BUTYL ACETATE battery, neurohistopathology, and operant
CAS: 123-86-4 behavior end points.6
There are no indications of mutagenic or
C6H12O2 cytogenic effects for n-butyl acetate.7
The 2003 ACGIH threshold limit value-
time-weighted average (TLV-TWA) for n-
Synonyms: Butyl ethanoate; acetic acid, butyl butyl acetate is 150 ppm (713 mg/m3) with a
ester TLV-STEL of 200 ppm (950 mg/m3).
C6H12O2 CH3COOC(CH3)3
Synonyms: 2-Butanol acetate; acetic acid, sec- Synonym: Acetic acid, tert-butyl ester
ondary butyl ester
Physical Form. Colorless liquid
Physical Form. Colorless liquid
Uses. Gasoline additive; lacquer solvent
Uses. In solvents, especially lacquer solvents;
textile sizes and paper coatings Exposure. Inhalation
REFERENCES
REFERENCES
1. ACGIH: sec-Butyl acetate. Documentation of the
threshold limit values and biological exposure 1. National Institute for Occupational Safety
indices, 7th ed, p 1. Cincinnati, OH, American and Health (NIOSH), US Dept. of Health,
Conference of Governmental Industrial Education, and Welfare: Reports and
Hygienists (ACGIH), 2001 Memoranda. The Registry of Toxic Effects
2. von Oettingen WF: The aliphatic acids and of Chemical Substances (RTECS). Acetic
their esters: Toxicity and potential dangers. acid, tert-butyl ester, RTECS #AF7400000,
AMA Arch Ind Health 21:2865, 1960 July 2000. http://www.cdc.gov/niosh/rtecs/
af70ea40.html
2. Nordic steering group for assessment of health
effects of chemicals: Health effects of selected
chemicals 45. n-butyl acetate, sec-butyl
acetate, tert-butyl acetate, iso-butyl acetate.
Nord 15:6382, 1999
100 n-BUTYL ACRYLATE
3. Oberly R, Tansy MF: LC50 values for rats Exposure. Inhalation; skin absorption
acutely exposed to vapors of acrylic and
methacrylic acid esters. J Toxicol Environ Toxicology. n-Butyl alcohol is an irritant of
Health 16:811, 1985 the eyes and mucous membranes and may
4. Carpenter CP et al: Range-nding toxicity cause central nervous system depression at very
data: List VIII. Toxicol Appl Pharmacol 28:313,
high concentrations.
1974
5. Englehardt G, Klimisch JJ: n-Butyl acrylate Chronic exposure of humans to concentra-
monomer: Cytogenetic investigations in the tions above 50200 ppm causes irritation of the
bone marrow of chinese hamsters and rats eyes with lacrimation, blurring of vision, and
after 4-day inhalation. Fundam Appl Toxicol photophobia.1,2
3:640, 1983 In a 10-year study of workers exposed to
6. DePass LR et al: Acrylic acid, ethyl acrylate, average concentrations of 100 ppm, no sys-
and butyl acrylate: Dermal oncogenicity temic effects were observed.1 Other reports
bioassays of acrylic acid, ethyl acrylate, and have suggested that long-term exposure may
butyl acrylate. J Toxicol Environ Health 14: cause effects on the auditory nerve resulting in
115120, 1984 hearing loss.3
7. Reininghaus W, Koestner A, Klimisch HJ:
Contact dermatitis of the hands may occur
Chroic toxicity and oncogenicity of inhaled
methyl acrylate and n-butyl acrylate in because of a defatting action of the liquid, and
Sprague-Dawley rats. Food Chem Toxicol 29: toxic amounts can be absorbed through the
329339, 1991 skin.4 Direct contact of the hands with n-butyl
8. IARC Monographs on the Evaluation of the Car- alcohol for 1 hour results in an absorbed dose
cinogenic Risk of Chemicals to Humans, Vol 71, that is four times that of inhalation of 50 ppm
Re-evaluation of some organic chemicals, for 1 hour.4
hydrazine and hydrogen peroxide, pp 359 No effects were observed in mice exposed
366. Lyon, International Agency for Re- to 3300 ppm for 7 hours, whereas exposure to
search on Cancer, 1999 6600 ppm produced prostration within 2 hours,
9. Merkle J, Klimisch HJ: n-Butyl acrylate: Pre- narcosis after 3 hours, and some deaths.4
natal inhalation toxicity in the rat. Fundam
Administered to pregnant rats by inhala-
Appl Toxicol 3:443447, 1983
10. Saillenfait AM, Bonnet P, Gallissot F, et al: tion 7 hours/day on days 119 of gestation,
Relative developmental toxicities of acrylates 8000 ppm caused reduced fetal weights, an
in rats following inhalation exposure. Toxicol increased incidence of skeletal malformations,
Sci 48(2):240254, 1999 and signicant maternal toxicity in the form of
narcosis and reduced feed consumption.5 At
3500 ppm for the same exposure time, there
were no fetal or maternal effects.
n-Butyl alcohol was not mutagenic in the
Ames Salmonella typhimurium assay.3 The odor
n-BUTYL ALCOHOL threshold is approximately 15 ppm, but after
CAS: 71-36-3 adaptation the threshold can increase to 10,000
ppm.4
C4H10O The 2003 ACGIH threshold limit ceil-
ing value (TLV-C) for n-butyl alcohol is
50 ppm (152 mg/m3) with a notation for skin
Synonyms: n-Butanol; butyric alcohol; propyl absorption.
carbinol; butyl hydroxide; 1-butanol
alcohol exposure. Am Ind Hyg Assoc Q 10: hours was lethal to ve of six rats.2 Mice repeat-
5359, 1949 edly exposed to a concentration of 5330 ppm
2. Tabershaw IR, Fahy JP, Skinner JB: Industrial for a total of 117 hours were narcotized but
exposure to butanol. J Ind Hyg Toxicol 26: survived.
328330, 1944 Administered by inhalation to pregnant
3. World Health Organization: Environmental
rats on days 119 of gestation for 7 hours/day,
Health Criteria 65 Butanols: Four Isomers, pp
942. International Programme on Chemical 7000 ppm caused an increased incidence in
Safety, Geneva, 1987 resorptions, reduced fetal weights, signicant
4. Rowe VK, McCollister SB: Alcohols. In maternal toxicity in the form of narcosis,
Clayton GD, Clayton FE (eds): In Pattys reduced feed consumption, and reduced weight
Industrial Hygiene and Toxicology, 3rd ed, Vol gain.3 At 3500 ppm some maternal toxicity was
2C, Toxicology, pp 45714578. New York, observed, but there were no fetal effects.
Wiley-Interscience, 1982 When instilled directly into a rabbit eye
5. Nelson BK, Brightwell WS, Krieg EF Jr: the liquid caused severe corneal injury, but it
Developmental toxicology of industrial alco- was not irritating to the skin of rabbits.2
hols: a summary of 13 alcohols administered sec-Butyl alcohol has an odor similar to,
by inhalation to rats. Toxicol Ind Health 6:
but less pungent than, n-butyl alcohol. The
373387, 1990
malodorous and irritating properties probably
prevent exposure to toxic levels.
The 2003 ACGIH threshold limit value-
time-weighted average (TLV-TWA) for sec-
butyl alcohol is 100 ppm (303 mg/m3).
sec-BUTYL ALCOHOL
CAS: 78-92-2
REFERENCES
C4H10O 1. Rowe VK, McCollister SB: Alcohols. In
Clayton GD, Clayton FE (eds): Pattys Indus-
trial Hygiene and Toxicology, 3rd ed, Vol 2C,
Synonyms: 2-Butanol; ethylmethyl carbinol; Toxicology, pp 45824585. New York, Wiley-
butylene hydrate; 2-hydroxybutane Interscience, 1982
2. Smyth HF Jr et al: Range-nding toxicity data:
Physical Form. Colorless liquid List V. AMA Arch Ind Hyg Occup Med
20:6168, 1954
Uses. Polishes, cleaning materials, paint 3. Nelson BK, Brightwell WS, Krieg EF Jr:
Developmental toxicology of industrial alco-
removers, fruit essences, perfumes, and
hols: a summary of 13 alcohols administered
dyestuffs; synthesis of methyl ethyl ketone;
by inhalation to rats. Toxicol Ind Health 6:
lacquer solvent 373387, 1990
Exposure. Inhalation
Uses. Plastics, lacquers, cellulose esters, fruit of tert-Butyl alcohol may prevent inadvertent
essences, perfumes, and chemical intermedi- exposure to toxic levels.
ates; additive to unleaded gasoline The 2003 ACGIH threshold limit value-
time-weighted average (TLV-TWA) for tert-
Exposure. Inhalation butyl alcohol is 100 ppm.
Uses. Intermediate for pharmaceuticals, male and female rat. Toxicol Appl Pharmacol 63:
dyestuffs, rubber chemicals, emulsifying 150152, 1982
agents, insecticides, synthetic tanning agents
REFERENCES REFERENCES
1. Beard RR, Noe JT: Aliphatic and alicyclic 1. Roubal J and Krivucova M: Hygienic problems
amines. In Clayton GD, Clayton FE (eds): in the application of tertiary butyl chromate as
Pattys Industrial Hygiene and Toxicology, 3rd ed, a passivation inhibitor of metal corrosion. Arch
rev, Vol 2B, Toxicology, pp 31353155. New Bewerbepath Gewerbehyg 17:589596, 1960
York, Wiley-Interscience, 1981 2. US Department of Health and Human Ser-
2. Hygienic Guide Series: n-Butylamine. Am Ind vices (NIOSH): Occupational Safety and Health
Hyg Assoc J 21:532533, 1960 Guidelines for Chemical Hazards-Supplement IV-
3. Cheever KL, Richards DE, Plotnick HB: OHG (Pub No 95121), pp 18. Occupational
Short communication. The acute oral toxicity safety and health guideline for tert-butyl chro-
of isomeric monobutylamines in the adult mate. Cincinnati, OH, 1995
n-BUTYL MERCAPTAN 105
Physical Form. Colorless liquid The 2003 ACGIH threshold limit value-
time-weighted average (TLV-TWA) for n-
Uses. Solvent; intermediate in the produc- butyl mercaptan is 0.5 ppm (1.8 mg/m3).
tion of insecticides and herbicides; gas odorant
Toxicology. n-Butyl mercaptan is a central 1. National Institute for Occupational Safety and
nervous system depressant. Health: Criteria for a Recommended Standard
Accidental exposure of seven workers to . . . Occupational Exposure to n-Alkane Mono
Thiols, Cyclohexanethiol, Benzenethiol. DHEW
concentrations estimated between 50 and
(NIOSH) Pub No 78213, Washington, DC,
500 ppm for 1 hour caused muscular weakness
US Government Printing Ofce, 1978
and malaise; six of the workers experienced 2. Ames RG, Gregson J: Mortality following
sweating, nausea, vomiting, and headache; cotton defoliation: San Joaquin Valley, Cali-
three experienced confusion, and one of the fornia, 19701990. J Occup Environ Med 37(7):
individuals lapsed into a coma for 20 minutes.1 812819, 1995
On admission to the hospital, all of the workers 3. Fairchild EJ, Stokinger HE: Toxicologic
had ushing of the face, increased rate of studies on organic sulfur compounds. 1. Acute
breathing, and obvious mydriasis. Six of the toxicity of some aliphatic and aromatic thiols
patients recovered within a day, but the most (mercaptans). Am Ind Hyg Assoc J 19:171189,
seriously affected patient experienced profound 1958
4. Thomas WC, Seckar JA, Johnson JT, et al:
weakness, dizziness, vomiting, drowsiness, and
Inhalation teratology studies of n-butyl mer-
depression.
captan in rats and mice. Fundam Appl Toxicol
In a proportional mortality study, exposure 8:170178, 1987
to butyl mercaptan, a degradation product of
cotton defoliants, did not account for a higher
respiratory mortality in cotton-growing areas
of California.2
In rats, the LC50 for 4 hours was 4020 ppm; o-sec-BUTYLPHENOL
effects were irritation of mucous membranes, CAS: 89-72-5
increased respiration, incoordination, stagger-
ing gait, weakness, partial skeletal muscle paral- C10H14O
ysis beginning in the hind limbs, light to severe
cyanosis, and mild to heavy sedation.3 Animals
that survived single near-lethal doses by the Synonyms: Phenol, o-sec-butyl; 2-(1-methyl-
intraperitoneal and oral routes frequently had propyl)phenol
liver and kidney damage at autopsy up to 20
days after treatment. The liquid dropped in the Physical Form. Liquid
eyes of rabbits caused slight to moderate irrita-
tion. No dermal changes were observed when Uses. A chemical intermediate in the
0.2 ml of a 20% solution was applied to the production of resins, plasticizers, and other
clipped skin of guinea pigs for 10 days.1 products
Female mice and rats exposed 6 hours/day
at concentrations of 10, 68, or 152 ppm during Exposure. Inhalation; skin absorption
gestation had reduced maternal weight gain
at the higher doses; embryotoxic effects and Toxicology. o-sec-Butylphenol is a skin, eye,
increased resorptions occurred in the mice and respiratory irritant.
exposed at 68 and 152 ppm.4 Acute occupational exposures have re-
The disagreeable, skunk-like odor is sulted in mild respiratory irritation as well as
detectable at about 0.00010.001 ppm.1 skin burns.1
p-tert-BUTYL TOLUENE 107
2. Lund SP, Simonsen L, Fries AS: Two weeks chemical form.1 Symptoms may include
inhalation exposure to 4-tert-butyltoluene tracheobronchitis, pneumonitis, pulmonary
causes persistent changes in visually evoked edema, and death. However, most acute intox-
potentials in rats. Pharmacol Toxicol 76(1): ications have been caused by inhalation of
3640, 1995 cadmium fume at concentrations that did not
3. Zeiger E, Anderson B, Haworth S, et al:
provide warning symptoms of irritation. Con-
Salmonella mutagenicity tests III. Results from
the testing of 255 chemicals. Environ Mutagen centrations of fume responsible for fatalities
9 (suppl 9):1110, 1987 have been 4050 mg/m3 for 1 hour or 9 mg/m3
for 5 hours.2 Nonfatal pneumonitis has
been reported from concentrations of 0.5
2.5 mg/m3, and relatively mild cases have been
attributed to even lower concentrations. After
an asymptomatic latent period of 410 hours
CADMIUM (and Compounds) there is characteristically nasopharyngeal irri-
CAS: 7440-43-9 tation, a feeling of chest constriction or sub-
sternal pain, cough, and dyspnea; there also
Cd may be headache, chills, muscle aches, nausea,
vomiting, and diarrhea.3,4 Pulmonary edema
may develop rapidly, with decreased vital
Compounds: Cadmium oxide; cadmium car- capacity and markedly reduced carbon monox-
bonate; cadmium chloride; cadmium sulfate; ide diffusing capacity.4 In about 20% of cases,
cadmium sulde dyspnea is progressive, accompanied by
wheezing or hemoptysis, and may result in
Physical Form. The metal is soft, ductile, death within 710 days after exposure; at
silver-white, electropositive; cadmium oxide autopsy the lungs are markedly congested and
may take the form of a colorless amorphous there is an intraalveolar brinous exudate, as
powder or red or brown crystals. well as alveolar cell metaplasia.3,4 Among sur-
vivors, the subsequent course is unpredictable;
Uses. The metal is used in electroplating, in most cases resolve slowly, but respiratory
solder for aluminum, as a constituent of easily symptoms may linger for several weeks, and
fusible alloys, as a deoxidizer in nickel plating, impairment of pulmonary function may persist
in process engraving, in cadmium-nickel bat- for months.4
teries, and in reactor control rods. Cadmium Longer-term inhalation exposure at lower
compounds are employed as TV phosphors, as levels leads to decreased lung function and
pigments in glazes and enamels, in dyeing and emphysema.1 Early minor changes in ventila-
printing, and in semiconductors and rectiers. tory functions may progress with continued
exposure, to respiratory insufciency.
Exposure. Inhalation; ingestion Chronic exposure to cadmium results in
renal damage. This damage can be identied by
Toxicology. Cadmium oxide fume is a severe increased urinary levels of b2-microglobulin,
pulmonary irritant; cadmium dust also is a retinol-binding protein, or other low-
pulmonary irritant, but it is less potent than molecular-weight proteins.1,5 Increasing
cadmium fume because it has a larger particle damage results in excretion of higher-
size. Chronic exposure is associated with molecular-weight proteins, indicating either
nephrotoxicity. Several inorganic cadmium glomerular damage or severe tubular damage.1
compounds cause malignant tumors in animals. The frequency of occurrence of proteinuria
Inhalation exposure to high levels of cad- increases with length of exposure; in one study,
mium fumes or dust is intensely irritating to persons exposed to cadmium compounds for
respiratory tissue.1 Particle size appears to be a less than 2 years had no proteinuria whereas
more important determinant of toxicity than most of those exposed for 12 years or more had
CADMIUM (and Compounds) 109
REFERENCES
Synonyms: Calcium saltcyanamide; calcium
carbimide; cyanamide (although this synonym 1. Grant WM: Toxicology of the Eye, 3rd ed, p 286.
commonly refers to hydrogen cyanamide) Springeld, IL, Charles C. Thomas, 1986
2. Arena JM: Poisoning, 4th ed, pp 236, 623.
Springeld, IL, Charles C. Thomas, 1979
Physical Form. White or gray crystalline
3. Brien JF et al: A study of the calcium
solid carbimide-ethanol interaction in man. Eur J
Clin Pharmacol 14:1331, 1978
Uses. Manufacture of calcium cyanide and 4. NCI: Bioassay of calcium cyanamide for pos-
dicyandiamide; formerly used as a defoliant and sible carcinogenicity. NCI Tech Rep Ser 163:
herbicide 1112, 1979
5. Prival MJ, Zeiger E: Chemicals mutagenic in
Exposure. Inhalation Salmonella typhimurium strain TA1535 but not
in TA100. Mutat Res 412:251260, 1998
Toxicology. Calcium cyanamide is an irritant.
Calcium cyanamide is severely irritating to
the eyes and skin and causes skin ulceration.1
Sensitization dermatitis has been reported in
0.51% of exposed workers. Inhalation of the CALCIUM HYDROXIDE
dust, presumably at high levels, has caused CAS: 1305-62-0
headache, tachypnea, hypotension, and pul-
monary edema.2 Calcium cyanamide does not Ca(OH)2
liberate cyanide when acidied or in vivo. The
lethal oral dose in humans is 4050 g. In
commercial form, calcium cyanamide may also Synonyms: Slaked lime; hydrated lime;
contain calcium hydroxide and calcium calcium hydrate
carbonate.
Calcium cyanamide is an inhibitor of alde- Physical Form. White, microcrystalline
hyde dehydrogenase, and concurrent intake of powder
112 CALCIUM OXIDE
Uses. In the manufacture of mortar, plaster, 3. Smyth HF Jr et al: Range-nding toxicity data:
whitewash, and paper pulp; in lubricants; in List VII. Am Ind Hyg Assoc J 30:470, 1969
drilling uids 4. Wands RC: Alkaline Materials. In Clayton
GD, Clayton FE (eds): Pattys Industrial
Exposure. Inhalation Hygiene and Toxicology, 3rd ed, rev, Vol 2B,
Toxicology, pp 30523053. New York, Wiley-
Interscience, 1981
Toxicology. Calcium hydroxide is a rela-
tively strong base and, therefore, a caustic
irritant of all exposed surfaces of the body
including the respiratory tract.
Calcium hydroxide is one of the most
common causes of severe chemical eye burns.1 CALCIUM OXIDE
In almost all cases there is a semisolid particu- CAS: 1305-78-8
late paste in contact with the cornea and con-
junctiva, tending to adhere and to dissolve CaO
slowly. Strongly alkaline calcium hydroxide
solution is formed and causes severe injury if
not removed promptly. Synonyms: Burnt lime; calx; lime; quicklime
The 1993 Annual Survey of Occupational
Injuries and Illnesses from the Bureau of Labor Physical Form. Crystals, white or grayish-
Statistics reported 110 cases of dermatitis white lumps or granular powder
attributed to calcium hydroxide (and other
calcium oxides) exposure; the skin disorders Uses. In construction materials; manufacture
resulted in a median of 9 days away from work, of steel, aluminum, and magnesium; as a scrub-
with 27% having more than 20 days away from bing agent to remove sulfur dioxide emissions
work.2 from smokestacks; manufacture of glass, paper,
The oral LD50 for rats is between 4.8 and and industrial chemicals; in fungicides, insecti-
11.1 g/kg.3 Rats administered tap water con- cides, and lubricants
taining 50 or 350 mg/l had reduced food intake
and were restless and aggressive at 2 months; Exposure. Inhalation
at 3 months they showed a loss in body weight,
decreased counts for erythrocytes and phago- Toxicology. Calcium oxide is an irritant of
cytes, and decreased hemoglobin.4 Autopsy the eyes, mucous membranes, and skin.
showed inammation of the small intestine and The irritant effects are probably due
dystrophic changes in the stomach, kidneys, primarily to its alkalinity, but dehydrating
and liver. and thermal effects also may be contributing
The 2003 ACGIH threshold limit value- factors.1 Strong nasal irritation was observed
time-weighted average (TLV-TWA) for from exposure to a mixture of dusts containing
calcium hydroxide is 5 mg/m3. calcium oxide in the range of 25 mg/m3, but
levels of 910 mg/m3 produced no observable
irritation.2 Inammation of the respiratory
tract, ulceration and perforation of the nasal
REFERENCES septum, and pneumonia have been attributed
to inhalation of calcium oxide dust; severe
1. Grant WM: Toxicology of the Eye, 3rd ed, pp
irritation of the upper respiratory tract ordi-
167172. Springeld, IL, Charles C. Thomas,
1986 narily causes persons to avoid serious inhala-
2. Burnett CA, Lushniak BD, McCarthy W, tion exposure.1,2
et al: Occupational dermatitis causing days Particles of calcium oxide can cause severe
away from work in U.S. private industry, 1993. burns of the eyes.3 It can produce skin burns
Am J Ind Med 34:568573, 1998 and ssuring and brittleness of the nails.4
CALCIUM SILICATE 113
The 2003 ACGIH threshold limit value- calcium silicate.1 A study of 104 wallastonite (a
time-weighted average (TLV-TWA) for naturally occurring calcium silicate mineral)
calcium oxide is 2 mg/m3. miners showed no relationship between the
prevalence of chronic bronchitis or airow
obstruction with increasing exposure.1 In a
REFERENCES cohort mortality study of wollastonite quarry
workers the observed numbers of deaths from
1. Calcium oxide. Documentation of TLVs and all cancers combined and lung cancer were
BEIs, 6th ed, pp 200201. Cincinnati, OH, lower than expected.2
American Conference of Governmental Effects of three commercially produced
Industrial Hygienists (ACGIH), 1991
calcium silicate insulation materials were exam-
2. Wands RC: Alkaline materials. In Clayton
GD, Clayton FE (eds): Pattys Industrial
ined in rats by inhalation and intraperitoneal
Hygiene and Toxicology, 3rd ed, rev, Vol 2B, injection.3 Exposure to 10 mg/m3 of respir-
Toxicology, pp 30533054. New York, Wiley- able dust for 7 hours/day, 5 days/week for 12
Interscience, 1981 months had no effect on the survival of treated
3. Grant WM: Toxicology of the Eye, 3rd ed, pp animals compared with controls. Although two
167172. Springeld, IL, Charles C. Thomas, pulmonary neoplasms, one malignant and one
1986 benign, were found in exposed animals, neither
4. Fisher AA: Contact Dermatitis, p 17. Philadel- was the cause of death, and the incidence was
phia, Lea & Febiger, 1973 not signicantly different from the control
group, where no tumors were found. One peri-
toneal mesothelioma was found in an animal
from one of the inhalation groups, but this was
CALCIUM SILICATE considered to be a spontaneous tumor as none
CAS: 1344-95-2 of over 100 animals injected intraperitoneally
with 25 mg of calcium silicate developed these
CaSiO3 tumors.
At concentrations of 10 and 100 mg/ml,
calcium silicate signicantly increased the fre-
Synonyms: Calcium hydrosilicate; calsil; quencies of chromosomal aberrations and sister
Microcel; Calo E; Florite R; Marimet 45; chromatid exchanges in peripheral human
tobermorite (crystalline form of synthetic blood lymphocytes.4
calcium silicate); wollastonite is a naturally The 2003 threshold limit value-time-
occurring brous form weighted average (TLV-TWA) for calcium
silicate is 10 mg/m3 for total dust containing
Physical Form. White powder no asbestos and <1% crystalline silica.
CALCIUM SULFATE
CaSO4
CAS: 7778-18-9 CAMPHOR
CAS: 76-22-2
CaSO42H2O
CAS: 10104-41-4 C10H16O
Uses. The insoluble anhydrite is used in Uses. Plasticizer for cellulose esters and
cement formulations and as a paper ller; the ethers; manufacture of plastics; in lacquers and
soluble anhydrite is used as a drying agent; the varnishes; in explosives; in pyrotechnics; as
hemihydrate is used for wall plaster and wall- moth repellant; as preservative in pharmaceu-
board; gypsum is used in manufacture of ticals and cosmetics
plaster of paris and portland cement.
Exposure. Inhalation; skin absorption
Exposure. Inhalation
Toxicology. Camphor is an irritant of the
Toxicology. Calcium sulfate is considered to eyes and the nose; at high concentrations it is
be a nuisance dust. a convulsant.
There have been no reports of adverse Camphor is readily absorbed from all sites
effects in humans exposed to calcium sulfate. of administration, producing a feeling of cool-
Excessive concentrations would be expected to ness on the skin, whereas oral doses cause a
cause reduced visibility and skin and upper sensation of warmth in the stomach.1
respiratory tract irritation.1 One report on Symptoms of vapor exposure in humans
gypsum miners attributed adverse effects to are irritation of the eyes and nose and anosmia;
respirable quartz rather than calcium these symptoms occur at concentrations above
sulfate.2 2 ppm.2 Heavy exposures cause nausea, anxiety,
The 2003 threshold limit value-time- confusion, headache, dizziness, twitching of
weighted average (TLV-TWA) is 10 mg/m3, facial muscles, spasticity, convulsions, and
total dust, containing no asbestos and <1% coma.1,3,4
crystalline silica. Most camphor poisonings in humans are
CAPROLACTAM 115
due to accidental ingestion.5 With mild 6. Koppel C et al: Camphor poisoning. Abuse of
poisoning, gastrointestinal tract symptoms are camphor as a stimulant. Arch Toxicol 51:
more common than neurological symptoms 101106, 1982
and include irritation of the mouth, throat, and 7. Grant WM: Toxicology of the Eye, 3rd ed,
stomach. Severe poisoning is characterized by pp 173. Springeld, IL, Charles C. Thomas,
1986
convulsions.
8. US Department of Health and Human Ser-
Ingestion of 610 g of camphor by two vices (NIOSH): Occupational Safety and Health
men resulted in psychomotor agitation and guidelines for chemical hazards-Supplement IV-
hallucinations.6 The probable lethal dose OHG (Pub No 95121), Occupational safety
for humans is in the 50500 mg/kg range.5 and health guideline for camphor, synthetic,
Camphor may be expected to be somewhat irri- pp 18. Cincinnati, OH, 1995
tating on contact with the eye, but no serious 9. Leuschner J: Reproductive toxicity studies of
eye injuries have been reported.7 d-camphor in rats and rabbits. Arzneimit-
Animal bioassays showed that camphor telforschung 47(2):1248, 1997
was not carcinogenic in rats injected subcuta-
neously; however, when the cancer promoter
croton oil was concurrently applied to the skin
of mice, 2 of 110 treated mice developed
carcinomas.8 CAPROLACTAM
Camphor was not teratogenic to rats or CAS: 105-60-2
rabbits when administered orally during the
fetal period of organogenesis at doses up C6H11NO
to 1000 mg/kg body weight (bw)/day or
681 mg/kg bw/day, respectively.9 Signs of
maternal toxicity included clonic convulsions, Synonyms: e-Caprolactam; 2-oxohexamethyl-
reduced motility, and reduced body weight gain eneimine; aminocaproic lactam
in rats and reduced food consumption and body
weight gain in rabbits. Physical Form. White crystalline solid
The 2003 ACGIH threshold limit
value-time-weighted average (TLV-TWA) for Uses. Monomer for manufacture of poly-
camphor is 2 ppm (12 mg/m3) with a short-term caprolactam (Nylon 6) used in carpets, textiles,
excursion limit of 3 ppm (19 mg/m3). clothing, and tires
Exposure. Inhalation
REFERENCES
Toxicology. Caprolactam (dust or vapor) is
1. Gosselin RE, Smith RP, Hodge HC: Clinical an irritant of the eyes, mucous membranes,
Toxicology of Commercial Products, Section III, respiratory tract, and skin and, rarely, a
5th ed, pp 8486. Baltimore, MD, Williams convulsant.
and Wilkins, 1984 Human test panel exposures to vapor
2. Gronka PA, Bobkoskie RL, Tomchick GJ, levels ranging from 53 to 521 mg/m3 resulted
Rakow AB: Camphor exposures in a packag- in eye and throat irritation in all those
ing plant. Am Ind Hyg Assoc J 30:276279, exposed.1 In a study of workers exposed to
1969
vapor over a period of 18 years at levels up to
3. Arnow R: Camphor poisoning. JAMA 235:
100 ppm, there were complaints of severe dis-
1260, 1976
4. Ginn HE et al: Camphor intoxication comfort from burning of the eyes, nose, and
treated by lipid dialysis. JAMA 203:164165, throat.2 Eye irritation did not occur at 25 ppm,
1968 but nose and throat irritation occurred in some
5. Segal S: Camphor: Who needs it? Pediatrics at 10 ppm.
62:404406, 1978 An earlier study of German workers
116 CARBARYL
1. Hayes WJ Jr: Clinical Handbook on Economic Toxicology. There are no well demonstrated
Poisons. Emergency Information for Treating Poi- health hazards to humans from acute exposure
soning, US Public Health Service Pub No 476, to carbon black.
pp 4446. Washington, DC, US Government Commercial carbon black is a spherical
Printing Ofce, 1963
colloidal form of nearly pure carbon particles
2. Hayes WJ Jr: Pesticides Studied in Man,
pp 438447. Baltimore, MD, Williams &
and aggregates with trace amounts of organic
Wilkins, 1982 impurities adsorbed on the surface. Potential
3. World Health Organization: Carbaryl. Envi- health effects usually are attributed to these
ronmental Health Criteria 153, pp 12251. impurities rather than to the carbon itself.
International Programme on Chemical Safety, Soots, by contrast, contain mixtures of par-
1994 ticulate carbon, resins, tars, and so on, in a
4. National Institute for Occupational Safety and nonadsorbed state.1
Health: Criteria for a Recommended Standard Carbon black particles are deposited in the
. . . Occupational Exposure to Carbaryl, DHEW lungs on inhalation exposure of humans. The
(NIOSH) Pub No 77107, pp 1796, 109 exposure may cause slight radiological changes
117. Washington, DC, US Government Print-
that vary because of different exposure circum-
ing Ofce, 1976
5. Best EM Jr, Murray BL: Observations on
stances, concomitant exposures to other com-
workers exposed to Sevin insecticide: A pre- pounds, and varying radiological techniques.1
liminary report. J Occup Med 10:507517, 1962 Reduction in lung function and bronchitis have
6. Mathur A, Bhatnagar P: A teratogenic study of been reported in some studies.
carbaryl in Swiss albino mice. Food Chem A signicant loss in pulmonary function
Toxicol 29:629632, 1991 was reported in a group of 125 Nigerian carbon
7. Lieske CN, Clark JH, Maxwell DM, et al: black workers exposed to levels of up to 34 mg/
Studies of the amplication of carbaryl toxic- m3.2 The most common respiratory symptom
ity by various oximes. Toxicol Lett 62:127137, was cough with phlegm, but radiograms were
1992 normal. Signicant annual declines in FEV1
8. Joint Meeting on Pesticide Residues ( JMPR):
and FVC and radiological lung changes were
Carbaryl. Pesticide residues in food. Tox-
icological evaluation addendum http://www.
reported in another group of 35 workers
inchem.org, 2001 exposed to concentrations less than 10 mg/m3.1
In contrast, a survey of over 500 carbon black
workers in the United States and in the United
Kingdom found no statistical difference in
CARBON BLACK spirometry, chest radiograph, physical exami-
CAS: 1333-86-4 nation, or reported symptoms.3 A 1988 report
on 913 men employed in the production and
handling of carbon black in the United States
also found no evidence of pulmonary function
effects from dust exposure, as determined by
Synonyms: Carbon; activated carbon; acety- spirometry.4
lene carbon; decolorizing carbon; actibon; A study of over 3000 carbon black workers
channel black; furnace black; thermal black; gas employed primarily in Western Europe deter-
black; lamp black; ultracarbon mined that smoking was the principal factor
affecting lung function in the workers and
Physical Form. Black crystal; powder that
exposure to carbon black had no more effect
varies in particle size and degree of aggregation
than that expected from a nuisance dust. There
Uses. In the rubber, plastic, printing, and was no evidence of any increased incidence
paint industries as a reinforcing agent and a of radiological abnormality in the workers
pigment surveyed.5 A follow-up on much of this same
CARBON BLACK 119
cohort found a correlation between small opac- implicated as a cocarcinogen in animal studies
ities of the lungs (category 0/1 or greater) and in the presence of high-fat diets and other
cumulative dust exposure.6 Exposure to carbon carcinogens.13
black was also associated with some increased The IARC has determined that there is
prevalence of respiratory effects including inadequate evidence in humans and sufcient
cough, sputum, and symptoms of chronic bron- evidence in experimental animals for the car-
chitis, as well as small decrements in lung func- cinogenicity of carbon black; there is also suf-
tion tests. These results are considered to be cient evidence in experimental animals for the
consistent with a nonirritant effect of carbon carcinogenicity of carbon black extracts.1
black dust on the airways combined with dust Most assays for mutagenicity are negative.1
retention in the lungs. The 2003 ACGIH threshold limit value-
A number of studies have examined the time-weighted average (TLV-TWA) for carbon
carcinogenic potential of chronic carbon black black is 3.5 mg/m3.
exposure. A retrospective cohort study of
1200 men employed at four carbon black plants
from 1935 to 1974 found no signicant REFERENCES
increase in total mortality, mortality from heart
disease, or mortality due to malignant neo- 1. IARC Monographs on the Evaluation of the
plasms.7 An update of this cohort through 1994 Carcinogenic Risk of Chemicals to Humans, Vol
found no increase in overall or cause-specic 65, printing processes and printing inks,
mortality.8 Elevated lung cancer standardized carbon black and some nitrocompounds, pp
149262. Lyon, International Agency for
mortality ratios (SMRs) were found at two of
Research on Cancer, 1996
ve United Kingdom factories manufacturing
2. Oleru UG, Elegbeleye OO, Enu CC, et al:
carbon black.9 However, lung cancer risk did Pulmonary function and symptoms of Niger-
not increase with cumulative exposure to ian workers exposed to carbon black in dry
carbon black or with duration of employment. cell battery and tire factories. Environ Res 39:
A cohort of Italian longshoremen exposed to 161168, 1983
high concentrations of carbon black had a 3. Crosbie WA et al: Survey of respiratory
signicantly increased frequency of bladder disease in carbon black workers in the UK
cancer.10 Limitations in the studies include and USA (abstr). Am Rev Respir Dis 119:209,
confounding concomitant exposures, lack of 1979
exposure data, and lack of consistent results 4. Robertson JM, Diaz JF, Fyfe IM, Ingalls
TH: A cross-sectional study of pulmonary
across studies.
function in carbon black workers in the
In animal studies signicant increases
United States. Am Ind Hyg Assoc J 49:161
in the incidences of lung tumors have been 166, 1988
observed in female rats after inhalation 5. Crosbie WA: The respiratory health of
exposure.1 Repeated inhalation by monkeys carbon black workers. Arch Environ Health
caused deposition of the dust in the lungs with 41:346353, 1986
minimal or no brous tissue proliferation.11 6. Gardiner K, Trethowan NW, Harrington
The major concern with carbon black JM, et al: Respiratory health effects of
exposure is the simultaneous exposure to poly- carbon black: a survey of European carbon
cyclic aromatic hydrocarbons that are strongly black workers. Br J Ind Med 50:10821096,
adsorbed to the respirable carbon black parti- 1993
7. Robertson JM, Ingalls TH: A mortality study
cles and from which PAHs may be elutriated in
of carbon black workers in the United States
vivo under conditions of human exposure.12
from 1935 to 1974. Arch Environ Health
However, in a number of studies, attempts to 35:181186, 1980
elutriate PAH with biological uids have been 8. Robertson JM, Inman KJ: Mortality in
largely unsuccessful, and prolonged extraction carbon black workers in the United States. J
with boiling aromatic solvents is required for Occup Environ Med 38(6):569570, 1996
quantitative desorption. Carbon black has been 9. Sorahan T, Hamilton L, van Tongeren M,
120 CARBON DIOXIDE
et al: A cohort mortality study of U.K. carbon a potent stimulus to respiration and both a
black workers, 19511996. Am J Ind Med depressant and an excitant of the central
39(2):158170, 2001 nervous system.
10. Puntoni R, Ceppi M, Reggiardo G, et al: Numerous human fatalities have occurred
Occupational exposure to carbon black and after people entered fermentation vats, wells,
risk of bladder cancer. Lancet 358(9281):
and silos where the air had been replaced
562563, 2001
11. Nau CA, Neal J, Stembridge VA, Cooley largely by carbon dioxide.1,2 In other cases,
RN: Physiological effects of carbon black. death or injuries may be caused by the toxicity
IV. Inhalation. Arch Environ Health 4:4561, of carbon dioxide alone and are not due to
1962 oxygen deprivation. At levels that are consid-
12. National Institute for Occupational Safety ered immediately dangerous to life and health,
and Health, US Department of Health, oxygen displacement by carbon dioxide may be
Education, and Welfare: Criteria for a Recom- as little as 1%.3 The most immediate and sig-
mended Standard . . . Occupational Exposure to nicant effects of acute exposure at high con-
Carbon Black. DHEW (NIOSH) Pub No centrations are those on the central nervous
78204, pp 199. Washington, DC, US system.1 Concentrations of 2030% (200,000
Government Printing Ofce, 1978
300,000 ppm) result in unconsciousness and
13. Pence BC, Buddingh F: Co-carcinogenic
effect of carbon black ingestion with dietary convulsions within 1 minute of exposure. At
fat on the development of colon tumors in concentrations of approximately 120,000 ppm,
rats. Toxicol Lett 37:177182, 1987 unconsciousness may be produced with longer
exposures of 823 minutes. Neurological
symptoms, including psychomotor agitation,
myoclonic twitches, and eye ickering, have
appeared after 1.5 minutes at 100,000
150,000 ppm.1 Inhalation of concentrations
CARBON DIOXIDE from 60,000 to 100,000 ppm may produce
CAS: 124-38-9 dyspnea, headache, dizziness, sweating, rest-
lessness, paresthesias, and a general feeling of
CO2 discomfort; at 50,000 ppm there may be a sen-
sation of increased respiration, but subjects
rarely experience dyspnea.4 After several hours
Synonym: Carbonic acid gas of exposure to 2% carbon dioxide (20,000
ppm), subjects develop headache and dyspnea
Physical Form. Colorless gas (solid is dry on mild exertion.5 Circulatory effects in
ice) humans exposed to carbon dioxide include
increases in heart rate and cardiac output.6
Uses/Source. By-product of ammonia pro- Adaptation to low levels, 1.53.0% carbon
duction, lime kiln operations, and fermenta- dioxide, has occurred with chronic exposure.1
tion; used in carbonation of beverages, as Carbon dioxide at room temperature will not
propellant in aerosols, and as dry ice for refrig- injure the skin, but frostbite may result from
eration. Exposures may occur in a variety of contact with dry ice or from the gas at low
work settings, including farm silos, fermenta- temperatures.
tion tanks, wells, shipping, mining, and re It is important to note that because carbon
ghting, and in frozen food industries utilizing dioxide is heavier than air, pockets of the gas
dry ice. may persist for some time in areas such as pits
unless ventilation is provided.
Exposure. Inhalation Limited experimental studies in test
animals have raised some concerns about the
Toxicology. Carbon dioxide usually is con- ability of carbon dioxide to harm reproduc-
sidered a simple asphyxiant, although it also is tive parameters. Acute exposures to 25,000
CARBON DISULFIDE 121
1. National Institute for Occupational Safety and Toxicology. Carbon disulde causes damage
Health: Criteria for a Recommended Standard to the central and peripheral nervous systems
Occupational Exposure to Carbon Dioxide. and may accelerate the development of, or
DHEW (NIOSH) Pub No 76-194, pp
worsen, coronary heart disease.
17105, 114126. Washington, DC, US Gov-
ernment Printing Ofce, 1976
Exposure of humans to 4800 ppm for 30
2. Williams HI: Carbon dioxide poisoning minutes causes coma and may be fatal.1 Carbon
report of eight cases, with two deaths. Br Med disulde intoxication can involve all parts of
J 2:10121014, 1958 the central and peripheral nervous systems,
3. Jacobs DE, Smith MS: Exposures to carbon including damage to the cranial nerves and
dioxide in the poultry processing industry. Am development of peripheral neuropathy with
Ind Hyg Assoc J 49:624629, 1988 paresthesias and muscle weakness in the
4. Smith TC et al: The therapeutic gases. In extremities, unsteady gait, and dysphagia.2 A
Gilman A et al. (eds): Goodman and Gilmans follow-up of workers with clinical and elec-
The Pharmacological Basis of Therapeutics, 7th tromyographic evidence of neuropathy attrib-
ed, pp 333335. New York, Macmillan Pub-
uted to carbon disulde exposure showed no
lishing, 1985
5. Schulte JH: Sealed environments in relation to
signicant improvement 10 years after expo-
health and disease. Arch Environ Health 8:438 sure was discontinued, suggesting a permanent
452, 1964 axonal neuropathy.3
6. Cullen DJ, Eger EI: Cardiovascular effects of In extreme cases of intoxication, a
carbon dioxide in man. Anesthesiology 41:345 Parkinsonism-like syndrome may result, char-
349, 1974 acterized by speech disturbances, muscle spas-
7. Vandemark NL, Schanbacher BD, Gomes ticity, tremor, memory loss, mental depression,
WR: Alterations in testes of rats exposed to and marked psychic symptoms; permanent dis-
elevated atmospheric carbon dioxide. J Reprod ability is likely.2 Psychosis and suicide are
Fertil 28:457459, 1972 established risks of overexposure to carbon
8. Haring OM: Cardiac malformations in rats
disulde.4
induced by exposure of the mother to carbon
dioxide during pregnancy. Circ Res 8:1218
Other reported effects of exposure to
1227, 1960 carbon disulde are ocular changes (blind
spot enlargement, contraction of peripheral
eld, corneal anesthesia, diminished pupil-
lary reexes, nystagmus, and microscopic
122 CARBON DISULFIDE
aneurysms in the retina), gastrointestinal dis- was associated with the high carbon disulde
turbances (chronic gastritis and achlorhydria), levels that previously existed in these work-
renal impairment (albuminuria, microhema- places.12,13 Additional cardiovascular effects
turia, elevated blood urea nitrogen, and observed in workers repeatedly exposed to
diastolic hypertension), and liver damage.2,5 carbon disulde are bradycardia, tachycardia,
Hearing loss to high-frequency tones has also and other arrhythmias.5
been reported.6 Conicting studies have appeared regard-
Effects commonly caused by repeated ing the ability of carbon disulde to affect
exposure to carbon disulde vapor are exem- reproductive function.6 Hypospermia, abnor-
plied by a group of workers with a time- mal sperm morphology, menstrual cycle
weighted average (TWA) exposure of 11.2 ppm irregularities, increased menstrual ow and
(range 0.9127 ppm) who complained of pain, and a slight increase in miscarriages have
headaches and dizziness; in other workers with been reported in some studies, whereas other
a TWA of 186 ppm (range 23389 ppm) studies have not found adverse effects. A retro-
complaints also included sleep disturbances, spective cohort study of 265 female workers
fatigue, nervousness, anorexia, and weight loss. exposed 15 years before the study to concen-
The end-of-the-day exposure coefcient of trations averaging 1.7 to 14.8 mg/m3 showed no
the iodine azide test on urine was a good signicant differences in rates of toxemia,
indicator of workers who were, or had been, spontaneous abortion, stillbirth, premature or
symptomatic.7 overdue delivery, or congenital malformation.14
Overexposure to carbon disulde has been However, exposed females had a higher inci-
associated with an increase in coronary heart dence of menstrual disturbances (primarily
disease. In a mortality study of viscose rayon irregularity) than the nonexposed group. Preg-
workers, 42% of deaths were certied to coro- nant rats and rabbits exposed at 20 and 40 ppm,
nary heart disease vs. 17% in unexposed 7 hours/day, showed no evidence of embry-
workers.8 A follow-up of this cohort showed a otoxicity or teratogenicity. In another report,
similar pattern with a standardized mortality hydrocephalia was observed in rats exposed
ratio (SMR) for ischemic heart disease of 172 to 32 and 64 ppm, 8 hours/day, throughout
in spinning operatives.9 This study also found gestation.6
that the risk declined after exposure ceased, Chronic exposure of animals for periods
suggesting a direct cardiotoxic or thrombotoxic less than 1 year has not shown a carcinogenic
effect of carbon disulde rather than an athero- potential for carbon disulde.6 Furthermore,
genic effect. A retrospective cohort mortality epidemiological studies do not support a
study of 10,418 men employed in the US rayon carcinogenic risk under moderate exposure
industry between 1957 and 1979 found excess conditions.15
deaths from arteriosclerotic heart disease Splashes of the liquid in the eye cause
among those potentially most heavily exposed immediate and severe irritation; dermatitis and
(242 vs. 195.6 expected).10 There also vesiculation may result from skin contact with
were excess deaths from suicide (29 vs. 18.8 the vapor or the liquid.1,2 Although ingestion
expected) in one of the four plants investigated. is unlikely to occur, it may cause coma and
In a Finnish cohort, removal from exposure of convulsions.1,2
workers with coronary risk factors and reduc- Both positive and negative results have
tion of levels to 10 ppm caused a dramatic been found in genotoxic assays.16
decrease in cardiovascular mortality.11 Recent Carbon disulde is foul-smelling, but the
cohort studies found that the prevalence of odor is not sufcient to give adequate warning
coronary heart disease (electrocardiogram of hazardous concentrations.
abnormalities and chest pain) was higher in The 2003 ACGIH threshold limit value-
carbon disulde-exposed workers; abnormali- time-weighted average (TLV-TWA) for carbon
ties were signicant in workers with long expo- disulde is 10 ppm (31 mg/m3) with a notation
sures (20 years), suggesting that coronary risk for skin absorption.
CARBON MONOXIDE 123
central nervous systems are particularly sensi- there may be electrocardiographic evidence of
tive to the effects of hypoxia.1,2 Most clinical a depression of the S-T segment; between 15%
manifestations are referable to the central and 25% there may be headache and nausea;
nervous system, but it is likely that myocardial levels below 15% rarely produce symptoms.
ischemia is responsible for many carbon The blood of cigarette smokers usually con-
monoxide-induced deaths.3 tains 210% and sometimes as high as 18%
With exposure to high concentrations carboxyhemoglobin, and nonexposed persons
(4000 ppm and above), transient weakness have an average level of 1%; heme metabolism
and dizziness may be the only premonitory is an endogenous source of CO.1
warnings before coma supervenes; the most Exposure of nonsmokers to 50 ppm for 68
common early aftermath of severe intoxication hours results in carboxyhemoglobin levels of
is cerebral edema.4,5 Severe visual disturbances 810%.13 Several investigators have suggested
also occur as a consequence of acute poisoning that the results of behavioral tests such as
in which there has been a period of uncon- time discrimination, visual vigilance, choice
sciousness.6 After recovery from coma, in cases response tests, visual evoked responses, and
with residual loss of vision, the pupils are reac- visual discrimination threshold may be altered
tive to light despite subject blindness, indicat- at levels of carboxyhemoglobin below 5%.1
ing that the damage is cortical in origin. Transient central nervous system symp-
Typically, complete recovery takes place in a toms or rapid death are not the only results of
few hours to a few days. Exposure to concen- CO poisoning.3 The occurrence of late, fatal
trations of 5001000 ppm causes the develop- demyelination is a rare but dreaded complica-
ment of headache, tachypnea, nausea, tion. Furthermore, it is inappropriate to
weakness, dizziness, mental confusion, and in assume that because a patient with CO poison-
some instances, hallucinations; the person is ing shows improvement, residual mental
commonly cyanotic.14 Because carboxyhemo- damage may not occur.3 A report of 63 patients
globin has a bright red color, occasionally studied 3 years after CO poisoning indicated
someone will exhibit the unusual combination that 13% showed gross neuropsychiatic
of hypoxia together with a bright red color of damage directly attributable to their CO
the ngernails, mucous membranes, and skin; intoxication, 33% showed a deterioration
however, this cherry-red cyanosis usually is of personality after poisoning, and 43%
seen only at autopsy.4 reported memory impairment.8 A syndrome of
Exposure to 50 ppm for 90 minutes may headache, fatigue, dizziness, paresthesias, chest
cause aggravation of angina pectoris; exposed pains, palpitations, and visual disturbances has
anginal patients may show a negative inotropic been associated with chronic carbon monoxide
effect (weakened force of myocardial contrac- poisoning.9
tion); 50 ppm for 120 minutes may cause aggra- Chronic carbon monoxide poisoning may
vation of intermittent claudication.7 be difcult to diagnose because carboxyhemo-
The clinical effects of CO exposure are globin levels correlate poorly with symptoms
aggravated by heavy labor, high ambient tem- and symptoms may be misdiagnosed as a viral
perature, and altitudes above 2000 feet; preg- syndrome or psychological depression. Distin-
nant women are particularly susceptible to the guishing features of chronic carbon monoxide
effects of CO.1 poisoning include the absence of myalgias,
The reaction to a given blood level of car- fever, sore throat, and adenopathy; simultane-
boxyhemoglobin is extremely variable; some ous illness in homebound family members and
persons may be in a coma with a carboxyhe- pets; and improvement with exposure to fresh
moglobin level of 38%, whereas others may air. The diagnosis can be conrmed by nding
maintain an apparently clear sensorium with a source of carbon monoxide in the home (e.g.,
levels as high as 55%. Levels of carboxyhemo- defective furnaces), workplace, or vehicle; neg-
globin over 60% usually are fatal; 40% is asso- ative screenings for other illnesses; abnormal
ciated with collapse and syncope; above 25% carboxyhemoglobin levels; and abatement of
CARBON MONOXIDE 125
symptoms when the CO source has been Carbon Monoxide. (HSM) 73-11000.
eliminated. Washington, DC, US Government Printing
Occupational exposure of New York City Ofce, 1972
tunnel ofcers to excess levels of CO was asso- 2. Olson KR: Carbon monoxide poisoning:
ciated with a 35% excess risk of arteriosclerotic Mechanisms, presentation, and controversies
in management. J Emerg Med 1:233243,
heart disease mortality.10 The excess risk was
1984
thought to be due to repeated, short-term 3. Winter PM, Miller JN: Carbon monoxide
peak exposures on the order of 400 ppm and poisoning. JAMA 236:15021504, 1976
appeared to be reversible on cessation of 4. Swinyard EA: Noxious gases and vapors. In
exposure. Goodman LS, Gilman A (eds): The Pharma-
A review of 60 case reports of carbon cological Basis of Therapeutics, 5th ed, pp
monoxide exposure during pregnancy found 900904, 910911. New York, Macmillan
fetal outcome related to maternal blood car- Publishing, 1975
boxyhemoglobin and maternal toxicity.11 In 5. Beard RR: Inorganic compounds of O, N,
cases in which the mother did not become and C. In Clayton GD, Clayton FE (eds):
unconscious, fetal outcome was generally Pattys Industrial Hygiene and Toxicology, Vol
2C, Toxicology, pp 41144124. New York,
good. However, where the mother experienced
Wiley-Interscience, 1982
unconsciousness or coma, fetal outcome 6. Grant WM: Toxicology of the Eye, 3rd ed,
tended to be poor (death or survival with pp 183186. Springeld, IL, Charles C.
anatomic or functional abnormalities). Anato- Thomas, 1986
mical malformations, including mongoloid- 7. Goldsmith JR, Aronow WS: Carbon mon-
type features, missing and deformed limbs, oxide and coronary heart disease: A review.
and oral cavity anomalies, also showed a Environ Res 10:236248, 1975
marked correlation to exposure during the rst 8. Smith J, Brandon S: Morbidity from acute
trimester. carbon monoxide poisoning at a three-year
Animal experiments support the develop- follow-up. Br Med J 1:318321, 1973
mental ndings found in humans and suggest 9. Kirkpatrick JN: Occult carbon monoxide
poisoning. West J Med 146:5256, 1987
that prenatal exposure at maternally nontoxic
10. Stern FB, Halperin WE, Hornung RW, et al:
levels may also damage the fetal central nervous Heart disease mortality among bridge and
system.12,13 Exposure of pregnant rats to tunnel ofcers exposed to carbon monoxide.
150 ppm produced only minor reductions in Am J Epidemiol 128:127688, 1988
pup birthweights, but evaluation of learning 11. Norman CA, Halton DM: Is carbon mon-
and memory processes suggested a functional oxide a workplace teratogen? A review and
decit in the central nervous system that per- evaluation of the literature. Ann Occup Hyg
sisted into adulthood of exposed offspring.12,13 34:335347, 1990
Congenital spinal deformities have been 12. Mactutus CF, Fechter LD: Prenatal exposure
reported in the offspring of mice exposed for 7 to carbon monoxide: Learning and memory
hours during gestation at doses of 200, 400, or decits. Science 223:409411, 1984
13. Mactutus CF, Fechter LD: Moderate prena-
600 ppm.14
tal carbon monoxide exposure produces per-
The 2003 ACGIH threshold limit value- sistent, and apparently permanent, memory
time-weighted average (TLV-TWA) for carbon decits in rats. Teratology 31:112, 1985
monoxide is 25 ppm (29 mg/m3). 14. Loder RT, Hernandez MJ, Lerner AL, et al:
The induction of congenital spinal deformi-
ties in mice by maternal carbon monoxide
REFERENCES exposure. J Pediatr Orthop 20(5):662666,
2000
1. National Institute for Occupational Safety
and Health, US Department of Health,
Education and Welfare: Criteria for a Recom-
mended Standard Occupational Exposure to
126 CARBON TETRABROMIDE
rillation.1 Exposure to high concentrations doses at which both substances are not consid-
results in symptoms of central nervous system ered toxic; effects include extensive hepatoxic-
depression including dizziness, vertigo, inco- ity characterized by total hepatic failure and
ordination, and mental confusion; abdominal greatly potentiated lethality.7
pain, nausea, vomiting, and diarrhea are fre- The mechanism of carbon tetrachlo-
quent.14 Cardiac arrhythmias and convulsions ride hepatotoxicity generally is viewed as an
have also been reported. Polycythemia fol- example of lethal cleavage, where the CCl3
lowed by anemia and hemodilution may occur. Cl bond is split in the mixed-function oxidase
Within a few days, jaundice may appear and system of the hepatocytes. After this cleavage
liver injury can progress to toxic necrosis. At damage may occur directly from the free radi-
the same time, acute nephritis may occur with cals (CCl and Cl) and/or from the formation
albumin, red and white blood cells, and casts in of toxic metabolites such as phosgene.4
the urine; there may be oliguria, anuria, and Animal studies demonstrate that carbon
increased nitrogen retention resulting in the tetrachloride produces hepatocellular carcino-
development of uremia. The no observed mas in the mouse, rat, and hamster.4 Mice
adverse effect level for acute human exposure administered 1250 or 2500 mg/kg approached
is 10 ppm for a 3-hour exposure.5 nearly a 100% incidence of hepatocellular
There are several reports of adverse effects carcinomas vs. 6% or less in various controls.
in workers who were repeatedly exposed to Hamsters receiving 190 and 380 mg/kg by
concentrations between 25 and 30 ppm; nausea, gavage had a 100% liver cell carcinoma
vomiting, dizziness, drowsiness, and headache incidence for those animals surviving past
were frequently noted.1 Chronic exposure has week 43.8
caused cases of various abnormalities of the Sensitivity to carbon tetrachloride-induced
eyes such as reduced visual eld. neoplasms varied widely among ve strains of
Carbon tetrachloride is absorbed through rats receiving twice-weekly subcutaneous injec-
the skin of humans, although much less readily tions of 2080 mg/kg as a 50% solution in corn
than from the lung.6 After use as a shampoo or oil.9
as a solvent for removal of adhesives from skin, A number of animal studies suggest that
a number of fatal or near-fatal cases have been hepatomas occur only after liver necrosis and
reported. It has been noted that these expo- brosis have occurred and, therefore, that
sures must have also involved high levels of carbon tetrachloride is not a direct liver car-
inhalation exposure as well as dermal exposure. cinogen.4 One early study, however, found that
It has been estimated that immersion of both liver necrosis and its associated chronic regen-
hands in the liquid for 30 minutes would yield erative state probably were not necessary for
an exposure equivalent to breathing 100 tumor induction, although a correlation was
500 ppm for 30 minutes. found between the degree of liver necrosis and
The liquid splashed in the eye causes pain the incidence of hepatomas.10
and minimal injury to the conjunctiva. Pro- In humans, cases of hepatomas have
longed or repeated skin contact with the liquid appeared years after acute exposure to carbon
may result in skin irritation and blistering.1,4 tetrachloride, however, none of the cases could
A number of substances including ethanol, establish a causal link between the exposure and
isopropyl alcohol, polybrominated biphenyls, development of neoplasms.4 Epidemiological
phenobarbital, and benzo(a)pyrene have been studies have also given inconclusive results.
shown to synergistically affect carbon tetra- A cancer mortality study of a population of
chloride toxicity.4 Alcohol has been a concomi- rubber workers reported a signicantly ele-
tant factor in many of the human cases of vated odds ratio relating carbon tetrachloride
poisoning, especially in cases in which severe with lymphatic leukemia, and lymphosarcoma
liver and kidney damage have occurred.2 Some and reticulum cell carcinoma.11,12 A recent ret-
substances such as chlordecone greatly poten- rospective cohort mortality study of aircraft
tiate the toxicity of carbon tetrachloride at maintenance workers found an increased risk of
128 CARBON TETRACHLORIDE
non-Hodgkin lymphoma and multiple 5. Stewart RD, Gay HH, Erley DS, et al:
myeloma among women, but not men, with Human exposure to carbon tetrachloride
carbon tetrachloride exposure.13 To date all the vapor-relationship of expired air concentra-
studies have been characterized by mixed expo- tions to exposure and toxicity. J Occup Med
sures and a lack of carbon tetrachloride data, 3:586590, 1961
6. US Department of Health and Human
which limits the evaluation of effects.
Services: Toxicological Prole for Carbon
The IARC has determined that there is Tetrachloride. Agency for Toxic Substances
sufcient evidence for carcinogenicity in and Disease Registry, Atlanta, GA, 1992
animals, inadequate evidence for carcinogenic- 7. Mehendale HM: Potentiation of halome-
ity in humans, and an overall evaluation that thane hepatotoxicity: Chlordecone and
carbon tetrachloride is possibly carcinogenic to carbon tetrachloride. Fundam Appl Toxicol
humans.14 4:295308, 1984
Carbon tetrachloride was fetotoxic to rats 8. Della Porta G et al: Induction with carbon
when administered on days 615 of gestation tetrachloride of liver cell carcinomas in ham-
at 300 or 1000 ppm, 7 hours/day; an increase in sters. J Natl Cancer Inst 26:855863, 1961
skeletal anomalies due to delayed development 9. Rueber MD, Glover EL: Cirrhosis and car-
cinoma of the liver in male rats given subcu-
was observed in the offspring. Signs of mater-
taneous carbon tetrachloride. J Natl Cancer
nal toxicity included weight loss and hepatic Inst 44:419427, 1970
damage.15 10. Eschenbrenner AB, Miller E: Studies on
The sweetish odor of carbon tetrachloride hepatomas-size and spacing of multiple doses
does not provide satisfactory warning of in the induction of carbon tetrachloride
exposure. hepatomas. J Natl Cancer Inst 4:385388,
The 2003 ACGIH threshold limit value- 1943
time-weighted average (TLV-TWA) for carbon 11. Wilcosky TC, Checkoway H, Marshall EG,
tetrachloride is 5 ppm (31 mg/m3) with a short- et al: Cancer mortality and solvent exposures
term excursion limit of 10 ppm (63 mg/m3), an in the rubber industry. Am Ind Hyg Assoc J
A3-animal carcinogen designation, and a nota- 45:809811, 1984
12. Checkoway H, Wilcosky T, Wolf P, et al: An
tion for skin absorption.
evaluation of the associations of leukemia and
rubber industry solvent exposures. Am J Ind
Med 5:239249, 1984
REFERENCES 13. Blair A, Hartge P, Stewart P, et al: Mortality
and cancer incidence of aircraft mainten-
1. National Institute for Occupational Safety ance workers exposed to trichloroethylene
and Health: Criteria for a Recommended Stan- and other organic solvents and chemicals:
dard . . . Occupational Exposure to Carbon Tetra- extended follow up. Occup Environ Med 55:
chloride. DHEW (NIOSH) Pub No 76-133, 16171, 1998
pp 1568, 84112. Washington, DC, US 14. IARC Monographs on the Evaluation of the
Government Printing Ofce, 1975 Carcinogenic Risk of Chemicals to Man, Vol 71,
2. Fassett DW: Toxicology of organic com- Re-evaluation of some organic chemicals,
pounds: A review of current problems. Annu hydrazine and hydrogen peroxide, pp
Rev Pharmacol 3:267274, 1963 401432. Lyon, International Agency for
3. von Oettingen WF: The Halogenated Research on Cancer, 1999
Aliphatic, Olenic, Cyclic, Aromatic, and 15. Schwetz DW et al: Embryo- and fetotoxicity
Aliphatic Aromatic Hydrocarbons Including of inhaled carbon tetrachloride, 1,1-
the Halogenated Insecticides, Their Toxicity and dichloroethane and methyl ethyl ketone in
Potential Dangers, pp 75112. US Public rats. Toxicol Appl Pharmacol 28:452464, 1974
Health Service Pub. No. 414. Washington
DC, US Government Printing Ofce, 1955
4. Health Assessment Document for Carbon
Tetrachloride. Cincinnati, OH, US Environ-
mental Protection Agency, Environmental
Criteria and Assessment Ofce, 1984
CATECHOL 129
papillomas and 31/50 squamous carcinomas, as chronic test of catechol using Fischer-344 rats
compared with incidences of 13/50 and 10/50 and B6C3F1 mice. 1981. Cited in NTP Exec-
for the B(a)P-only group, respectively. No utive Summary of Data, Catechol, pp 149, 1986
tumors occurred in the catechol-only, vehicle- 6. Hagiwara A, Takesada Y, Tanaka H, et al:
only, or untreated control groups. In a later Dose-dependent induction of glandular
stomach preneoplastic and neoplastic lesions
study, four dose levels of catechol in B(a)P were
in male F344 rats treated with catechol chron-
evaluated for carcinogenicity.8 The catechol- ically. Toxicol Pathol 29(2):180186, 2001
only B(a)P-treated groups had the following 7. Van Duuren BL, Katz C, Goldschmidt BM:
incidences of skin tumors: 0.25 mg catechol Cocarcinogenic agents in tobacco carcinogen-
+ B(a)P, 72%; 0.1 mg catechol + B(a)P, 66%; esis. J Natl Cancer Inst 51:703705, 1973
0.01 mg catechol + B(a)P, 18%; and 0.001 mg 8. Hecht SS, Carmella S, Furuya K, et al:
catechol + B(a)P, 24%. No skin tumors were Polynuclear aromatic hydrocarbons and cate-
observed in the vehicle-only control group, chol derivatives as potential factors in digestive
whereas 11% of the B(a)P-treated group and tract carcinogenesis. Environ Mutagens Car-
21% of the catechol-only treated groups had cinog Proc Int Conf 3:545556, 1982
skin tumors. It was determined that doses of 9. IARC Monographs on the Evaluation of the Car-
cinogenic Risk of Chemicals to Humans, Vol 71,
0.1 mg and above were cocarcinogenic but the
Re-evaluation of some organic chemicals,
lower doses were not.8 hydrazine and hydrogen peroxide, pp 433
The IARC has determined that there is 451. Lyon, International Agency for Research
sufcient evidence for the carcinogenicity of on Cancer, 1999
catechol in animals and that it is possibly car-
cinogenic to humans.9
Catechol was genotoxic in mammalian
cells in vitro, causing chromosomal aberrations
and sister chromatid exchanges.9 CELLULOSE (and Compounds)
The 2003 ACGIH threshold limit value- CAS: 9004-34-6
time-weighted average (TLV-TWA) is 5 ppm
(20 mg/m3) with a notation for skin absorption. (C6H10O5)n
Synonyms: None
REFERENCES
Physical Form. Natural cellulose is a highly
1. IARC Monographs on the Evaluation of the
crystalline, white solid with a molecular
Carcinogenic Risk of Chemicals to Man, Vol 15,
Some fumigants, the herbicides 2,4-D and weight varying from 300,000 to greater than
2,4,5-T, chlorinated dibenzodioxins and mis- 1,000,000.
cellaneous industrial chemicals, pp 155175.
Lyon, International Agency for Research on Uses/Sources. Wood contains 5070% cel-
Cancer, 1977 lulose; cotton and other textile bers of plant
2. Hirosawa I, Asaeda G, Arizono H, et al: origin contain 6595%; rayon is prepared by
Effects of catechol on human subjects. A eld dissolving natural cellulose and then precipi-
survey. Int Arch Occup Environ Health 37:107 tating it from solution, with some loss of crys-
114, 1976. tallinity. Cellulose is made into cellophane lm
3. Flickinger CW: The benzenediols: catechol,
and is used to form bers, resins, coatings and
resorcinol and hydroquinonea review of the
gums.
industrial toxicology and current industrial
exposure limits. Am Ind Hyg Assoc J 37:
596607, 1976 Exposure. Inhalation
4. Angel A, Rogers KJ: Convulsant action of
polyphenols. Nature 217:8485, 1968 Toxicology. Cellulose is inert and is classi-
5. National Toxicology Program: Report of sub- ed as a nuisance dust.
CHLORDANE 131
It has little, if any, adverse effect on the Exposure. Inhalation; skin contact
lung, and there are no reports of organic
disease or toxic effect.1 The health effects Toxicology. Cesium hydroxide is an irritant
attributed to wood, cotton, ax, jute, and hemp of the eyes.
are not attributable to their cellulose content The oral LD50 in rats was 1026 mg/kg.1 In
but rather to the presence of other substances. rabbits a 5% solution was irritating to abraded
Cellulose bers were found in the blood skin and extremely irritating in the eyes. No
and urine of human volunteers fed dyed cellu- evidence of skin sensitization was found in
lose; there were no ill effects.2 treated guinea pigs.
In animal studies of cellulose derivatives, There are no reports of adverse effects in
the only consistent effect of very high doses humans. By analogy to NaOH, the effects from
in the feed appears to be a reduction in the dust or mist could be expected to vary from
nutritional value of the feed, which manifests mild irritation of the upper respiratory tract to
itself as a decrease in body weight gain or an pneumonitis, depending on the severity of the
increase in food consumption.3 Doses up to exposure. The greatest industrial hazard is
5000 mg/kg/body weight/day, or 10% in the rapid tissue destruction of the eyes on contact
diet, have been found to be nontoxic. with the solid or a concentrated solution. If
The 2003 ACGIH threshold limit value- cesium hydroxide is not removed from the skin,
time-weighted average (TLV-TWA) for cellu- it is anticipated that burns will occur after a
lose is 10 mg/m3. period of time. Ingestion would be expected to
cause corrosion of the lips, mouth, tongue, and
pharynx, as well as abdominal pain.
REFERENCES The 2003 ACGIH threshold limit value-
time-weighted average (TLV-TWA) for cesium
1. Cellulose. Documentation of the TLVs and BEIs hydroxide is 2 mg/m3.
for Substances in Workroom Air, 6th ed, pp
241242. Cincinnati, OH, American Confer-
ence of Governmental Industrial Hygienists
(ACGIH), 1991 REFERENCE
2. Schreiber G: Ingested dyed cellulose in the
blood and urine of man. AMA Arch Environ 1. Johnson GT, Lewis TR, Wagner WD: Acute
Health 29:3942, 1974 toxicity of cesium and rubidium compounds.
3. Thomas WC, McGrath LF, Baarson KA, et al: Toxicol Appl Pharmacol 32:239245, 1975
Subchronic oral toxicity of cellulose acetate in
rats. Food Chem Toxicol 29:453458, 1991
CHLORDANE
CESIUM HYDROXIDE CAS: 57-74-9
CAS: 21351-79-1
C10H6C18
CsOH
after single exposures and cumulatively devel- Chlordecone intoxication in man. II. Ultra-
oped from daily repeated, individually inef- structure of peripheral nerves and skeletal
fective doses. In male rats, the oral LD50 was muscle. Neurology 28:631635, 1978
132 mg/kg.5 5. Allied Chemical Corporation: Toxicologi-
Reproductive studies showed that 14 pairs cal studies on decachlorooctahydro-1,3,4-
metheno-2H-cyclobuta[cd] pentalen-2-one
of mice that received 40 ppm chlordecone in
(Compound no. 1189) (Kepone). New York,
the diet for 2 months before mating and during Allied Chemical Corporation, March 1960
the test produced no litters, whereas 14 control 6. Swartz WJ, Mall GM: Chlordecone-induced
pairs produced 14 rst litters and 14 second follicular toxicity in mouse ovaries. Reprod
litters. Further studies in mice found that infer- Toxicol 3:203206, 1989
tility in chlordecone-exposed females was due 7. Laessig SA, Auger AP, McCarthy MM, et al:
to an absence or reduction in the number of Persistent neurobehavioral effects in Sprague-
ovulated oocytes. Prenatal exposure of rats has Dawley rats following prenatal exposure to the
also been shown to persistently alter neurobe- environmental estrogen, chlordecone. Toxicol-
haviors in adults.7 ogist 54(1):266, 2000
Chlordecone is thought to produce some 8. Agency for Toxic Substances and Disease Reg-
istry (ATSDR): Toxicological Prole for Mirex
of its reproductive outcomes by mimicking the
and Chlordecone, 343pp. US Department of
effects of excessive estrogens. The ability to Health and Human Services, Public Health
cause constant estrus and other estrogen-like Service, 1995
effects has been repeatedly conrmed in
rodents.3
Gestational exposure of rats and mice
caused embryo-/fetotoxicity and teratogenicity
at doses that were severely toxic to dams.8
Dermal exposure of male rabbits has been CHLORINATED DIBENZO-p-DIOXINS
reported to cause testicular atrophy.8 CAS: 1746-01-6 (2,3,7,8-TCDD)
Chronic exposure of mice and rats caused
an increase in liver tumors.8 Chlordecone is not C12H4Cl4O2
considered to be genotoxic but may act as a
tumor promoter.8
Chlordecone in blood is a good biomarker Synonyms: Chlorinated dibenzo-p-dioxins
of exposure because of chlordecones associa- (CDDs) are a family of 75 different compounds
tion with plasma proteins and its long half-life.7 commonly referred to as polychlorinated
The ACGIH has not established a thresh- dioxins. The CDD family is divided into eight
old limit value for chlordecone. groups of chemicals based on the number of
chlorine atoms in the compound. The groups
with two through eight chlorine atoms are
REFERENCES called dichlorinated dioxin (DCDD), trichlori-
nated dioxin (TrCDD), tetrachlorinated dioxin
1. Bureau of National Affairs: OSHA cites chem- (TCDD), pentachlorinated dioxin (PeCDD),
ical manufacturer, labels Kepone exposure hexachlorinated (HxCDD), heptachlorinated
catastrophe. Occup Safety Health Rep 5: dioxin (HpCDD), and octachlorinated dioxin
379380, 1975 (OCDD). The chlorine atoms can be attached
2. Bureau of National Affairs: Allied, Hooker
at any of eight positions. The name of each
Chemical rms named as defendants in
CDD indicates both the number and positions
worker suit. Occup Safety Health Rep 5:516517,
1975 of the chlorine atoms. For example, the CDD
3. Hayes WJ Jr, Laws ER Jr: Handbook of Pesticide with four atoms at positions 2,3,7, and 8 on the
Toxicology, Vol 2, Classes of Pesticides. New dioxin molecule is 2,3,7,8-TCDD, which is one
York, Academic Press,, pp 860869, 1991 of the most toxic of the CDDs to mammals and
4. Martinez AJ, Taylor JR, Dyck PJ, et al: the one that has received the most attention.
CHLORINATED DIBENZO-p-DIOXINS 135
Physical Form. Colorless solids or crystals years after initial onset.4,6 In some cases lesions
have resolved temporarily and then returned.
Sources. CDDs occur naturally and are also Scarring may result from the healing process.
produced by human activities.1 They are natu- Other skin effects have also been noted to
rally produced by the incomplete combustion accompany chloracne, such as hyperpigmenta-
of organic material by forest res and volcanic tion and hirsuitism (also known as hypertri-
action. CDDs may be formed during the chlo- chosis or abnormal distribution of hair).7
rine gas bleaching process formerly used by Peripheral and central nervous system
pulp and paper mills. They occur as contami- effects have been reported in case reports and
nants in the manufacturing process of certain epidemiological studies from exposure to
chlorinated organic compounds, such as CDDs and are associated with signs and symp-
chlorinated phenols. 2,3,7,8-TCDD is a toms of both central and peripheral nervous
by-product of the production of 2,4,5- system effects shortly after exposure. In some
trichlorophenol (2,4,5-TCP), which was used cases, the effects lasted several years. However,
to produce hexachlorophene, and 2,4,5- evaluation of individuals 537 years after the
trichlorophenoxyacetic acid (2,4,5-T, a compo- last exposure has not indicated any long-lasting
nent of the herbicide Agent Orange). Other abnormalities.8
chlorinated chemicals such as pentachlorophe- The IARC has classied 2,3,7,8-TCDD as
nol (PCP), used to preserve wood, do contain a Group I carcinogen, that is, an agent car-
some of the more highly chlorinated CDDs, cinogenic to humans.9 Statistically signicant
but not usually 2,3,7,8-TCDD. Currently, increases for all cancers were found in highly
CDDs are primarily released to the environ- exposed workers with longer latency periods.
ment during combustion of fossil fuels (coal, Although the standard mortality ratio (SMR)
oil, and natural gas) and wood and during values are low, they are consistent across
incineration processes (municipal and medical studies with the highest exposures, with a SMR
solid waste and hazardous waste). of 1.4. The evidence for site-specic cancers is
weaker, with suggestion of a possible relation-
Exposure. Ingestion; inhalation; skin contact ship between soft tissue sarcoma, non-Hodgkin
lymphoma, or respiratory tract cancer.. The
Toxicology. Chlorinated dibenzo-p-dioxins most important studies for the evaluation of
(CDDs) cause chloracne, may cause hepato- carcinogenicity were four cohort studies of
toxicity, immunotoxicity, reproductive toxicity, herbicide producers (one each in the United
developmental toxicity, and central nervous States and Netherlands, two in Germany) and
system toxicity, and are considered to be a one cohort of residents in a contaminated area
human carcinogen. in Seveso, Italy. The carcinogenicity of CDDs
The most obvious health effect in humans has been demonstrated in several animal
for exposure to CDDs is chloracne, a severe studies.
skin disease characterized by follicular hyperk- There is suggestive but inconclusive evi-
eratosis (comedones) occurring with or without dence of adverse cardiovascular effects in
cysts and pustules.24 Unlike adolescent acne, humans exposed to relatively high concentra-
chloracne may affect almost every follicle in an tions of CDDs.10 Increased deaths from
involved area, and it may be more disguring chronic heart disease were observed in the
than adolescent acne.5 Seveso cohort, but psychosocial factors could
Chloracne generally appears on the face not be ruled out. No clear dose-response rela-
and upper body but may extend to the upper tionships were seen among the Ranch Hand
arms, back, chest, abdomen, outer thighs, and cohort. Increased deaths from heart and circu-
genitalia. In milder cases, the lesions heal latory disease were reported among German
several months after exposure ends. In more workers exposed to CDDs. No evidence of
severe cases, the lesions may last for many years adverse cardiovascular effects was observed in
after exposure and have been observed up to 30 US workers.
136 CHLORINATED DIBENZO-p-DIOXINS
10. Bertazzi PA et al: Mortality in an area con- Love Canal. Fundam Appl Toxicol 12:303,
taminated by TCDD following an industrial 1989
accident. Med Lav 80:316, 1989 24. Viluksela M et al: Subchronic/chronic toxic-
11. Webb KB, et al: Medical evaluation of sub- ity of a mixture of four chlorinated dibenzo-
jects with known body levels of 2,3,7,8- p-dioxins in rats. I. Design, general
tetrachlorodibenzo-p-dioxin. J Toxicol observations, hematology, and liver concen-
Environ Health 28(2):183193, 1989 trations. Toxicol Appl Pharmacol 151:57, 1998
12. Pirkle J et al: Estimates of the half- 25. Viluksela M et al: Subchronic/chronic toxic-
life of 2,3,7,8-tetrachlorodibenzo-p-dioxin ity of a mixture of four chlorinated Dibenzo-
in Vietnam veterans of Operation Ranch p-dioxins in rats. II. Biochemical effects.
Hand. J Toxicol Environ Health 27:165, Toxicol Appl Pharmacol 151:70, 1998
1989
13. Michalck JE et al: Pharmacokinetics of
TCDD in veterans of Operation Ranch
Hand: 10 year follow-up. J Toxicol Environ
Health 47:209, 1996
14. Furst P et al: PCDD and PCDF levels in CHLORINATED DIPHENYL OXIDE
human milkdependence on the period of CAS: 55720-99-5
lactation. Chemosphere 18:439, 1989
15. Furst P et al: Human milk as a bioindicator C6H2Cl3OC6H2Cl (approximate)
for body burden of PCDDs, PCDFs, organo-
chlorine pesticides, and PCBs. Environ Health
Perspect 102:187, 1994
Synonyms: Chlorinated phenyl ethers; mono-
16. Schwetz BA et al: Toxicology of chlorinated
chlorodiphenyl oxide, dichlorodiphenyl oxide,
dibenzo-p-dioxins. Environ Health Perspect
5:87, 1973 etc., through hexachlorodiphenyl oxide
17. Olson JR et al: Toxicity of 2,3,7,8-
tetrachlorodibenzo-p-dioxin in the Golden Physical Form. Varies from colorless, oily
Syrian Hamster. Toxicol Appl Pharmacol 55:67, liquids to yellowish, waxy semisolids as the
1980 equivalents of chlorine increase from 1 to 6
18. Li X et al: Reproductive effects of 2,3,7,8-
tetrachlorodibenzo-p-dioxin (TCDD) in Uses. Chemical intermediates; in the electri-
female rats: Ovulation, hormonal regulation cal industry
and possible mechanisms. Toxicol Appl Phar-
macol 133:321, 1995
Exposure. Inhalation, skin absorption
19. Li X et al: Effects of 2,3,7,8-
tetrachlorodibenzo-p-dioxin (TCDD) on
estrous cyclicity and ovulation in female Toxicology. Chlorinated diphenyl oxide
Sprague-Dawley rats. Toxicol Lett 78:219, causes an acneform dermatitis (chloracne).
1995 Limited experience with humans has
20. Moore RW et al: Androgenic deciency shown that exposure to even small amounts of
in male rats treated with 2,3,7,8- the higher chlorinated derivatives, particularly
tetrachlorodibenzo-p-dioxin. Toxicol Appl hexachlorodiphenyl oxide, may result in ap-
Pharmacol 79:99, 1985 preciable acneform dermatitis.1 Chloracne
21. Barnes DG: Toxicity equivalents and EPAs is usually persistent and affects the face, ears,
risk assessment of 2,3,7,8-TCDD. Sci Total neck, shoulders, arms, chest, and abdomen
Environ 104:73, 1991.
(especially around the umbilicus and on the
22. Eadon G et al: Calculation of 2,3,7,8-
scrotum). The most sensitive areas are below
TCDD equivalent concentrations of complex
environmental contaminant mixtures. and to the outer side of the eye (malar crescent)
Environ Health Perspect 70:2217, 1986 and behind the ear.2 The skin is frequently dry
23. Silkworth JB et al: Immunotoxicity of with noninammatory comedones and pale
2,3,7,8-tetrachlorodibenzo-p-dioxin in a yellow cysts containing sebaceous matter and
complex environmental mixture from the keratin.
138 CHLORINE
No cases of systemic toxicity have been Uses. Metal uxing; sterilization of water
reported in humans. supplies and swimming pools; bleaching agent;
In laboratory animals, cumulative liver synthesis of chlorinated organic chemicals and
damage has resulted from repeated intake, and, plastics; pulp and paper manufacturing;
in general, the toxicity increases with the detinning and dezincing iron
degree of chlorination. Liver injury is char-
acterized by congestion and varying degrees Exposure. Inhalation
of fatty degeneration. In animals, these com-
pounds cause severe skin irritation with topical Toxicology. Chlorine is a potent irritant of
application.3 Animal experiments suggest that the eyes, mucous membranes, and skin; pul-
absorption from dermal application can result monary effects range from respiratory irrita-
in systemic toxicity, including liver injury and tion to edema. Chlorine reacts with tissue
weight loss. In guinea pigs, a single oral dose water to form hydrochloric and hypochlorous
of 0.050.1 g/kg of material containing four or acids.
more equivalents of chlorine resulted in death Mild mucous membrane irritation may
30 days after administration.1 occur at 0.216 ppm; eye irritation occurs
The 2003 ACGIH threshold limit value- at 78 ppm, throat irritation at 15 ppm, and
time-weighted average (TLV-TWA) for chlo- cough at 30 ppm.1 Toxic pneumonitis and
rinated diphenyl oxide is 0.5 mg/m3. pulmonary edema can be expected at 40
60 ppm. A level of 430 ppm is lethal after
30 minutes, and 1000 ppm is fatal after a few
REFERENCES
deep breaths.1,2 Other studies have shown that
1. Kirwin CJ Jr, Sandmeyer EE: Ethers. In at least some subjects develop eye irritation,
Clayton GD, Clayton FE (eds): Pattys Indus- headache, and cough at concentrations as low
trial Hygiene and Toxicology, 3rd ed, rev, Vol 2A, as 12 ppm.
Toxicology, pp 25462551. New York, Wiley- The location and the severity of respira-
Interscience, 1981 tory tract involvement are functions of both the
2. Crow KD: Chloracne (halogen acne). In concentration and the duration of exposure.
Marzulli FN, Maibach HI (eds): Dermatotoxi- With signicant exposures, laryngeal edema
cology, 2nd ed, pp 462470. New York, Hemi- with stridor, acute tracheobronchitis, and
sphere Publishing, 1983 chemical pneumonitis have been described.3
3. von Oettingen WF: The Halogenated Aliphatic,
Death at high exposure is mainly from respira-
Olenic, Cyclic, Aromatic, and Aliphatic-Aromatic
tory failure or cardiac arrest due to toxic pul-
Hydrocarbons Including the Halogenated Insecti-
cides, Their Toxicity and Potential Dangers. US monary edema.4 Bronchopneumonia may be a
Public Health Service Pub No 414, pp potentially lethal complication. In one acci-
311313. Washington DC, US Government dent, exposure of humans to unmeasured but
Printing Ofce, 1955 high concentrations for a brief period of time
caused burning of the eyes with lacrimation,
burning of the nose and mouth with rhinor-
rhea, cough, choking sensation, and substernal
CHLORINE pain.5 These symptoms were frequently
CAS: 7782-50-5 accompanied by nausea, vomiting, headache,
dizziness, and sometimes syncope. Of 33
Cl2 victims who were hospitalized, all suffered tra-
cheobronchitis, 23 progressed to pulmonary
edema, and, of those, 14 progressed to pneu-
Synonyms: None monitis.3 Respiratory distress and substernal
pain generally subsided within the rst 72
Physical Form. Greenish-yellow gas with an hours; cough increased in frequency and sever-
irritating odor ity after 23 days and became productive of
CHLORINE 139
thick mucopurulent sputum; cough disap- difference, and respiratory alkalosis. Mild tran-
peared by the end of 14 days. sient hyperchloremic metabolic acidosis, with
In another accidental exposure of ve chlo- a normal anion gap, has been described in a
rine plant workers and 13 nonworkers, rales, patient after chlorine inhalation, presumably
dyspnea, and cyanosis were observed in the related to systemic absorption of hydrochloric
most heavily exposed and cough was present in acid.10
nearly all the patients. Pulmonary function Some studies of survivors of massive
tests 2448 hours after exposure showed airway chlorine exposures have shown either persist-
obstruction and hypoxemia; these conditions ent obstructive or restrictive decits, but pre-
cleared within 3 months except in four of the exposure data on these patients were not
chlorine workers, who still showed reduced available. Persistent respiratory symptoms,
airway ow and mild hypoxemia after 1214 bronchial obstruction, and bronchial hyperre-
months.6 sponsiveness were observed in 82%, 23%, and
After acute exposures to chlorine gas, both 41 % of chronically exposed pulp mill workers,
obstructive and restrictive abnormalities on respectively, 1824 months after cessation of
pulmonary function tests have been observed. exposure.11 In most cases it is not known
Eighteen healthy subjects exposed after a leak whether prolonged symptoms after chlorine
from a liquid storage tank had diminished exposure are due to aggravation of preexisting
FEV1, FEF 2575%, and other ow rates conditions such as tuberculosis, asthma,
within 18 hours of exposure. Follow-up studies chronic obstructive pulmonary disease, or
at 1 and 2 weeks demonstrated resolution of heart disease.12,13
these abnormalities in the 12 subjects with an In high concentrations, chlorine irritates
initial chief complaint of cough, whereas the 6 the skin and causes sensations of burning and
subjects with a chief complaint of dyspnea had pricking, inammation, and vesicle forma-
persistently reduced ow rates. Repeat studies tion.12 Liquid chlorine causes eye and skin
in 5 months were normal in all patients studied burns on contact.14
except for mildly reduced ow rates in two Administered in the drinking water for 2
patients who were smokers.7 years, 0.050.3 mmol/kg/day did not cause a
Of 19 healthy persons exposed in an acci- clear carcinogenic response in rats or mice.15
dent at a pulp mill and tested within 24 hours, In general, animal studies have demon-
10 (53%) had a reduced FEV1 (less than 75%), strated no selective reproductive or teratogenic
and 13 (68%) had increased residual volumes effects of chlorine.2
(greater than 120%), suggesting obstruction The range of reported odor thresholds for
with air trapping. Periodic follow-up testing chlorine is 0.033.5 ppm; however, because of
over the next 700 days demonstrated gradual olfactory fatigue, odor does not always serve as
resolution of these abnormalities in all but an adequate warning of exposure.1
three subjects tested, who had persistently The 2003 ACGIH threshold limit value-
reduced FEV1. Two of these three patients time-weighted average (TLV-TWA) is 0.5 ppm
were smokers.8 In contrast, a study of four (1.5 mg/m3) with a short-term excursion limit
healthy patients exposed to a leak at a swim- of 1 ppm (2.9 mg/m3).
ming pool showed acute mild reductions in
forced vital capacity, total lung capacity, and
diffusing capacity, presumably related to mild
interstitial edema. All lung function impair- REFERENCES
ment was temporary and cleared entirely 1. Committee on Medical and Biological Effects
within one month. There was no residual lung of Environmental Pollutants, National
damage.9 Research Council: Chlorine and Hydrogen
In all of these studies, some subjects Chloride, pp 116123. Washington, DC,
acutely exhibited mild arterial hypoxemia, National Academy of Sciences, 1976
increases in alveolar-arterial oxygen tension 2. International Programme on Chemical
140 CHLORINE DIOXIDE
REFERENCES
CHLORINE TRIFLUORIDE
CAS: 7790-91-2 1. Horn HJ, Weir RJ: Inhalation toxicology of
chlorine triuoride. I. Acute and subacute
ClF3 toxicity. AMA Arch Ind Health 12:515521,
1955
2. Horn HJ, Weir RJ: Inhalation toxicology of
Synonym: Chlorine uoride chlorine triuoride. II. Chronic toxicity. AMA
Arch Ind Health 13:340345, 1956
Physical Form. Colorless gas, pale green 3. Boysen JE: Health hazards of selected rocket
propellants. Arch Environ Health 7:7175, 1963
liquid, or white solid
4. Dost FN, Reed DJ, Smith VN, Wang CH:
Toxic properties of chlorine triuoride. Toxicol
Uses. Fluorinating agent; incendiary; igniter Appl Pharmacol 27:527536, 1974
and propellant for rockets; in nuclear reactor
fuel processing; pyrolysis inhibitor for uoro-
carbon polymers
value (C-TLV) for chloroacetone is 1 ppm Sporadic cases of dermatitis due to primary
(3.8 mg/m3) with a notation for skin absorption. irritation by a-chloroacetophenone have been
reported.3,4 Allergic contact dermatitis to this
substance in chemical Mace has been docu-
REFERENCES mented by patch test evaluation, and it is said
to be a potent skin sensitizer.3,4
1. Sargent EV, Kirk GD, Hite M: Hazard evalu- Eye splashes cause marked conjunctivitis
ation of monochloroacetone. Am Ind Hyg Assoc and may result in permanent corneal damage.5
J 47:375378, 1986 The lacrimation threshold ranges from 0.3 to
2. Anonymous: Monochloraceton. Berater-
0.4 mg/m3, and the odor threshold is
gremium fuer umweltrelevante Altstoffe (BUA)
0.1 mg/m3.5
Vol 226, 71pp, 2001
In 14-day studies rats exposed to 4.8 mg/m3
showed excessive lacrimation, partial closure of
the eyelids, dyspnea, erythema, and weight
loss.6 During the rst week of exposure, a con-
centration of 19 mg/m3 was lethal to all rats
a-CHLOROACETOPHENONE whereas 10 mg/m3 was lethal to mice. In 2-year
CAS: 532-27-4 inhalation studies there was no evidence of car-
cinogenicity to mice exposed to 2 or 4 mg/m3
C6H5COCH2Cl or in male rats exposed to 1 or 2 mg/m3; equiv-
ocal evidence of carcinogenicity was present
in exposed female rats based on a marginal
Synonyms: 2-Chloro-1-phenylethanone; increase in broadenomas of the mammary
phenacyl chloride; phenyl chloromethyl gland.6 2-Chloroacetophenone was not muta-
ketone; tear gas; chemical Mace genic in bacterial assays, nor did it induce sister
chromatid exchanges in Chinese hamster ovary
Physical Form. Crystals (CHO) cells. A slight increase in chromosomal
aberrations was observed.
Uses. Chemical warfare agent (CN); princi- The 2003 ACGIH threshold limit value-
pal constituent in riot control agent Mace; in time-weighted average (TLV-TWA) for a-
tear gas formulations for personal protection chloroacetophenone is 0.05 ppm (0.32 mg/m3).
devices
periods of major organogenesis did not pro- 8. Kluwe WM, Dill G, Persings A, et al: Toxic
duce structural malformations.10 responses to acute, subchronic and chronic
Chlorobenzene was not mutagenic in a oral administrations of monochlorobenzene
variety of bacterial and yeast assays. Existing to rodents. J Toxicol Environ Health
data suggest that genotoxicity may not be an 15:745767, 1985
9. Nair RS, Barter JA, Schroeder RE, et al:
area of concern for chlorobenzene exposure in
A two generation reproduction study with
humans.11 monochlorobenzene vapor in rats. Fundam
Although the odor of chlorobenzene is Appl Toxicol 9:678686, 1987
pronounced and unpleasant, it is not sufcient 10. John JA, Hayes WC, Hanley TR Jr, et al:
to give warning of hazardous concentrations.1 Inhalation teratology study on mono-
The 2003 threshold limit value- chlorobenzene in rats and rabbits. Toxicol Appl
time-weighted average (TLV-TWA) for Pharmacol 76:365373, 1984
chlorobenzene is 10 ppm (46 mg/m3) with 11. Agency for Toxic Substances and Disease
an A3-conrmed animal carcinogen with Registry (ASTDR): Toxicological Prole for
unknown relevance to humans designation. Chlorobenzene. US Department of Health and
Human Services, Public Health Service, TP-
90-06, 1990
REFERENCES
burning sensation and deep pain in the eyes rily in the nasal passages and included hyper-
persisted for 25 minutes. Severe conjunctivi- plasia and squamous metaplasia of the respira-
tis lasted for 2530 minutes, and erythema of tory epithelium.
the eyelids with some blepharospasm was The 2003 ACGIH ceiling-threshold limit
present for 1 hour. There was a burning sensa- value (C-TLV) for o-chlorobenzylidene
tion in the throat with cough, followed by a malononitrile is 0.05 ppm (0.39 mg/m3) with a
constricting sensation in the chest; no therapy notation for skin absorption.
other than removal from exposure was
necessary.
At a concentration of 1.5 mg/m3, three of REFERENCES
four men developed headache during a 90-
minute exposure; one subject developed slight 1. Vaca FE, Myers JH, Langdorf M: Delayed
eye and nose irritation.2 On the skin, the pulmonary edema and bronchospasm after
powder caused a burning sensation, which was accidental lacrimator exposure. Am J Emerg
Med 14(4):402405, 1996
greatly aggravated by moisture; erythema and
2. Punte CL, Owens EJ, Gutentag PJ: Exposure
vesiculation resembling second-degree burns
to ortho-chlorobenzylidene malononitrile.
were produced. Both sensitization and subse- Arch Environ Health 6:366374, 1963
quent allergic contact dermatitis can result 3. Kanerva L, Tarvainen K, Pinola A, et al: A
from a single exposure.3 single accidental exposure may result in a
In animals, the manifestation of lethal tox- chemical burn, primary sensitization and aller-
icity is different after intravenous, intraperi- gic contact dermatitis. Contact Derm 31(4):
toneal, oral, and inhalation routes. After 229235, 1994
intravenous administration, there is rapid onset 4. BallantyneB, Swanston DW: The comparative
of signs characteristic of effects on the nervous acute mammalian toxicity of 1-chloroace-
system due to the alkylating properties of CS.4 tophenone (CN) and 2-chlorobenzylidene
malononitrile (CS). Arch Toxicol 40:7595,
High doses of intraperitoneal CS result in
1978
expression of the cyanogenic potential of the
5. Wild D, Eckhardt K, Harnasch D, et al: Geno-
malononitrile radical. By the oral route, local toxicity study of CS (ortho-chlorobenzylidene-
inammation in the gastrointestinal tract con- malononitrile) in Salmonella, Drosophila and
tributes to toxicity. Lethal toxicity from inhala- mice. Arch Toxicol 54:167170, 1983
tion is due to lung damage leading to asphyxia 6. Marrs TC, Colgrave HF, Cross NL, et al: A
or, in the case of delayed deaths, bronchop- repeated dose study of the toxicity of inhaled
neumonia secondary to respiratory tract 2-chlorobenzylidene malononitrile (CS)
damage. Rats survived a 10-minute exposure at aerosol in three species of laboratory animal.
1800 mg/m3, but 20 of 20 succumbed after Arch Toxicol 52:183198, 1983
60 minutes at 2700 mg/m3. 7. National Toxicology Program: Toxicology and
Carcinogenesis Studies of CS2 (94% o-Chloroben-
o-Chlorobenzylidene malononitrile did
zylidene Malononitrile) in F344/N Rats and
not cause a mutagenic response when tested in
B6C3F1 Mice. Technical Report No. 377.
a variety of assays that examined point muta- National Institutes of Health, Research
tions, germinal gene mutations, chromosomal Triangle Park, NC, 1990
breaks, and mitotic chromosome misdistribu-
tion.5 Although limited, a study of the repeated
inhalation toxicity of CS in mice, rats, and
guinea pigs did not nd a relationship between
tumors in a particular site and total dose of CS.6
F344N rats exposed at 0.075, 0.25, or 0.75 mg/
m3 and B6C3F1 mice exposed at 0.75 or
1.5 mg/m3 6 hours/day, 5 days/week for 2 years
had no compound-related incidences of neo-
plasm.7 Nonneoplastic lesions occurred prima-
CHLOROBROMOMETHANE 149
spray can propellants, refrigerator uids, and nephrosis was seen in male mice and female
pesticides; only small amounts currently pro- rats.
duced for laboratory use In the same 2-year gavage study, chlorodi-
bromomethane signicantly increased the inci-
Exposure. Inhalation; skin absorption; dence of hepatocellular adenomas, as well as
ingestion the combined incidence of hepatocellular ade-
nomas or carcinomas, in the high-dose female
Toxicology. Chlorodibromomethane is a mice. The incidence of hepatocellular carcino-
central nervous system (CNS) depressant at mas was signicantly increased in the high-
extremely high concentrations; it is toxic to dose male mice although the combined
the liver and kidneys of rodents and induces incidence of hepatocellular adenomas or
hepatocellular tumors in mice after long-term carcinomas was only marginally signicant.
exposure. Under the conditions of the gavage studies,
In animal studies, the oral LD50 typically there was no evidence of carcinogenicity in rats
ranges between 800 and 1200 mg/kg.1,2 Acute receiving doses of 40 or 80 mg/kg/day for 2
signs of intoxication include sedation, accid years; there was equivocal evidence of carcino-
muscle tone, ataxia, and prostration; death is genicity in male mice receiving 100 mg/kg/day
due to CNS depression. In cases in which death for 2 years and some evidence of carcinogenic-
does not occur until several days after acute ity in female mice receiving 50 or 100 mg/kg/
exposure, hepatic and renal injury may be the day for 2 years.
cause of death. There was no increase in tumor incidence
It should be noted that in humans oppor- in mice given chlorodibromomethane in drink-
tunities for exposure to acutely lethal doses ing water for life.7
of chlorodibromomethane are remote. In There is no clear epidemiological evidence
animals, no direct effects of oral exposure to for the carcinogenicity of chlorodibro-
chlorodibromomethane have been noted for momethane in humans. However, a number of
the respiratory, cardiovascular, hematologic, or studies suggest an association between chronic
musculoskeletal systems or on the skin or eyes. ingestion of trihalomethanes in chlorinated
One study indicated that short-term oral expo- drinking water and increased risk of bladder or
sure of mice to doses of 125 mg/kg/day could colon cancer.6 These studies cannot provide
produce signicant changes in both the information on whether any observed effects
humoral and the cell-mediated immune are due to chlorodibromomethane or to one or
systems.3 more of the hundreds of other by-products that
In the drinking water of rats, 137 and also are present in chlorinated drinking water.
165 mg/kg/day of chlorodibromomethane for The IARC has determined that there is
90 days produced mild toxicity in the liver; the limited evidence for the carcinogenicity of
observed vacuolar changes due to fatty inltra- chlorodibromomethane in experimental
tion were reversible after a 90-day recovery animals and that it is not classiable as to its
period.4 carcinogenicity to humans.7
Administered by gavage to rats and mice Chlorodibromomethane was not geno-
for 13 weeks, 250 mg/kg/day of chlorodibro- toxic in vivo but gave positive results in a
momethane caused hepatic and renal toxicity in number of in vitro assays.7,8
male and female rats and in male mice.5 Results No teratogenic effects were observed in
of 2-year gavage studies showed fatty meta- rats given 200 mg/kg/day during gestation.9 At
morphosis and cytoplasmic changes in the doses of 685 mg/kg/day, which caused marked
livers of rats receiving up to 80 mg/kg/day; in maternal toxicity, there were signicant
mice receiving up to 100 mg/kg/day of the decreases in litter size, gestational survival, and
chemical, hepatic lesions included necrosis postnatal body weight and survival.10
and hepatocytomegaly in males and calcica- A 2003 ACGIH threshold limit value
tion and fatty change in females.5,6 Evidence of (TLV) has not been established.
152 CHLORODIFLUOROMETHANE
mucous membranes, is toxic to the liver, and A cross-sectional survey of 205 capacitor
causes an acneform dermatitis (chloracne). It is manufacturing workers with a geometric mean
a liver carcinogen in animals. serum PCB level of 18.2 ppb, standard devia-
In humans, systemic effects are anorexia, tion (SD) 2.88, found no statistically signicant
nausea, edema of the face and hands, and correlations between PCB levels and clinical
abdominal pain.1 In a survey of 34 workers chemistry results, including SGOT, GGTP,
exposed to concentrations of up to 2.2 mg/m3, and LDH levels.4 The primary dielectric used
complaints were a burning sensation of the face in the plant was Aroclor 1242. However,
and hands, nausea, and a persistent (uncharac- another cross-sectional survey of 120 railroad
terized) body odor.1 One had chloracne, and transformer workers with mean plasma PCB
ve had an eczematous rash on the legs and levels of 33.4 ppb did reveal statistically signif-
the hands.1 Although hepatic function tests icant correlations of PCB level with serum
were normal, the mean blood level of triglyceride and SGOT (but not SGPT or
chlorodiphenyl in the exposed group was GGTP) levels.5 There was a signicant corre-
approximately 400 ppb, whereas none was lation between self-reported direct dermal
detected in the control group.1 contact with PCBs and the plasma PCB level.
Cases of mild to moderate skin irritation In a survey of 80 heavily exposed capacitor or
and chloracne have been reported in workers transformer manufacturing workers in Italy
exposed to 0.1 mg/m3 for several months. with mean blood PCB levels of about 340 ppb,
Levels of 10 mg/m3 were unbearably irritating, there was a correlation between blood PCB
presumably to mucous membranes and skin.2 levels and abnormal liver ndings (including
Chloracne does not appear to occur at concen- hepatomegaly and increased GGTP, SGOT,
trations below 0.1 mg/m3. and SGPT levels).6 Even in this latter group,
Chloracne usually is persistent and affects except for a few cases of chloracne, no other
the face, ears, neck, shoulders, arms, chest, and symptoms or ndings referable to PCB expo-
abdomen (especially around the umbilicus and sure were present. The biological signicance
on the scrotum). The most sensitive areas are of these generally mild elevations in serum
below and to the outer side of the eye (malar enzymes is also unclear.
crescent) and behind the ear. The skin fre- Industrial hygiene studies support the
quently is dry with noninammatory come- notion that the dermal and dermal/oral, rather
dones and pale yellow cysts containing than the respiratory, routes of exposure are
sebaceous matter and keratin. Evidence of liver the predominant contributors to body burden
disease often is seen in association with PCB- among workers occupationally exposed to
induced chloracne.3 PCBs.7
Some studies of occupationally exposed Serious adverse health effects were attrib-
groups have revealed evidence of liver injury by uted to PCBs after accidental ingestion in 1968
serum enzyme studies or other liver function by over 1000 Japanese people who ingested
tests. Adverse effect and dose-effect relation- PCB-contaminated rice bran oil for a period of
ships have not been consistent within and several months.8,9 The contamination of the
between studies, raising the possibility that oil (estimated 15002000 ppm) occurred when
other factors (e.g., alcohol intake, other expo- heat transfer pipes immersed in the oil during
sures) could be responsible.2 Review of these processing developed pin-sized holes. The
studies indicates that some liver effects may clinical aspects of the poisoning included chlo-
have occurred with repeated exposures at con- racne, brown pigmentation of the skin and
centrations below 0.1 mg/m3, assuming PCBs nails, distinctive hair follicles, increased eye
were responsible. Several deaths due to toxic discharge, swelling of eyelids, transient visual
hepatitis have been reported among workers disturbance, and systemic gastrointestinal
exposed to mixtures of PCBs with chlorinated symptoms with jaundice. In some patients,
naphthalenes; such effects have not been symptoms persisted 3 years after PCB exposure
observed with PCB exposure alone.2 was discontinued. Infants born to poisoned
CHLORODIPHENYL, 42% CHLORINE 155
mothers had decreased birth weights and different times in both plants. Although the
showed skin discoloration. Chemical analysis workers studied had positions involving greater
of the contaminated rice bran oil revealed exposure to PCBs than other workers in
signicant amounts of polychlorinated diben- the plants, historical levels of exposure were
zofurans (PCDFs) as well as PCBs.10 High con- unknown. Four of the ve cases of liver and
centrations of PCDFs were found in blood and biliary tract cancer occurred in women in plant
adipose tissue of Yusho victims. In contrast, in two. All ve workers were rst employed in the
a group of workers occupationally exposed to 1940s and early 1950s, when exposures were
PCBs, PCB levels were higher than in the presumed to be the highest, however, analysis
Yusho victims but PCDFs were not generally did not reveal that risk was associated with time
detected.10,11 Animal experiments have repro- since rst employment or length of employ-
duced some ndings seen in Yusho victims ment in PCB-exposed jobs. The small
with administration of PCDFs but not PCBs. number of cases was also noted.14
Thus it appears that PCDFs were the main A signicant excess risk of death from
causative agents in the induction of Yusho malignant melanoma (8 observed, 2.0
disease.10,11 expected) was observed in a cohort study of
Epidemiological studies have suggested an 3588 capacitor manufacturing workers exposed
association between occupational exposures to to Aroclor 1242 and then 1016.15
PCBs and cancer at several sites, particularly All PCB mixtures adequately tested in
the liver, biliary tract, intestines, and skin mice and rats have shown carcinogenic activ-
(melanoma).12 A cohort study of 544 male and ity.2 For example, of 20 rats fed Aroclor 1242
1557 female workers employed between 1946 at 100 ppm in the diet for 24 months, 11 devel-
and 1978 in an Italian capacitor manufacturing oped liver tumors, of which 3 were hepatomas.
plant using PCB mixtures (with 54%, then A signicant incidence of hepatocellular neo-
42% chlorine) found statistically signicant plasms was found in female rats but not males
excesses of total cancer deaths in males (14 obs. in another study of Arochlor 1242 in the diet.16
vs. 7.6 exp.) and females (12 obs. vs. 5.3 exp.), Evidence from bioassays suggests that the less
cancer of the gastrointestinal tract in males (6 highly chlorinated PCBs (e.g., Aroclor 1242)
obs. vs. 2.2 exp.) and hematologic neoplasms in have less carcinogenic potential than the more
females (4 obs. vs. 1.1 exp.)13 Of the six gas- highly chlorinated mixtures (e.g., Aroclor
trointestinal tract malignancies in males, the 1254).2
primary sites were stomach (2), pancreas (2), A number of agencies have determined
liver (1), and biliary tract (1). There was an that there is sufcient evidence of carcino-
excess of hematologic neoplasms in males (3 genicity in experimental animals for PCBs and
obs. vs. 1.1 exp.), but this excess was not statis- that they are a probable human carcinogen.12
tically signicant. The authors qualied their The genotoxicity of PCBs has been tested
conclusions regarding excess malignancies in in vivo and in vitro studies with generally
because of the small number of deaths in the negative results.12
cohort, the occurrence of some tumors in Reproductive effects in animals have
workers with minimal exposure or short included reduced implantation rate and pro-
latency intervals, and the disparate sites and longed estrus in rats and prolonged menstrua-
types of tumors. tion and decreased fertility in monkeys.12 In
An update of a retrospective cohort mor- male rats and mice gestational or lactational
tality study of 2588 US workers exposed to exposure can adversely affect sperm morphol-
PCBs in two capacitor manufacturing plants ogy and production. Comparison of the repro-
found a statistically signicant excess for cancer ductive histories of 200 women exposed to
of the liver and biliary passages [5 observed PCBs during the production of capacitors with
vs. 1.9 expected, standardized mortality ratio the histories of controls showed only a slight
(SMR) 263]. Both Aroclor 1254 (54% chlorine) relationship between estimated PCB levels in
and 1242 (42% chlorine) had been used at serum and decreased birth weight.17
156 CHLORODIPHENYL, 54% CHLORINE
membranes. It is toxic to the liver of animals, rats exposed at concentrations ranging from 25
and severe exposure may produce a similar to 200 ppm for 24 months; a small increase was
effect in humans. It also causes an acneform noted in the incidence of thyroid gland follic-
dermatitis (chloracne). It is a liver carcinogen ular cell adenomas in males.6 The tumors that
in animals. were produced were mostly benign and did not
Note. For a full description of the toxicol- curtail the natural life span of the animals. Evi-
ogy of this compound, see the entry for dence from bioassays suggests that the more
chlorodiphenyl, 42% chlorine immediately highly chlorinated PCBs (e.g., Arochlor 1254)
preceding this entry. Special characteristics have more carcinogenic potential than the less
of the 54% chlorine compound are given highly chlorinated mixtures (e.g., Arochlor
below. 1242).5
Rats exposed to 5.4 mg/m3 of the 54% Mortality studies provide suggestive evi-
chlorine compound for 7 hours daily for 4 dence that occupational exposure to PCBs
months showed increased liver weight and containing 54% chorine are associated with
injury to liver cells; 1.5 mg/m3 for 7 months cancer at several sites, particularly liver, biliary
also produced histopathologic evidence of liver tract, intestines, and skin.7
damage, which was considered to be of a Arochlor 54 was not mutagenic in Salmo-
reversible character.1 The minimal lethal dose nella assays; it was not genotoxic in rodent
when the liquid was applied to the skin of assays in vivo.7
rabbits was 1.5 g/kg.2 The vapor and the liquid Adverse reproductive effects have been
are moderately irritating to the eye; contact of observed in animals fed PCB in the diet.1 Fetal
the chemical with skin leads to removal of resorptions were common, and dose-related
natural fats and oils, with subsequent drying incidences of terata were found in pups and
and cracking of the skin.2 piglets when females were fed Arochlor 1254
After application of radiolabeled PCB, at 1 mg/kg/day or more. Long-term low-level
54% chlorine, to the skin of guinea pigs, 56% maternal exposure of rats before breeding and
of the applied dose was absorbed.3 throughout gestation and lactation caused
Administration of a PCB mixture (mean permanent hearing decits, decreased serum
chlorine content 54%) twice a week for 6 weeks thyroid hormones, and reproductive effects.8
via a stomach tube to rats at relatively low dose PCBs have been observed in human cord
levels led to histopathologic changes in the blood and in tissues of newborn humans and
liver, increases in cholesterol and triglyceride animals.1
levels, and serum enzyme increases. At the The 2003 threshold limit value-time-
2 mg/kg dose, centrilobular hepatic necrosis weighted average (TLV-TWA) is 0.5 mg/m3
and elevated cholesterol levels were observed. with a notation for skin and an A3-conrmed
Increases in bilirubin and triglyceride levels animal carcinogen with unknown relevance to
occurred only at 50 mg/kg and increases in humans designation.
SGOT (AST) and SGPT (ALT) only at doses
above 50 mg/kg.4
All PCB mixtures adequately tested in REFERENCES
mice and rats have shown carcinogenic activ-
ity.1 For example, hepatomas developed in 9 of 1. Treon JF, Cleveland FP, Cappel JW, Atchley
22 BALB/cj male mice fed Arochlor 1254 at RW: The toxicity of the vapors of Arochlor
1242 and Arochlor 1254. Am Ind Hyg Assoc Q
300 ppm for 11 months.5 Of 27 rats fed
17:204213, 1956
Arochlor 1254 at 100 ppm in the diet for 24
2. Hygienic Guide Series: Chlorodiphenyls. Am
months, 19 developed liver tumors, 6 of which Ind Hyg Assoc J 26:9294, 1965
were hepatomas, compared with 1 neoplastic 3. Werter RC et al: Polychlorinated biphenyls
nodule in 23 controls. A dose-dependent (PCBs): Dermal absorption, systemic elimina-
increase in liver tumors and a decrease in tion, and dermal wash efciency. J Toxicol
mammary gland tumors was observed in female Environ Health 12:511519, 1983
158 CHLOROFORM
Evidence for the carcinogenicity of chlo- appear to protect somewhat against chloroform
roform in experimental animals after chronic toxicity.1
oral administration includes statistically sig- The 2003 ACGIH threshold limit value-
nicant increases in renal epithelial tumors in time-weighted average (TLV-TWA) for
male rats, hepatocellular carcinomas in mice, chloroform is 10 ppm (49 mg/m3) with an A2-
and renal tumors in male mice.79 In these suspected human carcinogen designation.
studies, the carcinogenicity of chloroform is
organ specic to primarily the liver and
kidneys; these organs also are the target of
acute chloroform toxicity and covalent binding REFERENCES
by reactive intermediates (phosgene, carbene,
1. US Environmental Protection Agency:
chlorine ion) of chloroform metabolism.1
Health Assessment Document for Chloroform.
Typically, doses of chloroform that do not Final report. Washington, DC, Ofce of
produce necrosis are not carcinogenic. This Health and Environmental Assessment,
suggests that the increased proliferation of September 1985
liver and kidney cells during regeneration 2. National Institute for Occupational Safety
after necrosis may be involved in the develop- and Health: Criteria for a Recommended
ment of tumors.5,10 Furthermore, most studies Standard . . . Occupational Exposure to Chloro-
suggest that chloroform is not genotoxic, sup- form. DHEW (NIOSH) 75114. Washing-
porting the case for an epigenetic mechanism ton DC, US Government Printing Ofce,
of carcinogenicity. Chloroform also possesses 1974
3. Challen PJ, Hickish DE, Bedford J: Chronic
antitumorigenic properties when administered
chloroform intoxication. Br J Ind Med 15:
in the drinking water of animals previously
243249, 1958
treated with the hepatocarcinogens ethylni- 4. Winslow SG, Gerstner HB: Health aspects
trosourea and ethylnitrosamine or 1,2- of chloroforma review. Drug Chem Toxicol
dimethylhydrazine, a gastrointestinal tract 1:259275, 1978
carcinogen.11 5. Agency for Toxic Substances and Disease
Small increases in rectal, bladder, and Registry (ATSDR): Toxicological Prole for
colon cancer have been observed in several Chloroform, 294pp. US Department of Health
studies of human populations with chlorinated and Human Services, Public Health Service,
drinking water. Because other possible car- 1997
cinogens were present along with chloroform, 6. Mery S, Larson JL, Butterworth BE, et al:
Nasal toxicity of chloroform in male F-344
it is impossible to identify chloroform as the
rats and female B6C3F1 mice following a
sole carcinogenic agent. On the basis of suf-
1-week inhalation exposure. Toxicol Appl
cient animal evidence and limited epidemio- Pharmacol 125:214227, 1994
logical evidence, the IARC regards chloroform 7. National Cancer Institute (NCI). Report on
as a probable human carcinogen.12 Carcinogenesis Bioassay of Chloroform. PB-
In animals, chloroform causes some fetal 264018. Springeld, VA, National Technical
loss and delays in fetal development when Information Service, 1976
administered during gestation at levels of 8. Jorgenson TA, Meierhenry EF, Rushbrook
100 ppm or more.13 Teratogenic effects such as CJ, et al: Carcinogenicity of chloroform in
cleft palate were observed in the mouse only at drinking water to male Osborne Mendel rats
doses associated with maternal toxicity.14 and female B6C3F1 mice. Fundam Appl
Toxicol 5:760769, 1985
Several substances alter the toxicity of
9. Roe FJC, Palmer AK, Worden AN: Safety
chloroform in animalsmost probably by
evaluation of toothpaste containing chloro-
modifying the metabolism to a reactive inter- form. I. Long-term studies in mice. J Environ
mediate.1 Factors that potentiate chloroforms Pathol Toxicol 2:799819, 1979
toxic effects include ethanol, polybrominated 10. Hard GC, Boorman GA, Wolf DC: Re-
biphenyls, steroids, and ketones. Disulram, evaluation of the 2-year chloroform drinking
its metabolites, and a high-carbohydrate diet water carcinogenicity bioassay in Osborne-
160 bis(CHLOROMETHYL)ETHER
Mendel rats supports chronic renal tubule chemist by BCME has been reported.1
injury as the mode of action underlying the Increased frequency of chronic cough and low
renal tumor response. Toxicol Sci 53(2):237 end-expiratory ow rates has been described to
44, 2000 occur in a dose-related fashion with exposure
11. Daniel FB, DeAngelo AB, Stober JA, et al: to BCME and chloromethyl methyl ether
Chloroform inhibition of 1,2-dimethylhy-
(CMME).2
drazine-induced gastrointestinal tract tumors
in the Fisher 344 rat. Fundam Appl Toxicol 13: A retrospective study of 136 BCME
4045, 1989 workers employed at least 5 years revealed 5
12. IARC Monographs on the Evaluation of the Car- cases of lung cancer, which represented a nine-
cinogenic Risk of Chemicals to Humans, Vol 73, fold increase in lung cancer risks; 0.54 cases
Some chemicals that cause tumours of the would have been expected to occur in the plant
kidney of urinary bladder in rodents, and population.3 The predominant histologic type
some other substances, pp 131182. Lyon, of carcinoma was small cell undifferentiated.
International Agency for Research on Exposure ranged from 7.5 to 14 years, and the
Cancer, 1999 mean induction period was 15 years. In addi-
13. Murray FA, Schwetz BA, McBride JB, et al: tion, abnormal sputum cytology was observed
Toxicity of inhaled chloroform in pregnant
in 34% of 115 current workers with exposure
mice and their offspring. Toxicol Appl Phar-
macol 50:515522, 1979 to BCME for 5 or more years, as contrasted
14. Schwetz BA, Leong BKJ, Gehring PJ: with 11% in a control group.
Embryo- and fetotoxicity of inhaled chloro- In another study, 6 cases of lung cancer
form in rats. Toxicol Appl Pharmacol 25: occurred among 18 technical department
442451, 1974 workers, a group known to experience very
high BCME exposure; other cases of lung
cancer were reported among 50 production
workers.4 Oat cell carcinomas occurred in ve
of eight cases.
bis(CHLOROMETHYL)ETHER BCME is also found as an impurity (17%)
CAS: 542-88-1 in the related CMME. Fourteen cases of lung
cancer, mainly of oat cell type, were reported
ClCH2OCH2Cl in a chemical plant where exposure to CMME
occurred.5 In the reported epidemiological
studies, insufcient evidence is available to
Synonyms: BCME; chloromethyl ether; separate the carcinogenic effects of the two
chloro(chloromethoxy)methane; dichloro- compounds.6
methyl ether; symmetrical dichloro-dimethyl A follow-up of CMME (BCME) workers
ether; dimethyl-11-dichloroether found no increased risk of respiratory cancer
among those exposed less than 1 year to a 12-
Physical Form. Colorless liquid fold increase among those exposed 10 years or
more.7 Latency did not appear to be inversely
Uses. Chemical intermediate related to dose but, instead, peaked at approx-
imately 20 years from initial exposure. After
Exposure. Inhalation; skin absorption 30 years of observation 25 of 67 deaths in
CMME (BCME)-exposed chemical workers
To x i c o l o g y. b i s ( C h l o r o m e t h y l ) e t h e r were due to lung cancer (80% small cell carci-
(BCME) is a mucous membrane and respira- noma). Standardized mortality ratios were
tory irritant; it is a recognized human elevated among the moderately and heavily
carcinogen. exposed workers and peaked at 23.1 the rst
In humans, concentrations of 3 ppm are decade and then declined to 7.4 and 7.9 in later
reported to be distinctly irritating. A fatal case decades.8
of accidental acute poisoning of a research A cohort study of 1203 workers at an ion-
bis(CHLOROMETHYL)ETHER 161
exchange resin manufacturing plant in France pp C-25, C-27. Springeld, VA, NTIS
found a rate ratio of 5.5 for lung cancer for (USEPA), 1980
CMME (containing BCME)-exposed workers 2. Weiss W: Chloromethyl ethers, cigarettes,
compared with unexposed workers. There cough and cancer. J Occup Med 18:194199,
were 11 cases of lung cancer (10 small cell car- 1976
3. Lemen RA, Johnson WM, Wagoner JK, et al:
cinoma) among the 258 exposed workers vs. 8
Cytologic observations and cancer incidence
cases of lung cancer(1 small cell carcinoma) in following exposure to BCME. Ann NY Acad
the unexposed.9 Sci 271:7180, 1976
Features implicating BCME as the primary 4. Theiss AM, Hay W, Zeller H: Zur
causative carcinogenic agent in human studies Toxikologie von Dichlorodimethylather
include: a) early age at death, b) development Verdacht, auf kanzerogene Wirking
of lung cancer among nonsmokers as well as auch beim Menschen. (Toxicology of
cigarette smokers, and c) unusual histologic bis(chloromethyl)ethersuspicion of car-
type-small cell or oat cell carcinoma, rather cinogenicity in man.) Zentralbl Arbeitsmed
than the squamous cell carcinoma common 23:97102, 1973
among male smokers. 5. Figueroa WG, Raszkowski R, Weiss W:
Lung cancer in chloromethyl methyl ether
Exposure to 1 ppm for 6 hours/day, 5
workers. N Engl J Med 288:10961097,
days/week for 82 days caused lung tumors in 26 1973
of 47 animals, with an average of 5.2 tumors 6. IARC Monographs on the Evaluation of the
per tumor-bearing animal; 20 of 49 controls Carcinogenic Risk of Chemicals to Man, Vol 4,
developed lung tumors, with 2.2 tumors per Some aromatic amines, hydrazine and related
tumor-bearing animal.10 In 19 rats exposed to substances, N-nitroso compounds and mis-
0.1 ppm BCME 6 hours/day for 101 exposures, cellaneous alkylating agents, pp 231238.
ve squamous cell carcinomas of the lung and Lyon, International Agency for Research on
ve esthesioneuroepitheliomas arising from Cancer, 1974
the olfactory epithelium were observed.11 7. Maher KV, DeFonso LR: Respiratory cancer
Cutaneous application of 2 mg of BCME to among chloromethyl ether workers. J Natl
Cancer Inst 78:839843, 1987
mice three times/week for 325 days caused
8. Weiss W, Nash D: An epidemic of lung
papillomas in 13 of 20 animals; 12 of these cancer due to chloromethyl ethers. 30 years
papillomas progressed to squamous cell of observation. J Occup Environ Med 39(10):
carcinomas.12 10031009, 1997
In general, positive results were obtained 9. Gowers DS, DeFonso LR, Schaffer P,
when BCME was tested for mutagenicity in et al: Incidence of respiratory cancer among
vitro. It has also been reported to increase workers exposed to chloromethyl-ethers. Am
unscheduled DNA synthesis and the level of J Epidemiol 137:3142, 1993
transformed cells in in vitro assays.13 10. Leong BKJ, Macfarland HN, Reese WH Jr:
The IARC has concluded that there is suf- Induction of lung adenomas by chronic
cient evidence of carcinogenicity of BCME to inhalation of bis(chloromethyl)ether. Arch
Environ Health 22:663666, 1971
both humans and animals.14
11. Laskin S, Kuschner M, Drew RT, et al:
The 2003 ACGIH threshold limit value- Tumors of the respiratory tract induced by
time-weighted average (TLV-TWA) for inhalation of bis(chloromethyl)ether. Arch
bis(chloromethyl)ether is 0.001 ppm (0.0047 Environ Health 23:135136, 1971
mg/m3) with an A1-conrmed human carcino- 12. Van Duuren BL, Goldschmidt BM, Langseth
gen designation. L, et al: a-Haloethers; A new type of alkylat-
ing carcinogen. Arch Environ Health 16:
472476, 1968
REFERENCES 13. World Health Organization: Environmental
Health Criteria 201 Selected Chloralkyl Ethers,
1. Environmental Protection Agency: Ambient pp 179. International Programme on
Water Quality Criteria for Chloroalkyl Ethers, Chemical Safety, Geneva, 1998
162 CHLOROMETHYL METHYL ETHER
14. IARC Monographs on the Evaluation of Car- was squamous cell carcinoma; the cell type in
cinogenic Risks to Humans, Suppl 7, Overall one case was not determined.1
Evaluations of Carcinogenicity: An Updating In another study of 669 workers exposed
of IARC Monographs, Vols 142, pp 131 during 19481972, 19 died of lung cancer
132. Lyon, International Agency for although only 5.6 cases were expected.2 There
Research on Cancer, 1987
were higher relative risks for workers exposed
to intermediate to high levels of CMME for 1
or more years.2
In a study of 276 men exposed to CMME
and followed through 1980 at a plant in the
CHLOROMETHYL METHYL ETHER United Kingdom in operation since 1948,
CAS: 107-30-2 there were 10 deaths from lung cancer, with a
relative risk of 10.97 compared with an unex-
C2H5ClO posed group.3 The occurrence of lung cancer
appeared to be related to both the estimated
exposure level and the duration of exposure.
Synonyms: CMME; dimethylchloroether; Among a subgroup of 51 workers who began
methyl chloromethyl ether work after the process was enclosed in 1972, no
deaths from lung cancer had been observed
Physical Form. Colorless liquid through 1980. In another factory where 394
men had been exposed to CMME at lower
Uses. Chemical intermediate; preparation of estimated exposure levels, no excess of lung
ion-exchange resins cancer was observed.3
Lung cancer occurred at a higher rate
Exposure. Inhalation among potentially exposed CMME workers at
a factory in France (rate ratio 5.0 compared
Toxicology. Chloromethyl methyl ether with nonexposed workers and 7.6 compared
(CMME) exposure has been associated with an with an external referent population).4 The
increased incidence of human lung cancer. average age at diagnosis was 10.5 years lower
Among 111 CMME workers observed than nonexposed cases, and the predominantly
during a 5-year period, there were four cases of small cell cancers of the exposed were mostly
lung cancer; this was eight times the incidence oat cell type.
of a control group of plant workers with similar The most recent report of a cohort of
smoking histories.1 Evidence of a lung cancer CMME chemical workers followed for 30 years
risk was further supported by the retrospec- found 67 deaths with 25 attributable to lung
tive identication of a total of 14 cases among cancer and a dose-response relationship.5
chemical operators in a plant engaged in syn- Standardized mortality ratios were elevated
thesis of CMME. Except for one case of doubt- among the moderately and heavily exposed
ful exposure, the duration of exposure was 314 workers, peaking at 23.1 in the rst decade and
years, and the age at diagnosis ranged from then declining to 7.4 and 7.9 in later decades.
33 to 55 years. During the synthetic process, Small cell carcinoma accounted for 80% of
fumes were often visible. The employees con- the moderately and heavily exposed cases, and
sidered it a good day if the entire building had 3 of 12 heavily exposed cases occurred in
to be evacuated only three or four times per nonsmokers.
8-hour shift because of noxious fumes. Three It should be noted that commercial
of the men had never smoked, and one had CMME contains 17% of highly carcinogenic
smoked a pipe only; the other ten had smoked bis(chloromethyl)ether (BCME). In the
one or more packs of cigarettes per day. Oat reported epidemiological studies, insufcient
cell carcinoma was histologically conrmed in evidence is available to differentiate the
12 cases, whereas the doubtful exposure case carcinogenic effects of the two compounds.6
1-CHLORO-1-NITROPROPANE 163
Furthermore, when CMME is hydrolyzed, 4. Gowers DS, DeFonso LR, Schaffer P, et al:
HCl and formaldehyde are produced, which Incidence of respiratory cancer among
may recombine to form BCME. Therefore, workers exposed to chloromethyl-ethers. Am
although ndings may reect the carcino- J Epidemiol 137:3142, 1993
genicity of BCME, commercial-grade CMME 5. Weiss W, Nash D: An epidemic of lung
cancer due to chloromethyl ethers. 30 years
also must be considered to be a carcinogen,
of observation. J Occup Environ Med 39(10):
but perhaps of a lower potency than that of 10031009, 1997
BCME. 6. IARC Monographs on the Evaluation of the Car-
CMME is a mucous membrane and respi- cinogenic Risk of Chemicals to Man, Vol 4, Some
ratory irritant in both humans and animals.7,8 aromatic amines, hydrazine and related
Acute exposure of rats and hamsters resulted in substances, N-nitroso compounds and mis-
pulmonary edema and hemorrhage and necro- cellaneous alkylating agents, pp 239244.
tizing bronchitis.8 Human exposure to CMME Lyon, International Agency for Research on
has been reported to cause breathing difcul- Cancer, 1974
ties, sore throat, fever, and chills.7 An increased 7. Van Duuren BL, Goldschmidt BM, Langseth
frequency of chronic cough and low-end expi- L, et al: a-Haloethers: A new type of alkylat-
ing carcinogen. Arch Environ Health 16:
ratory ow rates has been observed in a dose-
472476, 1968
related fashion with exposure to CMME and 8. Ambient Water Quality Criteria for Chloroalkyl
BCME.9 Ethers, pp C-25, C-27. Springeld, VA,
Technical-grade CMME (contaminated National Technical Information Service, US
with BCME), on subcutaneous injection in Environmental Protection Agency, 1980
mice, has produced local sarcomas.6 Dermal 9. Weiss W: Chloromethyl ethers, cigarettes,
application of mice, followed by a phorbol ester cough and cancer. J Occup Med 18:194199,
promoter, resulted in an apparent excess of skin 1976
papillomas and carcinomas. Inhalation studies 10. IARC Monographs on the Evaluation of the Car-
in mice showed an equivocally increased occur- cinogenic Risk of Chemicals to Humans, Suppl 4,
rence of lung tumors compared with unexposed pp 6466. Lyon, International Agency for
Research on Cancer, 1982
controls.6
The IARC has concluded that there is
sufcient evidence for carcinogenicity of
technical-grade CMME to both humans and
animals.10 1-CHLORO-1-NITROPROPANE
ACGIH has designated chloromethyl CAS: 600-25-9
methyl ether as an A2-suspected human car-
cinogen; a numerical threshold limit value is CH3CH2CHClNO2
not recommended.
Synonyms: None
REFERENCES
Physical Form. Colorless liquid
1. Figueroa WG, Raszkowski R, Weiss W:
Lung cancer in chloromethyl methyl ether Uses. Fungicide
workers. N Engl J Med 288:10961097, 1973
2. DeFonso LR, Kelton SC Jr: Lung cancer
Exposure. Inhalation
following exposure to chloromethyl methyl
ether. Arch Environ Health 31:125130, 1976
3. McCallum RI, Woolley V, Petrie A: Lung Toxicology. 1-Chloro-1-nitropropane is an
cancer associated with chloromethyl methyl irritant of the eyes and mucous membranes. It
ether manufacture: An investigation at two is a pulmonary irritant in animals, and severe
factories in the United Kingdom. Br J Ind exposure is expected to cause the same effect in
Med 40:384389, 1983 humans.
164 CHLOROPENTAFLUOROETHANE
Systemic effects in humans have not been Uses. Refrigerant, aerosol propellant
reported.
The lethal oral dose in rabbits is 0.05 Exposure. Inhalation
0.10 g/kg, which is approximately ve times
more toxic than the nonchlorinated mononi- Toxicology. Chloropentauoroethane has
troparafn.1 Rabbits exposed to 2600 ppm for 2 low inhalation toxicity and little potential for
hours died, but 2200 ppm for 1 hour was non- cardiac sensitization.
lethal. Effects included irritation of the eyes Inhalation studies with chloropentauo-
and mucous membranes, and autopsy revealed roethane in anesthetized dogs, rats, and
pulmonary edema and cellular necrosis of the monkeys showed that exposure to 100,000
heart, liver, and kidneys.2,3 250,000 ppm, under certain conditions, caused
1-Chloro-1-nitropropane was mutagenic an increase in blood pressure, accelerated heart
in Salmonella assays both with and without acti- rate, depression of myocardial contractility and
vation.4 sensitized the heart to epinephrine.13 Com-
The 2003 ACGIH threshold limit value- pared with other chlorouorocarbons, it is
time-weighted average (TLV-TWA) for 1- ranked among the least potent for cardiac
chloro-1-nitropropane is 2 ppm (10 mg/m3). sensitization.4
In a NIOSH Health Hazard Evaluation of
refrigeration workers exposed far below the
REFERENCES threshold limit values (TLVs) for chloropenta-
uoroethane and chlorodiuoromethane, 27
1. Stokinger HE: Aliphatic nitro compounds, workers were medically evaluated.5,6 Seventy-
nitrates, nitrites. In Clayton GD, Clayton FE one percent complained of dizziness and
(eds): Pattys Industrial Hygiene and Toxicology, lightheadedness compared with twenty-one
3rd ed, rev, Vol 2C, Toxicology, pp 41624164.
percent of controls. Palpitations were reported
New York, Wiley-Interscience, 1982
in 36% of exposed and none of the non-
2. Machle W et al: The physiological response of
animals to certain mononitroparafns. J Ind exposed workers. No clinical neurological or
Hyg Toxicol 27:95102, 1945 electroneurophysiological abnormalities were
3. Browning E: Toxicity and Metabolism of Indus- detected in eight of the refrigeration repair
trial Solvents, pp 292293. Amsterdam, Else- workers followed for 3 years during continuous
vier, 1965 employment.6
4. Zeiger E, Anderson B, Haworth S, et al: Sal- Death from acute respiratory arrest has
monella mutagenicity tests: V. Results from the occurred after intentional inhalation of an
testing of 311 chemicals. Environ Mol Mutagen azeotrophic mixture of chlorodiuoromethane
19(suppl 21):2141, 1992 and chloropentauoroethane.7
REFERENCES
4. Aviado DM: Toxicity of aerosol propellants for a few seconds is temporarily disabling
in the respiratory and circulatory systems. X. because of irritant effects. Concentrations of
Proposed classication. Toxicology 3:321332, 0.30.37 ppm have resulted in painful eye irri-
1975 tation in 330 seconds.1
5. Health Hazard Evaluation Report No HETA- A man accidentally exposed to residual
81-043-1207, Refrigeration workers. Salt Lake
spray of undetermined concentration had dry
City, UT, DHHS, NIOSH, Cincinnati, OH,
1981 cough, and his nasal and pharyngeal mucosa
6. Campbell DD, Lockey JE, Petajan JH, et al: were red and edematous.2
Health effects among refrigeration repair In mice exposure to 9 ppm caused a 50%
workers exposed to uorocarbons. Br J Ind decrease in respiratory rate. Lesions included
Med 43:107111, 1986 ulceration and necrosis of the respiratory
7. Fitzgerald RL, Fishel CE, Bush LLE: Fatality epithelium and moderate damage to lung
due to recreational use of chlorodiuo- tissue.3 Rats administered, via oral gavage, 10,
romethane and chloropentauoroethane. J 20, 40, or 80 mg/kg for 10 consecutive days or
Forens Sci 38:476482, 1993 32 mg/kg for 90 consecutive days had inam-
mation, necrosis, acantholysis, hyperkeratosis,
and epithelial hyperplasia of the forestomach.4
Chloropicrin was genotoxic in bacterial
test systems.5
CHLOROPICRIN The 2003 ACGIH threshold limit value-
CAS: 76-06-2 time-weighted average (TLV-TWA) for
chloropicrin is 0.1 ppm (0.67 mg/m3).
CCl3NO2
REFERENCES
Synonyms: Trichloronitromethane; nitrochlo-
roform 1. Stokinger HE: Aliphatic nitro compounds,
nitrates, nitrites. In Clayton GD, Clayton FE
Physical Form. Colorless, slightly oily liquid (eds): Pattys Industrial Hygiene and Toxicology,
3rd ed, Vol 2C, Toxicology, pp 41644166.
New York, Wiley-Interscience, 1982
Uses. Fumigant for cereals and grains; a soil
2. TeSlaa G, Kaiser M, Biederman L, et al:
insecticide; war gas Chloropicrin toxicity involving animal and
human exposure. Vet Hum Toxicol 28:323324,
Exposure. Inhalation 1986
3. Buckley LA, et al: Respiratory tract lesions
Toxicology. Chloropicrin is a severe irritant induced by sensory irritants at the LD50
of the eyes, mucous membranes, skin, and concentrations. Toxicol Appl Pharmacol 74:417
lungs. 429, 1984
A lethal exposure for humans is stated to 4. Condie LW, Daniel FB, Olson GR, et al: Ten
be 119 ppm for 30 minutes, with death result- and ninety day toxicity studies of chloropicrin
in Sprague-Dawley rats. Drug Chem Toxicol
ing from pulmonary edema. Particular injury
17:125137, 1994
occurs in the medium and small bronchi.1
5. Giller S, Le Curieux F, Gauthier L, et al:
In addition to pulmonary irritation, human Genotoxic assay of chloral hydrate and
exposure results in lacrimation, cough, nausea, chloropicrin. Mutat Res 348:147152, 1995
vomiting, and skin irritation; persons injured
by inhalation of chloropicrin vapor are said to
be more susceptible to subsequent exposures.1
A concentration of 15 ppm could not be
tolerated longer than 1 minute even by persons
acclimated to chloropicrin; exposure to 4 ppm
166 b-CHLOROPRENE
gland, skin, mesentery, and zymbal gland 3. Baranski B: Effects of the workplace on fer-
tumors. tility and related reproductive outcomes.
Chloroprene did not cause a signicant Environ Health Perspect Suppl 101:8190, 1993
increase in chromosomal aberrations or sister 4. National Institute for Occupational Safety
chromatid exchanges in mice treated in vivo. and Health: Criteria for a Recommended Stan-
dard . . . Occupational Exposure to Chloroprene.
Both positive and negative results have been
DHEW (NIOSH) Pub No 77-210, pp
reported in a number of in vitro assays.8 1176. Washington DC, US Government
The IARC has determined that there is Printing Ofce, 1977
sufcient evidence in experimental animals for 5. Bulbulyan MA, Changuina OV, Zaridze DG,
the carcinogenicity of chloroprene and that it et al: Cancer mortality among Moscow shoe
is possibly carcinogenic to humans.8 workers exposed to chloroprene (Russia).
Exposure of male rats at concentrations of Cancer Causes Control 9(4):381387, 1998
1206277 ppm and of male mice at concentra- 6. Pell S: Mortality of workers exposed to
tions of 12152 ppm for 8 hours resulted in chloroprene. J Occup Med 20:2129, 1978
sterility or impotence in 13 of 19 rats and in 8 7. Li SQ, Dong QN, Liu YQ, et al: Epidemio-
of 14 mice vs. a mean of 0.5 in the two control logic study of cancer mortality among
chloroprene workers. Biomed Environ Sci 2:
groups. Degenerative changes in the testes
141149, 1989
were observed in some of the exposed animals. 8. IARC Monographs on the Evaluation of the
A signicant increase in embryonic mortality Carcinogenic Risk of Chemicals to Humans, Vol
was observed in female rats fertilized by males 71, Re-evaluation of some organic chemi-
exposed to 1 ppm 4 hours/day for 48 days.4,8 cals, hydrazine and hydrogen peroxide,
Hydrocephalus and cerebral herniation oc- pp 227250. Lyon, International Agency for
curred in all fetuses from rat dams given oral Research on Cancer, 1999
doses of 0.5 mg/kg during 14 days of preg- 9. von Oettingen WF, et al: 2-Chloro-butadiene
nancy. Inhalation of 1.11 ppm for 2 days of (chloroprene): Its toxicity and pathology and
pregnancy also caused increases in these anom- the mechanism of its action. J Ind Hyg Toxicol
alies.4,8 In another study, neither embryotoxic 18:240270, 1936
10. Clary JJ, et al: Toxicity of b-chloroprene (2-
nor convincing teratological effects were found
chlorobutadiene-1,3): Acute and subacute
after exposing rats at 1, 10, or 25 ppm.12 Ges- toxicity. Toxicol Appl Pharmacol 46:375384,
tational exposure of rabbits to 175 ppm did not 1978
result in observable toxicity to either the dam 11. National Toxicology Program (NTP): Toxi-
or the offspring.13 cology and Carcinogenesis Studies of Chloroprene
Contact with skin may cause chemical in F344/N Rats and B6C3F1 Mice (Inhalation
burns. Conjunctivitis and focal necrosis of the Studies). Technical Report Series 467, 367pp.
cornea have been reported from eye exposure.4 US Department of Health and Human
The 2001 ACGIH threshold limit value- Services, Public Health Service, 1998
time-weighted average (TLV-TWA) for b- 12. Culik R, et al: b-Chloroprene (2-chlorobuta-
chloroprene is 10 ppm (36 mg/m3) with a diene-1,3) embryotoxic and teratogenic
studies in rats (abstr no 194). Toxicol Appl
notation for skin absorption.
Pharmacol 37:172, 1976
13. Mast TJ, Evanoff JJ, Westerberg RB, et al:
Inhalation developmental toxicology studies:
developmental toxicity of chloroprene vapors
REFERENCES
in New Zealand White rabbitsnal report.
p 243, NTIS Technical Report (NTIS/
1. Nystrom AE: Health hazards in the chloro-
DE94-012384), 1994
prene industry and their prevention. Acta
Med Scand Suppl 132:5125, 1948
2. Sanotskii IV: Aspects of the toxicology of
chloroprene: Immediate and long-term
effects. Environ Health Perspect 17:8593,
1976
168 o-CHLOROSTYRENE
o-CHLOROSTYRENE CHLOROTHALONIL
CAS: 2039-87-4 CAS: 1897-45-6
C8H7Cl C6Cl4CN2
Technical-grade chlorothalonil was tested that cause tumours of the kidney or urinary
for possible carcinogenicity in rats and mice. In bladder in rodents, and some other substances,
rats, chlorothalonil was administered in the pp 183193. Lyon, International Agency for
diet at average doses of 5063 and 10,126 ppm Research on Cancer, 1999
for 80 weeks, followed by observation for
3031 weeks. Adenomas and carcinomas of the
renal tubular epithelium were observed.4 Mice
administered time-weighted average doses of
2688 or 5375 ppm (males) or 3000 or 6000 ppm
(females) showed no evidence of carcinogenic- o-CHLOROTOLUENE
ity.4 In other reports chlorothalonil produced CAS: 95-49-8
renal tubular tumors in male mice and
increased incidences of forestomach papillomas C7H7Cl
and carcinomas in males and females.5
Chlorothalonil was not mutagenic in a
variety of assays, nor did it bind to DNA.3 The Synonyms: 2-Chloro-1-methylbenzene; 2-
compound does not appear to have genotoxic chlorotoluene; Halso 99; o-tolyl chloride
potential and probably exerts its carcinogenic
action in rodents via a nongenotoxic mecha- Physical Form. Colorless liquid
nism.3 Rodent models may be a poor predictor
of carcinogensis in humans because of species Uses. Solvent; synthesis of dyes, pharmaceu-
differences in metabolic pathways leading to ticals, and synthetic rubber compounds
carcinogenesis in the kidney and the lack of a
comparable organ (forestomach) in humans.3 Exposure. Inhalation
The IARC has determined that there is
sufcient evidence for carcinogenicity of Toxicology. o-Chlorotoluene causes central
chlorothalonil in experimental animals and nervous system depression in animals and is
inadequate evidence in humans.5 expected to cause similar effects in humans.
An ACGIH threshold limit value has not Rats exposed for 6 hours to 4000 ppm
been adopted for chlorothalonil. became uncoordinated in 1.5 hours, followed
in another half-hour by prostration and
tremor.1 Rats exposed to 14,000 ppm exhibited
incoordination, vasodilation, labored respira-
tion, and narcosis, but all survived.
REFERENCES
In another study, mice, rats, and guinea
1. IARC Monographs on the Evaluation of Carcino- pigs were exposed to 4400 ppm.2 Mice devel-
genic Risks to Humans, Vol 30, Miscellaneous oped gasping, ataxia, and convulsions after 30
pesticides, pp 319326. Lyon, International minutes of exposure. Rats and guinea pigs
Agency for Research on Cancer, 1983 showed gasping, hyperpnea, ataxia, and con-
2. Eilrich GL, Chelsky M: Letters to the editor. vulsions after 45 minutes of exposure. All
Contact Dermatitis 25:141144, 1991 animals were comatose in 60 minutes. All mice
3. World Health Organization: Environmental and rats died, as did 7 of 10 guinea pigs.
Health Criteria 183 Chlorothalonil, pp 1130. Moderate skin irritation was noted on
Geneva, 1996
rabbit skin after application for 24 hours. A
4. National Cancer Institute: Bioassay of
single instillation into the eyes of rabbits pro-
Chlorothalonil for Possible Carcinogenicity, pp
viiviii. Bethesda, MD, National Institutes duced moderate conjunctival irritation that was
of Health, DHEW (NIH) Pub No 78-841, reversible by the fth day of observation.
1978 The 2003 threshold limit value-time-
5. IARC Monographs on the Evaluation of Carcino- weighted average (TLV-TWA) is 50 ppm
genic Risks to Humans, Vol 73, Some chemicals (259 mg/m3).
170 CHLORPYRIFOS
Chlorpyrifos was not carcinogenic in rats 4. Namba T, Nolte CT, Jackrel J, Grob D: Poi-
fed up to 3.0 mg/kg/day for 2 years.12 Although soning due to organophosphate insecticides.
many studies reported negative results, geno- Am J Med 50:475, 1971
toxic effects, including induction of micronu- 5. Chlorpyrifos. Documentation of the Threshold
clei, increases in sister chromatid exchanges Limit Values and Biological Exposure Indices, 7th
ed, 3pp. Cincinnati, OH, American Confer-
and chromosomal aberrations, have been
ence of Governmental Industrial Hygienists
reported in some studies.7 (ACGIH), 2001
In developmental studies skeletal varia- 6. Albers JW, Cole P, Greenberg RS, et al:
tions were observed in mice administered Analysis of chlorpyrifos exposure and human
gavage doses of 25 mg/kg/day during gestation, health: expert panel report. J Toxicol Environ
a level also causing signicant maternal toxic- Health B Crit Rev 2(4):301324, 1999
ity.13 Repeated intraperitoneal injection of 7. Agency for Toxic Substances and Disease
Dursban (active ingredient chlorpyrifos) to Registry (ATSDR): Toxicological Prole for
pregnant rats at doses of 0.03, 0.1, or 0.3 mg/kg Chlorpyrifos, pp 1179. US Department of
caused increased incidences of embryolethality, Health and Human Services, Public Health
physical abnormalities, and early postnatal neu- Service, 1997
8. Nolan RJ, et al: Chlorpyrifos: Pharmacoki-
rotoxicity.14 It was noted that the method of
netics in human volunteers. Toxicol Appl Phar-
exposure (ip) and solvents present in Dursban macol 73:815, 1984
may have contributed to the adverse effects. 9. Brenner FE, Bond GG, McLaren EA, et al:
More recent studies with chlorpyrifos indicate Morbidity among employees engaged in the
that it is especially damaging to the developing manufacture or formulation of chlorpyrifos.
brain, targeting diverse events in neural devel- Br J Ind Med 46:133137, 1989
opment, including cell proliferation and differ- 10. Calhoun RA, Dittenber DA, Lomax LG,
entiation, axonogenesis and synaptogenesis, et al: Chlorpyrifos: A 13-week nose-only
and synaptic function.15 Developmental neuro- vapor inhalation study in Fischer 344 rats.
toxicity may occur in the absence of overt Fundam Appl Toxicol 13:616618, 1989
maternal or fetal toxicity. 11. Capodicasa E, Scapellato ML, Moretto A,
et al: Chlorpyrifos-induced delayed polyneu-
The persistent strong odor is most likely
ropathy. Arch Toxicol 65:150155, 1991
due to the sulfur content of the pesticide. 12. McCollister SB, Kociba RJ, Humiston CG,
The 2003 ACGIH threshold limit value- et al: Studies of the acute and long-term oral
time-weighted average (TLV-TWA) for chlor- toxicity of chlorpyrifos (O,O-diethyl-O-
pyrifos is 0.2 mg/m3 with a notation for skin (3,5,6-trichloro-2-pyridyl)phosphoroth-
absorption. ioate). Fd Cosmet Toxicol 12:4561, 1974
13. Deacon MM, et al: Embryotoxicity and feto-
toxicity of orally administered chlorpyrifos in
REFERENCES mice. Toxicol Appl Pharmacol 54:3140, 1980
14. Muto MA, Lobelle F Jr, Bidanset JH, et al:
1. Koelle GB (ed): Cholinesterases and anti- Embryotoxicity and neurotoxicity in rats
cholinesterase agents. Handbuch der Experi- associated with prenatal exposure to
mentellen Pharmakologie, Vol 15, pp 989 Dursban. Vet Hum Toxicol 34:498501, 1992
1027. Berlin, Springer-Verlag, 1963 15. Qiao D, Seidler FJ, Tate CA, et al: Fetal
2. Koelle GB: Anticholinesterase agents. In chlorpyrifos exposure: adverse effects on
Goodman LS, Gilman A (eds): The Pharma- brain cell development and cholinergic bio-
cological Basis of Therapeutics, 5th ed, pp 456 markers emerge postnatally and continue
466. New York, Macmillan, 1975 into adolescence and adulthood (Research).
3. Hayes WJ Jr: Clinical Handbook on Economic Environ Health Perspect 111(4):53645, 2003
Poisons. Emergency Information for Treating
Poisoning. US Public Health Service Pub No
476, pp 1223, 3537. Washington, DC, US
Government Printing Ofce, 1963
172 CHROMIUM (Metal and Inorganic Compounds, as Cr)
Chromite ore roast mixed with sheep fat irritant dermatitis, sensitization dermatitis, and
implanted intrapleurally in rats produced sar- skin ulceration.9
comas coexisting with squamous cell carcino- Chromic Acid. Workers exposed to
mas of the lungs; the same material implanted chromic acid or chromates in concentrations of
in the thigh of rats produced brosarcomas.5 0.110.15 mg/m3 developed ulcers of the nasal
However, the IARC concluded that these septum and irritation of the conjunctiva,
studies were inadequate to fully evaluate the pharynx, and larynx, as well as asthmatic bron-
carcinogenicity of this compound.6 Other chitis.10 A worker exposed to unmeasured but
animal studies have found no increase in the massive amounts of chromic acid mist for 4
incidence of tumors with chromium metal and days developed severe frontal headache, wheez-
chromite ore.6 The IARC has determined that ing, dyspnea, cough, and chest pain on inspira-
there is inadequate evidence in humans and tion; after 6 months the worker still
animals for the carcinogenicity of metallic experienced chest pain on inspiration and
chromium and chromium(III) compounds. cough.10
Unlike nickel, chromium metal does not In an industrial plant in which the airborne
produce allergic contact dermatitis.7 Some chromic acid concentrations measured from
patients exhibit positive patch tests to divalent 0.18 to 1.4 mg/m3, moderate irritation of the
chromium compounds, but these compounds nasal septum and turbinates was observed after
are considerably less potent as sensitizers than 2 weeks of exposure, ulceration of the septum
hexavalent chromium compounds. A case of was present after 4 weeks, and there was per-
chromium (chromic) sulfate-induced asthma in foration of the septum after 8 weeks.10 A
a plating worker, conrmed by specic chal- worker exposed to an unmeasured concentra-
lenge testing and the presence of IgE anti- tion of chromic acid mist for 5 years developed
bodies, has been reported.8 jaundice and was found to be excreting signif-
These compounds do not appear to icant amounts of chromium; liver function
cause other effects associated with the hexava- was mildly to moderately impaired in four
lent chromium compounds, such as chrome other workers with high urinary chromium
ulcers, irritative dermatitis, or nasal septal excretion.10
perforation.7 Erosion and discoloration of the teeth has
been attributed to chromic acid exposure.
Papillomas of the oral cavity and larynx were
found in 15 of 77 chrome platers exposed for
an average of 6.6 years to chromic acid mist at
HEXAVALENT CHROMIUM air concentrations of chromium of 0.4 mg/m3.4
A concentrated solution of chromic acid in
Exposure. Inhalation the eye causes severe corneal injury; chronic
exposure to the mist causes conjunctivitis. Pro-
Toxicology. The water-soluble hexavalent longed exposure to chromic acid mist causes
chromium compounds such as chromic acid dermatitis, which varies from a dry, erythema-
mist and certain chromate dusts are severe irri- tous eruption to a weeping, eczematous
tants of the nasopharynx, larynx, lungs, and condition.
skin; exposure to certain hexavalent chromium Chromates. Epidemiological studies from
compounds, mainly water insoluble, appears to around the world have consistently shown
be related to an increased risk of lung cancer. excess risks for lung cancer in workers involved
Hexavalent chromium compounds have in chromate and chromate pigment produc-
been implicated as responsible for such effects tion.6 The epidemiological studies do not
as ulcerated nasal mucosa, perforated nasal clearly implicate specic compounds but do
septa, rhinitis, nosebleed, perforated eardrums, implicate chromium(VI) compounds.11 (A
pulmonary edema, asthma, kidney damage, recent report also implicated insoluble
erosion and discoloration of the teeth, primary chromium(III) as a cause of lung cancer in
174 HEXAVALENT CHROMIUM
chromate manufacturers, but it may be more where there has been a break in the epidermis
likely that insoluble chromium(VI) was in- and is believed to be due to a direct necrotiz-
volved instead.11,12) In one report the relative ing effect of the chromate ion. The ulcer is rel-
risk of dying from respiratory cancer among atively painless, heals slowly, and produces a
chromate workers was over 20 times the rate characteristic depressed scar. Sensitization der-
for a control population; the latent period was matitis with varying degrees of eczema has
relatively short.9 In most studies a positive cor- been reported numerous times and is the single
relation between duration of exposure and lung most common manifestation of chromium tox-
cancer death was found.13 Workers employed icity, affecting not only industrial workers but
in chromium-producing industries also had also the general population.9
signicantly increased nasal and sinus cavity The 2003 ACGIH threshold limit value-
cancers.14 time-weighted average (TLV-TWA) for
Some less soluble hexavalent chromium chromium metal and chromium(III) com-
compounds (lead chromate and zinc chromate pounds is 0.5 mg/m3 with an A4-not classiable
pigments; calcium chromate) are carcinogenic as a human carcinogen designation; for water-
in rats, producing tumors at the sites of admin- soluble chromium(VI) compounds the TLV-
istration by several routes. Lead chromate also TWA is 0.05 mg/m3, as Cr, with an
produces renal carcinomas after intramuscular A1-conrmed human carcinogen designation,
administration in rats.9 and for insoluble chromium(VI) compounds
The IARC has concluded that there is suf- it is 0.01 mg/m3, as Cr, also with an A1
cient evidence in humans for the carcino- designation.
genicity of chromium(VI) compounds as
encountered in the chromate production, chro-
mate pigment production, and chromate REFERENCES
plating industries. In experimental animals
there is sufcient evidence for the carcino- 1. Chromium. Documentation of the Threshold
genicity of calcium chromate, zinc chromates, Limit Values and Biological Exposure Indices, 7th
strontium chromate, and lead chromate.6 ed, 6pp. Cincinnati, OH, American Confer-
Chromium(VI) compounds have been ence of Governmental Industrial Hygienists
consistently genotoxic, inducing a wide variety (ACGIH), 2001
of effects including DNA damage, gene muta- 2. Princi F, Miller LH, Davis A, Cholak J: Pul-
tion, sister chromatid exchange, chromosomal monary disease of ferroalloy workers. J Occup
Med 4:301310, 1962
aberrations, cell transformation, and dominant
3. Mancuso TF, Hueper WC: Occupational
lethal mutations.6
cancer and other health hazards in a chro-
A variety of reproductive effects including mate plant: A medical appraisal. 1. Lung
testicular effects, alterations in sexual behavior, cancers in chromate workers. Ind Med Surg
and impaired fertility in females have been 20:358363, 1951
reported after high doses of chromium(VI) 4. Committee on Biological Effects of
compounds.11 These effects, reproductive tox- Atmospheric Pollutants, Division of
icity and testicular damage, were not replicated Medical Sciences, National Research
in a recent series of NTP studies in which mice Council: Chromium, pp 4273, 125145.
and rats were exposed to 400 ppm in the Washington, DC, National Academy of Sci-
diet.1517 ences, 1974
5. Hueper, WC: Experimental studies in metal
Chromium(VI) exposure during gestation
cancerigenesis. X. Cancerigenic effects of
caused developmental effects (increased fetal
chromite ore roast deposited in muscle tissue
mortality, decreased cranial ossication, and and pleural cavity of rats. AMA Arch Ind
decreased fetal body weight) in rodents in the Health 18:284291, 1958
absence of maternal toxicity.11 6. IARC Monographs on the Evaluation of Car-
Chrome ulcer, a penetrating lesion of the cinogenic Risks to Humans, Vol 49, Chromium,
skin, occurs chiey on the hands and forearms nickel and welding, pp 49256. Lyon, Inter-
CHROMYL CHLORIDE 175
REFERENCES
2. National Institute for Occupational Safety and matic hydrocarbons. There are, however, a
Health: Criteria for a Recommended Standard number of reports associating human cancer
. . . Occupational Exposure to Chromium(VI). and exposure to mixtures of polycyclic aromatic
DHEW (NIOSH) Pub No 76-129, Washing- hydrocarbons that include chrysene as a
ton, DC, US Government Printing Ofce, component, for example, among coke oven
1975
workers.3
3. De Flora S, Coppola R, Camoirano A, et al:
Mutagenicity and toxicity of chromyl chloride Chrysene was mutagenic to Salmonella
and its vapours. Carcinogenesis 1(7):5837, 1980 typhimurium in the presence of an exogenous
metabolic system. It induced sister chromatid
exchanges in one mouse study and chromo-
somal aberrations in one hamster study.2
Chrysene is metabolically activated to a 1,2-
diol-3,4-epoxide that is mutagenic and car-
CHRYSENE cinogenic in experimental animals and forms
CAS: 218-01-9 covalent adducts with DNA.2,4
The IARC has determined that there is
C18H12 limited evidence that chrysene is carcinogenic
to experimental animals.2 ACGIH has classied
chrysene as a conrmed animal carcinogen
Synonyms: 1,2-benzo[a]phenanthrene; 1,2- with unknown relevance to humans; a numer-
benzphenanthrene; benzo[a]phenanthrene; ical threshold limit value (TLV) is not
1,2,5,6-dibenzonaphthalene recommended.
early reports have found an increased stan- pp 337338. Lyon, International Agency for
dardized mortality ratio for gastric cancer, a Research on Cancer, 1997
recent matched case-control study found no
evidence of a dose-response relationship
between coal mining and gastric cancer. Evi-
dence from epidemiological studies for an COAL TAR PITCH VOLATILES
association between coal dust and lung cancer CAS: 65996-93-2
has not been consistent, with both excess
and decits reported.6 There is no exposure-
response relation with duration of exposure,
cumulative exposure, or radiographic evidence
of pneumoconiosis. Synonyms: CTPV; particulate polycyclic
In limited studies coal dust did not increase organic matter (PPOM); particulate polycyclic
the incidence of tumors in rats. There was no aromatic hydrocarbons (PPAH); polynuclear
evidence of mutagenicity after exposure of aromatics (PNAs)
rodents by inhalation or oral gavage.6
The IARC has determined that there is Physical Form. As stated by ACGIH:1
inadequate evidence in experimental animals
and in humans for the carcinogenicity of coal The pitch of coal tar is the black or dark
dust.6 brown amorphous residue that remains
The 2003 ACGIH threshold limit value- after the redistillation process. The
time-weighted average (TLV-TWA) for bitu- volatiles contain a large quantity of lower
minous or lignite coal dust is 0.9 mg/m3, molecular weight polycyclic hydrocarbons.
as respirable particulate; a TLV-TWA of As these hydrocarbons (naphthalene, uo-
0.4 mg/m3, as respirable particulate, is recom- rene, anthracene, acridine, phenanthrene)
mended for miners exposed to anthracite coal sublime into the air there is an increase of
dust. benzo(a)pyrene (BaP or 3,4-benzpyrene)
and other higher weight polycyclic
hydrocarbons in the tar and in the fumes.
Polycyclic hydrocarbons, known to be car-
REFERENCES cinogenic, are of this large molecular type.
1. Morgan WKC: Coal workers pneumoconio-
Sources/Uses. Occur as emissions from
sis. In Morgan WKC, Seaton A (eds): Occupa-
coke ovens, from coking of coal tar pitch, and
tional Lung Diseases, 2nd ed, pp 377488.
Philadelphia, PA, WB Saunders, 1984 from Soderberg aluminum reduction elec-
2. Morgan WKC, Burgess DB, Jacobson G, et al: trolytic cells; used for base coatings and paints;
The prevalence of coal workers pneumoco- for roong and paving; and as a binder for
niosis in US coal miners. Arch Environ Health carbon electrodes
27:221226, 1973
3. Atteld MD, Castellan RM: Epidemiological Exposure. Inhalation
data on US coal miners pneumoconiosis,
19601988. Am J Public Health 82:964970, Toxicology. Epidemiological evidence sug-
1992 gests that workers intimately exposed to the
4. Parkes WR: Occupational Lung Disorders, 2nd
products of combustion or distillation of bitu-
ed, p 178. London, Butterworths, 1982
minous coal are at increased risk of cancer at
5. Swaen GMH, Aerdts CWHM, Slangen JJM:
Gastric cancer in coal miners: Final report. Br many sites, including lungs, kidney, and skin.2
J Ind Med 44:777779, 1987 The chemical composition and particle
6. IARC Monographs on the Evaluation of Carcino- size distribution of coal tar pitch volatiles
genic Risks to Humans, Vol 68, silica, some (CTPV) from different sources are signicant
silicates, coal dust and para-aramid brils, variables in determining toxicity.3,4
COAL TAR PITCH VOLATILES 179
In a study of 22,010 US male aluminum rate.10 All of these rates are based on 5 or more
reduction workers with over 5 years employ- years of exposure in the job category. As the
ment in the industry, there was a slight positive length of employment increases, so does the
association with lung cancer [standardized mortality experience. For example, for employ-
mortality ratio (SMR) = 121], which was some- ees with 20 or more years of employment
what stronger in Soderberg workers (SMR = topside, the lung cancer rate is 20 times the
162).4 There was a slight, but not statistically expected rate. In addition to the risk of
signicant, excess of leukemia (SMR = 170) and lung cancer, the relative risk of mortality
lymphoma (SMR = 125) in potroom workers. from kidney cancer for all coke oven workers
In more detailed analysis of the mortality is 7.5.11
experience of this cohort up to year end 1977, A retrospective cohort study of 6635 male
the results of other studies relative to an excess workers employed for more than 15 years
of lung cancer were not conrmed, but there in seven Chinese factories found that the
were indications of a higher than expected SMRs for lung and liver cancer among those
mortality in pancreatic cancer, lymphohe- highly exposed to CTPV were 4.3 and 2.25,
matopoietic cancers, genitourinary cancer, respectively.12
nonmalignant respiratory disease, and benign Certain industrial populations exposed to
and unspecied neoplasms.6 coal tar products have a demonstrated risk
A case-cohort study of aluminum produc- of skin cancer. Substances containing poly-
tion plant workers showed a clear excess of lung cyclic hydrocarbons or polynuclear aromatics
cancer risk in men who had worked in Soder- (PNAs), which may produce skin cancer, also
berg potrooms in jobs with high exposure to produce contact dermatitis (e.g., coal tar pitch,
CTPV, and that the risk was not due to con- cutting oils).4 Although allergic dermatitis is
founding by smoking.7 The rate ratio for lung readily induced by PNAs in guinea pigs, it only
cancer rose with cumulative exposure to CTPV rarely is reported in humans from occupational
measured as benzene-soluble material to 2.25 contact with PNAs. Incidences in humans have
at 1019 mg/m3-years benzene-soluble matter resulted largely from the therapeutic use of coal
but did not rise with further exposure. tar preparations.6
A study in Canada of 5891 men in two Components of pitch and coal tar produce
aluminum reduction plants found the mortal- cutaneous photosensitization; skin eruptions
ity from lung cancer related to tar-years of usually are limited to areas exposed to ultravi-
exposure; the SMR for persons exposed for olet light.4,13,14 Most of the phototoxic agents
more than 21 years to the higher levels of tars will induce hypermelanosis of the skin; if
was 2.3 times that of persons not exposed to chronic photodermatitis is severe and pro-
tars.8 A follow-up study of this cohort through longed, leukoderma may occur.13 Some oils
1977 showed excess deaths from respiratory containing PNAs have been associated with
disease; pneumonia and bronchitis; malignant follicular and sebaceous gland changes, which
neoplasms of the stomach and esophagus, commonly take the form of acne.4
bladder, and lung; malignant neoplasms (all Coal tar fumes were mutagenic in a mod-
sites); Hodgkin disease; and hypertensive ied Ames test.15 Fumes generated at 316C
disease. Mortality from malignant neoplasms contained signicantly higher concentrations
of the bladder and lung was related to the of PAHs than those generated at 232C, and
number of tar-years and to years of exposure.9 the mutagenic activity generally paralleled the
Exposure to coke oven emissions is a cause PAH content.
of lung and kidney cancer. A major study of US Biological monitoring of 1-hydroxypyrene
coke oven workers showed that mortality from (a PAH metabolite) in urine has been a useful
lung cancer for full topside workers is 9 times indicator of PAH exposure in coke oven
the expected rate; for partial topside workers, workers.16
it is almost 2.5 times the expected rate; and for The 2003 ACGIH threshold limit value-
side oven workers, it is 1.7 times the expected time-weighted average (TLV-TWA) for coal
180 COBALT
tar pitch volatiles is 0.2 mg/m3 as benzene sol- Retrospective cohort study. J Occup Health
ubles, with an A1-conrmed human carcino- 39(4):325330, 1997
gen designation. 13. Committee on Biological Effects of Atmos-
pheric Pollutants, Division of Medical
Sciences, National Research Council: Parti-
culate Polycyclic Organic Matter, pp 166246,
REFERENCES
307354. Washington, DC, National
Academy of Sciences, 1972
1. Coal tar pitch volatiles. Documentation
14. National Institute for Occupational Safety
of TLVs and BEIs, 6th ed, pp 327329. Cincin-
and Health: Criteria for a Recommended
nati, OH, American Conference of Govern-
Standard . . . Occupational Exposure to Coal Tar
mental Industrial Hygienists (ACGIH),
Products. DHEW (NIOSH) Pub No 78-107.
1991
Washington, DC, US Government Printing
2. National Institute for Occupational Safety
Ofce, 1977
and Health, US Department of Health, Edu-
15. Machado ML, Beatty PW, Fetzer JC, et al:
cation, and Welfare: Criteria for a Recom-
Evaluation of the relationship between PAH
mended Standard Occupational Exposure to Coke
content and mutagenic activity of fumes from
Oven Emissions. (HSM) Pub No 73-11016, pp
roong and paving asphalts and coal tar pitch.
III-1III-14, V-1V-9. Washington, DC, US
Fundam Appl Toxicol 21:492499, 1993
Government Printing Ofce, 1973
16. Jongeneelen FJ: Biological exposure limit
3. Hittle DC, Stukel JJ: Particle size distribu-
for occupational exposure to coal tar pitch
tion and chemical composition of coal tar
volatiles at coke ovens. Int Arch Occup Environ
fumes. Am Ind Hyg Assoc J 37:199204,
Health 63:511516, 1992
1976
4. Scala RA: Toxicology of PPOM. J Occup Med
17:784788, 1975
5. Cooper C, Gaffey W: A Mortality Study of
Aluminum Workers. New York, The Alu-
minum Association, 1977
6. Rockette HE, Arena VC: Mortality studies COBALT
of aluminum reduction plant workers: Pot CAS: 7440-48-4
room and carbon department. J Occup Med
25:549557, 1983 Co
7. Armstrong B, Tremblay C, Baris D, et al:
Lung cancer mortality and polynuclear aro-
matic hydrocarbons: a case cohort study of
Synonyms: None
aluminum production workers in Arvida,
Quebec, Canada. Am J Epidemiol 139:
250262, 1994 Physical Form. Gray solid
8. Gibbs GW, Horowitz I: Lung cancer mortal-
ity in aluminum plant workers. J Occup Med Uses. Alloys; carbides; high-speed steels;
21:347353, 1979 paints, electroplating
9. Gibbs GW: Mortality of aluminum reduction
plant workers, 1950 through 1977. J Occup Exposure. Inhalation
Med 27:761770, 1985
10. Lloyd JW: Long-term mortality study of Toxicology. Cobalt causes skin irritation,
steelworkers. V. Respiratory cancer in coke allergic contact dermatitis, and occupational
plant workers. J Occup Med 13:5368, 1971
asthma; interstitial pulmonary brosis is asso-
11. Redmond CK, Ciocco A, Lloyd JW, Rush
ciated with exposure to hard metal dust (tung-
HW: Long-term mortality study of steel-
workers. VI. Mortality from malignant neo- sten and cobalt).
plasms among coke oven workers. J Occup In the occupational setting, exposure to
Med 14:621629, 1972 cobalt alone occurs primarily in the production
12. Liu N, Wang Z, Dong D, et al: Cancer of cobalt powders.1 With other industrial expo-
mortality among carbon workers in China: sures, such as hard metal exposure, additional
COBALT 181
agents modulate the toxicity of cobalt. Three weight and viability) after oral exposure to
types of lung disease have been reported in the cobalt at doses that also produced maternal
cemented tungsten carbide industry: (1) an toxicity.10
interstitial brotic process, (2) an interstitial Testicular atrophy was reported in rats
pneumonitis that often disappears when expo- exposed to 19 mg cobalt/m3 (as cobalt sulfate)
sure ceases, and (3) an obstructive airways syn- for 16 days.11 Male mice exposed for 13 weeks
drome. The latter may result from simple at 1.14 mg cobalt/m3 had a decrease in sperm
irritation, but in addition, a distinct form of motility, and at 11.4 mg cobalt/m3 there was
occupational asthma occurs.2 Cobalt, which is testicular atrophy; at the high dose female mice
used as a binder for the tungsten carbide crys- had a signicant increase in length of the
tals, has been implicated as the etiologic estrous cycle.11
agent.3,4 Rhabdomyosarcomas developed in rats
Among 12 workers who were engaged in injected intramuscularly with the powder of
the manufacturing of, or grinding with, tung- either pure cobalt metal or cobalt oxide.12 In
sten carbide tools and who developed intersti- other studies implantation of cobalt caused
tial lung disease, there were 8 deaths; serial local brosarcomas in rabbits, but inhalation
chest roentgenograms over a period of 312 studies in hamsters did not reveal any increase
years revealed gradually progressive densities in tumors from cobalt oxide.9 Lifetime expo-
of a linear and nodular nature that gradually sure to cobalt sulfate by inhalation resulted in
involved major portions of both lungs. Cough, increased incidence of alveolar/bronchiolar
production of scanty mucoid sputum, dyspnea neoplasms and a spectrum of inammatory,
on exertion, and reduced pulmonary function brotic, and proliferative lesions in the
occurred early in the course of the disease.4 respiratory tract of male and female rats and
Disease is seldom seen without at least 10 years mice.13
of exposure, but shorter periods have been Epidemiological studies to determine the
reported.3 carcinogenicity of cobalt in humans have been
The obstructive airways syndrome appears confounded by concurrent exposure to other
to be an allergic response and is characterized known carcinogens such as nickel and arsenic
by wheezing, cough, and shortness of breath and small study populations.14 A retrospective
while at work.2,4 There is no evidence that this cohort study of 874 women exposed to cobalt
type of disease progresses to interstitial bro- in two Danish porcelain factories did not
sis. In a report of nine cases, the syndrome demonstrate a signicant increased risk of
did not develop until after 618 months of developing lung cancer compared with the ref-
exposure.5 erence group.15 A signicant increase in lung
On screening 1039 tungsten carbide cancer risk was found in workers simultane-
workers, interstitial lung disease was observed ously exposed to cobalt and tungsten carbide
in 0.7% and work-related wheezing occurred when exposures during the last 10 years were
in 10.9%.6 ignored.16
Occupational exposure to cobalt dust has The IARC has determined that there is
been associated with cardiomyopathy charac- sufcient evidence that cobalt metal powder
terized by functional effects on the ventricles and cobaltous oxide are carcinogenic in exper-
and enlargement of the heart.7 imental animals and that they are possible
Cobalt and its compounds produce an human carcinogens.17
allergic dermatitis of an erythematous papular In mammalian cells in vitro cobalt com-
type that usually occurs in skin areas subjected pounds have caused DNA strand breaks, sister
to friction, such as the ankle, elbow exures, chromatid exchanges, and aneuploidy, but
and sides of the neck.8 Ocular effects have not chromosomal aberrations.17 Cobalt salts
included congestion of the conjunctiva.9 are generally nonmutagenic in prokaryotic
Animal studies have reported developmen- assays.18
tal effects (stunted fetuses and decreased pup The 2003 ACGIH threshold limit value-
182 COBALT HYDROCARBONYL
By analogy to nickel carbonyl, acute effects to copper dust and fumes.1 Exposure to con-
from animal exposures are expected to be pul- centrations of 13 mg/m3 for short periods
monary edema, congestion, and hemorrhage. resulted in altered taste response but no nausea;
In humans, nickel carbonyl causes an acute levels from 0.02 to 0.4 mg/m3 produced no
ulike syndrome that subsides and is followed complaints.
after 1236 hours by an acute respiratory syn- Typical MFF, a 24- to 48-hour illness
drome. Exposure to cobalt hydrocarbonyl may characterized by chills, fever, aching muscles,
be expected to produce similar effects. dryness in the mouth and throat, and headache,
Irritation may occur from skin or eye has been reported in several workers exposed
exposure.2 to copper fume.2,3 With MFF, leukocytosis
The 2003 threshold limit value-time- is usually present with counts of 12,000
weighted average (TLV-TWA) is 0.1 mg/m3 as 16,000/mm3; recovery is usually rapid, and
Co. there are no sequelae.4 Most workers develop
an immunity to these attacks, but it is quickly
lost, and attacks tend to be more severe on the
REFERENCES rst day of the workweek.4
It has recently been noted that if copper-
1. Palmes ED, Nelson N, Laskin S, Kuschner M: induced MFF does occur, it is a very rare
Inhalation toxicity of cobalt hydrocarbonyl. event.5 Despite extensive use of copper in many
Am Ind Hyg Assoc J 20:453468, 1959 industries, only a handful of MFF cases are
2. Occupational safety and health guidelines for
reported in the literature.5 Further limitations
chemical hazardsSupplement IV-OHG. Cobalt
Hydrocarbonyl. pp 18. Publications Dissem-
of these reports include possible contamination
ination, EID, National Institute for Occupa- of the fume by other substances more likely to
tional Safety and Health, Cincinnati, OH, have caused MFF, atypical symptoms and com-
1995 plaints, and lack of consistency among types of
work associated with symptoms. One reason
that MFF may have rarely been described after
copper exposure is that aerosolized copper par-
ticulates formed during welding, thermal
cutting, and other hot work are mostly greater
COPPER (Dust and Fume) than respirable or submicron size. Studies of air
CAS: 7440-50-8 in a brass foundry found that only 5% of the
total copper exposure was respirable (aerosol
Cu, CuO less than or equal to 1 mm), whereas 40% of the
zinc oxide exposures were to an aerosolized
particulate of respirable size.5
Synonyms: None Copper dust may cause respiratory irrita-
tion.1 Gastrointestinal effects including
Physical Form. Reddish solid anorexia, nausea, and occasional diarrhea have
been attributed to swallowing of the dust.1
Sources. Copper and brass manufacture; Lung damage after chronic exposure to
welding of copper-containing metals fumes in industry has not been described.6 The
higher incidence of respiratory cancer reported
Exposure. Inhalation in copper smelters is due to the presence of
arsenic in the ore.6
Toxicology. Copper fume causes irritation of Although unlikely in an occupational
the upper respiratory tract and metal fume setting, ingestion of copper salts may cause
fever (MFF), an inuenza-like illness. vomiting, abdominal pain, diarrhea, lethargy,
Respiratory, gastrointestinal, and dermal acute hemolytic anemia, renal and liver
effects have been observed in workers exposed damage, neurotoxicity, increased blood pres-
184 COTTON DUST, RAW
sure and respiratory rates, coma, and death.7 Source. Cotton processing
Transient irritation of the eyes has followed
exposure to a ne dust of oxidation products of Exposure. Inhalation
copper produced in an electric arc.8
The 2003 ACGIH threshold limit value- Toxicology. Raw cotton dust causes a respi-
time-weighted average (TLV-TWA) for copper ratory syndrome termed byssinosis.
is 0.2 mg/m3 for the fume and 1 mg/m3 for dusts The initial symptoms are chest tightness,
and mists as Cu. cough, wheezing, and dyspnea in varying
degrees of severity on the rst day of the work-
week (grade 1 byssinosis).13 Symptoms usually
REFERENCES disappear an hour or so after the individual
leaves work but may recur on the rst day of
1. Agency for Toxic Substances and Disease each workweek. With continued exposure the
Registry (ATSDR): Toxicological Prole for symptoms also appear on subsequent days of
Copper. US Department of Health and Human the workweek (grade 2 byssinosis) There
Services, Public Health Service, 143pp, 1990 usually is a decrease in the FEV1 and in vital
2. Committee on Medical and Biologic Effects of
capacity on the rst day of the workweek after
Environmental Pollutants: Copper, pp 5558.
Washington, DC, National Academy of Sci-
34 hours of exposure; the changes in airway
ences, 1977 resistance and decreased ow rates have been
3. Cohen SR: A review of the health hazards from attributed to narrowing of small airways due to
copper exposure. J Occup Med 16:621624, bronchoconstriction. Eventually, obstructive
1974 airway disease, which is irreversible, occurs
4. McCord CP: Metal fume fever as an immuno- (grade 3 byssinosis).
logical disease. Ind Med Surg 29:101106, 1960 Follow-up of cotton textile workers in
5. Borak J, Cohen H, Hethmon TA: Copper China found that workers who consistently
exposure and metal fume fever: lack of causal reported reversible symptoms such as chest
relationship. Am Ind Hyg Assoc J 61(6):832 tightness at work had signicantly greater 15-
836, 2000
year loss of FEV1, suggesting that long-term
6. Triebig G, Schaller KH: Copper. In Alessio L
et al. (eds): Biological Indicators for the Assessment
cotton dust exposure was associated with per-
of Human Exposure to Industrial Chemicals, manent obstructive impairments.4
pp 5766. Luxembourg, Ofce for Ofcial Although a loss in lung function has been
Publications of the European Communities, documented in cotton textile workers, no clear
1984 evidence of increased mortality has been
7. World Health Organization: Environmental reported.5 A review of 2895 consecutive autop-
Health Criteria 200 Copper, pp 1273. Geneva, sies showed no signicant differences in the
International Programme on Chemical Safety, prevalence of emphysema, interstitial brosis,
1998 or cor pulmonale between 283 employees of a
8. Grant WM: Toxicology of the Eye, 3rd ed, pp cotton textile mill and the general population.6
260269, Springeld, IL, Charles C. Thomas,
In another postmortem study of 49 cotton
1986
workers, the incidence of emphysema was
associated with cigarette smoking, with 16 of
36 smokers showing centrilobular emphysema
vs. 1 of 13 nonsmokers.7 Another study of
women with advanced byssinosis conrmed the
COTTON DUST, RAW association between emphysema and cigarette
smoking rather than cotton dust exposure.8
Two additional studies of cotton workers
Synonyms: None also found no excess mortality from respiratory
disease but differed in other ndings. In the
Physical Form. Fibers rst report of 3458 British cotton industry
COTTON DUST, RAW 185
worker, mortality from respiratory disease was below which zero prevalence is found.2 The
reduced overall, but for subjects who initially slopes of the prevalence-dustiness curves
reported byssinotic symptoms, the mortality obtained by different investigators vary
from respiratory disease was slightly raised, considerably.2
and it increased with length of service.9 The Gram-negative bacterial endotoxin has
mortality from lung cancer was lower than been implicated as one of the agents responsi-
expected, and it decreased with length of ble for respiratory illnesses due to cotton dust
service. A mortality study of 1065 women exposure.12
employed in Finnish cotton mills did not The 2003 ACGIH threshold limit value-
conrm low mortality from respiratory time-weighted average (TLV-TWA) for cotton
cancer.10 Instead, an increase in lung (3 vs. dust is 0.2 mg/m3.
1.9 expected) and gastrointestinal (13 vs. 6.6
expected) cancers was reported. Cotton dust
exposure also appeared to increase the morbid- REFERENCES
ity of renal disease and rheumatoid arthritis.
Exposure to textile dust increased the risk of 1. Harris TR, Merchant JA, Kilburn KH,
sinonasal cancer (squamous cell tumors and Hamilton JD: Byssinosis and respiratory dis-
adenomas) among women in a case control eases of cotton mill workers. J Occup Med
study in France.11 There was some evidence of 14:199206, 1972
a dose-response relationship, but because sub- 2. National Institute for Occupational Safety
jects had been exposed to various bers (cotton, and Health: Criteria for a Recommended
Standard . . . Occupational Exposure to Cotton
wool, synthetic) no specic association with
Dust. DHEW (NIOSH) Pub No 75118,
type of ber could be made.
pp 1260. Washington, DC, US Government
A syndrome known as mill fever, which Printing Ofce, 1974
may or may not be related to the development 3. Department of Labor: Standard for exposure
of byssinosis, has been described in some to cotton dust. Fed Reg 41:5649856525,
persons unaccustomed to breathing cotton 1976
dust.2 Shortly after exposure, there is develop- 4. Christiani DC, Wang XR, Pan L, et al: Lon-
ment of malaise, cough, fever, chills, and upper gitudinal changes in pulmonary function
respiratory symptoms; these may recur daily and respiratory symptoms in cotton textile
for days to months until acclimatization takes workers. Am J Respir Crit Care Med
place and symptoms disappear. Tolerance may 163(4):847853, 2001
5. Elwood PC, Sweetnam PM, Bevan C, et al:
be lost temporarily after a period of absence
Respiratory disability in ex-cotton workers.
from exposure, or if exposure to a greater con-
Br J Ind Med 43:580586, 1986
centration of dust occurs. The exact prevalence 6. Moran TJ: Emphysema and other chronic
of mill fever among new employees is lung disease in textile workers: An 18-year
unknown, but estimates range from 10% to autopsy study. Arch Environ Health 38:
80%.1 267276, 1983
Epidemiological studies have indicated 7. Pratt PC, Vollmer RT, Miller JA: Epidemiol-
that prevalence of byssinosis among cotton ogy of pulmonary lesions in nontextile and
workers can be correlated with the average cotton textile workersa retrospective
concentration of lint-free dust of particle size autopsy analysis. Arch Environ Health 35:
under 15 m in diameter and with the number of 133138, 1980
8. Honeybourne D, Pickering CAC: Physiolog-
years of exposure.2 Specically, in a follow-up
ical evidence that emphysema is not a feature
study of 66 cotton textile workers, with an addi-
of byssinosis. Thorax 41:611, 1986
tional 10 years of exposure, the prevalence of 9. Hodgson JT, Jones RD: Mortality of workers
byssinosis increased from 23% to 43% in the in the British cotton industry in 19681984.
female workers and from 23% to 52% in the Scand J Work Environ Health 16:113120,
male workers.10 1990
There is little evidence of a threshold 10. Koskela RS, Klockars M, Jarvinen E: Mor-
186 CRESOL (All Isomers)
tality and disability among cotton mill cerns of occupational exposure.1 Signs and
workers. Br J Ind Med 47:384391, 1990 symptoms related to skin contact are a burning
10. Zuskin E, Ivankovic D, Schachter EN, et al: sensation, erythema, skin peeling, localized
A ten-year follow-up study of cotton textile anesthesia, and, occasionally, ochronosis, a
workers. Am Rev Respir Dis 143:301305, darkening of the skin.1 Hypersensitivity also
1991
has been reported.2
11. Luce D, Gerin M, Morcet JF, et al: Sinonasal
cancer and occupational exposure to textile Cresols are rapidly absorbed through the
dust. Am J Ind Med 32:20510, 1997 skin, producing systemic effects.1 About 20 ml
12. Christiani DC, Wegman DH, Eisen EA, et of a 90% cresol solution accidentally poured
al: Cotton dust and Gram-negative bacterial over an infants head caused chemical burns,
endotoxin correlations in two cotton textile cyanosis, unconsciousness, and death within 4
mills. Am J Ind Med 23(2):333342, 1993 hours.3 Histopathologic examination showed
hepatic necrosis, cerebral edema, acute tubular
necrosis of the kidneys, and hemorrhagic
effusions from the peritoneum, pleura, and
pericardium. The blood contained 12 mg
CRESOL (All Isomers) cresol/100 dl.
CAS: 1319-77-3 Inhalation of appreciable amounts of cresol
vapor is unlikely under normal conditions
ortho-Cresol because of the low vapor pressure; however,
CAS: 95-48-7 hazardous concentrations may be generated at
elevated temperatures.1 Seven workers exposed
meta-Cresol to cresol vapor at unspecied concentrations
CAS: 108-39-4 for 1.53 years had headaches, which were fre-
quently accompanied by nausea and vomiting.1
para-Cresol Four of the workers also had elevated blood
CAS: 106-44-5 pressure, signs of impaired kidney function,
blood calcium imbalance, and marked tremors.
C7H8O Eight of ten subjects exposed to 1.4 ppm o-
cresol vapor experienced upper respiratory
tract irritation.1
Synonyms: Cresylic acid; tricresol; methyl- Several cases of ingestion have shown
phenol; o-cresol; m-cresol; p-cresol; cresol to be corrosive to body tissues and to
hydroxytoluene cause toxic effects on the vascular system, liver,
kidneys, and pancreas.1
Physical Form. Ortho- and para isomers are Rats survived 8 hours of inhaling air satu-
solids; the meta isomer and isomer mixtures are rated with the vapor.4 Irritation of the nose and
yellowish liquids eyes and some deaths were observed in mice
exposed to saturated concentrations 1 hour/day
Uses. Antiseptics; disinfectants; solvent; for 10 days.5 Animal experiments have pro-
insecticides; resins; ame-retardant plasticizers duced varying results with regard to con-
centrations necessary to produce death.1 In
Exposure. Skin absorption; inhalation general, the ortho and para isomers are consid-
ered equal in toxicity, with the meta isomer
Toxicology. All isomers of cresol cause skin regarded as the least toxic.1
and eye burns; exposure also may cause At doses that were maternally toxic, o- and
impairment of kidney and liver function, as p-isomers induced slightly elevated incidences
well as central nervous system and cardiovas- of minor variations in the offspring of exposed
cular disturbances. rats and rabbits.6
Skin and eye contact are the major con- Cresol isomers promoted dimethylbenzan-
CROTONALDEHYDE 187
for 150 days.2 In rats, guinea pigs, monkeys, Solvents, 2nd ed, Vol I, Hydrocarbons, pp
and dogs, exposed at either 224 ppm 8 hours/ 96104. New York, Elsevier, 1987
day, 5 days/week for 6 months or 30 ppm 7. Cushman JR, Norris JC, Dodd DE, et al:
continuously for 90 days, there were no Subchronic inhalation toxicity assessment of
adverse effects on symptoms, body weight, or cumene in Fischer 344 rats. J Am Coll Toxicol
14(2):129147, 1995
histology.8
8. Jenkins, LJ Jr, Jones RA, Siegel J: Long-term
Cumene was not a developmental toxicant inhalation screening studies of benzene,
in either rats or rabbits after exposure to levels toluene, o-xylene and cumene on experimen-
(1200 ppm and 2300 ppm, respectively) associ- tal animals. Toxicol Appl Pharmacol 16:818
ated with maternal toxicity.9 Most genotoxic 823, 1970
tests with cumene have been negative.10 9. Darmer KI, Neeper-Bradley TL, Cushman
The LD50 for penetration of rabbit skin JR, et al: Developmental toxicity of cumene
was 12.3 ml/kg after 14 days.4 Contact of the vapor in CD rats and New Zealand White
liquid with the skin causes erythema and irrita- rabbits. Int J Toxicol 16(2):119139, 1997
tion.11 Eye contamination may produce con- 10. World Health Organization: Concise Interna-
junctival irritation.1 tional Chemical Assessment Document 18,
Cumene, 1999 21pp. International programme
It generally is agreed that cumene has no
on chemical safely (IPCS), Geneva, 1999.
damaging effect on the hematopoietic system, 11. Gerarde HW: Toxicological studies on
despite its chemical similarity to benzene.5 hydrocarbons. AMA Arch Ind Health 19:
Furthermore, cumene is not anticipated to be 403418, 1959
a signicant carcinogenic hazard because it is
metabolically similar to toluene, a substance
that showed no carcinogenic activity in 2-year
inhalation studies.10
The 2003 ACGIH threshold limit value- CYANAMIDE
time-weighted average (TLV-TWA) is 50 ppm CAS: 420-04-2
(246 mg/m3) with a notation for skin absorption.
CH2N2
REFERENCES
Synonyms: Carbodiimide; cyanoamine; hydro-
1. Hygenic Guide Series: Cumene, Vol 1. Akron, gen cyanamide; cyanogen nitride; carbamo-
OH, American Industrial Hygiene Associa-
nitrile
tion, 1978
2. Sandmeyer EE: Aromatic hydrocarbons. In
Clayton GD, Clayton FE (eds): Pattys Indus- Physical Form. Crystalline solid
trial Hygiene and Toxicology, 3rd ed, Vol
2B, Toxicology, pp 33093310. New York, Uses. Fumigants, metal cleaners, production
Wiley-Interscience, 1981 of synthetic rubber, chemical synthesis
3. Werner HW, Dunn RC, von Oettingen WF:
The acute effects of cumene vapors in mice. Exposure. Ingestion; inhalation
J Ind Hyg Toxicol 26:264268, 1944
4. Smyth HF Jr, Carpenter CP, Weil CS: Toxicology. Cyanamide is an irritant of the
Range-nding toxicity data: List IV. AMA eyes, mucous membranes, and skin; it is an
Arch Ind Hyg Occup Med 4:119122, 1951
inhibitor of aldehyde dehydrogenase and can
5. Tegeris JS, Balster RL: A comparison of
cause an antabuse effect with ethanol
the acute behavioral effects of alkylbenzenes
using a functional observational battery in ingestion.
mice. Fundam Appl Toxicol 22:240250, Cyanamide is severely irritating and
1994 caustic to the eyes, skin, and respiratory tract.1
6. Lee EW: Cumene. In Snyder R (ed): Ethel Concurrent exposure to cyanamide and
Brownings Toxicity and Metabolism of Industrial ethanol produces tachycardia, decreased
190 CYANIDES
diastolic blood pressure, hypertension, in- Physical Form. Powders, granules, or akes
creased respiration rate, and symptoms of
alcohol intoxication, owing to a buildup of Uses. Extraction of gold and silver; electro-
acetaldehyde.2 plating; hardening of metals; coppering;
In a 6-month study of rats, oral doses of zincing; bronzing; manufacture of mirrors;
2.7 or 25 mg/kg/day caused no hepatic reclamation of silver from photographic lm;
changes.3 A two-generation study of reproduc- pesticides
tion and fertility in rats used oral doses of 2,
7, or 25 mg/kg/day.4 Maternal toxicity was Exposure. Inhalation; skin absorption;
observed. Decreases in dam weight, number of ingestion
corpora lutea, number of implantations, and
number of neonates was attributable to the Toxicology. The alkali salts of cyanide can
toxic effects in the dams. There were no nd- cause rapid death due to metabolic asphyxia-
ings in the F1 generation. tion.
The 2003 ACGIH threshold limit value- Cyanide ion exerts an inhibitory action
time-weighted average (TLV-TWA) for on certain metabolic enzyme systems, most
cyanamide is 2 mg/m3. notably cytochrome oxidase, the enzyme
involved in the ultimate transfer of electrons
to molecular oxygen.1 Because cytochrome
REFERENCES oxidase is present in practically all cells that
function under aerobic conditions, and because
1. Grant WM: Toxicology of the Eye, 3rd ed, p 286. the cyanide ion diffuses easily to all parts of the
Springeld, IL, Charles C. Thomas, 1986 body, cyanide quickly halts practically all cellu-
2. Hills BW, Venable HL: The interaction of lar respiration. The venous blood of a patient
ethyl alcohol and industrial chemicals. Am J
dying of cyanide is bright red and resembles
Ind Med 3:321333,1982
arterial blood because the tissues have not been
3. Obach R et al: Lack of hepatotoxicity after
long-term administration of cyanamide in rats: able to utilize the oxygen brought to them.2
a histological and biochemical study. Acta Cyanide intoxication produces lactic acidosis,
Pharmacol Toxicol 57:279284, 1985 the result of an increased rate of glycolysis and
4. Vallies J et al: A two-generation reproduction- production of lactic acid.3
fertility study of cyanamide in the rat. Phar- If large amounts of cyanide have been
macol Toxicol 61:2025, 1987 absorbed, collapse usually is instantaneous, the
patient falling unconscious, often with convul-
sions, and dying almost immediately. Symp-
toms of intoxication from less severe exposure
include weakness, headache, confusion, and
CYANIDES occasionally nausea and vomiting.1,2 The respi-
NaCN ratory rate and depth usually are increased ini-
CAS: 143-33-9 tially, at later stages respiration becoming slow
and gasping. Coma and convulsions occur in
KCN some cases. If cyanosis is present, it usually
CAS: 151-50-8 indicates that respiration either has ceased or
has been very inadequate for a few minutes. In
Ca(CN)2 one case of nonfatal ingestion of 600 mg of
CAS: 592-01-8 potassium cyanide, the clinical course was
marked by acute pulmonary edema and lactic
acidosis.3
Synonyms/compounds: Sodium cyanide; potas- Most reported cases of occupational
sium cyanide; calcium cyanide (black cyanide poisoning have involved workers with
cyanide) a mixture of repeated acute or subacute expo-
CYANOGEN 191
sures and chronic or prolonged low-level expo- although many individuals are unable to rec-
sures, making it unclear whether symptoms ognize the scent of bitter almonds.3
simply resulted from multiple acute exposures The 2003 ACGIH ceiling-threshold limit
with acute intoxication. Some symptoms per- value (C-TLV) for cyanide salts, as CN, is
sisted after cessation of such exposures, perhaps 5 mg/m3 with a notation for skin absorption.
because of the effect of anoxia from inhibi-
tion of cytochrome oxidase. Symptoms from
claimed chronic exposure are similar to those REFERENCES
reported after acute exposures, such as weak-
ness, nausea, headache, and vertigo.1 A study of 1. National Institute for Occupational Safety and
36 former workers in a silver-reclaiming facil- Health: Criteria for a Recommended Standard
ity, who were repeatedly exposed to cyanide, Occupational Exposure to Hydrogen Cyanide and
Cyanide Salts (NaCN, KCN, and Ca(CN)2).
demonstrated some residual symptoms 7 or
DHEW (NIOSH) Pub No 77-108, pp 3795,
more months after cessation of exposure; fre-
106114, 160173, 178. Washington, DC, US
quent headache, eye irritation, easy fatigue, loss Government Printing Ofce, 1976
of appetite, and epistaxis occurred in at least 2. Gosselin RE, Smith RP, Hodge HC: Clinical
30% of these workers.4 Changes in thyroid Toxicology of Commercial Products, Section III,
chemistry, without manifestations of hypothy- 5th ed, pp 123130. Baltimore, MD, Williams
roidism, have also been reported in cyanide- and Wilkins, 1984
exposed individuals. 3. Graham DL, Laman D, Theodore J, Robin
Cyanide solutions or cyanide aerosols ED: Acute cyanide poisoning complicated by
generated in humid atmospheres have been lactic acidosis and pulmonary edema. Arch
reported to cause irritation of the upper respi- Intern Med 137:10511055, 1977
4. Blanc P, Hogan M, Mallin K, et al: Cyanide
ratory tract (primarily nasal irritation) and
intoxication among silver-reclaiming workers.
skin.1 Skin contact with solutions of cyanide
JAMA 253:367371, 1985
salts can cause itching, discoloration, or corro- 5. National Toxicology Program: NTP Technical
sion, most likely due to the alkalinity of the Report on Toxicity Studies of Sodium Cyanide
solutions. Skin irritation and mild systemic (CAS No. 143-33-9) Administered in Drinking
symptoms (e.g., headache, dizziness) have been Water to F344/N Rats and B6C3F1 Mice. NIH
caused by solutions as dilute as 0.5% potassium Pub 94-3386. US Department of Health
cyanide.1 and Human Services, Public Health Service,
Skin contact with aqueous cyanide solu- 1993
tions for long periods has caused caustic burns; 6. Agency for Toxic Substances and Disease
these cases may be fatal because of signicant Registry (ATSDR): Toxicological Prole for
Cyanide, pp 1255. US Department of Health
skin absorption.1
and Human Services, Public Health Service,
Administered in the diet for 13 weeks to
1997
rats at 12.5 mg/kg/day, sodium cyanide caused
a number of reproductive effects including
decreases in testis weight and spermatid counts
in males and alterations in estrous and proe-
strous cycles in females.5 Adverse developmen- CYANOGEN
tal effects have been observed in rodents at CAS: 460-19-5
maternally toxic doses.6
No studies are available to evaluate the car- (CN)2
cinogenic risk of cyanide exposure in humans
or animals.6 The cyanide salts are not muta-
genic in a variety of genotoxic assays.6 Synonyms: Carbon nitride; dicyanogen;
At high levels, cyanide acts so rapidly that nitriloacetonitrile; oxalonitrile; prussite
its odor has no value as a warning.2 At lower
levels, the odor may provide some warning, Physical Form. Gas with almond-like odor
192 CYANOGEN
Uses. Organic synthesis; fuel gas for welding probably the result of an increased rate of gly-
and cutting heat-resistant metals; rocket and colysis and the production of lactic acid.4
missile propellant; fumigant Studies in rats suggested that cyanogen is
10-fold less acutely toxic than hydrogen
Exposure. Inhalation; eye or skin contact cyanide.1 In rats and monkeys exposed to 11 or
25 ppm cyanogen for 6 hours/day, 5 days/week
Toxicology. Cyanogen reacts with water, for 6 months, there were no effects on hema-
acids, and acid salts to produce hydrogen tologic or clinical chemistry values.6 Mean
cyanide, which causes death from metabolic body weights were reduced in rats at the higher
asphyxiation. level.
Exposure of humans to 16 ppm caused The 2003 ACGIH threshold limit value-
eye and nose irritation.1 A concentration of time-weighted average (TLV-TWA) is 10 ppm
270 ppm hydrogen cyanide has long been said (21 mg/m3).
to be immediately fatal to humans. A more
recent study, however, states that the estimated
LC50 to humans for a 1-minute exposure is REFERENCES
3404 ppm; 270 ppm would be fatal after 68
minutes, 181 ppm after 10 minutes, and 1. McNerney JM, Schrenk HH: The acute toxi-
135 ppm after 30 minutes.2 city of cyanogen. Am Ind Hyg Assoc J
If large amounts of cyanide have been 21:121124, 1960
2. National Institute for Occupational Safety and
absorbed, collapse usually is instantaneous, the
Health: Criteria for a Recommended Standard
patient falling unconscious, often with con-
Occupational Exposure to Hydrogen Cyanide Salts
vulsions, and dying almost immediately.2,3 (NaCN, KCN, and Ca[CN]2). DHEW
Symptoms of intoxication from less severe (NIOSH) Pub No 77-108, pp 3795, 106114,
exposure include weakness, headache, confu- 170173, 178. Washington, DC, US Govern-
sion, vertigo, fatigue, anxiety, dyspnea, and ment Printing Ofce, 1976
occasionally nausea and vomiting.24 The res- 3. Gosselin RE, Smith RP, Hodge HC: Clinical
piratory rate and depth usually are increased Toxicology of Commercial Products, Section III,
initially, and at later stages respiration becomes 5th ed, pp 123130. Baltimore, MD, Williams
slow and gasping. Coma and convulsions occur and Wilkins, 1984
in some cases. If cyanosis is present, it usually 4. Graham DL, Laman D, Theodore J, Robin
ED: Acute cyanide poisoning complicated by
indicates that respiration either has ceased or
lactic acidosis and pulmonary edema. Arch
has been very inadequate for a few minutes.
Intern Med 137:10511055, 1977
Chronic overexposure may cause dizziness, loss 5. National Institute for Occupational Safety and
of appetite, and weight loss.5 Health: Occupational Safety and Health Guide-
Cyanide ion exerts an inhibitory action lines for Chemical Hazards. Supplement IV-OHG
on certain metabolic enzyme systems, most (Pub. No. 95-121). Occupational safety and
notably cytochrome oxidase, the enzyme health guideline for cyanogen, 8p.Cincinnati,
involved in the ultimate transfer of electrons to OH, 1995
molecular oxygen.2 Because cytochrome 6. Lewis TR, Anger WK, Te Vault RK: Toxicity
oxidase is present in practically all cells that evaluation of subchronic exposures to
function under aerobic conditions, and because cyanogen in monkeys and rats. J Environ
Pathol Toxicol Oncol 5:151163, 1984
the cyanide ion diffuses easily to all parts of the
body, cyanide quickly halts practically all cellu-
lar respiration. The venous blood of a patient
dying of cyanide is bright red and resembles
arterial blood because the tissues have not been
able to utilize the oxygen brought to them.3
Cyanide intoxication produces lactic acidosis,
CYCLOHEXANE 193
REFERENCES
CYCLOHEXANOL
CAS: 108-93-0 1. Nelson KW: Sensory response to certain
industrial solvent vapors. J Ind Hyg Toxicol 25:
C6H11OH 282285, 1943
2. Rowe VK, McCollister SB: Alcohols. In
Clayton GD, Clayton FE (eds): Pattys Indus-
Synonyms: Hexahydrophenol; cyclohexyl trial Hygiene and Toxicology, 3rd ed, Vol 2C,
alcohol Toxicology, pp 46434649. New York, Wiley-
Interscience, 1982
3. Treon JF, Crutcheld WE Jr, Kitzmiller KV:
Physical Form. Colorless, viscous liquid The physiological response of animals to
cyclohexane, methylcyclohexane, and certain
Uses. Solvent for oils, resins, ethyl cellulose; derivatives of these compounds. J Ind Hyg
manufacture of soap, plastics Toxicol 25:323347, 1943
4. Maurer JK, Molai AL, Parker RD, et al:
Exposure. Inhalation; skin absorption Pathology of ocular irritation with acetone,
cyclohexanol, parauoroaniline, and formalde-
hyde in the rabbit low-volume eye test. Toxicol
Toxicology. Cyclohexanol causes irritation
Path 29(2):18799, 2001
of the eyes, nose, and throat; at high concen-
trations it causes narcosis in animals, and it is
expected that severe exposure will produce the
same effect in humans.
Human volunteers exposed to a vapor
concentration of 100 ppm for 35 minutes CYCLOHEXANONE
experienced eye, nose, and throat irritation.1 CAS: 108-94-1
Headache and conjunctival irritation have
resulted from prolonged exposure to exces- C6H10O
sive but undened concentrations.2
Rabbits exposed 6 hours/day to 272 ppm
over a 10-week period showed slight eye irrita- Synonyms: Pimelic ketone; hexanon; sextone
tion; at 997 ppm additional effects were saliva-
tion, lethargy, narcosis, mild convulsive Physical Form. Colorless liquid
movements, and some deaths.3 Lethal doses of
cyclohexanol produced slight necrosis of the Uses. Industrial solvent for cellulose acetate
myocardium and damage to the lungs, liver, resins, vinyl resins, rubber, and waxes; solvent-
and kidneys.3 The application of 10 ml of cyclo- sealer for polyvinyl chloride; in printing indus-
hexanol to the skin of a rabbit for 1 hour/day try; coating solvent in audio and videotape
for 10 days induced narcosis, hypothermia, production
tremors, and athetoid movements; necrosis,
exudative ulceration, and thickening of the skin Exposure. Inhalation; skin absorption
occurred in the area of contact.2 Ten micro-
liters applied directly to the cornea of rabbits Toxicology. Cyclohexanone causes eye,
caused moderate to severe irritation.4 nose, and throat irritation; at high concentra-
Mice fed diets containing 1% cyclohexanol tions, it produces lethargy and narcosis in
during gestation produced offspring with an animals, and it is expected that severe exposure
increased mortality during the rst 3 weeks of will cause the same effect in humans.
life.2 In most human subjects, exposure to
The 2003 threshold limit value-time- 25 ppm of the vapor for 5 minutes did not cause
weighted average (TLV-TWA) is 50 ppm effects, but 50 ppm was irritating, especially to
(206 mg/m3) with a notation for skin. the throat; exposure to 75 ppm resulted in more
196 CYCLOHEXANONE
noticeable eye, nose, and throat irritation.1 a patient with repeated direct contact with
One anecdotal case suggested that exposure 100% cyclohexanone solution.10
to cyclohexanone at high levels for many years The main metabolite of cyclohexanone is
may be associated with epileptic seizures.2 cyclohexanol, which is excreted in the urine.11
Rabbits exposed to 190 ppm for 6 A good correlation has been shown between
hours/day for 50 days showed slight liver and postshift urinary cyclohexanol levels (corrected
kidney injury. At 309 ppm there was slight con- for creatinine) and occupational exposure to
junctival irritation, and at 1414 ppm lethargy cyclohexanone.11
was observed. At 3082 ppm effects were inco- Cyclohexanone has an odor similar to pep-
ordination, salivation, labored breathing, permint, and harmful concentrations are not
narcosis, and some deaths.3 Five of six rats likely to be voluntarily tolerated.
survived exposure to 2000 ppm for 4 hours, but The 2003 ACGIH threshold limit value-
4000 ppm caused coma and death of all six. time-weighted average (TLV-TWA) for cyclo-
Narcosis, hypothermia, and decreased respira- hexanone is 25 ppm (100 mg/m3) with a
tion were observed in guinea pigs exposed to notation for skin absorption.
4000 ppm for 6 hours.4 Recovery from narcosis
was slow, and 3 of 10 animals died within 4 days
of exposure. REFERENCES
Rats and mice administered cyclohexanone
in their drinking water for 2 years showed mar- 1. Nelson KW et al: Sensory response to certain
ginal evidence of carcinogenic activity.5 Male industrial solvent vapors. J Ind Hyg Toxicol
25:282, 1943
rats receiving 3300 ppm had a 13% incidence
2. Jacobsen M, Baelum J, Bonde JP: Temporal
of adrenal cortex adenomas versus 2% in con- epileptic seizures and occupational exposure
trols; the incidence of this neoplasm did not to solvents. Occup Environ Med 51:429430,
increase in the higher dose males or in any of 1994
the female rats. Mice had a statistically signi- 3. Treon JF, Crutcheld WE Jr, Kitzmiller KV:
cant increase in incidence of lymphomas- The physiological response of animals to
leukemias among the females given 6500 ppm, cyclohexanone, methylcyclohexane and cer-
but not among the group given the higher tain derivatives of these compounds. II. Inha-
doses. Thus a dose-related trend in increased lation. J Ind Hyg Toxicol 25:323, 1943
neoplasms was not observed among any of the 4. Specht H, Miller JW, Valaer PJ, Sayers RR:
groups. Acute Response of Guinea Pigs to the Inhalation
of Ketone Vapors. National Institute of Public
The IARC has determined that there is
Health Bulletin No 176. Washington, DC,
inadequate evidence for the carcinogenicity of US Government Printing Ofce, 1940
cyclohexanone in experimental animals and 5. Lijinsky W, Kovatch RM: Chronic toxicity
that it is not classiable as to its carcinogenic- study of cyclohexanone in rats and mice. J
ity to humans.6 Natl Cancer Inst 77:941949, 1986
Rats exposed on gestation days 520 by 6. IARC Monographs on the Evaluation of
inhalation to concentrations of up to 500 ppm Carcinogenic Risks to Humans, Vol 71, Re-
for 7 hours/day showed no signicant fetotoxic evaluation of some organic chemicals,
effects.7 Depression of both maternal and hydrazine and hydrogen peroxide, p 1359,
fetal body weights, but no incidence of terato- Lyon, International Agency for Research on
genicity, occurred in rats exposed through Cancer, 1999
7. Samimi BS, Harris SB, DePeyster A: Fetal
inhalation at 1430 ppm during days 916 of
effects of inhalation exposure to cyclohexa-
gestation.8 none vapor in pregnant rats. Toxicol Ind Health
Eye contact with liquid cyclohexanone 5:10351043, 1989
may cause corneal injury.9 The liquid is a defat- 8. Schroeder RE: An Inhalation Teratology Study
ting agent, and prolonged or repeated skin in Rats with Cyclohexanone. Bio/Dynamics,
contact may produce irritation or dermatitis.9 Division of Biology and Safety Evaluation.
Allergic contact dermatitis has been reported in Submitted to Industrial Health Foundation,
CYCLOHEXIMIDE 197
Pittsburgh, PA. Final Report. Project No. 83- The liquid defats the skin on direct
2719, 1984 contact.
9. Hygienic Guide Series: Cyclohexanone. Am Cyclohexene was not mutagenic in Salmo-
Ind Hyg Assoc J 26:630, 1965 nella typhimurium with or without metabolic
10. Sanmartin O, de la Cuadra J: Occupational activation.4
contact dermatitis from cyclohexanone as a
The 2003 ACGIH threshold limit value-
PVC adhesive. Contact Dermatitis 27:189
190, 1992 time-weighted average (TLV-TWA) for cyclo-
11. Ong CN, Chia SE, Phoon WH, et al: Mon- hexene is 300 ppm (1010 mg/m3).
itoring of exposure to cyclohexanone through
the analysis of breath and urine. Scand J Work
Environ Health 17:430435, 1991
REFERENCES
ular, cloudy swelling of liver cells and cloudy Only limited information is available on
vacuolization of renal tubular epithelium.1 human exposures. Symptoms of acute exposure
Dogs exposed 39 times to 400 ppm for 6 hours to high concentrations are expected to be
followed by 16 exposures at 800 ppm had no ill excitement, loss of equilibrium, stupor, coma,
effects, as determined by observation, clinical and respiratory failure.1
tests, or histologic examination.1 Repeated Because cyclopentane is not sufciently
daily exposure in four species at 250 ppm for 6 stable to occur naturally in large quantities,
months also caused no symptoms. Applied to most exposures involve a mixture of sub-
the skin of rabbits, the liquid caused marked stances.1 In the Italian shoe industry, exposure
irritation, exudates in the pleural and peri- to glue solvents containing up to 18%
toneal cavities, and hyperemia of the kidneys.1 cyclopentane has been associated with
The dermal LD50 was 6.72 ml/kg for the polyneuropathy.2 However, it is assumed that
rabbit.2 n-hexane is present in these solvents and
The 2003 threshold limit value-time- accounts for the polyneuropathy.
weighted average (TLV-TWA) is 75 ppm In animal experiments high concentrations
(203 mg/m3). initially cause stimulation of the CNS and
then CNS depression.3 In mice, 15 minutes
at 60,000 ppm or 10 min at 80,000 produced
REFERENCES anesthesia; deaths occurred at concentrations
near those required to produce anesthesia,
1. Cyclopentadiene. Documentation of the thresh- indicating a small margin of safety between
old limit values and biological exposure indices, 7th narcotic and fatal concentrations. Mice ex-
ed, p 2. Cincinnati, OH, American Conference posed 6 hours/day for 90 days to 10,200 ppm
of Governmental Industrial Hygienists
had no substance-related abnormalities in
(ACGIH), 2001
clinical, neurofunctional, or pathologic
2. Smyth HF Jr, Carpenter CP, Weil CS, et al:
Range-nding toxicity data: List V. Arch Ind examinations.3
Hyg Occup Med 10:6168, 1954 In another report repeated exposures of
rats to 8000 ppm 6 hours/day for 12 weeks
resulted in decreased body weight gains in
females; no effects were found in males or
females exposed to up to 1100 ppm 6 hours/day
CYCLOPENTANE for 3 weeks.1
CAS: 287-92-3 Applied to the skin of guinea pigs
cyclopentane produced slight erythema and
C5H10 dryness.1 Instilled in rabbit eyes it is mildly
irritating.3
Cyclopentane was not mutagenic in the
Synonym: Pentamethylene Ames bacterial assay; it was also negative in
vitro in the mouse lymphoma assay and in the
Physical Form. Flammable, colorless liquid micronucleus test.3
Cyclopentane is considered a severe re
Uses. As a laboratory reagent; in the manu- hazard with a lower ammability limit of
facture of pharmaceuticals; found in solvents 15,000 ppm. The 2003 ACGIH threshold limit
and in petroleum ether; propellant pressurizing value-time-weighted average (TLV-TWA) for
agent cyclopentane is 600 ppm.
trial Hygiene and Toxicology, 3rd ed, Vol 2B, been exposed to 340 ppm p-cymene for 20 years
pp 32233226, New York, Wiley-Interscience, while working in a sulte pulp mill.2 There was
1981 also exposure to a variety of other substances
2. Abbritti G, Siracusa A, Cianchetti C, et al: during this time, including acetone, sulfur
Shoe-makers polyneuropathy in Italy: The dioxide, acetaldehyde, methyl alcohol, formic
aetiological problem. Br J Ind Med 33:9299,
acid, and terpenes. No similar cases of hema-
1976
3. Galvin JB, Marashi F: Cyclopentane. J Toxicol tologic effects following human exposure to p-
Environ Health A 58:5774, 1999 cymene have been reported.
The lowest lethal concentration for rats
was 5000 ppm for 45 minutes.3 At this concen-
tration, signs included dyspnea, twitching of
the whiskers, and ataxia, which were followed
by hyperreactivity to auditory stimuli. Other
CYMENE signs included rigid tails, carpopedal spasm,
o-Cymene generalized quivering, profuse salivation, and
CAS: 527-84-4 hypothermia. In mice, the LD50 was 4370 ppm;
effects were characteristic of central nervous
m-Cymene system excitation, such as tremor and convul-
CAS: 535-77-3 sions, which lasted for 23 hours.1 Inhibitory
effects of the central nervous system followed
p-Cymene over the next 48 hours and included lethargy,
CAS: 99-87-6 shallow breathing, and coma.
Rats exposed to 50 or 250 ppm p-cymene 6
C10H14 hours/day, 5 days/week for 4 weeks had a sig-
nicantly decreased yield of synaptosomal
protein in the brain, suggesting a decrease in
Synonyms: Isopropyltoluene; isopropylmethyl- the density and total number of synapses.4
benzene Subcutaneous injection of rabbits with 2 ml
of p-cymene for 2 days caused an increased
Physical Form. Colorless liquid with a sweet number of immature hematopoietic cells in the
aromatic odor peripheral blood.
On the skin, p-cymene may cause ery-
Uses. As a diluent for lacquers, varnishes, thema, dryness, and defatting. However, 4% p-
and dyes; in the production of resins; as a com- cymene in petroleum did not produce irritation
ponent of fragrances; also found as a by- in 25 humans after a 48-hour closed patch test
product in the manufacture of sulte paper or after 10 daily applications to the same spot
pulp on the backs of subjects.5 Undiluted p-cymene
applied to rabbit skin for 24 hours under occlu-
Exposure. Inhalation sion was moderately irritating. The LD50 by
skin absorption is greater than 5 g/kg in rabbits.
Toxicology. Cymene, which may occur in A threshold limit value (TLV) has not been
ortho, meta, or para forms, is an irritant of the established for o-, m-, or p-cymene.
skin and mucous membranes and may cause
central nervous system effects; in animals sub-
cutaneous injection has produced hematologic
REFERENCES
changes.
In a very early report, p-cymene produced 1. Lee EW: p-Cymene. In Snyder R (ed): Ethel
headache and nausea in volunteers who Brownings Toxicity and Metabolism of Industrial
ingested 34 g/day for 23 days.1 A severe case Solvents, 2nd ed, Vol I, Hydrocarbons, pp 105
of blood dyscrasia was found in a man who had 111. New York, Elsevier, 1987
202 DDT
2. Carlson GW: Aplastic anemia following expo- ication, convulsions may occur and there may
sure to products of the sulte pulp industry; be paresis of the hands.1 Ingestion of very large
a report of one case. Ann Intern Med 24: doses induces vomiting.1 Recovery is well
277284, 1946 advanced or complete in 24 hours except in the
3. Furnas DW, Hine CH: Neurotoxicity of some most serious cases; three persons who each
selected hydrocarbons. AMA Arch Ind Health
ingested an estimated 20 g of DDT showed a
18:915, 1958
4. Lam HR, Ladefoged O, Ostergaard G, et al: residual weakness of the hands after 5 weeks.
Four weeks inhalation exposure of rats to There are no conrmed reports of fatalities
p-cymene affects regional and synaptosomal occurring exclusively from ingestion of pure
neurochemistry. Pharmacol Toxicol 79(5):225 DDT. Heavy exposure to the dust may cause
230, 1996 skin and eye irritation.1
5. Opdyke DLJ: Monographs on fragrance raw Although chronic poisoning in humans has
materials. Food Cosmet Toxicol 12(3):385405, not been described, continued absorption of
1974 DDT by humans results in storage of DDT
and its metabolites, including DDE [2,2-bis( p-
chlorophenyl)-1,1-dichloroethylene], in fat.24
In a study of 20 workers exposed to DDT for
1119 years and with a calculated daily intake
DDT of 18 mg/person [calculated from DDA (2,2-
CAS: 50-29-3 bis(p-chlorophenyl)acetic acid) content in fat
and DDA excretion in urine], the sum of
C14H9Cl5 isomers and metabolites of DDT in the fat was
38647 ppm (compared with an average of
8 ppm for the general population); although
Synonyms: 1,1,1-Trichloro-2,2-bis( p-chlor- DDE was the major excretory product in the
ophenyl)ethane; dichlorodiphenyltrichloroe- general population, DDA was the major excre-
thane tory product in DDT-exposed workers.2
Large oral doses of DDT in rats caused
Physical Form. White crystalline solid focal and centrilobular necrosis of the liver.1
However, in clinical evaluation and laboratory
Uses. Insecticide; use banned in many tem- studies of 31 workers exposed to equivalent oral
perate-climate countries, but still widely used intakes of 3.618 mg daily for an average of 21
in the tropics years, there was no evidence of hepatotoxicity;
an observed increase in activity of hepatic
Exposure. Inhalation; skin absorption; inges- microsomal enzymes was not accompanied by
tion clinical evidence of detriment to general
health.5
Toxicology. DDT affects the nervous system The hepatocarcinogenicity of DDT by the
at high doses and causes paresthesias, tremor, oral route has been demonstrated and con-
and convulsions. rmed in several strains of mice. Liver cell
Ingestion by humans of 10 mg/kg is suf- tumors have been produced in both sexes and
cient to cause effects in some, and convulsions in CF mice were found to have metastasized to
have frequently occurred after ingestion of the lungs.6 However, the tumorigenic potential
16 mg/kg; 285 mg/kg has been taken without of DDT was negligible in monkeys after dosing
fatal results.1 The onset of effects, usually for 1522 years. Of 35 monkeys administered
occurring 2 or 3 hours after ingestion, is char- 20 mg DDT/kg, 5 days/week for 130 months,
acterized by paresthesias of the tongue, lips, only 1 developed hepatocellular carcinoma
and face; the subject soon develops tremor, a after a latency period of 20 years.7 Despite
sense of apprehension, dizziness, confusion, numerous studies, there is no conclusive,
malaise, headache, and fatigue; in severe intox- unequivocal, or consistent evidence linking
DECABORANE 203
DDT exposure to human cancers.8 The IARC Occupational exposures in insecticide applica-
has determined that there is sufcient evidence tion, and some pesticides, pp 17980. Lyon,
for the carcinogenicity of DDT in experimen- International Agency for Research on Cancer,
tal animals and that it is possibly carcinogenic 1991
to humans.6 7. Thorgeirsson UP, Dalgard DW, Reeves J,
et al: Tumor incidence in a chemical car-
Reproductive and developmental toxicity
cinogenesis study of nonhuman primates. Reg
have been reported in animal studies.8 Effects Toxicol Pharmacol 19:130151, 1994
are attributed to hormone-altering actions of 8. Agency for Toxic Substances and Disease
DDT isomers and/or metabolites. Registry (ATSDR): Toxicological Prole for
In mice, exposure to DDT during gesta- 4,4-DDT, 4,4-DDE, 4,4-DDD, 403pp. US
tion and in the neonatal stage has also caused Department of Health and Human Services,
developmental neurotoxicity, in the form of Public Health Service, 2000
behavioral decits in the learning process, that
persisted into adulthood. Human studies have
suggested that alterations in functions that are
hormonally controlled such as duration of lac-
tation, maintenance of pregnancy, and fertility DECABORANE
may occur from DDT exposure.8 CAS: 17702-41-9
DDT has given both positive and negative
results in a wide variety of genotoxic assays. In B10H14
general, it appears that DDT is not a signi-
cant genotoxic hazard at environmentally rele-
vant concentrations.8 Synonyms: Decaboron tetradecahydride, boron
The 2003 ACGIH threshold limit value- hydride
time-weighted average (TLV-TWA) for DDT
is 1.0 mg/m3 with an A3 conrmed animal car- Physical Form. Colorless to white crys-
cinogen with unknown relevance to humans talline solid
designation.
Uses. In rocket propellants; in polymer syn-
thesis; corrosion inhibitor; fuel additive; moth-
proong agent
REFERENCES
Exposure. Inhalation; skin absorption
1. Hayes WJ Jr: Pesticides Studied in Man, pp
180205. Baltimore, MD, Williams &
Wilkins, 1982 Toxicology. Decaborane affects the nervous
2. Laws ER Jr, Curley A, Biros FJ: Men with system and causes signs of both hyperexcitabil-
intensive occupational exposure to DDTa ity and narcosis.
clinical and chemical study. Arch Environ In humans, the onset of symptoms is fre-
Health 15:766755, 1967 quently delayed for 2448 hours after exposure;
3. Hayes WJ Jr, Dale WE, Pirkle CI: Evidence dizziness, headache, and nausea are common;
of safety of long-term, high, oral doses of other symptoms of mild intoxication include
DDT for man. Arch Environ Health 22: light-headedness, drowsiness, incoordination,
119135, 1971 and fatigue; more severe intoxication results in
4. Wolfe HR, Armstrong JF: Exposure of formu-
tremor, localized muscle spasms, and convul-
lating plant workers to DDT. Arch Environ
sive seizures.13 Muscle spasm usually subsides
Health 23:169176, 1971
5. Laws ER Jr, Maddrey WC, Curley A, Burse after 24 hours, whereas light-headedness and
VW: Long-term occupational exposure to fatigue may remain for up to 3 days.3
DDT. Arch Environ Health 27:318321, 1973 The 4-hour inhalation LC50 for mice was
6. IARC Monographs on the Evaluation of the Car- 26 ppm; signs included restlessness, depressed
cinogenic Risk of Chemicals to Man, Vol 53, breathing, generalized weakness, and corneal
204 DECALIN
opacities.4 Rats exhibited normal activity rane and pentaborane by inhalation. Arch Ind
during 4-hour exposures to concentrations Health 10:298304, 1954
ranging up to 95 ppm. 5. Krackow EH: Toxicity and health hazards of
Exposure of rabbits to 56 ppm for 6 hours boron hydrides. AMA Arch Ind Hyg Occup Med
was fatal; effects included dyspnea, coarse 8:335339, 1953
6. Svirbely JL: Toxicity tests of decaborane for
movements of the head, weakness, rigid
laboratory animals. I. Acute toxicity studies.
hindquarters, absence of eye reexes, and Arch Ind Health 11:132137, 1955
convulsive seizures.5 By percutaneous applica- 7. Svirbely JL: Toxicity tests of decaborane for
tion, the rabbit LD50 was 113 mg/kg.6 The laboratory animals. II. Effect of repeated
hazard from skin absorption is considered to be doses. Arch Ind Health 11:138141, 1955
high.7 8. Tadepalli AS, Buckley JP: Cardiac and periph-
Cumulative toxic effects occurred in eral vascular effects of decaborane. Toxicol Appl
various animal species receiving repeated small Pharmacol 29:210222, 1974
doses of decaborane by oral, intraperitoneal, or 9. Naeger LL, Leibman KC: Mechanisms of
cutaneous routes.7 The rate of recovery was decaborane toxicity. Toxicol Appl Pharmacol 22:
markedly delayed in some animal species sur- 517527, 1972
viving repeated doses compared with those that
had received a single, large dose. In dogs
repeatedly given oral doses of 3 mg/kg, the
effects on the central nervous system were not
pronounced but there was damage to the liver DECALIN
and kidneys. CAS: 91-17-8
Intravenous administration of 410 mg/kg
produced bradycardia and an initial transient C10H18
hypertensive effect in the anesthetized dog.8
Toxicity is thought to occur from the
decomposition of decaborane to a stable inter- Synonyms: Decahydronaphthalene;
mediate that in turn inhibits intracellular pyri- bicyclo(4.4.0)decane; naphthane
doxal phosphate-requiring enzymes.9
Rapid olfactory fatigue excludes odor as a Physical Form. Colorless liquid
satisfactory early warning device.2
The 2003 ACGIH threshold limit value- Uses. Solvent for naphthalene, fats, resins,
time-weighted average (TLV-TWA) for oils; alternate for turpentine in lacquers, shoe
decaborane is 0.05 ppm (0.25 mg/m3) with a polishes, and waxes; component in motor fuels
short-term excursion limit of 0.15 pm and lubricants
(0.75 mg/m3) and a notation for skin
absorption. Exposure. Inhalation
710 ppm for a 4-hour exposure, and in mice the known how this excessive protein accumulation
LC50 was 1085 ppm, also for a 4-hour expo- (specically, a2u-globulin, a low-molecular-
sure.2,4 A 4-hour inhalation exposure of eight weight glycoprotein) results in renal tubular
rats at 1000 ppm caused tremors, convulsions, cell death, but it does not appear to be caused
and death in three of the animals.5 through an autolytic process induced by lyso-
Subchronic exposure of rats, mice, and somal enzyme leakage. Studies have shown that
guinea pigs to 50 or 250 ppm, 6 hours/day for although decalin exposure induced enlarged
1 month produced different effects in the dif- lysosomes in renal tubular cells of treated male
ferent species. Rats exhibited increased cyto- rats, the lysosomes remained intact.8
plasmic hyaline droplet formation in the renal Other reports have conrmed the species-
tubule epithelium, whereas mice exposed to the and sex specicity for kidney toxicity by
higher concentration developed hepatocellular decalin. Relevance to human exposure has not
cytoplasmic vacuolization. Guinea pigs had been established.8
signs of alveolar irritation that was not dose Decalin was not mutagenic in bacterial
related.5 assays in vitro but caused a small but signicant
An additional, longer-term study of dogs, increase in micronucleated normochromatic
rats, and female mice exposed to 5 or 50 ppm erythrocytes in male mice treated in vivo.6
for 90 days was also conducted.2 No distinct The mild terpinelike odor of decalin may
exposure-related effects were noted in dogs or not provide adequate warning of exposure.
in female rats; mild, reversible liver damage was A threshold limit value (TLV) has not been
noted in mice. In male rats, decalin exposure established for decalin.
produced nephropathy.
Recent studies found clear evidence of car-
cinogenicity of decalin in male rats exposed for REFERENCES
2 years at 100 and 400 ppm, based on increased
incidences of renal tubule neoplasms; in- 1. Longacre SL: Decalin. In Snyder R (ed): Ethel
creased incidences of pheochromocytoma of Brownings Toxicity and Metabolism of Industrial
the adrenal medulla were also considered to Solvents, 2nd ed, Vol I, Hydrocarbons, pp
be exposure related.6 Neither neoplasms or 242249. New York, Elsevier, 1987
chemical-related kidney lesions occurred in 2. Gaworski CL, Haun CC, MacEwen JD, et al:
female rats. Equivocal evidence of carcino- A 90-day vapor inhalation toxicity study of
genicity was reported in female mice exposed decalin. Fundam Appl Toxicol 5:785793, 1985
3. Browning E: Cyclic hydrocarbons. 14.
at 25, 100, and 400 ppm for 2 years, based on
Decalin. In Toxicity and Metabolism of Industrial
marginally increased incidences of hepatocellu-
Solvents, pp 138140. New York, Elsevier,
lar and uterine neoplasms. Nonneoplastic 1965
lesions of the liver, including centrilobular 4. Gaworski CL, Leahey HF: Subchronic
hypertrophy and necrosis, were signicantly inhalation toxicity of decalin. pp 226237. Pro-
increased in male mice exposed at 400 ppm. ceedings, 10th Conference on Environmental Tox-
Additional studies of decalin exposure in icology, University of California, Irvine,
rats have characterized the specic sequence of November, 1979
renal alterations: rst the variable occurrence 5. Gage JC: The subacute inhalation toxicity of
of light-microscopically evident proximal con- 109 industrial chemicals. Br J Ind Med 27:
voluted tubule epithelial cell necrosis, presum- 118, 1970
6. National Toxicology Program: Toxicology and
ably a reection of cellular injury associated
Carcinogenesis Studies of Decalin (CAS No. 91-
with excessive protein accumulation (hyaline
17-8) in F344/N Rats and B6C3F1 Mice and a
droplets); then the occurrence of granular casts Toxicology Study of Decalin in Male NBR Rats
at the junction of the inner and outer bands of (Inhalation Studies), NTP TR 513, pp 195.
the outer zone of the medulla; and nally, Washington DC, US Department of Health
chronic nephrosis, occurring secondary to and Human Services, 2003
tubular obstruction by granular casts.7 It is not 7. Kanerva RL, McCracken MS, Alden CL,
206 DEMETON
of 7 or 10 mg/kg or as three consecutive doses Uses. Solvent for pigments, cellulose, resins,
of 5 mg/kg, demeton was found to be embry- oils, fats, and hydrocarbons; hydraulic brake
otoxic (decreased fetal weight and higher mor- uid; antifreeze
tality). A few minor skeletal abnormalities were
produced at the 5 mg/kg dose level.4 Exposure. Inhalation; minor skin absorption
Demeton was mutagenic in bacterial
assays.4 A single dose injected intraperitoneally Toxicology. Diacetone alcohol causes irrita-
induced chromosomal aberrations in the bone tion of the eyes and respiratory tract; at high
marrow of Syrian hamsters.5 concentrations it causes narcosis in animals,
The 2003 ACGIH threshold limit value- and it is expected that severe exposure will
time-weighted average (TLV-TWA) for cause the same effect in humans.
demeton is 0.01 ppm (0.11 mg/m3) with a nota- Most human subjects exposed to 100 ppm
tion for skin absorption. for 15 minutes complained of eye, nose, and
throat irritation; exposure to 400 ppm also
caused chest discomfort.1,2
REFERENCES Animals exposed to 2100 ppm for 13
hours exhibited restlessness, mucous mem-
1. Hayes WJ Jr: Organic phosphorus pesticides. brane irritation, and drowsiness.3 Rats exposed
In Pesticides Studied in Man, pp 284435. Bal- to 1500 ppm for 8 hours survived.4 Injection of
timore, MD, Williams & Wilkins, 1982 3 ml/kg or intragastric administration of 5 ml/
2. Koelle GB (ed): Cholinesterases and anti-
kg diacetone alcohol in rabbits caused respira-
cholinesterase agents. Handbuch der Experi-
tory depression, narcosis, and death.5 A tem-
mentellen Pharmakologie, Vol 15, pp 9891027.
Berlin, Springer-Verlag, 1963 porary decrease in the number of erythrocytes
3. Taylor P: Anticholinesterase agents. In Gilman in the blood of rats was observed for 14 days
AG et al. (eds): Goodman and Gilmans The after intragastric administration of 2 ml/kg of
Pharmacological Basis of Therapeutics, 7th ed, pp diacetone alcohol; hepatic lesions characterized
110129. New York, MacMillan, 1985 by vacuolization and granulation of the
4. World Health Organization: Data Sheets parenchymal cells were noted, but recovery was
on Pesticides No. 60. Demeton. pp 1 complete in 7 days.6
12.http://www.inchem.org/documents/pds/pds/ The liquid defats the skin and may produce
pest60_e.htm dermatitis with prolonged or repeat contact; in
5. Dzwonkowska A, Hubner H: Induction of
the eyes, it causes moderate to marked irrita-
chromosomal aberrations in the Syrian
tion and transient corneal damage.3
hamster by insecticides tested in vivo. Arch
Toxicol 58(3):152156, 1986 The odor threshold of diacetone alcohol is
0.28 ppm, which should provide adequate
warning of exposure.7
The 2003 ACGIH threshold limit value-
time-weighted average (TLV-TWA) for diace-
tone alcohol is 50 ppm (238 mg/m3).
DIACETONE ALCOHOL
CAS: 123-42-2
(CH3)2C(OH)CH2COCH3 REFERENCES
Clayton FE (eds): Pattys Industrial Hygiene dermatitis, blistering, and uticaria; in the eye it
and Toxicology, 3rd ed, Vol 2C, Toxicology, causes irritation and lacrimation. Repeated or
pp 47544756. New York, Wiley-Interscience, prolonged contact may result in sensitization.1
1982 Tests in symptomatic polyurethane foam
4. Smyth HF: Improved communication workers indicate that TDA does not produce
hygienic standards for daily inhalation. Am Ind
asthma.2
Hyg Assoc Q 17:129185, 1956
5. Walton DC, Kehr EF, Lovenhart AS: A TDA was tested for carcinogenicity in the
comparison of the pharmacological action diet of F344 rats at time-weighted average
of diacetone alcohol and acetone. J Pharmacol doses of 79, 176 (males), and 171 (females) ppm
33:175183, 1928 TDA for 103 weeks.3 Rats of both sexes
6. Keith HM: Effect of diacetone alcohol on had hepatocellular carcinomas or neoplastic
the liver of the rat. Arch Pathol 13:707712, nodules. The signicance of these tumors in
1932 both sexes was supported by a high incidence
7. National Institute for Occupational Safety and of associated nonneoplastic lesions of the liver.
Health: Occupational safety and health guidelines Female rats also had carcinomas or adenomas
for chemical hazards. Supplement II-OHG (Pub. of the mammary gland in a dose-related
No. 89-104). Occupational safety and health
manner and at a higher incidence than in con-
guideline for diacetone alcohol, pp 16.
Cincinnati, OH, 1988 trols. In mice fed dietary levels of 100 or
200 ppm TDA for 101 weeks females had
excess hepatocellular carcinomas, whereas no
tumor excess occurred in the male mice.
After in vivo administration in rats TDA
induced formation of both DNA and hemo-
globin adducts in a dose-dependent manner.4
2,4-DIAMINOTOLUENE TDA was mutagenic in bacterial assays.1
CAS: 95-80-7 TDA was a reproductive toxin in male rats.
Administration of 15 mg/kg body weight/day
C7H10N2 for 10 weeks resulted in a signicant reduction
in spermatogenesis, reduced weights of seminal
vesicles and epididymides, diminished circulat-
Synonyms: TDA; 2,4-TDA; toluene-2,4- ing testosterone, and an elevation in serum
diamine; 3-amino-p-toluidine; 1,3-diamino-4- luteinizing hormone.1 A study of 84 TDA-
methylbenzene exposed workers found no differences in sperm
count, sperm morphology, or other reproduc-
Physical Form. Crystalline solid tive parameters compared with nonexposed
workers.5
Uses. Intermediate in the production of A threshold limit value (TLV) for TDA has
toluene diisocyanate, which is used to produce not been assigned.
polyurethane; in the production of dyes
3. National Toxicology Program: Bioassay of 2,4- tory distress leading to pneumonitis and death
Diaminotoluene for Possible Carcinogenicity (CAS on the fourth day after exposure.1
No. 95-80-7). Technical Report Series No. A physician exposed to diazomethane from
162. Springeld, VA, National Technical a laboratory spill noted only a faint odor but
Information Service, US Department of immediately experienced severe headache,
Commerce, 1979
cough, mild anterior chest pain, generalized
4. Wilson PM, LA DK, Froines JR: Hemoglobin
and DNA adduct formation in Fischer-344 aching of muscles, and a sensation of over-
rats exposed to 2,4- and 2,6-toluene diamine. whelming tiredness.2 Within 5 minutes he was
Arch Toxicol 70(10):591598, 1996 stuporous, and on admission to a hospital he
5. Hamill PV, Steinberger E, Levine RJ, was markedly ushed and feverish; he recov-
Rodriguez-Rigau LJ, Lemeshow S, Avrunin ered in approximately 48 hours. Subsequent
JS: The epidemiologic assessment of male exposure to trace amounts of the gas produced
reproductive hazard from occupational wheezing, cough, and malaise, leading to the
exposure to TDA and DNT. J Occup Med suspicion that this substance may also have a
24:985993, 1982 sensitizing effect on the respiratory system.
Skin exposure has produced irritation and
denudation.3
Exposure of cats to 175 ppm for 10 minutes
resulted in pulmonary edema and hemorrhage,
with death occurring in 3 days.1 Limited animal
DIAZOMETHANE studies indicate that diazomethane is carcino-
CAS: 334-88-3 genic in mice (increased incident of lung
tumors after skin application) and rats (expo-
CH2N2 sure to the gas caused lung tumors).4 The
IARC has determined that there is limited evi-
dence of carcinogenicity in animals and that the
Synonyms: Azimethylene; diazirine agent is not classiable as to its carcinogenicity
to humans (Group 3).5
Physical Form. Yellow gas The warning properties of diazomethane
are poor.3
Uses. Powerful methylating agent for acidic The 2003 ACGIH threshold limit value-
compounds such as carboxylic acids, phenols, time-weighted average (TLV-TWA) for dia-
enols; not manufactured for sale and distribu- zomethane is 0.2 ppm (0.34 mg/m3).
tion because of toxicity and explosivity
Carcinogenic Risk of Chemicals to Man, Vol. 7, uated in a variety of short-term genetic toxi-
Some anti-thyroid and related substances, cology assays and was positive in most systems.5
nitrofurans and industrial chemicals, pp DBA undergoes metabolism to form several
223230. Lyon, International Agency for reactive intermediates. The 3,4-dihydrodiol
Research on Cancer, 1974 metabolite of DBA is thought to be further
5. IARC Monographs On the Evaluation of the
metabolized to a 3,4-diol-1,2-epoxide, the ulti-
Carcinogenic Risk of Chemicals to Man, Suppl
7, Overall evaluations of carcinogenicity: An mately mutagenic metabolite. Thus the geno-
updating of IARC monographs volumes 1 to toxicity of DBA is dependent on metabolic
42, p 61. Lyon, International Agency for activation, either exogenously supplied or
Research on Cancer, 1987 endogenously present, and the ratio of enzy-
matic activation and detoxication pathways.
The carcinogenic properties could also depend
on methyl substitution of DBA and the forma-
tion of an aralkylating metabolite.6
Most human exposure to DBA in the envi-
DIBENZ[a,h]ANTHRACENE ronment or workplace occurs when it is particle
CAS: 53-70-3 bound and a component of complex mixtures
of polycyclic aromatic hydrocarbons. Thus it
C22H14 has not been possible to study the effects of
human exposure to DBA alone.
The IARC considers that there is sufcient
Synonyms: DBA; dibenzo[a,h]anthracene; evidence that DBA is carcinogenic in experi-
1,2:5,6-dibenzanthracene mental animals and that it is probably carcino-
genic to humans.7
Physical Form. Colorless solid No threshold limit value (TLV) has been
assigned for DBA.
Sources. Dibenz[a,h]anthracene (DBA) is a
major component of polynuclear aromatic
hydrocarbons, also known as polycyclic aro- REFERENCES
matic hydrocarbons, and is usually bound to
small particulate matter present in urban air, 1. Berenblum I, Haran N: The inuence of
industrial and natural combustion emissions, croton oil and of polyethylene glycol-400 on
carcinogenesis in the forestomach of the
and cigarette smoke.
mouse. Cancer Res 15:510516, 1955
2. Bianciori C, Caschera F: The relation
Exposure. Inhalation between pseudo-pregnancy and the chemical
induction by four carcinogens of mammary
Toxicology. DBA produced carcinomas in and ovarian tumours in BALB/c mice. Br J
animals after oral or dermal exposure and injec- Cancer 16:722730, 1962
tion site tumors after subcutaneous or intra- 3. Wynder EL, Hoffman D: A study of tobacco
muscular administration. carcinogenesis. VII. The role of higher poly-
Mammary carcinomas and forestomach cyclic hydrocarbons. Cancer 12:10791086,
papillomas were observed in mice after gavage 1959
administration.1,2 DBA has also been shown to 4. Van Duuren BL et al: Carcinogenicity of epox-
ides, lactones, and peroxy compounds. VI.
cause skin papillomas and carcinomas in mice
Structure and carcinogenic activity. J Natl
when applied dermally 3 times/week for a life-
Cancer Inst 39:12171228, 1967
time.35 Subcutaneous injection of 1 mmol of 5. Agency for Toxic Substances and Disease
DBA three times weekly for 20 doses induced Registry: Toxicological Prole for
injection site sarcomas in 100% of female Dibenz[a,h]anthracene. ATSDR/TP-88/13, pp
Sprague-Dawley rats by 33 weeks.6 2340. Atlanta, GA, Public Health Service,
The genetic toxicity of DBA has been eval- Centers for Disease Control, 1990
DIBORANE 211
6. Flesher JW, Horn J, Lehner AF: Comparative caused pulmonary edema and hemorrhage and
carcinogenicity of picene and dibenz(a, temporary damage to the liver and kidneys.6
h)anthracene in the rat. Biochem Biophys Res Repeated exposure of dogs at about 5 ppm for
Commun 290:275279, 2002 6 hours/day resulted in death after 1025
7. IARC Monographs on the Evaluation of the exposures; 1 of 2 animals survived repeated
Carcinogenic Risk of Chemicals to Humans,
exposure at 12 ppm for 6 months.7 Repeated
Vol 32, Polynuclear aromatic compounds,
Part 1, Chemical, environmental and experi- respiratory insult was thought to be the under-
mental data, pp 299308. Lyon, International lying cause of death.
Agency for Research on Cancer, December In more recent studies the LD50 for male
1983 mice was 31.5 ppm for a 4-hour exposure.8
After exposure at 15 ppm for up to 8 hours,
decreased body weight and severe inamma-
tory changes in the lungs were seen in the mice.
Cellular inltration, bleeding, edema, and con-
gestion occurred in mice with the longest expo-
DIBORANE sures. At a dose of 5 ppm for 2 or 4 weeks,
CAS: 19287-45-7 increases in leukocytes and erythrocytes were
observed in addition to inammatory changes
B2H6 in the lungs.8 At concentrations of 0.2 or
0.7 ppm 6 hours/day, 5 days/week for 2 or 4
weeks, there was slight inltration of polymor-
Synonyms: Boroethane; boron hydride phous neutrophils in the peribronchiolar
region.9 In rats subacute exposures of 0.11 or
Physical Form. Gas 0.96 ppm 6 hours/day, 5 days/week for 8
weeks induced dose-related changes in the
Uses. High-energy fuel; reducing agent; ini- lungs, including increased neutrophil and
tiator of polymerization of ethylene, vinyl, and macrophage counts without evidence of
styrene; source of boron for the semiconductor histopathologic damage.10
industry The threshold of odor detection is approx-
imately 3.3 ppm; the repulsive odor is described
Exposure. Inhalation as rotten eggs, sickly sweet, musty, or foul.6
The 2003 ACGIH threshold limit value-
Toxicology. Diborane is a pulmonary irri- time-weighted average (TLV-TWA) for dibo-
tant. rane is 0.1 ppm (0.11 mg/m3).
In humans, overexposure results in a
sensation of tightness in the chest, leading to
precordial pain, shortness of breath, nonpro- REFERENCES
ductive cough, and sometimes nausea.14 Pro-
longed exposure to low concentrations causes 1. Lowe HJ, Freeman G: Boron hydride
headache, light-headedness, vertigo, chills, (boron) intoxication in man. AMA Arch Ind
and, less frequently, fever. Fatigue or weakness Health 16:523533, 1957
occurs and may persist for several hours; 2. Cordasco EM, Cooper RW, Murphy JV,
tremor or muscular fasciculations occur infre- Anderson C: Pulmonary aspects of some
toxic experimental space fuels. Dis Chest
quently and are usually localized and of short
41:6874, 1962
duration. Diborane gas has not been found to
3. Roush G Jr: The toxicology of the boranes.
have signicant effects on contact with skin or J Occup Med 1:4652, 1959
mucous membranes, although high concentra- 4. Rozendaal HM: Clinical observations on the
tions may cause eye irritation.5 toxicology of boron hydrides. AMA Arch Ind
The LC50 for rats was 50 ppm for 4 hours; Hyg Occup Med 4:257260, 1951
in other animal experiments, acute exposure 5. MCA, Inc.: Chemical Safety Data Sheet, SD-
212 1,2-DIBROMO-3-CHLOROPROPANE
84, Boron Hydrides, pp 57. Washington, DC, exposed male workers, 11 had abnormally low
MCA, Inc., 1961 sperm counts of less than 1 million/ml; all had
6. Holzmann RT (ed): Production of the Boranes been exposed for at least 3 years. None with
and Related Research, pp 289294, 329331, sperm counts above 40 million had been
433489. New York, Academic Press, 1967 exposed for more than 3 months.2
7. Comstock CC et al: Research Report No 258.
Subsequent studies in this and three other
Washington, DC, US Army Chemical Corps,
Medical Laboratories, March 1954 DBCP plants showed a total of more than 100
8. Uemura T, Omae K, Nakashima H, et al: cases of oligospermia or aspermia. Exposures in
Acute and subacute inhalation toxicity of one plant were estimated at 100600 ppb.1
diborane in male ICR mice. Arch Toxicol A larger clinical-epidemiological study of
69(6):397404, 1995 these men was undertaken to determine the
9. Nomiyama T, Omae K, Uemura T, et al: No- exposure-effect relationships involved. Of
observed-effect level of diborane on the res- 142 nonvasectomized men providing semen
piratory organs of male mice in acute and samples, 107 had been exposed to DBCP and
subacute inhalation experiments. J Occup 35 had not been exposed. There was a clear-cut
Health 37(3):157160, 1995 difference in both the distribution of sperm
10. Nomiyama T, Omae K, Ishizuka C, et al:
counts and the median counts between the
Evaluation of the subacute pulmonary and
testicular inhalation toxicity of diborane in exposed men and the nonexposed men. Of the
rats. Toxicol Appl Pharmacol 138(1):7783, exposed men, 13.1% were azoospermic, 16.8%
1996 were severely oligospermic, and 15.8% were
mildly oligospermic.3 A follow-up study
reported some recovery among 30 azoospermic
and oligospermic workers who had a minimum
of 18 months of exposure during 19761977.4
Of the 26 azoospermic subjects who voluntar-
1,2-DIBROMO-3-CHLOROPROPANE ily participated in follow-up, 19 (73.0%)
CAS: 96-12-8 showed evidence of spermatogenesis recovery.
Thirteen azoospermic subjects recovered to
C3H5Br2Cl normospermic levels; however, their mean
most recent sperm count (44.4 million/ml) was
signicantly lower than the mean (88.8
Synonyms: DBCP; dibromochloropropane million/ml) of the 17 oligospermic subjects
who recovered to normospermic levels. The
Physical Form. Colorless to yellow liquid lack of spermatogenesis recovery was deni-
tively shown to be job- and, possibly, age-
Uses. Formerly as an agricultural nemato- related. The follicle-stimulating hormone level
cide (use banned in the US in 1977) in 1977 was signicantly associated with
azoospermia, as well as the likelihood of return
Exposure. Inhalation; skin absorption to normospermia among the azoospermic sub-
jects. After 17 years of follow-up, it was deter-
Toxicology. 1,2-Dibromo-3-chloropropane mined that sperm count recovery tended to be
(DBCP) is a mild central nervous system evident within 3645 months of last exposure,
depressant and causes sterility in male workers with no improvement after that.5
due to a selective effect on seminiferous A recent cohort study of 26,000 workers
tubules. from 12 countries outside the US found that
DBCP has caused oligospermia and asper- after a median exposure to DBCP of 3 years,
mia in male workers.1 Initial documentation of 64% of the men overall, and 90% of the men
these effects occurred in workers engaged in studied from the Philippines, had azoospermia
the production of DBCP at an agricultural or oligospermia.6 The percentage of men with
chemical plant in Lathrop, California. Of 27 no children was 28.5% overall.
1,2-DIBROMO-3-CHLOROPROPANE 213
Male exposure to DCBP has also been multiple pesticide exposures, and lack of
associated with an increased frequency of spon- exposure data.14 The IARC has determined
taneous abortions in wives of exposed workers, that there is sufcient evidence in experimen-
but congenital abnormalities have not been tal animals for the carcinogenicity of DBCP
reported among children of workers who and that it is possibly carcinogenic to humans.14
received sufcient DBCP exposure to induce DBCP is a genotoxic in microbial and
oligospermia.7,8 mammalian assays.8 The mechanism for
Other effects reported by exposed workers DBCP-induced testicular toxicity may be
include headache, nausea, light-headedness, related to direct DNA damage. Binding of
and weakness.8 DBCP metabolites to testicular cell DNA has
In animal studies, effects of exposure been demonstrated. Alternatively, inhibition of
include increased mortality, gonadal atrophy, sperm carbohydrate metabolism could also
and carcinomas. The LC50 for rats was 368 ppm account for DBCP toxicity to epididymal
for 1 hour and 103 ppm for 8 hours.9 Irritation sperm.
of the eyes and respiratory tract was observed The odor of DBCP was detected at 1.7
at levels of 60 ppm and higher. Moderate ppm, the only level tested.8
depression of the central nervous system was The ACGIH has not established a thresh-
manifested as sluggishness and ataxia. old limit value (TLV) for 1,2-dibromo-3-
In rats of both sexes given 5066 exposures chloropropane.
to 12 ppm over 7090 days, 4050% of the
animals died.9 Although death was attributed to
lung infection, the most striking observation in
REFERENCES
males at autopsy was severe atrophy and degen-
eration of the testes. There were also degener- 1. Department of Labor: Emergency temporary
ative changes of the seminiferous tubules, standard for occupational exposure to 1,2
reduction in sperm count, and abnormal devel- dibromo-3-chloropropane (DBCP). Fed Reg
opment of sperm cells. Other effects were mild 42:45535, 1977
damage to the liver and kidneys. 2. Whorton D, Krauss RM, Marshall S, et al:
The liquid applied undiluted to the eye of Infertility in male pesticide workers. Lancet
a rabbit caused transient irritation.9 An LD50 of 2:12591261, 1977
1.4 g/kg was obtained when the material was 3. Whorton D, Milby TH, Krauss RM, et al:
applied undiluted for 24 hours to the rabbit Testicular function in DBCP exposed pesti-
cide workers. J Occup Med 21:161166, 1979
skin. Repeated application (20 times) to the
4. Olsen GW, Laham JM, Bodner KM, et al:
skin of a rabbit caused slight crustiness.
Determinants of spermatogenesis recovery
However, the dermis and subcutaneous tissue among workers exposed to 1,2-dibromo-3-
showed extensive necrosis. chloropropane. J Occup Med 32:979984,
In a study of carcinogenesis, DBCP was 1990
orally administered to rats and mice 5 5. Potashnik G, Porath A: Dibromochloro-
times/week at maximally tolerated doses and at propane (DBCP): a 17-year reassessment of
half those doses.1012 As early as 10 weeks after testicular function and reproductive perform-
initiation of treatment, there was a high inci- ance. J Occup Environ Med 37(11):12871292,
dence of squamous cell carcinomas of the 1995
stomach in both species. In female rats there 6. Slutsky M, Levin JL, Levy BS: Azospermia
and oligospermia among a large cohort of
were also mammary adenocarcinomas. Chronic
DBCP applicators in 12 countries. Int J Occup
inhalation resulted in carcinomas of the respi-
Environ Health 5(2):116122, 1999
ratory tract in mice and multiple site tumors in 7. Kharrazi M, Potashnik G, Goldsmith JR:
rats.13 Reproductive effects of dibromochloro-
Cohort studies have reported excess lung, propane. Isr J Med Sci 10:403406, 1980
liver, bilary, and cervical cancer but are limited 8. Agency for Toxic Substances and Disease
by small numbers, insufcient follow-up time, Registry (ATSDR): Toxicological Prole for 1,2-
214 2-N-DIBUTYLAMINOETHANOL
dibutylaminoethanol is 0.5 ppm (3.5 mg/m3) body weight have been reported in mice and
with a notation for skin absorption. rats.1 Oral administration to mice at lethal
doses produces weight loss, dyspnea, and
enlarged lungs with pulmonary edema and
REFERENCES hemorrhage. Repeated administration of BHT
causes impaired function and histologic
1. Cornish HH, Dambrauskas T, Beatty LD: changes in the liver, kidneys, and thyroid and
Oral and inhalation toxicity of 2-N-dibuty- impaired coagulation of the blood. On the skin
laminoethanol. Am Ind Hyg Assoc J 30:4651, or eye of rabbits it is slightly irritating, but it
1969
has no sensitizing effect in guinea pigs.
2. Smyth HF, Carpenter CP, Weil CS, et al:
Several chronic feeding studies have been
Range-nding toxicity data. List V. Arch Ind
Hyg Occup Med 10:6168, 1954 conducted in mice and rats. Results have been
3. US Department of Health and Human Ser- either no difference in tumor incidence or
vices (NIOSH): Occupational safety and health increased pulmonary tumors (mice) or pituitary
guidelines for chemical hazards. Supplement IV- adenomas (rats) at the low dose but not the
OHG (Pub No 95-121), Occupational safety high dose.24
and health guideline for 2-n-dibuty- The IARC has determined that there is
laminoethanol, pp 17. Cincinnati, OH, 1995 limited evidence for the carcinogenicity of
4. Zeiger E, Anderson B, Haworth S, et al: Sal- BHT in experimental animals.5
monella mutagenicity tests: III. Results from BHT has given primarily negative results
the testing of 255 chemicals. Environ Mol
in a large number of in vivo and in vitro geno-
Mutagen 9(suppl 9):1110, 1987
toxic assays.1
No signicant reproductive effects were
observed in three-generation toxicity studies in
mice administered up to 0.4% in the diet.6
The 2003 ACGIH threshold limit value-
2,6-DI-tert-BUTYL-p-CRESOL time-weighted average (TLV-TWA) for 2,6-di-
CAS: 128-37-0 tert-butyl-p-cresol is 2 mg/m3.
C15H24O
REFERENCES
Synonyms: BHT; butylated hydroxytoluene;
1. S. Hirzel Verlag: Butylated hydroxytoluene.
DBPC; 2,6-bis(1,1-dimethylethyl)-4-methyl- Beratergremium fuer umweltrelevante Altstoffe
phenol (BUA) 58:1124, 1994
2. Clapp NK, Tyndall RL, Sattereld LC, et al:
Physical Form. White, crystalline solid Selective sex-related modication of diethylni-
trosamine-induced carcinogenesis in BALB/c
Uses. Antioxidant used to preserve fat- mice by concomitant administration of buty-
containing foods and stabilize rubber, plastics, lated hydroxytoluene. J Natl Cancer Inst 61:
petroleum 177182, 1978
3. National Cancer Institute: Bioassay of Butylated
Exposure. Ingestion Hydroxytoluene (BHT) for Possible Carcinogenic-
ity (CAS No. 128-37-0). (Tech. Rep Ser No
150), Bethesda, MD, 1979
Toxicology. 2,6-Di-tert-butyl-p-cresol or 4. Hirose M, Shibata M, Hagiwara A, et al:
BHT is of relatively low acute toxicity in Chronic toxicity of butylated hydroxytoluene
animals, and there is no evidence of either in Wistar rats. Food Cosmet Toxicol 19:147151,
acute or chronic effects among exposed 1981
workers. 5. IARC Monographs on the Evaluation of the Car-
Oral LD50 values in the range of 2 g/kg cinogenic Risk of Chemicals to Humans, Vol 40,
216 DIBUTYL PHENYL PHOSPHATE
Some naturally occurring and synthetic food exposure male rats also had increased liver
components, furocoumarins and ultraviolet weights and decreased hematocrit values after
radiation, pp 161206. Lyon, International 13 weeks.
Agency for Research on Cancer, 1986 DBPP was administered to male and
6. Tanaka T, Oishi S, Takahashi O: Three gener- female rats in their diets in separate subchronic
ation toxicity study of butylated hydroxy-
(91 day) and two-generation reproduc-
toluene administered to mice. Toxicol Lett
66(3):295304, 1993 tion studies.2 Dose levels were 5, 50, and
250 mg/kg/day in both studies. In the repro-
duction study, cross-fostering was performed
between some high-exposure and control litter
offspring and dams after a second mating of F0
animals. Compared with control animals, body
DIBUTYL PHENYL PHOSPHATE weights were consistently lower in high-expo-
CAS: 2528-36-1 sure adult animals in both studies. High-expo-
sure rats in the subchronic study had decreased
C14H23PO4 erythrocyte counts and hematocrit and hemo-
globin levels. They also had increased liver
weights. In the reproduction study, mating and
Synonyms: DBPP; phosphoric acid, dibutyl fertility indices were comparable among the
phenyl ester parental animals in both generations, but sur-
vivability among high-exposure pups reared by
Physical Form. Slightly yellow liquid control dams appeared to be decreased.
Urinary bladder histopathologic changes, con-
Uses. Component in hydraulic uids sisting of mononuclear cell inltration and
transitional epithelial hyperplasia, were noted
Exposure. Inhalation; skin absorption in mid- and high-exposure rats from both
studies. The no observable adverse effect level
Toxicology. Dibutyl phenyl phosphate in both of these studies was 5 mg/kg/day.
(DBPP) has caused skin irritation in humans DBPP was tested for its potential to cause
after repeated or prolonged contact. organophosphorus compound-induced delayed
Skydrol 500B-4 re-resistant hydraulic neurotoxicity (OPIDN) in the adult hen.3 The
uid, a proprietary phosphate ester mixture acute oral LD50 of DBPP was estimated to be
composed principally of DBPP and tributyl 1,500 mg/kg and was used as a test dose. Hens
phosphate, was evaluated in an inhalation were given two doses of DBPP 21 days apart
study.1 Rats were exposed to respirable levels and killed 21 days after the second dose. None
of 5, 100, and 300 mg/m3 for 6 hours/day, 5 of the hens given DBPP exhibited nerve
days/week. After 6 weeks of exposure, 10 damage or clinical signs that were different
rats/sex/group were euthanized and assessed from untreated control animals. The results
for indications of toxicity. Another 15 suggest that DBPP is unlikely to cause OPIDN
rats/sex/group were studied after a total of 13 with any single sublethal dose.
weeks of exposure. The only clinical sign of DBPP is not considered to be a primary
toxicity was a reddish nasal discharge with irritant or a sensitizing agent based on patch
accompanying oral salivation in mid- and high- testing of 50 human volunteers.4 Repeated or
exposure animals of both sexes, indicative of an prolonged contact with the skin has caused
irritant response. Reduced body weights, drying and cracking of exposed skin.
increased liver weights, and decreased erythro- The 2003 ACGIH threshold limit value-
cyte counts, hemoglobin levels, and hematocrit time-weighted average (TLV-TWA) is
values were observed in high-exposure female 0.3 ppm (3.5 mg/m3) with a notation for skin
rats after 13 weeks of Skydrol exposure. High- absorption.
DIBUTYL PHTHALATE 217
(n-C4H9O)2(OH)PO
DIBUTYL PHTHALATE
CAS: 84-74-2
Synonyms: Dibutyl hydrogen phosphate; di-n-
butyl phosphate C16H22O4
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Synonyms: 1,2-Dichlorobenzene; dichloro-
1. Humphrey JH, McClelland M: Cranial nerve benzol; dichloricide
palsies with herpes following general anaes-
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County Hospital. Br Med J 1:315318,
1946
Uses. Organic synthesis (primarily 3,4-
2. Greim H, Wolff T, Hoer M, Lahaniatis E:
Formation of dichloroacetylene from
dichloroaniline); solvent; insecticide; dye
trichloroethylene in the presence of alkaline manufacture
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solvents. Arch Toxicol 256:7477, 1984
3. Saunders RA: A new hazard in closed envi- Toxicology. o-Dichlorobenzene is a skin and
ronment atmospheres. Arch Environ Health eye irritant. At high doses, it causes central
14:380384, 1967 nervous system depression and liver and kidney
4. US Department of Health and Human Ser-
damage in animals. Heavy exposure is expected
vices (NIOSH): Occupational safety and health
guidelines for chemical hazards. Supplement IV-
to produce the same effects in humans.
OHG (pub no 95121), Occupational safety In humans, eye irritation is not usually
and health guideline for dichloroacetylene, evident below 20 ppm but becomes noticeable
pp 18. Cincinnati, OH, 1995 at 2530 ppm and painful to some at 60
5. Henschler D, Broser F, Hopf HC: Polyneu- 100 ppm if exposures are for more than a few
ritis cranialis following poisoning with chlo- minutes duration.1 Some acclimation may
rinated acetylenes while handling vinylidene occur but not to a great extent. Workers
chloride copolymers. (Ger.) Arch Toxicol exposed to concentrations ranging from 1 to 44
26:6275, 1970 ppm and averaging 15 ppm showed no indica-
6. Reichert D, Liebaldt G, Henschler D: Neu- tion of injury or of untoward hematologic
rotoxic effects of dichloroacetylene. Arch
effect.2 Accidental exposure of 26 subjects to
Toxicol 37:2328, 1976
7. Reichert D, Henschler D, Bannasch P:
unspecied levels 8 hours/day for 4 days caused
Nephrotoxic and hepatotoxic effects of eye, nose, and throat irritation.3 Ten of the 26
dichloroacetylene. Food Cosmet Toxicol subjects reported dizziness, severe headache,
16:227235, 1978 fatigue, and nausea. Chromosome studies
8. Reichert D, Spengler U, Romen W, Hen- showed signicant alterations in the leukocytes
schler D: Carcinogenicity of dichloroacety- of exposed workers, which appeared reversible
lene: An inhalation study. Carcinogenesis 6 months later.
5:14111420, 1984 The liquid left on the skin may produce
9. Dekant W, Vamvakas S, Koob M, et al: A blistering, and later the area may become pig-
mechanism of haloalkene-induced renal car- mented.2 Sensitization dermatitis has been
cinogenesis. Environ Health Perspect 88:107
reported.2
110, 1990
10. IARC Monographs on the Evaluation of the Car-
Rats died from exposure to 977 ppm for 7
cinogenic Risk of Chemicals to Humans, Vol 71, hours but survived when exposed for only 2
Re-evaluation of some organic chemicals, hours; animals survived exposure to 539 ppm
hydrazine and hydrogen peroxide, p. 1381. for 3 hours but at necropsy showed marked
Lyon, International Agency for Research on centrilobular necrosis of the liver, as well as
Cancer, 1999 cloudy swelling of the tubular epithelium of the
p-DICHLOROBENZENE 221
kidney.2 During exposure rats exhibited 2. Hollingsworth RL, Rowe VK, Oyen R, et al:
drowsiness, unsteadiness, eye irritation, dif- Toxicity of o-dichlorobenzene. AMA Arch Ind
culty in breathing, and anesthesia. Several Health 17:180187, 1958
species of animals exposed for periods of 6 or 3. Zapata-Gayon C, et al: Clastogenic chromo-
7 months to 93 ppm for 7 hours daily showed somal aberrations in 26 individuals acciden-
tally exposed to ortho dichlorobenzene vapors
no adverse effects.2
in the National Medical Center in Mexico
Studies with male F344 rats have shown City. Arch Environ Health 37:231235, 1982
that o-dichlorobenzene was more toxic to the 4. Valentovic MA, Ball JG, Anestis D, et al: Acute
liver and kidneys than the meta- and para- hepatic and renal toxicity of dichlorobenzene
isomers after a single administration.4 In addi- isomers in Fischer 344 rats. J Appl
tion to isomer specicity, strain-specic Toxicol 13:17, 1993
differential toxicity has also been demon- 5. Stine ER, Gunawardhana L, Sipes IG: The
strated, with Sprague-Dawley rats being rela- acute hepatotoxicity of the isomers of
tively resistant to the acute hepatic toxicity of dichlorobenzene in Fischer-344 and Sprague-
o-dichlorobenzene.5 Dawley rats: isomer-specic and strain-specic
Repeated dermal application to rats was differential toxicity. Toxicol Appl Pharmacol 109:
472481, 1991
fatal.6 The liquid instilled in the rabbit eye pro-
6. US Environmental Protection Agency: Health
duced apparent distress and slight conjunctival Assessment Document for Chlorinated Benzenes,
irritation.2 Final Report. Washington, DC, Ofce of
There was no evidence of carcinogenicity Health and Environmental Assessment,
in rats or mice receiving 60 or 120 mg/kg January 1985
by gavage 5 times per week for 2 years.7 The 7. National Toxicology Program: Toxicology and
IARC has determined that there is evidence Carcinogenesis Studies of 1,2-Dichlorobenzene (o-
suggesting lack of carcinogenicity of o- Dichlorobenzene) (CAS No 95-50-1) in F344/N
dichlorobenzene in experimental animals and Rats and B6C3F1 Mice (Gavage Studies). TRS-
that there is inadequate evidence for carcino- 255. DHHS (NIH) Pub No 86-2511.
genicity in humans.8 Research Triangle Park, NC, US Department
of Health and Human Services, October
In in vivo genotoxic assays o-dichloroben-
1985
zene induced micronuclei in the bone marrow 8. IARC Monographs on the Evaluation of the Car-
of mice and was found to bind covalently cinogenic Risk of Chemicals to Man, Vol 73, Some
to DNA, RNA, and proteins.8 Furthermore, chemicals that cause tumours of the kidney of
a signicant and persistent increase in urinary bladder in rodents, and some other
chromosomal aberrations was observed in the substances, pp 223-5. Lyon, International
peripheral blood of accidentally exposed Agency for Research on Cancer, 1999
workers. 9. Hayes WC, Hanley Jr TR, Gushow KA, et al:
No developmental toxicity was evident in Teratogenic potential of inhaled dichloroben-
rats or rabbits exposed during gestation by zene in rats and rabbits. Fundam Appl Toxicol
inhalation to concentrations up to 400 ppm.9 5:190202, 1985
The odor of o-dichlorobenzene is percep-
tible to most people at 24 ppm.1
The 2003 ACGIH threshold limit value-
time-weighted average (TLV-TWA) for
o-dichlorobenzene is 25 ppm (150 mg/m3) p-DICHLOROBENZENE
with a short-term excursion limit of 50 ppm CAS: 106-46-7
(301 mg/m3).
C6H4Cl2
REFERENCES
1. Hygienic Guide Series: o-Dichlorobenzene. Synonyms: 1,4-Dichlorobenzene; p-chloro-
Am Ind Hyg Assoc J 25:320323, 1964 phenyl chloride; paracide
222 p-DICHLOROBENZENE
no effects on reproduction. Postnatal toxicity 10. Loeser F, Litcheld MH: Review of recent
in F1 and F2 litters was observed at the high toxicology studies on p-dichlorobenzene.
dose.11 Food Chem Toxicol 21:825832, 1983
p-Dichlorobenzene is not genotoxic in 11. Neeper-Bradley TL, Tyl RW, Fisher LC, et
both in vivo and in vitro assay systems.12 al: Reproductive toxicity study of inhaled
paradichlorobenzene (PDCB) vapor in CD
The 2003 ACGIH threshold limit value-
rats. Teratology 39:470471, 1989 (abst)
time-weighted average (TLV-TWA) for p- 12. Agency for Toxic Substances and Disease
dichlorobenzene is 10 ppm (60 mg/m3) with an Registry (ATSDR): Toxicological Prole for 1,4-
A3-animal carcinogen designation. Dichlorobenzene, 143pp. US Department of
Health and Human Services, Public Health
Service, 1998
REFERENCES
Existing animal data shows that DCB Studies in several test systems have shown
induces tumors at a variety of sites in several DCB to be genotoxic in vitro and in vivo and
animal species.2 suggest that this effect most likely mediates the
Of 111 rats given 20 mg of DCB by injec- carcinogenicity of the chemical.2 In vitro, DCB
tion or gastric intubation 6 days/week for has induced sister chromatid exchanges,
1020 months, 17 had tumors of the zymbal unscheduled DNA synthesis, and positive
gland (a specialized sebaceous gland adjacent to responses in bacterial Salmonella assays; in vivo
the external ear canal), 13 had mammary DCB induced micronuclei in polychromatic
tumors, 8 had skin tumors, 5 had malignant erythrocytes in male mice and fetuses.912
lymphomas, 3 had urinary bladder tumors, 3 Because of demonstrated potent carcino-
had salivary gland tumors, and 2 had intestinal genicity in multiple animal species, evidence of
tumors; no tumors were found in 130 control genotoxicity, and structural relationship to the
rats.3 known bladder carcinogen benzidine, DCB
Of 44 male rats fed 1000 ppm for 12 should be regarded as a probable human car-
months, 9 developed granulocytic leukemia cinogen and exposure by any route should be
and 8 developed zymbal gland tumors; avoided.2
mammary gland tumors were found in rats of 3,3-Dichlorobenzidene has no threshold
both sexes.4 limit value (TLV) exposure limit and is classi-
In hamsters, 0.3% DCB in the diet pro- ed as an A3, conrmed animal carcinogen
duced transitional cell carcinomas of the with unknown relevance to humans, and a
bladder and some liver cell tumors.5 Liver notation for skin absorption.
tumors were also found in mice exposed to
DCB.3 Female dogs fed 8 mg/kg/day for a
period of 67 years had hepatocellular carcino- REFERENCES
mas and papillary transitional cell carcinomas
of the urinary bladder; tumors were absent in 1. Gerarde HW, Gerarde DF: Industrial
untreated controls.6 experience with 3,3-dichlorobenzidine: an
Four of four beagle dogs administered epidemiological study of a chemical manu-
DCB by capsule for 7 years had bladder papil- facturing plant. J Occup Med 16:322
lary transitional cell carcinoma and three had 344, 1974
liver carcinoma; untreated controls had no liver 2. Agency for Toxic Substances and Disease
Registry (ASTDR): Toxicological prole for
or bladder neoplasms.2
3,3-Dichlorobenzidene (Update), 138pp. US
There are no reports in which DCB expo-
Department of Health and Human Services,
sure has been conclusively linked to cancer in Public Health Service, 1998
humans.1 However, DCB exposure may have 3. Pliss GB: Dichlorobenzidine as a blasto-
been a factor in some cases of bladder cancer mogenic agent. Vop Onkol 5:524533, 1959
attributed to benzidine, because these sub- 4. Stula EF, Sherman H, Zapp JA Jr,
stances are often produced together, and DCB Clayton JW Jr: Experimental neoplasia
also bears a close structural similarity to benzi- in rats from oral administration of
dine.7 A British plant handling 3,3- 3,3-dichlorobenzidine, 4,4-methylene-
dichlorobenzidine had a site incidence of bis(2-chloroaniline), and 4,4-methylene-
bladder cancer 23 times that predicted for bis(2-methylaniline). Toxicol Appl Pharmacol
31:159176, 1975
males employed between 1972 and 1987; the
5. Sellakumar AR, Montesano R, Safotti U:
cause of this apparent excess could not be iden-
Aromatic amines carcinogenicity in hamsters.
tied because of potential exposure to many Proc Am Assoc Cancer Res 10:78, 1969.
other chemicals.8 Since that time, the incidence 6. Stula EF, Barnes JR, Sherman H, et al: Liver
of bladder cancer appears to have fallen to and urinary bladder tumors in dogs from
background levels and has been attributed to an 3,3-dichlorobenzidine. J Environ Pathol
alteration in hygiene standards.8 Toxicol 1:475490, 1978
DICHLORODIFLUOROMETHANE 225
7. IARC Monographs on the Evaluation of the short time experienced signicant eye irritation
Carcinogenic Risk of Chemicals to Man, Vol 4, as well as central nervous system effects.1 The
Some aromatic amines, hydrazine and related effects disappeared within minutes after return
substances, N-nitroso compounds and mis- to fresh air. Exposure at 110,000 ppm for 11
cellaneous alkylating agents, pp 4955. Lyon, minutes caused a marked decrease in con-
International Agency for Research on
sciousness, amnesia, and cardiac arrhythmias;
Cancer, 1974
8. Leeser JE, Cowan JB: Epidemiology update at 40,000 ppm for 80 minutes, there was gen-
(Letters to the Editor): J Occup Med 35:892, eralized paresthesia, tinnitus, apprehension,
1993 and slurred speech.1 Two volunteers exposed to
9. Shiraishi Y: Hypersensitive character of 10,000 ppm for 2.5 hours showed slight psy-
Bloom syndrome B-lymphoblastoid cell lines chomotor impairment.2
usable for sensitive carcinogen detection. Chronic exposure of volunteers to
Mutat Res 175:179187, 1986 1000 ppm 8 hours/day for 17 days caused no
10. Ashby J, Mohammed R: UDS activity in the subjective symptoms, no cardiac abnormalities,
rat liver of the human carcinogens benzidene and no pulmonary function abnormalities.3
and 4-aminobiphenyl and the rodent car- Snifng aerosols of uorochlorinated
cinogens 3,3-dichlorobenzidine and Direct
hydrocarbons has caused sudden death from
Black 38. Mutagenesis 3:6971, 1988
11. Iba MM, Thomas PE: Activation of 3,3- cardiac arrest probably due to cardiac arrhyth-
dichlorobenzidine in rat liver microsomes mias from sensitization of the myocardium to
to mutagens: involvement of cytochrome P- epinephrine.4
450. Carcinogenesis 9:717723, 1988 Refrigerator repairers exposed to
12. Cihak R, Vontorvoka M: Benzidine and 3,3- dichlorodiuoromethane and chlorodiuo-
dichlorobenzidine (DCB) induce micronuclei romethane (peak exposures 130010,000 ppm)
in the bone marrow and the fetal liver of mice showed no clear connection between exposure
after gavage. Mutagenesis 2:267270, 1987 and cardiac arrhythmia as determined by
ambulatory electrocardiograms.5 The investi-
gators suggest that subjects with compromised
cardiac function may be more susceptible to
the arrhythmogenic potential of uorocar-
DICHLORODIFLUOROMETHANE bons but that in general, a higher exposure
CAS: 75-71-8 concentration, on the order of 100,000
200,000 ppm may be necessary to provoke car-
CCl2F2 diac arrhythmias.
In rats, when dichlorodiuoromethane was
administered at various concentrations with
Synonyms: Freon 12; Refrigerant 12; Isotron; 20% oxygen for 30 minutes, the following
Halon; Genetron 12; Frigen 12 effects were observed: 200,000 ppm, no observ-
able effects; 300,000 ppm, muscular twitching
Physical Form. Colorless gas and tremor; 800,000 ppm, coma, corneal
reexes absent; 800,000 ppm for 4 and 6 hours
Uses. Refrigerant; aerosol propellant; plas- was not lethal and the animals suffered no per-
tics; blowing agent manent effects.6 In a recent report 3- to 20-
minute exposure of rats to concentrations of
Exposure. Inhalation 140,000470,000 ppm induced in a dose-
dependent manner acute neurobehavioral
Toxicology. Dichlorodifluoromethane effects ranging from operant performance
causes central nervous system depression at decits, to motor and equilibrium decits, to
very high concentrations. anesthesia with occasional convulsions.7
Volunteers exposed to 200,000 ppm for a Chronic exposure of rats 6 hours/day for
226 1,3-DICHLORO-5,5-DIMETHYLHYDANTOIN
4. Klaunig JE, Ruch RJ, Pereira MA: Carcino- Toxicology. 1,2-Dichloroethylene causes
genicity of chlorinated methane and ethane central nervous system depression at high con-
compounds administered in drinking water centrations; liver, lung, and heart damage have
to mice. Environ Health Perspect 69:8995, been reported in animal studies.
1986 1,2-Dichloroethylene is a mixture of two
5. National Cancer Institute: Carcinogenesis Tech-
geometric isomers, cis and trans; the proportion
nical Report Series No. 66. Bioassay of 1,1-
Dichloroethane for Possible Carcinogenicity, of the cis isomer to the trans isomer varies from
NCI-CG-TR-66, Pub No 78-1316, 82pp. mixture to mixture, depending on the manu-
DHEW (NIH), 1978 facturers specications. The properties of the
6. NIOSH: Current Intelligence Bulletin 27. mixture are expected to be similar to those of
Chloroethanes: Review of Toxicity, Pub. No. 78- the individual isomers.
181, p 22. DHEW (NIOSH), 1978 There has been only one report of indus-
7. Schwetz BA et al: Embryo and fetoxicity trial poisoning, a fatality caused by very high
of inhaled carbon tetrachloride, 1,1- vapor inhalation in a small enclosure.1 The
dichloroethane and methyl ethyl ketone in isomeric concentration of the vapor was not
rats. Toxicol Appl Pharmacol 28:452464, 1974 reported, nor were the level and duration of the
8. Milman HA, Story DL, Riccio ES, et al:
exposure or symptoms of toxicity. In another
Rat liver foci and in vitro assays to detect ini-
tiating and promoting effects of chlorinated early report, exposure to the trans isomer at
ethanes and ethylenes. Ann NY Acad Sci 2200 ppm caused nausea, drowsiness, fatigue,
534:521530, 1988 vertigo, and increased intracranial pressure in
two human subjects.1
In mice, the LC50 for a single 6-hour
inhalation exposure was 22,000 ppm for the
trans isomer.2
1,2-DICHLOROETHYLENE A very limited rat study reported the fol-
CAS: 540-59-0 lowing after inhalation of the trans isomer: 8
hours at 3000 ppm was associated with patho-
cis-1,2-Dichloroethylene logic changes in the heart, described as brous
CAS: 156-59-2 swelling of the myocardium and hyperemia; at
1000 ppm for 1 day, pathologic changes in the
trans-1,2-Dichloroethylene lungs included pulmonary capillary hyperemia,
CAS: 156-60-5 alveolar septal distension, and pulmonary
edema; hematologic effects at this level
C2H2Cl2 included a reduction in the number of circu-
lating leukocytes and erythrocytes; pathologic
changes in the liver consisted of lipid accumu-
Synonyms: Acetylene dichloride; dichlor- lation and fatty degeneration following an 8-
oacetylene; 1,2-dichloroethene hour exposure at 200 ppm.3
In another report, the acute oral LD50 for
Physical Form. Colorless liquid trans-1,2-dichloroethylene administered by
gavage was 8000 mg/kg for male rats and
Uses. 1,2-Dichloroethylene is used as a 9900 mg/kg for female rats.4 Signs associated
solvent for organic materials and as an inter- with lethal doses included those of pulmonary
mediate in the synthesis of other chlorinated hyperemia and central nervous system depres-
compounds; it may be produced by the chlori- sion including ataxia, loss of righting reex, and
nation of acetylene but is often produced as a depressed respiration.
by-product in the manufacture of other chlori- Rats receiving approximate daily doses
nated compounds. of 500, 1500, or 3000 mg of trans-1,2-
dichloroethylene in their drinking water for 90
Exposure. Inhalation; ingestion; skin days had no signicant adverse effects as deter-
DICHLOROETHYL ETHER 229
nose with cough, lacrimation, and nausea; at genic Risks to Humans Vol 71, Re-evaluation
100 ppm there was some irritation, whereas at of some organic chemicals, hydrazine and
35 ppm there were no effects.1 hydrogen peroxide, pp 12651269. Lyon,
In guinea pigs, concentrations of 5001000 International Agency for Research on Cancer,
ppm were fatal after 58 hours of exposure; 1999
effects were immediate lacrimation and nasal
irritation, followed by unsteadiness and coma;
autopsy ndings were pulmonary edema, pul-
monary hemorrhage, and occasional com-
plete consolidation.1 Fatalities occurred when DICHLOROFLUOROMETHANE
300 mg/kg was applied dermally to guinea pigs CAS: 75-43-4
as a pure liquid for 24 hours.
Repeated oral administration of 300 mg/kg CHFCl2
daily to both sexes of two strains of mice for 80
weeks induced a signicant elevated incidence
of tumors, mostly hepatomas.2 Four other Synonyms: Dichloromonouoromethane; u-
limited studies in rats and mice using oral orodichloromethane; Freon 21; Refrigerant 21;
gavage, subcutaneous or intraperitoneal injec- FC-21
tion, and skin painting failed to conrm these
ndings.3 The IARC has determined that there Physical Form. Colorless gas
is limited evidence in animals and inadequate
evidence in humans for the carcinogenicity of Uses. Refrigerant gas; propellant gas
dichloroethyl ether.4
In general, positive results have been Exposure. Inhalation
obtained in mutagenicity studies.3
Skin application to animals resulted in ery- Toxicology. Dichlorouoromethane at high
thema and necrosis, and application to the eye concentrations causes asphyxia and cardiac
resulted in corneal necrosis.3 sensitization in animals; repeated or prolonged
The 2003 ACGIH threshold limit value- exposure to lower concentrations results in
time-weighted average (TLV-TWA) for liver damage.
dichloroethyl ether is 5 ppm (29 mg/m3) with Acute or chronic effects from human expo-
a short-term excursion limit of 10 ppm sure have not been reported. In liquid form this
(58 mg/m3) and a notation for skin absorption. substance may cause frostbite.
Exposure of guinea pigs to 400,000 ppm
with 18% oxygen was fatal, and death was
REFERENCES preceded by dyspnea, tremor, and con-
vulsive movements, but not narcosis.1 Animals
1. Schrenk HH, Patty FA, Yant WP: Acute died at 102,000 ppm with congested lungs,
response of guinea pigs to vapors of some kidneys, and liver but survived 52,000 ppm,
new commercial organic compounds. VII. showing tremor, incoordination, and irregular
Dichloroethyl ether. Pub Health Rep 48: breathing.1
13891398, 1933 In rats, 90 day exposures to 1000 and
2. Innes JRM, Ulland BM, Valerio MG, et al: 5000 ppm caused bilateral hair loss, extensive
Bioassay of pesticides and industrial chemicals
liver damage, and excessive mortality.2 The
for tumorigenicity in mice: A preliminary
chronic toxicity of dichlorouoromethane
note. J Natl Cancer Inst 42:11011114, 1969
3. World Health Organization: Environmental appears to be quite different from diuorinated
Health Criteria 201 Selected Chloroalkyl Ethers, methanes and more similar to the hepatotoxin
pp 175, International Programme on Chem- chloroform.3 In mice 100,000 ppm induced
ical Safety, 1998 arrhythmias and sensitized the heart to
4. IARC Monographs on the Evaluation of Carcino- epinephrine.
2,4-DICHLOROPHENOL 231
After exposure at 10,000 ppm on days 6 pulmonary edema and hemorrhage, with
through 15 of gestation, 15 of 25 pregnant damage to the heart, liver, and kidneys. At high
female rats had no viable fetuses or implanta- concentrations, effects included lacrimation,
tion sites on the uterine wall.3 increased nasal secretion, sneezing, cough, pul-
The 2003 ACGIH threshold limit value- monary rales, and weakness. Application of the
time-weighted average (TLV-TWA) for liquid to the skin of rabbits caused irritation
dichlorouoromethane is 10 ppm (42 mg/m3). and edema.1,2 This compound is considerably
more irritating to skin and mucous membranes
of animals than 1-chloro-1-nitropropane and
REFERENCES exhibits greater toxicity by inhalation.3
In Salmonella typhimurium assays 1,1-
1. von Oettingen WF: The Halogenated Aliphatic, dichloro-1-nitroethane was mutagenic in the
Olenic, Cyclic, Aromatic, and Aliphatic- TA100 and TA97 stains but not in TA1535 or
AromaticHydrocarbons Including the Halogenated TA98.4
Insecticides, Their Toxicity and Potential Dangers.
The 2003 ACGIH threshold limit value-
US Public Health Service, Pub No 414, pp
time-weighted average (TLV-TWA) for 1,1-
7375. Washington, DC, US Government
Printing Ofce, 1955 dichloro-1-nitroethane is 2 ppm (12 mg/m3).
2. Trochimowicz HJ et al: Ninety-day inhalation
toxicity studies on two uorocarbons. Toxicol
Appl Pharmacol 41:299 (abst), 1977 REFERENCES
3. Dichlorouoromethane. Documentation of
TLVs and BEIs, 6th ed, pp 434435. Cincin- 1. Machle W, Scott EW, Treon JF, et al: The
nati, OH, American Conference of Govern- physiological response of animals to certain
mental Industrial Hygienists, 1991 chlorinated mononitroparafns. J Ind Hyg
Toxicol 27:95102, 1945
2. Negherbon WO (ed): Handbook of Toxicology,
Vol. III, Insecticides, pp 212213. Philadel-
phia, PA, W. B. Saunders, 1959
3. Stokinger HE: Aliphatic nitro compounds,
1,1-DICHLORO-1-NITROETHANE nitrates, nitrites. In Clayton GD, Clayton FE
CAS: 594-72-9 (eds): Pattys Industrial Hygiene and Toxicology,
3rd ed, rev, Vol 2C, Toxicology, pp 41624164.
CH3CCl2NO2 New York, Wiley-Interscience, 1982
4. Zeiger E, Anderson B, Haworth S, et al: Sal-
monella mutagenicity tests. V. Results from the
Synonyms: Ethide testing of 311 chemicals. Environ Mol Mutagen
19(suppl 21):2141, 1992
Physical Form. Colorless liquid
Uses. Intermediate in production of her- bone marrow were depleted in rats fed
bicidal chlorophenoxy acids such as 2,4- 500 mg/kg/day for 13 weeks.4 Mice fed
dichlorophenoxyacetic acid 325 mg/kg/day or more for 13 weeks had
dose-related increases in hepatic necrosis.6
Exposure. Inhalation Feeding tests with rats and mice, for
periods up to 103 weeks, at doses as high as
Toxicology. 2,4-Dichlorophenol (2,4-DCP) 440 mg/kg/day for rats and 1300 mg/kg/day for
is an uncoupler of oxidative phosphorylation; mice showed no evidence of carcinogenic activ-
toxic manifestations include central nervous ity due to 2,4-DCP.5
system depression followed by increased respi- Topical application of 0.3% dimethylben-
ration, hyperthermia, increased blood pressure, zanthracene in benzene as an initiator followed
progressive weakness, and cyanosis. by twice-weekly application of 20% 2,4-DCP
A number of occupational fatalities have in benzene to mice produced papillomas in
been associated with acute dermal exposure to 75% and carcinomas in 6% at 24 weeks; 62%
heated liquid 2,4-DCP.1 In one case report, an had carcinomas after 39 weeks.7 There is no
accidental death was attributed to absorption of evidence that 2,4-DCP acting alone induces
2,4-DCP through the skin.2 A 33-year-old man papillomas or carcinomas.4
splattered portions of his right thigh and right The IARC has determined that there is
arm with a pure solution of 2,4-DCP while dis- evidence suggesting lack of carcinogenicity of
posing of industrial waste. He washed himself 2,4-DCP in experimental animals.8
without undressing, and shortly thereafter Female rats were given 3, 30, or 300 ppm
(within 20 min) he experienced a seizure and in drinking water from 3 weeks of age through
collapsed. Resuscitation efforts failed. It was breeding and parturition (Group 1) or for 24
determined that less than 10% of his body months (Group 2).9 Animals from Group 1
surface was contaminated, which resulted in were bred to untreated males at 90 days of
blood concentrations of 24.3 mg/l. Other age; litter sizes at 300 ppm were signicantly
drugs, including ethanol, were not detected in smaller than controls. The percentage of
a toxicological screen. The authors suggest that stillborn pups increased at all doses. In Group
the blood level of 2,4-DCP in this case is in 2, liver weights were signicantly increased in
accordance with lethal blood concentrations of the 300 ppm group. Spleen weights were
phenol that have been reported. higher and thymuses were smaller than in the
The oral LD50 in rats was 2830 mg/kg.3 control group. Delayed-type hypersensitivity
Typical effects associated with acute lethal responses in treated animals were signicantly
oral doses have included restlessness and suppressed compared with controls. Tumor
increased respiratory rate, which appear incidence, latency, or type was not different
quickly, followed shortly by tremors, convul- from controls.
sions, dyspnea, coma, and death.4 The primary In mammalian cells in vitro 2,4-DCP pro-
toxic mechanism is the uncoupling of oxidative duced chromosomal aberrations and induced
phosphorylation.4 unscheduled DNA synthesis; it was negative
In an NTP report, exposure of rats to con- for sister chromatid exchange in vivo and was
centrations as high as 2000 mg/kg/day in the mostly negative in bacterial assays.3
diet for up to 13 weeks did not cause mortal- Oral exposure of pregnant rats to
ity; 2600 mg/kg/day did not affect survival of 750 mg/kg/day for 10 gestational days induced
mice at this duration, but all mice died when slightly decreased fetal weight, delayed ossi-
exposed to 5200 mg/kg for 4 weeks.5 Renal cation of sternal and vertebral arches, and some
tubular necrosis was found in mice at the early embryonic deaths.10 Maternal deaths also
highest dose level, but no effect was seen occurred at this dose, indicating that 2,4-DCP
in mice fed 2600 mg/kg/day or in rats fed was not selectively toxic to embryos or fetuses.
2000 mg/kg for 13 weeks. No effects were noted in dams or offspring
Both erythroid and myelocytic elements of exposed at 375 mg/kg/day.
2,4-DICHLOROPHENOXYACETIC ACID 233
A threshold limit value (TLV) has not been Teratogenic assessment of 2,4-dichlorophe-
established for 2,4-dichlorophenol. nol in Fischer 344 rats. Fundam Appl Phar-
macol 13:635640, 1989
REFERENCES
Peripheral neuropathy has been reported tial exposure to Agent Orange (a 1:1 mixture of
to occur occasionally after exposure to 2,4-D and 2,4,5-T).15 A subsequent mortality
2,4-D, but more frequently after exposure to study of these veterans did nd an elevated
another phenoxyherbicide, 2,4,5-T (2,4,5- standardized proportionate mortality ratio for
trichlorophenoxyacetic acid) or its contami- soft tissue sarcoma, but it was not based on ade-
nants including 2,3,7,8-TCDD (2,3,7, quate numbers of deaths or adequate exposure
8-tetrachlorodibenzo-p-dioxin).5 A study of data.16
workers employed in the manufacture of 2,4-D A review of epidemiological studies of
and 2,4,5-T found a statistically signicant chlorophenoxy herbicides found no consistent
increased frequency of mild slowing of nerve or conclusive evidence linking 2,4-D to human
conduction velocity in the sural sensory and carcinogenesis. It was further stated that, in
median motor nerves; there were no associated general, animal studies, conducted under
symptoms.6 current test guidelines, have also shown no evi-
Several case-control studies of soft tissue dence of carcinogenicity supporting the results
sarcoma and lymphoma have suggested an of epidemiological studies.17
increased risk among workers exposed to phe- There were no indications of genotoxic
noxyacetic acid herbicides, including 2,4-D.7,8 potential for 2,4-D acid, or any of its deriva-
In one study involving primarily 2,4-D expo- tives, in bacterial assays, in unscheduled DNA
sure, there was an increased risk for malignant synthesis assay, or in mouse bone marrow
lymphoma of the non-Hodgkin type but not micronucleus tests.18,19
for soft tissue sarcomas.9 The IARC has A two- to threefold increased risk of birth
deemed the evidence implicating 2,4-D to be defects among children of Vietnam war veter-
inadequate.7 Concomitant exposure to other ans exposed to Agent Orange has been sug-
known carcinogenic substances and insufcient gested by several epidemiological studies, but
accumulation of person-years of observation these studies have been criticized on a number
are two of the primary limiting factors in estab- of grounds, including exposure assessment,
lishing the risks associated with 2,4-D expo- outcome verication, and potential for recall
sures.10,11 Large cohort studies of agricultural bias.20 Animal studies have not demonstrated
and forestry workers exposed to these herbi- clear-cut adverse effects of phenoxyherbicide
cides have not subsequently conrmed any exposure on reproductive outcomes.20,21
increased incidence of malignancy.7,12 For 878 2,4-D is readily absorbed through the skin;
chemical workers potentially exposed to 2,4-D therefore, measurements of ambient air con-
at any time between 1945 and 1983, an analy- centrations do not necessarily reect the total
sis by production area, duration of exposure, absorbed dose.22 Immunochemical determina-
and cumulative dose showed no patterns sug- tion of 2,4-D in urine has provided effective
gestive of a causal association between 2,4-D measurement of human exposure levels.
exposure and any particular cause of death.13 The 2003 ACGIH threshold limit value-
Particular attention was given to deaths from time-weighted average (TLV-TWA) for 2,4-D
brain neoplasms in this cohort, because a is 10 mg/m3.
recent unpublished study reported an increased
incidence of astrocytomas in male rats fed
45 mg/kg/day in the diet for 2 years. No brain
neoplasms were observed.13 Four additional REFERENCES
years of mortality follow-up on this cohort
1. Nielsen K, Kaempe B, Jensen-Holm J: Fatal
through 1986 has not revealed any patterns
poisoning in man by 2,4-diphenoxyacetic
suggestive of a causal association between 2,4- acid (2,4-D): Determination of the agent in
D exposure and any particular cause of death, forensic materials. Acta Pharmacol Toxicol
including cancer.14 A case-control study of 22:224234, 1965
Vietnam war-era veterans with soft tissue 2. Fraser AD, Isner AF, Perry RA: Toxicologic
sarcoma did not nd an association with poten- studies in a fatal overdose of 2,4-D,
1,3-DICHLOROPROPENE 235
Mecoprop, and Dicamba. J Forensic Sci 29: 14. Bloemen LJ, Mandel JS, Bond GG, et al: An
12371241, 1984 update of mortality among chemical workers
3. Seabury JH: Toxicity of 2,4-dichlorophe- potentially exposed to the herbicide 2,4-
noxyacetic acid for man and dog. Arch dichlorophenoxyacetic acid and its deriva-
Environ Health 7:202209, 1963 tives. J Occup Med 35:12081212, 1993
4. Hayes WJ Jr: Clinical Handbook on Economic 15. Kang HK et al: Soft-tissue sarcomas and mil-
Poisons, Emergency Information for Treating itary service in Vietnam: A case comparison
Poisoning, US Public Health Service Pub group analysis of hospital patients. J Occup
No 476, pp 106109. Washington, DC, US Med 28:12151218, 1986
Government Printing Ofce, 1963 16. Kogan MD, Clapp RW: Soft-tissue sarcoma
5. Kolmodin-Hedman B, Hoglund S, Akerblom mortality among Vietnam veterans in Massa-
M: Studies on phenoxy acid herbicides. I. chusetts, 19721983. Int J Epidemiol 17:39
Field Study: Occupational exposure to 43, 1988
phenoxy acid herbicides (MCPA, Dichloro- 17. Bond GG, Rossbacher R: A review of poten-
prop, Meco-prop, and 2,4-D) in agriculture. tial human carcinogenicity of the chloro-
Arch Toxicol 54:257265, 1983 phenoxy herbicides MCPA, MCPP, and
6. Singer R et al: Nerve conduction velocity 2,4-DP. Br J Ind Med 50:340348, 1993
studies of workers employed in the manufac- 18. Charles JM, Cunny HC, Wilson RD, et al:
ture of phenoxy herbicides. Environ Res 29: Ames assays and unscheduled DNA synthesis
297311, 1982 assays on 2,4-dichlorophenoxyacetic acid and
7. IARC Monographs on the Evaluation of the Car- its derivatives. Mutat Res 444:20716, 1999
cinogenic Risk of Chemicals to Humans: Chemi- 19. Charles JM, Cunny HC, Wilson RD, et al: In
cals, Industrial Processes and Industries Associated vivo micronucleus assays on 2,4-dichlorophe-
with Cancer in Humans, Suppl 4, pp 101103, noxyacetic acid and its derivatives. Mutat Res
211212. Lyon, International Agency for 444:22734,1999
Research on Cancer, 1982 20. Hatch MC, Stein ZA: Agent Orange and
8. Hardell L, Eriksson M: The association risks to reproduction: The limits of epidemi-
between soft-tissue sarcomas and exposure to ology. Teratogen Carcinogen Mutagen 6:185
phenoxyacetic acids. A new case-referent 202, 1986
study. Cancer 62:652656, 1988 21. EPA: Pesticide Fact Sheet: 2,4-D. Washington,
9. Hoar SK, Blair A, Holmes FF, et al: Agricul- DC, Environmental Protection Agency, 1986
tural herbicide use and risk of lymphoma and 22. Knopp D: Assessment exposure to 2,4-
soft-tissue sarcoma. JAMA 256:1141 dichlorophenoxyacetic acid in the chemical
1147, 1986 industry: results of a ve year biological mon-
10. Johnson ES: Review. Association between itoring study. Occup Environ Med 51:152159,
soft-tissue sarcomas, malignant lymphomas, 1994
and phenoxy herbicides/chlorophenols: evi-
dence from occupational cohort studies.
Fundam Appl Toxicol 14:219234, 1990
11. Bond GG, Bodner KM, Cook RR: Phenoxy
herbicides and cancer: Insufcient epi-
demiological evidence for a causal relation- 1,3-DICHLOROPROPENE
ship. Fundam Appl Pharmacol 12:172188, CAS: 542-75-6
1989
12. Wiklund K, Holme L: Soft-tissue sarcoma C3H4Cl2
risk in Swedish agricultural and forestry
workers. J Natl Cancer Inst 76:229234,
1986
Synonyms: 1,3-DCP; a-chloroallyl chloride;
13. Bond GG, Wetterstroem NH, Roush GJ, et
al: Cause specic mortality among employees 1,3-dichloropropylene; Telone; Telone II; DD
engaged in the manufacture, formulation, or fumigants
packaging of 2,4-dichlorophenoxyacetic acid
and related salts. Br J Ind Med 45: Physical Form. Clear to amber-colored
98105, 1988 liquid
236 1,3-DICHLOROPROPENE
Uses. Widely used as a preplanting soil fumi- 2 hours was lethal to rats, whereas brief expo-
gant for the control of nematodes sure at this concentration caused severe eye
irritation and loss of consciousness.9
Exposure. Inhalation; skin absorption Acute dermal application of dilute or full-
strength DCP rapidly produced erythema and
Toxicology. 1,3-Dichloropropene (1,3- edema in rats, rabbits, and guinea pigs.8
DCP) is an irritant of the eyes, mucous mem- Delayed-type hypersensitivity reactions and
branes, and skin; exposures in animals have contact sensitization have also been reported in
been associated with contact hypersensitivity guinea pigs and humans.8
and damage to the nasal tissues, lungs, liver, A carcinogenicity study in rats and mice
kidneys, and urinary bladder. It is considered to using a technical grade of 1,3-dichloropropene
be carcinogenic to experimental animals. administered by oral gavage 3 times/week for
A truck spill in 1985 resulted in exposure 104 weeks produced tumors of the urinary
of an estimated 80 people.1,2 Signs and symp- bladder, lung, and forestomach in mice and of
toms were headache in six persons, mucous the liver and forestomach in rats.10 The IARC
membrane irritation in ve, dizziness in ve, has determined that there is sufcient evidence
and chest discomfort in four. Eleven of 41 for animal carcinogenicity of technical-grade
persons tested had slightly elevated SGOT 1,3-dichloropropene but inadequate evidence
and/or SGPT values. In 28 persons interviewed for carcinogenicity to humans.5
12 weeks after exposure, complaints were In a subsequently published report,
headache in 12, abdominal discomfort in 6, an inhalation carcinogenicity study with
chest discomfort in 5, and malaise in 5. In one technical-grade material, rats and mice were
case the diagnosis was pneumonia, based on exposed to 0, 5, 20, or 60 ppm 6 hours/day, 5
persistent dyspnea and cough. days/week for up to 2 years.11 There were mor-
In a report of two reghters who were phologic changes in the nasal tissue of rats
simultaneously exposed at a chemical spill, exposed to 60 ppm and mice exposed to 20 and
lymphomas appeared simultaneously 6 years 60 ppm. Mice exposed to 20 or 60 ppm had
later and the individuals died within several hyperplasia of the epithelial lining of the
months of each other.3 The IARC noted that urinary bladder. Rats showed no increased
because reghters are exposed to a large tumor incidence. Male mice showed an
number of chemicals, the role of 1,3-dichloro- increased incidence of bronchioloalveolar ade-
propene could not be evaluated.4,5 nomas in the 60 ppm group.
Accidental ingestion of 1,3-DCP by a 27- Rats of both sexes were exposed in an
year-old-worker resulted in gastrointestinal inhalation reproduction study to technical-
distress, adult respiratory distress syndrome, grade 1,3-dichloropropene at 0, 10, 30, or
hematologic and hepatorenal impairment, and 90 ppm for 6 hours/day, 5 days/week, for two
death within 40 hours due to multiorgan generations.12 There were no adverse effects
failure.6 Initial symptoms, on hospital admit- on reproductive and neonatal parameters.
tance, included acute gastrointestinal distress, Parental effects were focal hyperplasia and/or
sweating, tachypnea, and tachycardia. The focal degenerative changes in the olfactory
chemical was toxicologically identied by epithelium at 90 ppm.
gas chromatography, and initial blood levels A number of genotoxic effects have been
were 1.13 mmol/l in blood and 0.20 mmol/l in reported for 1,3-DCP including increased
urine. DNA strand breaks, sister chromatid
The oral LD50 was 713 mg/kg in male rats exchanges, and mitotic aberrations in Chinese
and 470 mg/kg in females.7 (LD50 values as low hamster cells.8,13 It did not induce dominant
as 100 mg/kg have been reported for rats; this lethal mutations in the germ cells of male CD
range in values is attributed to different rat rats after inhalation of 150 ppm.14
strains and from differences in the 1,3-DCP The 2003 ACGIH threshold limit value-
formulations used.8) Exposure to 1000 ppm for time-weighted average (TLV-TWA) for 1,3-
2,2-DICHLOROPROPIONIC ACID 237
dichloropropene is 1 ppm (4.5 mg/m3) with a Mice (Gavage Studies). NTP Tech Rep Ser
notation for skin absorption and an A3- 269:9109, 1985
conrmed animal carcinogen with unknown 11. Lomax LG, Stott W, Johnson K, et al: The
relevance to humans designation. chronic toxicity and oncogenicity of inhaled
technical-grade 1,3-dichloropropene in rats
and mice. Fundam Appl Toxicol 12:418431,
1989
REFERENCES
12. Breslin WJ, Kirk H, Streeter C, et al: 1,3-
Dichloropropene: two-generation inhalation
1. Hayes Jr, WJ: Pesticides Studied in Man. pp
reproduction study in Fischer 344 rats.
162163. Baltimore, MD, Williams &
Fundam Appl Toxicol 12:129143, 1989
Wilkins, 1982
13. Martelli A, Allavena A, Ghia M, et al:
2. Flessel P, Goldsmith JR, Kahn E, Wesolowski
Cytotoxic and genotoxic activity of 1,3-
JJ: Acute and possible long-term effects of
dichloropropene in cultured mammalian
1,3-dichloropropene. Morbid Mortal Weekly
cells. Toxicol Appl Pharmacol 120:114119,
Rep 27:50, 1978
1993
3. Markovitz A, Crosby WH: A soil fumigant,
14. Gollapudi BB, Cieszlak FS, Day SJ, et al:
1,3-dichloropropene, as possible cause of
Dominant lethal test with rats exposed to 1,3-
hematologic malignancies. Arch Int Med 144:
dichloropropene by inhalation. Environ Mol
14091411, 1984
Mutagen 32(4):3519, 1998
4. IARC Monographs on the Evaluation of the
Carcinogenic Risks to Humans. Vol 41, Some
halogenated hydrocarbons and pesticide
exposures, pp 113130. Lyon, International
Agency for Research on Cancer, 1986
2,2-DICHLOROPROPIONIC ACID
5. IARC Monographs on the Evaluation of the Car-
cinogenic Risks to Humans, Suppl 7, Overall CAS: 75-99-0
Evaluations of Carcinogenicity: An Updating of
IARC Monographs Vol 142, pp 195196. CH3CCl2COOH
Lyon, International Agency for Research on
Cancer, 1987
6. Hernandez AF, Martin-Rubi JC, Ballesteros Synonyms: Dalapon; Dalzpon; Dowpon-M
JL, et al: Clinical and pathological ndings in
fatal 1,3-dichloropropene intoxication. Hum Physical Form. Colorless liquid; the com-
Exp Toxicol 13:303306,1994 mercial herbicide is light tan powder
7. Torkelson TR, Oyen F: The toxicity of 1,3-
dichloropropene as determined by repeated
Uses. Herbicide marketed as the sodium salt
exposure of laboratory animals. Am Ind Hyg
Assn J 38:217223, 1977 or a mixture of the sodium and magnesium salts
8. Agency for Toxic Substances and Disease used to control grasses in a wide variety of
Registry (ASTDR): Toxicological Prole for crops and in a number of noncrop applications,
1,3-Dichloropropene. 123pp. US Department such as along drainage ditches and railroads
of Health and Human Services, Public and in industrial areas.
Health Service, Sept 1992
9. US Department of Health and Human Ser- Exposure. Inhalation
vices (NIOSH): Occupational safety and health
guidelines for chemical hazards. Supplement IV- Toxicology. 2,2-Dichloropropionic acid is
OHG Pub No 95121, pp 18. Occupational
expected to be an irritant of the eyes, skin, and
safety and health guideline for 1,3-dichloro-
respiratory tract.
propene. Cincinnati OH, 1995
10. National Toxicology Program: Toxicology and Exposure at 27 ppm for an unspecied
Carcinogenesis Studies of Telone II (Technical time produced minimal respiratory irritation.1
Grade 1,3-Dichloropropene [CAS No. 542-75- The dry powder or a concentrated solution can
6] Containing 1.0% Epichlorohydrin as a be irritating to the eyes or skin if not removed
Stabilizer) in F344/N Rats and B6C3F1 by washing.2
238 DICHLOROTETRAFLUOROETHANE
Acute toxicity data indicate that it has a low in rats, no reproductive effects were found in
order of toxicity in mammals, with a range of rats administered Dalapon in the diet at levels
oral LD50 values of 49 g/kg.2 Short-term mul- up to 3000 ppm (150 mg/kg/day). The mean
tiple-dose studies suggest that the toxicity of weight of pups was depressed when pregnant
the compound is not cumulative. Cattle that rats received 1000 or 1500 mg/kg/day in the
received a 1 g/kg daily oral dose for 10 days diet during days 6 through 15 of gestation but
showed some signs of toxicity but rapidly not when they received 500 mg/kg/day. No
recovered when dosing ceased. Slight cloudy other effects on the fetuses were observed.
swelling of the convoluted tubules and hyper- Dichloropropionic acid was not mutagenic
trophy or swelling of the glomerular cells of the in a variety of assays. The 2003 threshold limit
kidney were the only ndings in a bull calf value-time-weighted average (TLV-TWA) is
receiving 1 g/kg/day. Dogs were dosed by 1 ppm (5.8 mg/m3).
gavage for an 81-day period, initially with
50 mg/kg/day, with dosages adjusted upward
until the animals were receiving 1000 mg/ REFERENCES
kg/day. Vomiting ensued at this high dose level,
and the study was terminated at 81 days. Except 1. US Department of Health and Human Ser-
for vomiting, no other signs of toxicity were vices (NIOSH): Occupational safety and health
evident. Extensive hematologic and biochemi- guidelines for chemical hazards. Supplement IV-
OHG (pub No. 95121), pp 18. Occupational
cal parameters were all normal, as were the
safety and health guideline for 2,2-dichloro-
organ-to-body weight ratios.
propionic acid., Cincinnati, OH, 1995
In a 97-day rat study, there were no effects 2. NTIS: Drinking Water Criteria Document for
in male rats fed Dalapon in the diet at levels up Dalapon; Final Draft. DART/T/91000934,
to 115 mg/kg/day. In female rats, there were NTIS Technical Report (NTIS/PB90-
slight, statistically signicant increases in 215427) April, 1990
average kidney weights at the 34.6 mg/kg/day
level. At 346 or 1150 mg/kg/day, both male and
female rats showed growth retardation,
increased liver and kidney weights, and slight
histopathologic changes in the liver and
kidneys. DICHLOROTETRAFLUOROETHANE
A 1-year study was conducted with dogs CAS: 76-14-2
that showed signicant increases in the average
kidney weight in animals receiving 100 mg/ C2Cl2F4
kg/day but not in those receiving 50 mg/kg/day.
All other parameters were comparable to
controls. Synonyms: Refrigerant 114; CFC-114; Freon
Signicant increases were noted in the 114; 1,2-dichloro-1,1,2,2-tetrauoroethane
kidney weight of rats receiving 50 mg/kg/day
for 2 years but not in those receiving 15 or Physical Form. Colorless gas
5 mg/kg/day. In a 2-year mouse study,
increased liver weights were noted at Uses. Refrigerant; aerosol propellant;
200 mg/kg/day in the diet. No associated solvent; re extinguisher
lesions were noted on histologic examination of
the livers. There were also increased incidences Exposure. Inhalation
of benign lung adenomas and cystadenomas of
the harderian gland in male mice fed Dalapon Toxicology. Dichlorotetrafluoroethane
for 2 years. No tumors were found in rats fed causes asphyxia at extremely high concentra-
Dalapon for 2 years. tions.
In a three-generation reproduction study Although dichlorotetrauoroethane has
DICHLORVOS 239
aggravated by exertion, involuntary twitchings, rial assays and in some cultured mammalian
fasciculations, and, eventually, paralysis. The cell assays.
most serious consequence is paralysis of the Developmental toxicity has not been
respiratory muscles. Effects on the central demonstrated in a variety of animal species
nervous system include giddiness, confusion, even in the presence of maternal toxicity.8
ataxia, slurred speech, CheyneStokes respira- The 2003 ACGIH threshold limit value-
tion, convulsions, coma, and loss of reexes. time-weighted average (TLV-TWA) for
The blood pressure may fall to low levels, and dichlorvos is 0.1 ppm (0.90 mg/m3) with a
cardiac irregularities including complete heart notation for skin absorption.
block may occur.
Complete symptomatic recovery usually
occurs within a week; increased susceptibility REFERENCES
to the effects of anticholinesterase agents per-
sists for up to several weeks after exposure. 1. Koelle GB (ed): Cholinesterases and anti-
Daily exposure to concentrations that are cholinesterase agents. Handbuch der Experi-
insufcient to produce symptoms after a single mentellen Pharmakologie, Vol. 15, pp 9891027.
Berlin, Springer-Verlag, 1963
exposure may result in the onset of symptoms.
2. Taylor P: Anticholinesterase agents. In Gilman
Continued daily exposure may be followed by
AG et al. (eds): Goodman and Gilmans Phar-
increasingly severe effects. macological Basis of Therapeutics, 7th ed, pp
In a study of 13 workers exposed for 110129. New York, Macmillan Publishing,
12 months to an average concentration of 1985
DDVP of 0.7 mg/m3, the erythrocyte choline- 3. Hayes WJ Jr: Toxicology of Pesticides, pp 379
sterase activity was reduced by approximately 428. Baltimore, MD, Williams & Wilkins,
35%, whereas the serum cholinesterase activity 1975
was reduced by 60%. The results of other 4. Menz M, Luetkemeir H, Sachsse K: Long-
tests and of thorough medical examination term exposure of factory workers to dichlorvos
conducted at regular intervals were entirely (DDVP) insecticide. Arch Environ Health
28:7276, 1971
normal.4
5. Mathias CGT: Persistent contact dermatitis
DDVP has been shown to cause a persist-
from the insecticide dichlorvos. Contact Derm
ent irritant contact dermatitis in one worker 9:217218, 1983
with negative patch tests and appears to be 6. Matsushita T et al: Allergic contact dermatitis
capable of inducing an allergic contact der- from organophosphorus insecticides. Ind
matitis.5,6 Health 23:145153, 1985
Although several epidemiological studies 7. Van Maele-Fabry G, Laurent C, Willems JL:
have suggested a positive association between Dichlorvos and carcinogenicity: A systemic
dichlorvos exposure and cancer, conclusions approach to a regulatory decision. Reg Toxicol
are limited because all have involved small Pharmacol 31:1321, 2000
study groups and exposure to several agents.7 8. IARC Monographs on the Evaluation of the
Carcinogenic Risk of Chemicals to Humans, Vol.
In animal studies chronic gavage administra-
53, Occupational exposures in insecticide
tion of dichlorvos caused a dose-related
application, and some pesticides, p 267. Lyon,
increase in papillomas of the forestomach in International Agency for Research on Cancer,
mice and a dose-related increase in mononu- 1991
clear-cell leukemia and an increased incidence
of pancreatic acinar cell adenomas in male rats.8
The IARC has determined that there is suf-
cient evidence for the carcinogenicity of
DDVP in experimental animals and inadequate
evidence in humans.8
DDVP was not genotoxic in various in vivo
mammalian assays.8 It was mutagenic in bacte-
DICYCLOPENTADIENE 241
3. Dicyclopentadiene. Materials Safety Data turbinates of both species.2 The lesions were
Sheet No 340, rev B. Corporate Research primarily centered in the olfactory epithelium
and Development, Schenectady, NY, February and were morphologically diagnosed as sub-
1984 acute, necrotizing inammation. Exposure-
related effects on organ weights were also seen;
rats had decreased liver weights, whereas in
mice, liver, spleen, kidney, and brain weights
were decreased and thymus weights increased.
The investigators suggested that these alter-
ations were secondary effects brought on by
DICYCLOPENTADIENYL IRON the nasal lesions. Exposures for 13 weeks in
CAS: 102-54-5 rats and mice at 0, 3.0, 10, or 30 mg/m3 caused
histopathologic lesions in the larnyx, trachea,
C10H10Fe lungs, and liver (kidneys only in mice) and most
notably in the nasal epithelium.3 Lesions in the
nasal olfactory epithelium consisted of pigment
Synonyms: Ferrocene; biscyclopentadienyl iron accumulation, necrotizing inammation, meta-
plasia, and epithelial regeneration. Although
Physical Form. Orange crystalline solid or increases in lung burdens of iron were found,
orange needles there were no exposure-related changes in
respiratory function, lung biochemistry,
Uses. In ultraviolet stabilizers and smoke bronchoalveolar lavage cytology, total lung
depressants for polymers; to increase the burn collagen, clinical chemistry, or hematology
rate of rocket propellants; to prevent erosion of parameters.
space capsule shields; to improve the viscosity Dogs receiving daily oral doses of
of lubricants; to catalyze polymerization reac- 300 mg/kg had a reversible drop in hemoglo-
tions; to catalyze combustion; some derivatives bin, packed cell volume, and erythrocyte count
used as hematinic agents during the rst 4 weeks of treatment.4 The
300 mg/kg/day eventually (time not specied)
Exposure. Inhalation; ingestion resulted in hepatic cirrhosis. The dicyclopen-
tadienyl iron-dosed animals had high (up to
Toxicology. Dicyclopentadienyl iron causes 3040 times those of controls) liver iron levels
changes in blood parameters and hepatic that remained elevated after the agent was dis-
cirrhosis. continued. Twenty-six months after the end of
The toxicological properties of dicy- dosing, the treated dogs had liver iron levels
clopentadienyl iron have not been extensively that were roughly 30 times higher than those
investigated. However, it has been used as a of controls. Testicular hypoplasia was evident
preventive and therapeutic iron deciency in males treated for 6 months.
drug, and its utilization is listed as tolerable. Of 20 mice given 28 weekly subcutaneous
In rats, the inhalation LD50 is greater than injections of 5 mg of dicyclopentadienyl iron,
150 mg/m3; various oral LD50 values ranging 17 survived 9 months and there were no
from 1000 to 2000 mg/kg have been cited.1 For tumors.5
mice, LD50 values of 6001550 mg/kg have The compound was not mutagenic in bac-
been reported. There were no fatalities in rats terial assays or genotoxic in sister chromatid
administered 10 treatments of 200 mg/kg over exchange assays but was immunotoxic, decreas-
a 2-week period. ing the rate of lymphocyte proliferation in
Repeated inhalation exposure of F344/N vitro.6
rats and B6C3F1 mice at 0, 2.5, 5.0, 10, 20, or The 2003 ACGIH threshold limit value-
40 mg of vapor for 6/hours/day for 2 weeks time-weighted average (TLV-TWA) for dicy-
caused exposure-related lesions in the nasal clopentadienyl iron is 10 mg/m3.
DIELDRIN 243
mortality study of 2384 persons employed 4. Brown VKH, Hunter CG, Richardson A: A
sometime between 1952 and 1982 at a Col- blood test diagnostic of exposure to aldrin
orado pesticide manufacturing facility found no and dieldrin. Br J Ind Med 21:283286, 1964
excess mortality rates attributable to occupa- 5. IARC Monographs on the Evaluation of the Car-
tional exposure.10 Similarly, a 23-year follow- cinogenic Risk of Chemicals to Man, Vol. 5,
Some organochlorine pesticides, pp 125156.
up of 570 dieldrin- and aldrin-exposed workers
Lyon, International Agency for Research on
found no increase in overall mortality rates or Cancer, 1974
mortality from liver cancer.11 6. Ashwood-Smith MJ: The genetic toxicology
Dieldrin is genotoxic in some assays, but it of aldrin and dieldrin. Mutat Res 86:137154,
does not appear to act directly on the DNA 1981
molecule.7 7. Agency for Toxic Substances and Disease
Accumulating evidence suggests that Registry (ATSDR): Toxicological Prole for
dieldrin is not a likely human carcinogen Aldrin/Dieldrin, pp 1303. US Department of
and that it acts as a species-specic hepatocar- Health and Human Services, Public Health
cinogen in mice through nongenotoxic Service, 2003
mechanisms.12 8. Ditraglia D, Brown DP, Namekata T,
et al: Mortality study of workers employed
Developmental effects have been noted in
at organochlorine pesticide manufacturing
animals after a single very large dose in midges- plants. Scand J Work Environ Health 7(suppl
tation. A dose of 30 mg/kg administered orally 4):140146, 1981
to pregnant golden hamsters during the period 9. Ribbens PH: Mortality study of industrial
of fetal organogenesis caused a high incid- workers exposed to aldrin, dieldrin and
ence of fetal deaths, congenital anomalies, and endrin. Int Arch Occup Environ Health 56:
growth retardation.13 No information was 7579, 1985
available on the health of the maternal animals, 10. Amoateng-Adjepong Y, Sathiakumar N,
but it should be noted that this dosage Delzell E, et al: Mortality among workers at
approaches reported LD50 values.7 No devel- a pesticide manufacturing plant. J Occup Med
opmental effects were observed in rats exposed 37(4):471478, 1995
11. de Jong G, Swaen GMH, Slangen JJM:
to concentrations as high as 6 mg/kg/day on
Mortality of workers exposed to dieldrin and
days 715 of gestation or in mice exposed up aldrin: a retrospective cohort study. Occup
to 4 mg/kg/day on days 614 of gestation.7 Environ Med 54(10):702707, 1997
Decreased fertility has been reported in some 12. Stevenson DE, Walborg EF Jr, North DW,
reproductive studies, and decreased postnatal et al: Monograph: Reassessment of human
survival after in utero exposure has also been cancer risk of aldrin-dieldrin. Toxicol Lett
observed.7 109(3):123186, 1999
The 2003 ACGIH threshold limit value- 13. Ottolenghi AD, Haseman JK, Suggs F: Ter-
time-weighted average (TLV-TWA) for diel- atogenic effects of aldrin, dieldrin, and endrin
drin is 0.25 mg/m3 with a notation for skin in hamsters and mice. Teratology 9:1116,
absorption. 1974
REFERENCES
DIEPOXYBUTANE
1. Hayes WJ Jr, Laws ER, Jr: Handbook of Pesti- CAS: 1464-53-5
cide Toxicology Vol. 2, Classes of Pesticides, pp
828839. New York, Academic Press, 1991
C4H6O2
2. Committee on Toxicology: Occupational
dieldrin poisoning. JAMA 172:20772080,
1960
3. Hoogendam I, Versteeg JPJ, de Vlieger M: Synonyms: 2,2-bioxirane; 1,1-bi(ethylene
Nine years toxicity control in insecticide oxide); butadiene diepoxide; butadiene dioxide;
plants. Arch Environ Health 10:441448, 1965 2,4-diepoxybutane; dioxybutadiene
DIETHANOLAMINE 245
Uses. Reacts with long-chain fatty acids to 13 weeks caused skin lesions characterized by
form ethanolamine soaps, which are used ulceration, inammation, hyperkeratosis, and
extensively as emulsiers, thickeners, wetting acanthosis. Other target organs in the skin
agents, and detergents in cosmetic formula- application study were similar, but less severe,
tions; also used as a dispersing agent in agri- than those observed in the drinking water
cultural chemicals; as a chemical intermediate; study. Differences in dose-response relation-
as a corrosion inhibitor ships between the two studies were attributed
to the limited dermal absorption of DEA in
Exposure. Inhalation rats.
In a follow-up study in mice, exposure to
Toxicology. In animal studies, target organs DEA, via drinking water or by topical applica-
of diethanolamine (DEA) toxicity have tion, caused dose-dependent toxic effects in the
included bone marrow, kidney, testis, skin, and liver (hepatocellular cytological alterations and
central nervous system. necrosis), kidney (nephropathy and tubular
Limited reports of DEA toxicity are avail- epithelial necrosis in males), heart (cardiac
able in humans. Clinical skin testing of cos- myocyte degeneration), and skin (site of appli-
metic products containing DEA showed mild cation: ulceration, inammation, hyperkerato-
skin irritation to concentrations above 5%.1 sis, and acanthosis).7 Doses ranged from 630 to
The oral LD50 in rats has ranged from 0.71 10,000 ppm in the drinking water and from 80
ml/kg to 2.83 g/kg.2,3 The effects of intraperi- to 1250 mg/kg in the topical application study.
toneal administration to rats of doses of 100 or In 2-year dermal studies there was no evi-
500 mg/kg were assessed at 4 and 24 hours after dence of carcinogenicity in rats but there was
dosing.4 In the liver and kidneys, there was clear evidence of carcinogenicity in mice based
cytoplasmic vacuolization. The high doses on increased incidences of liver neoplasms
caused renal tubular degeneration. In rats fed in males and females and increased incidences
0.17 g/kg for 90 days, effects included cloudy of renal tubule neoplasms in males.8 It has
swelling and degeneration of kidney tubules also been noted that in the presence of N-
and fatty degeneration of the liver.3,5 nitrosating agents, DEA may give rise to N N-
Rats exposed to doses of DEA ranging nitrosodiethanolamine, a known animal
from 160 to 5000 ppm in drinking water for 13 carcinogen.1 The IARC has determined that
weeks exhibited dose-dependent hematologic there is limited evidence for the carcinogenic-
changes, tubular necrosis of the kidney with ity of diethanolamine in experimental animals
decreased renal function, demyelination of the and inadequate evidence in humans.9
brain and spinal cord, and degeneration of the DEA was not mutagenic in bacterial assays,
seminiferous tubules.6 Hematologic changes nor did it induce signicant sister chromatid
consisted of a moderate, poorly regenerative exchanges or chromosomal aberrations in cul-
anemia that did not appear to involve hemoly- tured cells.8
sis but rather decreased hematopoiesis. Renal The mechanism of DEA toxicity is
tubular epithelial necrosis was more pro- unknown but may be related to its high tissue
nounced in female rats than males. Demyeli- accumulation and effects on phospholipid
nation in the brain was not associated with metabolism, resulting in alterations in mem-
apparent neurological signs, but long-term brane structure and function.7
effects of this lesion are unknown. Degenera- The liquid applied to the skin of rabbits
tion of the seminiferous tubule epithelium was under semiocclusion for 24 hours on 10 con-
associated with dose-related decreases in testis secutive days caused only minor irritation.1
and epididymis weights with reduced sperm With long contact time, DEA is irritating to
motility and sperm count in the cauda epi- rabbit eyes at concentrations of 50% and
didymidis. above.1 Toxicity resulting from direct contact
In the same study, topical application of may be in part due to irritation associated with
DEA doses ranging from 32 to 500 mg/kg for the alkalinity of this chemical.7
DIETHYLAMINE 247
When DEA was administered cutaneously 10. Marty MS, Neeper-Bradley TL, Neptun DA,
to pregnant rats and rabbits during organo- et al: Developmental toxicity of die-
genesis, developmental toxicity (skeletal varia- thanolamine applied cutaneously to CD rats
tions) was observed only in the rat and only at and New Zealand White rabbits. Reg Toxicol
doses causing signicant maternal toxicity.10 Pharmacol 30:169181, 1999
The 2003 ACGIH threshold limit value-
time-weighted average (TLV-TWA) is 3 ppm
(13 mg/m3).
DIETHYLAMINE
REFERENCES
CAS: 109-89-7
1. Beyer KH Jr et al: Final report on the safety
assessment of triethanolamine, diethan- (C2H5)2NH
olamine and monoethanolamine. J Am Coll
Toxicol 2:193235, 1983
2. Smyth HF Jr, Weil CS, West JS, Carpenter Synonyms: Diethamine; N-ethyl-ethanamine
CP: An exploration of joint toxic action. II.
Equitoxic versus equivolume mixtures. Toxicol Physical Form. Colorless liquid
Appl Pharmacol 17:498503, 1970
3. Mellon Institute: Submission of Data by Uses. In the rubber and petroleum in-
FDA. Mellon Institute of Industrial
dustry; in otation agents; in resins, dyes,
Research, University of Pittsburgh, Special
pharmaceuticals
Report on the Acute and Subacute Toxicity of
Mono-, Di-, and Triethanolamine, Carbide and
Carbon Chem Div, UCC Industrial Fellow- Exposure. Inhalation
ship No 274-13 (Report 13-67), 1950
4. Grice HC et al: Correlation between serum Toxicology. Diethylamine is an irritant of
enzymes, isozyme patterns, and histologically eyes, mucous membranes, and skin.
detectable organ damage. Food Cosmet Toxicol Volunteers exposed to concentrations
9:847, 1971 increasing from 0 to 12 ppm for 60 minutes
5. Smyth HF Jr et al: Range-nding toxicity (average concentration 10 ppm) reported dis-
data, List IV. AMA Arch Ind Hyg Occup Med tinct nasal and eye irritation and moderate to
4:119122, 1951
strong odor detection.1 Acute nasal reactions,
6. Melnick RL, Mahler J, Bucher JR, et al:
as determined by acoustic rhinometry and rhi-
Toxicity of diethanolamine. 1. Drinking
water and topical application exposures in nomanometry, were not observed with expo-
F344 rats. J Appl Toxicol 14:19, 1994 sure to 25 ppm for 15 minutes.
7. Melnick RL, Mahler J, Bucher JR, et al: Tox- Exposure to high vapor concentrations
icity of diethanolamine. 2. Drinking water may cause severe cough and chest pain; heavy,
and topical application exposures in B6C3F1 repeated, or prolonged exposure could result in
mice. J Appl Toxicol 14:1119, 1994 pulmonary edema.2,3 Contact of the liquid with
8. National Toxicology Program: Toxicology eyes causes corneal damage. In one reported
and Carcinogenesis Studies of Diethanolamine case, the liquid splashed into the eye caused
in F344/N Rats and B6C3F1 Mice (Dermal intense pain.4 Despite emergency irrigation
Studies), Technical Report 478, 211pp. US
and treatment, the cornea became swollen and
Department of Health and Human Services,
cloudy; some permanent visual impairment
Public Health Service, 1999
9. IARC Monographs on the Evaluation of the Car- resulted. Prolonged or repeated contact of the
cinogenic Risk of Chemicals to Humans, Vol. 77, eyes with the vapor at concentrations slightly
Some industrial chemicals, pp 349379. below the irritant level often results in corneal
Lyon, International Agency for Research on edema with consequent foggy vision and the
Cancer, 2000 appearance of haloes around lights.1 Dermal
248 2-DIETHYLAMINOETHANOL
contact with the liquid causes vesiculation and 7. Lynch DW, Moorman WJ, Stober P, et al:
necrosis of the skin.3 Subchronic inhalation of diethylamine vapor
In rats, exposure to the saturated vapor is in Fischer-344 rats: organ system toxicity.
lethal in 5 minutes and the 4-hour inhalation Fundam Appl Toxicol 6:559565, 1986
LC50 is 4000 ppm.5 8. British Industrial Biological Research Associa-
tion: BIBRA Toxicity Prole of Diethylamine and
Rabbits repeatedly exposed to 50 ppm for
Its Hydrochloride. Technical Report, pp 17.
7 hours/day, 5 days/week for 6 weeks showed Carshalton, UK, 1997
corneal damage, pulmonary irritation, moder- 9. Amoore JE, Hautala E: Odor as an aid to
ate peribronchitis, and slight thickening of the chemical safety: odor thresholds compared
vascular walls; at 100 ppm, for the same expo- with threshold limit values and volatilities for
sure period, there was striking parenchymatous 214 industrial chemicals in air and water dilu-
degeneration of the heart muscle in all exposed tion. J Appl Toxicol 3:272290, 1983
animals.6
Sneezing, tearing, reddened nose, and
lesions of the nasal mucosa were observed in
rats exposed at 200 ppm for 6.5 hours/day, 5
days/week for 24 weeks.7 Histopathologic
examinations showed squamous metaplasia, 2-DIETHYLAMINOETHANOL
suppurative rhinitis, and lymphoid hyperplasia CAS: 100-37-8
of the respiratory epithelium.
No evidence of mutagenicity was seen (C2H5)2NCH2CH2OH
in Ames bacterial assays.8 Diethylamine has
an ammonia-like odor that is detectable at
0.13 ppm.9 Synonyms: Diethyl ethanolamine; DEAE;
The 2003 ACGIH threshold limit value- N,N-diethylethanolamine
time-weighted average (TLV-TWA) for
diethylamine is 5 ppm (15 mg/m3) with Physical Form. Colorless liquid
a short-term excursion limit of 15 ppm
(45 mg/m3) and an A4-not classiable as a Uses. Anticorrosive agent; chemical inter-
human carcinogen designation; there is a nota- mediate for the production of emulsiers,
tion for skin absorption. detergents, solubilizers, cosmetics, drugs, and
textile nishing agents
REFERENCES
Exposure. Inhalation; skin absorption
1. Lundqvist GR, Yamagiwa M, Pedersen OF, et
al: Inhalation of diethylamineacute nasal To x i c o l o g y. 2 - D i e t h y l a m i n o e t h a n o l
effects and subjective response. Am Ind Hyg (DEAE) is an irritant of the eyes, mucous
Assoc J 53:181185, 1992 membranes, and skin in animals.
2. MCA, Inc.: Chemical Safety Data Sheet SD-97, An attempt by a laboratory worker to
Diethylamine, pp 1516. Washington, DC, remove animals from an inhalation chamber
MCA, Inc, 1971 containing approximately 100 ppm resulted in
3. Hygienic Guide Series: Diethylamine. Am Ind nausea and vomiting within 5 minutes after a
Hyg Assoc J 21:266267, 1960 eeting exposure; no irritation of the eyes or
4. Grant WM: Toxicology of the Eye, 3rd ed, p 333.
throat was noted during this brief exposure.1
Springeld, IL, Charles C. Thomas, 1986
Other persons in the same room also com-
5. Smyth HF Jr, et al: Range-nding toxicity
data, List IV. AMA Arch Ind Hyg Occup Med plained of a nauseating odor but showed no ill
4:109122, 1951 effects.
6. Brieger H, Hodes WA: Toxic effects of expo- Through a leak in the steam heating
sure to vapors of aliphatic amines. Arch Ind system, DEAE was released into the air of a
Hyg Occup Med 3:287291, 1951 large ofce building, and irritative symptoms of
DIETHYLENE TRIAMINE 249
were no treatment-related skin tumors, nor was Physical Form. Colorless or very pale amber
there any evidence of an increased incidence liquid
of internal tumors. Systemic effects were also
absent, indicating limited absorption of the Uses. Plasticizer in polyvinyl chloride lms,
compound. sheeting, extrusions, and plastisols; solvent and
In the eye, solutions of 15% or more emollient in cosmetics
caused lasting corneal damage but a 5% solu-
tion only caused minor injury.2 The injury Exposure. Inhalation; skin contact
caused by single applications appears to be
attributable to the highly alkaline character Toxicology. Diethylhexyl adipate (DEHA) is
of DETA, rather than to some other innate of low acute toxicity but is carcinogenic in mice
toxicity.1 by the oral route.
DETA has a strong ammonia-like odor, There are no reports of effects in humans
but it does not provide adequate warning of from specic exposure to DEHA, but fumes
hazardous concentrations.3 generated at high temperatures may cause
The 2003 ACGIH threshold limit value- throat and eye irritation.1
time-weighted average (TLV-TWA) for dieth- DEHA has a low acute toxicity as indicated
ylene triamine is 1 ppm (4.2 mg/m3) with a by the relatively high oral LD50 in rats of
notation for skin absorption. 9.1 g/kg.2 Skin absorption is expected to be
low because the dermal LD50 in rabbits is
15 g/kg.
REFERENCES In an NTP carcinogenicity study, rats and
mice of both sexes were fed DEHA at 12,000
1. Grant WM: Toxicology of the Eye, 3rd ed, p 336. and 25,000 ppm in the diet for 103 weeks.3
Springeld, IL, Charles C. Thomas, 1986 DEHA was noncarcinogenic in rats but caused
2. Beard RR, Noe JT: Aliphatic and alicyclic hepatocellular carcinomas in female mice in
amines. In Clayton GD and Clayton FE (eds.):
both dose groups and hepatocellular adenomas
Pattys Industrial Hygiene and Toxicology, 3rd rev
in males at the higher dose. The species differ-
ed, Vol. 2B, Toxicology, pp 31463164. New
York, Wiley-Interscience, 1981 ence in carcinogenicity is consistent with a
3. Hygienic Guide Series: Diethylene triamine. greater extent of peroxisome proliferation in
Am Ind Hyg Assoc J 21:268269, 1960 liver of mice as compared to rats.4
4. Leung HW, Van Miller JP: Effects of diethyl- The IARC has determined that there is
enetriamine dihydrochloride following 13 limited evidence of carcinogenicity of DEHA
weeks of dietary dosing in Fischer 344 rats. in experimental animals and that it is not clas-
Food Chem Toxicol 35(5):481487, 1997 siable as to its carcinogenicity to humans.4
5. DePass LR, Fowler EH, Weil CS: Dermal DEHA was not mutagenic or genotoxic in
oncogenic studies on various ethyleneamines a variety of assays, nor did it covalently bind to
in male C3H mice. Fundam Appl Toxicol
DNA in vivo.4
9:807811, 1987
Exposure of rats to DEHA during organo-
genesis caused an increased frequency of vari-
ations and retardations in the fetuses at doses
below the maternally toxic range.4
DIETHYLHEXYL ADIPATE The liquid in contact with the skin of
CAS: 103-23-1 rabbits under occlusion for 24 hours produced
mild skin irritation.5 In the eye, examination
C22H42O4 after 24 hours revealed no irritation from
DEHA.
The ACGIH has not established a thresh-
Synonyms: DEHA; bis(2-ethylhexyl) adipate; old limit value (TLV) for diethylhexyl
octyl adipate adipate.
DI(2-ETHYLHEXYL) PHTHALATE 251
rodents occurs by a nongenotoxic mechanism is withdrawn from the diet before sexual matu-
involving peroxisome proliferation.3 The rity is reached.
central element in developing liver cancer in There are no reported reproductive or
rodents is the activation of a nuclear receptor developmental effects in humans.4
in rodent liver, peroxisome proliferator- The 2003 ACGIH threshold limit value-
activated receptor (PPARa), which leads to time-weighted average (TLV-TWA) for
increased activity of peroxisomal enzymes and DEHP is 5 mg/m3 with an A3-conrmed
is accompanied by increased cell replication.6 animal carcinogen with unknown relevance to
Humans have low liver expression of PPARa humans notation.
and are refractory to peroxisome proliferators.4
Therefore, the mechanism by which DEHP
REFERENCES
increases tumors in rats and mice is not con-
sidered relevant to humans.3 The IARC deter- 1. Thomas JA, Thomas MJ: Biological effects
mined that there is sufcient evidence for the of di-(2-ethylhexyl) phthalate and other
carcinogenicity of DEHP in mice and rats and phthalic acid esters. Crit Rev Toxicol 13:283
inadequate evidence in humans.3 317, 1984
Embryolethal and teratogenic effects have 2. Lawrence WH, Malik M, Turner JE, et al: A
been reported in animal studies. DEHP admin- toxicological investigation of some acute,
istration in the diet of mice throughout gesta- short-term and chronic effects of administer-
tion resulted in an increased incidence of ing di-2-ethylhexyl phthalate (DEHP) and
exophthalmia, exencephaly, tail defects, major other phthalate esters. Environ Res 9:111,
1975
vessel malformations, and skeletal defects at
3. IARC Monographs on the Evaluation of the Car-
doses (0.10% and 0.15%) that produced mater-
cinogenic Risk of Chemicals to Humans, Vol 77,
nal toxicity and at a dose (0.05%) that did not Some industrial chemicals, pp 4143. Lyon,
produce signicant maternal toxicity.7 There International Agency for Research on
were also increased resorptions and late fetal Cancer, 2000
deaths, a decreased number of live fetuses, and 4. Agency for Toxic Substances and Disease
reduced fetal weights at the two higher dose Registry (ATSDR): Toxicological Prole for
levels. In contrast, DEHP was not teratogenic Di(2-Ethylhexyl) Phthalate, 291pp. US
in rats at the doses tested but did produce Department of Health and Human Services,
maternal and some embryofetal toxicity at Public Health Service, 2002
1.0%, 1.5%, and 2.0% of the diet. Inhalation 5. National Toxicology Program: Carcinogenesis
Bioassay of Di-(2-Ethylhexyl) Phthalate (CAS
exposure of up to 0.3 mg/l, 6 hours/day during
No 117-81-7) in Fischer 344 Rats and B6C3F1
gestation failed to produce developmental tox-
Mice (Feed Study). DHHS (NIH) Pub No 82-
icity in rats.8 1773, NTP-80-37, pp 1127. Washington,
Mice given diets containing 0.1% and DC, US Government Printing Ofce, March
0.3% DEHP for 7 days before and during a 98- 1983
day cohabitation period had dose-dependent 6. Doull J, Cattley R, Elcombe C: A cancer risk
decreases in male and female fertility and in the assessment of di(2-ethylhexyl)phthalate:
number of pups born alive.9 application of the new U.S. EPA risk assess-
DEHP-induced testicular injury has been ment guidelines. Reg Toxicol Pharmacol 29:
reported in a number of studies.4,10 Adminis- 327357, 1999
tration of 20,000 mg/kg in the diet of rats pro- 7. Tyl RW, Price CJ, Marr MC, et al: Develop-
mental toxicity evaluation of dietary di-(2-
duced seminiferous tubular degeneration and
ethylhexyl) phthalate in Fischer 344 rats and
testicular atrophy within 7 days, 12,500 mg/kg
CD-1 mice. Fundam Appl Toxicol 10:395412,
produced similar effects within 90 days, and 1988
6000 ppm was effective by the end of 2 years of 8. Merkle J, Klimisch H, Jack R: Developmen-
exposure. Testicular damage has been found to tal toxicity in rats after inhalation exposure
be more severe in young rats than in older rats, of di-(2-ethylhexyl) phthalate (DEHP).
and damage appears to be reversible if DEHP Toxicol Lett 42:215223, 1988
DIETHYL PHTHALATE 253
9. Lamb JC, Chapin RE, Teague J, et al: Repro- The 2003 ACGIH threshold limit value-
ductive effects of four phthalic acid esters time-weighted average (TLV-TWA) for
in the mouse. Toxicol Appl Pharmacol 88: diethyl ketone is 200 ppm (705 mg/m3) with a
255269, 1987 TLV-short-term excursion limit (TLV-STEL)
10. Dostal LA, Chapin RE, Stefanski SA, et al: of 300 ppm (1057 mg/m3).
Testicular toxicity and reduced Sertoli cell
numbers in neonatal rats by di-(2-ethylhexyl)
phthalate and the recovery of fertility as
adults. Toxicol Appl Pharmacol 95:104121, REFERENCES
1988
1. Diethyl Ketone. Material Safety Data Sheet No
478, Corporate Research and Development,
Schenectady, NY, March 1982
2. Smyth HF Jr, Carpenter CP, Weil CS, et al:
Range-nding toxicity data List V. Arch Ind
DIETHYL KETONE
Hyg Occup Med 10:6168, 1954
CAS: 96-22-0 3. British Industrial Biological Research Associa-
tion: BIBRA Toxicity Prole of Diethyl Ketone.
C2H5COC2H5 Technical Report 173, pp 14. Carshalton,
UK, 1988
4. Amoore JE, Hautala E: Odor as an aid to
Synonyms: 3-Pentanone, DEK, dimethylace- chemical safety: odor thresholds compared
tone, methacetone, propione with threshold limit values and volatilities for
214 industrial chemicals in air and water dilu-
Physical Form. Colorless liquid tion. J Appl Toxicol 3:272290, 1983
Exposure. Inhalation
DIETHYL PHTHALATE
Toxicology. Diethyl ketone is expected to be CAS: 84-66-2
an irritant and central nervous system depres-
sant at high concentrations. C6H4(COOC2H5)2
Limited toxicological information is avail-
able for diethyl ketone. Based on analogy with
other methyl ketones, high vapor concentra- Synonyms: 1,2-benzenedicarboxylic acid diethyl
tions are expected to irritate the conjunctiva of ester; DEP
the eyes and mucous membranes of the nose
and throat.1 Excessive inhalation may produce Physical Form. Colorless liquid
dizziness, headache, nausea, vomiting, and
ataxia. Uses. Plasticizer for cellulose ester plastic
In rats a 4-hour exposure at 8000 ppm was lms and sheets; in molded plastics; manufac-
fatal to four of six animals.2 There were no turing varnishes; cosmetics
neurotoxic effects in rats given repeated oral
doses.3 Exposure. Inhalation
The liquid applied to rabbit skin caused
mild irritation, and 50 mg instilled in the eye Toxicology. Diethyl phthalate (DEP) is of
produced moderate irritation. Repeated skin low toxicity.
contact would be expected to cause dermatitis Exposure to the heated vapor may produce
by defatting.1 some transient irritation of the nose and
A distinct acetone-like odor is detectable at throat.1 Although skin sensitization to DEP is
2 ppm.4 extremely rare, it has been reported.2 No sys-
254 DIETHYL SULFATE
temic effects are known pertaining to its occu- 3. Agency for Toxic Substances and Disease
pational use. Registry (ATSDR): Toxicological Prole for
The lowest lethal doses in rabbits and Diethyl Phthalate, 125pp. US Department of
guinea pigs were determined to be 4.0 and Health and Human Services, Public Health
5.0 g/kg, respectively, when administered by Service, 1995
4. Shibko SI, Blumenthal H: Toxicology of
gavage.3 There were no adverse effects in rats
phthalic acid esters used in food-packaging
fed 1.25 g/kg/day or in dogs fed 2.5 g/kg/day material. Environ Health Perspect 3:131, 1973
for 6 weeks or more.4 5. National Toxicology Program: Toxicology and
Male rats dermally administered 300 ml, 5 Carcinogenesis Studies of Diethyl-Phthalate in
days/week for 4 weeks had increased relative F344/N Rats and B6C3F11 Mice (Dermal
liver and kidney weights.5 There was no evi- Studies) with Dermal Initiation/Promotion Study
dence of carcinogenic activity in male or female of Diethylphthalate and Dimethylphthalate in
rats receiving up to 300 ml/day, 5 days/week for Male Swiss (CD-1) Mice. NTP Technical
2 years.5 Equivocal evidence of carcinogenicity Report Series 429:1278, 1995
was seen in mice receiving up to 30 ml/day for 6. Price CJ, Sleet RB, George JD, et al: Devel-
103 weeks based on increased incidences of opmental toxicity evaluation of diethyl phtha-
late (DEP) in CD rats (abst). Teratology
hepatocellular neoplasms.5
39:473474, 1989
Diethyl phthalate administered in the diet 7. Field EA, Price CJ, Sleet RB, et al: Devel-
to rats during major organogenesis increased opmental toxicity evaluation of diethyl and
the incidence of fetal lumbar ribs only at dimethyl phthalate in rats. Teratology 48:3344,
3200 mg/kg/day, a maternally toxic dose.6 In 1993
another report, there also was an increased
incidence of supernumerary ribs, but no other
embryo/fetal effects, in the offspring of rats fed
5% DEP on gestational days 615; maternal
toxicity was evident as reduced body weight DIETHYL SULFATE
gain.7 CAS: 64-67-5
No effects on the male reproductive
system have been found in rats in a number of C4H10O4S
investigations.3
DEP was not mutagenic in bacterial assays,
nor did it induce chromosomal aberrations in Synonyms: Diethyl monosulfate; ethyl
Chinese hamster ovary (CHO) cells; with sulfate; sulfuric acid diethyl ester; diethyl
metabolic activation it did cause sister chro- tetraoxosulfate
matid exchanges in CHO cells.5
The 2003 ACGIH threshold limit value- Physical Form. Colorless, oily liquid
time-weighted average (TLV-TWA) for
diethyl phthalate is 5 mg/m3. Uses. As an ethylating agent; as an accelera-
tor in the sulfation of ethylene; intermediate in
the production by one method of ethyl alcohol
REFERENCES from ethylene and sulfuric acid
volatile and considered less acutely toxic than alkylating agent.4 It induced unscheduled DNA
dimethyl sulfate, which has been shown to synthesis in human cells in vitro. It induced
produce severe irritation to mucous mem- chromatid breaks in mouse embryos treated
branes and the respiratory tract.1,2 transplacentally and dominant lethal mutations
Animal experiments demonstrated an oral in mice, as well as a variety of mutagenic and
LD50 of 350 mg/kg in the rat and 647 mg/kg in clastogenic effects in rodent cells in vitro.3
the mouse. The lowest dose by inhalation that A threshold limit value (TLV) has not been
resulted in death in the rat was 250 ppm for a established for diethyl sulfate.
4-hour exposure.2
An historical cohort study of 743 workers
at a plant manufacturing isopropyl alcohol and REFERENCES
ethanol showed excess mortality (standardized
mortality ratio of 504) from upper respiratory 1. Sandodonata J: Monographs on Human Exposure
(laryngeal) cancers, based on four cases. These to Chemicals in the Workplace: Diethyl Sulfate.
employees had spent most of their time Syracuse, NY, Syracuse Research Corporation,
1985
working in the strong acid-ethanol plant,
2. Sandmeyer EE: In Clayton GD, Clayton FE
which produced high concentrations of diethyl
(eds): Pattys Industrial Hygiene and Toxicology,
sulfate.3 A subsequent case-control study 3rd ed, rev, pp 20942096. New York, Wiley-
nested in an expanded cohort at this plant indi- Interscience, 1981
cated that the increased risk was related to 3. IARC Monographs on the Evaluation of the Car-
exposure to sulfuric acid.3 An association cinogenic Risk to Humans, Vol 54, Occupational
between estimated exposure to diethyl sulfate exposures to mists and vapours from strong
and risk for brain tumor (gliomas) was sug- inorganic acids and other industrial chemicals,
gested in a study of workers at a petrochemical pp 213228. Lyon, International Agency for
plant. The IARC has noted that there has been Research on Cancer, 1992
no measurement of exposure to diethyl sulfate 4. IARC Monographs on the Evaluation of the Car-
cinogenic Risk to Humans, Vol 71, Re-evaluation
in these studies and that concomitant exposure
of some organic chemicals, hydrazine and
to mists and vapors from strong inorganic
hydrogen peroxide, pp 14051415. Lyon,
acids, primarily sulfuric acid, may play a role in International Agency for Research on Cancer,
increasing these risks.3 1999
Local tumors were produced in rats after
subcutaneous administration for 49 weeks. A
small group of rats receiving 25 or 50 mg/kg
diethyl sulfate by gavage had a low incidence of
squamous cell carcinomas of the forestomach, DIFLUORODIBROMOMETHANE
whereas 6 of 24 animals had benign papillomas CAS: 75-61-6
of the forestomach. In another experiment, a
single subcutaneous dose of diethyl sulfate CF2Br2
(85 mg/kg) was administered to three pregnant
rats on day 15 of gestation. Malignant tumors
of the nervous system were observed in 2 of 30 Synonyms: Halon 1202; Freon 12-B2
offspring on days 285 and 541. No tumors of
this type had been observed in controls. Physical Form. Colorless liquid or gas
The IARC has determined that there is
sufcient evidence for the carcinogenicity of Uses. Fire-extinguishing agent
diethyl sulfate in experimental animals and
inadequate evidence of carcinogenicity in Exposure. Inhalation
humans; overall, it should be regarded as prob-
ably carcinogenic to humans.4 Toxicology. Difluorodibromomethane
Diethyl sulfate is a potent direct-acting causes respiratory irritation and narcosis in
256 DIGLYCIDYL ETHER
animals, and severe exposure is expected to and skin; hematopoietic effects have been
produce the same effects in humans. observed in animals.
No effects have been reported from indus- Because of its toxicity, DGE generally is
trial exposures. not used outside experimental laboratories.1
Rats exposed to 4000 ppm for 15 minutes No systemic effects have been reported in
showed pulmonary edema, whereas 2300 ppm humans.
daily for 6 weeks resulted in the death of more The LC50 for mice was 30 ppm for 4 hours,
than half of the animals.1 At 2300 ppm dogs but exposure at 200 ppm for 8 hours was not
showed rapid and progressive signs of intoxica- lethal to rats.2 Rabbits exposed to 24 ppm for
tion after a few days of exposure, with weakness 24 hours had leukocytosis at autopsy. There
and loss of balance followed by convulsions. At were acute changes in the lungs and kidneys as
autopsy, these dogs had pulmonary congestion, well as atrophied testes.3 At 12 ppm, there was
centrilobular necrosis of the liver, and evidence thrombocytopenia and at 6 ppm, basophilia.
of central nervous system damage. Other dogs In rats, three or four exposures at 20 ppm
tolerated daily exposures of 350 ppm for 7 for 4 hours produced intense cytoplasmic
months without signs of intoxication. basophilia, grossly distorted lymphocytic
The 2003 ACGIH threshold limit value- nuclei with indistinct cellular membranes, and
time-weighted average (TLV-TWA) for diu- lowered leukocyte and marrow cell counts.3
orodibromomethane is 100 ppm (858 mg/m3). Repeated exposure of rats to 3 ppm caused
increased mortality, decreased body weight,
and leukopenia. Exposures to 0.3 ppm did not
REFERENCES cause signicant changes. Cutaneous applica-
tions greater than 100 mg/kg also caused
1. ACGIH: Documentation of the Threshold leukopenia, weight loss, and death.
Limit Values and Biological Exposure Indices. The oral LD50 was 0.17 g/kg in mice and
Diuorodibromomethane. 7th ed, 2pp. 0.45 g/kg in rats; following intragastric admin-
Cincinnati, OH, American Conference of
istration, effects were incoordination, ataxia,
Governmental Industrial Hygienists, 2001
depressed motor activity, and coma.2
Diglycidyl ether is extremely damaging to
skin, producing ecchymoses and necrosis. In
one long-term study, skin painting three times
per week for 1 year caused hyperkeratosis,
DIGLYCIDYL ETHER epithelial hyperplasia, and skin papillomas.4
CAS: 2238-07-5 Instilled in rabbit eyes, DGE is a severe
irritant. Exposure to vapor at 3 ppm for 24
C6H10O3 hours produced erythema and edema of the
conjuctiva in rabbits, and at 24 ppm, corneal
opacity was produced.3
Synonyms: Bis(2,3-epoxy propyl)ether; DGE; DGE was mutagenic in bacterial test
di(2,3-epoxypropyl) ether systems.5
The 2003 ACGIH threshold limit value-
Physical Form. Colorless liquid time-weighted average (TLV-TWA) for digly-
cidyl ether is 0.1 ppm (0.53 mg/m3).
Uses. Diluent for epoxy resins; stabilizer of
chlorinated organic compounds
REFERENCES
Exposure. Inhalation; skin absorption
1. National Institute for Occupational Safety and
Toxicology. Diglycidyl ether (DGE), causes Health: Criteria for a Recommended Standard
severe irritation of the eyes, respiratory tract, . . . Occupational Exposure to Glycidyl Ethers.
DIISOBUTYL KETONE 257
DHEW (NIOSH) Pub No 78-166. Washing- The liquid is a defatting agent, and pro-
ton, DC, US Government Printing Ofce, longed or repeated skin contact may cause
1978 dermatitis.
2. Hine CH, et al: The toxicology of glycidol and Although diisobutyl ketone may be more
some glycidyl ethers. Arch Ind Health 14: toxic and irritative than lower-molecular-
250264, 1956
weight ketones at equivalent concentration, it
3. Hine CH, et al: Effects of diglycidyl ether on
blood of animals. Arch Environ Health 2:3144, poses less of an inhalation hazard because of its
1961 relatively low volatility.1
4. McCammon CJ, Kotkin P, Falk HL: The can- Exposure of female rats to 2000 ppm for 8
cerogenic potency of certain diepoxides. Proc hours caused narcosis, and 7 of 12 rats died;
Assoc Cancer Res 2:229230, 1957 however, male rats survived the same treat-
5. US Department of Health and Human Ser- ment, as did both sexes of one other strain of
vices (NIOSH): Occupational safety and health rats.2 Damage to the lungs, liver, and kidneys
guidelines for chemical hazards. Supplement II- was observed at autopsy. Repeated exposures to
OHG (pub No. 89-104), pp 16. Occupational rats over 30 days resulted in increased liver and
safety and health guideline for diglycidyl ether kidney weights at 920 and 530 ppm, but there
potential human carcinogen. Cincinnati, OH,
were no effects at 125 ppm.2 Renal hyalin
1988
droplet nephrosis was seen in male rats exposed
to 905 and 300 ppm 6 hours/day for 9 days;
the signicance of this effect to humans is
questionable.4
DIISOBUTYL KETONE There was no evidence of genotoxcity in a
CAS: 108-83-8 number of in vitro assay systems.5
The 2003 ACGIH threshold limit value-
[(CH3)2CHCH2]2CO time-weighted average (TLV-TWA) for
diisobutyl ketone is 25 ppm (145 mg/m3).
Physical Form. Colorless liquid 1. National Institute for Occupational Safety and
Health: Criteria for a Recommended Standard
. . . Occupational Exposure to Ketones, (NIOSH)
Uses. Solvent; dispersant for resins; interme-
Pub No 78-174, pp 7980, 134, 187. Wash-
diate in the synthesis of pharmaceuticals and
ington, DC. US Government Printing Ofce,
insecticides June 1978
2. Carpenter CP, Pozzani UC, Weil CS: Toxicity
Exposure. Inhalation and hazard of diisobutyl ketone vapors. AMA
Arch Ind Hyg Occup Med 8:377381, 1953
Toxicology. Diisobutyl ketone vapor is an 3. Silverman L, Schulte HF, First MW: Further
irritant of the eyes and mucous membranes; at studies on sensory response to certain indus-
high concentrations it causes narcosis in trial solvent vapors. Ind Hyg Toxicol 28:
animals, and it is expected that severe exposure 262266, 1946
will produce the same effect in humans.1 4. Dodd DE, Losco PE, Troup CM, et al: Hyalin
droplet nephrosis in male Fischer-
Human subjects exposed to 100 ppm for 3
344 rats following inhalation exposure of
hours noted slight lacrimation and throat irri-
diisobutyl ketone. Toxicol Ind Health 3(4):
tation, and slight headache and dizziness on 443457, 1987
returning to fresh air.2 In another study, the 5. British Industrial Biological Research Associa-
majority of subjects experienced eye irritation tion: BIBRA Toxicity Prole of Diisobutyl Ketone.
above 25 ppm, and nose and throat irritation Technical Report 460, pp 16. Carshalton,
above 50 ppm within 15 minutes.3 UK, 1995
258 DIISOPROPYLAMINE
Synonyms: N-(1-methylethyl)-2-propanamine
REFERENCES
Physical Form. Colorless liquid
1. Treon JF, Sigmon H, Kitzmiller KV, Heyroth
Uses. Chemical intermediate; used to adjust FF: The physiological response of animals to
the pH of cosmetic formulations respiratory exposure to the vapors of diiso-
propylamine. J Ind Hyg Toxicol 31:142145,
1949
Exposure. Inhalation; skin absorption
2. Pang SNJ: Final report on the safety assess-
ment of diisopropylamine. J Am Coll Toxicol
Toxicology. Diisopropylamine is an eye irri- 14(3):182192, 1995
tant in humans; it is a pulmonary irritant in
animals, and severe exposure is expected to
produce the same effect in humans.
Workers exposed to concentrations
between 25 and 50 ppm complained of distur-
bances of vision described as haziness.1 In DIMETHOXYETHYL PHTHALATE
two instances, there were also complaints of CAS: 117-82-8
nausea and headache. Prolonged skin contact
with an irritant of this nature is likely to cause C6H4[COOCH2CH2OCH3]2
dermatitis.
Exposure of several species of animals to
2207 ppm for 3 hours was fatal; effects were Synonyms: DMEP; 1,2-benzenedicarboxylic
lacrimation, corneal clouding, and severe irri- acid bis(2-methyoxy-ethyl)ester; bis (meth-
tation of the upper respiratory tract; at autopsy oxyethyl) phthalate; dimethyl cellosolve
ndings included pulmonary edema and phthalate
hemorrhage. Repeated exposure to 600 ppm,
7 hours/day for 40 days caused deaths in all Physical Form. Light colored, clear liquid
rabbits and some guinea pigs; cats and rats sur-
vived but had cloudiness of the cornea with loss Uses. Plasticizer; solvent
of vision. It was determined that the ocular
effects of diisopropylamine are due to direct Exposure. Inhalation
contact with the vapor, as no corneal effects
occurred from subcutaneous injection in Toxicology. Dimethoxyethyl phthalate
guinea pigs. (DMEP) causes teratogenic, reproductive, and
In guinea pigs, 5% diisopropylamine fetotoxic effects in animals.
caused dermal irritation with repeated expo- Acute lethality data indicate that DMEP
sures, but it was not a sensitizer.2 The irritative exhibits slight to moderate toxicity. The oral
properties of diisopropylamine have been LD50 in rats ranged from 3.2 to 6.4 g/kg.1
attributed to its alkaline pH, which is neutral- Exposure of rats to 1595 ppm for 6 hours
ized in some formulations. caused deaths of all animals, whereas 770 ppm
Conicting results have been reported in for 6 hours was not lethal.2 The dermal LD50
bacterial mutagen assays; diisopropylamine was in guinea pigs was greater than 10 ml/kg, sug-
not genotoxic in DNA repair assays in vitro.2 gesting very little absorption.
DIMETHYLACETAMIDE 259
route for 3 or more days as a therapeutic trial; by gavage to rats caused treatment-related
they experienced depression, lethargy, confu- malformations of the fetal heart, major vessels,
sion, and disorientation; on the last (fourth or and oral cavity but only at levels (400 mg/
fth) day of therapy or within 24 hours there- kg/day) that also produced signicant maternal
after, the patients had visual and auditory hal- toxicity and other indicators of fetal toxicity
lucinations, perceptual distortions, and at times including increased postimplantation loss and
delusions; after 24 hours these effects gradually skeletal variation.8 Pregnant rats exposed 6
subsided.2 hours/day on days 615 of gestation to 30, 100,
The median lethal concentration was or 300 ppm had maternal toxicity at the highest
2475 ppm in rats, and repeated exposures dose but no signicant increase in the
caused liver injury.3 Male mice exposed to 480 incidence of external, visceral, or skeletal
ppm 6 hours/day for 10 exposures showed no malformations.9
signs of clinical toxicity, but mild degeneration In practice, the dermal absorption factor
and atrophy of the seminiferous tubules was is considered to be so signicant that no air
observed at necropsy.4 No pathologic changes concentration, however low, will provide
were seen in adult rats similarly exposed. Pre- protection if skin contact with the liquid is
pubescent mice were more sensitive to DMAC; permitted.
10 exposures at 490 ppm caused 20% mortality, The 2003 ACGIH threshold limit value-
labored breathing, lethargy, and tremors. His- time-weighted average (TLV-TWA) for
tologic lesions included testicular seminiferous dimethylacetamide is 10 ppm (36 mg/m3) with
tubule hypertrophy, hepatocellular necrosis a notation for skin absorption.
and hypertrophy, lymphoid organ atrophy,
bone marrow hypoplasia, and adrenal cortical
necrosis. In another study repeated exposure of REFERENCES
rats to a concentration of 195 ppm for 6 months
resulted in focal necrosis of the liver; exposure 1. ACGIH: Dimethyl acetamide. Documentation
to 40 ppm for the same period of time caused of TLVs and BEIs, 6th ed, pp 477478. Cincin-
no adverse effects.5 nati, OH, American Conference of Govern-
Dimethylacetamide was not oncogenic in mental Industrial Hygienists, 1991
either mice or rats exposed to 25, 100, or 350 2. Weiss AJ, et al: Dimethylacetamide: A hitherto
ppm 6 hours/day, 5 days/week for 18 months unrecognized hallucinogenic agent. Science
(mice) or 2 years (rats).6 Compound-related 136:151152, 1962
3. Kennedy GL Jr, Sherman H: Acute and sub-
morphologic changes were found in the liver of
chronic toxicity of dimethylformamide and
both species at the highest doses.
dimethylacetamide following various routes
Rabbits receiving dermal exposures of of administration. Drug Chem Toxicol 9(2):
2000 mg/kg showed anorexia and weakness fol- 147170, 1986
lowed in many instances by cyanosis and 4. Ventine R, Hurtt ME, Frame SR, et al: Inhala-
death.3 tion toxicology of dimethylacetamide
The approximate lethal dose for skin (DMAC) in mice and rats: age-related effects
absorption in pregnant rats and rabbits was 7.5 on lethality and testicular injury. Inhalation
and 5.0 g/kg, respectively.7 Cutaneous applica- Toxicol 9(2):141156, 1997
tion of DMAC resulted in a marked incidence 5. Horn HJ: Toxicology of dimethylacetamide.
of embryo mortality at doses that did not affect Toxicol App Pharmacol 3:1224, 1961
6. Malley LA, Slone TW Jr, Makovec GT, et al:
maternal body weight or produce any signs of
Chronic toxicity/oncogenicity of dimethylac-
maternal toxicity. Teratogenic effects (three
etamide in rats and mice following inhalation
fetuses from one dam with encephalocele; one exposure. Fundam Appl Toxicol 28:8093, 1995
of eight with diffuse subcutaneous edema) were 7. Stula EF, Krauss WC: Embryotoxicity in
found in rats only when DMAC was applied on rats and rabbits from cutaneous application
gestation days 10 and 11 at a total dose of 2400 of amide-type solvents and substituted ureas.
mg/kg.7 In another study, DMAC administered Toxicol Appl Pharmacol 41:3555, 1977
DIMETHYLAMINE 261
2. IARC Monographs on the Evaluation of Carcino- Few reports of industrial experience are
genic Risk to Man, Vol 8, Some aromatic azo available from which to form an accurate
compounds, pp 125146. Lyon, International appraisal of its health hazards; it is said to be
Agency for Research on Cancer, 1975 less potent than aniline as a cause of methe-
3. Nelson SA, Woodward G: Tumors of the moglobin, but more of a central nervous system
urinary bladder, gall bladder and liver in dogs
depressant. The effects of methemoglobinemia
fed o-aminoazotoluene or p-dimethylaminoa-
zobenzene. J Natl Cancer Inst 13:14971509, are cyanosis (especially of the lips, nose, and
1953 earlobes), weakness, dizziness, and severe
4. Druckrey H, Kupfmuller K: Quantitative headache.1
analyse der krebsentstehung. Z Naturforsch In dogs, the repeated subcutaneous injec-
3b:254266, 1948 tion of 1.5 g caused vomiting, weakness,
5. Druckrey H: Quantitative aspects in chemical cyanosis, methemoglobinemia, and hyperglob-
carcinogenesis. In Trichaut R (ed): Potential ulinemia.2 Rats survived an 8-hour exposure to
Carcinogenic Hazards from Drugs. UICC concentrated vapor.3 The single-dose oral LD50
Monograph Series 7:6078, 1967 for rats was 1.41 ml/kg, and the single-dose
6. Fare G: Rat skin carcinogenesis by topical dermal LD50 for rabbits was 1.77 ml/kg.
applications of some azo dyes. Cancer Res 26:
Continuous exposure of rats by inhalation
24052408, 1966
7. Tsuda S, Matsusaka N, Madarame H, et al: to 0.0055 and 0.3 mg/m3 for 100 days resulted
The comet assay in eight mouse organs: results in methemoglobinemia, lowered erythrocyte
with 24 azo compounds. Mutat Res 465:1126, hemoglobin, leukopenia and reticulocytosis,
2000 and reduced muscle chronaxie.4 Doses up to
8. Stokinger HE: Occupational carcinogenesis. 500 mg/kg administered by gavage to rats and
In Clayton GD, Clayton FE (eds): Pattys mice for 13 weeks caused cyanosis and
Industrial Hygiene and Toxicology, 3rd ed, rev, decreased motor activity, as well as hemo-
Vol. IIB, Toxicology, p 2893. New York, siderosis in the spleen liver, kidney, and testes.5
Wiley-Interscience, 1981 Bone marrow hyperplasia was observed in
rats, and mice had increased hematopoiesis
in the liver. In general, all toxic effects
could be attributed to chronic methemo-
N,N-DIMETHYLANILINE globinemia, erythrocyte destruction, and
CAS: 121-69-7 erythrophagocytosis.
Mice and rats administered up to 30 mg/kg
C6H5N(CH3)2 by gavage, 5 days/week for 103 weeks had an
increased incidence of forestomach papillomas
(female mice) and an increase in splenic sarco-
Synonyms: Dimethylphenylamine; aminodi- mas (male rats) that exceeded normal historical
methylbenzene (Note: also known as dimethyl- controls.6
aniline, which is a synonym for xylidine) IARC has determined that there is inade-
quate evidence in humans for the carcino-
Physical Form. Yellow to brown oily liquid genicity of N,N-dimethylaniline and limited
evidence in animals.4 Overall, N,N-dimethyl-
Uses. Intermediate in the manufacture of aniline is not classiable as to its carcinogenic-
dyes; solvent; rubber vulcanizing agent and ity in humans.
stabilizer N,N-Dimethylaniline induced gene muta-
tion, sister chromatid exchange, and chromo-
Exposure. Inhalation; skin absorption somal aberrations in cultured mammalian
cells. It was not mutagenic in Salmonella
Toxicology. N,N-Dimethylaniline absorp- typhimurium.4
tion causes anoxia due to the formation of The liquid was slightly irritating to the
methemoglobin. clipped skin of rabbits within 24 hours of a
264 DIMETHYL CARBAMOYL CHLORIDE
1. Beard RR, Noe JT: Aromatic nitro amino Physical Form. Liquid
compounds. In Clayton GD, Clayton FE (eds):
Pattys Industrial Hygiene and Toxicology, 3rd ed, Uses. As a chemical intermediate in the
Vol 2A, Toxicology, pp 24132489. New York, manufacture of carbamate drugs and pesticides
Wiley-Interscience, 1981
2. von Oettingen WF: The Aromatic Amino and
Nitro Compounds, Their Toxicity and Potential
Exposure. Inhalation
Dangers. US Public Health Service Publication
No 271, pp 1516. Washington, DC, US Toxicology. Dimethyl carbamoyl chloride is
Government Printing Ofce, 1941 a skin, eye, and respiratory irritant; it is car-
3. Smyth HF Jr et al: Range-nding toxicity data: cinogenic in experimental animals by skin
List VI. Am Ind Hyg Assoc J 23:95107, 1962 application and by subcutaneous or intraperi-
4. IARC Monographs on the Evaluation of the Car- toneal injection.
cinogenic Risks to Humans, Vol 57, Occupational One case of eye irritation and one of
exposures of hairdressers and barbers and impaired liver function have been observed
personal use of hair colourants; some hair
in workers exposed to dimethyl carbamoyl
dyes, cosmetic colourants, industrial dyestuffs
and aromatic amines, pp 337350. Lyon,
chloride.1
International Agency for Research on Cancer, When rats were exposed to saturated
1993 vapors ve of six or six of six died after 1 or 2
5. Abdo KM, Jokinen MP, Hiles R: Sub- hours, respectively. Dimethyl carbamoyl chlo-
chronic (13-week) toxicity studies of N,N- ride damaged the mucous membranes of the
dimethylaniline administered to Fischer 344 nose, throat, and lungs and caused difculty in
rats and B6C3F1 mice. J Toxicol Environ Health breathing, sometimes several days after expo-
29:7788, 1990 sure.1 Rats tolerated an 8-minute exposure to
6. US National Toxicology Program: Toxicology the saturated vapors and survived 14 days after
and Carcinogenesis Studies of N,N-Dimethylani- exposure. Fifty-one of 100 rats exposed 6
line (CAS No. 121-69-7) in F344/N Rats and
hours/day for 15 days at 10 ppm succumbed.
B6C3F1 Mice (Gavage Studies). NTP TR 360,
NIH Pub No. 90-2815, US Department of
Applied to the skin of rats and rabbits, the
Health and Human Services, 1989 undiluted liquid produced skin irritation, with
subsequent degeneration of the epidermis;
skin sensitization tests in guinea pigs were
negative.
In long-term animal studies, dimethyl
carbamoyl chloride produced local tumors by
each of three routes of administration.2 Two
milligrams applied to the skin of mice three
times/week for 492 days caused skin papillomas
in 40 of 50 animals; of these, 30 progressed to
skin carcinomas. After weekly subcutaneous
injections of 5 mg for 26 weeks, 36 of 50 female
DIMETHYLFORMAMIDE 265
disease, indicating that DMF was the causative time-weighted average (TLV-TWA) for
agent of the outbreak.4 dimethylformamide is 10 ppm (30 mg/m3) with
Case reports of testicular cancer in leather a notation for skin absorption.
tannery workers and aircraft mechanics have
suggested an association with DMF, but further
epidemiological studies have not conrmed the REFERENCES
relationship.58
A case control study of four plants where 1. Hazard Data Bank: Sheet No 77. Dimethyl
DMF was produced or used showed no statis- formamide. The Safety Practitioner, pp 4849.
tically signicant association between ever May, 1986
2. Potter HP: Dimethylformamide-induced
having been exposed to DMF and subsequent
abdominal pain and liver injury. Arch Environ
development of cancers of the buccal cavity and
Health 27:340341, 1973
pharynx, liver, prostate, and testes and malig- 3. Redlich CA, Beckett WS, Sparer J, et al:
nant melanoma.9 Although prostate cancer was Liver disease associated with occupational
signicantly elevated at one plant when exam- exposure to the solvent dimethylformamide.
ined by plant site, it did not appear to be related Ann Int Med 108:680686, 1988
to exposure level or duration. 4. Fleming LE, Shalat SL, Redlich CA: Liver
The IARC has determined that there is injury in workers exposed to dimethylfor-
inadequate evidence for the carcinogenicity of mamide. Scand J Work Environ Health 16:
dimethylformamide in humans.7 289292, 1990
In both mice and rats exposed 6 hours/day 5. Levine SM, Baker DB, Langrigan PJ, et al:
Testicular cancer in leather tanners exposed
5 days/week for 12 weeks, the no-effect dose
to dimethylformamide (Letter). Lancet
was below 150 ppm and the maximum tolerated
2:1153, 1987
dose was below 600 ppm. At doses of up to 6. Ducatman AM, Conwell DE, Crawl J: Germ
1200 ppm there were few signs of overt toxic- cell tumors of the testicle among aircraft
ity, and at necropsy the only treatment related repairman. J Urol 136:834836, 1986
lesions occurred in the liver.10 Subchronic 7. IARC Monographs on the Evaluation of
studies in monkeys showed no exposure-related Carcinogenic Risks to Humans Vol 71, Re-
adverse health effects or reproductive effects evaluation of some organic chemicals,
after exposure 6 hour/day, 5 days/week for 13 hydrazine and hydrogen peroxide, p 545.
weeks to concentrations of up to 500 ppm.11 Lyon, International Agency for Research on
Chronic inhalation studies in rodents Cancer, World Health Organization, 1999
8. World Health Organization: Concise Inter-
found no increase in tumors.7 The IARC has
national Chemical Assessment Document 31,
determined that there is evidence suggesting
N,N-Dimethylformamide. International
lack of carcinogenicity of DMF in animals. Programme on Chemical Safety. Geneva,
Metabolic studies of DMF show quantitative 2001
differences in human and rodent pathways, 9. Walrath J, Fayerweather WE, Gilby PG, et
suggesting that rodent studies may not be al: A case-control study of cancer among Du
indicative of human results.12 Pont employees with potential for exposure
Inhalation and epicutaneous exposures of to dimethylformamide. J Occup Med 31:
DMF by rats have produced no teratogenic 432438, 1989
effects and only slight evidence of embryotox- 10. Craig DK, Wier RJ, Wagner W, et al: Sub-
icity at levels producing some maternal chronic inhalation toxicity of dimethylfor-
mamide in rats and mice. Drug Chem Toxicol
toxicity.13,14
7:551571, 1984
In a number of short-term assays, DMF
11. Hurtt ME, Placke ME, Killinger JM, et al:
was not mutagenic or genotoxic.15 Inconsistent 13-Week inhalation toxicity study of
results have been reported in human in vivo dimethylformamide (DMF) in Cynomolgus
studies for sister chromatid exchange and chro- monkeys. Fundam Appl Toxicol 18:596601,
mosomal aberration frequencies.8 1992
The 2003 ACGIH threshold limit value- 12. Mraz J, Cross H, Gescher A, et al:
1,1-DIMETHYLHYDRAZINE 267
Differences between rodents and humans able conditions; in a few of these cases fatty
in the metabolic toxication of N,N- inltration of the liver was also demonstrated
dimethylformamide. Toxicol Appl Pharmacol by liver biopsy, although alcohol intake may
98:507516, 1989 have been a factor in some cases.3
13. Kennedy GL Jr: Biological effects of Exposure of dogs to 111 ppm for 3 hours
acetamide, formamide and their monomethyl
caused vomiting, convulsions, and death; at
and dimethyl derivatives. CRC Crit Rev Toxicol
17:129182, 1986 autopsy, pulmonary edema and hemorrhage
14. Hansen E, Meyer O: Embryotoxicity and ter- were present but were believed to be a second-
atogenicity study in rats dosed epicutaneously ary manifestation of the convulsive seizures
with dimethylformamide (DMF). J Appl rather than a primary effect of the agent.4 Dogs
Toxicol 10:333338, 1990 repeatedly exposed to 25 ppm developed
15. Antoine JL, Arany J, Leonard A, et al: Lack vomiting, diarrhea, ataxia, convulsions, and
of mutagenic activity of dimethylformamide. hemolytic anemia.4 At 5 ppm for 26 weeks dogs
Toxicology 26(34):207212, 1983 had slightly decreased body weight, hemolytic
anemia, and hemosiderosis of the spleen.5
Applied to the shaved skin of dogs the
liquid was mildly irritating and rapidly
absorbed; the dermal LD50 was between
1,1-DIMETHYLHYDRAZINE 1.2 and 1.7 g/kg.6 In the eye, it caused mild
CAS: 57-14-7 conjunctivitis.7
Administration of 0.1% in the drinking
C2H8N2 water of 50 male and 50 female Swiss mice
resulted in a high incidence of angiosarcomas
in various organs (79%); tumors of the lungs
Synonyms: asym-Dimethylhydrazine; un- (71%), kidneys (10%), and liver (7%) were also
symmetrical dimethylhydrazine; dimazine; observed.8 In another study, mice given daily
UDMH gavage doses of 0.5 mg, 5 days/week for 40
weeks showed inconclusive evidence of lung
Physical Form. Colorless liquid tumor induction.7 Chronic inhalation of 1,1-
dimethylhydrazine by rats produced benign
Uses. Base in rocket fuel formulations; inter- tumors of the lung and pituitary.9 A broad dis-
mediate in organic synthesis tribution of tumors occurred in mice after
inhalation, with the respiratory system and
Exposure. Inhalation; skin absorption liver most severely affected. Lesions of the
respiratory system included inammation and
Toxicology. 1,1-Dimethylhydrazine is a res- other indications of chronic insult including a
piratory irritant and convulsant; it is carcino- variety of rare, but benign, tumors of the upper
genic in experimental animals. respiratory system and the more common lung
Accidental human exposures have resulted adenoma; liver lesions included a variety of
in eye irritation, choking sensation, chest pain, benign and malignant tumors. These lesions
dyspnea, lethargy, nausea, and skin irritation.1 were seen sporadically at 0.05 ppm.
On the basis of the results of exposure in dogs, The carcinogenic risk to humans has not
the effects expected in humans from exposure been determined, but 1,1-dimethylhydrazine is
for 60 minutes are: 100 ppm, irritation of eyes classied as a suspected human carcino-
and mucous membranes; 200 ppm, marked gen based on animal results. The National
central nervous system stimulation and perhaps Institute for Occupational Safety and Health
death; 900 ppm, convulsions and death.2 Im- (NIOSH) has also noted that the role of
pairment of liver function (elevated SGPT nitrosodimethylamine, a contaminant of
levels) has been reported in 47 of 1193 workers 1,1-dimethylhydrazine, must be considered
exposed to 1,1-dimethylhydrazine under vari- in evaluating the tumorigenicity of 1,1-
268 DIMETHYL HYDROGEN PHOSPHITE
The acute oral LD50 values for dimethyl species variations in carcinogenicity are most
hydrogen phosphite were 3300 and 3000 mg/ likely attributable to other factors, with metab-
kg body weight (bw) for male and female olism playing only a minor role.7 The IARC
Fischer 344/N rats, respectively, and 2800 mg/ determined that there is limited evidence for
kg bw for male B6C3F1 mice.1 the carcinogenicity of dimethyl hydrogen
Rats exposed to airborne levels of 934 ppm, phosphite in experimental animals and that it
6 hours/day for 3 days died.2 Effects observed is not classiable as to its carcinogenicity to
included irritation of the skin, eyes, and humans.8
mucous membranes, neuromuscular impair- Limited data indicate that DMHP may
ment, and lung congestion. Rats exposed to have testicular effects; calcication and atrophy
431 ppm, 6 hours/day for 5 days survived but of the testes were observed in mice in the
exhibited the same irritant effects as seen at course of chronic and subchronic oral studies
934 ppm. at 200 mg/kg for 103 weeks and 375 and
In a month-long study, rats were exposed to 750 mg/kg for 13 weeks, respectively.6
12, 35, 119, or 198 ppm for 6 hours/day, 5 Dimethyl hydrogen phosphite was not
days/week.3,4 In the high-dose group, 27 of 40 mutagenic to several strains of Salmonella
animals were dead by day 27; in the 119 ppm typhimurium, but it did cause sister chromatid
group, 2 animals died on days 14 and 23. There exchanges and chromosomal aberrations in the
was neurological impairment at 198 ppm and Chinese hamster CHO line.1
119 ppm that usually reversed by the following An ACGIH threshold limit value (TLV)
morning. Necrosis and purulent inammation has not been established for dimethyl hydrogen
of the skin were thought to be the only lesions phosphite.
that may have caused death. Although there was
treatment-related irritation of the eyes and REFERENCES
nares, there was no treatment-related irritation
of the trachea or lungs. Lenticular opacities 1. IARC Monographs on the Evaluation of Carcino-
occurred at 35 ppm and above, which progressed genic Risks to Humans, Vol 48, Some ame
to cataracts in the 119 and 198 ppm groups. In retardants and textile chemicals, and exposures
rats killed 2 weeks after treatment, the process in the textile manufacturing industry, pp
of cataract formation had stopped; at 4 weeks the 8593. Lyon, International Agency for
formation of normal lens bers was evident. Research on Cancer, 1990
Rats treated with 200 mg/kg/day by gavage 2. Mobil Research and Development Corpora-
tion. TSCA sec. 8(e)Submission 8EHQ-0381-
for 4, 5, or 6 weeks showed early treatment-
0366 Follow-up. A Five Day InhalationToxicity
related changes in the lungs (signicant
Study of MCTR-174-79 in the Rat. Performed
increases in serum angiotensin) and possible by Bio/dynamics Inc, Washington, DC, Ofce
preneoplastic changes in the forestomach, of Toxic Substances, US Environmental Pro-
characterized by epithelial hyperplasia, hyper- tection Agency, 1981
keratosis, subepithelial and submucosal inam- 3. Mobil Oil Corporation. TSCA sec. 8(e) Sub-
mation, and edema.5 mission 8EHQ-0381-0366 Follow-up. A Four
In a carcinogenic study, male and female Week Inhalation Toxicity Study in the Rat. Pre-
rats were given DMHP by gavage 5 days/week pared by Bio/dynamics, Inc, Washington, DC,
for 103 weeks.6 At 200 mg/kg, there were Ofce of Toxic Substances, US Environmen-
increases in alveolar/bronchiolar carcinomas, tal Protection Agency, 1981
4. Mobil Oil Corporation. TSCA sec. 8(e)
squamous cell carcinomas of the lung, and car-
Submission 8EHQ-0381-0366 Follow-up.
cinomas of the stomach in male rats. Neoplas-
Histopathologic Observations on a Four Week
tic lesions did not occur in mice after similar Inhalation Toxicity Study of MCTR-242-79 in the
treatments. Species-dependent differences in Rat. Prepared by Toxicity Research Laborato-
the metabolism of DMPH were limited to ries, Ltd, Washington, DC, Ofce of Toxic
more rapid metabolism and elimination by Substances, US Environmental Protection
mice compared with rats. Therefore, the Agency, 1981
270 DIMETHYL METHYLPHOSPHONATE
5. Nomeir AA, Uraih LC: Pathological and bio- than 6000 mg/kg for mice.1 Clinical signs
chemical effects of dimethyl hydrogen phos- reported in rats and mice after doses of up to
phite in Fischer 344 rats. Fundam Appl Toxicol 6810 mg/kg included inactivity, unsteady gait,
10:114124, 1988 and prostration. In 15-day studies, compound-
6. National Toxicology Program: NTP Technical related deaths occurred at 5000 mg/kg/day and
Report on the Toxicology and Carcinogenesis
above in rats and at 10,000 mg/kg/day in mice;
Studies of Dimethyl Hydrogen Phosphite (CAS
No 868-85-9) in F344 Rats and B7CSF the only compound-related lesions observed
Mice(Gavage Studies). NTP TR 287. Research were stomach lesions in the mice.
Triangle Park, NC, National Toxicology DMMP administered to male Fischer rats
Program, 1984 by gavage 5 days/week for 90 days at dosages
7. Nomeir AA, Matthews HB: Metabolism and of 250, 500, 1000, and 2000 mg/kg caused a
disposition of dimethyl hydrogen phosphite dose-related decrease in sperm count, sperm
in rats and mice. J Toxicol Environ Health motility, and the male fertility index.2 When
51(50):489501, 1997 mated, treated males sired fewer litters with
8. IARC Monographs on the Evaluation of Carcino- fewer pups per litter, and untreated dams had
genic Risks to Humans, Vol 71, Re-evaluation more resorptions. The percentage of resorp-
of some organic chemicals, hydrazine and
tions was 6.1% in the control group and
hydrogen peroxide, p 1437. Lyon, Interna-
tional Agency for Research on Cancer, 1999 increased to 14.9%, 37.8%, and 79.1% in the
250, 500, and 1000 mg/kg groups, respectively.
Histologic abnormalities of the testis were only
observed in the high-dose group and were
characterized by lack of spermatogenesis or by
degeneration, vacuolization, and necrosis of
DIMETHYL METHYLPHOSPHONATE cells in the spermatogenic tubules. Microscopic
CAS: 756-79-6 changes of the prostate were also observed in
some of the high-dose animals, whereas abnor-
C3H9O3P malities of the kidney (tubular cell regenera-
tion, hyalin droplet degeneration, and cellular
inltrate) were seen in some animals from each
Synonyms: Phosphonic acid, methyl-, of the dosed groups.
dimethyl ester; DMMP Further study of the reproductive lesions
in male rats showed morphologic alterations
Physical Form. Solid in Sertoli cells and elongating spermatids, as
well as functional defects in spermatozoa after
Uses. As a ame retardant, a preignition administration of 1750 mg/kg for up to 12
additive for gasoline, an antifoam agent, a plas- weeks.3
ticizer and stabilizer, a textile conditioner, and In chronic studies, DMMP was adminis-
an antistatic agent; used experimentally to tered by gavage in corn oil for up to 2 years at
mimic the physical and spectroscopic (but not doses of 500 or 1000 mg/kg/day to rats and at
biological) properties of anticholinesterase doses of 1000 or 2000 mg/kg/day to mice.1,4
agents Survival in dosed male rats was reduced, due in
part to renal toxicity. Lesions of the kidney
Exposure. Inhalation included increased severity of spontaneous
age-related nephropathy including calcica-
Toxicology. Dimethyl methylphosphonate tion, hyperplasia of the tubular and transitional
(DMMP) administered to male rats is a repro- epithelium, tubular cell adenocarcinomas, and
ductive toxicant and carcinogen. Effects in transitional cell papillomas and carcinomas.
humans are unknown. Similar lesions were not seen in female rats or
The acute oral LD50 is estimated to be in mice of either sex, although reduced survival
greater than 3000 mg/kg for rats and greater in male mice prevented adequate analysis. The
2,4-DIMETHYLPHENOL 271
3. Lehman AJ: Insect repellents. Assoc Food Drug moist mucosal surface it is slowly hydrolyzed
Ofce US Q Bull 19:8799, 1955 into sulfuric acid, methanol, and methyl hydro-
4. Draize J, et al: Toxicological investigations gen sulfate.1 The methanol can be absorbed
of compounds proposed for use as insect into the circulation, leading to neurotoxic
repellents. J Pharmacol Exp Ther 93:2639, effects, whereas the sulfuric acid and methyl
1948
hydrogen sulfate induce severe irritative and
5. Lawrence WH, et al: Toxicological investiga-
tion of some acute, short-term, and chronic erosive actions to the mucosa.
effects of administering di-2-ethylhexyl Several human deaths have occurred from
phthalate (DEHP) and other phthalate esters. occupational exposure, and it has been esti-
Environ Res 9:111, 1975 mated that inhalation of 100 ppm for 10
6. Singh AR, Lawrence WH, Autian J: Terato- minutes would be fatal.2,3 A major cause of
genicity of phthalate esters in rats. J Pharma- mortality in DMS intoxication is respiratory
col Sci 61:5155, 1972 failure, a consequence of mucosal inammation
7. Field EA, Price CJ, Sleet RB, et al: Devel- and edema of major airways and of noncardio-
opmental toxicity evaluation of diethyl and genic pulmonary edema. Often, exposure of
dimethyl phthalate in rats. Teratology 48:3344, humans produces no immediate effects other
1993
than occasional slight eye and nose irritation;
8. Ostby J, Price M, Furr J, et al: Perinatal expo-
sure to the phthalates DEHP, BBP, DINP but after a latent period of up to 10 hours or more,
not DEP, DMP or DOTP permanently alters there is onset of headache and giddiness with
androgen-dependent tissue development in intense conjunctival irritation, photophobia,
Sprague-Dawley rats. Biol Reprod 62(suppl 1): and angioneurotic edema, followed by inam-
1845, 2000 mation of the pharyngolaryngeal mucosa, dys-
9. Kozumbo WJ, Rubin RJ: Mutagenicity and phonia, aphonia, dysphagia, productive cough,
metabolism of dimethyl phthalate and its bind- oppression in the chest, dyspnea, and
ing to epidermal and hepatic macromolecules. cyanosis.2,4 Vomiting and diarrhea may inter-
J Toxicol Environ Health 33:2946, 1991 vene.2,4 Dysuria may occur for 34 days; there
may be persistence of laryngeal edema for up
to 2 weeks and of photophobia for several
months. Other effects include delirium, fever,
convulsions, and coma as well as damage to
DIMETHYL SULFATE heart, liver, and kidneys.2,5 The long-term
CAS: 77-78-1 sequelae of acute DMS poisonings has been
examined in 62 patients followed for 212
(CH3)2SO4 years.1 Hoarseness remained in 33% of the
moderately to severely intoxicated patients.
Mild ventilatory disturbances were demon-
Synonyms: Sulfuric acid dimethyl ester; DMS strated in ve cases, and mild to moderate pul-
monary function abnormalities were observed
Physical Form. Colorless, oily liquid in three patients. No abnormalities were found
in ECG and routine blood examinations. No
Uses. Methylating agent in the manufacture evidence of pulmonary neoplasms was found
of many organic chemicals on follow-up chest X rays. In another case
there was persistent cough and mucopurulent
Exposure. Inhalation; skin absorption sputum 10 months after exposure, with
repeated infective episodes, probably second-
Toxicology. Dimethyl sulfate (DMS) is ary to mucosal damage by DMS.6 It was not
highly toxic; it is a severe irritant of the eyes, known whether more extensive brosis would
mucous membranes, and skin; it is carcinogenic develop with time.
in experimental animals. Contact of the liquid with the eyes or skin
When DMS comes into contact with a will cause very severe burns because of its pow-
274 DIMETHYL SULFATE
erful vesicant action.2 In an incident of moder- (0.5 mg/m3) with a notation for skin absorp-
ate skin contact with the liquid, generalized tion and an A2-suspected human carcinogen
intoxication occurred even though there was designation.
prompt treatment of the skin; vapor inhalation
was for a few minutes at the most.5
In mice and rats, inhalation at 0.14.0 ppm REFERENCES
throughout pregnancy caused preimplantation
losses and embryotoxic effects including anom- 1. Ying W, Jing X, Qin-wai W: Clinical report on
alies of the cardiovascular system.3 In another 62 cases of acute dimethyl sulfate intoxication.
study, no signicant fetal effects were detected Am J Ind Med 13:455462, 1988
2. Browning E: Toxicity and Metabolism on Indus-
in rats exposed to 1.5 ppm 6 hours/day during
trial Solvents, pp 713721. Amsterdam, Else-
days 7 through 16 of gestation. At this dose
vier Publishing, 1965
maternal toxicity was evidenced by reduced 3. World Health Organization: Environmental
food consumption and body weight gain.7 Health Criteria 48, Dimethyl Sulfate, 55pp.
Dimethyl sulfate is carcinogenic to animals Geneva, 1985
after its inhalation or subcutaneous injection, 4. ACGIH: Dimethyl Sulfate. Documentation of
producing mainly local tumors, and after pre- the TLVs and BEIs, 6th ed, pp 497499. Cincin-
natal exposure, producing tumors of the nati, OH, American Conference of Govern-
nervous system.8 Of 15 rats surviving exposure mental Industrial Hygienists (ACGIH), 1991
to 10 ppm 1 hour/day for 19 weeks, 3 developed 5. Fassett DW: Esters. In Patty FA (ed): Industrial
squamous cell carcinoma of the nasal cavity, 1 Hygiene and Toxicology, 2nd ed, Vol 2, Toxicol-
ogy, pp 19271930. New York, Interscience,
developed a glioma of the cerebellum, and
1963
another developed lymphosarcoma of the
6. Ip M, Wong KL, Wong KF: Lung injury in
thorax with metastases in the lungs. Several dimethyl sulfate poisoning. J Occup Med
early deaths from inammation of the nasal 31:141143, 1989
cavity and pneumonia were also reported.8 A 7. Alvarez L, Hurtt ME, Kennedy GL Jr: De-
statistically signicant increase in lung adeno- velopmental toxicity of dimethyl sulfate by
mas was observed in a group of 90 mice inhalation in the rat. Drug Chem Toxicol
exposed at 4 ppm for 4 hours/day, 5 days/week. 20(1-2):99-114, 1997
A single intravenous dose of 20 mg/kg given to 8. IARC Monographs on the Evaluation of the Car-
8 pregnant rats on day 15 of gestation induced cinogenic Risks of Chemicals to Humans, Vol 71,
malignant tumors, including 3 tumors of the Re-evaluation of some organic chemicals,
hydrazine and hydrogen peroxide, pp 575
nervous system, in 7 of 59 offspring that were
588. Lyon, International Agency for Research
observed for over 1 year.9
on Cancer, 1999
Despite anecdotal case reports of cancer in 9. IARC Monographs on the Evaluation of the Car-
exposed individuals, no signicant increase in cinogenic Risk of Chemicals to Man, Vol 4, Some
mortality or deaths from lung cancer was found aromatic amines, hydrazine and related sub-
in a group of workers exposed for various stances, N-nitroso compounds and miscella-
periods between 1932 and 1972.3,8 neous alkylating agents, pp 271276. Lyon,
The IARC has determined that there is International Agency for Research on Cancer,
sufcient evidence for the carcinogenicity of 1974
dimethyl sulfate to experimental animals and
inadequate evidence in humans; overall, it
should be regarded as probably carcinogenic to
humans.8
Dimethyl sulfate is a potent genotoxic
chemical and can directly alkylate DNA both
in vivo and in vitro.3,8 The 2003 ACGIH
threshold limit value-time-weighted average
(TLV-TWA) for dimethyl sulfate is 0.1 ppm
DINITROBENZENE (all isomers) 275
ished sperm production, decreased cauda epi- 2. Hamblin DP: Aromatic nitro and amino
didymal sperm reserves, nonmotile spermato- compounds. In Patty FA (ed): Industrial
zoa, atypical sperm motility, decreased weights Hygiene and Toxicology, 2nd ed, Vol 2, Toxi-
of the testes and epididymis, and seminiferous cology, pp 21052131, 21382140. New
tubular atrophy were also observed. Sperm York, Interscience, 1963
3. MCA, Inc.: Chemical Safety Data Sheet SD-21,
production was also decreased in males dosed
Nitrobenzene, pp 56, 1214. Washington,
at 1.5 mg/kg/day. Single acute exposure of rats DC, MCA, Inc, 1967
to 48 mg/kg caused alterations in testis weight 4. Hazards Evaluations and Technical Asst
and sperm motility; histologic changes in- Branch, NIOSH: Methemoglobin due to
cluded maturation depletion of mid- and late occupational exposure to dinitrobenzene
spermatids and immature germ cells in the epi- Ohio 1986. MMWR 37:353354, June 10,
didymis.9 Fertilizing ability was lost by 56 1988
weeks after treatment, and some animals failed 5. Okubo T, Shigeta S: Anemia cases after acute
to recover within 5 months. Susceptibility to m-dinitrobenzene intoxication due to an
the reproductive effects of m-DNB varied with occupational exposure. Ind Health 20:297
the age of the animals in this study. Increases 304, 1982
6. Grant WM: Toxicology of the Eye, 2nd ed, p
in plasma lactate dehydrogenase isozyme C4
409. Springeld, IL, Charles C. Thomas,
(LDH-C4) were found to precede noticeable 1974
histologic ndings of testicular damage in 7. Cody TE, Witherup S, Hastings L, et al:
rats.10 LDH-C4 may be used as a biochemical 1,3-Dinitrobenzene: Toxic effects in vivo and
marker of acute testicular damage. in vitro. J Toxicol Environ Health 7:829847,
Marked differences in species suscep- 1981
tibility to m-DNB have also been observed.11 8. Linder RE, Hess RA, Strader LF: Testicular
Hamsters showed no testicular lesions at dose toxicity and infertility in male rats treated
levels up to 50 mg/kg, whereas damage to rat with 1,3-dinitrobenzene. J Toxicol Environ
testicular tubules was readily apparent at Health 19:477489, 1986
25 mg/kg. Similarly, m-DNB induced substan- 9. Linder RE, Strader LF, Barbee RR, et al:
Reproductive toxicity of a single dose of
tially less methemoglobin in the hamster than
1,3-dinitrobenzene in two ages of young
in the rat (15% vs. 80% at 25 mg/kg dose). male rats. Fundam Appl Toxicol 14:284298,
Follow-up studies have demonstrated that 1990
m-DNB exerts a direct effect on the germinal 10. Reader SJC, Shingles C, Stonard MD: Acute
epithelium and not through alterations in testicular toxicity of 1,3-dinitrobenzene and
hypothalamic and pituitary control of gonadal ethylene glycol monomethyl ether in the rat:
function.12 No reproductive effects have been evaluation of biochemical effect markers
reported in humans. and hormonal responses. Fundam Appl Toxicol
In vitro studies show that m-DNB is muta- 16:6170, 1991
genic in Salmonella typhimurium.13 11. Obasaju MF, Katz DF, Miller MG: Species
The 2003 ACGIH threshold limit value- differences in susceptibility to 1,3-dini-
trobenzene-induced testicular toxicity and
time-weighted average (TLV-TWA) for all
methemoglobinemia. Fundam Appl Toxicol
isomers of dinitrobenzene is 0.15 ppm (1.0 mg/ 16:257266, 1991
m3) with a notation for skin absorption. 12. Rehnberg GL, Linder RE, Goldman JM, et
al: Changes in testicular and serum hormone
concentrations in the male rat following
REFERENCES treatment with m-dinitrobenzene. Toxicol
Appl Pharmacol 95:255264, 1988
1. von Oettingen WE: The Aromatic Amino and 13. Agency for Toxic Substances and Disease
Nitro Compounds, Their Toxicity and Potential Registry (ATSDR): Toxicological Prole for 1,3-
Dangers, US Public Health Service Bulletin Dinitrobenzene and 1,3,5-Trinitrobenzene. pp
No 271, pp 94103. Washington, DC, US 1139, US Department of Health and
Government Printing Ofce, 1941 Human Services, Public Health Service, 1995
DINITRO-o-CRESOL 277
often exhibited compensated anemia, an 1980 and with at least 1 day on a job with prob-
adaptive response to the DNT exposure. able DNT exposure.8 The six observed cases
Neurological signs were noted in one were statistically signicant based on com-
dog receiving 10 mg/kg/day of 2,4-DNT for parison with an internal referent group of
8 weeks and consisted of tremors followed unexposed workers. The authors noted the
by extensor rigidity; minimal signs in other limitations of a small number of workers with
animals consisted of incoordination and stiff- long duration of exposure and the lack of quan-
ness, particularly in the hind legs.1 titative information on exposure levels to DNT
A chronic study in rats showed isomer- and other chemicals. A retrospective cohort
specic hepatocarcinogenesis in F344 rats. study of this same population did not nd
Administration of 7 or 14 mg/kg/day of 2,6- increased mortality from ischemic heart
DNT for 1 year produced hepatocellular car- disease.9
cinomas in 85% and 100% of the animals, The IARC has determined that there is
respectively.4 The majority of the tumors had sufcient evidence in experimental animals for
a trabecular pattern, and pulmonary meta- the carcinogenicity of 2,4 DNT and 2,6-DNT;
stases were present. In contrast, a diet of there is inadequate evidence in humans for the
27 mg/kg/day of 2,4-DNT for 1 year caused carcinogenicity of 2,4-, 2,6-, and 3,5-DNT.10
no tumors. Treatment with 35 mg/kg/day of Animal studies have shown that oral expo-
technical-grade DNT, containing 76% 2,4- sure to DNT can result in adverse effects on
DNT and 18% 2,6-DNT, resulted in a 47% reproduction. Observed effects have included
incidence of hepatocellular tumors. The results decreased sperm production, testicular atrophy,
demonstrated that the 2,6-isomer is a potent changes in Sertoli cell morphology, degener-
and complete hepatocarcinogen, under the test ated seminiferous tubules, and decreased fertil-
conditions, whereas the 2,4-isomer is nonhep- ity.1 It has been suggested that DNT acts on
atocarcinogenic. The results also explain the Sertoli cells, resulting in both inhibition of
inconsistent results that had been reported in spermatogenesis and changes in testicular-
previous bioassays: In an initial study by the pituitary endocrine activity.11 A study of 30
National Cancer Institute (NCI) 2,4-DNT was workers exposed to DNT and other chemicals
found to be nonhepatogenic, whereas a CIIT found a decrease in sperm counts relative to
study produced a 100% incidence in the same controls, a slight change in one category of
strain with a technical-grade DNT.5,6 In the abnormal sperm, and a slight increase in spon-
NCI bioassay 2,6-DNT comprised less than taneous abortions for wives.1 Other studies
5% of the DNT, whereas in the CIIT study it reported no detectable differences in sperm
was over 18% of the mixture. Chronic studies levels or fertility rates as a result of occupa-
are not available on the other isomers. tional exposure.12
In an attempt to determine whether the Dinitrotoluene was not found to be ter-
carcinogenicity observed in animal studies was atogenic after oral administration to rats;
predictive for humans, the mortality experience embryo/fetal toxicity was observed only at a
of ammunitions workers with opportunity for dose that also produced 46.2% maternal mor-
substantial DNT exposure was examined. No tality.13
evidence of carcinogenic effect was found, but The DNTs appear to cause mutations in
an unsuspected excess of ischemic heart disease Salmonella typhimurium assays after metabolic
was noted. Additional analyses showed evi- activation.12 In vivo 2,4-DNT causes unsched-
dence of a 15-year latency period and suggested uled DNA synthesis in rat hepatocytes and
a relationship with duration and intensity of chromosomal aberrations in human lympho-
exposure.7 cytes; both 2,4- and 2,6-DNT have induced
A study of nearly 5000 DNT-exposed DNA adducts in rat liver.12
workers found an excess of liver and biliary All six isomers have been found to be non-
cancer among those employed at least 5 irritating in the eye of rabbits. Applied to the
months at the study facility between 1949 and skin of rabbits, 2,4-, 2,6-, and 3,5-DNT were
DIOXANE 281
nonirritating whereas 2,3-, 3,4-, and 2,5-DNT processes and printing inks, carbon black and
were mildly to moderately irritating.1 some nitrocompounds, pp 30968. Lyon,
The 2003 ACGIH threshold limit value- International Agency for Research on
time-weighted average (TLV-TWA) for Cancer, 1996
dinitrotoluene is 0.2 mg/m3 (0.03 ppm) with 11. Bloch E, Gondos B, Gatz M, et al: Repro-
ductive toxicity of 2,4-dinitrotoluene in the
an A3-conrmed animal carcinogen with
rat. Toxicol Appl Pharmacol 94:466472, 1988
unknown relevance to humans designation and 12. Agency for Toxic Substances and Disease
a notation for skin absorption. Registry (ATSDR): Toxicological Prole for
2,4-Dinitrotoluene and 2,6-Dinitrotoluene
(Update), 195pp. US Department of Health
and Human Services, Public Health Service,
REFERENCES
1998
13. Price CJ, Tyl RW, Marks TA, et al: Terato-
1. Rickert DE, Butterworth BE, Popp JA:
logic evaluation of dinitrotoluene in the
Dinitrotoluene: acute toxicity, oncogenicity,
Fischer 344 rat. Fundam Appl Toxicol
genotoxicity, and metabolism. CRC Crit Rev
5:948961, 1985
Toxicol 13:217234, 1983
2. Lane RW, Simon GS, Dougherty RW, et al:
Reproductive toxicity and lack of dominant
lethal effects of 2,4-dinitrotoluene in the
male rat. Drug Chem Toxicol 8:265280,
1985 DIOXANE
3. Lee CC, Hong CB, Ellis HV, et al: Sub-
CAS: 123-91-1
chronic and chronic toxicity studies of 2,4-
dinitrotoluene. Part II. CD rats. J Am Coll
Toxicol 4:243256, 1985 C4H8O2
4. Leonard TB, Graichen ME, Popp JA: Dini-
trotoluene isomer-specic hepatocarcino-
genesis in F344 rats. J Natl Cancer Inst 79: Synonyms: 1,4-Diethylene dioxide; diethylene
13131319, 1987 ether; 1,4-dioxacyclohexane; 1,4-dioxane; p-
5. National Cancer Institute: Bioassay of 2,4- dioxane; dioxyethylene ether
dinitrotoluene for possible carcinogenicity. CAS
No. 121-14-2. NCI-CG-TR-54. US Depart- Physical Form. Colorless liquid
ment of Health, Education and Welfare,
Public Health Service, National Institutes of
Uses. Solvent; stabilizer in chlorinated
Health, 1978
solvents
6. Chemical Industry Institute of Toxicology:
CIIT Chemical Safety Studies Dinitrotoluene
Final Report, docket No. 12362. Research Exposure. Inhalation; skin absorption
Triangle Park, NC, CIIT, 1979
7. Levine RJ, Andjelkovich DA, Kersteter SL, et Toxicology. Dioxane is an irritant of the eyes
al: Heart disease in workers exposed to dini- and mucous membranes; on prolonged expo-
trotoluene. JOM 28:811816, 1986 sure it is toxic to the liver and kidneys. It is car-
8. Stayner LT, Dannenberg AL, Bloom T, et al: cinogenic in experimental animals.
Excess hepatobiliary cancer mortality among Human volunteers exposed to 50 ppm for
munitions workers exposed to dinitrotoluene. 6 hours reported eye irritation throughout the
JOM 35:291296, 1993
exposure.1 At 300 ppm for 15 minutes there
9. Stayner LT, Danneberg AL, Thun M, et al:
was transient eye, nose, and throat irritation.2
Cardiovascular mortality among munitions
workers exposed to nitroglycerin and dini- Exposure to 1600 ppm for 10 minutes caused
trotoluene. Scand J Work Environ Health 18: immediate burning of the eyes with lacrima-
3443, 1992 tion, and at 5500 ppm for 1 minute slight
10. IARC Monographs on the Evaluation of Car- vertigo was also noted.3
cinogenic Risk to Humans, Vol 65, Printing Five deaths due to heavy exposure for 5
282 DIOXANE
weeks were reported.4 Signs and symptoms of bacterial assays, chromosomal aberration
poisoning included epigastric pain, anorexia, assays, sister chromatid exchange assays, and
and vomiting, followed by oliguria, anuria, Chinese hamster ovary (CHO) micronucleus
coma, and death. At autopsy, there was liver assays have produced negative results; the
necrosis, kidney damage, and edema of the in vivo mouse liver micronucleus assay was
lungs and brain. Another fatal case involved a positive after oral administration of up to
1-week exposure to levels ranging from 208 to 3000 mg/kg.15
605 ppm and possibly higher with concurrent The IARC has determined that there is
skin exposure.5 Epigastric pain, increased blood sufcient evidence of carcinogenicity to
pressure, convulsions and unconsciousness animals and inadequate evidence in humans
preceded death. Studies of workers exposed at and that dioxane is possibly carcinogenic to
levels up to 24 ppm for periods of up to 50 years humans.11
found no increase in chronic disease, no excess Administered to rats by gavage on days
total deaths, no excess cancer deaths, and no 615 of gestation, 1.0 ml/kg/day caused slight
common cause of death.6 embryo and maternal toxicity in the form of
Applied to human skin, dioxane causes reduced weights. There were no teratogenic
dryness without other signs of irritation; hyper- effects.16
sensitivity has been reported.6 The warning properties are inadequate to
In animal experiments, guinea pigs prevent overexposure. Although dioxane has a
exposed to 30,000 ppm for 3 hours exhibited low odor threshold (36 ppm), it is not unpleas-
narcosis after 87 minutes and died within 2 ant and individuals acclimatize within a few
days.7 The LC50 for rats was 14,000 ppm for minutes.6
4 hours.8 Repeated exposure of several animal The 2003 ACGIH threshold limit value-
species to 1000 ppm produced damage to time-weighted average (TLV-TWA) for
kidneys and liver, and repeated inhalation of dioxane is 25 ppm (90 mg/m3) with a notation
800 ppm over 30 days resulted in fatal kidney for skin absorption.
injury in some exposed rabbits.7,9
The liquid applied to rabbit and guinea pig
skin was rapidly absorbed and produced signs REFERENCES
of incoordination and narcosis. Repeated appli-
cations caused liver and kidney damage.6 1. Young JD, Braum WH, Rampy LW: Phar-
Instilled in a rabbits eye dioxane produced macokinetics of 1,4-dioxane in humans.
J Toxicol Environ Health 4:507520, 1977
hyperemia and purulent conjunctivitis.10
2. Silverman L, Schulte HF, First MW: Further
High doses of dioxane by oral administra- studies on sensory response to certain indus-
tion produced malignant tumors of the nasal trial solvent vapors. J Ind Hyg Toxicol 28:
cavity and liver in rats, and tumors of the liver 262266, 1946
and gallbladder in guinea pigs.11 Rats adminis- 3. Yant WP: Acute response of guinea pigs to
tered either 0.5% or 1.0% (vol/vol) in the vapors of some new commercial organic
drinking water had squamous cell carcinomas compoundsVI. Dioxan. Pub Health Rep
of the nasal turbinates; hepatocellular adeno- 45:20232032, 1930
mas were seen in the dosed females.12 In 4. Barber H: Haemorrhagic nephritis and
another study, inhalation of 111 ppm, 7 necrosis of the liver from dioxane poisoning.
hours/day, 5 days/week for 2 years did not Guys Hosp Rep 84:267280, 1934
5. Johnstone RT: Death due to dioxane? Arch
result in any increased tumor incidence in
Ind Health 20:445447, 1959
rats.13 6. National Institute for Occupational Safety
A mortality study of 165 workers who had and Health: Criteria for a Recommended Stan-
been exposed to low concentrations of dioxane dard . . . Occupational Exposure to Dioxane.
(since 1954) did not show any increased cancer DHEW (NIOSH) Pub No 77-226. Wash-
risk.14 ington, DC, US Government Printing
Most tests for genotoxic activity including Ofce, 1977
DIPHENYLAMINE 283
(C6H5)2NH
REFERENCES
Synonyms: N-phenylbenzeneamine; N-pheny- 1. Dutch Expert Committee on Occupational
laniline; N,N-diphenylamine; N-diphenylani- Standards (DECOS): Health Council of the
line; DPA Netherlands. pp 1 21, 1997
284 1,2-DIPHENYLHYDRAZINE
2. Thomas JO, Ribelin WE, Woodward JR, tality in the high-dose females. In mice mor-
Deeds F: The chronic toxicity of dipheny- tality was increased for males and females at
lamine for dogs. Toxicol Appl Pharmacol 11: 52 mg/kg/day. The cause(s) of the mortality in
184194, 1967 the rats and mice was not indicated. Statisti-
3. Thomas JO, et al: Chronic toxicity of dipheny- cally increased incidences of interstitial inam-
lamine to albino rats. Toxicol Appl Pharmacol
mation of the lungs were observed in treated
10:362374, 1967
4. Clegg S, et al: Identication of a toxic impu- male rats and in low-dose females but not in
rity in commercial diphenylamine. J Environ mice. Treatment also produced degenerative
Sci Bull B16:125130, 1981 alterations in the liver of rats (fatty metamor-
5. Florin I, et al: Screening of tobacco smoke phosis) and female mice (coagulative necrosis),
constituents for mutagenicity using the Ames and in treated male rats there was stomach
test. Toxicology 15:219232, 1980 hyperkeratosis and acanthosis. In these same
animal studies, 1,2-diphenylhydrazine caused
increased incidences of hepatocellular carci-
noma and zymbal gland carcinomas in male
rats; neoplastic nodules of the liver and
mammary adenocarcinomas were observed in
1,2-DIPHENYLHYDRAZINE female rats; and in female mice, there was
CAS: 122-66-7 an increased incidence of hepatocellular
carcinomas.
C12H12N2 Animals did not show histologic alterations
in reproductive organs in chronic studies, but
reproductive function was not evaluated.1,2
Synonyms: Hydrazobenzene; N,N-diphenyl- 1,2-Diphenylhydrazine is a solid with a
hydrazine; sym-diphenylhydrazine low vapor pressure at ambient temperature,
which makes inhalation exposure of this
Physical Form. White, crystalline solid substance in the vapor state unlikely. Expo-
sure to dusts of 1,2-diphenylhydrazine is
Uses. Formerly used as a starting material in conceivable.2
the production of benzidine for dyes; produc- Limited information is available on the
tion of certain drugs. metabolism of 1,2-diphenylhydrazine.2 Two of
the known metabolites, aniline and benzidine,
Exposure. Ingestion; inhalation; skin may contribute to the toxicity and/or carcino-
absorption genicity of the substance.
A threshold limit value (TLV) has not been
Toxicology. 1,2-Diphenylhydrazine is a liver established for 1,2-diphenylhydrazine.
toxin in rodents and appears to be carcinogenic
in experimental animals.
No information is available on the toxicity
of 1,2-diphenylhydrazine in humans. REFERENCES
In rats and mice given 1,2-diphenylhy-
drazine in the diet for 4 weeks, the lethal ranges 1. National Cancer Institute (NCI): Bioassay of
were 54 mg/kg/day and above for rats and Hydrazobenzene for Possible Carcinogenicity.
Technical Report Series No. 92, DHEW Pub.
390 mg/kg/day and above for mice.1 Gross
No. (NIH) 781342, Bethesda, MD, National
pathologic examinations showed intestinal
Institutes of Health, 1978
hemorrhages in mice that died. 2. Agency for Toxic Substances and Disease
Chronic oral administration (78 weeks Registry (ASTDR): Toxicological Prole for
treatment, followed by observation) of 4 or 1,2-Diphenylhydrazine, 71pp. Atlanta, GA, US
15 mg/kg/day in male rats and 2 or 5 mg/kg/day Dept of Health and Human Service, Public
in females caused signicantly increased mor- Health Service, 1990
DIPROPYL KETONE 285
to produce cataracts, and a clear dose-response (Pesticide residues in food: 1993 evaluations
relationship has been established in chronic Part II Toxicology), Joint Meeting on Pesticide
feeding studies in animals. At a level of Residues. http://www.inchem.org/documents/
1000 ppm complete opacities occurred in rats jmpr/jmpmono/v93pr06.htm
within 6 months; at 50 ppm for 12 months only
some of the animals exhibited slight opacities.1
Lens opacities developed within 11 months in
dogs fed 15 mg/kg/day and within 17 months
at 5 mg/kg/day.3 Dogs tolerated 1.7 mg/kg/day
for 4 years without developing cataracts. DISULFIRAM
Rats exposed to 1.9 mg/m3 for 4 hours/day, CAS: 97-77-8
6 days/week for 5 months showed inamma-
tory changes in the peribronchial and perivas- C10H20N2S4
cular connective tissues.5 Long-term studies
have shown no carcinogenic potential.3,5 Most
mutagenicity data suggest that diquat is not Synonyms: Antabuse; bis(diethylthiocar-
mutagenic.1 bamoyl) disulde; TETD; tetraethylthiuram
In a multigeneration study of reproductive disulde; Thiuram E
effects, levels of 500 or 125 ppm did not effect
fertility, litter production, or litter size and Physical Form. White crystalline solid
did not cause congenital abnormalities.6 Lens
opacities were found in the parents and F1 and Uses. Rubber accelerator and vulcanizer, as
F2 generation receiving 500 ppm, but not at the an activator of thiazole accelerators, and as a
125 ppm level. plasticizer in neoprene; pharmaceutical grade
The 2003 ACGIH threshold limit value- used in treatment of alcoholism
time-weighted average (TLV-TWA) for diquat
is 0.5 mg/m3 for total dust and 0.1 mg/m3 for Exposure. Inhalation
the respirable fraction of dust; there is a nota-
tion for skin absorption. Toxicology. Disulram affects the central
nervous system, thyroid, and skin; in combina-
tion with alcohol it causes an Antabuse-
alcohol syndrome.
REFERENCES Small doses of disulram reportedly can
cause effects on thyroid iodine uptake and
1. Hayes WJ Jr, Laws ER Jr: Handbook of Pesticide
Toxicology, Vol 3, Classes of Pesticides. pp thyroid gland hypertrophy.1 It may also
13761380. New York, Academic Press, produce dermatitis and acneform rashes.
1991 Most of the human experience with disul-
2. Jones GA, Vale JA: Mechanisms of toxicity, ram has come from its use as an avoidance
clinical features, and management of diquat therapy for alcoholism. Metabolites of dis-
poisoning: a review. Clin Toxicol 38(2):123 ulram inhibit aldehyde dehydrogenase, re-
128, 2000 sulting in elevated levels of acetaldehyde after
3. Clark DG, Hurst EW: The toxicity of diquat. ethanol ingestion. Side effects include ush-
Br J Ind Med 27:51, 1970 ing of the face, tachycardia, severe headache,
4. Crabtree HC, Lock EA, Rose MS: Effects of
apprehension, hyperpnea, hypotension, dizzi-
diaquat on the gastrointestinal tract of rats.
ness, nausea, vomiting, and fainting.2 Severe
Toxicol Appl Pharmacol 41:585595, 1977
5. Bainova A, Zlateva M, Vulcheva VI: Chronic reactions may include convulsions, myocardial
inhalation toxicity of dipyridilium herbicides. infarction, and marked respiratory depression.1
Khig Zdraveopazvane 15: 25, 1972 Disulram metabolites include diethyl-
6. International Programme on Chemical Safety: dithiocarbamate and its metabolites, the
JMPR Monographs and Evaluations. 860 Diquat. moieties that irreversibly inhibit aldehyde
288 DISULFOTON
1. NIOSH: Occupational safety and health guide- Uses. Systemic insecticide and acaracide
lines for chemical hazards. Supplement IV-OHG.
Disulram. pp 18. Publications Dissemina- Exposure. Inhalation; skin absorption
tion, EID, National Institute for Occupational
Safety and Health, Cincinnati, OH, 1995 Toxicology. Disulfoton is an anticholineste-
2. Petersen EN: The pharmacology and toxicol- rase agent.
ogy of disulram and its metabolites. Acta Exposure to disulfoton can result in inhi-
Psychiatr Scand Suppl 369:713, 1992
bition of cholinesterase activity in blood and at
3. Johansson B: A review of the pharmacokinet-
nerve synapses of muscles, secretory organs,
ics and pharmacodynamics of disulram and
its metabolites. Acta Psychiatr Scand Suppl 369: and nervous tissue in the brain and spinal cord.1
1526, 1992 Central nervous system signs and symptoms
4. Kane FJ Jr: Carbon disulde intoxication from include anxiety, restlessness, depression of res-
overdosage of disulram. Am J Psychiatry 127: piratory and circulatory centers, ataxia, convul-
690694, 1970 sions, and coma.
5. Keefe EB, Smith FW: Disulram hypersensi- Nicotinic signs of intoxication include
tivity hepatitis. JAMA 230:435436, 1974 muscle weakness, tremor and fasciculations,
6. Eisen HJ, Ginsberg AL: Disulram hepato- and involuntary twitching. Muscle weakness
toxicity. Ann Int Med 83:673675, 1975 that affects the respiratory muscles may con-
7. von Hintzenstern J, Heese A, Koch HU, et al:
tribute to dyspnea and cyanosis. Tachycardia
Frequency, spectrum and occupational rele-
may result from stimulation of sympathetic
vance of type IV allergies to rubber chemicals.
Contact Derm 24:244252, 1991 ganglia in cardiac tissue and may mask the
8. National Toxicology Program: Bioassay of bradycardia due to the muscarinic action on the
Tetraethylthiuram Disulde for Possible Carcino- heart. Nicotinic action at the sympathetic gan-
genicity (CAS No. 97-77-9). Technical Report glion may also result in pallor, high blood pres-
Series No. 166. Springeld, VA, National sure, and hyperglycemia.
DIVINYL BENZENE 289
Muscarinic signs include miosis, increased pp 131149. New York, Macmillan Pub,
salivation, sweating, urination and defecation, 1990
vomiting and nausea, and increased bronchial 2. Yashiki M, Kojima T, Ohtani M, et al: Deter-
secretions. mination of disulfoton and its metabolites in
Severe signs and symptoms of disulfoton the body uids of a Di-Syston intoxication
case. Forensic Sci Int 48:145154, 1990
intoxication (miosis, salivation, monoplegia)
3. Agency for Toxic Substances and Disease
were observed in a man within 23 hours of Registry (ASTDR): Toxicological Prole for
consuming 34 tablespoons of disulfoton.2 Five Disulfoton, pp 1219. US Department of
volunteers received an oral dose of 0.75 mg/day Health and Human Services, Public Health
for 30 days without an adverse effect on plasma Service, 1995
or erythrocyte cholinesterase.3
Oral LD50 values between 6.2 and
12.5 mg/kg body weight (bw) for males and
between 1.9 and 4.2 mg/kg bw for females have
been reported in rats.3 Inhalation LC50 values
for rats were 290 mg/m3 in males and 63 mg/m3 DIVINYL BENZENE
for females. CAS: 1321-74-0
Tolerance to repeated or sublethal expo-
sures of disulfoton has been demonstrated.3 C10H10
Typically, the cholinergic symptoms
(tremors, fasiculations, excessive salivation)
disappear with increasing duration of exposure Synonyms: Diethenylbenzene; DVB; 1,4-
but the acetylcholinesterase activity remains divinyl benzene; vinylstyrene
depressed.
There was no evidence of a carcinogenic Physical Form. Straw-colored liquid
response in mice fed 2.08 mg/kg/day for
23 months or in beagle dogs fed up to Uses. Comonomer for preparation of cross-
0.098 mg/kg/day for 2 years.3 linked polymers in production of ion exchange
Disulfoton was not fetotoxic or teratogenic beads and gel permeation chromatography
in the offspring of rabbits administered doses polystyrene beads; polymerization monomer
of 1.5 mg/kg/day, which caused clinical signs of for synthetic rubber, drying oils, and casting
maternal toxicity.3 resins
Equivocal results have been reported in
genotoxic assays, including positive and nega- Exposure. Inhalation
tive results in bacterial assays and sister chro-
matid exchange studies. Mutagenic potential Toxicology. Divinyl benzene is an irritant of
was not demonstrated in assays for chromoso- eyes, nose, and mucous membranes.
mal aberrations, nor did disulfoton induce Mild respiratory irritation occurred in
micronuclei in mice exposed in vivo.3 workers exposed to 0.44 ppm divinyl
The 2003 ACGIH threshold limit value- benzene.1 Mild irritation was also reported
time-weighted average (TLV-TWA) for disul- from skin and eye contact.
foton is 0.1 mg/m3 with a notation for skin A single 2-hour exposure of ve rats to
absorption. fume generated from polymerizing divinyl
benzene at 120C yielded a level of 27,317 ppm
and produced peripheral vasodilation, lethargy,
REFERENCES salivation, bilateral corneal opacity, and
dyspnea.2 When the temperature of the poly-
1. Taylor P: Anticholinesterase agents. In Gilman merizing divinyl benzene was kept at 80C,
AG et al. (eds): Goodman and Gilmans The yielding a concentration in the chamber of
Pharmacological Basis of Therapeutics, 8th ed, 3312 ppm, effects were ataxia, tachypnea,
290 ENDOSULFAN
ocular irritation, and rhinitis. Exposure of rats 5. Kligerman AD, Morgan DL, Doerr CL, et al:
for 7 hours to 645 ppm resulted in no observ- Cytogenic effects in mice of divinylbenzene-
able effects. 55 inhalation. Mutat Res 370(2):107113,
Male and female mice exposed at 0, 25, 50, 1996
or 75 ppm 6 hours/day, 5 days/week for up 2
weeks had concentration-dependent changes in
the olfactory epithelium; hepatocellular necro-
sis was observed at the highest dose, and some
male mice also had transient tubular damage in ENDOSULFAN
the kidneys.3 CAS: 115-29-7
Instillation of 0.1 ml into the eyes of
rabbits for 30 seconds caused irritation and C9H6Cl6O3S
conjunctivitis, the latter of which was still
present 8 days later.4 On the abdominal skin
of rabbits, a mixture of divinyl benzene and Synonyms: Thiodan
ethyl vinyl benzene repeatedly applied and
occluded for 2 weeks caused slight erythema, Physical Form. Technical endosulfan is a
edema, and moderated exfoliation at the semiwaxy solid containing 9095% of a 70% :
application site. 30% mixture of the a and b stereoisomers
Divinyl benzene was weakly genotoxic in
vivo, inducing a dose-dependent increase in Uses. Insecticide
sister chromatid exchanges and an increase
in the frequency of chromosome aberrations in Exposure. Inhalation
male mice exposed at concentrations of up to
75 ppm for 3 days.5 Toxicology. Endosulfan is a convulsant.
The 2003 ACGIH threshold limit value- Convulsions were reported in nine workers
time-weighted average (TLV-TWA) for divinyl exposed to the endosulfan-containing insecti-
benzene is 10 ppm (53 mg/m3). cide Thiodan during bagging of the product.1
Other effects noted before the convulsions
were malaise, nausea, vomiting, dizziness, con-
fusion, and weakness. Level and duration of ex-
REFERENCES posure were not indicated. Similar symptoms
(tonic and clonic convulsions, vomiting, confu-
1. Dow Chemical Company: Communication to
sion, and muscular twitchings) were reported
the TLV Committee. In ACGIH: Documenta-
tion of the TLVs and BEIs. 6th ed, pp 540542. in 18 cases of endosulfan overexposure during
Cincinnati, OH, American Conference of spraying operations.2
Governmental Industrial Hygienists, 1991 Accidental or intentional ingestion of
2. Leong BKJ, Rampy LW, Kociba RJ: Pre- endosulfan has resulted in death in humans. In
liminary Studies on the Toxicological Properties two cases of suicide, the dose was up to 100 ml
of Divinyl Benzene. Unpublished Report. of Thiodan, and in three other poisonings
Midland, MI, Chemical Biology Research, the doses were not specied.3 Initial signs of
Dow Chemical USA, January 28, 1986 poisoning included gagging, vomiting, diar-
3. Morgan DL, Mahler JF, Wilson RE, et al: Tox- rhea, agitation, writhing, cyanosis, dyspnea,
icity of divinylbenzene-55 for B6C3F1 mice in
and coma.
a two-week inhalation study. Fundam Appl
Signs of acute endosulfan intoxication in
Toxicol 39(2):89100, 1997
4. Henck JW: Divinyl benzeneHP (7085%): animals are similar to those seen in humans and
Acute Toxicological Properties and Industrial Han- include hyperexcitability, dyspnea, decreased
dling Hazards. Unpublished Report. Midland, respiration, ne tremor, and tonic-clonic con-
MI, Toxicology Research Laboratory, Dow vulsions. Oral LD50 values range from
Chemical Company, June 18, 1980 7.4 mg/kg in male mice to 40125 mg/kg for
ENDRIN 291
male rats.46 Female rats were 45 times more 1284. US Department of Health and Human
sensitive to acute effects than male rats.5 Services, Public Health Service, 2000
In a 2-year carcinogenicity study rats and 7. National Toxicology Program: Bioassay of
mice were fed endosulfan in the diet for the Endosulfan for Possible Carcinogenicity (CAS
No. 115-29-7). Technical Report Series No.
rst 80% of their life span and then observed
62. Springeld, VA, National Technical Infor-
for the remaining 20%.7 In rats there was a mation Service, US Department of Com-
high incidence of toxic nephropathy in both merce, 1978
sexes and testicular atrophy in males. In both 8. Hack R, Ebert E, Leist KH: Chronic toxicity
species high early morality was observed in the and carcinogenicity studies with the insecticide
male groups, and no conclusions could be endosulfan in rats and mice. Food Chem Toxicol
drawn regarding carcinogenicity. There was no 33(11):941950, 1995
evidence of carcinogenicity in the female mice 9. Dalsenter PR, Dallegrave E, Mello JRB, et al:
or rats. In another study dietary concentrations Reproductive effects of endosulfan on male
of 75 ppm for rats and 18 ppm for mice caused offspring of rats exposed during pregnancy
increased incidence of enlarged kidneys and and lactation. Hum Exp Toxicol 18(9):583589,
1999
progressive glomerulonephrosis in rats but no
increased tumor incidence.8
Equivocal results have been found in geno-
toxic assays, but endosulfan was mutagenic and
clastogenic and induced effects on cell cycle
kinetics in various in vivo and in vitro tests.6 ENDRIN
In reproductive studies, male rats treated CAS: 72-20-8
at 3.0 mg/kg from day 15 to 21 of gestation had
reduced sperm production in adulthood.9 C12H8Cl6O
The 2003 ACGIH threshold limit
value-time-weighted average (TLV-TWA) is
0.1 mg/m3 with a notation for skin absorption. Synonyms: 2,7:3,Dimethanonaphth(2,3-
b)oxirene; Compound 269; Experimental
Insecticide 269
REFERENCES
Physical Form. White, crystalline solid
1. Ely TS, Macfarlane JW, Galen WP, et al: Con-
vulsions in thiodan workers. J Occup Med
Uses. All uses of endrin in the United States
9:3537, 1967
2. Chugh SN, Dhawan R, Agrawal N, et al:
were canceled by the manufacturer in 1986;
Endosulfan poisoning in northern India: A formerly used as an insecticide, avicide, and
report of 18 cases. Int J Clin Pharm Ther rodenticide
36(9):474477, 1998
3. Terziev Z, Dimitrova N, Rusev F: Forensic Exposure. Inhalation; skin absorption;
medical and forensic chemical study of acute ingestion
lethal poisonings with thiodan. Folia Med 16:
325329, 1974 Toxicology. Endrin is an insecticide with
4. Gupta PK, Murthy RC, Chandra SV: Toxicity high acute toxicity that primarily affects the
of endosulfan and manganese chloride: cumu- central nervous system.
lative toxicity rating. Toxicol Lett 7:221228,
In humans, the rst effect of endrin intox-
1981
5. Hoechst: Summary and Evaluation of the Toxic-
ication is frequently a sudden epileptiform con-
ity Data for EndosulfanSubstance Technical. vulsion that may occur from 30 minutes to
Frankfurt, Germany, Hoechst, Project no 87- up to 10 hours after overexposure; it lasts for
643, 1990 several minutes and is usually followed by a stu-
6. Agency for Toxic Substances and Disease porous state for 15 minutes to 1 hour.1,2 Severe
Registry: Toxicological Prole for Endosulfan, pp poisoning results in repeated violent convul-
292 ENDRIN
sions and, in some cases, status epilepticus.3 liver.1 The IARC has concluded that animal
The electroencephalogram (EEG) may show bioassays in mice and rats have been inadequate
dysrhythmic changes that frequently precede to evaluate the carcinogenicity of endrin.7
convulsions; withdrawal from exposure usually Limited studies of endrin-exposed workers
results in a normal EEG within 16 months.2 have not detected increased mortality due to
In most cases, recovery is rapid, but headache, cancer.8 Tumor-promoting effects were not
dizziness, lethargy, weakness, and anorexia demonstrated when endrin was tested in com-
may persist for 24 weeks.2 In less severe bination with subminimal quantities of chemi-
cases of endrin intoxication, the complaints cals known to be carcinogenic to animals.5
are headache, dizziness, leg weakness, abdom- Endrin was not mutagenic in several in
inal discomfort, nausea, vomiting, insomnia, vitro microbial or mammalian cell assays.5,8
agitation, and, occasionally, slight mental The 2003 ACGIH threshold limit value-
confusion.1,3 time-weighted average (TLV-TWA) for endrin
Poisonings resulting in convulsions have is 0.1 mg/m3 with a notation for skin
occurred in manufacturing workers. Recovery absorption.
after occupational exposures is usually com-
plete within 24 hours. Unlike dieldrin, which
persists in the body, endrin is rapidly elimi- REFERENCES
nated from the body and apparently does not
accumulate, even in fatty tissue.3,4 However, 1. Jager KW: Aldrin, Dieldrin, Endrin and Telo-
endrin is the most acutely toxic of the cyclodi- drinAn Epidemiological and Toxicological Study
ene compounds, which also include chlordane, of Long-Term Occupational Exposure, pp 7887,
217218, 225234. Amsterdam, Elsevier Pub-
heptachlor, dieldrin, and aldrin.4
lishing, 1970
Ingestion of endrin has resulted in numer-
2. Coble Y, Hildebrandt P, Davis J, et al: Acute
ous fatalities.2,4 In one nonfatal incident, inges- endrin poisoning. JAMA 202:489493, 1967
tion of bread made with endrin-contaminated 3. Hayes WJ Jr: Pesticides Studied in Man, pp
our caused sudden convulsions in three 247251. Baltimore, MD, Williams &
people; in one person the serum endrin level Wilkins, 1982
was 0.053 ppm 30 minutes after the convulsion 4. Anon: Acute convulsions associated with
and 0.038 ppm after 20 hours; in the other two endrin poisoningPakistan. MMWR 33:687
cases, no endrin was detected in the blood at 688, 693, 1984
8.5 or 19 hours, respectively, after convulsions. 5. World Health Organization: Environmental
The oral dose that causes death has been esti- Health Criteria 130 Endrin. International Pro-
gramme on Chemical Safety, Geneva, 1992
mated to be approximately 10 mg/kg body
6. Ottolenghi AD, Haseman JK, Suggs F: Ter-
weight; the single oral dose that causes convul-
atogenic effects of aldrin, dieldrin, and endrin
sions was estimated to be 0.251.0 mg/kg body in hamsters and mice. Teratology 9:1116, 1974
weight.5 7. IARC Monographs on the Evaluation of the Car-
In animal studies repeated dermal applica- cinogenic Risk of Chemicals to Man, Vol 5, Some
tion of endrin has caused convulsions and death organochlorine pesticides, pp 157171. Lyon,
without irritation to the skin.5 International Agency for Research on Cancer,
Single doses of 2.5 mg/kg of endrin admin- 1974
istered orally to pregnant golden hamsters 8. Agency for Toxic Substances and Disease Reg-
during the period of fetal organogenesis caused istry (ATSDR): Toxicological Prole for Endrin
a high incidence of fetal death, congenital and Endrin Aldehyde, pp 1191. US Depart-
ment of Health and Human Services, Public
anomalies, growth retardation, and maternal
Health Service, 1996
toxicity.6 Administered over three generations
to rats, endrin did not induce reproductive
effects.5
Rats fed a diet of 50 or 100 ppm endrin for
2 years developed degenerative changes in the
ENFLURANE 293
CHF2OCF2CHClF REFERENCES
epichlorohydrin exposure with lung cancer and and related compounds on the reproductive
also heart disease mortality have not been con- organs and fertility of the male rat. J Reprod
rmed.17 In a recent mortality study update of Fertil 38:379386, 1974
863 employees with exposure to epichlorohy- 7. John JA et al: Inhalation toxicity of epich-
drin there were no excess deaths from heart lorohydrin: Effects on fertility in rats and
rabbits. Toxicol Appl Pharmacol 68:415423,
disease, lung cancer, or nonmalignant respira-
1983
tory disease for employees with 20 or more 8. Marks TA et al: Teratogenic evaluation of
years after rst exposure.18 epichlorohydrin in the mouse and rat and
The carcinogenic risk to humans cannot be glycidol in the mouse. J Toxicol Environ Health
fully assessed, however, because of mixed expo- 9:8796, 1982
sures, limited number of deaths, and indeter- 9. Venable JR et al: A fertility study of male
minate levels and duration of exposure. The employees engaged in the manufacture of
IARC has determined that there is sufcient glycerine. J Occup Med 22:8791, 1980
evidence of carcinogenicity in animals and 10. Wester PW et al: Carcinogenicity study with
inadequate evidence in humans and that epichlorohydrin (CEP) by gavage in rats.
epichlorohydrin is probably carcinogenic to Toxicology 36:325339, 1985
11. Konishi Y, Kawabata A, Denda A, et al:
humans.19
Forestomach tumors induced by orally
Epichlorohydrin is a direct-acting administered epichlorohydrin in male Wistar
mutagen by virtue of its activity as an alkylat- rats. Gann 71:922923, 1980
ing agent.20 It causes genetic damage in most 12. Laskin S, Sellakumar AR, Kuschner M, et al:
bacterial and mammalian test systems in vivo Inhalation carcinogenicity of epichlorohy-
and in vitro.19,20 drin in noninbred Sprague-Dawley rats. J
The proposed 2003 ACGIH threshold Natl Cancer Inst 65:751757, 1980
limit value-time-weighted average (TLV- 13. Van Duuren BL et al: Carcinogenic activity
TWA) for epichlorohydrin is 0.1 ppm of alkylating agents. J Natl Cancer Inst 53:
(0.38 mg/m3) with an A2-suspected human 695700, 1974
carcinogen designation and a notation for skin 14. Tassignon JP, Bos GD, Craigen AA, et al:
Mortality in European cohort occupationally
absorption.
exposed to epichlorohydrin (ECH). Int Arch
Occup Environ Health 51:325336, 1983
15. Bond GG, Flores GH, Shellenberger RJ, et
REFERENCES al: Mortality among a large cohort of chem-
ical manufacturing employees. J Natl Cancer
1. NIOSH: Criteria for a Recommended Standard Inst 75:859869, 1985
. . . Occupational Exposure to Epichlorohydrin. 16. Tsai SP, Cowles SR, Lynne-Tackett D, et al:
DHEW (NIOSH) Pub No 76-206, p 152. Morbidity prevalance study of workers with
National Institute for Occupational Safety potential exposure to epichlorhydrin. Br J Ind
and Health, US Department of Health, Med 47:392399, 1990
Education and Welfare. Washington, DC, 17. Enterline PE, Henderson V, Marsh G:
US Government Printing Ofce, 1976 Mortality of workers potentially exposed to
2. Picciano D: Cytogenic investigation of occu- epichlorohydrin. Br J Ind Med 47:6976,
pational exposure to epichlorohydrin. Mutat 1990
Res 66:169173, 1979 18. Tsai SP, Gilstrap EL, Ross CE: Mortality
3. Beck MH, King CM: Allergic contact study of employees with potential exposure
dermatitis to epichlorohydrin in a solvent to epichlorohydrin: A 10 year update. Occup
cement. Contact Derm 9:315, 1983 Environ Med 53(5):299304, 1996
4. Freuder E, Leake CD: The toxicity of 19. IARC Monographs on the Evaluation of the Car-
epichlorohydrin. Univ Calif Berk Publ Phar- cinogenic Risk of Chemicals to Humans, Vol 71,
macol 2:6977, 1941 Re-evaluation of some organic chemicals,
5. Gage JC: The toxicity of epichlorohydrin hydrazine and hydrogen peroxide, pp
vapour. Br J Ind Med 16:1114, 1959 603628. Lyon, International Agency for
6. Cooper ERA et al: Effects of a-chlorohydrin Research on Cancer, 1999
296 EPN
20. Giri AK: Genetic toxicology of epichloro- After ingestion, gastrointestinal effects,
hydrin: a review. Mutat Res 386:2538, such as anorexia, nausea, vomiting, abdominal
1997 cramps, and diarrhea, appear within 15 minutes
to 2 hours. After skin absorption, localized
sweating and muscular fasciculations in the
immediate area usually occur within 15
minutes to 4 hours; skin absorption is some-
EPN what greater at higher ambient temperatures
CAS: 2104-64-5 and is increased by the presence of dermatitis.2,3
With severe intoxication by all routes, an
C14H14NO4PS excess of acetylcholine at the neuromuscular
junctions of skeletal muscle causes weakness
aggravated by exertion, involuntary twitchings,
Synonyms: O-ethyl O-p-nitrophenyl phenyl- fasciculations, and eventually paralysis. The
phosphonothioate; EPN-300 most serious consequence is paralysis of the
respiratory muscles. Effects on the central
Physical Form. Light yellow to brown solid nervous system include giddiness, confusion,
ataxia, slurred speech, CheyneStokes respira-
Uses. Acaricide; insecticide tion, convulsions, coma, and loss of reexes.
The blood pressure may fall to low levels, and
Exposure. Inhalation; skin absorption; cardiac irregularities, including complete heart
ingestion block, may occur.13
Complete symptomatic recovery usually
Toxicology. EPN is an anticholinesterase occurs within a week; increased susceptibility
agent. to the effects of anticholinesterase agents per-
A few deaths have been reported after poi- sists for up to several weeks after exposure.
soning by EPN, most resulting from suicidal Daily exposure to concentrations that are
ingestion, but at least one death has been asso- insufcient to produce symptoms after a single
ciated with EPN spraying. It is moderately to exposure may result in the onset of symptoms.
highly toxic in animals, but less potent than Continued daily exposure may be followed by
parathion.1 increasingly severe effects.
Signs and symptoms of overexposure are No signicant effects on plasma or red
caused by the inactivation of the enzyme blood cell cholinesterase activity occurred in
cholinesterase, which results in the accumula- volunteers given 6 mg of EPN for up to 47
tion of acetylcholine at synapses in the nervous days; 9 mg appears to be the threshold for
system, skeletal and smooth muscle, and secre- toxicity.4
tory glands.13 The sequence of the develop- Delayed neuropathy characterized by
ment of systemic effects varies with the route distal axonal degeneration is a systemic health
of entry. The onset of signs and symptoms is effect caused by some organophosphate pesti-
usually prompt but may be delayed up to 12 cides and is not due to anticholinesterase inhi-
hours. After inhalation, respiratory and ocular bition. EPN is neurotoxic to atropine-
effects are the rst to appear, often within a few protected hens, producing polyneuropathy
minutes of exposure. Respiratory effects progressing to paralysis and some deaths after
include tightness in the chest and wheezing ingestion of 510 mg/kg/day. There are no
owing to bronchoconstriction and excessive reports, however, of neurotoxicity from EPN
bronchial secretion; laryngeal spasm and exces- in humans.1
sive salivation may add to the respiratory dis- EPN was not teratogenic or fetotoxic to
tress; cyanosis may also occur. Ocular effects mice at maternally nontoxic doses.5
include miosis, blurring of distant vision, The 2003 ACGIH threshold limit value-
tearing, rhinorrhea, and frontal headache. time-weighted average (TLV-TWA) for EPN
1,2-EPOXYBUTANE 297
is 0.5 mg/m3 with a notation for skin absorp- Toxicology. 1,2-Epoxybutane exposure
tion. causes body weight effects and nasal lesions in
experimental animals; chronic exposure is car-
cinogenic to rats but not to mice.
REFERENCES No adverse effects from 1,2-epoxybutane
exposure have been reported in humans.
1. Hayes WJ Jr: Organic phosphorus pesticides. All rats exposed to 6550 ppm died during
In Pesticides Studied in Man, pp 284435. Bal- the 4-hour exposure period; at 2050 ppm ocular
timore, MD, Williams & Wilkins, 1982 discharge and dyspnea were observed, and eye
2. Koelle GB (ed): Cholinesterases and anti-
irritation occurred at the 1400 ppm level.1 In
cholinesterase agents. Handbuch der Experi-
mice, 2050 ppm was lethal to all and 1420 ppm
mentellen Pharmakologie, Vol 15, pp 9891027.
Berlin, Springer-Verlag, 1963 was lethal to four of ve mice of each sex. In
3. Taylor P: Anticholinesterase agents. In Gilman 14-day studies, mortality was seen at 3200 ppm
AG et al (eds): Goodman and Gilmans The in male rats and at 1600 ppm in female rats
Pharmacological Basis of Therapeutics, 7th ed, pp and mice of both sexes. Compound-related
110129. New York, Macmillan Publishing, lesions included pulmonary hemorrhage and
1985 rhinitis in rats at 1600 ppm and nephrosis in
4. Moeller HC, Rider JA: Plasma and red blood mice at 800 ppm; nal body weights of sur-
cell cholinesterase activity as indications of the viving animals were signicantly reduced
threshold of incipient toxicity of ethyl-p-nitro- compared with the controls in these exposure
phenyl thionobenzenephosphonate (EPN) and
groups.
malathion in human beings. Toxicol Appl Phar-
No deaths were observed in rats at con-
macol 4:123130, 1962
5. Courtney KD, Andrews JE, Springer J, et al: centrations up to 800 ppm or in mice up to
Teratogenic evaluation of the pesticides 400 ppm in an NTP study lasting 13 weeks
Baygon, Carbofuran, Dimethoate, and EPN. J (6 hours/day, 5 days/week). Nasal cavity lesions
Environ Sci Health B 20(4):373406, 1985 and reduced body weight were seen in rats
exposed at 800 ppm. In mice, renal tubular
necrosis was found at 800 ppm, a dose that was
lethal. Inammation of the nasal turbinates was
observed in female mice at 100 ppm and above
and in male mice at 200 ppm and above. In an
1,2-EPOXYBUTANE earlier study, slight growth retardation was
CAS: 106-88-7 observed in rats and mice exposed at 600 ppm
for 13 weeks; inammatory and degenerative
C4H8O changes in the nasal mucosa were observed in
both species. Myeloid hyperplasia in bone
marrow occurred in male rats only.2 No effects
Synonyms: 1,2-Butene oxide; butylene oxide; were noted at 75 or 150 ppm.
1,2-butylene epoxide; ethyl ethylene oxide; Rats exposed for 2 years to 400 ppm had
ethyl oxirane increased incidence of papillary adenomas of
the nasal cavity; the incidences of alveolar/
Physical Form. Colorless liquid with bronchiolar adenomas or carcinomas (com-
pungent odor bined) were also increased in the male rats, but
not in the females.1 Nonneoplastic lesions of
Uses. Primarily used as a stabilizer for chlo- the nasal cavity included inammation, epithe-
rinated hydrocarbon solvents; also used as a lial hyperplasia, and squamous metaplasia of
chemical intermediate in the production of the nasal epithelium, as well as atrophy of the
butylene glycols olfactory sensory epithelium. Mice exposed at
50 or 100 ppm for 2 years had no signicant
Exposure. Inhalation increases in the incidence of neoplastic lesions
298 EPOXY RESINS
of the nasal cavity. Treatment-related nonneo- with and without epoxy stabilizers, in mice. J
plastic nasal changes were similar to those seen Cancer Res Clin Oncol 107:149156, 1984
in rats. 4. Van Duuren BL, Langseth L, Goldschmidt
In a combined-exposure experiment oral BM, et al: Carcinogenicity of epoxides, lac-
administration of trichloroethylene containing tones, and peroxy compounds. VI. Structure
and carcinogenic action. J Natl Cancer Inst
1,2-epoxybutane induced squamous cell carci-
39:12171228, 1967
nomas of the forestomach in mice, whereas 5. IARC Monographs on the Evaluation of Carcino-
administration of the trichloroethylene alone genic Risk to Humans, Vol 71, Re-evaluation of
did not.3 some organic chemicals, hydrazine and hydro-
A 10% solution applied to the shaved skin gen peroxide, pp 629640. Lyon, International
of mice three times per week for 77 weeks Agency for Research on Cancer, 1999
caused no visible skin reaction and no tumors.4 6. Hardin BD, Niemeier RW, Sikov MR, et al:
The IARC has determined that there is Reproductive-toxicologic assessment of the
limited evidence for the carcinogenicity of 1,2- epoxides ethylene oxide, propylene oxide,
epoxybutane in experimental animals and that butylene oxide, and styrene oxide. Scand J
it is possibly carcinogenic to humans.5 Work Environ Health 9:94102, 1983
7. Weil CS, Condra N, Haun C, et al: Experi-
Exposure to 1000 ppm before and during
mental carcinogenicity and acute toxicity of
gestation did not cause any teratogenic effects representative epoxides. Am Ind Hyg Assoc J
in rats; fetal growth and viability were not 24:305325, 1963
affected despite depressed maternal body
weight gain.6 Rabbits exposed at 250 or
1000 ppm 7 hours/day during gestational days
0 to 24 had maternal deaths at both exposure
concentrations. No teratogenic effects were
observed, although the pregnancy rate was EPOXY RESINS
reduced in the high-dose group. 1,2-Epoxybu- CAS: 61788-97-4
tane is a direct-acting alkylating agent, and it is
genotoxic in a wide range of assays.5
Instilled in the eyes of rabbits, 1,2-
epoxybutane caused corneal injury.7
A threshold limit value (TLV) has not been Synonyms: Epoxies; Epon resins
established for 1,2-epoxybutane, although US
manufacturers have recommended a voluntary Physical Form. Uncured resins are long-
time-weighted average-threshold limit value of chained prepolymers that are viscous liquids or
40 ppm. solids; the cured resins are strong, solid
polymers
Uncured resins are oligomers of relatively low burns.3 They can cause skin irritation and sen-
molecular weight that may be a liquid or a sitization and respiratory tract irritation. Eye
solid. Before epoxy resins can become useful irritation with conjunctivitis and corneal edema
products, they must be cured, with the addition (resulting in halos around lights) may occur.
of a curing agent. Curing involves the cross- Asthmatic symptoms suggesting respiratory
linkage by polymerization of the reactive epoxy tract sensitization have been described.1 In ski
groups into a three-dimensional matrix. manufacturing workers using epoxy resins, 3-
In addition to the two primary compo- (dimethylamino) propylamine has been shown
nents, several other components may be to cause declines in FEV1 and ow rates and
included: diluents/solvents, llers, and pig- work-related respiratory symptoms (e.g.,
ments. Diluents, which may represent 1015% cough, chest tightness).4
of resin volume, are added primarily to reduce Aromatic amines are generally solids and
viscosity. There are two types of diluents: reac- less irritating than aliphatic amines. 4,4-Meth-
tive and nonreactive. Reactive diluents, prima- ylene dianiline (MDA) has caused outbreaks of
rily the glycidyl ethers, contain epoxy groups, reversible toxic hepatitis, apparently after skin
which will take part in the curing process. Non- absorption. Severe symptoms, including ele-
reactive diluents include a variety of organic vated AST, alkaline phosphatase, and bilirubin
solvents. Some uncured resins (liquids) are and liver enlargement, have been observed in
primary skin irritants or sensitizers or both. some workers using it as a curing agent with
Toxicity generally decreases with increase in epoxy resins.5 m-Phenylenediamine is a strong
molecular weight and epoxy number. The irritant and allergic sensitizer; like MDA, it
resins with the greatest potential for sensitiza- stains the skin and nails yellow.2 4,4-
tion are those with molecular weights under Diaminodiphenyl sulfone (DDS) is tumori-
500.2 None of the uncured resins possesses sig- genic in experiments animals.1
nicant volatility; thus inhalation poses little Acid anhydrides can cause severe eye and
hazard.1 The vast majority of epoxy resins are skin irritation and burns, depending on the
manufactured by the reaction between concentration and duration of contact.1 Inhala-
epichlorohydrin and bisphenol A, producing tion of high concentrations can cause signi-
DGEBA (diglycidyl ether of bisphenol A) cant respiratory tract irritation. Phthalic
resins. After the initial manufacture of uncured anhydride (PA), tetrachlorophthalic anhydride
resin, epichlorohydrin is probably not present (TCPA), and trimellitic anhydride can induce
during the subsequent mixing and polymeriza- asthma in epoxy resin workers; frequently a
tion steps. dual (immediate and late) asthmatic response
has been documented. Specic IgE antibodies
Toxicology. The toxicity of epoxy resin on RAST testing have been demonstrated in
systems results from the toxicity of the various patients with TCPA asthma.6 One worker
components, each of which must be developed asthma on grinding epoxy resin
considered. cured with phthalic anhydride, presumably due
Curing agents account for much of the to release of some unreacted residual phthalic
potential hazard associated with use of epoxy anhydride during grinding of a cured
resins.1,2 There are several major types of moulding.7
curing agents: aliphatic amines, aromatic Polyamides, reaction products of aliphatic
amines, cycloaliphatic amines, acid anhydrides, amines and fatty acids, are considerably less
polyamides, and catalytic curing agents. The toxic than the aliphatic amines but are moder-
latter two types are true catalysts, in that they ately irritating to the skin and extremely irri-
do not participate in the curing process. tating to the eyes.1,2
The aliphatic amines, including triethylene Isophorone diamine, a cycloaliphatic
tetramine (TETA) and diethylene triamine amine, has been reported to cause skin sensiti-
(DETA), are highly alkaline (pH 1314), zation.7
caustic, and volatile and may cause severe Glycidyl ethers, reactive diluents in epoxy
300 EPOXY RESINS
resin systems, are characterized by the presence systems. These solvents may dehydrate and
of the 2,3-epoxypropyl group and an ether defat the skin, which may render the skin more
linkage to another organic group. Virtually all vulnerable to the irritating and sensitizing
of these substances are liquids with low vapor components of epoxy resin formulations.1,2
pressures at room temperature. Dermal contact Fillers used in epoxy resins are normally
is the major route of exposure. Vapor pressures inert, nely divided powders. Common llers
become more appreciable at higher tempera- include calcium carbonate, clay (bentonite),
tures, which may occur during the curing talc, silica, diatomaceous earth, and asbestos.
process. Some glycidyl ethers commonly used Workers exposed to excessive amounts of
in epoxy resin systems are allyl glycidyl ether some of these dusts may experience lung
(AGE), n-butyl glycidyl ether (BGE), o-cresyl damage.1
glycidyl ether (CGE), isopropyl glycidyl ether The curing process renders the resin
(IGE), phenyl glycidyl ether (PGE), resorcinol essentially inert and nontoxic. At room tem-
diglycidyl ether, and 1,4-butanediol diglycidyl perature, full curing may take several days;
ether.1,8 In humans exposed to glycidyl ethers, incompletely cured resins may cause skin irri-
adverse effects have generally been limited to tation and sensitization.1 Respiratory symp-
irritation and sensitization.8 PGE and BGE toms may result from inhalation of cured epoxy
have produced severe skin irritation in humans, dusts during grinding, presumably due to
causing burns and blistering. AGE has pro- release of residual curing agent.1,7 Skin irrita-
duced skin and eye irritation in humans. Skin tion and sensitization have been associated with
sensitivity to AGE, BGE, and PGE has been epoxy resin exposure.
documented in some humans occupationally Dermatitis from epoxy resin components
exposed to epoxy resins.1,8 In animals, glycidyl usually develops rst on the hands, particularly
ethers have produced central nervous system between the ngers, in the nger webs, on the
(CNS) effects, including muscular incoordina- dorsum of the hands, and on the wrists. It may
tion, reduced motor activity, agitation and vary in severity from erythema to a marked
excitement, deep depression, narcotic sleep, bullous eruption.2 When sensitization occurs,
and coma. PGE has produced CNS depression the eruption is typically pruritic, with small
with dermal administration; BGE and AGE vesicles on the ngers and hands resembling
have produced depression after inhalation dyshidrotic eczema. The eruption may spread
exposure.8 Experimental inhalation of glycidyl to other areas of the body that accidentally
ethers has resulted in pulmonary irritation and contact resin components, such as the face and
inammation, including pneumonitis and neck. In highly sensitized individuals, vapors
peribronchiolitis. For example, rats exposed to from the curing agent or reactive diluents may
PGE at 10 ppm for 7 hours/day, 5 days/week cause recurrence of itching and redness in the
for 10 weeks had peribronchial and perivas- absence of direct skin contact.2
cular inammatory inltrates. Exposure to Prevention of epoxy dermatitis requires
some glycidyl ethers, usually by injection, has meticulous attention to avoiding skin contact
been demonstrated to produce testicular during mixing and application, use of protec-
abnormalities, alteration of leukocyte counts, tive clothing such as PVC gloves, good house-
atrophy of lymphoid tissue, and bone marrow keeping, regular hand washing before eating
cytotoxicity.8 and breaks, and prohibition of eating and
Solvents used as nonreactive diluents smoking in the work area. In some cases, sen-
include acetone, cellosolve, methyl ethyl sitized workers may need to be completely
ketone, methyl isobutyl ketone, methylene removed from the work area and further
chloride, 1,1,1-trichloroethane, toluene, and exposure.2
xylene. Skin and eye irritation and, in higher There are no reports of carcinogenic,
concentrations, CNS depression and respira- mutagenic, teratogenic, or reproductive effects
tory irritation may result from exposure to to humans from uncured resins, curing agents,
these solvents as diluents for epoxy resin or glycidyl ethers, but there are some positive
ETHANE 301
animal studies.1,8 Animal experiments using 7. Ward MJ, Davies D: Asthma due to grinding
DGEBA resins have generally indicated no car- epoxy resin cured with phthalic anhydride.
cinogenic activity but are inconclusive.1 Digly- Clin Allerg 12:165168, 1982
cidyl resorcinol ether administered by gavage 8. National Institute for Occupational Safety and
to rats and mice for 2 years caused an increased Health: Criteria for a Recommended Standard
. . . Occupational Exposure to Glycidyl Ethers,
incidence of forestomach tumors.9 Mutagenic-
DHEW (NIOSH) Pub 78-166. Washington,
ity tests using various liquid and solid epoxy DC, US Government Printing Ofce, 1978
resins have yielded some positive and some 9. Murthy ASK, McConnell EE, Huff JE, et al:
negative results.1 Forestomach neoplasms in Fischer F344/N
Of the aromatic amine curing agents, rats and B6C3F1 mice exposed to diglycidyl
diaminodiphenyl sulfone is tumorigenic in resorcinol etheran epoxy resin. Food Chem
animal experiments, whereas 4,4-methylenedi- Toxicol 28:723729, 1990
aniline is a suspect animal carcinogen.1 Many
of the glycidyl ethers produce a mutagenic
response in the Ames assay and in some other
short-term tests.8 Glycidyl ethers are rapidly
metabolized to less cytotoxic substances and ETHANE
rapidly conjugate with skin proteins on dermal CAS: 74-84-0
contact. Their low volatility decreases the pos-
sibility of signicant systemic absorption via CH3CH3
inhalation. Together, these factors reduce the
likelihood of conjugation with nuclear macro-
molecules in somatic or germ cells, which Synonyms: Bimethyl; dimethyl; methyl-
otherwise might result in carcinogenic or methane; ethyl hydride
teratogenic effects.8
A threshold limit value (TLV) is not estab- Physical Form. Colorless gas
lished for epoxy resins.
Uses. In the production of ethylene, vinyl
chloride, and chlorinated hydrocarbons; as a
REFERENCES component of bottled fuel gas
quate warning of hazardous concentrations, the human skin for 1.5 hours caused marked
and ethane itself is odorless.1 erythema.1
The ACGIH has not assigned a numerical Dogs and cats exposed to 990 ppm for 4
threshold limit value (TLV) for occupational days survived, but four of six guinea pigs died
exposure to ethane because the limiting factor from exposure to 233 ppm for 1 hour; patho-
is the available oxygen, the minimal content logic changes were chiey those of pulmonary
which should be 18% by volume under normal irritation, with some nonspecic changes in
atmospheric pressure; at concentrations below the liver and kidneys.1 In animals exposed re-
those required to produce severe oxygen peatedly to 66100 ppm there was some mor-
deprivation, ethane presents an explosive tality during the 2430 days of exposure, and
hazard.1 all animals were lethargic.2 No mortality or
pathology resulted from 90-day continuous
exposure of dogs to 26 ppm, of rats to 12 ppm,
REFERENCES or of guinea pigs to 15 ppm.2 The liquid
produced moderate irritation on the skin of
1. ACGIH: Ethane. Documentation of the Thresh- rabbits and severe irritation in the eyes of
old Limit Values and Biological Exposure Indices, rabbits.1
7th ed, p 2. Cincinnati, OH, American Con- In one study ethanolamine administered
ference of Governmental Industrial Hygienists
by gavage to pregnant rats on days 615 of ges-
(ACGIH), 2001
tation at levels of 50, 300, or 500 mg/kg/day
2. Sax NI: Dangerous Properties of Industrial Mate-
rials, 6th ed, p 313. New York, Van Nostrand caused dose-dependent increases in intrauter-
Reinhold Co, Inc, 1984 ine deaths, malformations, and intrauterine
growth retardation.3 Sex of the pups and
intrauterine position with respect to contingu-
ous rat siblings were important factors in the
degree of development exhibited. Contrary to
these ndings, no signs of developmental toxi-
ETHANOLAMINE city or increased incidences of malformations
CAS: 141-43-5 were observed in another study in rat fetuses
or pups gavaged at doses of up to 450 mg/kg/
NH2CH2CH2OH day on days 615 of gestation.4 At this dose
maternal toxicity was evidenced by decreases
in feed consumption and body weight gains.
Synonyms: 2-Aminoethanol; 2-hydroxyethy- Ethanolamine was not developmentally toxic
lamine; ethylolamine; colamine; monoethano- after dermal application during gestation at
lamine exposure levels up to 225 mg/kg/day for rats
and 75 mg/kg/day for rabbits.5 Maternal effects
Physical Form. Colorless liquid were observed in both species at these doses
and consisted of signicant increases in the
Uses. As a chemical intermediate; corrosion incidence of skin irritation/lesions and mater-
inhibitor; in the production of cosmetics, nal body weight effects.
detergents, paints, and polishes The odor is described as ammonia-like or
musty at 25 ppm but is detected by means of a
Exposure. Inhalation; skin absorption sensation at 3 ppm.2
The 2003 ACGIH threshold limit value-
Toxicology. Ethanolamine is an eye and res- time-weighted average (TLV-TWA) for
piratory tract irritant. ethanolamine is 3 ppm (7.5 mg/m3) with a
No systemic effects from industrial expo- short-term excursion level (STEL) of 6 ppm
sure have been reported. The liquid applied to (15 mg/m3).
2-ETHOXYETHANOL 303
7. Doe JE: Ethylene glycol monoethyl ether Cats exposed to 9000 ppm for 8 hours
and ethylene glycol monoethyl ether acetate suffered irritation and labored breathing;
teratology studies. Environ Health Perspect 20,000 ppm for 45 minutes caused deep narco-
57:3341, 1984 sis, and 43,000 ppm for 1416 minutes was
8. World Health Organization: Environmental fatal; at autopsy, ndings were pulmonary
Health Criteria 115, Methoxyethanol, 2-
edema with hemorrhage and hyperemia of the
Ethoxyethanol, 2- and Their Acetates, pp 187.
International Programme on Chemical respiratory tract.3 Repeated exposure of rabbits
Safety (IPCS), Geneva, 1990 to 4450 ppm resulted in secondary anemia with
9. Kim Y, Lee NR, Sakai T, et al: Evaluation of leukocytosis, hyperemia, and damage to the
exposure to ethylene glycol monoethyl ether liver.3
acetates and their possible haematological In mice ethyl acetate at 2000 ppm for
effects on shipyard painters. Occup Environ 20 minutes produced acute neurobehavioral
Med 56(6):378382, 1999 effects including changes in posture, decreased
10. Sohnlein B, Letzel S, Welte D, et al: arousal, increased tonic/clonic movements, dis-
Occupational chronic exposure to organic turbances in gait, and delayed righting reexes.
solvents. Int Arch Occup Environ Health Some handling-induced convulsions and slight
64:479484, 1993
lacrimation were also observed.4
Ethyl acetate was not mutagenic in bacte-
rial assays; it was not genotoxic in a number
of in vivo assays but did cause chromosomal
damage in hamster cells in vitro.5
ETHYL ACETATE Ethyl acetate has a fruity odor detectable
CAS: 141-78-6 at 10 ppm.6
The 2003 ACGIH threshold limit value-
CH3COOC2H5 time-weighted average (TLV-TWA) for ethyl
acetate is 400 pm (1440 mg/m3).
Ethyl acrylate was negative in most geno- 9. DePass LR, Fowler EH, Meckley DR, et al:
toxic assays. Dermal oncogenicity bioassays of acrylic
Exposure of pregnant rats to 150 ppm 6 acid, ethyl acrylate and butyl acrylate. J
hours/day during days 615 of gestation caused Toxicol Environ Health 14:115120, 1984
some maternal toxicity and a slight, but not sta- 10. National Toxicology Program: Carcinogenesis
Studies of Ethyl Acrylate (CAS No 140-88-5) in
tistically signicant, increase in malformed
F344/N Rats and B6C3F1 Mice (Gavage
fetuses; at 50 ppm, there was neither maternal Studies). Technical Report Series 259, DHHS
toxicity nor an adverse effect on the fetus.13 (NIH) Pub No 87-2515, pp 1224. Research
One drop of the liquid instilled in the eye Triangle Park, NC, National Institutes of
of the rabbit caused corneal necrosis within Health, 1986
24 hours.4 11. Ghanayem BI, Sanchez IM, Maronpot RR, et
The odor is detectable below 1 ppm and al: Relationship between the time of sus-
should serve as a good warning property.1,4 tained ethyl acrylate forestomach hyperplasia
The 2003 ACGIH threshold limit value- and carcinogenicity. Environ Health Perspect
time-weighted average (TLV-TWA) for ethyl 101 (S5):277280, 1993
acrylate is 5 ppm (21 mg/m3) with a short-term 12. Walker AM, Cohen AJ, Loughlin JE, et al:
Mortality from cancer of the colon or rectum
excursion limit of 15 ppm (61 mg/m3) and an
among workers exposed to ethyl acrylate and
A2-suspected human carcinogen designation. methyl methacrylate. Scand J Work Environ
Health 17:719, 1991
13. Murray JS et al: Teratological evaluation
REFERENCES
of inhaled ethyl acrylate in rats. Toxicol Appl
Pharmacol 60:106111, 1981
1. Hygienic Guide Series: Ethyl acrylate. Am
Ind Hyg Assoc J 27:571574, 1966
2. IARC Monographs on the Evaluation of the Car-
cinogenic Risk of Chemicals to Humans, Vol 71,
Re-evaluation of some organic chemicals,
hydrazine and hydrogen peroxide, pp
144757. Lyon, International Agency for ETHYL ALCOHOL
Research on Cancer, 1999 CAS: 64-17-5
3. Opdyke DLJ: Monographs on fragrance raw
materials, ethyl acrylate. Food Cosmet Toxicol C2H5OH
Suppl 13:801802, 1975
4. Pozzani UC, Weil CS, Carpenter CP: Suba-
cute vapor toxicity and range-nding data for
Synonyms: Ethanol; algrain; anhydrol; ethyl
ethyl acrylate. J Ind Hyg Toxicol 31:311316,
1949 hydrate; ethyl hydroxide; grain alcohol
5. Treon JR et al: The toxicity of methyl and
ethyl acrylate. J Ind Hyg 31:317326, 1949 Physical Form. Clear, colorless, mobile,
6. Ghanayem BI, Maronpot RR, Matthews HB: ammable liquid
Ethyl acrylate-induced gastric toxicity: I.
Effect of single and repetitive dosing. Toxicol Uses. Solvent
Appl Pharmacol 80:323335, 1985
7. Ghanayem BI, Burka LT, Matthews HB: Exposure. Inhalation; ingestion
Ethyl acrylate distribution, macromolecular
binding, excretion and metabolism in male
Toxicology. Ethyl alcohol is an irritant of the
Fisher 344 rats. Fundam Appl Toxicol 9:389
eyes and mucous membranes and causes central
397, 1987
8. Miller RR, Young JT, Kociba RJ, et al: nervous system depression; chronic excessive
Chronic toxicity and oncogenicity bioassay ingestion is associated with developmental
of inhaled ethyl acrylate in Fischer 344 rats effects and various cancers.
and B6C3F1 mice. Drug Chem Toxicol 8:142, Few adverse effects have been reported in
1985 humans from dermal or inhalation exposures in
ETHYL ALCOHOL 309
4-hour exposure to 3000 ppm, whereas expo- rienced eye irritation, but tolerance developed
sure to 6000 ppm for 8 hours caused death in rapidly; 2000 ppm caused lacrimation, nasal
all exposed mice and in four of six rats; all irritation, and vertigo; 5000 ppm produced
animals developed signs of eye and respiratory intolerable irritation of the eyes and nose.1
tract irritation; varying degrees of ataxia, pros- When chronic exposures exceeded
tration, respiratory distress, and narcosis were 100 ppm, complaints included fatigue, sleepi-
observed.1 Surviving animals recovered with no ness, headache, and mild irritation of the eyes
apparent adverse effects. and respiratory tract.2
The 2003 ACGIH threshold limit value- The rate of absorption of ethyl benzene
time weighted average (TLV-TWA) for ethyl through the skin of the hand and the forearm
amyl ketone is 25 ppm (131 mg/m3). in human subjects was 2233 mg/cm2/hour,
indicating that skin absorption could be a major
route of uptake of liquid ethyl benzene.3,4
REFERENCES In guinea pigs, exposure to 10,000 ppm
caused immediate and intense eye and nose
1. Krasavage WJ et al: Ketones. In Clayton GD, irritation, ataxia, narcosis, and death in 23
Clayton FE (eds): Pattys Industrial Hygiene and hours; 5000 ppm was lethal during or after 8
Toxicology, 3rd ed, Vol 2C, Toxicology, pp hours of exposure; 2000 ppm produced ataxia in
47674768. New York, Wiley-Interscience,
8 hours, and 1000 ppm caused eye irritation.1
1982
Inhalation of ethyl benzene at 600 ppm for
2. British Industrial Biological Research Asso-
ciation: BIBRA Toxicity Prole of 5-Methyl-3- 186 days by rats and guinea pigs resulted in
Heptanone. Technical Report 462, pp 16. slight changes in liver and kidney weights and
Carshalton, UK, 1995 slight testicular histopathology in rabbits and
monkeys.5 Exposure of rabbits to 230 ppm
4 hour/day for 7 months resulted in changes in
blood cholinesterase activity, leukocytosis,
reticulocytosis, and dystrophic changes in the
liver and kidneys.6
ETHYL BENZENE Exposure to 782 ppm for 4 weeks caused an
CAS: 100-41-4 increase in platelet counts in male rats and an
increase in total leukocyte count in female rats;
C8H10 hematologic parameters did not change for
mice or rabbits exposed to the same or higher
concentrations.7 Despite its chemical similarity,
Synonyms: Ethylbenzol; phenylethane ethyl benzene does not appear to cause the
same damage to the hematopoietic system as
Physical Form. Colorless liquid benzene.8
In chronic inhalation studies rats and mice
Uses. Primarily used in the production of were exposed to 0, 75, 250, or 750 ppm 6
styrene; also used as an industrial solvent, as a hours/day, 5 days/week for 104 weeks.9 For
constituent of asphalt and naptha, and as an male rats exposed at 750 ppm survival was
antiknock agent in aviation and motor fuels decreased, and the incidence of renal tubule
neoplasms and testicular adenomas was
Exposure. Inhalation; skin absorption increased. The ndings from an extended eval-
uation of the kidneys showed a signicant
Toxicology. Ethyl benzene is an irritant of increase in the incidences of renal tubule
the skin eyes and mucous membranes; at high adenoma and hyperplasia in high-dose males
concentrations it causes neurological and res- and females. In high-dose mice there were
piratory depression. increased incidences of alveolar/bronchiolar
Humans exposed briey to 1000 ppm expe- neoplasms in males, whereas females had
312 ETHYL BROMIDE
Toxicology. Ethyl bromide is a respiratory and lung may also have been related to expo-
irritant and causes hepatic and renal toxicity; at sure to ethyl bromide. For female F344/N rats,
high concentrations, it causes narcosis. there was equivocal evidence of carcinogenic
The former use of ethyl bromide as a activity, as indicated by marginally increased
human anesthetic (at concentrations approach- incidences of neoplasms of the brain and lung.
ing 100,000 ppm) produced respiratory In the high-dose rats, alveolar epithelial hyper-
irritation and caused some fatalities, either plasia was increased, as were the incidences of
immediately, due to respiratory or cardiac epithelial hyperplasia and squamous metaplasia
arrest, or delayed, due to effects on the liver, of the nasal cavity. For male B6C3F1 mice,
kidneys, or heart.1 At autopsy, ndings were there was equivocal evidence of carcinogenic
pulmonary edema and marked fatty degenera- activity, based on marginally increased inci-
tion of the liver, kidneys, and heart. Relatively dences of neoplasms of the lung. There was
little experience with this substance in industry clear evidence of carcinogenic activity for
has been reported, but exposure of volunteers female B6C3F1 mice, as indicated by neo-
to 6500 ppm for 5 minutes produced vertigo, plasms of the uterus.
slight headache, and mild eye irritation.1 The IARC has determined that there is
Guinea pigs exposed to 50,000 ppm for 98 limited evidence in experimental animals for
minutes died within an hour after exposure.2 the carcinogenicity of ethyl bromide and that
Exposure to 24,000 ppm for 30 minutes was it is not classiable as to its carcinogenicity to
fatal within 3 days; at autopsy, ndings were humans.5
pulmonary edema and centrilobular necrosis Ethyl bromide was mutagenic in Salmo-
of the liver; exposure to 3200 ppm for 9 hours nella assays with and without microsomal
produced lung irritation, and death occurred activation when tested in an enclosed system;
after 15 days. The 1-hour LC50 was it also induced sister chromatid exchange in
27,000 ppm for male rats and 16,200 ppm for Chinese hamster ovary cells.4
mice.3 Applied to the skin of mice, the liquid pro-
In inhalation studies conducted by the duced local necrosis.6 Prolonged or repeated
National Toxicology Program, acute, sub- contact of ethyl bromide to the skin may lead
chronic, and chronic effects of ethyl bromide to signicant absorption of the compound.
were examined in mice and rats.4 All mice and Instilled in rabbit eyes, it was an irritant.
three of ve female rats died before the end of The etherlike odor of ethyl bromide is
a 4-hour exposure to 5000 ppm; rats and mice detectable only at concentrations well above
exposed to 2000 ppm 6 hours/day died before 200 ppm and, therefore, will not give warning
the end of 14-day studies. In 14-week studies, of hazardous concentrations.6
1600 ppm was lethal to some animals and The 2003 ACGIH threshold limit value-
caused compound-related lesions including time-weighted average (TLV-TWA) for ethyl
muscle atrophy and atrophy of the testis and bromide is 5 ppm (22 mg/m3) with a notation
uterus thought to be secondary to body weight for skin absorption.
loss; rats also had minimal to moderate multi-
focal mineralization in the cerebellum and
minimal-to-severe hemosiderosis of the spleen. REFERENCES
A variety of effects (dependent on species
and sex) were seen in the 2-year studies with 1. von Oettingen WF: The Halogenated Aliphatic,
Olenic, Cyclic, Aromatic, and Aliphatic-Aromatic
exposures of 100, 200, or 400 ppm 6 hours/day,
Hydrocarbons Including the Halogenated Insecti-
5 days/week.4 There was some evidence of car-
cides, Their Toxicity and Potential Dangers. US
cinogenic activity of ethyl bromide for male Public Health Service Pub No 414, pp
F344/N rats, as indicated by increased inci- 134138. Washington, DC, US Government
dences of pheochromocytomas of the adrenal Printing Ofce, 1955
gland (control, 8/40; 100 ppm, 23/45; 200 ppm, 2. Sayers RR, Yant WP, Thomas BGH, Berger
18/46; 400 ppm, 21/46), neoplasms of the brain LB: Physiological response attending exposure
314 ETHYL BUTYL KETONE
to vapors of methyl bromide, methyl chloride, Exposure of rats at 700 ppm 72 hours/week for
ethyl bromide and ethyl chloride. Public Health 24 weeks was also without neurotoxic effect.3
Bull 185:156, 1929 Extremely large gavage doses, 2 g/kg/day, 5
3. Vernot EH et al: Acute toxicity and skin days/week for 14 weeks, were required to
corrosion data for some organic and inorganic produce signs of neurotoxicity; two of two rats
compounds and aqueous solutions. Toxicol Appl
had hindlimb weakness and tail drag.4 Neu-
Pharmacol 42:417412, 1977
4. National Toxicology Program: Toxicology and ropathology showed central-peripheral-distal
Carcinogenesis Studies of Bromoethane (Ethyl axonapathy characterized by giant axonal
Bromide) (CAS NO. 74-96-4) in F344/N Rats swelling and neurolamentous hyperplasia.4
and B6C3F Mice (Inhalation Studies), NTP-TR Dropped into rabbit eyes or applied to skin
363 NIH Pub No 90-2818, pp 1186. US the liquid has caused mild irritation.1
Dept Health and Human Services, 1989 The 2003 ACGIH threshold limit value-
5. IARC Monographs on the Evaluation of Carcino- time-weighted average (TLV-TWA) for ethyl
genic Risks to Humans, Vol 71, Re-evaluation of butyl ketone is 50 ppm (234 mg/m3).
some organic chemicals, hydrazine and hydro-
gen peroxide, pp 13051307. Lyon, Interna-
tional Agency for Research on Cancer, 1999
REFERENCES
6. Hygienic Guide Series: Ethyl bromide. Am Ind
Hyg Assoc 26:192195, 1978
1. Smyth HF Jr, Carpenter CP, Weil CS: Range-
nding toxicity data, List III. J Ind Hyg Toxicol
31:6062, 1949
2. Homan ER, Maronpot RR: Neurotoxic evalu-
ation of some aliphatic ketones. Toxicol Appl
Pharmacol 45:312 (abst), 1978
ETHYL BUTYL KETONE 3. Katz GV et al: Comparative neurotoxicity and
CAS: 106-35-4 metabolism of ethyl n-butyl ketone and methyl
n-butyl ketone in rats. Toxicol Appl Pharmacol
C7H14O 52:153158, 1980
4. ODonoghue JL et al: Further studies on
ketone neurotoxicity and interactions. Toxicol
Synonyms: 3-Heptanone; EBK Appl Pharmacol 72:201209, 1984
Toxicology. Ethyl chloride at high con- of female mice exposed at 15,000 ppm, 6
centrations causes central nervous system hours/day for 102 weeks had highly malignant
depression. uterine carcinomas vs. none (0/49) in the
In the past, concentrations of 40,000 ppm controls.6 The incidence of hepatocellular car-
were used clinically to produce anesthesia.1 cinomas was also increased. Male mice had an
Sudden and unforeseen fatalities from ethyl increase in alveolar and bronchial adenomas,
chloride anesthesia have been reported. Con- but results were confounded by poor survival.
centrations of 20,000 ppm or above have Both male and female rats had marginally sig-
reportedly caused increased respiratory rate, nicant increases in epithelial tumors and brain
cardiac depression, dizziness, eye irritation, and astrocytomas, respectively. More recent studies
abdominal cramps.1 Exposure to 19,000 ppm have suggested that the mechanism of uterine
resulted in mild analgesia after 12 minutes, tumor induction in mice is species specic, is a
and 13,000 ppm caused slight symptoms of high-dose phenomenon, and may be related
inebriation.2 to glutathione conjugation rather than other
Chronic effects from industrial exposure metabolic pathways.7
have not been reported, although skin absorp- The genotoxic potency of ethyl chloride
tion is said to occur. In liquid form this sub- appears to be low. It was negative in in vivo
stance may cause frostbite. micronucleus tests, but it has produced both
Guinea pigs exposed to 40,000 ppm positive and negative results in bacterial gene
appeared uncoordinated in 3 minutes, had eye mutation assays.1
irritation, and were unable to stand after 40 The IARC has determined that there is
minutes; some animals died from exposure for limited evidence in experimental animals for
9 hours, but exposure for 4.5 hours was non- the carcinogenicity of ethyl chloride and that it
fatal; histopathologic changes in the lungs, is not classiable as to its carcinogenicity to
liver, and kidneys were observed in euthanized humans.8
animals of the latter group.3 The 2003 ACGIH threshold limit value-
Two-week repeated exposure of rats and time-weighted average (TLV-TWA) for ethyl
dogs to 4000 or 10,000 ppm caused no treat- chloride is 100 ppm (264 mg/m3) with an A3-
ment-related effects except for slight increases animal carcinogen designation and a notation
in liver-to-body weight ratios in male rats.4 for skin absorption.
Similarly, the only observed effect in mice
exposed for 11 days, 23 hour/day at up to
5000 ppm was an increase in relative liver
REFERENCES
weight and a slight increase in hepatocellular
vacuolation.5 Neurobehavioral observation, 1. Agency for Toxic Substances and Disease
clinical chemistry, hematology studies, and Registry (ATSDR): Toxicological Prole For
necropsy failed to show other effects, indicat- Chloroethane, pp 1145. US Department of
ing that ethyl chloride was well tolerated Health and Human Services, Public Health
despite the unusually long exposure periods. Service, 1998
Histopathologic examination of reproduc- 2. von Oettingen WF: The Halogenated Aliphatic,
tive organs showed no evidence of toxicity in Olenic, Cyclic, Aromatic, Aliphatic-Aromatic
rats and dogs exposed at 10,000 ppm for 2 Hydrocarbons Including the Halogenated Insecti-
weeks or rats and mice exposed at 19,000 ppm cides, Their Toxicity and Potential Dangers. US
Public Health Service Pub No 414, pp
for 13 weeks.4,6
128134. Washington, DC, US Government
Pregnant mice exposed to 5000 ppm, 6
Printing Ofce, 1955
hours/day on days 615 of gestation had no 3. Sayers RR, Yant WP, Thomas BH, Burger LB:
overt maternal toxicity; there was slightly Physiological response attending exposure to
delayed ossication of skull bones in the vapors of methyl bromide, methyl chloride,
offspring.1 ethyl bromide and ethyl chloride. Public Health
In a chronic inhalation study 86% (43/50) Bull 185:156, 1929
316 ETHYLENE
4. Landry TD, Ayres JA, Johnson KA, et al: experience unconsciousness, and death may
Ethyl chloride: a two-week inhalation toxic- occur at 8% oxygen. Exposure to 37% for 15
ity study and effects on liver non-protein minutes may result in memory disturbances.1
sulfhydryl concentrations. Fundam Appl Toxicol Ethylene inhaled at 11.5 g/m3 (10,000 ppm)
2:230234, 1982 for 4 hours was hepatotoxic in rats pretreated
5. Landry TD, Johnson KA, Phillips JE, et al:
with the polychlorinated biphenyl Arochlor
Ethyl chloride: 11-day continuous exposure
inhalation toxicity study in B6C3F1 mice. 1254, given orally at a dose of 300 mmol/kg daily
Fundam Appl Toxicol 13:516522, 1989 for 3 days to induce liver enzymes. It is not toxic
6. National Toxicology Program (NTP): Techni- without such treatment.2,3
cal Report on the Toxicology and Carcinogenesis Rats exposed to 300, 1000, or 3000 ppm
Studies of Chloroethane in F344/N Rats and 6 hours/day, 5 days/week for up to 2 years
B6C3F1 Mice. NIH Pub No 89-2801, 1989 showed no statistically signicant evidence of
7. Fedtke N, Certa H, Ebert R, et al: Species dif- chronic toxicity or oncogenic effects.4 (A sub-
ferences in biotransformation of ethyl chlo- sequent review of the same data by other
ride. II. GSH-dependent metabolism. Arch investigators found that the incidence of
Toxicol 68:217223, 1994 mononuclear cell leukemia was somewhat
8. IARC Monographs on the Evaluation of Carcino-
increased in both sexes at the highest dose
genic Risk to Humans. Vol 71, Re-evaluation of
some organic chemicals, hydrazine and hydro- level.5) Metabolic studies in rats and mice
gen peroxide, p 1345. Lyon, International indicate that ethylene may be metabolized to
Agency for Research on Cancer, 1999 ethylene oxide, an agent with genotoxic and
carcinogenic potential.2,5
Rats and mice exposed 6 hours/day, 5 days/
week for 4 weeks to concentrations of up to
3000 ppm did not have increased frequencies of
ETHYLENE micronucleus formation in the bone marrow.6
CAS: 74-85-1 Ethylene was not genotoxic in Salmonella
typhimurium.2
C2H4 The IARC has determined that there is
inadequate evidence of carcinogenicity of eth-
ylene in humans and experimental animals.2
Synonyms: Ethene; acetene; bicarburetted Ethylene is not irritating to the skin and
hydrogen; oleant gas eyes.1 The gas has a faintly sweet odor that
probably does not provide adequate warning of
Physical Form. Colorless gas hazardous concentrations. Owing to the highly
ammable and explosive characteristics of
Uses. Chemical intermediate in the manu- ethylene, it should be handled cautiously.1
facture of polyethylene, ethylene oxide, ethyl- The ACGIH regards ethylene as a simple
ene dichloride, and ethyl benzene; used as a asphyxiant and does not recommend a thresh-
fruit and vegetable ripening agent old limit value because the limiting factor is
available oxygen. The menimal oxygen cordent
Exposure. Inhalation should be 18% by volume under normal
axmospheric pressure.
Toxicology. Ethylene is of low toxicity and
has traditionally been regarded as a simple
asphxiant.
REFERENCES
Concentrations of less than 2.5% are phys-
iologically inert; at very high concentrations, 1. Sandmeyer EE: Aliphatic Hydrocarbons. In
there may be narcosis, unconsciousness, and Clayton GD, Clayton FE (eds): Pattys Indus-
asphyxia due to oxygen displacement.1 Humans trial Hygiene and Toxicology, 3rd ed, Vol 2B,
exposed to as much as 50% ethylene in air, Toxicology, pp 31983199. New York, Wiley-
where the oxygen is decreased to 10%, may Interscience, 1981
ETHYLENE CHLOROHYDRIN 317
2. IARC Monographs on the Evaluation of Carcino- Exposure to the vapor has caused irritation
genic Risks to Humans, Vol 60, Some industrial of the eyes, nose, and throat; visual distur-
chemicals, pp 4571. Lyon, International bances; vertigo, incoordination, and paresthe-
Agency for Research on Cancer, 1994. sias; and nausea and vomiting.2,3 More severe
3. Connolly RB, Jaeger RJ: Acute hepatotoxicity exposure has also caused headache, severe
of ethylene and halogenated ethylenes after
thirst, delirium, low blood pressure, cyanosis,
PCB pretreatment. Environ Health Perspect 21:
131, 1977 collapse, shock, and coma. In some cases, there
4. Hamm TE Jr, Guest D, Dent JG: Chronic have been albumin, casts, and red blood cells in
toxicity and oncogenicity bioassay of inhaled the urine.
ethylene in Fischer-344 rats. Fundam Appl Ethylene chlorohydrin is highly irritating
Toxicol 4:473478, 1984 to mucous membranes but produces little
5. Rostron C: Ethylene metabolism and carcino- reaction on contact with rabbit skin.1 Toxic
genicity. Food Chem Toxicol 24:70, 1985 amounts can be absorbed through the skin
6. Vergnes JS, Pritts IM: Effects of ethylene on without causing dermal irritation; the dermal
micronucleus formation in the bone marrow of LD50 for rabbits is 68 mg/kg.4 This value extra-
rats and mice following four weeks of inhala- polated to humans suggests that a volume
tion exposure. Mutat Res 324(3):8791, 1994
slightly more than a teaspoon could be lethal
with prolonged contact.4
The liquid instilled in rabbit eyes caused
moderately severe injury, but human eyes have
recovered from corneal burns within 48 hours.5
ETHYLENE CHLOROHYDRIN Inhalation exposures of 15 minutes/day
CAS: 107-07-3 at concentrations of approximately 1000 ppm
were fatal to rats within a few days.6
ClCH2CH2OH In 2-year dermal studies, there was no evi-
dence of carcinogenicity in rats given 50 or
100 mg/kg/day or mice given 7.5 or 15 mg per
Synonyms: b-Chloroethyl alcohol; glycol animal per day.1 Increased risks for pancreatic
chlorohydrin; 2-chloroethanol cancer and lymphopoietic cancers associated
with a chlorohydrin plant that primarily
Physical Form. Colorless liquid produced ethylene chlorohydrin have been
attributed to by-products of the process includ-
Uses. Production of ethylene glycol and eth- ing ethylene dichloride; ethylene chlorohydrin
ylene oxide; solvent for cellulose acetate, cellu- itself has not been associated with the occur-
lose ethers, and various resins rence of tumors.7 A more recent study of a
different cohort of ethylene and propylene
Exposure. Inhalation; skin absorption chlorohydrin production workers found no
increased risk of pancreatic, lymphopoietic, or
Toxicology. Ethylene chlorohydrin is an hematopoietic cancers.8
irritant of the skin and eyes and is toxic to the Signicant levels of fetotoxicity and
liver, kidneys, cardiovascular system, and maternal toxicity, but no teratogenicity, were
central nervous system. found in rabbits administered 36 mg/kg/day
Several human fatalities have resulted from intravenously.9
inhalation, dermal contact, or ingestion of Skin contact is particularly hazardous
ethylene chlorohydrin. Typically, neurotoxic because the absence of signs of immediate irri-
symptoms were described, and death was tation prevents any warning when the skin is
attributed to cardiac and respiratory collapse.1 wetted by the substance.3
One fatality was caused by exposure to an esti- The 2003 ACGIH ceiling-threshold limit
mated 300 ppm for 2.25 hours.2 In another fatal value (C-TLV) for ethylene chlorohydrin is
case, autopsy showed pulmonary edema and 1 ppm (3.3 mg/m3) with a notation for skin
damage to the liver, kidneys, and brain.2 absorption.
318 ETHYLENEDIAMINE
with other chemicals to which the subject was 2. Fisher AA: Contact Dermatitis, 2nd ed, pp
exposed.6 4041. Philadelphia, PA, Lea and Febiger,
A study of EDA-sensitized workers (as 1973
determined by EDA-associated rhinitis, cough- 3. Baer R, Ramsey DL, Biondi E: The most
ing, and wheezing) in an industrial popula- common contact allergens. Arch Dermatol
108:7478, 1973
tion suggested that smoking may decrease the
4. North American Contact Dermatitis Group:
latency between rst exposure to EDA and The frequency of contact sensitivity in North
onset of respiratory symptoms.7 America 197274. Contact Derm 1:277280,
Exposure of rats to 4000 ppm for 8 hours 1975
was uniformly fatal, whereas 2000 ppm was 5. Nielsen M, Jorgensen J: Persistence of con-
not lethal.8 Rats exposed daily for 30 days to tact sensitivity to ethylenediamine. Contact
484 ppm did not survive; injury to lungs, liver, Derm 16:275276, 1987
and kidneys was observed; at 132 ppm there was 6. Lam S, Chan-Yeung M: Ethylenediamine-
no mortality.1 induced asthma. Am Rev Resp Dis 121:151
In chronic studies nonneoplastic effects on 155, 1980
the liver (pleomorphic changes to hepatocytes) 7. Aldrich FD, Strange AW, Geesaman RE:
Smoking and ethylene diamine sensitization
have been observed in rats after oral dosing
in an industrial population. J Occup Med 29:
at 45 mg/kg body weight (bw)/day for 2 years, 311314, 1987
with no effects seen at 9 mg/kg bw/day.9,10 It 8. Smyth HF Jr et al: Range-nding toxicity
was not carcinogenic in lifetime skin paint- data: List IV. AMA Arch Ind Hyg Occup Med
ing studies in mice. Ethylenediamine was not 4:119122, 1951
genotoxic in a variety of in vivo and in vitro 9. Hermnsky SJ, Yang R SH, Garman RH,
tests.11 et al: Chronic toxicity and carcinogenicity
No reproductive toxicity was found in rats studies of ethylenediamine dihydrochloride
exposed to 0.50 g/kg/day for two generations.12 by dietary incorporation in Fischer 344 rats.
A reduction in body weight gain and changes Food Chem Toxicol 37(7):76576, 1999
in liver and kidney weights were observed in 10. World Health Organization: Concise Inter-
national Chemical Assessment Document 15.
the F0 and F1 parent rats. A microscopic liver
1,2-Diaminoethane (Ethylenediamine), 24pp.
lesion occurred in the F1 rats, with a greater Geneva, International Programme on Chem-
prevalence and severity in the females. In ical Safety, 1999
developmental toxicity studies signs of fetotox- 12. Slesinski RS et al: Assessment of genotoxic
icity and developmental delays occurred only at potential of ethylenediamine: In vitro and in
maternally toxic doses.10 vivo studies. Mutat Res 124:299314, 1983
In the eye of a rabbit, the liquid caused 11. Yang RSH et al: Two-generation repro-
extreme irritation and corneal damage; partial duction study of ethylenediamine in Fischer
corneal opacity was produced by a 5% solu- 344 rats. Fundam Appl Toxicol 4:539546,
tion.8 The undiluted liquid applied to the 1984
shaved skin of rabbits and left uncovered pro-
duced severe irritation and necrosis.8
The 2003 ACGIH threshold limit value-
time weighted average (TLV-TWA) for ethyl-
enediamine is 10 ppm (25 mg/m3) with a ETHYLENE DIBROMIDE
notation for skin absorption. CAS: 106-93-4
C2H4Br2
REFERENCES
Uses. A fumigant (now banned for soil and failure. At lower concentrations, death due to
grain use); in gasoline as a lead scavenger; pneumonia occurred as a result of injury to the
chemical intermediate in the industrial synthe- lungs and was delayed for up to 12 days after
sis of other brominated compounds exposure.
Four species of animals tolerated daily
Exposure. Inhalation; skin absorption inhalation of 25 ppm for 6 months without
adverse effects.3
Toxicology. Ethylene dibromide (EDB) is a Application of a 10% solution or the
severe mucous membrane, eye, and skin irri- undiluted liquid to rabbit skin caused marked
tant. It is a testicular toxicant and causes liver CNS depression and death within 24 hours.3 A
and kidney damage; it is carcinogenic in exper- dermal LD50 of 400 mg/kg was estimated.1
imental animals. An increased incidence of skin carcinomas
In an early report, accidental use of ethyl- and lung tumors has been found in mice re-
ene dibromide as a human anesthetic produced ceiving repeated skin applications.4 Rats and
general weakness, vomiting, diarrhea, chest mice chronically exposed to 10 or 40 ppm had
pains, coughing, shortness of breath, cardiac increased incidence of an tumors at multiple
insufciency, and uterine hemorrhaging.1 sites.5 Animal studies have shown increased
Death occurred 44 hours after inhalation. Post- toxic and carcinogenic effects when EDB is
mortem examination showed upper respira- administered with disulram, a widely used
tory tract irritation, swelling of the pulmonary drug in alcoholism control programs.6
lymph glands, advanced states of parenchy- Human epidemiological studies to observe
matous degeneration of the heart, liver, and carcinogenic effects are inconclusive because
kidneys, and hemorrhages in the respiratory of small cohort size, incomplete exposure data,
tract. and insufcient latencies.7
Two workers collapsed while inside a tank EDB is toxic to the male reproductive
that was later found to contain a 0.10.3% system in several species.
EDB solution.2 Removed after 2045 minutes Testicular atrophy was seen in rats and
in the tank, one man was intermittently coma- mice with chronic gavage administration of
tose, and the other was delirious and com- 41 or 107 mg/kg day, respectively.8 Abnormal
bative. Both experienced vomiting, diarrhea, spermatozoa and decreased spermatozoic con-
abdominal pain, and burning of the eyes and centration occurred in bulls fed EDB.9
throat. Metabolic acidosis and acute renal and Intraperitoneal injection of 10 mg/kg for 5
hepatic failure ensured. Death occurred 12 and days to male rats caused a decrease in average
64 hours later, respectively, despite supportive litter size in females mated 3 weeks after
measures. exposure and no litters after 4 weeks.10 Con-
Skin contact produces intensive burning tinuous exposure to 32 ppm during gestation
pain preceding hyperemia that develops into caused minor skeletal anomalies in rats and
blisters.1 Skin sensitization has been reported.1 mice.11
Acute exposure of experimental animals Adverse reproductive effects have also
resulted in adverse effects similar to those been reported in humans. Fumigators chroni-
described for humans. Rats did not survive cally exposed to EDB showed statistically
when exposed to the vapor for longer than 6 signicant decreases in sperm count and per-
minutes at 3000 ppm; minimum lethal concen- centages of viable and motile sperm and
tration for an 8-hour exposure was 200 ppm; increases in sperm with specic abnormalities
these exposures caused hepatic necrosis, pul- compared with controls.12 Decrease in sperm
monary edema, and cloudy swelling of renal velocity and semen volume has been reported
tubules.3 Depression of the central nervous in another group of fumigators who were
system (CNS) was observed in rats exposed at exposed to EDB seasonally.13 No adverse
higher concentrations, and deaths occurred effects were found on sperm counts of 50
within 24 hours from respiratory or cardiac workers exposed to less than 5.0 ppm.14
ETHYLENE DICHLORIDE 321
Ethylene dibromide is a potent mutagen, 10. Edwards K, Jackson H, Jones A: Studies with
producing a broad spectrum of mutations in a alkylating estersII. A chemical interpreta-
variety of in vivo and in vitro assays and binds tion through metabolic studies of the infer-
covalently with DNA in vivo.15,16 tility effects of ethylene dimethanesulphonate
The IARC has determined that there is and ethylene dibromide. Biochem Pharmacol
19:17831789, 1970
inadequate evidence in humans but sufcient
11. Short RD Jr, Minor JL, Ferguson B, et al:
evidence in experimental animals for the car- Toxicity Studies of Selected Chemicals, Task I
cinogenicity of ethylene dibromide. An overall The Developmental Toxicity of Ethylene Dibro-
evaluation of probably carcinogenic to humans mide Inhaled by Rats and Mice During
is given.16 A threshold limit exposure limit has Organogenesis. Report No EPA-560/6-76-
not been assigned by ACGIH. 018. Washington, DC, US Environmental
Protection Agency, Ofce of Toxic Sub-
stances, 1976
12. Ratcliffe JM, Schrader SM, Steenland K,
REFERENCES
et al: Semen quality in papaya workers with
long term exposure to ethylene dibromide. Br
1. National Institute for Occupational Safety
J Ind Med 44:317326, 1987
and Health. Criteria for a Recommended Stan-
13. Schrader SM, Turner TW, Ratcliffe JM: The
dard . . . Occupational Exposure to Ethylene
effects of ethylene bromide on semen quality:
Dibromide. DHEW (NIOSH) Pub No 77-
a comparison of short-term and chronic
221. Washington, DC, US Governmental
exposure. Reprod Toxicol 2:191198, 1988
Printing Ofce, 1977
14. Ter Haar G.: An investigation of possible
2. Letz GA, Pond SM, Osterloh JD, et al: Two
sterility and health effects from exposure to
fatalities after acute occupational exposure
ethylene dibromide. In Banbury Report 5
to ethylene dibromide. JAMA 252:2428
Ethylene Dichloride: A Potential Health Risk? pp
2431, 1984
167188. Cold Spring Harbor, NY, Cold
3. Rowe VK, Spencer HC, McCollister DD,
Spring Harbor Laboratory, 1980
et al: Toxicity of ethylene dibromide deter-
15. Agency for Toxic Substances and Disease
mined on experimental animals. AMA Arch
Registry (ATSDR): Toxicological Prole for
Ind Hyg Occup Med 6:158173, 1952
1,2-Dibromoethane. TP-91/13, 148pp, US
4. Van Duuren BL, Goldschmidt BM, Loewen-
Department of Health and Human Services,
gart G, et al: Carcinogenicity of halogenated
Public Health Service, 1992
olenic and aliphatic hydrocarbons in mice.
16. IARC Monographs on the Evaluation of
J Natl Cancer Inst 63:14331439, 1979
Carcinogenic Risks to Humans, Vol 71, Re-
5. National Cancer Institute: Carcinogenesis
evaluation of some organic chemicals,
Bioassay of 1,2-Dibromoethane (Inhalation
hydrazine and hydrogen peroxide, pp
Study), TR-210 (CAS No106-93-4), Car-
64169. Lyon, International Agency for
cinogenesis Testing Program. DHHS (NIH)
Research on Cancer, 1999
Pub No 81-1766. Washington, DC, US
Government Printing Ofce, 1981
6. Wong LCK, Winston JM, Hong CB,
et al: Carcinogenicity and toxicity of 1,2-
dibromoethane in the rat. Toxicol Appl Phar-
macol 63:155165, 1982 ETHYLENE DICHLORIDE
7. Ott MG, Scharnweber HC, Langner RR: CAS: 107-06-2
Mortality experience of 161 employees
exposed to ethylene dibromide in two pro-
C2H4Cl2
duction units. Br J Ind Med 37:163168, 1980
8. National Cancer Institute: Bioassay of 1,2-
Dibromoethane for Possible Carcinogenicity.
Bethesda, MD, NTIS no. PB 288428, 1978 Synonyms: 1,2-Dichloroethane; dichloro-
9. Amir D, Colcani R: Effect of dietary ethyl- ethane; ethylene chloride
ene dibromide on bull semen. Nature 206:
99100, 1965 Physical Form. Colorless liquid
322 ETHYLENE DICHLORIDE
Uses. Manufacture of vinyl chloride; anti- given phenobarbital along with ethylene
knock agent; fumigant, insecticide; degreaser dichloride.
compounds; rubber cements Eye contact with either the liquid or high
concentrations of vapor causes immediate dis-
Exposure. Inhalation; ingestion comfort with conjunctival hyperemia and slight
corneal injury; corneal burns from splashes
Toxicology. Ethylene dichloride is a central recover quickly with no scarring. Prolonged
nervous system depressant and causes injury to skin exposure, as from contact with soaked
the liver and kidneys; in chronic gavage studies clothing, produces severe irritation, moderate
it is carcinogenic to experimental animals. edema, and necrosis; systemic effects may
In one fatality, exposure to concentrated ensue as the liquid is readily absorbed through
vapor in a tank for 30 minutes caused drowsi- the skin.2
ness, nausea, and respiratory distress; coma For intermediate-duration studies, the
developed 20 hours after initial exposure.1 lethal oral dose depended on the method of
Serum levels of lactate and ammonia were administration.6,7 Administered in the drink-
increased, followed by elevation of glutamic ing water for 13 weeks, 8000 ppm was relatively
transaminases, lactic dehydrogenase, and crea- nontoxic to two strains of rats, causing elevated
tine phosphokinase. Ornithine carbamyl liver weights and minimal histologic evidence
transferase and glutamic oxaloacetic transami- of kidney damage in female F344/N rats.
nase of mitochondrial origin were remarkably Gavage administration of 240 mg/kg in male
high. Multiple organ failure developed, and rats and 300 mg/kg in females for 13 weeks was
the patient died in cardiac arrhythmia on the lethal; necrosis of the cerebellum occurred in
fth day. At autopsy, the lungs were severely one-third of the treated animals.
congested and edematous; diffuse degenerative Chronic administration by gavage of 95 or
changes of the myocardium, extensive cen- 47 mg/kg/ day for 78 weeks caused a signicant
trilobular necrosis of the liver, and acute increase in hemangiosarcomas of the circula-
tubular necrosis of the kidneys were noted. tory system in rats.8 Squamous cell carcinomas
Workers exposed to 10200 ppm com- of the forestomach were signicantly increased
plained of lacrimation, dizziness, insomnia, in male rats, and high-dose females had
vomiting, constipation, and anorexia; liver increased incidences of mammary gland ade-
tenderness on palpation, epigastric pain, and nocarcinomas and broadenomas. A variety of
elevated urobilinogen were observed.2 Impair- tumors have been similarly induced in mice.8
ment of the central nervous system and Intraperitoneal and inhalation studies in
increased morbidity, especially diseases of the animals have not shown a signicant carcino-
liver and bile ducts, were found in workers genic response.9,10
chronically exposed to ethylene dichloride at Pronounced increases were seen for total
concentrations below 40 ppm and averaging cancer, lymphatic and hematopoietic cancers,
1015 ppm.2 and leukemia in a mortality study of chlorohy-
Ingestion of quantities estimated between drin production workers.11 The investigators
8 and 200 ml have been reported to be lethal, attributed the excesses to ethylene dichloride
with a toxic response similar to that of cases of exposure based on probable exposures of the
inhalation.3,4 workers; however, concomitant exposure to
Interactions between ethylene dichloride other chemicals precludes identifying the
and other substances have been reported in etiologic agent(s).
animal studies. Specically, a combination Ethylene dichloride has been shown to
treatment with disulram caused testicular alkylate DNA, and it is genotoxic in a variety
atrophy (not seen with either agent alone) and of in vivo and in vitro assays.10 It was not feto-
lowered the ethylene dichloride dose at which toxic or teratogenic in rats, rabbits, or mice at
liver effects occurred.5 Increased hepatotoxic- doses that were not maternally toxic.10
ity has also been observed in some animals The IARC has determined that there is
ETHYLENE GLYCOL 323
4 weeks complained of throat irritation and effects on kidney function (based on urinary
headache.2 At 56 ppm, there was more pro- concentrations of albumin, b-N-acetyl-
nounced irritation of the upper respiratory glucosaminidase, b2-microglobulin, and
tract, and at 80 ppm of aerosol, the irritation retinol-binding protein) in a small group of
and cough were intolerable. aircraft workers (some of whom wore protec-
The chief hazard from ethylene glycol is tive breathing equipment) exposed to ethylene
associated with ingestion of large quantities in glycol vapor or mist during deicing operations.5
a single dose. Several metabolites are respon- The effects of the liquid in the eyes of
sible for the clinical syndrome, which can be rabbits are immediate signs of moderate dis-
divided into three stages.3 During the rst 12 comfort with mild conjunctivitis but no signif-
hours, central nervous system manifestations icant corneal damage.6 In one human incident
predominate. If the intoxication is mild, the of a splash in the eye, there was reversible con-
patient appears to be drunk but without the junctival inammation.7 The liquid produces
breath odor of alcohol. In more severe cases, no signicant irritant action on the skin.
there will be convulsions and coma. Other In developmental studies, maternal deaths
signs may include nystagmus, ophthalmople- from kidney failure occurred at 2000 mg/
gia, papilledema, depressed reexes, and kg/day in rabbits and at 3000 mg/kg/ day in
tetanic convulsions. The central nervous mice.8 Rat dams survived 5000 mg/kg/day.9
system manifestations are related to the alde- Developmental toxicity including teratogenic-
hyde metabolites of ethylene glycol, which ity occurred in mice and rats at doses of 500
reach their maximum concentrations 612 and 1250 mg/kg/day, respectively. Maternal
hours after ingestion. toxicity was not evident at these levels.8 Rabbit
In the second stage, cardiopulmonary fetuses did not exhibit developmental toxicity,
symptoms become prominent, consisting of even at doses that were maternally lethal.9 No
mild hypertension, tachypnea, and tachycardia. teratogenic effects were observed in rats and
Widespread capillary damage is assumed to be mice after inhalation or dermal exposure, sug-
the primary lesion. If the patient survives the gesting that route of exposure is critical to
rst two stages, renal complications may be producing fetal effects.9 Ethylene glycol was
expected at 2472 hours postingestion. Albu- not a selective reproductive toxin in a three-
minuria and hematuria are common ndings, generation study or repeated-dose studies in
and oxalate crystals are excreted in the urine. rodents.10
Glycoaldehyde, glycolic acid, and glyoxylate No evidence of a carcinogenic effect was
are the putative agents for kidney damage.3 found in mice or rats administered up to
The most signicant laboratory ndings 1000 mg/kg/day for 2 years or in female mice
in ethylene glycol intoxication are severe fed up to 50,000 ppm or males fed up to 25,000
metabolic acidosis from the accumulation of ppm ethylene glycol in the diets for 2 years.11,12
glycolate and the presence of high anion gap.3 Ethylene glycol was found to be nonmuta-
Low arterial pH and bicarbonate levels are genic in the Salmonella typhimurium assays; it
often observed. Nonspecic ndings are did not induce sister chromatid exchanges or
leukocytosis and increased amounts of pro- chromosomal aberrations in Chinese hamster
tein in the cerebrospinal uid. Chelation ovary cells.12
of calcium oxalate may cause hypocalcemia, The 2003 ACGIH ceiling threshold limit
which, when severe enough, can lead to tetany value (C-TLV) for ethylene glycol as an aerosol
and cardiac dysfunction.3 The minimum lethal is 39 ppm (100 mg/m3).
dose is on the order of 100 ml in adults,
although much higher doses have reportedly
been survived.4 REFERENCES
There is limited information on effects
from occupational exposures. In a cross- 1. Troisis FM: Chronic intoxication by ethylene
sectional survey, there was no evidence of glycol vapour. Br J Ind Med 7:65, 1950
ETHYLENE GLYCOL DINITRATE 325
2. Wills JH, Coulston F, Harris ES, et al: Physical Form. Oily liquid
Inhalation of aerosolized ethylene glycol by
man. Clin Toxicol 7:463, 1974
3. Linnanvuo-Laitinen M, Huttunen K: Ethyl- Uses. As an explosive usually mixed with
ene glycol intoxication. Clin Toxicol 24:167 nitroglycerin (NG) in the manufacture of
174, 1986 dynamite
4. Parry MF, Wallach R: Ethylene glycol poi-
soning. Am J Med 57:143150, 1974 Exposure. Inhalation; skin absorption. Data
5. Grin M, Patrice S, Bgin D, et al: A study on toxic effects are reported chiey from indus-
of ethylene glycol exposure and kidney func-
trial exposures to ethylene glycol dinitrate
tion of aircraft de-icing workers. Int Arch
Occup Environ Health 69:255265, 1997 (EGDN)-NG mixed vapors.
6. McDonald TO, Roberts MD, Borgman AR:
Ocular toxicity of ethylene chlorohydrin and Toxicology. EGDN causes vasodilation and
ethylene glycol in rabbits eyes. Toxicol Appl cardiac effects.
Pharmacol 21:143150, 1972 Intoxication results in a characteristic
7. Sykowsky P: Ethylene glycol toxicity. Am J intense, throbbing headache, presumably due
Ophthalmol 34:15991600, 1951
to cerebral vasodilation, often associated with
8. Price CJ, Kimmell CA, Tyl RW, et al: The
developmental toxicity of ethylene glycol in dizziness and nausea and occasionally with
rats and mice. Toxicol Appl Pharmacol 81: vomiting and abdominal pain.1,2 More severe
113127, 1985 exposure also causes hypotension, ushing,
9. Tyl RW, Price CJ, Marr MC, et al: De- palpitation, low levels of methemoglobinemia,
velopmental toxicity evaluation of ethylene delirium, and depression of the central nervous
glycol by gavage in New Zealand White system. Aggravation of these symptoms after
rabbits. Fundam Appl Toxicol 20:402412,1993 alcohol ingestion has been observed. On
10. World Health Organization: Concise Interna- repeated exposure, a tolerance to headache
tional Chemical Assessment Document 45 develops but is usually lost after a few days
(CICAD). Ethylene Glycol: Human Health without exposure. At times, persistent tachy-
Aspects, pp 138. International Programme
cardia, diastolic hypertension, and reduced
on Chemical Safety (IPCS), 2002
11. DePass LR, Garman RH, Woodside MD, et pulse pressure have been observed. On rare
al: Chronic toxicity and oncogenicity studies occasions, a worker may have an attack of
of ethylene glycol in rats and mice. Fundam angina pectoris a few days after cessation of
Appl Toxicol 7:566572, 1986 repeated exposures, a manifestation of cardiac
12. National Toxicology Program: Toxicology and ischemia. Sudden death due to unheralded
Carcinogenesis Studies of Ethylene Glycol in cardiac arrest has also been reported under
B6C3F1 Mice (Feed Studies). NTP TR 413, these circumstances.3
NIH Pub No. 91-3144, US Department of Volunteers exposed to the vapor of a
Health and Human Services, Public Health mixture of EGDN and NG at a combined con-
Service, National Institutes of Health, 1993 centration of 2 mg/m3 experienced headache
and a fall in blood pressure within 3 minutes of
exposure; a mean concentration of 0.7 mg/m3
for 25 minutes also produced lowered blood
pressure and slight headache.4
ETHYLENE GLYCOL DINITRATE A mortality study of 4061 workers, em-
CAS: 628-96-6 ployed in a Scottish explosives factory and fol-
lowed from 1965 to 1980, revealed an excess of
CH2NO3CH2NO3 deaths from acute myocardial infarction in the
younger group of workers exposed to both NG
and EGDN. This excess was not observed in
Synonyms: EGDN; nitroglycol; 1,2-dinitroe- workers considered to have been exposed to
thane NG only.5
326 ETHYLENE GLYCOL MONOBUTYL ETHER
EGDN is readily absorbed through the tions (300600 ppm) of the vapor for several
intact skin. hours would be expected to cause respiratory
The 2003 ACGIH threshold limit value- and eye irritation, narcosis, and damage to the
time-weighted average (TLV-TWA) for ethyl- kidney and liver.1
ene glycol dinitrate is 0.05 ppm (0.3 mg/m3) Human subjects exposed to 195 ppm for
with a notation for skin absorption. 8 hours had discomfort of the eyes, nose,
and throat, although there were no objective
signs of injury and no increase in erythrocytic
REFERENCES fragility.2 Similar symptoms occurred at
113 ppm for 4 hours.2 No clinical signs of
1. Trainor DC, Jones RC: Headaches in explo- adverse effects or subjective complaints
sive magazine workers. Arch Environ Health 12: occurred among seven male volunteers exposed
231234, 1966 to 20 ppm for 2 hours.3
2. Einert CE et al: Exposure to mixtures of nitro-
Statistically signicant decreases in hema-
glycerin and ethylene glycol dinitrate. Am Ind
tocrit and increases in mean corpuscular hemo-
Hyg Assoc J 24:435447, 1963.
3. Carmichael P, Lieben J: Sudden death in globin concentration have been reported in
explosives workers. Arch Environ Health 7:424 men occupationally exposed to 0.46
439, 1963 0.75 ppm EGBE for 16 years.4 It was noted
4. Lund RP, Haggendal J, Johnsson G: With- that changes were small, showed no relation-
drawal symptoms in workers exposed to nitro- ship to exposure concentration, and were still
glycerin. Br J Ind Med 25:136138, 1968 within normal biological variability.
5. Craig R, Gillis CR, Hole DJ, et al: Sixteen year Although not relevant to occupational
follow-up of workers in an explosives factory. exposure, ingestion of EGBE has resulted
J Soc Occup Med 35:107110, 1985 in respiratory, cardiovascular, hematologic,
hepatic, renal, ocular ,and metabolic effects.4
The 4-hour LC50 values were 486 ppm for
male rats and 450 ppm for female rats; toxic
effects included narcosis, respiratory difculty,
ETHYLENE GLYCOL MONOBUTYL and kidney damage.5 Acute or prompt deaths
ETHER are likely to be due to the narcotic effects of the
CAS: 111-76-2 substance, whereas delayed deaths are usually
attributable to congested lungs and severely
C4H9OCH2CH2OH damaged kidneys. In a 9-day study, rats exposed
to 245 ppm, 6 hours/day had signicant depres-
sion of red blood cell count and hemoglobin
Synonyms: Butyl cellosolve; 2-butoxy ethanol; with increases in nucleated erythrocytes, retic-
EGBE; EGMBE ulocytes, and lymphocytes.5 Decreased body
weight gains and increased liver weights were
Physical Form. Colorless liquid also found. Toxic effects showed substantial
reversal 14 days after exposure. In a 90-day
Uses. Widely used solvent and cleaning study, only mild hematologic alterations were
agent observed in rats exposed to 77 ppm 30 hours/
week. Repeated gavage administration to rats
Exposure. Inhalation; skin absorption of 222, 443, or 885 mg/kg/day for 90 days
caused a signicant dose-dependent decrease in
Toxicology. Ethylene glycol monobutyl hemoglobin concentration and red blood cell
ether (EGBE) is an irritant of the eyes and counts.6 Secondary effects included increased
mucous membranes, and in animals it is a spleen weights, splenic congestion, and in-
hemolytic agent. creased hemosiderin deposition in the liver and
Exposure of humans to high concentra- kidneys. EGBE had no adverse effects on
ETHYLENE GLYCOL MONOBUTYL ETHER 327
testes, bone marrow, thymus, or white blood EGBE affected reproductive parameters
cells. The mechanism for EGBE-induced red including the number of litters per pair; the
blood cell depression in rats is unknown, but number of live pups per litter; the proportion
acid metabolites may be involved.3,4 There of pups born alive; and adjusted live pup
appear to be strikingly different hematologic weights only at levels (1% and 2% in drinking
effects among species; differences in metabo- water) that resulted in signicant mortality
lism are probably responsible.5 It has been sug- of the dams.10,11 In males, testis and epididymis
gested that the hematologic effects are of lesser weights were normal, as were sperm number
consequence in humans in contrast to rodents and motility even at generally toxic doses.11 At
because acute exposures of 200 ppm produced the 0.5% dose level, EGBE did not signi-
no alterations in erythrocyte fragility.3 cantly affect the fertility or reproductive per-
Two-year inhalation studies revealed formance of either rst- or second-generation
equivocal evidence of carcinogenic activity in mice.10
female rats based on the increased combined Daily skin application to rabbits of
incidences of benign or malignant pheochro- 150 mg/kg as a 43.8% aqueous solution for 13
mocytoma (mainly benign) of the adrenal weeks caused no adverse effects.9 The LD50 for
medulla and no evidence of carcinogenic rabbits was 0.45 ml/kg (0.40 g/kg) when con-
activity in male rats exposed to 31.2, 62.5, or ned to the skin for 24 hours.1 The liquid is not
125 ppm; there was some evidence of carcino- signicantly irritating to the skin and is not a
genic activity in male mice based on increased skin sensitizer; instilled directly into the eye it
incidences of hemangiosarcoma of the liver and produces pain, conjunctival irritation, and tran-
in female mice based on increased incidences sient corneal injury.1,12
of forestomach squamous cell papilloma or car- The 2003 ACGIH threshold limit value-
cinoma (mainly papilloma).7 Increased inci- time-weighted average (TLV-TWA) for
dences of forestomach neoplasms in male and ethylene glycol monobutyl ether is 20 ppm
female mice occurred in groups in which ulcer- (97 mg/m3) with a notation for skin absorption.
ation and hyperplasia were also present. A mild
regenerative anemia and effects secondary to
the anemia were also noted.
EGBE did not induce sister chromatid REFERENCES
exchanges or chromosomal aberrations in
mammalian cell assays in vitro, and in vivo it 1. Rowe VK, Wolf MA: Derivatives of glycols.
In Clayton GD, Clayton FE (eds): Pattys
did not induce micronuclei in bone marrow
Industrial Hygiene and Toxicology, 3rd ed, rev,
cells of rodents. It was not mutagenic in
Vol 2C, Toxicology, pp 39313030. New
bacterial assays with or without metabolic York, Wiley-Interscience, 1982
activation.7 2. Carpenter CP et al: The toxicity of butyl
EGBE appears to be less hazardous than cellosolve solvent. AMA Arch Ind Health
other monoalkyl ethers of ethylene glycol with 14:114131, 1956
regard to reproductive effects.5 Mice treated 3. Johanson G, Kronborg H, Naslund PH, et al:
orally with 1000 mg/kg for 5 weeks had no Toxicokinetics of inhaled 2-butoxyethanol
change in absolute or relative testis weights.8 (ethylene glycol monobutyl ether) in man.
Exposure of pregnant rats at 100 ppm or rabbits Scand J Work Environ Health 12:594602,
at 200 ppm during organogenesis resulted in 1986
4. Agency for Toxic Substances and Disease
maternal toxicity and embryotoxicity, including
Registry (ATSDR): Toxicological Prole for 2-
decreased number of viable implantations per
Butoxyethanol and 2-Butoxyethanol Acetate,
litter.9 Slight fetotoxicity in the form of poorly 357pp. US Department of Health and
ossied or unossied skeletal elements was also Human Services, Public Health Service, 1998
observed in rats. Teratogenic effects were not 5. Dodd DE, Snellings WM, Maronpot RR,
observed in either species.9 et al: Ethylene glycol monobutyl ether: Acute
In continuous breeding studies in mice 9-day and 90-day vapor inhalation studies in
328 ETHYLENE OXIDE
been consistent with a distal dying-back Hospital staff exposed to ethylene oxide in
axonopathy with secondary demyelination, sterilizing operations during pregnancy were
similar to that seen with other peripheral neu- found to have a higher frequency of sponta-
rotoxins, such as n-hexane.5 An animal model neous abortions (16.7%) compared with a
of distal axonal degeneration with pathologic control group (5.6%) by a questionnaire study.
conrmation has been described in rats Analysis of a hospital discharge register con-
exposed to 500 ppm ethylene oxide 3 times/ rmed the ndings. The association persisted
week for 13 weeks.7 No signicant neurophy- after analysis for potential confounding factors,
siological effects were found in nonhuman such as age and smoking status.16 Adverse
primates after chronic exposures at 50 or reproductive effects were also noted in ethyl-
100 ppm.8 ene oxide-exposed dental assistants who had a
Two epidemiological studies of workers twofold increase in spontaneous abortions
exposed to ethylene oxide revealed increased and preterm and postterm births compared to
rates of leukemia.9,10 In one study, two cases unexposed dental assistants.17 There is animal
of leukemia (0.14 expected) and three stomach evidence of adverse reproductive effects,
cancers (0.4 expected) were observed. The including decreased fertility and reduced sperm
other study found three cases of leukemia count and motility in males and increased fetal
(0.2 expected). Because these workers had losses and malformed fetuses in females.18
exposures to other potential carcinogens, the Ethylene oxide is a potent genotoxic agent
ndings cannot be linked with certainty to eth- in a wide variety of prokaryotic and eukaryotic
ylene oxide. The small cohort size, the small assays and induces dose-related increases in the
number of deaths, and uncertainties about formation of adducts with DNA and hemoglo-
exposure level have also been noted.11 A bin.11 In humans it causes increases in the fre-
number of other studies have not found an quency of chromosomal aberrations and sister
increased rate of cancer mortality from ethyl- chromatid exchange in peripheral lymphocytes
ene oxide exposure. A mortality study of over after acute, high exposures with sampling a few
18,000 ethylene oxide workers from 14 plants days after exposure.19
producing medical supplies and foodstuffs did The 2003 ACGIH threshold limit value-
not nd an excess of leukemia or brain, time-weighted average (TLV-TWA) for ethyl-
stomach, or pancreatic cancers.12 There was, ene oxide is 1 ppm (1.8 mg/m3) with a notation
however, an increase in non-Hodgkin lym- for skin absorption and an A2-suspected human
phoma in male workers. A follow-up of 1896 carcinogen designation.
ethylene oxide production workers did not nd
an increase in mortality from leukemia, non- REFERENCES
Hodgkin lymphoma, or brain, pancreatic, or
stomach cancers.13 1. Glaser ZR: Special Occupational Hazard Review
In a chronic inhalation bioassay in rats with Central Recommendations for the Use of
exposed for 6 hours/day, 5 days/week for 2 Ethylene Oxide as a Sterilant in Medical Facili-
years to 100, 33, or 10 ppm ethylene oxide, ties. DHEW (NIOSH) Pub No 77-200.
there was a dose-related increased occurrence Washington, DC, US Governmental Print-
of mononuclear cell leukemia in both sexes at ing Ofce, 1977
all concentrations. There was also an increased 2. Sexton RJ, Henson EV: Experimental ethyl-
occurrence of primary brain tumors at 100 and ene oxide human skin injuries. AMA Arch Ind
Hyg Occup Med 2:549564, 1950
33 ppm in both sexes and peritoneal mesothe-
3. Hollingsworth RL et al: Toxicity of ethylene
liomas arising from the testicular serosa at 100
oxide determined on experimental animals.
and 33 ppm in male rats.14 AMA Arch Ind Health 13:217117, 1956
The IARC has determined that there is 4. Jacobson KH, Hackley EB, Feinsilver L: The
limited evidence in humans for the carcino- toxicity of inhaled ethylene oxide and propy-
genicity of ethylene oxide and sufcient evi- lene oxide vapors. AMA Arch Ind Health 13:
dence in experimental animals.15 237244, 1956
330 ETHYLENE THIOUREA
5. Finelli PF, Morgan TF, Yaar I, et al: Ethylene risk of spontaneous abortion, preterm birth,
oxide-induced polyneuropathy: A clinical and and postterm birth. Epidemiology 7(4):
electrophysiologic study. Arch Neurol 40: 363368, 1996
419421, 1983 18. Landrigan PJ, Meinhardt TJ, Gordon J,
6. Kuzuhara S: Ethylene oxide polyneuropathy: et al: Ethylene oxide: An overview of toxico-
Report of 2 cases with biopsy studies of logic and epidemiologic research. Am J Ind
nerve and muscle. Clin Neurol 22:707713, Med 6:103115, 1984
1982 19. Preston RJ: Cytogenetic effects of ethylene
7. Ohnishi A et al: Ethylene oxide induces oxide, with an emphasis on population
central peripheral distal axonal degeneration monitoring. Crit Rev Toxicol 29(3):263282,
of the lumbar primary neurones in rats. Br J 1999
Ind Med 42:373379, 1985
8. Setzer JV, Brightwell WS, Russo JM, et al:
Neurophysiological and neuropathological
evaluation of primates exposed to ethylene
oxide and propylene oxide. Toxicol Ind Health
12(5):667682, 1996 ETHYLENE THIOUREA
9. Hogstedt C, Malmqvist N, Wadman B: CAS: 96-45-7
Leukemia in workers exposed to ethylene
oxide. JAMA 241:11321133, 1979 C3H6N2S
10. Hogstedt C, Aringer L, Gustavsson A: Epi-
demiologic support for ethylene oxide as a
cancer-causing agent. JAMA 255:15751578,
Synonyms: ETU; imidazolidinethione; 2-
1986
imidazoline-2-thiol; 2-mercaptomidazoline
11. Agency for Toxic Substances and Disease
Registry (ATSDR): Toxicological Prole for
Ethylene Oxide. TP-90-16, 109pp. US Physical Form. White crystalline solid
Department of Health and Human Services,
Public Health Service, 1990 Uses. Accelerator in the curing of poly-
12. Steenland K, Stayner L, Halperin W, et al: chloroprene (neoprene) and polyacrylate
Mortality among workers exposed to ethyl- rubber; intermediate in the manufacture of
ene oxide. N Engl J Med 324:14021407, antioxidants, insecticides, fungicides, dyes,
1991 pharmaceuticals, and synthetic resins
13. Teta MJ, Benson LO, Vitale JN: Mortality
study of ethylene oxide workers in chemical
Exposure. Inhalation
manufacturing: a 10 year update. Br J Ind
Med 50:704709, 1993
14. Snellings W, Weil C, Maronpot R: A two- Toxicology. Ethylene thiourea (ETU) is an
year inhalation study of the carcinogenic antithyroid substance and animal carcinogen.
potential of ethylene oxide in Fischer 344 Clinical examination and thyroid function
rats. Toxicol Appl Pharmacol 75:105117, tests carried out over a period of 3 years on
1984 13 exposed workers showed one subgroup, the
15. IARC Monographs on the Evaluation of the Car- mixers, to have signicantly lower levels of
cinogenic Risk of Chemicals to Humans, Vol 60, total thyroxine than other workers; one person
Some industrial chemicals, pp 73145. Lyon, had an appreciably raised level of thyroid-
International Agency for Research on stimulating hormone and was considered to
Cancer, 1994
be hypothyroid.1 There was no evidence of
16. Hemminki K, Mutinen P, Saloniemi I, et al:
any clinical effect in any of the workers. Back-
Spontaneous abortion in hospital staff
engaged in sterilizing instruments with ground air concentrations at the plants gener-
chemical agents. Br Med J 285:14611463, ally ranged up to 240 mg/m3, but levels up to
1982 330 mg/m3 were registered on one individuals
17. Rowland AS, Baird DD, Shore DL, et al: personal sampler.
Ethylene oxide exposure may increase the Two previous studies found only slight
ETHYLENE THIOUREA 331
differences in total thyroxine and triiodothy- further notes that because ethylene thiourea
ronine in exposed workers (concentrations produces thyroid tumors in animals by non-
unspecied). genotoxic mechanisms it would not be exp-
In groups of rats fed 125 or 625 ppm for up ected to produce thyroid cancer in humans
to 90 days, marked increases in serum thyroid- exposed to concentrations that do not alter
stimulating hormone were found.2 The high- thyroid hormone homeostasis.8
dose group also exhibited decreases in iodide ETU was a potent teratogen in rats at
uptake by the thyroid and in serum triiodothy- doses that produced no maternal toxicity or
ronine and thyroxine levels. The majority of fetal deaths.9 At doses greater than 10 mg/kg,
rats at both these exposure levels had enlarged, there were neural tube closure defects, hydro-
red thyroids. Clinical signs of poisoning in- cephalus, and other brain malformations and
cluded excessive salivation, hair loss, and scaly limb defects.9 Neural tube defects appear to be
skin texture by day 8 in the 625 ppm group. the result of secondary reopening from exces-
The no-effect level for dietary ETU in rats was sive uid pressure rather than lack of original
considered to be 25 ppm. closure of the neural tube.10 Other anomalies
In rats, ETU produced a high incidence of observed in rats included the urogenital and
follicular carcinoma of the thyroid after oral ocular systems. Treatment only on gestation
administration in three studies.35 Doses in one day 11 with ETU primarily caused hydro-
of these studies were 5, 25, 125, 250, or nephrosis.11 Doses of 80 mg/kg decreased the
500 ppm.2 At the two highest dose levels, brain weight of rabbits. ETU was also terato-
animals of both sexes had thyroid carcinomas, genic after oral dosing in cats and mice and
although male rats had a higher incidence. The after skin and inhalation exposures in rats.11
lower dose levels produced thyroid follicular ETU was not a potent genotoxic agent in
hyperplasia. ETU is believed to induce thyroid a variety of assays.8 At present, there is no
tumors through the suppression of thyroxin threshold limit value (TLV) for ETU.12
synthesis, which in turn triggers hypersecretion
of thyroid stimulating hormone by the pitu-
itary; prolonged thyroid-stimulating hormone REFERENCES
secretion may result in follicular cell hypertro-
phy, hyperplasia, adenomas, and carcinomas of 1. Smith DA: Ethylene thiourea: Thyroid func-
the thyroid.1 In mice, repeated oral adminis- tion in two groups of exposed workers. Br J
tration of the maximal tolerated dose of Ind Med 41:362366, 1984
2. Freudenthal RI et al: Dietary subacute toxic-
215 mg/kg ETU produced liver tumors.6
ity of ethylene thiourea in the laboratory rat.
A recent study conrmed that ethylene
J Environ Pathol Toxicol 1:147161, 1977
thiourea was carcinogenic in male and female 3. Graham SL, et al: Effects of one year admin-
rats as shown by increased incidences of istration of ethylene thiourea upon the
thyroid follicular cell neoplasms after treat- thyroid of the rat. J Agric Feed Chem 21:324,
ment of up to 250 ppm in the diet for 2 years.7 1973
In mice, concentrations ranging from 100 to 4. Graham SL, et al: Effects of prolonged eth-
1000 ppm for 2 years caused liver and pituitary ylene thiourea ingestion on the thyroid of the
tumors in addition to thyroid tumors. Perina- rat. Food Cosmet Toxicol 13:493, 1975
tal exposure up to 8 weeks followed by a 5. Weisburger EK, et al: Carcinogenicity tests
control diet for 2 years was not carcinogenic in of certain environmental and industrial
chemicals. J Natl Cancer Inst 67:75, 1981
rats or mice. Combined perinatal-adult ETU
6. IARC Monographs on the Evaluation of Car-
exposures produced the same carcinogenic
cinogenic Risks of Humans. Overall Evaluations
effects as adult-only exposures. of Carcinogenicity: An updating of IARC Mono-
The IARC has determined that there is graphs, Vol 142, Suppl 7, pp 207208. Lyon,
inadequate evidence in humans for the car- International Agency for Research on
cinogenicity of ethylene thiourea and sufcient Cancer, 1987
evidence in experimental animals. The agency 7. Chhabra RS, Eustis S, Haseman JK, et al:
332 ETHYLENIMINE
1. Reinhardt CF, Brittelli MR: Heterocyclic Toxicology. Ethyl ether causes eye and res-
and miscellaneous nitrogen compounds. In piratory irritation, and, at high concentrations,
Clayton GD, Clayton FE (eds): Pattys Indus- it produces central nervous system depression
trial Hygiene and Toxicology, 3rd ed, rev, Vol 2A, and narcosis.
Toxicology, pp 26722676. New York, Wiley-
Concentrations of ethyl ether ranging
Interscience, 1981
2. Theiss AM et al: Aziridines. In International
from 100,000 to 150,000 are required for
Labor Ofce: Encyclopaedia of Occupational induction of human anesthesia; however, expo-
Health and Safety, Vol I, AK, pp 228230. sure at this concentration may also produce
New York, McGraw-Hill, 1983 fatalities from respiratory arrest.1,2 Mainte-
3. Carpenter CP, Smyth HF Jr, Shaffer CB: nance of surgical anesthesia is achieved at
The acute toxicity of ethylene imine to small 50,000 ppm, and the lowest anesthetic limit is
animals. J Ind Hyg Toxicol 30:26, 1948 19,000 ppm.1 Continued inhalation of
4. Hygienic Guide Series: Ethyleneimine. Am 2000 ppm in human subjects may produce
Ind Hyg Assoc J 26:8688, 1965 dizziness; however, concentrations up to 7000
5. Silver SD, McGrath FP: A comparison of ppm have been tolerated by some workers for
acute toxicities of ethyleneimine and ammonia
variable periods of time without untoward
to mice. J Ind Hyg Toxicol 30:79, 1948
6. IARC Monographs on the Evaluation of the
effects.3 Initial symptoms of acute overexposure
Carcinogenic Risk of Chemicals to Man, Vol 9, include vomiting, respiratory tract irritation,
Some azirdines, N-, S- and O-mustards and headache, and either depression or excitation.
selenium. Lyon, International Agency for In some persons, chronic exposure results in
Research on Cancer, 1975 anorexia, exhaustion, headache, drowsiness,
7. ACGIH: Ethyleneimine. Documentation of dizziness, excitation, and psychic disturbances.2
the TLVs and BEIs, 5th ed, p 258. Cincinnati, Albuminuria has been reported.1 Tolerance
OH, American Conference of Governmental may be acquired through repeated exposures.2
Industrial Hygienists, 1986 Ethyl ether is a mild skin irritant; repeated
8. IARC Monographs on the Evaluation of the Car- exposure causes drying and cracking.2 The
cinogenic Risk of Chemicals to Humans, Vol 71,
vapor is irritating to the eyes, and the undiluted
Re-evaluation of some organic chemicals,
hydrazine and hydrogen peroxide, pp 337
liquid in the eyes causes painful inammation
344. Lyon, International Agency for Research of a transitory nature.3 Human subjects found
on Cancer, 1999 200 ppm irritating to the nose, but not to the
eyes or throat.4
Rats gavaged daily with 3500 mg/kg/day
for up to 13 weeks showed marked toxicity
including mortality, decreased food intake, and
ETHYL ETHER body weight loss.5
CAS: 60-29-7 The 2003 ACGIH threshold limit value-
time-weighted average (TLV-TWA) for ethyl
C2H5OC2H5 ether is 400 ppm (1210 mg/m3) with a short-
term excursion limit (STEL) of 500 ppm
(1520 mg/m3).
Synonyms: Diethyl ether; ethoxyethane; ethyl
oxide; ether; anesthesia ether; sulfuric ether
REFERENCES
Physical Form. Colorless liquid 1. Sandmeyer EE, Kirwin CJ Jr: Ethers. In
Clayton GD, Clayton FE (eds): Pattys Indus-
Uses. Solvent in the manufacture of dyes, trial Hygiene and Toxicology, 3rd ed, rev, Vol 2A.
plastics, and cellulose acetate rayon; anesthetic Toxicology, pp 25072511. New York, Wiley-
agent Interscience, 1981
334 ETHYL FORMATE
2. Hygienic Guide Series: Ethyl ether. Am Ind The liquid is only slightly irritating to the
Hyg Assoc J 27:8587, 1966 skin, but dropped into the eye it causes mod-
3. MCA, Inc.: Chemical Safety Data Sheet SD- erate injury to the cornea.3
29, Ethyl Ether, pp 1718. Washington, DC, The 2003 ACGIH threshold limit value-
MCA, Inc, 1965 time-weighted average (TLV-TWA) for ethyl
4. Nelson KW et al: Sensory response to certain
formate is 100 ppm (303 mg/m3).
industrial solvent vapors. J Ind Hyg Toxicol
25:282285, 1943
5. EPA: Rat Oral Subchronic Study with Ethyl
Ether. Prepared by American Biogenics REFERENCES
Corporation for the Ofce of Solid Waste,
Washington, DC, 1986 1. ACGIH: Ethyl formate. Documentation of the
TLVs and BEIs, 6th ed, pp 633634. Cin-
cinnati, OH, American Conference of Gov-
ernmental Industrial Hygienists (ACGIH),
1991
2. Smyth HF Jr: Improved communication
ETHYL FORMATE hygienic standards for daily inhalation. Am Ind
CAS: 109-94-4 Hyg Assoc Q 17:129185, 1956
3. Smyth HF Jr, et al: Range-nding toxicity
HCOOC2H5 data: List V. AMA Arch Ind Hyg Occup Med
10:6168, 1954
4. Sandmeyer EE, Kirwin CJ: Esters. In Clayton
Synonyms: Formic ether; ethyl methanoate; GD, Clayton FE (eds): Pattys Industrial
ethyl formic ester Hygiene and Toxicology, 3rd ed, Vol 2A, Toxi-
cology, pp 22632267. New York, Wiley-
Interscience, 1981
Physical Form. Clear liquid
Exposure. Inhalation
2-ETHYLHEXYL ACRYLATE
Toxicology. Ethyl formate causes irritation CAS: 103-11-7
of the eyes and nose; at very high concentra-
tions it causes narcosis in animals, and it is C11H20O2
expected that severe exposure will produce the
same effect in humans.
In humans, a concentration of 330 ppm Synonyms: EHA, 2-propenoic acid 2-ethyl-
caused slight irritation of the eyes and rapidly hexyl ester
increasing nasal irritation.1 No chronic sys-
temic effects have been reported in humans.2 Physical Form. Colorless liquid; commercial
Rats survived 4 hours of inhalation at form contains hydroquinone (1000 ppm) or
4000 ppm, but 8000 ppm was fatal to ve of six hydroquinone methyl ether (15 or 200 ppm) to
animals.3 Cats exposed to 5000 ppm for 20 prevent polymerization
minutes showed eye irritation; 10,000 ppm for
80 minutes caused narcosis followed by death.1 Uses. As a plasticizing co-monomer for the
Pulmonary edema and death were observed in production of resins used in adhesives, latex,
dogs exposed to 10,000 ppm for 4 hours.4 paints, textile and leather nishes, and coatings
When applied to the skin of mice, ethyl for paper
formate showed no evidence of tumorigenic
activity in 10 weeks.4 Exposure. Inhalation; skin contact
ETHYLIDENE NORBORNENE 335
Toxicology. By analogy to effects caused by 3. DePass LR, Maronpot RR, Weil CS: Dermal
other acrylates, 2-ethylhexyl acrylate (EHA) is oncogenicity bioassays of monofunctional
expected to be an irritant of the eyes, nose, and and multifunctional acrylates and acrylate-
skin. based oligomers. J Toxicol Environ Health
Dermal sensitization to EHA has been 16:5560
4. Wenzel-Hartung RP, Brune H, Klimisch HJ:
documented from exposure to its presence in
Dermal oncogenicity study of 2-ethylhexyl
adhesive tape.1 This potential has been con- acrylate by epicutaneous application in male
rmed in the guinea pig.2 C3H/HeJ mice. J Cancer Res Clin Oncol 115:
In a lifetime dermal oncogenesis study in 543549, 1989
mice, 20 mg EHA in acetone was applied 3 5. Mellert W, Kuhborth B, Gembardt C, et al:
times weekly for their lifespan.3 There were 40 Two year carcinogenicity study in the male
mice in the group at the start of the study. Two NMRI mouse with 2-ethylhexyl acrylate by
animals developed squamous cell carcinomas, epicutaneous administration. Food Chem Toxicol
and four other animals had squamous cell 32:233237, 1994
papillomas. The rst tumor was observed after 6. IARC Monographs on the Evaluation of Carcino-
11 months of treatment. None of the acetone- genic Risks to Humans. Vol 60, Some industrial
chemicals, pp 475486. Lyon, International
treated controls developed tumors. There was
Agency for Research on Cancer, 1994
an apparent increase in the frequency of 7. Saillenfait AM, Bonnet P, Gallissot F, et al:
chronic nephritis in the EHA-treated mice Relative developmental toxicities of acrylates
(68% compared with 15% in controls). Treat- in rats following inhalation exposure. Toxicol
ment with EHA may have exacerbated the Sci 48(2):240254, 1999
onset and development of this condition, which
is normally seen in aged mice.
In another study, skin tumors, including
papillomas, squamous cell carcinomas, and
malignant melanomas, were seen in mice receiv- ETHYLIDENE NORBORNENE
ing skin applications of 21% or 86.5% EHA in CAS: 16219-75-3
25 ml of acetone three times per week for 2 years.4
No skin tumors were observed in another C9H12
strain of mice receiving up to 85% EHA in
acetone for up to 2 years. Hyperkeratosis and
hyperplasia occurred in all treated groups.5 Synonyms: Ethylidenebicyclo(2,2,1)hep-2-
The IARC has determined that there is ene; ENB; 2-norbornene, 5-ethylidene
limited evidence in experimental animals and
inadequate evidence in humans for the car- Physical Form. Colorless liquid (stabilized
cinogenicity of ethylhexyl acrylate.6 with 100 ppm of tert-butyl catechol because of
Administered to pregnant rats 6 hours/day its reactivity with oxygen)
during days 620 of gestation, doses of 50, 75,
or 100 ppm caused no evidence of maternal Uses. As third monomer in EPDM (ethyl-
toxicity or signicant developmental effects.7 ene-propylene diene monomer)
An ACGIH threshold limit value has not
been established for EHA. Exposure. Inhalation
The 4-hour LC50 values varied in different et al: Investigation of the developmental toxi-
species from 730 ppm for mice to 3100 ppm for city potential of 5-ethylidene-2-norbornene
rabbits.1 In rats lower concentrations of vapor vapor in the CDN rat. Int J Occup Med Toxicol
produced narcotic and irritant effects including 4(3):371381, 1995
hypoactivity, ataxia, prostration, lacrimation, 5. Ballantyne B, Cawley TJ: Toxicology update.
5-Ethylidene-2-norbornene. J Appl Toxicol 19:
and nasal discharge. Higher, near-lethal con-
291294, 1999
centrations caused tremors and convulsions.2 6. Ballantyne B: In vitro genetic toxicology inves-
Beagle dogs exposed at 93 ppm for 7 hours/ tigations with 5-ethylidene-2-norbornene. Tox
day, 5 days/week for a total of 89 exposures Subs Mech 17(2):133151, 1998
showed testicular atrophy, hepatic lesions, and
slight blood changes.1 Less marked effects were
seen at 61 ppm and no effects were seen at
22 ppm. Rats similarly exposed to 237 ppm
exhibited testicular atrophy, hepatic lesions,
and hydrothorax. In a more recent study, rats ETHYL MERCAPTAN
exposed 6 hours/day for 14 weeks at concen- CAS: 75-08-1
trations up to 150 ppm showed histopathologic
changes in the thyroid gland.3 C2H5SH
Minimal fetoxicity (skeletal variations) was
observed in the offspring of rats treated at 100
and 354 ppm for 6 hours/day on gestation days Synonyms: Ethanethiol; ethyl hydrosulde;
615; maternal toxicity was also evident at ethyl sulfhydrate; ethyl thioalcohol; thio-
these doses.4 ethanol; thioethyl alcohol
Applied to the skin of animals a 4-hour
occluded dose produced mild to moderate ery- Physical Form. Colorless liquid with a per-
thema and edema.2 Similar contact for 24 hours sistent leeklike odor
resulted in marked erythema, necrosis, and
ulceration.5 Instilled in rabbit eyes, the liquid Uses. Stenching agent for liqueed petro-
has caused mild conjunctival hyperemia. leum gases; adhesive stabilizer; manufacture of
Ethylidene norbornene was not mutagenic plastics, insecticides, and antioxidants
or clastogenic in a variety of in vitro assays.6
The 2003 ACGIH ceiling-threshold limit Exposure. Inhalation
value (C-TLV) for ethylidene norbornene is
5 ppm (25 mg/m3). Toxicology. Ethyl mercaptan causes irrita-
tion of mucous membranes; at high concentra-
tions it causes narcosis in animals, and it is
REFERENCES expected that severe exposure will cause the
same effects in humans.
1. Kinkead ER, Pozzani UC, Geary DL, Car- At concentrations below those necessary
penter CP: The mammalian toxicity of ethyli- to produce toxic effects, ethyl mercaptan is
dene norbornene. Toxicol Appl Pharmacol 20: extremely malodorous and voluntary exposure
250259, 1971 to high concentrations is unlikely to occur.
2. Ballantyne B, Myers RC, Klonne DR: Com- Observations on humans are limited to a single
parative acute toxicity and primary irritancy
brief report of exposure of workers to 4 ppm for
of the ethylidene and vinyl isomers of nor-
3 hours daily over 510 days; the workers expe-
bornene. J Appl Toxicol 17(4):211221, 1997
3. Ballantyne B, Norris JC, Dodd DE, et al: rienced headache, nausea, fatigue, and irrita-
Short-term and subchronic repeated exposure tion of mucous membranes.1
studies with ethylidene-2-norbornene vapor in In animals, ethyl mercaptan vapor causes
the rat. J Appl Toxicol 17(4):197210, 1997 mucous membrane irritation, narcosis, and, at
4. Neeper-Bradley TL, Ballantyne B, Losco PE, near-lethal levels, by analogy to other mercap-
N-ETHYLMORPHOLINE 337
tans, it may produce pulmonary edema. It Uses. Catalyst in polyurethane foam produc-
appears to be severalfold less acutely toxic than tion
hydrogen sulde or methyl mercaptan.
In rats, the LD50 for 4 hours was 4420 ppm; Exposure. Inhalation; skin absorption
effects included irritation of mucous mem-
branes, increased respiration, incoordination, Toxicology. N-ethylmorpholine is an irritant
staggering gait, weakness, partial skeletal of the eyes and mucous membranes; prolonged
muscle paralysis, light to severe cyanosis, and exposure to low concentrations causes corneal
mild to heavy sedation.2 edema.
Animals that survived single near-lethal In an experimental study, humans exposed
doses by the intraperitoneal and oral routes fre- to 100 ppm for 2.5 minutes experienced irrita-
quently had liver and kidney damage at autopsy tion of eyes, nose, and throat, whereas 50 ppm
up to 20 days after treatment.2 The liquid produced lesser irritation.1 Distortion of vision
dropped in the eyes of rabbits caused slight to can occur at levels much lower than those
moderate irritation. Chronic inhalation expo- that cause irritation. Workers exposed to low
sures in rats, mice, and rabbits over 5 months vapor concentrations (311 ppm) for several
showed no signicant effects at 40 ppm.1 hours reported temporary fogged vision with
The odor threshold of ethyl mercaptan rings around lights.2 Corneal edema has been
is approximately 0.25 ppb.3 The 2003 ACGIH observed in workers when air concentrations of
threshold limit value-time-weighted average substituted morpholines exceed 40 ppm. The
(TLV-TWA) for ethyl mercaptan is 0.5 ppm symptoms usually appear at the end of the
(1 mg/m3). workday and clear within 34 hours after ces-
sation of exposure.3
The liquid instilled in the eye of a rabbit
REFERENCES
caused corneal haziness with sloughing and
1. ACGIH: Ethyl mercaptan. Documentation of irregularities of the surface characteristic of
the TLVs and BEIs, 6th ed, pp 636637. Cincin- severe desiccation.3 On the skin of a rabbit, the
nati, OH, American Conference of Govern- undiluted liquid produced no reaction, surpris-
mental Industrial Hygienists (ACGIH), 1991 ingly unlike unsubstituted morpholine, which
2. Fairchild EJ, Stokinger HE: Toxicologic is a severe skin irritant.4
studies on organic sulfur compounds1. The 2003 ACGIH threshold limit value-
Acute toxicity of some aliphatic and aromatic time-weighted average (TLV-TWA) for N-
thiols (mercaptans). Am Ind Hyg Assoc J ethylmorpholine is 5 ppm (24 mg/m3) with a
19:171189, 1958 notation for skin absorption.
3. Windholz M, Budavari S, Stroumtsos LY,
Fertig MN (eds): The Merck Index, 9th ed,
p 4990. Rahway, NJ, Merck, 1976
REFERENCES
Uses. Organothiophosphate insecticide effects in humans has been described for fen-
thion, in which effects developed 2496 hours
Exposure. Inhalation; skin absorption after poisoning.5 Patients developed paralysis
of proximal limb muscles, neck exors, motor
Toxicology. Fenthion is an anticholine- cranial nerves, and respiratory muscles.
sterase agent and may also cause delayed neu- Fenthion has also exhibited delayed neu-
rotoxicity and ocular damage. rotoxicity in which the initial cholinergic crisis
Signs and symptoms of overexposure are was delayed 5 days and recurred 24 days after
caused by the inactivation of the enzyme ingestion.6,7 Psychosis was a persistent mani-
cholinesterase, which results in the accumula- festation. Because of the high lipid solubility
tion of acetylcholine at synapses in the nervous of fenthion, toxin analysis of repeated fat
system, skeletal and smooth muscle, and secre- biopsies was an essential component of patient
tory glands. The sequence of the development management.6
of systemic effects varies with the route of In a study designed to determine the
entry. The onset of signs and symptoms is potential retinal changes in 79 subjects exposed
usually prompt but may be delayed up to 12 to fenthion, 15 of the 79 workers examined had
hours.14 macular changes, characterized by perifoveal
After inhalation, respiratory and ocular irregularity of pigmentation and hypopigmen-
effects are the rst to appear, often within a few tation of 1/81/3 disk diameter.8 Symptoms
minutes after exposure. Respiratory effects reported were diminution of vision, bright light
include tightness in the chest and wheezing due aversion, ashes of light, black dots in front
to bronchoconstriction and excessive bronchial of eyes, and visual blurring. Other causes of
secretion; laryngeal spasms and excessive sali- macular involvement in these workers was
vation may add to the respiratory distress, and excluded. Mean exposure duration of subjects
cyanosis may also occur. Ocular effects include with macular involvement was 7.9 years.
miosis, blurring of distant vision, tearing, rhi- A series of studies originating from Japan
norrhea, and frontal headache. reported a more advanced visual disease syn-
After ingestion, gastrointestinal effects, drome, Saku disease, which correlated with
such as anorexia, nausea, vomiting, abdominal increasing organophosphate exposure.9 Ocular
cramps, and diarrhea appear within 15 minutes effects are dose dependent and range in sever-
to 2 hours. After skin absorption, localized ity from lentricular changes to the more serious
sweating and muscular fasciculations in the histopathologic changes in the ciliary body and
immediate area usually occur within 15 retina.
minutes to 4 hours; skin absorption is some- Although the association between Saku
what greater at higher ambient temperatures disease and organophosphate exposure remains
and is increased by the presence of dermatitis.3 controversial (lack of similar reports from
With severe intoxication by all routes, an around the world, poor quality of some of the
excess of acetylcholine at the neuromuscular Japanese studies, and the similarity of Saku
junctions of skeletal muscle causes weakness disease symptoms with common ocular dis-
aggravated by exertion, involuntary twitchings, eases) animal studies have also shown the
fasciculation and, eventually, paralysis. The occurrence of ocular toxicity from organophos-
most serious consequence is paralysis of the phate exposure.10 Acute exposure to fenthion
respiratory muscles. Effects on the central in rats has been associated with long-term
nervous system include giddiness, confusion, changes in electroretinograms, whereas
ataxia, slurred speech, CheyneStokes respira- chronic exposure has produced permanent
tion, convulsions, coma, and loss of reexes. ocular degeneration. A single 100 mg/kg dose
The blood pressure may fall to low levels, and of fenthion administered subcutaneously to rats
cardiac irregularities, including complete heart caused a long-lasting perturbation in mus-
block, may occur.2 carinic receptor function.11
An intermediate syndrome of neurotoxic Two-year feeding studies in rats (3
340 FERBAM
75 ppm) and mice showed no indication of car- Residues in Food1995. Toxicology Evalua-
cinogenic effects.12,13 Fenthion was not terato- tions, 1996
genic in tests on mice and rats.12,14 13. National Cancer Institute: Carcinogenesis
The 2003 ACGIH threshold limit Technical Report Series, No. 103, 1979
value-time-weighted average (TLV-TWA) is 14. World Health Organization: 1975 Evaluation
of Some Pesticide Residues in Food. Geneva,
0.2 mg/m3 with a notation for potential skin
1976
absorption.
REFERENCES
logic basis, SVFs have been studied for their Health and Safety Partnership Program
carcinogenic potential. Several decades of (HSPP) that includes: a voluntary permissible
research using rodents exposed by inhalation exposure level (PEL) in the workplace of 1
have conrmed that SVF pulmonary effects ber/cc, a respiratory protection program for
are determined by the Three Ds, ber dose specied tasks, continued workplace air moni-
(lung), dimension, and durability.5 Inhaled toring, and, where possible, the development of
short bers are cleared from the lung relatively ber formulations that do not persist in the
quickly by mobile phagocytic cells, but long lung. Refractory ceramic ber manufacturers
bers persist until they dissolve or fragment. have implemented a Product Stewardship
However, several relatively biopersistent SVFs Program that includes: a recommended expo-
induced chronic inammation, lung scarring sure guideline of 0.5 bers/cc; a 5-year work-
(brosis), and thoracic neoplasms. Thus biop- place air monitoring program; and research
ersistence of bers is now generally recognized into the development of high-temperature-
as a key determinant of the toxicological poten- resistant, biosoluble bers.
tial of SVFs. On the skin, berglass bers cause intense
Neither the epidemiological studies of pruritis as a result of the bers penetrating the
human exposure nor the animal studies have skin and causing an eruption consisting of small
shown a marked hazardous effect from glass- erythematous follicular papules.6 Fiberglass
wool. Any effect that might exist is small. Using dermatitis clinically presents as patchy folli-
estimates of the risk associated with exposure culitus or subacute dermatitis.
to chrysotile asbestos at high exposures and
doses, a determination was made of how much
less risky an exposure to glasswool bers might REFERENCES
be.4 For a given ber count, glasswool is calcu-
lated to be 510 times less risky. The risk for a 1. IARC Monographs on the Evaluation of Car-
nonsmoking installer of glasswool ber insula- cinogenic Risks to Humans, Vol 43, Man-made
tion who wears a respirator is about 6 in a mineral bres and radon, 300 pp. Lyon, Inter-
national Agency for Research on Cancer, 1988
million and might be zero per year. This means
2. Greim H (ed): Occupational Toxicants, Vol 8,
that out of a million installers there might be
critical data evaluation for MAK values and
six lung cancers from this cause every year, or classication of carcinogens, Commission for
out of 10,000 installers there might be one in the investigation of health hazards of chemical
16 years. The low risk of 6 in a million per year compounds in the work area, p 195. New York,
of a worker blowing glasswool is consistent VCH, 1997
with the fact that no one has found any cancer 3. Brown RC: Carcinogenicity of the insulation
attributable to the manufacture or installation wools: reassessment of the IARC evaluation.
of glass wool bers despite diligent searches. Regul Toxicol Pharmacol 14:1223, 1991
Nonetheless, common sense suggests that any 4. Wilson R: A risk assessment for exposure to
installer of blown glasswool ber insulation glass wool. Regul Toxicol Pharmacol 30:96109,
1999
should wear a respirator.
5. Hesterberg TW: Synthetic vitreous bers: a
Research demonstrating the relationship
review of toxicology research and its impact
between biopersistence and SVF toxicity has on hazard classication. Crit Rev Toxicol
provided a scientic basis for hazard classica- 31:153, 2001
tion and regulation of SVFs. For a nonhaz- 6. Hurwitz S: Clinical Pediatric Dermatology, A
ardous classication, legislation recently passed Textbook of Skin Disorders of Childhood and
by the European Union requires a respirable Adolescence, p 65. Philadelphia, PA, W. B.
insulation wool to have a low lung biopersis- Saunders, 1981
tence or be noncarcinogenic in laboratory rats.
US berglass and mineral wool industries
and the Occupational Health and Safety Ad-
ministration (OSHA) have formed a voluntary
344 FLUORANTHENE
strain of rats that ingested up to 13.7 mg/day Pattys Industrial Hygiene and Toxicology, 4th
for 2 years.10 ed, Vol 2F, Toxicology, pp 44714476. New
NaF was not mutagenic in bacterial assays. York, John Wiley and Sons, 1994
Although uoride has been shown to be clas- 4. WHO: Fluorides and Human Health, pp
togenic in a variety of cell types, the mecha- 225271. Geneva, World Health Organiza-
tion, 1970
nism of clastogenicity has been attributed to
5. Committee on Biologic Effects of Atmos-
the effect of uoride on the synthesis of pro- pheric Pollutants, Division of Medical Sci-
teins involved in DNA synthesis and/or repair, ences, National Research Council: Fluorides,
rather than direct interaction between uoride pp 163221. Washington, DC, National
and DNA.6 In general, there was no effect Academy of Sciences, 1971
on sperm morphology or the frequency of 6. World Health Organization: Environmental
chromosomal aberrations, micronuclei, sister Health Criteria 227. Fluorides, p 231. Interna-
chromatid exchange, or DNA strand breaks in tional Programme on Chemical Safety
rodents treated in vivo.6 (IPCS), 2002
No adverse effects on fetal development 7. Grandjean P, Juel K, Jensen OM: Mortality
were found in rats or rabbits administered u- and cancer morbidity after heavy occupa-
tional uoride exposure. Am J Epidemiol
oride in the drinking water during gestation.6
121:5764, 1985
Fluoride concentration in the urine has 8. Grandjean P, Olsen J, Jensen OM, et al:
been used as a biological indicator of uo- Cancer Incidence and mortality in workers
ride.11,12 Most absorbed uoride is excreted exposed to uoride. J Natl Cancer Inst 84:
rapidly in the urine. A portion is stored in bone, 19031909, 1992
but a nearly equal amount is mobilized from 8. IARC Monographs on the Evaluation of Car-
bone and excreted. Some storage of uoride cinogenic Risks to Humans. Overall Evaluations
occurs from the ingestion of as little as 3 mg/ of Carcinogencity: An Updating of IARC Mono-
day. Evidence from several sources indicates graphs Vol 1 to 42, Suppl 7, pp 208210. Lyon,
that urinary uoride concentrations not International Agency for Research on
exceeding 5 mg/l in preshift samples taken Cancer, 1987
9. National Toxicology Program: Technical
after 2 days off work are not associated with
Report on the Toxicology and Carcinogenesis
detectable osteosclerosis and that such changes Studies of Sodium Fluoride in F344/N Rats and
are unlikely at urinary levels of 58 mg/l.11 B6C3F1 Mice (Drinking Water Studies). NTP
Preshift urinary uoride concentration is TR 393. DHEW Publ No. NIH 90-2848,
considered to be a measure of the workers 1990
body (skeletal) burden of uoride, whereas 10. Maurer JK, Cheng MC, Boysen BG: Two-
the postshift sample is taken to be representa- year carcinogenicity study of sodium uoride
tive of exposure conditions during that work in rats. J Natl Cancer Inst 82:11181126,
shift. 1990
The 2003 ACGIH threshold limit value- 11. Biological Monitoring Guides: Fluorides. Am
time-weighted average (TLV-TWA) for uo- Ind Hyg Assoc J 32:274279, 1971
12. Largent EJ: Rates of elimination of uoride
rides is 2.5 mg/m3, as F.
stored in the tissues of man. AMA Arch Ind
Hyg Occup Med 6:3742, 1952
REFERENCES
REFERENCES
Synonyms: None
1. Largent EJ: Fluorine and compounds. In
Physical Form. Yellow gas International Labor Ofce: Encyclopaedia of
Occupational Health and Safety, Vol 1, AK,
Uses. Conversion of uranium tetrauoride to pp 557559. New York, McGraw-Hill, 1971
uranium hexauoride; oxidizer in rocket fuel 2. Ricca PM: Exposure criteria for uorine
systems; manufacture of various uorides and rocket propellants. Arch Environ Health 12:
uorocarbons 339407, 1966
3. Ricca PM: A survey of the acute toxicity of ele-
Exposure. Inhalation mental uorine. Am Ind Hyg Assoc J 31:2229,
1970
Toxicology. Fluorine is a severe irritant of 4. Hygienic Guide Series: Fluorine. Am Ind Hyg
the eyes, mucous membranes, skin, and lungs. Assoc J 26:624627, 1965
Because uorine is the most reactive of 5. Keplinger ML, Suissa LW: Toxicity of uorine
the elements, free uorine is rarely found in short-term inhalation. Am Ind Hyg Assoc J 29:
nature. Fluorine reacts with water to produce 1018, 1968
ozone and hydrouoric acid.1 In humans, the
inhalation of high concentrations causes laryn-
geal spasm and bronchospasm, followed by the
delayed onset of pulmonary edema.2,3 At sub-
lethal levels, severe local irritation and laryn- FORMALDEHYDE
geal spasm will preclude voluntary exposure CAS: 50-00-0
to high concentration unless the individual is
trapped or incapacitated.2 Two human subjects HCHO
found momentary exposure to 50 ppm intoler-
able; 25 ppm was tolerated briey, but both
subjects developed sore throat and chest pain Synonyms: Methanal; formic aldehyde;
that persisted for 6 hours.4 Short-term expo- oxomethane; oxymethylene; methylene oxide;
sures to concentrations up to 10 ppm were tol- methyl aldehyde
erated without discomfort.3
The LC50 in mice for 60 minutes was Physical Form. Gas (Note: formalin is a
150 ppm; effects were irritation of the eyes and 3750% solution by weight of formaldehyde
nose and the delayed onset of labored breath- gas.)
ing and lethargy; autopsy ndings included
marked pulmonary congestion and hemor- Uses. Manufacture of formaldehyde resins,
rhage.5 Mice exposed to sublethal concentra- which are used as adhesives in particle board,
tions had pulmonary irritation and delayed plywood, and insulating materials; countertops
development of focal necrosis in the liver and and wall paneling; coating to fabrics to impart
kidneys.5 permanent press characteristics; manufacture
A blast of uorine gas on the shaved skin of rubber, photographic lm, leather, cosmet-
of a rabbit caused a second-degree burn; lower ics, embalming uids, insulation; disinfectants
concentrations cause severe burns of insidious and fumigants
onset resulting in ulceration, similar to those
produced by hydrogen uoride.1,4 Exposure. Inhalation
348 FORMALDEHYDE
as a single gavage dose; in other studies there exceeded 1 ppm.4,15 The relative risk went from
was no effect on sperm in mice after adminis- 2.1 for those who resided in mobile homes for
tration of 100 mg/kg/day for 5 days, nor were 19 years to 5.5 for those who resided for over
there changes in reproductive function in rats 10 years. A relative risk of 6.7 for nasopharyn-
treated with 0.1 ppm in the drinking water for geal cancer was found for people with both
6 months. occupational and residential exposure.15,16
Formaldehyde has been shown to be car- Slight excesses in the occurrence of lung
cinogenic in two strains of rats, resulting in cancer have been noted in several studies. In a
squamous cell cancers of the nasal cavity after large cohort mortality analysis of 26,000
repeated inhalation of about 14 ppm. In one workers there were signicant excesses of lung
study, 51 of 117 male and 42 of 115 female cancer in those with more than 20 years since
Fischer 344 rats developed this tumor, but no initial formaldehyde exposure.17 Reanalysis of
nasal tumors were seen at 0 or 2 ppm. No other these same data has also shown a signicant
neoplasm was increased signicantly. In a trend of increasing lung cancer risk with
similar study of mice, this nasal tumor occurred increasing formaldehyde exposure.18 In the
in two male mice at 14.3 ppm. None of the other large study of industrial workers there
excesses was statistically signicant except for was a signicant excess of mortality from lung
the high-exposure rats.10 cancer at one plant where 73% of workers were
A large number of epidemiological studies exposed to formaldehyde at levels estimated to
have now been completed on persons with be over 2 ppm.19 An additional 8-year follow-
potential exposure to formaldehyde. Although up of this cohort found no cases of nasopha-
a variety of excess cancers, including brain, ryngeal cancer (vs. 1.3 expected), one nasal
bladder, colon, skin, kidney, and leukemias, cancer death (vs. 1.7 expected), and slight
have been reported, the evidence for a possible excesses of lung cancer, respiratory disease, and
involvement of formaldehyde is strongest for stomach cancer that did not correlate with esti-
respiratory cancers.11 A case-control study of mated cumulative dose or time since rst expo-
men with histologically conrmed primary sure.20 An enlarged and updated cohort study
epithelial cancer of the nasal cavities or acces- of formaldehyde-exposed workers from a US
sory sinuses found an increased relative risk of chemical plant found statistically signicantly
approximately 2 for nasal cancer, particularly elevated SMRs for total mortality, ischemic
squamous cell carcinoma, in formaldehyde- heart disease, nonmalignant respiratory disease
exposed workers.12 Another case control study and cancers of the lung, skin, and central
of 759 histologically veried cancers of the nervous system; among long-term workers
nasal cavity showed an association between there was no clear evidence of an association
squamous cell carcinoma and formaldehyde between lung cancer mortality and formalde-
exposure.13 Among industrial workers exposed hyde exposure.21 The authors suggested that
to formaldehyde-containing particulates, the unmeasured occupational or nonoccupational
risk of death from cancer of the nasopharynx factors may have played a role in the signicant
increased with cumulative exposure to for- excesses found in short-term workers.
maldehyde from a standardized mortality Although the results of certain of the
ratio (SMR) of 192 for <0.5 ppm-years to 403 published cancer studies have been challenged
for 0.5 to <5.5 ppm-years and 746 for >5.5 (concomitant exposure to other chemicals,
ppm-years.14 The ve workers with formalde- small sample sizes, smoking habits, inadequate
hyde exposure who died from nasopharyngeal statistical treatment), the IARC has deter-
cancer had held jobs where exposures had mined that the body of evidence suggests suf-
excursions to levels exceeding 4 ppm. An cient evidence for carcinogenicity to animals
increased risk of nasopharyngeal cancer was but limited evidence for carcinogenicity to
found among individuals who resided in mobile humans.11,22 It has also been suggested that
homes where exposure to formaldehyde aver- formaldehyde is not carcinogenic at low levels
aged as much as 0.5 ppm and easily reached or based on the evidence that formaldehyde is
350 FORMALDEHYDE
formed naturally in food, it is a normal human seizures from formaldehyde. Arch Environ
metabolite, and a threshold for carcinogenicity Health 49:3744, 1994
exists in animal experiments.9 9. Restani P, Galli CL: Oral toxicity of
Formaldehyde was genotoxic in both in formaldehyde and its derivatives. Crit Rev
vitro and in vivo assays. In vitro, it induced Toxicol 21:315328, 1991
10. Kers W et al: Carcinogenicity of formalde-
DNA-protein cross-links, DNA single-strand
hyde in rats and mice after long-term
breaks, chromosomal aberrations, sister chro- inhalation exposure. Cancer Res 43:4382
matid exchange, and gene mutations in human 4392, 1983
and rodent cells. In vivo it induced chromoso- 11. IARC Monographs on the Evaluation of Car-
mal anomalies in lung cells and micronuclei cinogenic Risks to Humans, Vol 62, Wood
in the gastrointestinal mucosa in treated rats. dust and formaldehyde, p 217. Lyon, Inter-
Overall, formaldehyde is considered to be national Agency for Research on Cancer,
weakly genotoxic, with good evidence of an 1995
effect at site of contact, but less convincing 12. Hayes RB et al: Cancer of the nasal cavity and
evidence at distal sites.23 paranasal sinuses and formaldehyde expo-
The odor is perceptible to previously unex- sure. Int J Cancer 37:487492, 1986
13. Olsen JH, Asnaes S: Formaldehyde and the
posed persons at or below 1 ppm.
risk of squamous cell carcinomas of the
The 2003 ACGIH threshold limit value- sinonasal cavities. Br J Ind Med 43:769774,
ceiling (TLV-C) is 0.3 ppm (0.37 mg/m3) with a 1986
notation for sensitization and an A2-suspected 14. Blair A et al: Cancers of the nasopharynx
human carcinogen designation. and oropharynx and formaldehyde exposure.
J Natl Cancer Inst 78:191192, 1987
15. Vaughan TL et al: Formaldehyde and cancers
REFERENCES of the pharynx, sinus, and nasal cavity. II.
Residential exposures. Int J Cancer
1. National Institute for Occupational Safety 38:685688, 1986
and Health: Criteria for a Recommended Stan- 16. Vaughan TL et al: Formaldehyde and cancers
dard . . . Occupational Exposure to Formalde- of the pharynx, sinus, and nasal cavity. I.
hyde. DHEW (NIOSH) Pub No. 77-126, pp Occupational exposures. Int J Cancer
2181. Washington, DC, US Government 38:677685, 1986
Printing Ofce, 1976 17. Blair A Stewart P, OBerg M et al: Mortality
2. Casteel SW et al: Formaldehyde: Toxicology among industrial workers exposed to formal-
and hazards. Vet Hum Toxicol 29:3133, 1987 dehyde. J Natl Cancer Inst 76:10711084,
3. Nordman H, Keskmen H, Tuppurainen M: 1986
Formaldehyde asthmarare or overlooked? 18. Sterling TD, Weinkam JJ: Mortality from
J Allergy Clin Immunol 75(1):9199, 1985 respiratory cancers (including lung cancer)
4. Department of Labor, Occupational Safety among workers employed in formaldehyde
and Health Administration: Occupational industries. Am J Ind Med 25:593602,
Exposure to Formaldehyde: Final Rule. Fed 1994
Reg 52(233):4616846312, December 4, 1987 19. Acheson ED, Barnes HR, Gardner MJ et al:
5. Horvath EP et al: Effects of formaldehyde on Formaldehyde in the British chemical indus-
the mucous membranes and lungs. JAMA try. An occupational cohort study. Lancet
259:701707, 1988 1:611616, 1984
6. Schoenberg JB, Mitchell CA: Airway disease 20. Gardner MJ, Pannett B, Winter PD et al: A
caused by phenolic (phenolformaldehyde) cohort study of workers exposed to formalde-
resin exposure. Arch Environ Health 30: hyde in the British chemical industry: an
574577, 1975 update. Br J Ind Med 50:827834, 1993
7. Chang CC, Gershwin ME: Perspectives on 21. Marsh GM, Stone RA, Esmen NA et al: Brief
formaldehyde toxicity: separating fact from communications. Mortality patterns among
fantasy. Reg Toxicol Pharmacol 16:150160, chemical plant workers exposed to formalde-
1992 hyde and other substances. J Natl Cancer Inst
8. Kilburn K: Neurobehavioral impairment and 86:384386, 1994
FORMIC ACID 351
22. Ad Hoc Panel: Epidemiology of chronic produce serious burns of the mouth and esoph-
occupational exposure to formaldehyde. agus.3 Other clinical features include gastroin-
Report of the Ad Hoc Panel on Health testinal irritation, vomiting, hematemesis,
Aspects of Formaldehyde. Toxicol Ind Health and abdominal pain.5 Cicatricial stenosis may
4:7790, 1988 appear after recovery. The major complications
23. World Health Organization: Concise Interna-
are acute renal failure and disseminated intra-
tional Chemical Assessment Document (CICAD)
40. Formaldehyde. pp 168. Geneva, Interna- vascular coagulation; pulmonary aspiration
tional Programme on Chemical Safety with a secondary pneumonia may occur. Occa-
(IPCS), 2002 sionally a direct toxic pneumonitis may also
occur.
Formic acid is an inhibitor of cytochrome
oxidase at the terminal end of the respiratory
chain in mitochondria and causes histotoxic
hypoxia at the cellular level.6,7 Therefore,
FORMIC ACID
persons with cardiovascular disease may be
CAS: 64-18-6
considered at special risk to the affects of
formic acid.6
HCOOH
Both positive and negative results have
been reported in mutagenicity studies,
although acidic experimental conditions
Synonyms: Methanoic acid; formylic acid,
were indicated in most cases of positive
hydrogen carboxylic acid
mutagenicity.8
The 2003 ACGIH threshold limit value-
Physical Form. Colorless liquid
time-weighted average (TLV-TWA) for formic
acid is 5 ppm (9.4 mg/m3) with a short-term
Uses. Preservative of silage; reducer in
excursion limit of 10 ppm (19 mg/m3).
dyeing wool; lime descaler; pH adjustor in cos-
metic products
REFERENCES
Exposure. Inhalation
1. Henson EV: Toxicology of the fatty acids.
Toxicology. Formic acid vapor is a severe J Occup Med 1:339345, 1959
2. von Oettingen WF: The aliphatic acids and
irritant of the eyes, mucous membranes, and
their esters-toxicity and potential dangers.
skin.
AMA Arch Ind Health 20:517522, 530531,
Exposure causes eye irritation with 1959
lacrimation, nasal discharge, throat irritation, 3. Guest D et al: Aliphatic Carboxylic Acids. In
and cough.1 A worker splashed in the face with Clayton GD, Clayton FE (eds): Pattys Indus-
hot formic acid developed marked dyspnea trial Hygiene and Toxicology, 3rd ed, rev, Vol 2C,
with dysphagia and died within 6 hours.2 Toxicology, pp 49034909. New York, Wiley-
Workers exposed to a mixture of formic and Interscience, 1982
acetic acids at an average concentration of 4. Liesivuori J, Laitinen J, Savolainen H: Kinetics
15 ppm of each complained of nausea.3 Twelve and renal effects of formic acid in occupation-
farmers exposed to 7.3 mg formic acid/m3 for ally exposed farmers. Arch Toxicol 66:522524,
1992
8 hours had increased renal ammoniagenesis
5. Moore DF, Bentley AM, Dawling S et al:
and urinary calcium at 30 hours after exposure.4
Folinic acid and enhanced renal elimination
The liquid on the skin causes burns with in formic acid intoxication. Clin Toxicol 32:
vesiculation; keloid formation at the site of the 199204, 1994
burn often results.2 Although ingestion of the 6. Liesivuori J, Kettunen A: Farmers exposure to
liquid is unlikely in ordinary industrial use, the formic acid vapour in silage making. Ann Occup
highly corrosive nature of the substance can Hyg 27:327329, 1983
352 FUEL OILS
1. IARC Monographs on the Evaluation of Car- Physical Form. Colorless to reddish brown
cinogenic Risks to Humans, Vol 45, Occupa- oily liquid
tional exposures in petroleum rening: crude
oil and major petroleum fuels, p 159. Lyon,
International Agency for Research on Uses. Solvent rening of lubricating oils,
Cancer, 1989 resins, and other organic materials; as insecti-
2. Reidenberg MM et al: Acute renal failure cide, fungicide, germicide; an intermediate for
due to nephrotoxins. Am J Med Sci 24:7125, tetrahydrofuran, furfural alcohol, phenolic and
1964 furan polymers
3. Porter HO: Aviators intoxicated by inhala-
tion of JP-5 fuel vapors. Aviat Space Environ
Med 61:654, 1990 Exposure. Inhalation; skin absorption
4. Carpenter CP et al: Petroleum hydrocarbon
toxicity studies: XI. Animal and human Toxicology. Furfural is an irritant of the
response to vapors of deodorized kerosene. eyes, mucous membranes, and skin and is a
Toxicol Appl Pharmacol 36:443, 1976
central nervous system depressant.
5. Morrison I, Sprague P: Kerosene pneumonia:
Its incidence in Perth and case history of a
Although the vapor is an irritant, the liquid
recent fatality. Australas Radiol 20:118, 1976 has a relatively low volatility so that inhalation
6. Santhanakrishnan BR, Chitra S: Accidental by workers of signicant quantities is unlikely.1
kerosene poisoning in infants and children. Exposure of workers to levels of 1.914 ppm
Indian J Pediatr 45:265, 1978 caused complaints of eye and throat irritation
7. Dudin AA et al: Accidental kerosene inges- and headache.1 The liquid or vapor is irritating
tion: A three-year prospective study. Ann Trop to the skin and may cause dermatitis, allergic
Paediatr 11:155, 1991 sensitization, and photosensitization.2 Dermal
8. Zucker AR et al: Management of kerosene- absorption has been found to be signicant in
induced pulmonary injury. Crit Care Med 14: humans. A 15-minute whole-hand immersion
303, 1986
in the liquid resulted in absorption of an
9. Mosconi G et al: Kerosene burns: a new
case. Contact Dermatitis 19:314, 1988
amount equivalent to an 8-hour inhalation
10. Tagami H, Ogino A: Kerosine dermatitis: exposure of 1020 mg/m3 (35 ppm) vapor.3
Factors affecting skin irritability to kerosine. Exposure of cats to 2800 ppm for 30
Dermatologica 146:123, 1973 minutes resulted in fatal pulmonary edema.1
11. Agency for Toxic Substances and Disease Inhalation of 260 ppm for 6 hours was fatal to
Registry (ATSDR): Toxicological Prole for rats but produced no deaths in mice or rabbits.2
Fuel Oils, pp 1204. US Department of Slight liver changes were seen in dogs exposed
Health and Human Services, Public Health daily to 130 ppm for 4 weeks.2 Symptoms after
Service, 1995 oral administration of 50 to 100 mg/kg in rats
were weakness, ataxia, coma, and death.1
Rats exposed at 40 ppm 1 hour/day for
periods of 7, 15, or 30 days had pulmonary irri-
tation, parenchymal injury, and regenerative
proliferation of pneumocytes, the severity of
which depended on duration of exposure.
354 FURFURYL ALCOHOL
Survival was reduced in groups of rats and excretion of furfural in man. Int Arch Occup
receiving 90 mg/kg/day for 13 weeks by gavage, Environ Health 41:159168, 1978
and cytoplasmic vacuolization of hepatocytes 4. Gupta GD, Misra A, Agarwal DK: Inhalation
was increased in exposed males. In mice cen- toxicity of furfural vapours: an assessment
trilobular coagulative necrosis and/or multi- of biochemical response in rat lungs. J Appl
Toxicol 11:343347, 1991
focal subchronic inammation of the liver
5. National Toxicology Program: Toxicology and
occurred at doses up to 1200 mg/kg.5 Carcinogenesis Studies of Furfural in F344/N
In 2-year gavage studies there was some Rats and B6C3F, Mice (Gavage Studies), pp
evidence of carcinogenic activity in male rats 176. US Department of Health and Human
based on increased incidences of cholangiocar- Services, NTP TR 382, 1990
cinomas and bile duct dysplasia and brosis. 6. World Health Organization: Concise Interna-
There was also some evidence of carcinogenic- tional Chemical Assessment Document (CICAD),
ity in female mice based on increased inci- Document 21. 2-Furaldehyde, 2000
dences of hepatocellular adenomas. Male mice 7. Feron VJ, Kruysse A: Effects of exposure
showed clear evidence of carcinogenicity based to furfural vapor in hamster simultaneously
on increased incidences of hepatocellular treated with benzo(a) pyrene or diethylni-
trosamine. Toxicology 11:127144, 1978
adenomas and carcinomas.5 The development
8. IARC Monographs on the Evaluation of Carcino-
of liver tumors may be related to the chronic genic Risks to Humans. Vol 63, Dry cleaning,
inammatory effects noted at this site.6 In some chlorinated solvents and other industrial
another experiment with hamsters, exposure to chemicals, pp 409429. Lyon, International
furfural vapor 7 hours/day, 5 days/week for 1 Agency for Research on Cancer, 1995
year caused irritation of the nasal mucosa and
growth retardation but no evidence of carcino-
genic effects.7
The IARC has determined that there is
limited evidence in animals and inadequate evi-
dence in humans for the carcinogenicity of fur- FURFURYL ALCOHOL
fural.8 Overall, furfural is not classiable as to CAS: 98-00-0
its carcinogenicity to humans.
Furfural was genotoxic in vitro in mam- C6H6O2
malian cells, causing chromosomal aberrations,
gene mutations, and sister chromatid ex-
changes; it was not mutagenic in a number of Synonyms: 2-Furyl carbinol; 2-furanmeth-
bacterial assays.6,8 anol; furfural alcohol
The 2003 ACGIH threshold limit value-
time-weighted average (TLV-TWA) for fur- Physical Form. Colorless liquid that turns
fural is 2 ppm (7.9 mg/m3) with a notation for dark in air
skin absorption.
Uses. Solvent for cellulose ethers, esters,
resins, and dyes; liquid propellant; binder in
foundry cores; manufacture of resins including
REFERENCES furfuryl alcohol resin (furan resin) and furfuryl
alcohol-formaldehyde resins
1. Brabec MJ: Aldehydes and acetals. In Clayton
GD, Clayton FE (eds): Pattys Industrial
Exposure. Inhalation; skin absorption
Hygiene and Toxicology, 3rd ed, Vol 2A, Toxi-
cology, pp 26652666. New York, Wiley-
Interscience, 1981 Toxicology. Furfural alcohol is an eye, nose,
2. Hygienic Guide Series: Furfural. Am Ind Hyg and throat irritant; exposure to high con-
Assoc J 26:196, 1965 centrations causes central nervous system
3. Flek J, Sedisec V: The absorption, metabolism depression.
FURFURYL ALCOHOL 355
Workers exposed to 8.6 and 10.8 ppm in a of carcinogenic activity in female rats based on
foundry core-making operation experienced no marginally increased incidences of neoplasms
discomfort, but two persons exposed to 15.8 of the nose and renal tubule neoplasms. Male
ppm (and 0.33 ppm formaldehyde) experienced mice had some evidence of carcinogenic
lacrimation and a desire to leave the area. In activity based on increased incidences of renal
another foundry core-making operation, no tubule neoplasms.
ill effects were seen after exposures of about Furfuryl alcohol was not mutagenic in a
616 ppm.1 variety of Salmonella typhimurium strains, but it
Large doses injected subcutaneously in did induce sister chromatid exchanges in cul-
dogs caused depressed respiration, lowered tured Chinese hamster ovary cells.7 No muta-
body temperature, salivation, diarrhea, diure- genic effects were detected in vivo in bone
sis, and signs of narcosis.2 marrow cells of male mice treated with furfuryl
In rats exposed to 700 ppm, effects in- alcohol.
cluded excitement followed by eye irritation The odor is detectable at 8 ppm.4 Mixing
and drowsiness.3 The rat LC50 for 4 hours was with acids results in polymerization, a highly
233 ppm.4 Repeated daily exposure of rats to an exothermic reaction that may result in
average of 19 ppm caused moderate respiratory explosions.1
irritation.3 Intravenous injection into rabbits The 2003 ACGIH threshold limit value-
and cats caused depression of the central time-weighted average (TLV-TWA) for fur-
nervous system; death occurred at doses of fural alcohol is 10 ppm (40 mg/m3) with a
8001400 mg/kg.5 short-term excursion limit (STEL) of 15 ppm
Eye contact in rabbits resulted in reversible (60 mg/m3) and a notation for skin absorption.
inammation and corneal injury with opacity.1
Animal experiments indicated that the liquid is
well absorbed through the skin with a dose- REFERENCES
related mortality; mild skin irritation may
also result from contact.1 Prolonged inhala- 1. National Institute for Occupational Safety and
tion exposures of rats to 25, 50, and 100 ppm Health: Criteria for a Recommended Standard
resulted in decreased weight gain and, at the . . . Occupational Exposure to Furfuryl Alcohol.
two highest doses, biochemical changes in the DHEW (NIOSH) Pub No. 79-133. Washing-
brain suggestive of mitochondrial damage, glial ton, DC, US Government Printing Ofce,
cell degeneration, and early demyelization.6 1979
2. Erdmann E: Uber das Kaffeeol und die Phys-
Rats and mice exposed to 31, 63, or
iologische Wirkung des darin Enthaltenen
125 ppm 6 hours/day for 16 days developed
Furfuralkols. Arch Exp Pathol Pharmacol 48:
lesions in the nasal respiratory epithelium 233261, 1902
and/or olfactory epithelium, and the severity of 3. Comstock CC, Oberst FW: Inhalation Toxicity
the lesions generally increased with increasing of Aniline, Furfuryl Alcohol and Their Mixtures
exposure concentrations.7 Clinical ndings in Rats and Mice. Chemical Corps Medical
included dyspnea, hypoactivity, and nasal and Laboratories Research Report No. 139,
ocular discharge. At 250 ppm all animals died October 1952
within 4 days. In 2-year inhalation studies at 4. Jacobson KH et al: The toxicology of an
doses of 2, 8, or 32 ppm rats and male mice had aniline-furfuryl alcohol-hydrazine vapor mix-
increased incidences of nonneoplastic lesions ture. Am Ind Hyg Assoc J 19:91100, 1958
5. Fine EA, Wills JH: Pharmacologic studies
of the nose and increased severity of
of furfuryl alcohol. Arch Ind Hyg Occup Med
nephropathy; female mice had increased inci-
1:625632, 1950
dences of nonneoplastic lesions of the nose 6. Savelainen H, Pfafi P: Neurotoxicity of fur-
and corneal degeneration.7 In addition, there furyl alcohol vapor in prolonged inhalation
was some evidence of carcinogenicity in male exposure. Environ Res 31:20427, 1983
rats based on increased incidences of combined 7. National Toxiciology Program: Toxicology and
neoplasms of the nose and equivocal evidence Carcinogenesis Studies of Furfuryl Alcohol in
356 GASOLINE
F344/N Rats and B6C3F1 Mice (Inhalation or if the liquid remains in continued contact
Studies), pp 1248. US Department of Health with the skin, a severe chemical burn can occur.
and Human Services, NTP TR 482, 1999 Repeated exposures may cause defatting of the
skin.
On ingestion, gasoline produced local
irritation, central nervous system depression,
and congestion and capillary hemorrhage in
GASOLINE visceral organs.5 Aspiration of the liquid into
CAS: 8006-61-9 the lungs produced chemical pneumonitis.
Intentional use of leaded gasoline as an
intoxicant has resulted in encephalopathy from
the tetraethyl lead.6 Other neurological effects
from chronic exposure include postural tremor,
Synonyms: Motor fuel; petrol ataxia, abnormal gait, affected speech, head-
aches, and memory loss.7 Octane improving
Physical Form. Liquid gasoline is a complex additives to gasoline, such as methylcyclopen-
mixture of at least 150 hydrocarbons with tadienyl manganese tricarbonyl (MMT), do
about 6070% alkanes, 2530% aromatics, and not appear to inuence toxicity, based on acute
69% alkenes. The small-chain, low-carbon- animal tests.5,8
numbered components are more volatile and Blood dyscrasias have been noted in
thus in higher percentages in the vapor phase humans acutely and chronically exposed to
than the larger and heavier molecules.1 The gasoline, but these effects are most likely due
concentrations of aromatics, the more toxic of to benzene, and the incidence of these ndings
the components, are depleted to about 2% in has decreased as the benzene content in gaso-
the vapor phase. The light alkanes, the less line has decreased.7
toxic components, are enriched to about 90%. In a 2-year inhalation study, rats and mice
Benzene is also present and represents a com- were exposed to 0, 67, 292, or 2056 ppm 6
ponent of major concern. hours/day, 5 days per week.9 The major nding
was a time- and dose-related increase in the
Uses. Fuel for spark-ignited internal com- incidence of kidney lesions in the male rats.
bustion engines These lesions consisted of cortical multifocal
tubular basophilia (indicative of areas of cell
Exposure. Inhalation regeneration), protein casts, and interstitial
inammation. There was epithelial cell
Toxicology. Gasoline is an irritant of the shedding, and the casts were found within
eyes and mucous membranes and is a central dilated renal tubules commonly at the corti-
nervous system depressant. comedullary junction.
Exposure of humans to 900 ppm for 1 hour The pattern of renal tubule degeneration,
caused slight dizziness and irritation of the regeneration, dilation, and hyalin deposition
eyes, nose, and throat.2 At 2000 ppm for 1 hour, (termed light hydrocarbon nephropathy) is
there was dizziness, mucous membrane irrita- produced in male rats of three strains (Sprague-
tion, and anesthesia; 10,000 ppm caused nose Dawley, Fischer-344, and Harlan-Wistar), but
and throat irritation in 2 minutes, dizziness in not in female rats of those strains or in male or
4 minutes, and signs of intoxication in 410 female mice, cats, dogs, or monkeys.5 In three
minutes.2 At high concentrations, coma and instances, male rats that showed light hydro-
death may result in a few minutes without any carbon nephropathy at 3 months developed
accompanying respiratory struggle or post- tumors after 2 years. The hydrocarbons
mortem signs of anoxia.3 most likely associated with light hydrocarbon
On skin contact, gasoline vaporizes rapidly nephropathy were branched-chain aliphatic
and has little if any irritant effect.4 If occluded, compounds containing at least 6 and probably
GASOLINE 357
not more than 810 carbon atoms.10 Aromatic excursion limit of 500 ppm (1480 mg/m3) and
hydrocarbons were without activity. Additional an A3-conrmed animal carcinogen with un-
mechanistic studies suggest that rat renal known relevance to humans notation
tumors involve a rat-specic protein a2u-
globulin. This protein binds with branched
aliphatics, which then accumulate in renal
tubule cells, resulting in cell death and, in turn, REFERENCES
a proliferative sequence that increases renal
tubule tumors.5,11 The a2u-globulin protein is 1. Page NP, Mehlman M: Health effects of
species specic to rats and gender specic to gasoline refueling vapors and measured expo-
sures at service stations. Toxicol Ind Health 5:
males.
869890, 1989
It does not appear that the nephrotoxicity
2. Sandmeyer EE: Aromatic hydrocarbons.
attributable to a2u-globulin syndrome is rele- In Clayton GD, Clayton FE (eds): Pattys
vant to humans. Most epidemiological studies Industrial Hygiene and Toxicology, 3rd ed, Vol
have not shown an association between gaso- 2B, Toxicology, pp 33853387. New York,
line exposure and renal cancer risk.12 However, Wiley-Interscience, 1981
a recent case-control study from Finland 3. Reese E, Kimbrough RD: Acute toxicity of
reported a signicant association between gasoline and some additives. Environ Health
renal cell cancer and gasoline that was dose Perspect 101(suppl 6):115131, 1993
dependent.13 4. Weaver NK: Gasoline toxicology, implica-
In general, gasoline is not considered to be tions for human health. Ann NY Acad Sci 534:
441451, 1988
genotoxic.7
5. Scala RA: Motor gasoline toxicity. Fundam
The IARC concluded that limited evidence
Appl Toxicol 10:553562, 1988
exists for the carcinogenicity of unleaded gaso- 6. Fortenberry JD: Gasoline snifng. Am J Med
line in animals.14 The epidemiological studies 79:740744, 1985
were inadequate in demonstrating increased 7. Agency for Toxic Substances and Disease
carcinogenic risk in humans.14 The IARC Registry (ATSDR): Toxicological Prole for
Working Group did note that some compo- Automotive Gasoline, 196pp. US Department
nents of gasoline, especially benzene, are of Health and Human Services, Public
carcinogenic in humans, and concluded that Health Service, 1995
gasoline is possibly carcinogenic in humans. 8. Abbott PJ: Methylcyclopentadienyl man-
Although anecdotal reports have suggested ganese tricarbonyl (MMT) in petrol: the
toxicological issues. Sci Total Environ
a link between gasoline exposure during preg-
67:247255, 1987
nancy and developmental effects in humans,
9. MacFarland HN, Ulrich CE, Holdsworth
animal studies have not conrmed the toxicity CE, Kitchen DN, Halliwell WH, Blum SC:
of gasoline in the fetus.13,15 Rats exposed to A chronic inhalation study with unleaded
1600 ppm during days 615 of gestation had no gasoline vapor. J Am Coll Toxicol 3:231248,
evidence of maternal toxicity or adverse effects 1984
on the fetuses. In a two-generation reproduc- 10. Scala RA: Comments on Structure-Activity
tive toxicity study, rats exposed 6 hours daily Relationships, Summary and Concluding
at concentrations up to 20,000 mg/m3 (appro- Remarks, pp 14. Unpublished addendum to
ximately 50% of the lower explosive limit) Workshop on the Kidney Effects of Hydro-
showed no fertility, reproductive, or fetal carbons. Boston, 1984
11. Raabe GK: Review of the carcinogenic
effects.16 There were no treatment-related
potential of gasoline. Environ Health Perspect
effects in parental animals and no microscopic
101(suppl 6):3538, 1993
changes other than hyalin droplet nephropathy 12. Mclaughlin JK: Renal cell cancer and expo-
in the kidneys of male rats. sure to gasoline: a review. Environ Health Per-
The 2003 ACGIH threshold limit value- spect 101(suppl 6):111114, 1993
time-weighted average (TLV-TWA) for gaso- 13. Partanen T, Heikkila P, Hernberg S, et al:
line is 300 ppm (890 mg/m3) with a short-term Renal cell cancer and occupational exposure
358 GERMANIUM TETRAHYDRIDE
to chemical agents. Scand J Work Environ Degenerative changes were observed in the
Health 17:231239, 1991 liver and kidney of rodents exposed to high
14. IARC Monographs on the Evaluation of Car- one-time concentrations of 0.261.4 g/m3.2,3
cinogenic Risks to Humans, Vol 45, Occupa- Nonspecic changes in the blood were also
tional exposures in petroleum rening; crude observed.3 Nervous system effects, including
oil and major petroleum fuels, pp 159201.
excitation, impairment of locomotor activity,
Lyon, International Agency for Research on
Cancer, 1989 listlessness, hypothermia, and convulsions,
15. Skalko RG: Reproductive and developmental were observed in mice before death following
toxicity of the components of gasoline. En- inhalation exposure to 2 g/m3.3
viron Health Perspect 101(Suppl 6):143149, The 2003 ACGIH threshold limit value-
1993 time-weighted average (TLV-TWA) for ger-
16. Riley AJ, Nessel CS, McKee RH, et al: manium tetrahydride is 0.2 ppm (0.63 mg/m3).
Assessment of the reproductive toxicity
potential of gasoline vapor in a two-genera-
tion study in rats. Toxicologist 54(1):395, REFERENCES
2000
1. Gerber GB, Leonard A: Mutagenicity, car-
cinogenicity and teratogenicity of germanium
compounds. Mutat Res 387(3):141146, 1997
2. Furst A: Biological testing of germanium.
Toxicol Ind Health 3:167181, 1987
3. Vouk VB: Germanium. In Friberg L, Nord-
GERMANIUM TETRAHYDRIDE berg GF, and Vouk VB (eds): Handbook on the
CAS: 7782-65-2 Toxicology of Metals, 2nd ed. pp 255263. Ams-
terdam, Elsevier, 1986
GeH4
Exposure. Inhalation
Synonyms: Cidex (2% alkaline glutaraldehyde
Toxicology. Germanium tetrahydride is re- aqueous solution); 1,5-pentanedial; glutaric
ported to be a hemolytic agent; at high con- dialdehyde; glutaral
centrations it also causes neurotoxicity and
damage to the liver and kidneys. Physical Form. Colorless crystalline solid,
Although the general toxicity of germa- soluble in water and organic solvents
nium is low, the tetrahydride gas is highly toxic
at a level of 100 ppm and can cause death at Uses. As broad-spectrum antimicrobial cold
150 ppm from hemolysis.1 There is little in- sterilant/disinfectant for hospital equipment; as
formation on the toxicity of this compound to tanning agent for leather; as tissue xative; as
humans. It is reported that inhalation by cross-linking agent for proteins; as preservative
humans of germanium tetrahyride may cause in cosmetics; as therapeutic agent for warts,
lung problems, but no details were given.2 hyperhidrosis, and dermal mycotic infections;
Germanium tetrahydride was lethal to in X ray processing solutions and lm emul-
mice after inhalation of 610 mg/m3 for 4 hours.2 sion; as a disinfectant in the beauty industry
GLUTARALDEHYDE 359
3. Fisher AA: Reactions to glutaraldehyde with Uses. Stabilizer in the manufacture of vinyl
particular reference to radiologists and X-ray polymers; chemical intermediate in prepara-
technicians. Cutis 28:113122, 1981 tion of glycerol, glycidyl ethers, esters, and
4. Corrado OJ, Osman J, Davies RJ: Asthma amines; in pharmaceuticals; in sanitary
and rhinitis after exposure to glutaraldehyde chemicals
in endoscopy units. Hum Toxicol 5:325327,
1986
5. Norback D: Skin and respiratory symptoms Exposure. Inhalation
from exposure to alkaline glutaraldehyde in
medical services. Scand J Work Environ Health Toxicology. Glycidol is an irritant of the
14:366371, 1988 eyes, upper respiratory tract, and skin; at high
6. Kie1-Swierczynska M, Krecisz B: Occupa- concentrations it causes narcosis in animals,
tional allergic contact dermatitis in hair- and it is expected that severe exposure will have
dressers due to glutaraldehyde. Contact Derm the same effect in humans. It is carcinogenic
44(3):185186, 2001 and mutagenic in experimental animals.
7. Slesinski RS, Hengler WC, Guzzie PJ, et al: The acute hazard to humans from vapor
Mutagenicity evaluation of glutaraldehyde in exposure appears to be relatively slight, as
a battery of in vitro bacterial and mammalian
ample warning in the form of eye, nose, and
test systems. Food Chem Toxicol 21:621629,
1983 throat irritation occurs at low concentrations;
8. Zissu D, Gagnaire F, Bonnet P: Nasal and no chronic effects have been reported in
pulmonary toxicity of glutaraldehyde in mice. humans.1
Toxicol Lett 71:5362, 1994 The LC50 in mice was 450 ppm for a 4-
9. National Toxicology Program: Toxicology hour exposure; in rats, the LC50 for 8 hours
and Carcinogenesis Studies of Glutaraldehyde in was 580 ppm; labored breathing, lacrimation,
F344/N Rats and B6C3F1 Mice (Inhalation salivation, and nasal discharge were seen, and
Studies), NTP TR 490, pp 1233. US pneumonitis was observed at autopsy.1 Rats
Department of Health and Human Services, repeatedly exposed to 400 ppm showed only
Public Health Service, 1999 slight eye irritation and mild respiratory dis-
10. Neeper-Bradley TL, Butler BL, Fisher LC,
tress, with no evidence of systemic toxicity.
et al: Two-generation reproduction study
with glutaraldehyde (GA) in the drinking The oral LD50 was 0.45 g/kg for mice and
water of CD rats. Toxicologist 15(1):165, 0.85 g/kg for rats; symptoms included central
1995 nervous system depression characterized by in-
11. Ballantyne B, Myers RC, Blaszcak DL: Inu- coordination, ataxia, coma, and death.1 Animals
ence of alkalinization of glutaraldehyde surviving exposure showed reversible excitation
biocidal solutions on acute toxicity, primary and tremor; lacrimation and labored breathing
irritancy, and skin sensitization. Vet Hum also were observed. In 16-day studies, focal
Toxicol 39(6):340346, 1997 demyelination of the brain occurred in mice
given 300 mg/kg/day by gavage.2 In the same
study, male rats receiving 300 mg/kg/day had
edema and degeneration of the epididymal
stroma and atrophy of the testes. Longer expo-
GLYCIDOL sures of 13 weeks resulted in cerebellar necro-
CAS: 556-52-5 sis and demyelination of the medulla, renal
tubular cell degeneration, and thymic lym-
C3H6O2 phoid necrosis in rats and demyelination of the
medulla and thalamus and renal tubular cell
degeneration in mice. A reduction in sperm
Synonym: 2,3-Epoxy-1-propanol; oxirane- count and sperm motility and testicular
methanol atrophy occurred in males of both species at
doses up to 300 mg/kg/day or 400 mg/kg/
Physical Form. Colorless liquid day for mice and rats, respectively.2 Glycidol
GRAPHITE (natural) 361
involved in the manufacture of carbon elec- light bulb laments; found in all zirconium-
trodes have now been reported to have devel- containing minerals
oped this condition after exposures after 1940.3
However, the variability in clinical ndings that Exposure. Inhalation
characterizes these cases suggests a mixed dust
exposure. Toxicology. Hafnium dust is very low in tox-
Synthetic graphite injected peritoneally in icity. No health hazards have been recognized
mice produces a reaction characteristic of an from the industrial handling of hafnium
inert material. On the basis of experimental powder other than those arising from re or
evidence, and the rarity of reports of adverse explosion.1
effects of exposure in humans, it is concluded Hafnium salts are mild irritants of the eye
that pure synthetic graphite acts only as an and the skin and have produced liver damage
inert dust. in animals.2 In mice, the LD50 of hafnyl
The 2003 ACGIH threshold limit value- chloride by intraperitoneal injection was
time-weighted average (TLV-TWA) for 112 mg/kg.2 In cats, intravenous administration
synthetic graphite (except graphite ber) is of hafnyl chloride at 10 mg/kg was fatal. Rats
2 mg/m3. fed a diet containing 1% for 12 weeks showed
slight changes in the liver, consisting of perin-
uclear vacuolization of the parenchymal cells
REFERENCES and coarse granularity of the cytoplasm.1 The
application of 1 mg of hafnium chloride to the
1. Lister WB, Wimborne D: Carbon pneumoco- eyes of rabbits produced transient irritation.
niosis in a synthetic graphite worker. Br J Ind Topical application of hafnium chloride crystals
Med 29:108110, 1972 to unabraded rabbit skin produced transient
2. Hanoa R: Graphite pneumoconiosis. A review
edema and erythema; application to abraded
of etiologic and epidemiologic aspects. Scand J
skin caused ulceration.2
Work Environ Health 9:303314, 1983
3. Petsonk EL: Pneumoconiosis in carbon Cell proliferation and benign local tumors
electrode workers. J Occup Med 30:887891, occurred in mice given a single intradermal
1988 injection of hafnium oxychloride.3 Hafnocene
dichloride induced DNA adducts when incu-
bated with mammalian DNA.3
The 2003 ACGIH threshold limit
value-time-weighted average (TLV-TWA) is
0.5 mg/m3.
HAFNIUM (and compounds)
CAS: 7440-58-6
REFERENCES
Hf
1. MCA, Inc.: Chemical Safety Data Sheet, SD-92,
Zirconium and Hafnium Powder, pp 510.
Washington, DC, MCA, Inc, 1966
Compounds: Hafnium chloride (HfCl4); 2. Haley TJ, Raymond K, Komesu N, Upham
hafnyl chloride (HfOCl4); hafnium dioxide HC: The toxicologic and pharmacologic ef-
(HfO2) fects of hafnium salts. Toxicol Appl Pharmacol 4:
238246, 1962
Physical Form. Hard, shiny, ductile stainless 3. BIBRA Working Group: Toxicity Prole.
steel-colored metal or dull gray powder Hafnium and its Compounds. pp 15. British
Industrial Biological Research Assoc.,
Uses/Sources. Obtained in mining and Carshalton, England, 1994
purication of the metal; used in control rods
in nuclear reactors and in manufacture of
364 HALOTHANE
HELIUM HEPTACHLOR
CAS: 7440-59-7 CAS: 76-44-8
He C10H5Cl7
9 expected), but this was not statistically Registry (ATSDR): Toxicological Prole for
signicant.6 Heptachlor/Heptachlor Epoxide. TP-92/11,
The IARC has determined that there is 131pp. US Department of Health and
sufcient evidence in experimental animals for Human Services, Public Health Service, 1993
the carcinogenicity of heptachlor and there 6. Wang HH, MacMahon B: Mortality of
workers employed in the manufacture of
is inadequate evidence of carcinogenicity in
chlordane and heptachlor. J Occup Med 21:
humans.7 Heptachlor is considered possibly 745748, 1979
carcinogenic to humans.7 7. IARC Monographs on the Evaluation of the Car-
Heptachlor was not mutagenic in bacterial cinogenic Risk of Chemicals to Humans, Vol 79,
assays, but it did cause gene mutations in Some thyrotropic agents, pp 41192. Lyon,
rodent cells and unscheduled DNA synthesis in International Agency for Research on
human broblasts.7 Cancer, 2001
Prenatal and perinatal exposure to hep- 8. Moser VC, McDaniel KL, Harris MW, et al:
tachlor has resulted in developmental effects. Neurobehavioral and cognitive outcomes of
Rats exposed from gestational day 12 up to perinatal/juvenile exposure to heptachlor in
postnatal day 42 (at 3 mg/kg/day) had persist- rats. Neurotoxicology 22(1):148149, 2001
9. Purkerson-Parker S, McDaniel KL, Moser
ent neurobehavioral changes, most notably in
VC: Effects of developmental exposure to
spatial learning and memory.8 There were also heptachlor on the cholinergic system in rats.
alterations in the cholinergic system as evi- Toxicologist 66(1-S):131, 2002
denced by a signicant decrease in muscarinic 10. Dodson SM, Landreth KS, Piktel DA, et al:
acetylcholine receptors.9 In mice, prenatal Hematotoxic effects of prenatal exposure to
exposure resulted in changes in hematopoietic heptachlor. Toxicologist 60(1):215, 2001
progenitor cell numbers as measured by
colony-forming cell assays.10
The 2003 ACGIH threshold limit
value-time-weighted average (TLV-TWA) for
heptachlor is 0.05 mg/m3 with an A3-animal
carcinogen designation and a notation for skin HEPTACHLOR EPOXIDE
absorption. CAS: 1024-57-3
C10H5Cl7O
REFERENCES
Synonyms: Epoxyheptachlor; 1,4,5,6,7,8,8a-
1. Hayes WJ Jr: Pesticides Studied in Man,
pp 233234. Baltimore, MD, Williams & heptachloro-2,3-epoxy-3a,4,7,7a-tetra-hydro-
Wilkins, 1982 4,7-methanoindene
2. von Oettingen WF: The Halogenated
Aliphatic, Olenic, Cyclic, Aromatic, and Physical Form. White crystalline solid
Aliphatic-Aromatic Hydrocarbons Including the
Halo-genated Insecticides, Their Toxicity and Sources. Not commercially produced;
Potential Dangers, US Public Health Service formed as a metabolite of heptachlor in
Pub No 414, pp 326327. Washington, DC, mammals
US Government Printing Ofce, 1955
3. Mestitzova M: On reproduction studies and
Exposure. Consequent to exposure to
the occurrence of cataracts in rats after long-
heptachlor
term feeding of the insecticide heptachlor.
Experientia 23:4243, 1967
4. Council on Pharmacy and Chemistry: The Toxicology. Heptachlor epoxide is a liver
present status of chlordane. JAMA 158: carcinogen in rodents.
13641367, 1955 Heptachlor epoxide is a metabolic product
5. Agency for Toxic Substances and Disease of heptachlor.1
368 n-HEPTANE
Heptachlor epoxide is more toxic then 2. Agency for Toxic Substances and Disease
heptachlor.2 The acute oral LD50 for hep- Registry (ATSDR): Toxicological Prole for Hep-
tachlor epoxide in rodents and rabbits ranged tachlor/Heptachlor Epoxide, TP-92/11, 131pp.
from 39 to 144 mg/kg.2 After dietary exposure US Department of Health and Human Ser-
of rats, heptachlor epoxide caused hepatic cell vices, Public Health Service, 1993
3. IARC Monographs on the Evaluation of the Car-
vacuolization at all dose levels (0.510 ppm for
cinogenic Risk of Chemicals to Humans, Vol 79,
up to 108 weeks). Degeneration, hepatomegaly, Some thyrotropic agents, pp 41192. Lyon,
and regeneration were also reported. Like International Agency for Research on Cancer,
heptachlor, the ability of heptachlor epoxide 2001
to induce lethality after acute exposure may
involve its ability to interfere with nerve action
or release of neurotransmitters and to inhibit
the function of the receptor for g-aminobutyric
acid.2
In two three-generation studies with rats n-HEPTANE
administered heptachlor, heptachlor epoxide, CAS: 142-82-5
or a mixture of the two in the diet, the number
of resorbed fetuses increased and the fertility CH3(CH2)5CH3
decreased with succeeding generations. No
adverse effects on reproductive capacity were
reported in male mice receiving single oral Synonyms: Dipropyl methane; heptyl hydride;
doses of 7.5 or 15 mg/kg heptachlor : hep- heptane
tachlor epoxide (25% : 75%) in a dominant
lethal assay.2 Heptachlor epoxide has been Physical Form. Volatile, ammable liquid
found in tissues of stillborn infants, indicating
transplacental transfer.2 Uses. As standard in testing knock of gaso-
Mice fed heptachlor epoxide in the diet at line engines; solvent
10 mg/kg for 24 months showed a signicant
excess of liver carcinomas. In another study, Exposure. Inhalation
an excess of liver carcinomas was observed in
female rats given 5 and 10 mg/kg in the diet.3 Toxicology. n-Heptane causes central ner-
The IARC has concluded that there is suf- vous system depression.
cient evidence that heptachlor epoxide is car- Human subjects exposed to 1000 ppm
cinogenic in experimental animals and that it is for 6 minutes, or to 2000 ppm for 4 minutes,
possibly carcinogenic to humans.3 The major- reported slight vertigo.1 At 5000 ppm for
ity of genotoxic assays suggest that heptachlor 4 minutes, effects included marked vertigo,
epoxide is not genotoxic.2 inability to walk a straight line, hilarity, and
The 2003 ACGIH threshold limit incoordination, but there were no complaints
value-time-weighted average (TLV-TWA) for of eye, upper respiratory tract, or mucous
heptachlor epoxide is 0.05 mg/m3 with an A3- membrane irritation. In some subjects, a 15-
conrmed animal carcinogen designation with minute exposure at 5000 ppm produced a state
unknown relevance to humans and a notation of stupor lasting for 30 minutes after exposure.
for skin absorption. These subjects also reported loss of appetite,
slight nausea, and a taste resembling gasoline
for several hours after exposure.
REFERENCES Dermal application resulted in immediate
irritation characterized by erythema and
1. Hayes WJ Jr: Pesticides Studied in Man, hyperemia. The subjects complained of painful
pp 233234. Baltimore, MD, Williams & burning sensation, and, after 5 hours, blisters
Wilkins, 1982 formed on the exposed areas.2
HEXACHLOROBENZENE 369
children born to porphyric mothers did not demonstrated in rats after exposure to up to
survive.2 Other manifestations included the 120 mg/kg/day during organogenesis. Cleft
development of a condition resembling por- palate and renal agenesis were observed in
phyria cutanea tarda, with abnormal porphyrin mice at 100 mg/kg/day.1 Parameters such as
metabolism and skin lesions, hyperpigmenta- fertility index and gestational indices have
tion, liver enlargement, hirsutism, short stature not been affected in rats at HCB doses up to
(in affected children), thyroid enlargement, 40 ppm.8
painless arthritis, and neurological ndings, No excess of cancer was reported in two
including weakness, paresthesias, cog wheeling, follow-up studies of affected individuals in
and myotonia.3 A study of 32 of the affected Turkey about 2030 years after consumption
individuals demonstrated that abnormal por- of contaminated grain had ceased.9,10 In mice,
phyrin metabolism and symptoms persisted liver tumors were observed after exposure to
20 years after HCB ingestion.1 More recent HCB at 1224 mg/kg/day in the diet, but not
occupational studies have also associated in- at 6 mg/kg/day.1 Hepatomas, hepatocellular
halation of HCB with immunologic effects carcinomas, bile duct adenomas, and renal cell
including decreased neutrophil activity and adenomas were observed in rats after dietary
increased immunoglobulins and susceptibility administration.11 Liver tumors were also
to infection.2 observed in 100% of surviving females and
In rodents, the liver is a primary target 16% of males after dietary administration to
organ for HCB effects. Exposure to 2000 ppm rats for 90 weeks. In another study, increased
in the diet caused increased porphyrin levels, incidence of parathyroid adenomas and adrenal
microscopic lesions in the liver, elevation of pheochromocytomas were observed in male
serum enzyme levels, and induction of liver and female rats and liver neoplastic nodules
microsomal enzymes.4 Male rats exposed at in females of the F1 generation in a two-
40 ppm in the diet for 130 weeks developed generation feeding study.
chronic nephrosis, and renal tubular damage The IARC has determined that there is
was noted in rats exposed to 10 mg/kg/day for sufcient evidence for carcinogenicity of HCB
15 weeks.5 Nephropathy is dependent upon the in experimental animals and that it is possibly
presence of a2u-globulin and is specic to male carcinogenic to humans.11
rats.6 Exposure of animals to 100, 200, or In an in vivo experiment in rats, HCB did
500 ppm in the diet caused a 2.5- to 3-fold not induce dominant lethal mutations. Chro-
increase in thyroid size.7 HCB has been mosomal aberrations were not induced in cul-
demonstrated to cause hyperparathyroidism tured Chinese hamster ovary cells, nor were
and osteosclerosis in another study of rats.5 mutations induced in bacteria.2,11 HCB does
HCB is immunotoxic in a number of animal not appear to be genotoxic.
studies, interfering with humoral and cellular In animal studies, HCB is not a skin or eye
immune functions in dogs, rats, mice, and irritant and does not sensitize the guinea pig.12
monkeys.2 The 2003 ACGIH threshold limit
There is no information on in utero devel- value-time-weighted average (TLV-TWA) for
opmental effects in humans exposed to HCB, hexachlorobenzene is 0.002 mg/m3 with an A3-
but oral exposure of young children has caused conrmed animal carcinogen with unknown
small or atrophied hands, short stature, relevance to humans designation and a notation
pinched facies, osteoporosis of the carpal, for skin absorption.
metacarpal, and phalangeal bones, and painless
arthritic changes.2 HCB has been demon-
strated to cross the placenta in humans and in REFERENCES
rodents.1 HCB residues have been detected in
human milk and adipose tissue and in the blood 1. IARC Monographs on the Evaluation of Car-
of the umbilical cord of newborn infants and cinogenic Risk to Humans, Vol 20, Some halo-
their mothers. Teratogenic effects were not genated hydrocarbons, pp 155178. Lyon,
HEXACHLOROBUTADIENE 371
whereas those exposed to 1 ppm were not HCBD intermediates formed in the kidney
adversely affected.4 may account for HCBD-induced renal
A 30-day dietary study at 30, 65, and carcinogenesis.8
100 mg/kg/day in rats found renal toxicity in Reproductive indices, including pregnancy
the form of increased kidney-to-body weight rate, gestational survival, neonatal survival, or
ratio and renal tubular degeneration, necrosis, morphologic alterations in neonates were not
and regeneration. Other adverse effects in- affected when male and female rats were fed up
cluded reduced body weight gain at 10 mg/ to 20 mg/kg/day for 90 days before mating and
kg/day and minimal hepatocellular swelling at during gestation and lactation.9
100 mg/kg/day.2 The 2003 ACGIH threshold limit value-
In a chronic dietary study, ingestion by rats time-weighted average (TLV-TWA) for hexa-
of 20 mg/kg/day for up to 2 years resulted chlorobutadiene is 0.02 ppm (0.24 mg/m3) with
in a statistically signicant increase in renal a notation for skin absorption and an A3-
tubular adenomas and adenocarcinomas, some conrmed animal carcinogen with unknown
of which metastasized to the lungs.5 Other relevance to humans designation.
toxicological effects included decreased body
weight gain, increased mortality, increased
excretion of urinary coproporphyrin, increased REFERENCES
terminal weights of the kidneys, and increased
renal tubular epithelial hyperplasia. At the 1. IARC Monographs on the Evaluation of the Car-
intermediate dose level of 2.0 mg/kg/day, cinogenic Risk of Chemicals to Man, Vol 20, Some
halogenated hydrocarbons, pp 179193. Lyon,
effects were limited to an increased excretion
International Agency for Research on Cancer,
of urinary coproporphyrin and increased
1979
hyperplasia of the renal tubular epithelium. 2. Kociba RJ, Schwetz BA, Keyes DG, et al:
Lifetime ingestion of the lowest dose level of Chronic toxicity and reproductive studies of
0.2 mg/kg/day caused no treatment-related hexachlorobutadiene in rats. Environ Health
effects. Perspect 21:4953, 1977
HCBD did not produce skin tumors after 3. Gage JC: The subacute inhalation toxicity of
repeated application or show initiating activity 109 industrial chemicals. Br J Ind Med 27:
in a two-stage initiation-promotion study in 115, 1970
mice.6 4. Dow Chemical Co (Midland, MI) unpublished
The IARC has determined that there is data: Cited by Torkelson TR and Rose VK. In
Clayton G, Clayton FE (eds): Pattys Industrial
limited evidence for the carcinogenicity of
Hygiene and Toxicology, 3rd ed, rev, Vol 2B,
HCBD in experimental animals and that it
Toxicology, p 3582. New York, Wiley-
is not classiable as to its carcinogenicity in Interscience, 1981
humans.6 5. Kociba RJ, Keyes DG, Jersey GC, et al:
Studies of the mutagenicity of HCBD and Results of a two year chronic toxicity study
its metabolites concluded that HCBD exerts with hexachlorobutadiene in rats. Am Ind Hyg
genotoxic effects after metabolic activation.7 Assoc J 38:589602, 1977
This hypothesis may be important for the 6. IARC Monographs on the Evaluation of the Car-
evaluation of the carcinogenic potential, as cinogenic Risk to Humans, Vol 73, Some chem-
it is generally accepted that a minimum risk icals that cause tumours of the kidney or
threshold for genotoxic substances cannot urinary bladder in rodents, and some other
substances, pp 27794. Lyon, International
be assigned. Alternatively, it has also been
Agency for Research on Cancer, 1999
reported that HCBD induces little genotoxic-
7. Reichert D, Neudecker T, Schutz: Mutagenic-
ity in vivo and that renal tumors have been ity of hexachlorobutadiene, perchlorobutenoic
observed only at doses that induce severe acid and perchlorobutenoic acid chloride.
chronic nephrosis. Accordingly, chronic cyto- Mutat Res 137:8993, 1984
toxicity to the renal proximal tubular cells by 8. Dekant W, Vamvakas S, Anders MW: Bioacti-
HEXACHLOROCYCLOPENTADIENE 373
vation of hexachlorobutadiene by glutathione threshold limit values did not lead to clinically
conjugation. Food Chem Toxicol 28:285293, signicant effects on the liver or kidney as
1990 determined by biochemical function tests.3
9. Schweitz BA, Norris JM, Kociba RJ, et al: Hexachlorocyclopentadiene appears to be
Results of a reproduction study in rats fed diets more toxic when inhaled than when ingested.4
containing hexachlorobutadiene. Toxicol Appl
The reported oral LD50 is 425 mg/kg for rats
Pharmacol 42:387398, 1977
and 680 mg/kg for mice. The 4-hour LC50
values range from 1.6 to 3.5 ppm for rats and
mice. Rats, rabbits, and guinea pigs exposed to
0.15 ppm for 7 hours/day, 5 days/week, for 30
weeks survived.5 Exposure at 0.34 ppm caused
HEXACHLOROCYCLOPENTADIENE death in mice and rats after 20 exposures.
CAS: 77-47-4 Effects observed were lacrimation, salivation,
gasping respiration, and tremor. Severe pul-
C5Cl6 monary edema and acute necrotizing bron-
chitis and bronchiolitis were evident, as were
degenerative changes in the brain, heart, liver,
Synonyms: HCCPD; HCCP; HEX; per- adrenal glands, and kidneys. The liquid on the
chlorocyclopentadiene skin of monkeys caused severe irritation.5
Exposure of rats to 0.5 ppm 6 hours/day,
Physical Form. Yellow to amber-colored 5 days/week, for 2 weeks caused lesions in
liquid the olfactory and bronchiolar epithelium along
with inammatory exudate in the lumens of the
Uses. Intermediate in the manufacture of respiratory tract.6
chlorinated pesticides; intermediate in the In a 13-week oral gavage study in rats and
manufacture of ame retardants mice at doses up to 150 mg/kg/day, there was
irritation of the forestomach in both sexes of
Exposure. Inhalation both species and a high incidence of toxic
nephrosis in the females only of both species.7
Toxicology. Hexachlorocyclopentadiene is a There was no evidence of carcinogenicity
lacrimator and severe irritant of the mucous in rats or mice exposed to 0.01, 0.05, or 0.2 ppm
membranes, respiratory tract, and skin. for 6 hours/day for 2 years.8 Pigmentation of
A large amount of hexachlorocyclopenta- the respiratory epithelium occurred in both
diene was dumped into a municipal sewage species, and squamous metaplasia of the laryn-
system and caused exposure to 145 sewage geal epithelium occurred in female rats. Geno-
treatment workers.1,2 Exposures were estimated toxic assays have been uniformly negative.
to range from less than 0.05 ppm to 20 ppm No evidence of teratogenicity was found
for several seconds to 15 minutes. The major after oral exposure in three species.4
complaints were eye irritation, headache, and The 2003 ACGIH threshold limit
throat irritation. Medical examination of 41 value-time-weighted average (TLV-TWA) is
workers 3 days after the exposure showed pro- 0.01 ppm (0.11 mg/m3).
teinuria and elevation of serum lactic dehydro-
genase levels. These ndings had resolved 3
weeks later.
REFERENCES
In a recent study of male operators
employed in a chemical plant, it was concluded 1. Morse DL, Kominsky JR, Wisseman CL,
that long-term exposure to a mixture of chlo- Landrigan PJ: Occupational exposure to hexa-
rinated hydrocarbons, including hexachlorocy- chlorocyclopentadiene. How safe is sewage?
clopentadiene, below or near the current JAMA 241:21772179, 1979
374 HEXACHLOROETHANE
2. Kominsky JR, Wisseman CL, Morse DL: Toxicology. Hexachloroethane is an eye irri-
Hexachlorocyclopentadiene contamination of tant and causes kidney and central nervous
a municipal waste-water treatment plant. Am system effects in animals. At high doses, it is
Ind Hyg Assoc J 41:5526,1980 carcinogenic to mice.
3. Boogaard PJ, Rocchi, PSJ, van Sittert NJ: Exposure of workers to fumes from hot
Effects of exposure to low concentrations of
hexachloroethane resulted in blepharospasm,
chlorinated hydrocarbons on the kidney and
liver of industrial workers. Br J Ind Med 50: photophobia, lacrimation, and reddening of the
331339, 1993 conjunctiva but no corneal injury or permanent
4. World Health Organization: Hexachlorocy- damage.1 No chronic effects have been re-
clopentadiene. Environmental Health Criteria ported from industrial exposure, although sig-
120. pp 1126. Geneva, International nicant skin absorption is said to occur.2
Programme on Chemical Safety (IPCS), Rats exposed to 5900 ppm for 8 hours
1991 showed ataxia, tremor, and convulsions and two
5. Treon JF, Cleveland FP, Cappel J: AMA Arch of six died.1 At 260 ppm for 8 hours there were
Ind Health 11:459, 1955 no toxic signs, but repeated exposure to this
6. Rand GM et al: Effects of inhalation exposure concentration 6 hours/day, 5 days/week caused
to hexachlorocyclopentadiene on rats and
tremor, red exudate around the eyes, and some
monkeys. J Toxicol Environ Health 9:743760,
1982 deaths after 4 weeks. Dogs exposed at 260 ppm
7. Abdo KM, Montgomery CA, Kluwe WM, developed tremor, ataxia, hypersalivation, and
et al: Toxicity of hexachlorocyclopentadiene: facial muscular fasiculations and held their
Subchronic (13-week) administration by eyelids closed during the exposure; three of
gavage to F344 rats and B6C3F1 mice. J Appl four survived 6 weeks of repeated exposures.
Toxicol 4:7581, 1984 No treatment-related effects were found in
8. National Toxicology Program: Toxicology and a number of species repeatedly exposed at
Carcinogenesis Studies of Hexachlorocyclopentadi- 48 ppm.1
ene (CAS No 77-47-4) in F344 Rats and B6C3F1 Rats fed 62 mg/kg/day for 16 weeks exhib-
Mice (Inhalation Studies), NTP TR 437, NIH ited no overt toxicity.2 Kidney effects char-
Pub No 93-3168. US Department of Health
acterized by increased kidney weights and
and Human Services, Public Health Service,
1994 microscopic changes (tubular atrophy, degen-
eration, hypertrophy and/or dilation) were
observed in males at 15 and 62 mg/kg/day; in
females tubular atrophy and degeneration of
the kidneys were observed only at the highest
dose. Both sexes also had increased liver
HEXACHLOROETHANE weights at 62 mg/kg/day.2
CAS: 67-72-1 The dermal LD50 for male rabbits was
greater than 32 g/kg.2 Applied to rabbit skin for
CCl3CCl3 24 hours, the dry material caused no skin irri-
tation whereas a water paste caused slight
redness.1 In the eyes of ve of six rabbits, 1 g of
Synonyms: Carbon hexachloride; perchlo- the crystal overnight caused moderate corneal
roethane opacity, iritis, severe swelling, and discharge.
Gavage administration of 590 and
Physical Form. Colorless crystals 1179 mg/kg/day to mice for 78 weeks caused a
signicant increase in the incidence of hepato-
Uses. Chemical intermediate in the manu- cellular carcinomas, whereas no increase in
facture of pyrotechnics, insecticides, and other these tumors was observed in rats given 212 or
chlorinated materials 423 mg/kg/day. A nonsignicant increase in
renal tumors was seen in rats, and tubular
Exposure. Inhalation; skin absorption nephropathy occurred in both species.3 In 2-
HEXACHLORONAPHTHALENE 375
year gavage studies, there was clear evidence of chloroethane in the rat. Drug Chem Toxicol
carcinogenicity in male rats administered 20 8:155169, 1985
mg/kg, 5 days/week, based on increased inci- 3. National Cancer Institute: Bioassay of Hexa-
dences of renal neoplasms.4 Marginally chloroethane for Possible Carcinogenicity, TR-68.
increased incidences of pheochromocytomas of DHEW Pub No (NIH) 781318. Washing-
ton, DC, US Government Printing Ofce,
the adrenal gland may also have been related to
1978
hexachloroethane administration in males. 4. National Toxicology Program: Toxicology and
There was no evidence of carcinogenicity for Carcinogenesis Studies of Hexachloroethane (CAS
female rats administered 80 or 160 mg/kg for No 67-72-1) in F344/N Rats (Gavage Studies).
the 2-year duration, although the severity of NTP TR 361 NIH Pub No 89-2816, pp
nephropathy was increased in dosed females as 1120. US Department of Health and Human
well as males.4 Services, 1989
The IARC has determined that there is 5. IARC Monographs on the Evaluation of the Car-
sufcient evidence for the carcinogenicity of cinogenic Risks of Chemicals to Humans, Vol 73,
hexachloroethane in animals and that it is Some chemicals that cause tumours of the
possibly carcinogenic to humans.5 Hexachlo- kidney of urinary bladder in rodents, and
some other substances, pp 295306. Lyon,
roethane was not mutagenic in a variety of in
International Agency for Research on Cancer,
vitro assays.6 1999
In limited studies hexachloroethane did 6. Agency for Toxic Substances and Disease
not appear to be a selective reproductive or Registry (ATSDR): Toxicology Prole for
developmental toxin at doses below those Hexachloroethane, pp 1146. Atlanta, GA, US
causing maternal toxicity.6 Department of Health and Human Services,
Hexachloroethane has a camphorlike Public Health Service, 1997
odor, readily sublimes, and, when heated to 7. Selden A, Nygren M, Kvarnlof A, et al:
decomposition, emits phosgene.1 Sublimation Biological monitoring of hexachloroethane.
of hexachloroethane may contribute to expo- Int Arch Occup Environ Health 65:S111S114,
sure control problems. Sedimented hexa- 1993
chloroethane dust may accumulate on
uorescent tube illuminators and other warm
surfaces and act as an exposure reservoir,
adding to exposure levels.7
Hexachloroethane exposure can be deter- HEXACHLORONAPHTHALENE
mined from blood plasma. In one group of CAS: 1335-87-1
workers, plasma levels increased nearly 100-
fold despite the use of personal protective C10H2Cl6
equipment.7
The 2003 ACGIH threshold limit value-
time-weighted average (TLV-TWA) is 1 ppm Synonyms: Halowax 1014
(9.7 mg/m3) with an A2-suspected human car-
cinogen designation and a notation for skin Physical Form. Waxy yellow-white solid
absorption.
Uses. In synthetic wax; in electric wire insu-
lation; in lubricants
REFERENCES
Exposure. Inhalation; skin absorption
1. Weeks MH, Angerhofer RA, Bishop R, et al:
The toxicity of hexachloroethane in laboratory Toxicology. Hexachloronaphthalene is toxic
animals. Am Ind Hyg Assoc J 40:187199, 1979 to the liver and causes chloracne.
2. Gorzinski SJ et al: Subchronic oral toxicity, Human fatalities due to acute yellow
tissue distribution and clearance of hexa- atrophy of the liver have occurred with
376 HEXAFLUOROACETONE
repeated exposure to penta- and hexachloron- facturing plant during World War II. Am J Ind
aphthalene.1,2 Air measurements showed Med 30(2):225233, 1996
concentrations averaging 12 mg/m3. Other 4. Ward EM, Ruder AM, Suruda A, Smith AB,
workers experienced jaundice, nausea, indiges- Fessler-Flesch CA, Zahm SH: Cancer mortal-
tion, and weight loss. ity patterns among female and male workers
employed in a cable manufacturing plant
The most common problem, a severe
during World War II. JOM 36(8):860866,
acneform dermatitis termed chloroacne, typi- 1994
cally occurs from long-term contact with 5. Deichmann WB: Halogenated cyclic hydro-
the fume or dust or shorter contact with the carbons. In Clayton GD, Clayton FE (eds):
hot vapor.3 The reaction is usually slow to Pattys Industrial Hygiene and Toxicology, 3rd ed,
appear and may take months to return to Vol 2B, Toxicology, pp 36693675. New York,
normal. Wiley-Interscience, 1981
An excess mortality of cirrhosis of the liver 6. World Health Organization: Concise Interna-
was observed in 9028 workers employed from tional Chemical Assessment Document (CICAD)
1940 to 1944 at a cable manufacturing plant 34, Chlorinated Napthalenes, pp 140. Geneva,
with chlorinated naphthalene exposure. Cir- 2001
rhosis deaths were similarly elevated in a sub-
cohort of 460 individuals who had shown
symptoms of chloracne.3 A cancer mortality
study of this same subcohort found an excess of
two rare causes of death, malignant neoplasm HEXAFLUOROACETONE
of the esophagus and benign and unspecied CAS: 684-16-2
neoplasms.4
Repeated exposure of rats to an average C3F6O
concentration of 8.9 mg/m3 of a mixture of
penta- and hexachloronaphthalene produced
jaundice and was fatal; the liver showed a Synonyms: HFA; acetone, hexauoro; per-
marked fatty degeneration and centrilobular uoro-2-propanone; peruoroacetone; 1,1,1,
necrosis.5 At 1.16 mg/m3, minor liver injury still 3,3,3-hexauoro-2-propanone
occurred.
Cattle developed severe systemic disease Physical Form. Colorless gas, which reacts
(bovine hyperkeratosis) during a 5- to 10-day vigorously with water to form hydrates
oral exposure to 1.72.4 mg/kg/day of the
higher-chlorinated napthalenes.6 Uses. In the synthesis of polymer, pharma-
The 2003 ACGIH threshold limit value- ceutical, and agricultural chemicals; solvent for
time-weighted average (TLV-TWA) for hexa- polyamides, polyesters, and polyacetals; in the
chloronaphthalene is 0.2 mg/m3 with a notation synthesis of hexauoroisopropanol
for skin absorption.
Exposure. Inhalation; skin absorption
whereas the trachea, spleen, liver, kidney, and The liquid is a severe skin irritant; one
urinary bladder appeared normal.2 drop of the dihydrate produced marked ery-
The oral LD50 for the trihydrate in rats is thema and blanching to guinea pig skin, but
190 mg/kg; moderate signs of central nervous no irritation was seen when diluted to 10%.1,3
system depression were observed that abated in Instilled in rabbit eyes hexauoroacetone
the survivors after 2 days.2 sesquihydrate produced severe, extensive injury
LC50 values of 900, 570, 275, and 200 ppm including corneal opacity, scar tissue, and
have been reported in rats for exposure times chronic conjunctivitis.
of 0.5, 1, 3, and 4 hours, respectively.1 Expo- The 2003 ACGIH threshold limit value-
sure of rats to 200 ppm or above for 4 hours time-weighted average (TLV-TWA) for hexa-
caused injury to the liver, kidneys, and thymus.3 uoroacetone is 0.1 ppm (0.68 mg/m3) with a
Pulmonary edema and congestion were seen notation for skin absorption.
in the lungs, and surviving males had testicles
that were small on gross examination and
microscopically showed aspermatogenesis, de- REFERENCES
struction of the stem cells, and effects on the
interstitial tissue. 1. Kennedy GL Jr: Toxicology of uorine-
Exposure of rats and beagle dogs to 12 ppm containing monomers. Crit Rev Toxicol 21:
for 6 hours/day, 5 days/week for 13 weeks pro- 149170, 1990
2. Borzelleca JF, Lester D: Acute toxicity of some
duced severe testicular damage and slight
perhalogenated acetones. Toxicol Appl Pharma-
hypoplasia of the spleen, thymus, lymph nodes,
col 7:592, 1965
and bone marrow.4 In the rats both immature 3. EI du Pont de Nemours & Co, Inc: Inhalation
and mature spermatids no longer appeared in toxicity of hexauoroacetone compounds.
the seminiferous tubules; no spermatozoa were Haskell Laboratory Report No 46-62. Wilming-
noted in the epididymal tubules.5 Normal sper- ton, DE, January 25, 1962
matogenesis was only partly restored at 84 days 4. EI du Pont de Nemours & Co, Inc: Thirteen
after exposure.5 Similar exposure at 0.1 ppm week inhalation exposures of rats and dogs to
caused no effects. hexauoroacetone (HFA). Haskell Laboratory
Hexauoroacetone sesquihydrate was ap- Report No 4-71. Wilmington, DE, January 7,
plied dermally to male rats at doses of 13, 39, 1971
5. Lee KP, Kennedy GL Jr: Testicular toxicity of
or 130 mg/kg/day for 14 days.6 All rats devel-
rats exposed to hexauoroacetone (HFA) for
oped severe testicular atrophy at the highest
90 days. Toxicology 67(3):249265, 1991
dose, whereas 50% of the animals at the 6. Gillies PJ, Lee KP: Effects of hexauoroace-
medium dose had the same effects. No effects tone on testicular morphology and lipid
were observed at the low dose. metabolism in the rat. Toxicol Appl Pharmacol
In a teratology study, hexauoroacetone 68:188197, 1983
trihydrate was applied to the skin of pregnant 7. Brittelli MR, Culik R, Dashiell OL,
rats from days 6 to 16 of gestation.7 Teratogenic Fayerweather WE: Skin absorption of hexa-
effects were seen at 5 and 25 mg/kg/day and uoroacetone: Teratogenic and lethal effects in
consisted of gross external, internal soft the rat fetus. Toxicol Appl Pharmacol 47:3540,
tissue, and skeletal abnormalities. Malforma- 1979
8. Mullin LS, Valentine R, Chromey NC: Hexa-
tions (soft cleft palate), external variations
uoroacetone developmental toxicity in rats.
(edema and subcutaneous hemorrhages),
Toxicologist 10(1):41, 1990
delayed ossications, and skeletal variations
(extra ribs) were increased in rats exposed by
inhalation to 7 ppm, 6 hours/day on gestation
days 716.8 Fewer live fetuses, increased
resorptions, and lower fetal weights were also
observed. Dams exhibited no signs of maternal
toxicity except for increased liver weights.
378 HEXAMETHYLENE DIISOCYANATE
found that sensory functions were regained 2,5-hexanedione levels have been attributed to
earlier than motor functions and that abnormal variable use of protective clothing.
color vision and muscle atrophy persisted up to The neurotoxic properties of n-hexane are
4 years.7 potentiated by exposure to methyl ethyl ketone
One anecdotal report has suggested that (qv). Because other compounds may also have
prolonged exposure (30 years) to low-grade this effect, human exposure to mixed solvents
levels of n-hexane (10100 mg/m3) may also containing any neurotoxic hexacarbon com-
cause polyneuropathy.8 pound should be minimized.9
Experimental animals continuously ex- The 2003 ACGIH threshold limit
posed to pure n-hexane developed the same value-time-weighted average (TLV-TWA) for
clinical, electrophysiological, and histopatho- n-hexane is 50 ppm (176 mg/m3).
logic changes found in humans exposed to
mixed vapors containing n-hexane.9 Continu-
ous inhalation by rats of 400 ppm caused axon-
apathy.10 In contrast, intermittent exposure REFERENCES
of rats to 10,000 ppm 6 hours/day, 5 days/week
for 13 weeks caused only slight paranodal 1. Patty FA, Yant WP: Report of Investigations
axonal swelling.11 It is postulated that 2,5- Odor Intensity and Symptoms Produced by Com-
hexanedione, a metabolite of n-hexane and mercial Propane, Butane, Pentane, Hexane, and
purported neurotoxic agent, must build to an Heptane Vapor, No 2979. US Dept of Com-
merce, Bureau of Mines, 1929
effective concentration. With continuous
2. Drinker P, Yaglou CP, Warren MF: The
exposure there is no recovery during each day
threshold toxicity of gasoline vapor. J Ind Hyg
or week. Toxicol 25:225232, 1943
Chronic exposure to commercial hexane 3. Elkins HB: Chemistry of Industrial Toxicology,
solvent (51% n-hexane) at concentrations up to p 101. New York, John Wiley & Sons,
9000 ppm was not carcinogenic to F-344 rats 1959
or to male B6C3F1 mice but did result in an 4. National Institute for Occupational Safety
increased incidence of liver tumors in female and Health: Criteria for a Recommended
mice.12 It is unclear what components of the Standard . . . Occupational Exposure to Alkane
hexane mixture caused the neoplasms.13 (C5-C8). DHEW (NIOSH) Pub No 77-151.
In genotoxic assays, commercial hexane, Washington, DC. US Government Printing
Ofce, 1977
consisting of n-hexane and other six-carbon
5. Jorgensen NK, Cohr KH: n-Hexane and its
isomers, did not produce chromosomal muta-
toxicological effects. Scand J Work Environ
tions either in vitro or in vivo.14 Results have Health 7:157168, 1981
generally been negative in bacterial assays and 6. Chang YC: An electrophysiological follow up
in other mammalian cell assays.13 Morphologic of patients with n-hexane polyneuropathy.
alterations in sperm were noted in one inhala- Br J Ind Med 48: 1217, 1991
tion study in rats.13 7. Chang YC: Patients with n-hexane induced
In regard to reproductive effects, the o polyneuropathy: a clinical follow up. Br J Ind
nly difference found in rats exposed to 1000 Med 47:485489, 1990
ppm during gestation was in their offspring, 8. Barregard L, Sallsten G, Nordborg C, et al:
which weighed less than expected at ages 16 Polyneuropathy possibly caused by 30 years
of low exposure to n-hexane. Scand J Work
weeks.15
Environ Health 17: 205207, 1991
Urinary concentration of 2,5-hexanedione
9. Spencer PS, Schaumburg HH, Sabri MI,
has been used in the biological monitoring of et al: The enlarging view of hexacarbon
workers exposed to n-hexane and is considered and neurotoxicity. CRC Crit Rev Toxicol 7:
to be a reliable indicator of alveolar and per- 279356, 1980
cutaneous absorption.16 Variability between 10. Schaumburg NH, Spencer PS: Degeneration
environmental concentrations of n-hexane and in central and peripheral nervous systems
382 sec-HEXYL ACETATE
produced by pure n-hexane: An experimental similar exposure would cause the same effect in
study. Brain 99:183192, 1976 humans.
11. Cavender FL et al: A 13-week vapor inhala- Human volunteers exposed to 100 ppm for
tion study of n-hexane in rats with emphasis 15 minutes experienced eye irritation and
on neurotoxic effects. Fundam Appl Toxicol 4: objected to the odor and taste; nose and throat
191201, 1984
irritation occurred at levels greater than
12. Daughtrey W, Newton P, Rhoden R, et al:
Chronic inhalation carcinogenicity study of 100 ppm.1 No chronic or systemic effects in
commercial hexane solvent in F-344 rats and humans have been reported.
B6C3F1 mice. Toxicol Sci 48(1):2129, 1999 Four of six rats survived exposure to
13. Agency for Toxic Substances and Disease 4000 ppm for 4 hours, but 8000 ppm was lethal
Registry (ASTDR): Toxicological Prole for n- to all animals.2
Hexane pp 1230. US Department of Health The liquid was poorly absorbed through
and Human Services, Public Health Service, rabbit skin but did cause moderate irritation.2,3
1999 Little corneal injury resulted from eye
14. Daughtrey WC, Putman DL, Duffy J, instillation.3
et al: Cytogenetic studies on commercial The 2003 ACGIH threshold limit
hexane solvent. J Appl Toxicol 14:161165,
value-time-weighted average (TLV-TWA) for
1994
15. Bus JS et al: Perinatal toxicity and metabo- sec-hexyl acetate is 50 ppm (295 mg/m3).
lism of n-hexane in Fischer-344 rats after
inhalation exposure during gestation. Toxicol
Appl Pharmacol 511:295302, 1979 REFERENCES
16. Cardona A, Marhuenda D, Marti J, et al: Bio-
logical monitoring of occupational exposure 1. Silverman L, Schulte HF, First MW: Fur-
to n-hexane by measurement of urinary 2,5- ther studies on sensory response to certain
hexanedione. Int Arch Occup Environ Health industrial solvent vapors. J Ind Hyg Toxicol 28:
65:7174, 1993 262266, 1946
2. Smyth HF Jr, Carpenter CP, Weil CS, Pozzani
UC: Range-nding toxicity data. Arch Ind Hyg
Occup Med 10:6168, 1954
3. Carpenter CP et al: Range-nding toxicity
sec-HEXYL ACETATE data: List VIII. Toxicol Appl Pharmacol 28:
313319, 1974
CAS: 108-84-9
C8H16O2
HEXYLENE GLYCOL
Synonyms: Methyl amylacetate; 4-methyl CAS: 107-41-5
pentyl 2-acetate; 1,3-dimethylbutyl acetate;
methyl isoamyl acetate C6H14O2
Toxicology. sec-Hexyl acetate causes irrita- Uses. Fuel and lubricant additive; solvent in
tion of the eyes and upper respiratory tract; at cosmetics; solvent in petroleum rening; cou-
concentrations approaching saturation it causes pling agent in hydraulic brake uid and print-
narcosis in animals, and it is expected that ing inks; gasoline anti-icer additive
HMX 383
related growth depression; dogs also had animal carcinogen with unknown relevance to
increased mortality and developed depressed humans notation is assigned.
erythrocyte counts, hematocrit values, and
hemoglobin concentrations at higher doses;
there were no effects in monkeys.1 Lipid dep- REFERENCES
osition in the kidneys of monkeys has been
reported after intraperitoneal administration of 1. National Institute for Occupational Safety
hydrazine.1 and Health: Criteria for a Recommended
Studies in rats have shown that acute doses Standard Occupational Exposure to Hydrazines.
DHEW (NIOSH) 78-172. Washington, DC,
of hydrazine cause hepatic steatosis accom-
US Government Printing Ofce, June 1978
panied by depletion of ATP and reduced
2. Comstock CC, Lawson LH, Greene EA,
glutathione (GSH) and hepatic accumulation Oberst FW: Inhalation toxicity of hydrazine
of triglycerides. Biochemical effects from vapor. AMA Arch Ind Hyg Occup Med 10:
repeated exposure, however, included deple- 476490, 1954
tion of triglycerides and induction of nitrophe- 3. Sotanieme E et al: Hydrazine toxicity in the
nol hydroxylase activity in addition to changes humanreport of a fatal case. Ann Clin Res
in other microsomal enzymes.5 3:3033, 1971
Hydrazine or hydrazine salts are carcino- 4. Jacobson KG et al: The acute toxicity of the
genic in mice after oral administration (pul- vapors of some methylated hydrazine deriva-
monary adenocarcinoma; hepatocarcinoma) tives. Arch Ind Health 12:609616, 1955
5. Jenner AM, Timbrell JA: Effect of acute and
or intraperitoneal injection (pulmonary carci-
repeated exposure to low doses of hydrazine
noma) and in rats after oral administration
on hepatic microsomal enzymes and bio-
(pulmonary adenocarcinoma).6 Hydrazine in- chemical parameters in vivo. Arch Toxicol 68:
duced a signicantly greater incidence of nasal 240245, 1994
tumors, primarily benign, in rats and in ham- 6. IARC Monographs on the Evaluation of the
sters after 1 year of intermittent inhalation Carcinogenic Risk of Chemicals to Man, Vol 71,
exposure at levels up to 5.0 ppm.7 Re-evaluation of some chemicals, hydrazine
A group of 427 hydrazine facility workers and hydrogen peroxide, pp 9911013. Lyon,
followed through 1992 showed no increased International Agency for Research on
risk for lung cancer, cancer of the digestive Cancer, 1999
system, other cancers, or mortality from other 7. Vernot EH et al: Long-term inhalation
toxicity of hydrazine. Fundam Appl Toxicol
causes as compared with referent values,
5:10501064, 1985
regardless of the degree of exposure.8
8. Morris J, Densem JW, Wald NJ, et al:
In other case reports, choroidal melanoma Occupational exposure to hydrazine and
was observed in one man who had been subsequent risk of cancer. Occup Environ Med
exposed to hydrazine for 6 years, and chronic 52(1):4345, 1995
myeloid leukemia was reported in two patients 9. Albert DM, Puliato CA: Choroidal
with long-lasting exposure to hydrazine.9,10 melanoma: Possible exposure to industrial
Hydrazine induces gene mutations in bac- toxins. N Engl J Med 296:634635, 1977
teria, yeast and Drosophila, and in vivo treat- 10. Freund M, Eisert J, Anagnou J, et al: Zwei
ment of rodents results in the formation of Falle von chronisch myeloisher Leukamie
DNA adducts.6 mit Hydrazin-Exposition. Zbl Arbeitsmed 35:
375377, 1985
The IARC has determined that there is
sufcient evidence for the carcinogenicity of
hydrazine to animals and inadequate evidence
for humans.6
The 2003 ACGIH threshold limit
value-time-weighted average (TLV-TWA) for
hydrazine is 0.1 ppm (0.13 mg/m3) with a nota-
tion for skin absorption. An A3-conrmed
386 HYDROGENATED TERPHENYLS
sure of humans to 5 ppm for several minutes Relative acute toxicities of hydrogen uoride,
caused nose and throat irritation in most hydrogen chloride, and hydrogen bromide
persons, and a few were affected at concentra- in nose- and pseudo-mouth-breathing rats.
tions of 34 ppm.1 At 35 ppm irritation of the Fundam Appl Toxicol 16:636655, 1991
throat has been observed after short exposure;
more severe exposures result in pulmonary
edema and laryngeal spasm.2 Concentrations of
14002100 ppm were reported to be lethal in
exposures lasting a few minutes.2 Solutions in
contact with the eyes, skin, or mucous mem- HYDROGEN CHLORIDE
branes may cause burns.3 CAS: 7647-01-0
The 1-hour inhalation LC50 was 2860 ppm
for rats and 815 ppm for mice.4 Rats exposed to HCl
1300 ppm for 30 min and euthanized 24 hours
after exposure showed tissue injury conned to
the nasal region, including epithelial and sub- Synonyms: HCl; hydrochloric acid, aqueous;
mucosal necrosis, accumulations of inamma- muriatic acid
tory cells and exudates, and the extravasation
of erythrocytes.5 Intratracheal administration Physical Form. Colorless gas (aqueous solu-
of the same dose produced some mortality tion is hydrochloric acid)
and major tissue disruption in the trachea,
including epithelial, submucosal, glandular, Uses. Production of chlorinated organic
and cartilage necrosis, and accumulations of chemicals; production of dyes and dye inter-
inammatory cells and exudates. mediates; steel pickling; oil well acidizing
The 2003 ACGIH ceiling-threshold limit operations to dissolve subsurface dolomite or
value (C-TLV) for hydrogen bromide is 3 ppm limestone; formed during thermal decomposi-
(9.9 mg/m3). tion of PVC
Exposure. Inhalation
tion allowable for prolonged exposure.3 In one which chronic exposure to 10 ppm, 6 hours/day
study, workers chronically exposed to hydrogen for life did not cause any neoplastic lesions.11
chloride did not exhibit the pulmonary func- The IARC has determined that there is
tion changes observed in naive subjects exposed inadequate evidence for the carcinogenicity of
to similar concentrations; this observation sug- hydrogen chloride in experimental animals and
gests acclimatization of the workers to hydro- humans.10
gen chloride.4 Hydrogen chloride was not mutagenic in
Ten young adult asthmatics showed no bacteria, but it did cause chromosomal aberra-
adverse respiratory health effects after multiple tions in mammalian cell assays.10
inhalation challenge with 0.8 and 1.8 ppm Warning properties are good, and most
hydrogen chloride.5 people can detect 5 ppm.1
Exposure of the skin to a high concentra- The 2003 short-term excursion limit
tion of the gas or to a concentrated solution of (STEL)/ceiling for hydrogen chloride is 5 ppm
the liquid (hydrochloric acid) will cause burns; (7.5 mg/m3).
repeated or prolonged exposure to dilute
solutions may cause dermatitis.2 Erosion of
exposed teeth may also occur from repeated or REFERENCES
prolonged exposure. Although ingestion is
unlikely, hydrochloric acid causes severe burns 1. Committee on Medical and Biologic Effects
of the mouth, esophagus, and stomach with of Environmental Pollutants: Chlorine and
consequent pain, nausea, and vomiting.6 Hydrogen Chloride, pp 138144. Washington,
DC, National Academy of Sciences, 1976
Exposure of mice to 1300 ppm for 30
2. MCA, Inc.: Chemical Safety Data Sheet SD-39,
minutes caused tissue injury to the nasal region Hydrochloric Acid, pp 56, 2426. Washing-
including epithelial and submucosal necrosis ton, DC, MCA, Inc, 1970
and accumulations of inammatory cells and 3. Henderson Y, Haggard HW: Noxious Gases,
exudates.7 Mice administered the same concen- p 126. New York, Reinhold, 1943
tration by tracheal tubes (to simulate mouth 4. Toyama T, Kondo T, Nakamura K: Environ-
breathing) had major tissue damage in the ments in acid aerosol producing workplaces
trachea including epithelial, submucosal, glan- and maximum ow rate of workers. Jpn J Ind
dular, and cartilage necrosis; peripheral lung Health 4:1522, 1962
damage was manifested by histopathologic 5. Stevens B, Koenig JQ, Rebolledo V, et al:
changes in the larger conducting airways. Respiratory effects from the inhalation of
hydrogen chloride in young adult asthmatics.
Rodent studies may be of limited value in
JOM 34:923926, 1992
determining human effects because of their 6. Poteshman NL: Corrosive gastritis due to
increased sensitivity compared with primates. hydrochloric acid ingestion. Am J Roentgenol
A comparison of the lethality data indicates Radium Ther Nucl Med 99:182185, 1967
that the mouse (LLD = 3200 ppm, 5 min) 7. Stavert DM, Archuleta DC, Behr MJ, et al:
is more sensitive than the rat (LLD = Relative acute toxicities of hydrogen uoride,
15,25032,250 ppm, 5 min) or the baboon hydrogen chloride, and hydrogen bromide
(LLD = 16,57030,000 ppm, 5 min).8 For in nose- and pseudo-mouth-breathing rats.
longer exposure periods, the LLD for Fundam Appl Toxicol 16:636655, 1991
the rat and baboon also diverge: For a 8. Hinderer RK, Kaplan HL: Assessment of the
30-minute exposure, the LLD is less than inhalation toxicity of hydrogen chloride gas
to man, pp 24. Dangerous Properties of
3000 ppm for rats and greater than 5000 ppm
Industrial Materials Report, Van Nostrand
for baboons. Reinhold, Mar/Apr 1986
None of three US industry-based case- 9. Bond GG, Flores GH, Stafford BA, et al:
control studies suggested an association be- Lung cancer and hydrogen chloride expo-
tween exposure to hydrogen chloride and sure: results from a nested case control
cancers of the lung, brain, or kidney.9,10 This study of chemical workers. J Occup Med
result was consistent with a rodent bioassay in 33:958961, 1991
HYDROGEN CYANIDE 389
10. IARC Monographs on the Evaluation of the Car- duces lactic acidosis, the result of an increased
cinogenic Risk of Chemicals to Humans, Vol 54, rate of glycolysis and production of lactic
Occupational exposures to mists and vapours acid.3
from sulfuric acid and other strong inorganic A concentration of 270 ppm hydrogen
acids, pp 189211. Lyon, International cyanide has long been quoted as being imme-
Agency for Research on Cancer, 1992
diately fatal to humans. A more recent study,
11. Sellakumar AR, Snyder CA, Solomon JJ,
et al: Carcinogenicity of formaldehyde and however, states that the estimated LC50 to
hydrogen chloride in rats. Toxicol Appl Phar- humans for a 1-minute exposure is 3404 ppm.1
macol 81:401406, 1985 Others state that 270 ppm is fatal after 68
minutes, 181 ppm after 10 minutes, and
135 ppm after 30 minutes.1
If large amounts of cyanide have been
absorbed, collapse is usually instantaneous,
the patient falling unconscious, often with
HYDROGEN CYANIDE convulsions, and dying almost immediately.1,2
CAS: 74-90-8 Symptoms of intoxication from less severe
exposure include weakness, headache, confu-
HCN sion, vertigo, fatigue, anxiety, dyspnea, and
occasionally nausea and vomiting. Respiratory
rate and depth are usually increased initially,
Synonyms: Hydrocyanic acid; aero liquid and at later stages respiration becomes slow
HCN; prussic acid; formonitrile and gasping. Coma and convulsions occur in
some cases. If cyanosis is present, it usually
Physical Form. Colorless gas liquefying at indicates that respiration has either ceased or
26C (may be found in the workplace both as has been very inadequate for a few minutes.
a liquid and a gas) Hydrogen cyanide has recently been
recognized in signicant concentrations in
Uses. Rodenticide and insecticide; fumigant; some res, as a combustion product of wool,
chemical intermediate for the manufacture of silk, and many synthetic polymers; it may play
synthetic bers, plastics, and nitrites a role in toxicity and deaths from smoke
inhalation.4
Exposure. Inhalation; skin absorption; Most reported cases of chronic cyanide
ingestion poisoning involve workers with a mixture of
repeated acute or subacute exposures, making
Toxicology. Hydrogen cyanide can cause it unclear whether symptoms resulted simply
rapid death due to metabolic asphyxiation. from multiple acute exposures with acute
Cyanide ion exerts an inhibitory action intoxication or from prolonged, chronic expo-
on certain metabolic enzyme systems, most sure. Some symptoms persisted after cessation
notably cytochrome oxidase, the enzyme of such exposures, perhaps because of the effect
involved in the ultimate transfer of electrons of anoxia from inhibition of cytochrome
to molecular oxygen.1 Because cytochrome oxidase. Symptoms from chronic exposure are
oxidase is present in practically all cells that similar to those reported after acute exposures,
function under aerobic conditions, and because such as weakness, nausea, headache, and
the cyanide ion diffuses easily to all parts of the vertigo.1 A study of 36 former workers in a
body, cyanide quickly halts practically all cellu- silver reclaiming facility chronically exposed to
lar respiration. The venous blood of a patient cyanide demonstrated some residual symptoms
dying of cyanide poisoning is bright red and 7 or more months after cessation of exposure;
resembles arterial blood because the tissues frequent headache, eye irritation, easy fatigue,
have not been able to utilize the oxygen loss of appetite, and epistaxis occurred in at
brought to them.2 Cyanide intoxication pro- least 30% of these workers.5
390 HYDROGEN FLUORIDE
1. National Institute for Occupational Safety and Exposure. Inhalation; skin contact
Health: Criteria for a Recommended Standard
. . . Occupational Exposure to Hydrogen Cyanide Toxicology. Hydrogen uoride (HF), as a
and Cyanide Salts (NaCN, KCN, and Ca(CN)2).
gas, is a severe respiratory irritant and, in solu-
DHEW (NIOSH) Pub No 77-108, pp 3795,
106114, 170173, 178. Washington, DC, US tion, causes severe and painful burns of the skin
Government Printing Ofce, 1976 and eyes.
2. Gosselin RE, Smith RP, Hodge HC: Clinical From accidental, occupational, and volun-
Toxicology of Commercial Products, Section III, tary exposures, it is estimated that the lowest
5th ed. pp 123130. Baltimore, MD, Williams lethal concentration for a 5-minute human
& Wilkins, 1984 exposure to HF is in the range of 50250 ppm.1
3. Graham DL, Laman D, Theodore J, Robin The LC50 values for 5, 15, and 60 minutes are
ED: Acute cyanide poisoning complicated by considered to be 500800 ppm, 4501000 ppm,
lactic acidosis and pulmonary edema. Arch and 30600 ppm, respectively.1 Inhalation of
Intern Med 137:10511055, 1977 HF produces transient choking and coughing.
4. Becker CE: The role of cyanide in res. Vet
After an asymptomatic period of several hours
Hum Toxicol 27:487490, 1985
5. Blanc P et al: Cyanide intoxication among up to 12 days, fever, cough, dyspnea, cyanosis,
silver-reclaiming workers. JAMA 253:367 and pulmonary edema may develop.
371, 1985 Death from pulmonary edema occurred
6. Hygienic Guide Series: Hydrogen Cyanide. within 2 hours in three of six workers splashed
Am Ind Hyg Assoc J 31:116119, 1970 with 70% solution, despite prompt shower-
7. Agency for Toxic Substances and Disease Reg- ing with water. The HF concentration in the
istry (ATSDR): Toxicological Prole for Cyanides, breathing zone was estimated to be above
pp 1255. US Department of Health and 10,000 ppm.2 A chemist exposed to HF splashes
Human Services, Public Health Service, 1997 on the face and upper extremities developed
pulmonary edema 3 hours after exposure and
died 10 hours later.3 Persistent respiratory
symptoms, including hoarseness, coughing ts,
and nosebleeds, but with normal pulmonary
function, were observed in one subject who
survived a massive exposure. Acute renal failure
of uncertain cause has also been documented
after an ultimately fatal inhalation exposure.4
HYDROGEN FLUORIDE 391
effects of 10-minute exposure to hydrogen Exposure for a short period of time to mist
uoride in rats and derivation of a short-term or diffused spray may cause stinging of the eyes
exposure limit for humans. Regul Toxicol Phar- and lacrimation.1,2 Splashes of the liquid in the
macol 27(3):20716, 1998 eyes may cause severe damage including ulcer-
9. Largent EJ: FluorosisThe Health Aspects ation of the cornea; there may be a delayed
of Fluorine Compounds, pp 3439, 4348.
appearance of damage to the eyes, and corneal
Columbus, OH, Ohio State University Press,
1961 ulceration has, on rare occasions, appeared
10. Dibbell DG et al: Hydrouoric acid burns even a week or more after exposure.1
of the hand. J Bone Joint Surg 52A:931936, Skin contact with the liquid for a short
1970 time will cause a temporary whitening or
11. Reinhardt CF, Hume WG, Linch AL, bleaching of the skin; if splashes on the skin are
Wetherhold JM: Hydrouoric acid burn not removed, erythema and the formation of
treatment. Am Ind Hyg Assoc J 27:166171, vesicles may occur.1 Although ingestion is
1966 unlikely to occur in industrial use, it may cause
12. Wetherhold JM, Shepherd FP: Treatment irritation of the upper gastrointestinal tract;
of hydrouoric acid burns. J Occup Med 7: decomposition of the hydrogen peroxide will
193195, 1965
result in the rapid liberation of oxygen, which
13. Grant WM: Toxicology of the Eye, 3rd ed,
pp 490492. Springeld, IL, Charles C. may distend the esophagus or stomach and
Thomas, 1986 cause severe damage.
Repeated exposure of dogs to 7 ppm for
6 months caused sneezing, lacrimation, and
bleaching of hair; at autopsy, there was local
atelectasis.4
A number of investigators have shown that
HYDROGEN PEROXIDE (90%) hydrogen peroxide in vitro leads to genetic
CAS: 7722-84-1 damage and cell death through the formation
of free radicals.5 It is not known whether such
90% H2O2 damage presents a danger to the mammalian
organism or whether various enzymes protect
against damage.
Synonyms: Dihydrogen dioxide; Peroxide Chronic studies in mice found adenomas
and carcinomas of the duodenum after oral
Physical Form. Liquid administration. The IARC has determined that
there is limited evidence in experimental
Uses. Synthesis of compounds; bleaching animals for the carcinogenicity of hydrogen
agent, especially for textiles and paper; disin- peroxide and inadequate evidence in humans.6
fectant; rocket fuel An additional hazard is the possibility of
explosion when higher-strength hydrogen
Exposure. Inhalation peroxide is mixed with organic compounds
and violent decomposition if contaminated by
Toxicology. Hydrogen peroxide is an irritant metallic ions or salts.3 Because hydrogen
of the eyes, mucous membranes. and skin. peroxide is such a strong oxidizer, it can set
In humans, inhalation of high concentra- re to combustible materials when spilled on
tions of vapor or mist may cause extreme them.3
irritation and inammation of the nose and The 2003 ACGIH threshold limit value-
throat.1,2 Severe systemic poisoning may also time-weighted average (TLV-TWA) is 1 ppm
cause headache, dizziness, vomiting, diarrhea, (1.4 mg/m3).
tremors, numbness, convulsions, pulmonary
edema, unconsciousness, and shock.3
HYDROGEN SELENIDE 393
2. Buchan RF: Industrial selenosis. J Occup Med slightly lower levels the gas may be rapidly
3:439456, 1947 absorbed through the lungs into the blood,
3. Banerjee BD, Dwivedi S, Singh S: Acute which initially induces hypernea followed by
hydrogen selenide gas poisoning admissions apnea.
in one of the hospitals in Delhi, India: case The sequelae of acute poisoning appear
report. Hum Exp Toxicol 16:2768, 1997
to be quite variable and depend on duration of
4. Hygienic Guide Series: Hydrogen selenide.
Am Ind Hyg Assoc J 20:514515, 1959 exposure as well as level of exposure. Patients
5. Levy LS, Shackleton S, Smillie MV: Criteria who have been unconscious in high levels of
Document for Hydrogen Selenide Occupational hydrogen sulde atmosphere for longer than
Exposure Limits. pp 158, 1992 5 min may have persistent neurological and
neuropsychological impairment years after ex-
posure as a result of hydrogen sulde-induced
hypoxia.6
Subacute intoxication refers to the effects
caused by continuous exposure for up to several
HYDROGEN SULFIDE hours to concentrations ranging from 100 to
CAS: 7783-06-4 1000 ppm.15 Pulmonary edema is a potentially
fatal complication of intoxication and is com-
H2S mon after exposure to 250 ppm for prolonged
periods of time. Symptoms of gastrointestinal
disturbances, including nausea, abdominal
Synonyms: Sulfureted hydrogen; hydrosulfu- cramps, vomiting, and severe diarrhea, have
ric acid been reported and frequently occur in subacute
intoxication.
Physical Form. Gas Exposure to levels above 50 ppm for 1 hour
can produce acute conjunctivitis with pain,
Sources. By-product of many industrial lacrimation, and photophobia; in severe form,
processes; around oil wells and in areas where this can progress to keratoconjunctivitis and
petroleum products are processed, stored, or vesiculation of the corneal epithelium. Pro-
used; decay of organic matter; occurs naturally longed exposure to 50 ppm also causes rhinitis,
in coal, natural gas, oil, volcanic gases, and pharyngitis, bronchitis, and pneumonitis.
sulfur springs. Reports of adverse effects of hydrogen
sulde on humans due to chronic intoxication
Exposure. Inhalation are less well established. It has been postulated
that exposures below 50 ppm over long periods
Toxicology. Hydrogen sulde is an irritant may cause certain neuroasthenic symptoms
of the eyes and respiratory tract at low con- such as fatigue, headache, dizziness, and irri-
centrations; at higher levels, it causes respira- tability. Others suggest that the signs and
tory paralysis with consequent asphyxia and is symptoms referred to as chronic poisoning are
rapidly fatal. actually the results of recurring acute exposures
Hydrogen sulde intoxication in humans or the sequelae of acute poisoning.
has generally been categorized as acute, suba- A number of toxicological mechanisms
cute, or chronic, depending on the nature of have been proposed for hydrogen sulde: At
the predominant clinical signs and symptoms.1 extremely high concentrations it may exert a
Acute intoxication refers to the effects of a direct paralyzing effect on respiratory centers;
single exposure to massive concentrations that hydrogen sulde is also known to inhibit
rapidly produce signs of respiratory distress. cytochrome c oxidase, resulting in altered
Inhalation of 1000 ppm or more can cause oxidative metabolism; it can also disrupt
coma after a single breath and can be rapidly critical disulde bonds in essential cellular
fatal owing to respiratory paralysis.15 At proteins.5
HYDROQUINONE 395
REFERENCES C6H4(OH)2
Toxicology. Hydroquinone is moderately cant decits in total mortality and deaths due
toxic and primarily affects the eyes. to cancer.7
Acute exposure to quinone vapor and Oral LD50 values of 70, 200, and
hydroquinone dust causes conjunctival 550 mg/kg have been reported for cats, dogs,
irritation, whereas chronic exposure produces and guinea pigs, respectively.5 In 14-day
changes characterized as: (1) brownish discol- and 13-week studies mice administered up to
oration of the conjunctiva and cornea conned 500 mg/kg by gavage and rats administered
to the interpalpebral tissue; (2) small opacities up to 1000 mg/kg had lethargy, tremors, and
of the cornea; and (3) structural changes in the convulsions.8 The CNS, forestomach, and
cornea that result in loss of visual acuity.1,2 liver were identied as target organs in both
The pigmentation changes are reversible, but species, and renal toxicity was identied in
the more slowly developing structural changes rats.
in the cornea may progress. Pigmentation may In 2-year studies rats were given 0, 25, or
appear with less than 5 years of exposure, but 50 mg/kg hydroquinone by gavage 5 days/
this is uncommon and usually is not associated week whereas doses for mice were 0, 50, or
with serious injury to the eye.2 100 mg/kg on the same schedule.8 There was
Ingestion of 512 g of hydroquinone has evidence of carcinogenicity in male rats as indi-
been reported to be fatal.35 In one nonfatal cated by increased incidences of tubular cell
case of hydroquinone ingestion of approxi- adenomas of the kidney, in female rats as shown
mately 1 g, tinnitus, dyspnea, cyanosis, and by increases in mononuclear cell leukemia, and
extreme sleepiness were observed.3 Although in female mice based on increases in hepato-
acute, high-dose oral ingestion produces cellular neoplasms, mainly adenomas. There
noticeable central nervous system (CNS) was no evidence of carcinogenicity in male
effects in humans, no effects have been mice.
observed in workers exposed to lower concen- Pellets of cholesterol containing 2 mg of
trations in actual industrial situations.3 No hydroquinone implanted in mice bladders
signs of toxicity were found in subjects who caused an excessive number of bladder carci-
ingested 300500 mg hydroquinone daily for nomas.4 In other studies, rats fed up to 1%
35 months.6 hydroquinone in their diets for 2 years did not
Repeated skin contact with hydroquinone develop tumors, nor did hydroquinone initiate
creams (generally 5% or more hydroquinone) signicant numbers of tumors in mice skin
produced skin irritation, allergic sensitization, painting studies.3,4
dermatitis, and depigmentation.3 Excessive The IARC has determined that there is
use of skin-lightening preparations containing inadequate evidence in humans for the car-
hydroquinone has produced severe and irre- cinogenicity of hydroquinone and limited evi-
versible cutaneous damage.5 Deleterious effects dence in experimental animals.4
start with darkening and coarsening of the Pregnant rats given up to 300 mg/kg
skin, followed by a hyperpigmented papular hydroquinone by gavage on the 6th through
condition. Histologically there is increased 15th day of gestation had a slight but signi-
basophilia of the collagen, followed by the for- cant reduction in body weight gain and feed
mation of yellow bers that swell and break consumption. This effect was associated with
down to form an amorphous eosinophilic a slightly reduced mean fetal body weight, but
material. no other signicant effects were noted in
One mortality study of a cohort of workers the rat conceptus.9 In rabbits hydroquinone at
with at least 6 months exposure to hydro- 150 mg/kg on gestation days 618 produced
quinone at exposure concentrations of 0.1 minimal developmental alterations in the pres-
6.0 mg/m3 for the dust and from less than 0.1 ence of maternal toxicity.10 On the basis of
to 0.3 for the vapor (estimated 8-hour time- these studies it was concluded that hydro-
weighted averages) found statistically signi- quinone is not selectively toxic to the develop-
HYDROXYLAMINE (and Salts) 397
ing conceptus and does not appear to be a 10. Murphy SJ, Schroeder RE, Blacker AM et al:
developmental toxicant.9 A study of developmental toxicity of hydro-
Hydroquinone induces alterations of the quinone in the rabbit. Fundam Appl Toxicol 19:
DNA in eukaryotic cells (micronuclei, chro- 214221, 1992
mosomal aberrations and disintegrations) but is
nonmutagenic in Salmonella tester strains with
or without metabolic activation.5
The 2003 ACGIH threshold limit value-
time-weighted average (TLV-TWA) for HYDROXYLAMINE (and Salts)
hydroquinone is 2 mg/m3. CAS: 7803-49-8
NH2OH
REFERENCES
1. Anderson B, Oglesby F: Corneal changes Synonyms: Oxammonium; hydroxyl ammo-
from quinone-hydroquinone exposure. AMA nium
Arch Ophthalmol 59:495501, 1958
2. Sterner JH, Oglesby FL, Anderson B: Physical Form. Colorless akes or crystals.
Quinone vapors and their harmful effects. I.
Corneal and conjunctival injury. J Ind Hyg Uses. Reducing agent used in photographic
Toxicol 29:6073, 1947
processing, leather tanning, manufacturing of
3. National Institute for Occupational Safety
nylon and other polymers; as a stabilizer for
and Health: Criteria for a Recommended
Standard . . . Occupational Exposure to Hydro- natural rubber; to prevent the development of
quinone. DHEW (NIOSH) Pub No 78-155, objectionable tastes and odors during the ren-
p 182. Washington, DC, US Government ing of fatty materials.
Printing Ofce, 1978
4. IARC Monographs on the Evaluation of the Exposure. Inhalation
Carcinogenic Risk of Chemicals to Man, Vol 71,
Re-evaluation of some organic chemicals, Toxicology. Hydroxylamine and its salts are
hydrazine and hydrogen peroxide, pp 691 irritants of eyes, mucous membranes, and skin;
719. Lyon, International Agency for higher levels cause methemoglobinemia.
Research on Cancer, 1999
Workers exposed to hydroxylamine sulfate
5. Devillers J, Boule P, Vasseur P et al: Envi-
for 1 day at unspecied air levels showed blood
ronmental and health risks of hydroquinone.
Ectoxic Environ Saf 19:327354, 1990 methemoglobinemia concentrations of 25%.1
6. Carlson AJ, Brewer NR: Toxicity studies Dusts and mists of hydroxylamine sulfate
on hydroquinone. Proc Soc Exp Biol Med are irritants of the mucous membranes and
84:684688, 1953 eyes. Although details are lacking, repeated
7. Pifer JW, Hearne FT, Swanson FA et al: Mor- exposure to the sulfate is reported to have
tality study of employees engaged in caused respiratory sensitization with asthma-
the manufacture and use of hydroquinone. like symptoms.
Int Arch Occup Environ Health 67(4): 26780, Hydroxylamine hydrochloride is highly
1995 irritating to the skin, eyes, and mucous mem-
8. Kari FW, Bucher J, Eustis SL et al: Toxicity
branes and has caused contact dermatitis in
and carcinogenicity of hydroquinone in
workers exposed for 260 days.2 Hydroxy-
F344/N rats and B6C3F1 mice. Food Chem
Toxicol 9:737747, 1992 lamine itself is only moderately irritating to the
9. Krasavage WJ, Blacker AM, English C et al: skin. Hydroxylamine sulfate on the skin of
Hydroquinone: a developmental toxicity rabbits was irritating at levels as low as a 10-mg
study in rats. Fundam Appl Toxicol 18: dose.3 It is considered to be a potential skin
370375, 1992 sensitizer.
398 HYDROXYLAMINE (and Salts)
C6H10O3 C9H8
REFERENCES
Synonyms: IP; 2,3-phenylenepyrene; o-pheny-
lenepyrene; indeneopyrene 1. IARC Monographs on the Evaluation of the Car-
cinogenic Risk of Chemicals to Humans, Vol 3,
Physical Form. Yellow solid Certain polycyclic aromatic hydrocarbons and
heterocyclic compounds, pp 229237. Lyon,
Uses. A component of polynuclear aromatic International Agency for Research on Cancer,
1973
hydrocarbons, also known as polycyclic aro-
2. Hoffman D, Wynder EL: Beitrag zur Car-
matic hydrocarbons, usually bound to small cinogenen wirking von Dibenzopyrenen. Z
particulate matter present in urban air, indus- Krebsforsch 68:137, 1966
trial and natural combustion emissions, and 3. Agency for Toxic Substances and Disease
cigarette smoke. Registry (ASTDR): Toxicological Prole for Poly-
cyclic Aromatic Hydrocarbons (PAHS) (Update), p
Exposure. Inhalation 468. Atlanta, GA, US Department of Health
and Human Services, Public Health Service,
Toxicology. Indenol(1,2,3-cd)pyrene (IP) is a 1995
4. IARC Monographs on the Evaluation of the Car-
complete carcinogen and an initiator for skin
cinogenic Risk of Chemicals to Man, Suppl 7,
carcinogenesis in the mouse.1 Overall evaluations of carcinogenicity: An
Groups of female mice were painted with updating of IARC Monographs Volumes 1 to
IP either in dioxane or in acetone, three times 42, p 64. Lyon, International Agency for
weekly for 12 months.2 A concentration of Research on Cancer, 1987
0.1% produced a total of six papillomas and
three carcinomas, the rst tumors appearing at
9 months. A concentration of 0.5% produced a
total of seven papillomas and ve carcinomas,
the rst tumors appearing at 3 months. INDIUM (and Compounds)
The same study demonstrated that 10 CAS: 7440-74-6
paintings at 2-day intervals for a total dose of
250 mg IP initiated skin carcinogenesis. In 30 In
mice subsequently treated with croton oil in
acetone, a total of 10 papillomas in 5 animals
was produced. Synonyms: Indium sesquioxide; indium
A statistically signicant dose-related in- trichloride; indium nitrate; indium antimonide;
creased incidence of epidermoid carcinomas of indium arsenide; indium phosphide
the lung and thorax was seen in rats that
received lung implants of IP for life. Physical Form. Solid
IP was mutagenic in bacterial assays and
was positive for in vitro cell transformation; in Uses. In the manufacture of semiconductors,
vivo it binds to mouse skin DNA.3 injection lasers, and solar cells; in the manu-
The IARC has determined that there is facture of glass, graphite, and cathode oscillo-
sufcient evidence for the carcinogenicity of graphs; in metal alloys to prevent corrosion and
IP in animals.4 No human data are available metal fatigue
because exposures typically involve chemical
mixtures containing numerous polynuclear Exposure. Inhalation
INDIUM (and Compounds) 401
Toxicology. Indium (In) and compounds based on increased incidences of benign and
cause injury to the lungs, liver and kidneys in malignant neoplasms of the lung.6 Increased
animals. incidences of pheochromocytoma of the
There are no reports of toxicity in humans. adrenal medulla in males and females were also
When indium was applied to the skin there was considered to be exposure related. There was
no evidence of irritation. also clear evidence of carcinogenic activity in
A range of oral LD50 values have been B6C3F1 mice based on increased incidences of
reported in animals depending on the route of malignant neoplasms of the lung and benign
administration and compound type.1 Adminis- and malignant neoplasms of the liver in males
tered parenterally to rats, rabbits, and dogs and increased incidences of benign and malig-
indium trichloride (InCl3) had an acute lethal nant neoplasms of the lung in females.6
dose range from 0.33 to 3.6 mg of In/kg.2 In cellular studies indium exposure has
Indium sesquioxide (In2O3) was less toxic, with been associated with a general suppression of
intraperitoneal doses of 955 mg/kg fatal to all protein synthesis and the induction of heme
rats within 9 days. Gross signs of In poisoning oxygenase, which in turn is associated with the
from intraperitoneal or intravenous adminis- reduction of enzyme activities dependent on
tration have included reduced food and water cytochrome P-450.7 The signicance of these
consumption, with accompanying weight loss, alterations in the synthesis and maintenance
and degenerative changes in the liver and of various enzyme systems in relation to a
kidneys.13 possible carcinogenic response has not been
When ingested by rats In2O3 was practi- determined.8
cally nontoxic; incorporated in the diet 8% for Indium arsenide and indium phosphide
3 months caused no effects on growth mortal- caused testicular damage in hamsters after
ity or tissue morphology.1 InCl3 caused marked repeated intratracheal administration. Both
growth depression at 4% in the diet over the materials decreased reproductive organ weight
same period. and caudal sperm count and caused severe
A single intratracheal dose of 1.3 mg In/kg histopathologic changes in the testes.9
as InCl3 given to female Fischer 344 rats caused Single intravenous injection of InCl3 in
severe upper and lower pulmonary damage that pregnant rats caused reduced fetal weights and
was present 8 weeks after dosing.4 In addition, fetal malformations primarily in the tail.10 In
damage to the alveolar and bronchial/bronchi- mice similarly treated, indium did not cause
olar epithelial cells initiated inammatory and fetal malformations although it reduced fetal
repair processes that led to the rapid develop- weight and caused fetal mortality.
ment of brosis. No signicant increases in the frequency of
In another report, rats exposed to the micronucleated normochromatic erythrocytes
sesquioxide (In2O3) dust by inhalation at levels were found in mice exposed to indium phos-
ranging from 24 to 97 mg/m3 for a total of 224 phide for 14 weeks.6
hours, had widespread alveolar edema and The 2003 ACGIH threshold limit value-
alteration of the alveolar walls resembling time-weighted average (TLV-TWA) for
alvelolar proteinosis in which alveolar clear- indium and compounds as In is 0.1 mg/m3.
ance was reduced.5 The lesion exhibited no
change during exposure or after a 12-week
postexposure period, including no evidence of
wound healing or brosis. Lack of a brotic REFERENCES
response in this study may be due to the rela- 1. Stokinger HE: The metals. In Clayton GD
tive insolubility of In2O3 (compared with InCl3) and Clayton FE (eds): Pattys Industrial
and less reactivity with biomembranes.4 Hygiene and Toxicology, 3rd ed rev, Vol 2A
In 2-year inhalation studies of indium Toxicology, pp 16541661. New York,
phosphide there was clear evidence of carcino- Wiley-Interscience, 1981
genic activity in male and female F344/N rats 2. Downs WK, Scott JK, Steadman LT,
402 IODINE
Maynard EA: Energy Report UR-588, Uses. Synthesis of organic chemicals; photo-
Rochester, NY, University of Rochester, graphic lm; as a disinfectant in drinking water
November 1959
3. McCord CP, Meek SF, Harrold GC, Huess- Exposure. Inhalation; ingestion; skin
ner CE: Physiologic properties of indium and absorption
its compounds. Ind Hyg Toxicol 24:243254,
1942
4. Blazka ME, Dixon D, Haskins E, et al: Pul- Toxicology. Iodine is an irritant of the eyes,
monary toxicity to intratracheally adminis- mucous membranes, and skin; it is a pulmonary
tered indium trichloride in Fischer 344 rats. irritant in animals, and it is expected that severe
Fundam Appl Toxicol 22:231239, 1994 exposure will cause the same effect in humans.
5. Leach LJ, Scott JK, Armstrong RD, et al: Exposed workers (concentration and time
AEC R&D Report UR-590. Rochester, NY, unspecied) experienced a burning sensation
University of Rochester, 1961 in the eyes, lacrimation, blepharitis, rhinitis,
6. National Toxicology Program: Toxicology and stomatitis, and chronic pharyngitis; after brief
Carcinogenesis Studies of Indium Phosphide in accidental exposure in a laboratory, technicians
F344/N Rats and B6C3F1 Mice (Inhalation reported headache and a feeling of tightness in
Studies). NTP Technical Report Series 499,
the chest.1,2
340 pp. US Department of Health and
Human Services, Public Health Service, Iodine is an essential nutritional element
2001 and is required by the thyroid.3 However,
7. Woods JS, Carver GT, Fowler BA: Altered ingestion of as little as 23 g may be fatal.
regulations of hepatic heme metabolism by Ingestion may cause corrosive effects such as
indium chloride. Toxicol Appl Pharmacol 49: edema of the glottis, with asphyxia, aspiration
455461, 1979 pneumonia, pulmonary edema and shock, vom-
8. Fowler BA, Yamauchi H, Conner EA, et al: iting, and bloody diarrhea.4 The central
Cancer risks for humans from exposure to the nervous system, cardiovascular and renal toxi-
semiconductor metals. Scand J Work Environ city following acute iodine ingestion appear to
Health 19 (Suppl 1):101103, 1993 be due to the corrosive gastroenteritis and
9. Omura M, Yamazaki K, Tanaka A, et al:
resultant shock. Vomiting, hypotension, and
Changes in the testicular damage caused by
indium arsenide and indium phosphide in circulatory collapse may be noted after severe
hamsters two years after intratracheal instil- intoxication.
lations. J Occup Health 42(4):196204, 2000 Chronic absorption of iodine causes
10. Nakajima M, Takahashi H, Sasaki M, et al: iodism, a syndrome characterized by insom-
Species differences in the developmental tox- nia, conjunctivitis, rhinitis, bronchitis, tremor,
icity of indium between rats and mice. Tera- tachycardia, parotitis, diarrhea, and weight
tology 62(3):41A, 2000 loss.4,5 Iodine absorbed by the lungs is changed
to iodide and eliminated, mainly in the
urine.
In an experimental investigation, four
human subjects tolerated 0.57 ppm iodine
vapor for 5 minutes without eye irritation but
IODINE all experienced eye irritation in 2 minutes at
CAS: 7553-56-2 1.63 ppm.3 In patients exposed to air saturated
with iodine vapor for 34 minutes for thera-
I2 peutic purposes, there was brown staining of
the corneal epithelium and subsequent sponta-
neous loss of the layer of tissue; recovery
Synonyms: None occurred within 23 days.6 Iodine in crystalline
form or in strong solutions is a severe skin irri-
Physical Form. Crystalline solid, blue-black tant; it is not easily removed from the skin, and
scales or plates the lesions resemble thermal burns with brown
IODOFORM 403
The 2003 ACGIH threshold limit pellants; as an industrial gas carrier and general
value-time-weighted average (TLV-TWA) for fuel source
isoamyl alcohol is 100 ppm (361 mg/m3) with a
short-term excursion limit (STEL) of 125 ppm Exposure. Inhalation
(452 mg/m3).
Toxicology. Isobutane is of generally low
toxicity; at extremely high concentrations, it
may produce cardiac effects and narcosis.
REFERENCES
Humans exposed to isobutane at concen-
1. Nelson KW et al: Sensory response to certain trations of 250, 500, or 1000 ppm for periods
industrial solvent vapors. J Ind Hyg Toxicol of 1 minute to 8 hours did not exhibit any unto-
25:282285, 1943 ward physiological responses as determined by
2. Smyth HF Jr: Improved communication continuous ECG telemetry, spirometric meas-
hygienic standards for daily inhalation. Am Ind ures, blood count, urinalysis, and a battery of
Hyg Assoc Q 17:129185, 1956 cognitive tests.1 Repetitive exposures at 500
3. Munch JC: Aliphatic alcohols and alkyl esters: ppm for up to 8 hours/day for 10 days also were
Narcotic and lethal potencies to tadpoles and without any measurable untoward effect.
to rabbits. J Ind Med 41:3133, 1972 In mice, exposure to 520,000 ppm was
4. Schilling K, Kayser M, Deckardt K, et al: Sub-
lethal to 100% of the animals within an average
chronic toxicity studies of 3-methyl-1-butanol
of 28 minutes.2 Near the LC50 dose, mice
and 2-methyl-1-propanol in rats. Hum Exp
Toxicol 16(12):7226, 1997 exhibit central nervous system depression,
5. Rowe VK, McCollister SB: Alcohols. In rapid and shallow respiration, and apnea.3 At
Clayton, GD, Clayton FE (eds): Pattys Indus- concentrations of 350,000 ppm, loss of posture
trial Hygiene and Toxicology, 3rd ed, rev, Vol 2C, occurred after 25 minutes; exposure to 150,000
Toxicology, pp 45944599. New York, Wiley- ppm for 60 minutes or 230,000 ppm for 26
Interscience, 1982 minutes produced light anesthesia.
6. Klimisch HJ, Hellwig J: Studies on the pre- In dogs, 450,000 ppm for 10 minutes
natal toxicity of 3-methyl-1-butanol and caused anesthesia; exposure to 200,000 ppm for
2-methyl-1-propanol in rats and rabbits fol- 10 minutes produced respiratory depression,
lowing inhalation exposure. Fundam Appl
bronchospasm, and decreased pulmonary
Toxicol 27(1):7789, 1995
compliance.2,4
Isobutane has been found to sensitize the
myocardium to epinephrine in various animal
studies. Concentrations of 50,000 ppm pre-
disposed the dog heart to cardiac arrythmias
induced by catecholamines.5 Monkeys admin-
ISOBUTANE istered 50,000100,000 ppm for 5 minutes via
CAS: 75-28-5 tracheal cannulation had tachycardia, arrhyth-
mias, and myocardial depression.6 Cases of
C4H10 sudden death due to fatal cardiac arrhythmias
have been reported in humans intentionally
inhaling isobutane.7
Synonyms: 2-Methylpropane; trimethyl- Repeated exposure of monkeys to 4000
methane ppm for up to 90 days caused no signs of
toxicity.8
Physical Form. Colorless gas The vapor exerts no effect on the skin or
the eyes.
Uses. In the production of propylene glycols The 2003 ACGIH threshold limit
and oxides and polyurethane foams and resins; value-time-weighted average (TLV-TWA) for
as component of motor fuels and aerosol pro- isobutene is 800 ppm (1900 mg/m3).
408 ISOBUTYL ACETATE
CH3COOCH2CH(CH3)2
ISOBUTYL ALCOHOL
CAS: 78-83-1
Synonyms: Acetic acid, isobutyl ester; 2-
methylpropyl acetate (CH3)2CHCH2OH
The 2003 ACGIH threshold limit value- tion hazard because of its relatively low
time-weighted average (TLV-TWA) for volatility.2
isooctyl alcohol is 50 ppm (266 mg/m3) with a Repeated exposures of animals at con-
notation for skin absorption. centrations of 50 ppm or more resulted in
evidence of damage to kidney and lung and,
to a lesser extent, liver damage. No effects,
REFERENCES however, were seen at 25 ppm. More recent
feeding studies with pure compound in rats,
1. Scala RA, Burtis EG: Acute toxicity of a mice, and beagle dogs have not demonstrated
homologous series of branch-chain primary specic toxicity.3
alcohols. Am Ind Hyg Assoc J 34:493499, A 2-year gavage study at 250 and 500 mg/
1973
kg demonstrated a dose-related statistically sig-
2. Union Carbide Corporation: Unpublished
nicant excess of tubular cell adenomas and
data cited in Rowe VK, McCollister SB, Alco-
hols. In Clayton GD, Clayton FE (eds): Pattys adenocarcinomas of the kidney in male rats, a
Industrial Hygiene and Toxicology, 3rd ed, Vol number of preputial gland tumors in dosed
2C, Toxicology, pp 46204623. New York, male rats, and a probable increased incidence
Wiley-Interscience, 1982 of hepatocellular neoplasms in high-dose male
mice.3
Studies indicate that renal effects may be
specic to certain strains of male rats that syn-
thesize a2u-globulin.4 Monkeys, guinea pigs,
ISOPHORONE dogs, mice, female rats. and male NBR rats
CAS: 78-59-1 that do not synthesize the hepatic form of a2u-
globulin do not develop renal disease in
C9H14O response to isophorone.
Isophorone does not induce gene muta-
tions in bacteria, chromosomal aberrations in
Synonyms: Isoacetophorone; Isoforon; trime- vitro, DNA repair in primary rat hepatocytes,
thyl cyclohexenone or bone marrow micronuclei in mice. Positive
effects were observed only in the absence of an
Physical Form. Water-white liquid exogenous metabolic system in L5178YTK +/-
mouse mutagenesis assays as well as in a sister
Uses. Solvent for lacquers, resins, and chromatid exchange assay.5 The weight of evi-
plastics dence of all mutagenicity data supports the
contention that isophorone is not a potent
Exposure. Inhalation; skin absorption DNA-reactive compound.5
Pregnant rats and mice were exposed 6
Toxicology. Isophorone is an irritant of the hours/day on days 615 of gestation to atmos-
eyes and mucous membranes. pheres containing 0, 143, 285, or 656 mg/m3 (0,
Human subjects exposed briey to 25 ppm 25, 50, or 115 ppm) isophorone. At the highest
experienced irritation of the eyes, nose, and atmospheric concentration there was evidence
throat.1 Workers exposed to 58 ppm for 1 of maternal toxicity, which showed as reduced
month complained of fatigue and malaise, food consumption, alopecia, and cervical or
which disappeared when air levels were anogenital staining in the rats and reduced
reduced to 14 ppm.2 Repeated or prolonged body weights in the mice. Comprehensive
skin contact with the liquid may cause uterine and fetal examinations did not show any
dermatitis because of its defatting action.2 signicant teratogenic or fetotoxic effects in F-
Although it may be more toxic and irritative 344 rats or CD-1 mice.5
than lower-molecular-weight ketones at equiv- The 2003 ACGIH ceiling-threshold limit
alent concentrations, it poses less of an inhala- value (C-TLV) for isophorone is 5 ppm
ISOPHORONE DIISOCYANATE 411
(28 mg/m3) with an A3-animal carcinogen des- Toxicology. Isophorone diisocyanate (IPDI)
ignation with unknown relevance to humans is an irritant and sensitizer of the respiratory
notation. tract and the skin.
By analogy to toluene diisocyanate, expo-
sure of humans to sufcient concentrations is
REFERENCES expected to cause irritation of the eyes, nose,
and throat; a choking sensation; and a produc-
1. Silverman L, Schulte HF, First MW: Further tive cough of paroxysmal type with retrosternal
studies on sensory response to certain indus- soreness and chest pain.1,2
trial solvent vapors. J Ind Hyg Toxicol 28: Higher concentrations would be expected
262266, 1946
to produce a sensation of oppression or con-
2. National Institute for Occupational Safety and
striction of the chest. There may be bronchitis
Health: Criteria for a Recommended Standard
. . . Occupational Exposure to Ketones. DHEW and severe bronchospasm; pulmonary edema
(NIOSH) Pub No 78-173, pp 1242. Wash- may also occur. On cessation of exposure, the
ington, DC, US Government Printing Ofce, symptoms may persist for 37 days.3
June 1978 Although the acute effects may be severe,
3. Bucher JR, Huff J, Kluwe WM: Toxicology their importance is overshadowed by respira-
and carcinogenesis studies of isophorone in tory sensitization in susceptible persons. The
F344 rats and B6C3F1 mice. Toxicology 39: onset of symptoms of sensitization may be
208219, 1986 insidious, becoming progressively more pro-
4. Dietrich DR, Swenberg JA: NCI-Black Reiter nounced with continued exposure over a period
(NBR) male rats fail to develop renal disease
of days to months. Initial symptoms are often
following exposure to agents that induce a-
nocturnal dyspnea and/or nocturnal cough
2u-globulin (a2u) nephropathy. Fundam Appl
Toxicol 16:749762, 1991 with progression to asthmatic bronchitis.1
5. WHO working group: Environmental Health A 50-year-old spray painter developed
Criteria 174, Isophorone. pp 184. Geneva, severe asthma soon after the introduction of
Ofce of Publications, World Health Organi- a new paint containing IPDI.3 A bronchial
zation, 1995 challenge test with the paint gave a positive
response.
In another case, a spray painter developed
tightness of the chest and dyspnea shortly after
using a paint containing IPDI.4 The symptoms
disappeared after a few days off work but
recurred shortly after resumption of work.
ISOPHORONE DIISOCYANATE IPDI has been shown to provoke allergic
CAS: 4098-71-9 dermatitis in exposed workers.5
Skin and eye irritation in rabbits is consid-
C12H18N2O2 ered moderate.1
The 2003 ACGIH threshold limit value-
time-weighted average (TLV-TWA) is 0.005
Synonyms: IPDI; 3-isocyanatomethyl-3,5,5- ppm (0.045 mg/m3).
trimethyl cyclohexylisocyanate
2. Elkins HB, McCarl GW, Brugsch HG, Fahy groups exposed to 891 or 441 ppm. A con-
JP: Massachusetts experience with toluene centration-related increase in absolute and rel-
diisocyanate. Am Ind Hyg Assoc J 23:265272, ative spleen weight in the 441 and 891 ppm
1962 groups was accompanied by extramedullary
3. Clarke CW, Aldons PM: Isophorone diiso- hematopoiesis and brown pigment accumula-
cyanate induced respiratory disease. Aust NZ J
tion in the spleen. The no observed adverse
Med 11:290292, 1981
4. Tyrer FH: Hazards of spraying with two-pack effect level was 30 ppm.
paints containing isocyanates. J Soc Occup Med The 2003 ACGIH threshold limit value-
29:2224, 1979 time-weighted average (TLV-TWA) is 25 ppm
5. Lachapelle JM, Lachapelle-Ketelaer MJ: (106 mg/m3) with a notation for skin
Cross-sensitivity between isophorone diamine absorption.
and isophorone diisocyanate (IPDI). Contact
Derm 5:55, 1979
REFERENCES
1. Arts JHE, Reuzel PGJ, Woutersen RA, Kuper
CF, Falke HE, Klimisch HJ: Repeated-dose
2-ISOPROPOXYETHANOL (28-day) inhalation toxicity of isopropyl ethyl-
ene glycol ether in rats. Inhal Toxicol 4:4355,
CAS: 109-59-1
1992
(CH3)2CHOCH2CH2OH
ve of six animals after 4 hours; 16,000 ppm for high doses it causes central nervous system
4 hours was fatal to one of six rats.2 The oral depression.
LD50 for rats was 6.75 g/kg.2 Human subjects exposed to 400 ppm for
Isopropyl acetate was negative in most 35 minutes experienced mild irritation of the
genotoxic test systems but was a weak inducer eyes, nose, and throat; at 800 ppm, the irrita-
of aneuploidy.3 tion was not severe but the majority of subjects
The 2003 ACGIH threshold limit value- considered the atmosphere uncomfortable.1
time-weighted average (TLV-TWA) is Occupational poisoning by isopropyl
250 ppm (1040 mg/m3) with a short-term alcohol has not been reported. Toxicity in
excursion limit (STEL)/ceiling of 310 ppm humans is based largely on accidental inges-
(1290 mg/m3). tion. An oral dose of 25 ml in 100 ml of water
produced hypotension, facial ushing, bra-
dycardia, and dizziness. Other symptoms
REFERENCES following ingestion have included vomiting,
depression, headache, coma, and shock.2 Renal
1. Silverman L, Schulte HF, First MW: Further insufciency, including anuria followed by
studies on sensory response to certain indus- oliguria, nitrogen retention, and edema, may
trial solvent vapors. J Ind Hyg Toxicol 28: be a complication of isopropyl alcohol poison-
262266, 1946
ing. Estimates of fatal doses are between 160
2. Smyth HF Jr, Carpenter CP, Weil CS, Pozzani
and 240 ml. Death following ingestion often
UC: Range-nding toxicity data. List V. Arch
Ind Hyg Occup Med 10:6168, 1954 occurs in 2436 hours from respiratory paraly-
3. Dutch Expert Committee on Occupational sis.2 In a recent report, a newborn was exposed
Standards (DECOS): Isopropyl acetate. Health- for 2 hours to 70% isopropyl that had been
based recommended occupational exposure limit. accidentally placed in the humidier of the
pp 137. Health Council of the Netherlands infants ventilator.3 Despite supportive care, he
(Gezondheidsraad), 1997 became cyanotic, bradycardic, then asystolic
12.5 hours after exposure and died.
Studies indicate that isopropyl alcohol may
be substantially better absorbed by the dermal
route than had previously been believed,
ISOPROPYL ALCOHOL although signicant toxicity by this route
CAS: 67-63-0 would require prolonged exposure.4 Delayed
dermal absorption rather than inhalation may
CH3CHOHCH3 account for a number of pediatric poisonings
that have occurred after repeated or prolonged
sponged bathing with isopropyl alcohol to
Synonyms: Isopropanol; 2-propanol; dimethyl reduce fever. In several cases symptoms have
carbinol included respiratory distress, stupor, and
coma.2 Recovery was complete within 36
Physical Form. Colorless liquid hours. Hypersensitivity characterized by
delayed eczematous reactions have occasionally
Uses. Manufacture of acetone; solvent; in been observed after dermal contact with iso-
skin lotions, cosmetics, and pharmaceuticals; propyl alcohol.2
most commonly available commercially as Rats exposed to 12,000 ppm for 4 hours
rubbing alcohol (70% isopropanol) survived, but exposure for 8 hours was lethal to
half the animals.5 Mice exposed to 3250 ppm
Exposure. Inhalation; ingestion for 460 minutes developed ataxia, prostration,
and nally narcosis. Guinea pigs exposed to
Toxicology. Isopropyl alcohol is an irritant 400 ppm for 24 successive hours had slight
of the eyes and mucous membranes; at very changes in the mucosa of the nose and trachea,
414 ISOPROPYL ALCOHOL
whereas exposure to 5500 ppm for the same used concurrently with carbon tetrachloride in
amount of time caused severe pathologic an industrial setting.
degeneration of the respiratory mucosa.6 In the The odor threshold for isopropyl alcohol
eye of a rabbit, 70% isopropyl alcohol caused is 40200 ppm.
conjunctivitis, iritis, and corneal opacity.5 The 2003 ACGIH threshold limit value-
Early epidemiological studies suggested an time-weighted average (TLV-TWA) for iso-
association between the manufacture of iso- propyl alcohol is 400 ppm (983 mg/m3) with a
propyl alcohol and paranasal sinus cancer.7,8 short-term excursion limit (STEL) of 500 ppm
The risk for laryngeal cancer may also have (1230 mg/m3).
been elevated in these workers.8 The increased
cancer incidence, however, appears to be asso-
ciated with some aspect of the strong-acid REFERENCES
manufacturing process rather than the iso-
propyl alcohol itself. It is unclear whether the 1. Nelson KW et al: Sensory response to certain
cancer risk is due to the presence of diisopropyl industrial solvent vapors. J Ind Hyg Toxicol
sulfate, which is an intermediate in the process, 25:282285, 1943
to isopropyl oils, which are formed as by- 2. Zakhari S et al: Isopropanol and Ketones in the
products, or to other agents, such as sulfuric Environment, pp 354. Cleveland, OH, CRC
acid.8 Press, 1977
In mice and rats exposed to 500, 2500, or 3. Vicas IM, Beck R: Fatal inhalation isopropyl
5000 ppm 6 hours/day, 5 days/week for up to alcohol poisoning in a neonate. J Toxicol Clin
Toxicol 31:473481, 1993
104 weeks, the only neoplastic lesion showing
4. Martinez TT, Jaeger RW, deCastro FJ, et al:
an increased incidence was interstitial cell
A comparison of the absorption and metabo-
(Leydig cell) adenomas in male rats. The tumor lism of isopropyl alcohol by oral, dermal and
was not considered to be treatment related inhalation routes. Vet Hum Toxicol 28:233
because of its occurrence in control rats.9 236, 1986
The IARC has determined that there is inade- 5. Rowe VK, McCollister SB: Alcohols. In
quate evidence for the carcinogenicity of iso- Clayton GD, Clayton FE (eds): Pattys Indus-
propyl alcohol in experimental animals and trial Hygiene and Toxicology, 3rd ed, rev, Vol
humans.10 2C, Toxicology, pp 45614571. New York,
No evidence of teratogenicity was Wiley-Interscience, 1982
observed in rats treated with doses of up to 6. Ohashi Y, Nakai Y, Ikeoka H, et al: An exper-
imental study on the respiratory toxicity of
1200 mg/kg/day on gestation days 615 or in
isopropyl alcohol. J Appl Toxicol 8:6771,
rabbits administered up to 480 mg/kg/day on
1987
gestation days 618.11 No evidence of develop- 7. Weil CS, Smyth HF Jr, Nale TW: Quest for
mental toxicity, as determined by pathologic a suspected industrial carcinogen. J Ind Hyg
ndings, organ weights, or behavioral tests, was Occup Med 5:535547, 1952
observed in rats administered up to 1200 8. IARC Monographs on the Evaluation of Car-
mg/kg/day on gestation day 6 through postna- cinogenic Risks to Humans. Suppl 7, Overall
tal day 21.12 evaluations of carcinogenicity: An updating
When absorbed, isopropyl alcohol is oxi- of IARC Monographs Volumes 1 to 42, pp
dized in the liver at the hydroxyl moiety and 229230. Lyon, International Agency for
converted to acetone.13 Occupational exposure Research on Cancer, 1987
9. Burleigh-Flayer H, Garman R, Neptun D, et
to isopropyl alcohol can be biomonitored by
al: Isopropanol vapor inhalation oncogenicity
means of urinalysis for acetone after exposures
study in Fischer 344 rats and CD-1 mice.
as low as 70 ppm.13 The acetone metabolite Fundam Appl Toxicol 36(2):95111, 1997
may also be responsible for the enhanced toxi- 10. IARC Monographs on the Evaluation of the Car-
city of carbon tetrachloride following pretreat- cinogenic Risk of Chemicals to Humans, Vol 71,
ment of animals with isopropyl alcohol.2 Extra Re-evaluation of some organic chemicals,
caution is in order when isopropyl alcohol is hydrazine and hydrogen peroxide, pp 1027
N-ISOPROPYLANILINE 415
to parafns but are unsaturated (double and was chosen by the authors as being more
triple C-C bonds) with lower hydrogen-to- typical of military occupational exposure to jet
carbon ratios, are the most reactive of the fuels. Nevertheless, the results may suggest
hydrocarbons, and are allowed at only 5% by that JP-4 and JP-7 are not carcinogenic to
volume in JP-4. Benzene is present as a con- humans.
taminant at less than 0.5% in JP-4. Other Acute (24 hours) dermal application of
ingredients of lesser importance are sulfur 2 g/kg JP-4 or JP-7 to rabbits did not result in
and sulfur compounds as well as additives mortality. However, they did cause severe skin
to improve performance (antioxidants, metal erythema and edema 24 hours after exposure.79
deactivators, fuel system icing inhibitors, cor- Somewhat at odds with these irritation poten-
rosion inhibitors, static dissipater additives).2 tial ndings, there was no evidence of primary
ocular irritation after application of JP-4 or JP-
Uses. JP-4 and JP-7 (jet propellant-4 and jet 7 to the eyes of rabbits.710
propellant-7) are used by the US Air Force as
aircraft fuels.
REFERENCES
Exposure. Skin contact and absorption;
inhalation 1. TSCA Interagency Testing Committee:
Information Review. Petroleum Middle Distillate
Toxicology. JP-4 and J-7 cause central Fuels. No. IR-470. Rockville, MD, CRCS,
nervous system depression and skin irritation. Inc., Dynamac Corp, 1985
2. CRC: Handbook of Aviation Fuel Properties.
Accidental exposure of a pilot during a fuel
Report no. 53. Atlanta, GA, Coordinating
leak to JP-4 at levels estimated to be between
Research Council Inc., 1984
3000 and 7000 ppm produced signs of neuro- 3. Dudek WG: Aviation and other gas turbine
logical intoxication, but cardiovascular and pul- fuels. In Grayson M (ed.): Kirk-Othmer Ency-
monary function appeared normal on clinical clopedia of Chemical Technology, 3rd ed, Vol 3,
examination.4 The pilot had a staggering gait, p 328. New York, John Wiley & Sons, 1978
mild muscular weakness, decreased responsive- 4. Davies NE: Jet fuel intoxication. Aerospace
ness to painful stimuli, and slight slurring of Med 35:481, 1964
speech. The effects were not evident 36 hours 5. Bruner RH et al: The toxicologic and
after exposure. oncogenic potential of JP-4 jet fuel vapors in
Chronic exposure (12 months) of rats and rats and mice; 12-month intermittent inhala-
tion exposures. Fundam Appl Toxicol 20:97,
mice to 1000 or 5000 mg/m3 JP-4 did not cause
1993
respiratory tract irritation or pulmonary lesions
6. US Air Force: Tumorigenic Evaluation of Jet
in rats at the end of the exposure or at 12 Fuels JP-TS and JP-7. Report No. AAMRL-
months after exposure.5 An increase of intersti- TR-91-0020. Wright-Patterson Air Force
tial cell tumors was observed in the testis 12 Base, OH: Aerospace Medical Research
months after exposure. No effect on the inci- Laboratory, Aerospace Medical Division, Air
dence of neoplastic tumors was seen in mice in Force Systems Command, 1991
the same study. A 1-year JP-7 exposure study 7. Clark CR et al: Comparative acute toxicity of
to rats at 750 mg/m3 produced no toxicologi- shale oil and petroleum derived distillates.
cally signicant treatment-related neoplastic Toxicol Ind Health 6:1005, 1989
lesions in mice or rats except for a small 8. Dennis MW: Acute Dermal LD50 Toxicity
Study E-2B, E6-B, E-8, E-14B, E-10, E-11, E-
increase in incidence of C-cell adenomas and
12 with cover letter dated 03/31/82. Docu-
kidney adenomas in male rats.6 However, these
ment no. 88-8100360, Washington DC, US
tumors are of the type that are considered to Environmental Protection Agency, Ofce of
be specic to the male rat and not relevant to Toxic Substances, 1982
humans or other animals. The exposure period 9. US Air Force: The acute irritation and sen-
in these two studies was 1 year, rather than the sitization potential of JP-4, JP-7, JP-8, and
typical 2-year lifetime period. This time period JP-TS jet fuels. In Toxic Hazards Research Unit
420 KETENE
Annual Technical Report. Report no. AMRL- later against otherwise lethal exposures to
TR-84-001, Document no. AD-147857/7. pulmonary edema-producing agents.2 A high
Wright-Patterson Air Force Base, OH, Aero- degree of tolerance to the acute effects of
space Medical Research Laboratory, Aero- ketene itself has also been reported.3 Chronic
space Medical Division, Air Force Systems pulmonary changes including brosis and
Command, 1984
emphysema may also result from repeated
10. Walter MK: Primary Eye Irritation Study E-1,
E-3, E-5, and E-13B. Document no. 88- acute exposures.
8200416, Washington, DC, US Environ- By analogy to effects on the skin caused by
mental Protection Agency, Ofce of Toxic other severe irritants, repeated or prolonged
Substances, 1982 exposure is expected to cause dermatitis.
The 2003 ACGIH threshold limit value-
time-weighted average (TLV-TWA) for ketene
is 0.5 ppm (0.86 mg/m3) with a short-term
excursion limit (STEL) of 1.5 ppm (2.6 mg/m3).
KETENE
CAS: 463-51-4
REFERENCES
CH2CO
1. Treon JF et al: Physiologic response of animals
exposed to airborne ketene. J Ind Hyg Toxicol
Synonyms: Ethenone; carbomethene; keto- 31:209218, 1949
2. Stokinger HE: Toxicologic interactions of
ethylene
mixtures of air pollutants. Int J Air Poll 2:
313326, 1960
Physical Form. Gas 3. Mendenhall RM, Stokinger HE: Tolerance
and cross-tolerance development to atmos-
Uses. Organic chemical syntheses; conver- pheric pollutants ketene and ozone. J Appl
sion of higher acids into their anhydrides; for Physiol 14:923926, 1959
acetylation in the manufacture of cellulose
acetate and aspirin
Exposure. Inhalation
LEAD (Inorganic Compounds)
Toxicology. Ketene is a severe pulmonary CAS: 7439-92-1
irritant in animals and is expected to produce
the same effect in humans. Pb
For mice, monkeys, cats, and rabbits
the concentrations that caused death after a
10-minute exposure were 50, 200, 750, and Synonyms/Compounds: Metallic lead; lead
1000 ppm, respectively.1 Few signs appeared oxide; lead salts; inorganic lead
during the exposure period, but after a latent
period of variable duration there was dyspnea, Physical Form. Solid
cyanosis, and signs of severe pulmonary
damage; death was often preceded by convul- Uses. Storage batteries; paint; ink; ceramics;
sions. Signicant pathologic changes were con- automobile radiator repair; ammunition
ned to the lungs and consisted of generalized
alveolar edema and congestion. Several species Exposure. Inhalation; ingestion
tolerated exposure to 1 ppm for 6 hours/day for
6 months without apparent chronic injury.1 Toxicology. Prolonged absorption of lead or
Exposure of mice to concentrations in excess of its inorganic compounds results in severe gas-
5 ppm for 10 minutes protected mice 314 days trointestinal disturbances and anemia; with
LEAD (Inorganic Compounds) 421
more serious intoxication, there is neuromus- trast, children are particularly sensitive to lead-
cular dysfunction, whereas the most severe lead related neurobehavioral effects.
exposure may result in encephalopathy. Mild neurophysiological changes, includ-
The onset of symptoms of lead poisoning ing reductions in motor and sensory nerve
or plumbism is often abrupt; presenting conduction velocities (sometimes still within
complaints may include weakness, weight the normal range), have been documented in
loss, lassitude, insomnia, and hypotension.14 lead-exposed workers compared with control
Associated with these is a disturbance of the groups, with blood lead levels less than 40 mg/
gastrointestinal tract, such as constipation, 100 ml blood.9 A prospective follow-up study of
anorexia, and abdominal discomfort, or actual workers with blood lead levels of 3050 mg/
colic, which may be excruciating. Physical signs 100 ml blood demonstrated mild slowing of
are usually facial pallor, malnutrition, abdomi- conduction velocities.10
nal tenderness, and pallor of the eye grounds. Nephropathy has been associated with
The anemia often associated with lead poison- chronic lead poisoning.2,3,11 A study of two large
ing is of the hypochromic, normocytic type, cohorts of heavily exposed lead workers fol-
with reduction in mean corpuscular hemoglo- lowed through 1980 demonstrated a nearly
bin; stippling of erythrocytes and reticulocyto- threefold excess of deaths attributed to chronic
sis are evident. On gingival tissues, a line or nephritis or other hypertensive disease, pri-
band of punctate blue or blue-black pigmenta- marily kidney disease.12 Most of the excess
tion (lead line) may appear, but only in the deaths occurred before 1970, among men who
presence of poor dental hygiene; this is not began work before 1946, suggesting that
pathognomonic of lead poisoning.3 current lower levels of exposure may reduce the
Occasionally the alimentary symptoms are risk. Experimental animal studies suggest there
relatively slight and are overshadowed by neu- may be a threshold for lead nephrotoxicity, and
romuscular dysfunction, accompanied by signs in workers, nephropathy occurred only in those
of motor weakness, which may progress to with blood levels over 62 mg/dl for up to 12
paralysis of the extensor muscles of the wrist years.13
(wrist drop) and less often of the ankles (foot The role of chronic low-level lead expo-
drop).2,3 Encephalopathy, the most serious sure in the pathogenesis of hypertension
result of lead poisoning, frequently occurs in remains controversial. Although results have
children due to the ingestion of inorganic lead been mixed, overall, the studies may suggest a
compounds, but rarely in adults, except from small positive association between blood lead
exposure to organic lead.14 and blood pressure.14
Subtle, often subclinical, neurological After absorption, inorganic lead is distrib-
effects have been demonstrated in workers uted in the soft tissues, with the highest con-
with relatively low blood lead levels, below centrations being in the kidneys and the liver.4
4060 mg/100 ml blood. Performance of lead In the blood, nearly all circulating inorganic
workers on various neuropsychological tests lead is associated with the erythrocytes.4 Over
was mildly reduced, relative to a control group, a period of time, the lead is redistributed, being
at mean levels of 49 mg/100 ml blood and, in a deposited mostly in bone and also in teeth and
prospective follow-up study, at levels between hair.3,4 Lead absorption is cumulative; elimina-
30 and 45 mg/100 ml blood.57 In some of these tion of lead from the body is slow, requiring
studies, the lead-exposed workers reported sig- considerably longer than the period of stor-
nicantly more complaints of nonspecic sub- age of toxic amounts.1,4 Asymptomatic lead
jective symptoms, such as anxiety, depressed workers, when subjected to a sudden increase
mood, poor concentration, and forgetfulness.5 in exposure to and absorption of lead, often
However, a recent evaluation of 21 studies respond with an episode of typical lead poison-
found inadequate evidence of decreased neu- ing.1 Removal of the worker from exposure to
robehavioral test performance in adults with abnormal quantities of lead often leads to a
cumulative low-level exposure to lead.8 In con- seemingly sudden and apparently complete
422 LEAD (Inorganic Compounds)
recovery; this has occurred even when the indi- malformations in humans.22 Excessive exposure
vidual has a considerable quantity of residual to lead during pregnancy has resulted in neu-
lead in the body.1 rological disorders in infants; low levels of
Available human epidemiological studies exposure may be related to neurobehavioral
are inadequate to assess lead carcinogenicity decits or delays.16
because of the lack of quantitative exposure In battery workmen with a mean occupa-
data for lead, the lack of consistency across tional exposure to lead of 8.5 (123) years, and
studies, and the possibility of confounding with blood lead concentrations of 5375 mg/
exposures.15,16 A study of 4347 lead-exposed 100 ml of blood, there was an increased fre-
workers in a copper smelter failed to demon- quency of abnormalities of sperm, including
strate any signicant excess of neoplasms.17 A hypospermia, compared with a control group.23
study of two large cohorts of lead workers The 2003 ACGIH threshold limit value-
(3519 battery plant workers and 2300 lead time-weighted average (TLV-TWA) for lead,
production workers) followed through 1980 including elemental and inorganic compounds
demonstrated statistically signicant elevation as Pb, is 0.05 mg/m3 with an A3-conrmed
in the standardized mortality ratio (SMR) for animal carcinogen with unknown relevance to
gastric (SMR = 168) and lung (SMR = 125) humans designation.
cancer in the battery plant workers only. Citing
the absence of prior evidence from other
studies for these associations, and their inabil-
ity to assess and correct for possible confound- REFERENCES
ing factors (such as diet, alcohol, and smoking),
1. Kehoe RA: Occupational lead poisoning.
the authors considered these ndings incon-
Clinical types. J Occup Med 14:298300,
clusive. There were no excess deaths from 1972
malignancies of the kidney or other sites in 2. National Institute for Occupational Safety
either cohort.12 and Health: Criteria for a Recommended Stan-
There are several reports that certain lead dard. . . . Occupational Exposure to Inorganic
compounds, including lead acetate and lead Lead, DHEW (HSM) Pub No. 73-22020.
phosphate, administered to animals in high Washington, DC, US Government Printing
doses are carcinogenic, primarily producing Ofce, 1972
renal tumors.18,19 (Note: Those salts demon- 3. Committee on Biologic Effects of Atmos-
strating carcinogenicity in animals are soluble, pheric Pollutants, Division of Medical
Sciences, National Research Council: Lead
whereas human beings are primarily exposed to
Airborne Lead in Perspective. Washington, DC,
insoluble metallic lead and lead oxide.)
National Academy of Sciences, 1972
Genotoxic assays both in vivo and in vitro 4. Klaassen CD: Heavy metals and heavy-metal
have shown positive and negative results.16 antagonists. In Goodman LS, Gilman AG
Reproductive effects from lead exposure (eds): Goodman and Gilmans The Pharmaco-
have been documented in animals and human logical Basis of Therapeutics, 6th ed, pp 1616
beings of both sexes. High occupational expo- 1622. New York, Macmillan Publishing,
sure levels in pregnant women have been 1980
associated with increased incidences of 5. Jeyaratnam J et al: Neuropsychological
spontaneous abortions, miscarriages, and still- studies on lead workers in Singapore. Br J Ind
births.16 Some studies also seem to indicate Med 43:626629, 1986
6. Williamson AM, Teo RKC: Neurobehavioral
that prenatal exposure to lower levels of lead
effects of occupational exposure to lead. Br J
may increase the risk of preterm delivery and
Ind Med 43:374380, 1986
reduced birth weight.20 Lead penetrates the 7. Mantere P et al: A prospective follow-up
placental barrier and has caused congenital study on psychological effects in workers
abnormalities in animals.3,21 There is no con- exposed to low levels of lead. Scand J Work
clusive evidence, however, that low-level lead Environ Health 10:4350, 1984
exposure leads to an increased incidence of 8. Balbus-Kornfeld JM, Stewart W, Bolla KI
LEAD ARSENATE 423
et al: Cumulative exposure to inorganic lead prenatal lead exposure in the human: I.
and neurobehavioral test performance in Effects on the fetus and newborn. Reprod
adults: an epidemiological review. Occup Toxicol 6:919, 1992
Environ Med 52:212, 1995 23. Lancranjan I, Popescu HI, Gavanescu O
9. Chen Z et al: Peripheral nerve conduction et al: Reproductive ability of workmen occu-
velocity in workers occupationally exposed to pationally exposed to lead. Arch Environ
lead. Scand J Work Environ Health 11(suppl 4): Health 30:396401, 1975
2628, 1985
10. Seppalainem AM, Hernberg S, Vesanto R
et al: Early neurotoxic effects of occupational
lead exposure: A prospective study. Neurotox-
icology 4:181192, 1983
LEAD ARSENATE
11. Vitale LF, Joselow MM, Wedeen RP, Pawlow
M: Blood leadan inadequate measure of CAS: 10102-48-4
occupational exposure. J Occup Med 17:155
156, 1975 Pb3(AsO4)2
12. Cooper WC, Wong O, Kheifets L: Mortal-
ity among employees of lead battery plants
and lead-producing plants. 19471980. Scand Synonyms: Arsinette; Ortho L10 Dust;
J Work Environ Health 11:331345, 1985 Gypsine; Soprabel; Talbot
13. Beck BD: Symposium overview: An update
on exposure and effects of lead. Fundam Appl Physical Form. White powder (required to
Toxicol 18:116, 1992
be colored pink in most of US)
14. Hertz-Picciotto I, Croft J: Review of the rela-
tion between blood lead and blood pressure.
Epidemiol Rev 15:352373, 1993 Uses. Insecticide; control of tapeworms in
15. Steenland K, Boffeta P: Lead and cancer in cattle, goats, sheep
humans: where are we now? Am J Ind Med
38(3):2959, 2000 Exposure. Inhalation; ingestion
16. Agency for Toxic Substances and Disease
Registry (ATSDR): Toxicological Prole for Toxicology. Lead arsenate may cause lead
Lead. 587pp. US Department of Health and and/or arsenic intoxication; arsenic symptoms
Human Services, Public Health Service, 1999 likely predominate in acute intoxication,
17. Gerhardsson L, Lundstrom NG, Nordberg whereas prolonged inhalation of lead arsenate
G et al: Mortality and lead exposure: A ret-
may induce the symptoms of lead intoxication.1
rospective cohort study of Swedish smelter
Some of the effects of acute arsenic intox-
workers. Br J Ind Med 43:707712, 1986
18. Mao P, Molnar JJ: The ne structure and his- ication are nausea, vomiting, diarrhea, and irri-
tochemistry of lead-induced renal tumors in tation; inammation and ulceration of the
rats. Am J Pathol 50:571581, 1967 mucous membranes and skin; and kidney
19. Boyland E, Dukes CE, Grover PL, Mitchley damage.2 Among the effects of chronic arsenic
BCV: The induction of renal tumors by feed- poisoning are increased pigmentation and
ing lead acetate to rats. Br J Cancer 16:283 keratinization of the skin, dermatitis, and
288, 1962 epidermoid carcinoma. Other effects seen after
20. Andrews KW, Savitz DA, Hertz-Picciotta I: ingestion, but which are not common from
Prenatal lead exposure in relation to gesta- industrial exposure, are muscular paralysis,
tional age and birth weight: a review of epi-
visual disturbances, and liver and kidney
demiologic studies. Am J Ind Med 26:1332,
damage.2
1994
21. Ferm VH, Carpenter SJ: Developmental Effects of lead intoxication include damage
malformations resulting from the administra- to the central and peripheral nervous systems,
tion of lead salts. Exp Mol Pathol 7:208213, to the kidneys, and to the blood-forming ele-
1967 ments, which may lead to anemia.3 Symptoms
22. Ernhart CB: A critical review of low-level include colic, loss of appetite, and constipation;
424 LEAD CHROMATE
excessive tiredness and weakness; and nervous 2. Department of Labor: Standard for exposure
irritability. In peripheral neuropathy, the dis- to inorganic arsenic. Fed Reg 40:33923404,
tinguishing clinical feature of lead intoxication 1975
is a predominance of motor impairment, with 3. Department of Labor: Occupational exposure
minimal or no sensory abnormalities. There to lead. Fed Reg 40:4593445948, 1975
4. Nelson WC, Lykins MH, Mackey J et al:
is a tendency for the extensor muscles of the
Mortality among orchard workers exposed to
hands and feet to be affected. Lead intoxication lead arsenate spray: A cohort study. J Chron Dis
has also resulted in kidney damage with few, if 26:105118, 1973
any, symptoms appearing until permanent 5. Neal PA et al: A study of the effect of lead
damage has occurred. arsenate exposure on orchardists and con-
A mortality study in 1973 of a cohort of sumers of sprayed fruit. US Public Health
1231 individuals (primarily orchardists who Service Bull No. 267, pp 47165, 171181.
had participated in a 1938 mortality study) Washington, DC, US Government Printing
found that excess mortality did not occur con- Ofce, 1941
sistently from exposure to lead arsenate spray.4,5 6. Tollestrup K, Daling JR, Allard J: Mortality in
However, in a recent analysis of this same a cohort of orchard workers exposed to lead
arsenate pesticide spray. Arch Environ Health
cohort, the causes of death were determined for
50(3):221229, 1995
three different levels of exposureorchardists 7. Ott MG, Holder BB, Gordon HL: Respiratory
(involved in preparing and spraying), interme- cancer and occupational exposure to arseni-
diates (infrequent exposure to spray), and con- cals. Arch Environ Health 29:250255, 1974
sumers. In male orchardists and intermediates 8. IARC Monographs on the Evaluation of the Car-
there was a higher risk of dying from all causes cinogenic Risk of Chemicals to Humans, Vol 23,
of death, and for exposed male intermediates Some metals and metallic compounds, pp 39
there was a greater risk of mortality due to 41. Lyon, International Agency for Research
coronary heart disease.6 Two other independ- on Cancer, 1980
ent studies reported a signicant excess of lung
cancer among other cohorts of this same pop-
ulation.2 In a study of workers engaged in the
formulation and packaging of lead arsenate and
calcium arsenate, there was an excess of lung LEAD CHROMATE
cancer, which was dose related.7 In vineyard CAS: 7758-97-6
workers chronically exposed to lead, calcium,
and copper arsenate dust in Germany and PbCrO4
France, there are numerous reports of skin
cancer, including basal cell and squamous cell
carcinomas, as well as lung cancer.8 Synonyms: Chrome yellow; CI pigment
The IARC has concluded that there is suf- yellow 34; CI 77600
cient evidence that inorganic arsenic com-
pounds, including lead arsenate, are skin and Physical Form. Yellow crystals or powder,
lung carcinogens in humans.8 insoluble in water
The 2003 ACGIH threshold limit value-
time-weighted average (TLV-TWA) for lead Uses. Pigment
arsenate as Pb3(AsO4)2 is 0.15 mg/m3.
Exposure. Inhalation
REFERENCES
Toxicology. Lead chromate is a suspected
1. Clarkson TW: Inorganic and organometal human lung carcinogen and can cause chronic
pesticides. In Hayes WJ Jr, Laws ER Jr (eds): lead poisoning.
Handbook of Pesticide Toxicology, Vol 2, pp 531 Lead chromate could potentially pose a
537. New York, Academic Press, 1991 double hazard and cause signs and symptoms
LEAD CHROMATE 425
of chronic lead intoxication (severe gastroin- that nearly half of the samples at the three facil-
testinal disturbances, anemia, neuromuscular ities reached or exceeded the OSHA standards
dysfunction, nephritis, and encephalopathy), for lead and chromium.
and chromium VI toxicity (sensitization der- Chronic animal studies have also yielded
matitis, primary irritant dermatitis, ulcerated varying results. Intratracheal implantation of
nasal mucosa and skin, and nephropathy), lead chromates in rats failed to signicantly
although the latter has not been specically increase the carcinogenic response after 2
observed from lead chromate. years.5 Intrapleural administration caused a 9%
Lead poisoning from lead chromate in the incidence of lung tumors in rats within 1921
chromate pigment industry has been docu- months.6 Intramuscular injection resulted in
mented.1 Evidence of lung cancer attributable lymphomas, renal tumors, brosarcomas, and
solely to lead chromate in the industry has rhabdomyosarcomas at the site of injection in
not been consistent.2,3 Long-term mortality rats.7
was studied in a group of 57 chromate pigment The IARC has concluded that there is
workers who suffered clinical lead poisoning, sufcient evidence in experimental animals and
mostly between 1930 and 1945.1 One death was in humans for the carcinogenicity of lead
attributed to lead poisoning, and there were chromate.8
signicant excesses of deaths from nephritis The 2003 ACGIH threshold limit value-
and cerebrovascular disease. The deaths from time-weighted average (TLV-TWA) for lead
nephritis followed service exceeding 10 years, chromate is 0.05 mg/m3 as Pb and 0.012 mg/m3
whereas the risk of cerebrovascular disease was as Cr with an A2-suspected human carcinogen
unrelated to duration of exposure and even designation.
affected men employed for under 1 year. Other
contemporary workers at the factories showed
no excess mortality from cerebrovascular REFERENCES
disease.
Lung cancer mortality among 1152 men 1. Davies JM: Long term mortality study of
working at three English chromate pigment chromate pigment workers who suffered
factories was studied from the 1930s1940s lead poisoning. Br J Ind Med 41(2):170178,
until 1981.2 Workers exposed only to lead 1984
chromate at one factory experienced no 2. Davies JM: Lung cancer mortality among
increased risk in cause-specic mortality. workers making lead chromate and zinc chro-
mate pigments at three English factories. Br J
Workers at two other factories were exposed to
Ind Med 41(2):158169, 1984
both lead and zinc chromate, and lung cancer
3. Equitable Environmental Health, Inc: An Epi-
mortality was signicantly raised among those demiologic Study of Workers in Lead Chromate
with high or medium exposure for at least 1 Plants. Final report submitted to Dry Color
year before 1955. After that time working con- Manufacturers Assoc, June 25, 1976
ditions were improved, and workers starting 4. NIOSH: Current Intelligence Bulletin 4, Chrome
after that date did not have excess lung cancer Pigment. 6 pp. Cincinnati, OH, US Depart-
deaths. The results provided no indication that ment of Health and Human Services, 1976
lead chromate induced lung cancer, even under 5. Levy LS, Martin PA, Bidstrup PL: Investiga-
conditions conducive to lead poisoning. tion of the potential carcinogenicity of a range
In contrast, another study of 548 men at of chromium containing materials on rat lung.
Br J Ind Med 43:243256, 1986
three lead chromate facilities showed that
6. Heuper WC: Environmental carcinogenesis
workers exposed at two of the facilities had a
and cancers. Cancer Res 21:842857, 1961
threefold excess of lung cancer.3,4 Workers at 7. Furst A, Schlauder M, Sasmore DP: Tumori-
the third facility, who had zinc chromate expo- genic activity of lead chromate. Cancer Res 36:
sure as well as lead chromate exposure, had a 17791783, 1976
signicant excess of lung cancer and stomach 8. IARC Monographs on the Evaluation of the Car-
cancer. An industrial hygiene survey indicated cinogenic Risk of Chemicals to Humans, Vol 49,
426 LINDANE
Physical Form. White crystals that darken 1. Spiegl CJ et al: Acute inhalation toxicity of
on exposure to light lithium hydride. AMA Arch Ind Health 14:
468470, 1956
2. Cracovaner AJ: Stenosis after explosion of
Uses. Reducing agent; condensing agent
lithium hydride. Arch Otolaryngol 80:8792,
with ketones and acid esters; desiccant; as a 1964
source of hydrogen 3. Stokinger HE: The metals. In Clayton GD,
Clayton FE (eds): Pattys Industrial Hygiene and
Exposure. Inhalation; ingestion Toxicology, 3rd ed, rev, Vol 2A, Toxicology,
pp 17281740. New York, Wiley-Interscience,
Toxicology. Lithium hydride is a severe irri- 1981
tant of the eyes, mucous membranes, and skin. 4. Gosselin RE et al: Clinical Toxicology of
The toxicity of lithium hydride differs Commercial Products, 5th ed. p. 105. Baltimore,
markedly from that of the soluble salts of MD, Williams & Wilkins, 1984
lithium because of its vigorous chemical reac-
tivity with water, which produces acute irrita-
tion and corrosion of biological tissues.1
The explosion of a cylinder of lithium
hydride led to eye contact and swallowing of a
small amount of the dust by a technician.2 The
resulting burns caused scarring of both corneas
and strictures of the larynx, trachea, bronchi,
and esophagus; death occurred 10 months later.
MAGNESIUM OXIDE FUME 429
Exposure. Inhalation
Synonyms: None
Toxicology. Magnesite is considered to be a
nuisance dust. Physical Form. Fume
Among 619 workers in a magnesite plant
with 620 years of employment, 13 cases of Sources. From manufacture of refractory
pneumoconiosis were observed, mainly among crucibles, re bricks, magnesia cements, boiler
workers exposed to calcined magnesite.1 The scale compounds
workers were exposed to dust from crude or
calcined magnesite that also contained 13% Exposure. Inhalation
silicon dioxide.
In several reports, the severity of the pneu- Toxicology. Magnesium oxide fume is an
moconioses caused by the action of magnesite irritant of the eyes and nose.
ore dusts was found to be a function of the crys- Examination of 95 workers exposed to an
talline silica content.2 unspecied concentration of magnesium oxide
Adverse health effects have not been dust revealed slight irritation of the eyes and
reported for workers exposed to magnesite nose; the magnesium level in the serum of 60%
containing no asbestos and <1% crystalline of those examined was above the normal upper
silica.3 No cases of human systemic magnesium limit of 3.5 mg/dl.1 No evidence of any pul-
intoxication from inhalation of magnesite have monary inammatory response was found in six
been reported. volunteers after short-term (36 min) exposure
The 2003 ACGIH threshold limit value- to high concentrations (137.0 mg/m3) of ne
time-weighted average (TLV-TWA) for mag- and ultrane magnesium oxide particles.2
nesite is 10 mg/m3, total dust containing no In a very early report, experimental sub-
asbestos and <1% crystalline silica. jects exposed to fresh magnesium oxide fume
developed metal fume fever, an illness similar
to inuenza; effects were fever, cough, oppres-
sion in the chest, and leukocytosis.3 After the
REFERENCES
introduction of a new process resulting in
1. Zeleneva NI: Hygienic, clinical and experi- exposure to magnesium oxide fume in the
mental data on magnesite pneumoconiosis. 1980s, several German foundry workers devel-
Gig Truda Prof Zabol 14:2124, 1970 oped recurrent occupational fever that was also
2. Tokmurzina PU, Dzangosina DM: The bio- interpreted as metal fume fever.4
logical aggressiveness of some types of dust The 2003 ACGIH threshold limit value-
430 MALATHION
time-weighted average (TLV-TWA) for mag- anticholinesterase agents are caused by the
nesium oxide fume is 10 mg/m3. inactivation of the enzyme cholinesterase,
which results in the accumulation of acetyl-
choline at synapses in the nervous system,
REFERENCES skeletal and smooth muscle, and secretory
glands.14 After inhalation of extremely high
1. Stokinger HE: The metals. In Clayton GD, concentrations of malathion, ocular and res-
Clayton FE (eds): Pattys Industrial Hygiene piratory effects may appear simultaneously.
and Toxicology, 3rd ed, Vol 2, Toxicology, pp Ocular effects include miosis, blurring of
17401748. New York, Wiley-Interscience,
distant vision, tearing, rhinorrhea, and frontal
1981
headache. Respiratory effects include tightness
2. Kuschner WG, Wong H, DAlessandro A
et al: Human pulmonary responses to experi- in the chest, wheezing, laryngeal spasms, and
mental inhalation of high concentration ne excessive salivation. Peripheral effects include
and ultrane magnesium oxide particles. excessive sweating, muscular fasciculations,
Environ Health Perspect 105(11):12341237, and weakness. Effects on the central nervous
1997 system include giddiness, confusion, ataxia,
3. Drinker KR, Thomson RM, Finn JL: Metal slurred speech, and convulsions. After inges-
fume fever. The effects of inhaled magnesium tion, anorexia, nausea, vomiting, abdominal
oxide fume. J Ind Hyg 9:187192, 1927 cramps, and diarrhea also appear.
4. Hartmann AL, Hartmann W, Buhlmann AA: Malathion itself has only a slight direct
[Magnesium oxide as cause of metal fume
inhibitory action on cholinesterase, but one
fever]. Schweiz Med Wochenschr 113(21):766
of its metabolites, malaoxon, is an active
770, 1983 (German)
inhibitor.4 Both malathion and malaoxon are
rapidly detoxied by esterases in the liver and
other organs. This rapid metabolism is the
apparent reason for the lower toxicity of
malathion compared with other organophos-
MALATHION phates. Malaoxon inactivates cholinesterase
CAS: 121-75-5 by phosphorylation of the active site of the
enzyme to form the dimethylphosphoryl
C10H19O6PS2 enzyme. Over the following 2448 hours
there is a process, called aging, of conversion
to the monomethylphosphoryl enzyme.
Synonyms: Diethyl mercaptosuccinate, S- Aging is of clinical interest in the treatment of
ester with O,O-dimethyl phosphorodithioate; poisoning, because cholinesterase reactivators
Malathon; carbophos; Cythion 4049 such as pralidoxime (2-PAM, Protopam)
chloride are ineffective after aging has
Physical Form. Colorless to light amber occurred.
liquid The relative safety of malathion to humans
has been demonstrated repeatedly. In a group
Uses. Insecticide of workers with an average exposure of
3.3 mg/m3 for 5 hours (maximum of 56 mg/m3),
Exposure. Inhalation; skin absorption; the cholinesterase levels in the blood were not
ingestion signicantly lowered and no one exhibited
signs of cholinesterase inhibition.5 In a human
Toxicology. Malathion is an antichol- experiment in which four men were exposed 1
inesterase agent, but it is of a relatively hour daily for 42 days to 84.8 mg/m3, there was
low order of toxicity in comparison with other moderate irritation of the nose and the con-
organophosphates. junctiva, but there were no cholinergic signs or
Signs and symptoms of intoxication by symptoms.6
MALATHION 431
13. Huff JE, Bates R, Eustis SL et al: Malathion bronchitis, and, in some cases, asthma.3 In one
and malaoxon: Histopathological reexamina- case, a worker exposed to dust concentrations
tion of the National Cancer Institutes car- below 1 mg/m3 developed cough, rhinitis,
cinogenesis studies. Environ Res 37:154173, breathlessness, and wheezing about 1 month
1985 after initial exposure.4 Symptoms developed
14. IARC Monographs on the Evaluation of the Car-
within minutes of exposure to the dust, which
cinogenic Risk of Chemicals to Humans, Vol 30,
Miscellaneous pesticides, pp 103129. Lyon, occurred during the loading of chemicals into
International Agency for Research on a reactor. Within 3 months his symptoms wors-
Cancer, 1983 ened, and he was admitted to the hospital for
15. Windham GC, Titenko-Holland N, Osorio an acute asthmatic attack. The patient had a
AM et al: Genetic monitoring of malathion- positive challenge test to maleic anhydride but
exposed agricultural workers. Am J Ind Med was negative to phthalic anhydride, to which he
1998 33(2):164174, 1998 was concomitantly exposed. In another report,
occupational allergic IgE-mediated rhinocon-
junctivitis and contact urticaria from maleic
anhydride was conrmed in a worker who pre-
sented with rhinitis, dyspnea, conjunctivitis,
MALEIC ANHYDRIDE and itchy wheals.5
CAS: 108-31-6 The dust on dry skin may result in a
delayed burning sensation, but, on moist skin,
C4H2O3 the sensation is almost immediate, producing
erythema, which may progress to vesiculation.3
Prolonged or repeated exposure also may cause
Synonyms: 2,5-Furandione; cis-butenedioic dermatitis.
anhydride; toxilic anhydride In rats maleic anhydride has an oral LD50
of 1050 mg/kg. It is corrosive to the skin and
Physical Form. White crystalline solid eyes of rabbits with a dermal LD50 of 2620
mg/kg.6 An inhalation study of rats, hamsters,
Uses. In the manufacture of polyester resins, and monkeys exposed to 1.1, 3.3, or 9.8 mg/m3,
fumaric acid, agricultural pesticides, and alkyl respectively, 6 hours/day, 5 days/week for 6
resins months revealed dose-related signs of nasal and
ocular irritations including discharge, sneezing,
Exposure. Inhalation gasping, and coughing for all species.6 No
treatment-related effects were observed in
Toxicology. Maleic anhydride is a severe hematology, clinical chemistry, urinalysis, and
irritant of the eyes; it is an irritant and sensi- pulmonary function tests. Although micro-
tizer of both the skin and respiratory tract and scopic evaluation showed evidence of nasal
may produce asthma on repeated exposure. irritation, there was no evidence of systemic
Workers exposed to vapors from heated toxicity directly attributable to maleic
maleic anhydride developed an intense burning anhydride.
sensation in the eyes and throat, with cough In a study in which rats were injected sub-
and vomiting; exposure to high fume concen- cutaneously with 1 mg of maleic anhydride in
trations caused photophobia, double vision, oil twice weekly for 61 weeks, two of three sur-
and a visual phenomenon of seeing rings viving animals developed brosarcomas, which
around lights.1,2 Exposure of humans to a con- appeared 80 weeks after the start of the exper-
centration of 1.52 ppm resulted in nasal irrita- iment.7 Administered in the diet of rats for 2
tion within 1 minute and eye irritation after years, it was not carcinogenic.8
1520 minutes.3 Among workers repeatedly Pregnant rats treated orally with up to
exposed to 1.252.5 ppm, effects were ulcera- 140 mg/kg/day from day 6 to day 15 of gesta-
tion of nasal mucous membranes, chronic tion had no treatment-related effects on fetal
MANGANESE (and Compounds) 433
symptoms tend to persist or even progress in uptake of manganese from the lung (often
the absence of additional exposure.5 assumed at 100%) compared with the gas-
Exposure levels associated with advanced trointestinal tract (35%).12 Freshly formed
manganism typically have been very high; 150 manganese oxide fumes at high concentrations
cases were found in three mines where levels may cause metal fume fever. This inuenza-like
reached 450 mg/m3.2 More recent studies illness is characterized by chills, fever, sweat-
report cases showing neurological symptoms ing, nausea, and cough. The syndrome begins
and a few signs at lower concentrations. Of 36 412 hours after exposure and lasts for 24 hours
workers exposed to magnesium dioxide dust without causing permanent damage.13
ranging from 6.8 to 42.2 mg/m3, 8 exhibited Anecdotal reports have suggested that
symptoms of manganism.6 Neurological exposure to high levels of manganese dusts
screening of 117 workers with exposures results in decreased libido, impotence, and
greater than 5 mg/m3 revealed 7 cases with decreased fertility.11 In animal studies, growth
denite signs and symptoms.7 Comparison of and maturation of the testes was delayed after
369 workers exposed to 0.320 mg/m3 sug- oral exposure.14 Intratracheal administration
gested that slight neurological disturbances of a single dose of 160 mg manganese/kg in
may occur at exposures less than 5 mg/m3, but rabbits resulted in degeneration of the seminif-
the disturbances seem to be more prevalent at erous tubules with loss of spermatogenesis and
higher exposures.8 Low-level exposure to man- complete infertility within 8 months.15
ganese ranging from 0.19 to 1.39 mg/m3 for Repeated subcutaneous or intraperitoneal
145 years has reportedly caused alterations in injection of manganese dichloride caused
neurophysiological and psychological parame- increased incidences of lymphosarcomas in
ters that were interpreted as preclinical signs of mice.16 Chronic oral exposure of rats to man-
manganism.9 Neurological testing of man- ganese sulfate led to a slight increase in pan-
ganese oxide-exposed workers showed reduced creatic tumors that was not dose responsive.11
hand steadiness and reaction times, which were There is no information relating manganese
signicantly associated with blood manganese exposure to cancer occurrence in humans.11
and with years of manganese exposure, Genotoxic assays have yielded mixed results.11
respectively.10 The 2003 ACGIH threshold limit value-
One of the striking aspects of manganism time-weighted average (TLV-TWA) for man-
is its similarity to Parkinson disease.11 In both ganese as Mn is 0.2 mg/m3.
conditions neuropathologic changes occur in
the basal ganglia with selective destruction of
dopaminergic neurons. REFERENCES
An association between manganese expo-
sure and pulmonary effects including pneumo- 1. EPA: Health Assessment Document for
nia, chronic bronchitis, and airway disability Manganese. Final reportPB84-229954, pp
has been observed. Extrapolation from animal 1353. Washington, DC, US Environmental
studies suggests that it is unlikely that man- Protection Agency, 1984
ganese could be the sole etiologic agent 2. Rodier J: Manganese poisoning in Moroccan
responsible for serious pathologic changes in miners. Br J Ind Med 12:2135, 1955
the lungs. Instead, it is possible that suscepti- 3. Cook DG, Fahn S, Brait KA: Chronic man-
bility to infection is increased.1 ganese intoxication. Arch Neurol 30:5964,
1974
Acute poisoning by manganese is rare but
4. Hine CH, Pasi A: Manganese intoxication.
may occur after ingestion of large amounts
West J Med 123:101107, 1975
of manganese compounds or from inhalation. 5. Barbeau A et al: Role of manganese in dysto-
Inhaled manganese compounds tend to nia. Adv Neurol 14:339352, 1976
produce more severe toxicity than ingested 6. Emara AM, El-Ghawabi SH, Madkour OI et
manganese compounds. This is probably al: Chronic manganese poisoning in the dry
attributable to the difference in route-specic battery industry. Br J Ind Med 28:7882, 1971
MANGANESE CYCLOPENTADIENYL TRICARBONYL 435
Physical Form. Silver-white heavy liquid tremor and behavioral changes will increase
metal with exposures to concentrations of 0.1 mg/m3
or higher.2
Uses. Electrical apparatus; measurement On signicant inhalation of metallic
and control systems such as thermometers and mercury vapors, some people (primarily chil-
sphygmomanometers; agricultural and indus- dren) exhibit a syndrome known as acrodynia,
trial poisons; catalyst; antifouling paint; dental or pink disease. Symptoms include severe leg
practice; gold mining cramps, irritability, erythema, and subsequent
Exposure. Inhalation; skin absorption; peeling of the hands, nose, and soles of the
ingestion feet.6
Renal damage has been reported after both
Toxicology. Acute exposure to high concen- acute and chronic exposure.6,7 Mercury is
trations of mercury vapor causes severe respi- known to accumulate in the kidneys, and case
ratory damage, whereas chronic exposure to studies have described increased creatinine
lower levels is primarily associated with central excretion, proteinuria, hematuria, and degen-
nervous system damage and renal effects. eration of the convoluted tubules in exposed
Inhalation of mercury vapor may produce individuals. Increased levels of the urinary
a metal fume fever-like syndrome, including enzyme NAG (N-acetyl-b-glycosaminidase),
chills, nausea, general malaise, tightness in compared with controls, have been observed in
the chest, and respiratory symptoms.1 High chronically exposed workers.8,9
concentrations cause corrosive bronchitis and Ingestion of mercuric salts causes corrosive
interstitial pneumonitis.2 In the most severe ulceration, bleeding, and necrosis of the gas-
cases, the patient will succumb because of res- trointestinal tract, usually accompanied by
piratory insufciency.2 In one episode involv- shock and circulatory collapse.2,4 If the patient
ing four workers, it was estimated that survives the gastrointestinal damage, renal
mercurial pneumonitis resulted from exposure failure occurs within 24 hours owing to necro-
for several hours to concentrations ranging sis of the proximal tubular epithelium, followed
between 1 and 3 mg/m3.3 by oliguria, anuria, and uremia. Chronic low-
With chronic exposure to mercury vapor, dose exposure to mercury salts, or probably
early signs are nonspecic and include weak- even elemental mercury vapor, may also induce
ness, fatigue, anorexia, loss of weight, and dis- an immunologic glomerular disease.2,4
turbances of gastrointestinal function.2 This Applied locally, mercury may cause sensi-
syndrome has been termed asthenic-vegetative tization dermatitis.1,2
syndrome, or micromercurialism. At higher In several epidemiological studies, no
exposure levels, a characteristic mercurial increased risk for congenital abnormalities,
tremor appears, beginning with intentional stillbirths, or spontaneous abortions was
tremors of ngers, eyelids, and lips, and may observed with occupational exposure to
progress to generalized trembling of the entire mercury.6 Exposure of pregnant rats on gesta-
body and violent chronic spasms of the extrem- tional days 1015 at 0.5 mg/m3 resulted in
ities.2,4 Parallel to the development of tremor, an increased incidence of resorptions; gross
mercurial erethism develops. This is character- cranial defects occurred at this dose when it was
ized by behavioral and personality changes, administered throughout the entire gestational
increased excitability, loss of memory, insom- period.10
nia, and depression. In severe cases, delirium Intraperitoneal injection of metallic
and hallucination may occur. Another charac- mercury in rats has produced sarcomas.1 The
teristic feature of mercury intoxication is sarcomas develop without exception at those
severe salivation and gingivitis. Chronic sites in direct contact with the metal, suggest-
changes in the cornea and lens have also been ing a foreign body reaction rather than chem-
described.5 ical carcinogenesis. Mercuric chloride was
It has been estimated that the probability tested for carcinogenicity in 2-year gavage
of manifesting typical mercurialism with studies in mice and rats.11 Three of 49 high-
438 MERCURY (Alkyl Compounds)
dose male mice had renal tubule tumors, and 6. Agency for Toxic Substances and Disease
in rats there was an increase in squamous cell Registry (ASTDR): Toxicological Prole for
papillomas of the forestomach in males. Mercury, pp 1617. US Department of
There is no conclusive evidence from epi- Health and Human Services, Public Health
demiological studies that mercury increases Service, 1999
7. Zalups RK, Lash LH: Advances in under-
cancer risk in humans.12 In the few studies in
standing the renal transport and toxicity of
which increases have been reported, concomi- mercury. J Toxicol Environ Health 42:144,
tant exposure to other known carcinogens has 1994
confounded the results. The IARC has deter- 8. Barregard L, Hultberg B, Schutz A et al:
mined that there is inadequate evidence in Enzymuria in workers exposed to inorganic
humans for the carcinogenicity of mercury and mercury. Int Arch Occup Health 61:6569,
mercury compounds.12 In animals there is inad- 1988
equate evidence for carcinogenicity of metallic 9. Piikivi L, Ruokonen A: Renal function and
mercury and limited evidence for the carcino- long-term low mercury vapor exposure. Arch
genicity of mercuric chloride. Environ Health 44:146149, 1989
Genotoxic assays have given both positive 10. Steffek AJ, Clayton R, Siew C et al: Effects
of elemental mercury vapor exposure on
and negative results.6
pregnant Sprague-Dawley rats. Teratology
Blood and urine mercury concentrations 35(2):59 (abst), 1987
are commonly used as biomarkers of mercury 11. National Toxicology Program: NTP Technical
exposure.6 Report on the Toxicology and Carcinogenesis
The 2003 ACGIH threshold limit value- of Mercuric Chloride (CAS No. 7487-94-7)
time-weighted average (TLV-TWA) for ele- in F344/N Rats and B6C3F1 Mice (Gavage
mental and inorganic mercury is 0.025 mg/m3, Studies), TR 408. Research Triangle Park,
as Hg, and for aryl mercury compounds is NC, US Department of Health and Human
0.1 mg/m3, as Hg; there is a notation for skin Services, Public Health Service, National
absorption and an A4-not classiable as a Institutes of Health, 1991
human carcinogen designation. 12. IARC Monographs on the Evaluation of Car-
cinogenic Risks to Humans, Vol 58, Beryllium,
cadmium, mercury, and exposures in the glass
manufacturing industry, pp 289324, Lyon,
REFERENCES
International Agency for Research on
Cancer, 1993
1. National Institute for Occupational Safety
and Health: Criteria for a Recommended Stan-
dard . . . Occupational Exposure to Inorganic
Mercury. DHEW (NIOSH) Pub No 73-
11024. Washington, DC, US Government
Printing Ofce, 1973
2. Berlin M: Mercury. In Friberg L et al (eds): MERCURY (Alkyl Compounds)
Handbook on the Toxicology of Metals, 2nd CAS: Varies with compound
ed, Vol II, Specic metals, pp 387445.
Amsterdam, Elsevier, 1986 RHgX
3. Milne J, Christophers A, De Silva P: Acute
mercurial pneumonitis. Br J Ind Med 27:
334338, 1970 Compounds: Methyl mercury; ethyl mercury
4. Goyer RA: Toxic effects of metals. In Klaasen
chloride, dimethyl mercury
CD et al. (eds): Casarett and Doulls Toxicology.
The Basic Science of Poisons, 3rd ed, pp
605609. New York, Macmillan Publishing, Physical Form. Colorless liquids
1986
5. Rosenman KD et al: Sensitive indicators Uses. Fungicides in seed dressings, folial
of inorganic mercury toxicity. Arch Environ sprays; preservative solutions for wood, paper
Health 41:208215, 1986 pulp, textiles, and leather
MERCURY (Alkyl Compounds) 439
adenomas and adenocarcinomas in male mice.9 American National Standard Acceptable Concen-
The IARC has determined that there is inade- trations of Organo (Alkyl) Mercury, ANSI
quate evidence in humans for the carcino- Z37.30-1969. New York, American National
genicity of mercury compounds but there is Standards Institute, 1970
9. Agency for Toxic Substances and Disease
sufcient evidence for the carcinogenicity of
Registry (ATSDR): Toxicological Prole for
methyl mercury chloride in experimental
Mercury, pp 1617. US Department of
animals.10 Organomercury compounds exert a Health and Human Services, Public Health
direct effect on chromosomes by inhibiting the Service, 1999
spindle mechanism, resulting in clastogenic 10. IARC Monographs on the Evaluation of Car-
effects.10 cinogenic Risks to Humans, Vol 58, Beryllium,
Methyl mercury vapor is detectable by cadmium, mercury, and exposures in the glass
smell at concentrations well below those that manufacturing industry, pp 289330. Lyon,
on intermittent exposure could prove International Agency for Research on
hazardous.11 Cancer, 1993
The 2003 ACGIH threshold limit 11. Junghans RP: A review of the toxicity of
methyl mercury compounds with application
value-time-weighted average (TLV-TWA) is
to occupational exposures associated with
0.01 mg/m3, as Hg, with a short-term exposure
laboratory uses. Environ Res 31:131, 1983
limit (STEL) of 0.03 mg/m3 and a notation for
skin absorption.
REFERENCES
MESITYL OXIDE
1. Berlin M: Mercury. In Friberg L et al: Hand- CAS: 141-79-7
book on the Toxicology of Metals, 2nd ed, Vol II,
Specic metals, pp 418445. Amsterdam, (CH3)2CCHCOCH3
Elsevier, 1986
2. Inskip MJ, Piotrowski JK: Review of the
health effects of methylmercury. J Appl Synonyms: Methyl isobutenyl ketone; iso-
Toxicol 5:113133, 1985 propylideneacetone; 4-methyl-3-pentene-2-
3. Anoni: Maximum allowable concentrations of one
mercury compounds. Arch Environ Health
19(6):891905, 1969 Physical Form. Oily, colorless liquid
4. Rustam H, Von Burg R, Amin-Zaki L, El
Hassani S: Evidence for a neuromuscular dis-
order in methylmercury poisoningclinical Uses. Solvent; chemical intermediate
and electrophysiological ndings in moderate
to severe cases. Arch Environ Health 30: Exposure. Inhalation
190195, 1975
5. Dinman BD, Evans EE, Linch AL: Organic Toxicology. Mesityl oxide is an irritant of the
mercuryenvironmental exposure, excre- eyes and mucous membranes; at high concen-
tion, and prevention of intoxication in its trations it causes narcosis in animals, and it is
manufacture. AMA Arch Ind Health 18: expected that severe exposure will produce the
248260, 1958 same effect in humans.
6. Valcinkas J et al: Neurobehavioral assessment Human subjects exposed to 25 ppm for 15
of Mohawk Indians for subclinical indications
minutes experienced eye irritation; at 50 ppm,
of methyl mercury neurotoxicity. Arch
Environ Health 41:269272, 1986 there was also nasal irritation and a persistent
7. Dales LG: The neurotoxicity of alkyl unpleasant taste that remained with many sub-
mercury compounds. Am J Med 53:219232, jects 36 hours after the exposure.1 Liquid
1972 mesityl oxide produces dermatitis with sus-
8. American National Standards Institute, Inc.: tained skin contact.2
METHACRYLIC ACID 441
Rats and guinea pigs exposed 8 hours/day term exposure to various airborne irritants in
to 500 ppm for 10 days had nose and eye irri- rats. J Appl Toxicol 10:8386, 1990
tation and developed slight kidney injury; slight 6. Shell Chemical Corporation: Toxicity Data
liver and lung injury were observed in a few Sheet SC: 57-106. Mesityl Oxide. Ind Hyg Bull,
animals; 13 of 20 animals died from 30 expo- 1957
7. National Institute for Occupational Safety and
sures of 8 hours each at 500 ppm, whereas all
Health: Criteria for Recommended Standard . . .
animals tested at 250 ppm survived.3,4 Guinea Occupational Exposure to Ketones. DHEW
pigs exposed to 2000 ppm for up to 422 minutes (NIOSH) Pub No. 78-173. Washington, DC,
died during or after exposure. Signs of eye and US Government Printing Ofce, 1978
respiratory tract irritation with gradual loss of
corneal and auditory reexes preceded coma
and death.
Exposure of rats to irritant levels of mesityl
oxide (above 137 ppm) caused leucopenia.5
This hematologic effect was regarded as an METHACRYLIC ACID
associative response to the sensory irritation, CAS: 79-41-4
which can act as a stressor to laboratory
animals. C4H6O2
The strong peppermint or honeylike odor
is detectable at 12 ppm; severe overexposure is
unlikely because of local irritation and odor; Synonyms: 2-Methyl-2-propenoic acid; 2-
however, olfactory fatigue may occur.3,6 methylenepropionic acid; a-methacrylic acid
The irritation and systemic effects result-
ing from mesityl oxide exposure appear to be Physical Form. Colorless liquid
more serious than those produced by the lower
ketones.7 Uses. Manufacture of methacrylic resins and
The 2003 ACGIH threshold limit value- plastics
time-weighted average (TLV-TWA) is 15 ppm
(60 mg/m3) with a short-term excursion limit Exposure. Inhalation; skin absorption
(STEL)/ceiling of 25 ppm (100 mg/m3).
Toxicology. Methacrylic acid is an irritant of
the eyes, nose, throat, and skin and is corrosive
on contact.
REFERENCES
Rats exposed to 1300 ppm 5 hours/day for
1. Silverman L, Schulte HF, First MW: Further 5 days showed nose and eye irritation but no
studies on sensory response to certain indus- adverse ndings in blood and urine tests.1
trial solvent vapors. J Ind Hyg Toxicol 28: Exposure of rats to 300 ppm 6 hours/day for
262266, 1946 20 days resulted in no clinical signs, but
2. Shell Chemical Corporation: Safety Data Sheet histopathologic ndings showed slight renal
SC: 57105. Mesityl Oxide, pp 13. Ind Hyg congestion.
Bull, 1957 Applied to the depilated guinea pig
3. Smyth HF Jr, Seaton J, Fischer L: Response of abdomen for 24 hours under an occlusive wrap,
guinea pigs and rats to repeated inhalation of the liquid produced severe irritation.2 The
vapors of mesityl oxide and isophorone. J Ind
liquid also produced severe irritation when
Hyg Toxicol 24:4650, 1942
instilled in rabbit eyes.
4. Specht H, Miller JW, Valaer PJ, Sayers RR:
Acute response of guinea pigs to the inhalation Rats exposed to 300 ppm, 6 hours/day,
of ketone vapors. Natl Inst Health Bull No. 176, during gestation days 620 showed no sign of
1940 developmental toxicity; maternal toxicity was
5. Brondeau MT, Bonnet P, Guenier JP, et al: evidenced by a signicant decrease in body
Adrenal-dependent leucopenia after short- weight gain and food consumption.3
442 METHANE
The 2003 ACGIH threshold limit value- are asymptomatic while breathing air contain-
time-weighted average (TLV-TWA) is 20 ppm ing 1621% oxygen by volume.3 Oxygen
(70 mg/m3). concentrations of 1216% cause tachypnea,
tachycardia, and slight incoordination; con-
centrations of 1014% cause exhaustion on
REFERENCES minimal exertion; and at 610% nausea, vom-
iting, and unconsciousness occur.3 At concen-
1. Gage JC: The subacute inhalation toxicity of trations less than 6% convulsions and cardiac
109 industrial chemicals. Br J Ind Med 27:1, arrest ensue.3
1970 Methane exposure can occur in coal miners
2. Guest D, Katz GV, Astill BD: Aliphatic car-
when methane is trapped within coal seams.
boxylic acids. In Clayton GD, Clayton FE
Because methane is lighter than air, it accumu-
(eds): Pattys Industrial Hygiene and Toxicology,
3rd ed, Vol 2C, Toxicology, pp 49524958. lates rst at the top of an enclosed space;
New York, Wiley-Interscience, 1982 loss of consciousness and collapse thus can be
3. Saillenfait AM, Bonnet P, Gallissot F, et al: lifesaving.2
Developmental toxicities of methacrylic acid, On the skin, liqueed methane can cause
ethyl methacrylate, n-butyl methacrylate, and frostbite.1,2
allyl methacrylate in rats following inhalation The ACGIH has not assigned a numerical
exposure. Toxicol Sci 50(1):136145, 1999 threshold limit value (TLV) for occupational
exposure to methane because the limiting
factor is the available oxygen, the minimal
content of which should be 18% by volume
under normal atmospheric pressure; at con-
METHANE centrations below those required to produce
CAS: 74-82-8 any severe oxygen deprivation, methane pres-
ents an explosive and ammable hazard.4
CH4
REFERENCES
Synonyms: Marsh gas, methyl hydride
1. Sandmeyer EE: Aliphatic hydrocarbons. In
Physical Form. Colorless gas Clayton GD, Clayton FE (eds): Pattys Indus-
trial Hygiene and Toxicology, 3rd ed, Vol 2B,
Toxicology, p 3180. New York, Wiley-
Uses/Sources. As a constituent in cooking
Interscience, 1981
and illuminating gas; in the production of
2. Low LK, Meeks JR, Mackerer CR: Methane.
ammonia, methanol, and chlorohydrocarbons; In Snyder R (ed): Ethel Brownings Toxicity and
it occurs in natural gas and is produced by the Metabolism of Industrial Solvents, 2nd ed, Vol 1,
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Elsevier Science Publishing, 1987
Exposure. Inhalation 3. Osbern LN: Simple asphyxiants. Environmen-
tal and Occupational Medicine. pp 285288, 1983
Toxicology. Methane acts as a simple 4. ACGIH: Methane. Documentation of the
asphyxiant by causing oxygen deprivation at Threshold Limit Values and Biological Exposure
very high concentrations. Indices. 7th ed, p 2. Cincinnati, OH, American
Conference of Governmental Industrial
Methane is practically inert and has no
Hygienists, 2001
demonstrated physiological or toxicological
effects.1,2 Methane can cause asphyxiation in
healthy individuals only when it is present in
very high concentrations or when atmospheric
oxygen has been otherwise reduced. Humans
METHOMYL 443
CH3OCH2CH2OH
REFERENCES
methoxyethanol is 5 ppm (16 mg/m3) with a 12. El-Zein RA, Abdel-Rahman SZ, Morris DL:
notation for skin absorption. Exposure to ethylene glycol monomethyl
ether: clinical and cytogenetic ndings. Arch
Environ Health 57(4):371376, 2002
13. Johanson G: Toxicity review of ethylene
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glycol monomethyl ether and its acetate
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1. Zavon MR: Methyl cellosolve intoxication.
14. Smialowicz RJ, Riddle MM, Luebke RW,
Am Ind Hyg Assoc J 24:3641, 1963
et al: Immunotoxicity of 2-methoxyethanol
2. Ohi G, Wegman DH: Transcutaneous ethyl-
following oral administration in Fischer 344
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the work setting. J Occup Med 20:675676,
1991
1978
15. Exon JH, Mather GG, Bussiere JL, et al:
3. Rowe VK, Wolf MA: Derivatives of glycols.
Effects of subchronic exposure of rats to 2-
In Clayton GD, Clayton FE (eds): Pattys
methoxyethanol or 2-butoxyethanol: thymic
Industrial Hygiene and Toxicology, 3rd ed, rev,
atrophy and immunotoxicity. Fundam Appl
Vol 2C, Toxicology, pp 39113919. New
Toxicol 16:830840, 1991
York, Wiley-Interscience, 1982
16. Williams WC, Riddle MM, Copeland CB,
4. Grant D, Sulsh S, Jones HB, et al: Acute tox-
et al: Immunological effects of 2-
icity and recovery in the hemopoietic system
methoxyethanol administered dermally or
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orally to Fischer 344 rats. Toxicology 98(13):
monomethyl and monobutyl ethers. Toxicol
215223, 1995
Appl Pharmacol 77:187200, 1985
17. National Institute for Occupational Safety
5. National Institute for Occupational Safety
and Health: Criteria for a Recommended Stan-
and Health: NIOSH Current Intelligence
dard: Occupational Exposure to Ethylene Glycol
Bulletin 39, Glycol Ethers. DHHS (NIOSH)
Monomethyl Ether, Ethylene Glycol Monoethyl
Pub No 83-112, p 22. Washington, DC, US
Ether, and Their Acetates. Pub No 91-119,
Government Printing Ofce, May 2, 1982
Cincinnati, OH, US Department of Health
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and Human Services, Public Health Service,
inhalation toxicity of ethylene glycol
1991
monomethyl ether and propylene glycol
monomethyl ether in rats and mice. Toxicol
Appl Pharmacol 61:368377, 1981
7. Hanley TR Jr, et al: Comparison of the
teratogenic potential of inhaled ethylene
glycol monomethyl ether in rats, mice and
rabbits. Toxicol Appl Pharmacol 75:409422,
2-METHOXYETHYL ACETATE
1984
8. Nagano K et al: Embryotoxic effects of CAS: 110-49-6
ethylene glycol monomethyl ether in mice.
Toxicology 20:335343, 1981 CH3COOCH2CH2OCH3
9. Horton VL, Sleet RB, John-Greene JA, et al:
Developmental phase-specic and dose-
related teratogenic effects of ethylene glycol Synonyms: Ethylene glycol monomethyl ether
monomethyl ether in CD-1 mice. Toxicol Appl acetate; EGMEA; 2-MEA; methyl cellosolve
Pharmacol 80:108118, 1985 acetate; methyl glycol acetate
10. Scott WJ, Fradkin R, Wittfoht W, et al: Ter-
atologic potential of 2-methoxyethanol and
Physical Form. Colorless liquid
transplacental distribution of its metabolite,
2-methoxyacetic acid, in non-human pri-
mates. Teratology 39:363373, 1989 Uses. Lacquer industry; textile printing;
11. Feuston MH, Kerstetter SL, Wilon PD: manufacture of photographic lm, coatings,
Teratogenicity of 2-methoxyethanol applied and adhesives
as a single dermal dose to rats. Fundam Appl
Toxicol 15:448456, 1990 Exposure. Inhalation; skin absorption
448 4-METHOXYPHENOL
REFERENCE
The approximate LC50 for mice exposed males occurred concomitant with reduced body
to airborne concentrations for 1 hour was weight.9
630 ppm, and for a 4-hour exposure it was The liquid was rapidly absorbed through
400 ppm.1 Exposure to 75 ppm for 8 hours the skin of a rabbit and caused death after
caused no deaths, but respiratory difculties 3 hours at a dose of 2.0 ml/kg.1 Skin irritation
and convulsions were observed. In a study at the site of application was negligible. One
with rats exposed at concentrations between drop in the eye of a rabbit caused transient
3180 and 5700 ppm the clinical symptoms, irritation.
rapid unconsciousness with convulsions and The 2003 ACGIH threshold limit value-
lethality, suggested that the acute toxicity time-weighted average (TLV-TWA) for
is predominantly caused by metabolically methylacrylonitrile is 1 ppm (2.7 mg/m3) with a
formed cyanide.2 Cyanide reacts readily notation for skin absorption.
with cytochrome oxidase in mitochondria and
inhibits cellular respiration. Cyanide antidotes
were also effective against methylacrylonitrile REFERENCES
toxicity. Metabolic studies have suggested that
methylacrylonitrile may also exert toxic effects 1. McOmie WA: Comparative toxicities of
by directly interacting with the cytoplasmic methacrylonitrile and acrylonitrile. J Ind Hyg
(hemoglobin) and membrane proteins of red Toxicol 31:113, 1949
blood cells.3 A signicant decrease in the 2. Peter H, Bolt HM: Effect of antidotes of the
red blood cell count and in the level of acute toxicity of methacrylonitrile. Int Arch
Occup Environ Health 55:175177, 1985
hemoglobin, probably from hemolysis, has
3. Cavazos R Jr, Farooqui MYH, Day WW,
been observed after methacrylonitrile
et al: Disposition of methacrylonitrile in rats
administration.4 and distribution in blood components. J Appl
The oral LD50 was 2025 mg/kg in mice Toxicol 9:5357, 1989
and 2550 mg/kg in rats.5 Symptoms included 4. Samikkannu T, Vasanthakumari V, Devaraj
weakness, tremors, cyanosis, and convulsions. SN: Haematological and erythrocyte mem-
When beagle dogs were exposed 7 hours/day, brane changes induced by methacrylonitrile.
5 days/week to 13.5 ppm over a period of 90 Toxicol Lett 92(1):1520, 1997
days, two of three animals exhibited convul- 5. Hartung R: Cyanides and nitriles. In Clayton
sions and loss of motor control in the hind GD, Clayton FE (eds): Pattys Industrial
limbs about halfway through the exposure Hygiene and Toxicology, 3rd ed, rev, Vol 2C,
Toxicology, pp 48674868. New York, Wiley-
period.6 No effects occurred at 3.2 ppm.
Interscience, 1972
In 2-year gavage studies of mice (adminis-
6. Pozzani UC, Kinhead ER, King JJ: The mam-
tered 1.5, 3, or 6 mg/kg/day) and rats (admin- malian toxicity of methacrylonitrile. Am Ind
istered 3, 10, or 30 mg/kg/day) there was no Hyg Assoc J 29:202, 1968
evidence of carcinogenic activity.7 Signicant 7. National Toxicology Program (NTP): Toxicol-
increases in nonneoplastic lesions of the nose ogy and Carcinogenesis Studies of Methacryloni-
and liver occurred in high-dose rats.7 trile in F344N Rats and B6C3F1 Mice (Gavage
Methacrylonitrile was not mutagenic in Studies). NTP Technical Report Series No.
Salmonella or Drosophila assays; it was also neg- 497, pp 1226, 2001
ative in the micronucleus test.7 8. George JD, Price CJ, Marr MC, et al: Evalu-
Prenatal exposure of rats and rabbits to ation of the developmental toxicity of
methacrylonitrile in Sprague-Dawley rats and
doses of methylacrylonitrile that did not induce
New Zealand White rabbits. Fundam Appl
toxicity in the adults also did not induce devel-
Toxicol 34(2):249259, 1996
opmental toxicity in the fetus.8 Methylacry- 9. Wolfe GW, Delaney JC: Final Report on the
lonitrile was also determined not to be a Reproductive Toxicity of Methacrylonitrile (CAS
selective reproductive toxin. In a continuous #126-98-7) Administered in Diet to Sprague-
breeding study in rats, doses that caused Dawley Rats. NTIS Technical Report
decreases in epididymal sperm density of F1 (NTIS/PB97-176390), 1997
METHYL ALCOHOL 453
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METHYLAL
CAS: 109-87-5 1. Weaver FL Jr, Hough AR, Highman B,
Fairhall LT: The toxicity of methylal. Br J Ind
CH2(OCH3)2 Med 8:279283, 1951
2. Gage JC: The subacute inhalation toxicity
of 109 industrial chemicals. Br J Ind Med
Synonyms: Dimethoxymethane; formal; meth- 27:118, 1970
ylene dimethyl ether
dosis has been found to closely parallel the in sensorimotor development in males, and
severity of poisoning.1 Accumulated evidence a severe wasting syndrome in females after
suggests that chronic exposure to 12008300 1 year.9
ppm can lead to impaired vision.1 Exposure to There is no evidence from animal studies
vapor concentrations ranging from 365 to 3080 to suggest that methyl alcohol is carcinogenic,
ppm may result in blurred vision, headache, but the lack of an appropriate animal model is
dizziness, and nausea.4 noted.7 In general, it was not genotoxic in a
In the eyes, the liquid has caused super- variety of in vivo and in vitro assays.7,8
cial lesions of the cornea that were of a non- The 2003 ACGIH threshold limit
serious nature.1 Prolonged or repeated skin value-time-weighted average (TLV-TWA) for
contact will cause dermatitis, erythema, and methyl alcohol is 200 ppm (262 mg/m3) with a
scaling.1 short-term excursion limit (STEL) of 250 ppm
The presence of an asymptomatic latent (328 mg/m3) and a notation for skin absorption.
period after ingestion suggests that methyl
alcohol must be metabolized before toxicity is
fully manifest.1 This concept also explains the REFERENCES
discrepancy between plasma concentrations of
methyl alcohol and clinical signs of toxicity.5 1. National Institute for Occupational Safety and
Furthermore, methyl alcohol poisoning is ame- Health, US Department of Health, Education
liorated by ethanol, a substance with greater and Welfare: Criteria for a Recommended Stan-
afnity than methyl alcohol for alcohol dehy- dard Occupational Exposure to Methyl Alcohol.
DHEW (NIOSH) 76148, pp 6875. Wash-
drogenase, which is responsible for the initial
ington, DC, US Government Printing Ofce,
step in metabolism.5 The metabolite formate
1976
appears to be the mediator of ocular injury and 2. Henson EV: The toxicology of some aliphatic
acidosis.6 The individual variations in activity alcoholsPart II. J Occup Med 1:497502,
of the alcohol dehydrogenase systems, which 1960
are responsible for the oxidative metabolism of 3. Grant WM: Toxicology of the Eye, 3rd ed, pp
methyl (and ethyl) alcohol, may well account 591596. Springeld, IL, Charles C. Thomas,
for the wide variation in the individual 1986
responses observed with methyl alcohol 4. Frederick LJ et al: Investigation and control of
poisoning.1 occupational hazards associated with the use of
Metabolic differences also account for the spirit duplicators. Am Ind Hyg Assoc J 45:
5155, 1984
great species variability in methyl alcohol
5. Ekins BR et al: Standardized treatment of
toxicity with humans and nonhuman primates
severe methanol poisoning with ethanol and
being uniquely sensitive.7 (A relatively poor hemodialysis. West J Med 142:337340, 1985
ability to metabolize the methanol- 6. Osterloh JD et al: Serum formate concentra-
metabolized formate in these species leads to tions in methanol intoxication as a criterion for
increased blood formate levels and subsequent hemodialysis. Ann Intern Med 104:200203,
metabolic acidosis and neuronal toxicity.) 1986
In developmental animal studies, methyl 7. World Health Organization: Environmental
alcohol produced malformations in mice and Health Criteria 196 Methanol, pp 1160,
rats after inhalation of 15,000 or 20,000 ppm, Geneva, International Programme on Chemi-
respectively, for 67 hours/day during gesta- cal Safety (IPCS), 1997
8. Lington AW, Bevan C: Alcohols. In Clayton
tion; slight maternal toxicity was also
GD and Clayton FE (eds): Pattys Industrial
observed.8 A recent study in Macaca fasicularis
Hygiene and Toxicology, 4th ed, rev, Vol IID,
monkeys exposed to 200, 600, or 1800 ppm Toxicology, pp 26002609. New York, Wiley-
methyl alcohol before and during pregnancy Interscience, 1994
found exposure-associated effects in the off- 9. Burbacher T, Grant K, Sheppard L, et al:
spring including low arousal of neonates, Reproductive and offspring developmental ef-
changes in visual recognition memory, delays fects following maternal inhalation exposure to
METHYL n-AMYL KETONE 455
methanol in nonhuman primates. Govt Reports caused pulmonary edema at 1 week; associated
Announcements & Index (GRA&I), Issue 10, interstitial pneumonitis progressed to brosis.3
2002 (The authors note that methylamine, a
metabolite of methyl isocyanate, may con-
tribute to the pulmonary brosis found in
Bhopal victims who were exposed to massive
amounts of methyl isocyanate.)
In the eyes of rabbits, one drop of a 5%
METHYLAMINE aqueous solution caused conjunctival hemor-
CAS: 74-89-5 rhage, supercial corneal opacities, and
edema.4 On the skin of animals, a 40% solution
CH3NH2 caused necrosis.1
The ammonia-like odor is detectable at
less than 5 ppm.
Synonyms: Monomethylamine; aminomethane The 2003 ACGIH threshold limit value-
time-weighted average (TLV-TWA) is 5 ppm
Physical Form. Gas (6.4 mg/m3) with a short-term excursion limit
(STEL)/ceiling of 15 ppm (19 mg/m3).
Uses. Tanning and dyeing industries; fuel
additive; chemical intermediate in the pro-
duction of pharmaceuticals, insecticides, and REFERENCES
surfactants
1. Beard RR, Noe JT: Aliphatic and alicyclic
Exposure. Inhalation amines. In Clayton GD, Clayton FE (eds):
Pattys Industrial Hygiene and Toxicology, 3rd ed,
rev, Vol 2B, Toxicology, pp 31353173. New
Toxicology. Methylamine is a severe irritant
York, Wiley-Interscience, 1981
of the eyes and skin; in animals repeated
2. Kinney LA, Valentine R, Chen HC, et al:
inhalation causes upper respiratory tract Inhalation toxicology of methylamine. Inhal
irritation. Toxicol 2:2935, 1990
In humans, brief exposure at 20100 ppm 3. Sriramachari S, Jeevaratnam K: Comparative
is said to produce transient irritation of the toxicity of methyl isocyanate and its hydrolytic
eyes, nose, and throat.1 No symptoms of irrita- derivatives in rats. II. Pulmonary histopathol-
tion are produced from longer exposures at less ogy in the subacute and chronic phases. Arch
than 10 ppm. On the basis of the irritant prop- Toxicol 69(1):4551, 1994
erties of methylamine, it is possible that severe 4. Grant WM: Toxicology of the Eye, 3rd ed, pp
exposure may cause pulmonary edema. 606607. Springeld, IL, Charles C. Thomas,
1986
In rats, when administered orally as the
base in a 40% aqueous solution, the LD50 was
0.10.2 g/kg.1 Repeated exposures of rats at
750 ppm 6 hours/day, 5 days/week for 2 weeks
caused severe body weight loss, liver damage, METHYL n-AMYL KETONE
hematopoietic abnormalities, and some CAS: 110-43-0
deaths.2 Histopathologic effects, which were
also observed with similar dosing at 250 ppm, CH3COC5H11
included necrosis and ulceration of the respira-
tory mucosa of the nasal turbinates and atrophy
with regeneration of the olfactory mucosa. Synonym: 2-Heptanone; methyl pentyl
Repeated exposures at 75 ppm produced mar- ketone
ginal changes in the olfactory mucosa.
Inhalation exposure of rats to 19 mmol/l Physical Form. Liquid
456 N-METHYL ANILINE
recovered within 6 months.5 In two cases of killed in a moribund state. At 160 ppm for
chronic methyl bromide poisoning there were 6 hours/day there was high mortality in rats
central neurological symptoms (dizziness, and mice. Primary target organs were the
unstable gait, and reduced visual acuity) fol- brain, kidney, nasal cavity, heart, adrenal gland,
lowed by peripheral neuropathy that persisted liver, and testis. Nephrosis was likely a major
for at least 2 years.6 cause of morbundity and death of mice,
It is unlikely that bromide ion resulting whereas neuronal necrosis may have been the
from metabolic conversion of methyl bromide principal lesion contributing to the early death
plays a signicant role in the toxicity of methyl of some rats. At 66 ppm, rats and guinea pigs
bromide.7 Blood bromide levels after methyl showed no response for up to 6-month expo-
bromide poisoning are much lower than those sure but rabbits and monkeys developed
associated with intoxication by inorganic paralysis within 3 months; the paralysis was
bromide salts. Concentrations of 100 mg/l have particularly severe in rabbits, which also had
been associated with death following methyl pulmonary lesions. No toxic response was
bromide exposure, whereas blood bromide observed at 17 ppm.
levels of 1000 mg/l or greater have been Repeated exposure at 70 ppm of female rats
observed after therapeutic administration of before and during pregnancy did not cause
inorganic bromides in the absence of signs of maternal or embryo toxicity, but severe neuro-
intoxication.8 A recent report of six methyl toxicity and mortality were produced in
bromide poisonings showed serum bromide rabbits.13 No developmental effects were noted
concentrations at the time of hospital admis- in fetuses of rats or rabbits administered methyl
sion to be a poor predictor of survival.8 One bromide by gavage during gestation despite
fatal case had an antemortem bromide level toxicity to dams at the highest dose.14 In a two-
of 108 mg/l, whereas a survivor measured generation reproduction study of rats fed diets
321 mg/l. In another instance, nine workers containing 500 ppm total bromine, food con-
exposed to 200 ppm or more on two consecu- sumption was lower in the F1 parental females
tive days had varying symptoms ranging from and F2 pups had lowered body weights.15 No
headache to severe reactive myoclonus and other treatment-related changes were found
convulsions.9 A direct association between for clinical signs, estrous cycle, sperm count
serum bromide concentrations and neurologi- and morphology, mating, fertility, gestation,
cal symptoms was absent. litter size, pup viability, and gross or
Contact with the eye by the gas or liquid histopathologic examination.
resulted in transient irritation and conjunctivi- In a 90-day study, 50 mg/kg administered
tis.10 Minor skin exposure to the liquid pro- by gavage 5 days per week caused squamous
duced erythema and edema.11 Prolonged or cell carcinomas of the forestomach in 13 of 20
repeated contact resulted in deeper burns with rats; a dose-related incidence of hyperplasia
delayed vesiculation.11 It is doubtful that sig- was observed at the 2 and 10 mg/kg levels.16 A
nicant cutaneous absorption occurs. Although second study using the same experimental
victims of skin exposure may show symptoms design found that the early hyperplastic lesions
of neurotoxicity, inhalation is considered the of the forestomach regressed after discontinu-
likely cause.11 ation of treatment and should not be consid-
Toxicological studies in animals indicate ered neoplasms.17 Rats fed diets containing
a steep concentration-response curve for 500 ppm total bromine after fumigation with
methyl bromide and clear species and sex dif- methyl bromide for 2 years showed no evidence
ferences in sensitivity.12 Inhalation exposure up of a carcinogenic response.18 Inhalation of up
to 120 ppm 6 hours/day for 13 weeks resulted to 90 ppm, 6 hours/day, 5 days/week for 29
in 17% mortality in male mice but no mortal- months caused degenerative and hyperplastic
ity in female mice or rats of either sex. No changes of the nasal olfactory epithelium, an
methyl bromide-induced histologic lesions increased incidence of lesions in the heart,
were observed in either species, including mice hyperkeratosis in the esophagus and forestom-
METHYL BROMIDE 459
such central nervous system damage is perma- Hygiene and Toxicology, 3rd ed, Vol 2C, Toxi-
nent, whereas the peripheral nervous system cology, pp 47414747. New York, Wiley-
shows regeneration.9 Interscience, 1982
Testicular atrophy of the germinal epithe- 2. Bos PMJ, de Mik G, Bragt PC: Critical
lium was seen in male rats administered review of the toxicity of methyl n-butyl
ketone: risk from occupational exposure. Am
660 mg/kg by gavage for 90 days.10 A reduction
J Ind Med 20:175194, 1991
in total circulating white blood cells has also 3. Billmaier D, Yee HT, Allen N, et al: Periph-
been reported after MBK exposure.1 eral neuropathy in a coated fabrics plant. J
Pregnant rats exposed to 1000 or 2000 ppm Occup Med 16:665671, 1974
MBK during 21 days of gestation had reduced 4. Mendell JR, Saida K, Ganansia MF, et al:
weight gain; a signicant decrease in the Toxic polyneuropathy produced by methyl
number and weight of live offspring was also n-butyl ketone. Science 185:787789, 1974
observed in the high-dose group. Behavioral 5. Allen N, Mendell JR, Billmaier DJ, et al:
alterations, including decits in avoidance con- Toxic polyneuropathy due to methyl n-butyl
ditioning and increased activity, occurred in the ketone. Arch Neurol 32:209218, 1975
offspring of both groups.11 6. Gilchrist MA, et al: Toxic peripheral poly-
neuropathy. Morb Mort Weekly Rep 23:910,
2,5-Hexanedione was found to be a major
1974
metabolite of MBK in several animal species; 7. Johnson BL, Anger WK, Setzer JV, et al:
peripheral neuropathy occurred in rats Neurobehavioral effects of methyl n-butyl
after daily subcutaneous injection of 2,5- ketone and methyl n-amyl ketone in rats
hexanedione at a dose of 340 mg/kg 5 days/ and monkeys: A summary of NIOSH inves-
week for 19 weeks.1214 Nonneurotoxic tigations. J Environ Path Toxicol 2:113133,
aliphatic monoketones, such as methyl ethyl 1979
ketone, enhance the neurotoxicity of MBK. In 8. Spencer PS, Schaumburg HH, Raleigh RL,
one rat study, the longer the carbon chain et al: Nervous system degeneration pro-
length of the nonneurotoxic monoketone, the duced by the industrial solvent methyl
greater the potentiating effect on MBK. It is n-butyl ketone. Arch Neurol 32:219222,
1975
expected that exposure to a subneurotoxic dose
9. Schaumberg HH, Spencer PS: Environmen-
of MBK, plus high doses of some aliphatic tal hydrocarbons produce degeneration in
monoketones, would also produce neurotoxic- cat hypothalamus and optic tract. Science 199:
ity. In addition, MBK itself potentiates the 199200, 1978
toxicity of other chemicals.2 10. Krasavage WJ, ODonoghue JL, DiVincenzo
MBK can cause mild eye irritation and GD, et al: The relative neurotoxicity of
minor transient corneal injury. Repeated skin methyl-n-butyl ketone and n-hexane and
contact may be irritating because of the their metabolites. Toxicol Appl Pharmacol 52:
ability of MBK to defat the skin, resulting in 433441, 1980
dermatitis.1 11. Peters MA, Hudson PM, Dixon RL: The
MBK has an acetone-like odor detectable effect of totigestational exposure to methyl-
n-butyl ketone has on postnatal development
at 0.076 ppm.15
and behavior. Ecotoxicol Environ Safety 5:291
The 2003 ACGIH threshold limit value- 306, 1981
time-weighted average (TLV-TWA) is 5 ppm 12. Scala RA: Hydrocarbon neuropathy. Ann
(20 mg/m3) with a TLV-short-term excursion Occup Hyg 19:293299, 1976
limit (STEL) of 10 ppm (40 mg/m3) and a nota- 13. Raleigh RL, Spencer PS, Schaumberg HH:
tion for skin absorption. Methyl-n-butyl ketone. J Occup Med 17:286,
1975
14. Granvil CP, Sharkawi M, Plaa GL: Metabolic
REFERENCES fate of methyl n-butyl ketone, methyl
isobutyl ketone and their metabolites in mice.
1. Krasavage WJ, et al: Ketones. In Clayton Toxicol Lett 70:263267, 1994
GD, Clayton FE (ed.): Pattys Industrial 15. ASTDR (Agency for Toxic Substances and
462 METHYL CHLORIDE
Disease Registry): Toxicological Prole for 2- gait; symptoms disappeared over a period of
Hexanone. 92pp. US Department of Health 13 months after removal from exposure.1 In
and Human Services, Public Health Service, one study, however, 10 of 24 survivors of
Atlanta, GA, 1992 methyl chloride poisoning experienced mild
neurological or psychiatric sequelae 13 years
after the incident.4 Subsequent follow-up of
this same small cohort 20 years later also
revealed an excess mortality from cardiovascu-
METHYL CHLORIDE lar diseases and an elevated risk for all cancers
CAS: 74-87-3 and lung cancer in particular.5
Concentrations ranging from 150,00 to
CH3Cl 300,000 ppm are expected to kill most animals
in a short time; levels of 20,00040,000 are
considered dangerous within 60 minutes.
Synonyms: Chloromethane; monochlorome- Mice exposed continuously to 100 ppm
thane or intermittently to 400 ppm for 11 days had
histopathologic evidence of brain lesions char-
Physical Form. Colorless gas acterized by degeneration and atrophy of the
granular layer of the cerebellum.6 Daily expo-
Uses. As a chemical intermediate, especially sure of mice to 1000 ppm for 2 years induced
in industrial methylating reactions; as a a functional limb muscle impairment and
blowing agent for plastic foams; rarely as a atrophy of the spleen.7 At 2400 ppm adminis-
refrigerant tered daily, there were renal and hematopoietic
effects and the mice were moribund by day 9.6
Exposure. Inhalation For rats exposed to 3500 ppm 6 hours/day for
up to 12 days, clinical signs included severe
Toxicology. Methyl chloride is a central diarrhea, incoordination of the forelimbs, and,
nervous system depressant; it may cause kidney in a few animals, hind limb paralysis and
and liver damage, and it is a reproductive toxin convulsions.8
and a teratogen in experimental animals. Daily exposure of male rats to 1500 ppm
Human fatalities have occurred from a for 10 weeks caused severe testicular degener-
single severe exposure or prolonged exposures ation; no males sired litters during a subsequent
to lower concentrations.1 Acute poisoning in 2-week breeding period.9
humans is characterized by a latent period of An increase in fetal heart defects was
several hours, followed by dizziness, drowsi- observed in mice after 12 days of repeated
ness, staggering gait and slurred speech; exposure in utero to 500 ppm.10
nausea, vomiting and diarrhea; double vision; Rats (F344) and mice (B6C3F1) were
weakness, paralysis, convulsions, cyanosis, and exposed at 0, 50, 225, or 1000 ppm 6 hours/day,
coma.13 Renal or hepatic damage and anemia 5 days/week for 2 years. An excess of tumors
may also occur. Recovery from an acute expo- was found only in male mice of the highest
sure usually occurs within 56 hours but may exposure group; cystadenomas and adenomas
take as long as 30 days or more in massive expo- of the renal cortex and papillary cystadenomas
sures.1 Recurrence of symptoms after apparent were reported.11,12 Subsequent mechanistic
recovery without further exposure has been studies have shown that methyl chloride does
observed in the immediate postexposure not exhibit direct methylation of DNA in
period. Six workers chronically exposed to vivo.12 It has been suggested that methyl
200400 ppm for 23 weeks developed symp- chloride, at high doses, is metabolically
toms of intoxication including confusion, blur- transformed to formaldehyde, which causes
ring of vision, slurred speech, and staggering DNA-protein cross-links and DNA single-
METHYL 2-CYANOACRYLATE 463
strand breaks.13 It has also been noted that such 9. Hamm TE Jr: Reproduction in Fischer-344
a mechanism is not likely to be operative in rats exposed to methyl chloride by inhalation
humans at low exposure concentrations.12 for two generations. Fundam Appl Toxicol 5:
Methyl chloride was mutagenic to bacteria 568577, 1985
and genotoxic in a number of mammalian cell 10. Wolkowski-Tyl R et al: Evaluation of heart
malformations in B6C3F1 mouse fetuses in-
systems in vitro.14 It gave positive results in the
duced by in utero exposure to methyl chlo-
dominant lethal test in rats in vivo.14 ride. Teratology 27:197206, 1983
NIOSH recommends that methyl chloride 11. NIOSH. Current Intelligence Bulletin 43.
be considered a potential occupational terato- Monohalomethanes. Methyl Chloride CH3Cl
gen and carcinogen.11 Methyl Bromide CH3Br Methyl Iodide CH3I.
The IARC states that there is inadequate DHHS(NIOSH) Pub No 84117, p 22. Sept
evidence for the carcinogenicity of methyl 27, 1984
chloride to experimental animals and humans.14 12. Bolt HM, Gansewendt B: Mechanisms of
The 2003 ACGIH threshold limit value- carcinogenicity of methyl halides. CRC Rev
time-weighted average (TLV-TWA) for methyl Toxicol 23:237253, 1993
chloride is 50 ppm (103 mg/m3) with a short- 13. Ristau C, Bolt HM, Vangala RR: Formation
and repair of DNA lesions in kidneys of male
term excursion limit (STEL)/ceiling of 100 ppm
mice after acute exposure to methyl chloride.
(207 mg/m3) and a notation for skin absorption. Arch Toxicol 64:254256, 1990
14. IARC Monographs on the Evaluation of the
REFERENCES Carcinogenic Risk of Chemicals to Humans,
Vol 71, Re-evaluation of some organic chem-
1. Scharnweber HC, Spears GN, Cowles SR: icals, hydrazine and hydrogen peroxide, pp
Chronic methyl chloride intoxication in six 737747. Lyon, International Agency for
industrial workers. J Occup Med 16:112113, Research on Cancer, 1999
1974
2. Spevak L, Nadj V, Felle D: Methyl chloride
poisoning in four members of a family. Br J
Ind Med 33:272274, 1976
3. Hansen H, Weaver NK, Venable FS: Methyl METHYL 2-CYANOACRYLATE
chloride intoxication. AMA Arch Ind Hyg CAS: 137-05-3
Occup Med 8:328334, 1953
4. Gudmundsson G: Letter. Methyl chloride
C5H5NO2
poisoning 13 years later. Arch Environ Health
32:236237, 1977
5. Rafnsson V, Gudmundsson G: Long-term
follow-up after methyl chloride intoxication. Synonyms: Mecrylate; methyl cyanoacrylate
Arch Environ Health 52(5):355359, 1997
6. Landry TD, Quast JF, Gushow TS, et al: Physical Form. Colorless liquid
Neurotoxicity of methyl chloride in continu-
ously versus intermittently exposed female Uses. In high-bond strength, fast-acting
C57BL/6 mice. Fundam Appl Toxicol 5:8798, glues (e.g., Krazy Glue); surgical use as tissue
1985 adhesive
7. Pavokv KL et al: Major ndings in a twenty-
four month inhalation toxicity study of
Exposure. Inhalation
methyl chloride in mice and rats. Toxicologist
2:161, 1982
8. Morgan KT, Swenberg JA, Hamm TE Jr, Toxicology. Methyl 2-cyanoacrylate is an
et al: Histopathology of acute toxic response irritant of the eyes and nose and can induce
in rats and mice exposed to methyl chloride occupational asthma.
by inhalation. Fundam Appl Toxicol 2:293299, Nose and eye irritation occur at levels of
1982 25 ppm; at 20 ppm there is lacrimation and
464 METHYLCYCLOHEXANE
rhinorrhea, and concentrations greater than 2. Lozewicz S, Davison AG, Hopkirk A, et al:
50 ppm produce painful irritation.1 Occupational asthma due to methyl methacry-
A 52-year-old man exposed to undeter- late and cyanoacrylates. Thorax 40:836839,
mined concentrations of methyl cyanoacrylate 1985
in an adhesive developed respiratory symptoms 3. World Health Organization: Concise Interna-
tional Chemical Assessment Document (CICAD)
after 1 month on the job.2 Eleven weeks after
36, Methyl Cyanoacrylate and Ethyl Cyanoacry-
stopping work, the patient was challenged by late. pp 119. International Programme on
working with the adhesive for 25 minutes. This Chemical Safety (IPCS), Geneva, 2001
provoked a 42% fall in FEV1 15 hours after 4. ACGIH: Methyl 2-cyanoacrylate. Documenta-
the challenge and symptoms of rhinitis during tion of the TLVs for Substances in Workroom
most of the day. Other studies have linked ex- Air, 6th ed, pp 965966. Cincinnati, OH,
posure to methyl 2-cyanoacrylate with occur- American Conference of Governmental
rences of asthma, but no conclusions can be Hygienists, 1991
drawn regarding whether asthma was induced 5. Grant WM: Toxicology of the Eye, 3rd ed,
by an allergenic or irritation mechanism p 291. Springeld, IL, Charles C. Thomas,
because challenge concentrations were directly 1986
6. Morgan SJ, Astbury NJ: Inadvertent self
irritant.3
administration of superglue: a consumer
The LC50 in rats was 101 ppm for 6 hours.4 hazard. Br Med J 289:226227, 1984
Repeated exposure of rats to 31.3 ppm, 6 7. Rietveld ED, Garnaat MA, Seutter-Berlage F:
hours/day, 5 days/week, for 12 exposures Bacterial mutagenicity of some methyl 2-
caused no signs of mucous membrane irrita- cyanoacrylates and methyl 2-cyano-3-
tion. The acute dermal toxicity is low, with the phenylacrylates. Mutat Res 188:97104, 1987
dermal LD50 in guinea pigs being greater than
10 ml/kg.
When methyl 2-cyanoacrylate was applied
as an adhesive to rabbit or human eyes, some
reports described corneal haze and inamma- METHYLCYCLOHEXANE
tion; other reports with highly puried mate- CAS: 108-87-2
rial indicated less toxicity.5 Mistaken use in
the eyes as eyedrops has caused immediate C7H14
brief smarting and rm gluing of the eyelids
together.6 Acetone on a swab can be used to
unglue the lids and remove the glue from the Synonyms: Cyclohexylmethane; hexahydro-
cornea with minimal, if any, injury to the toluene
corneal epithelium.5
Methyl 2-cyanoacrylate was positive in the Physical Form. Colorless liquid
Ames test with and without activation by
metabolic enzymes.7 Uses. Solvent; organic synthesis
The 2003 ACGIH threshold limit value-
time-weighted average (TLV-TWA) for Exposure. Inhalation
methyl 2-cyanoacrylate is 2 ppm (9.1 mg/m3)
with a short-term excursion limit (STEL) of Toxicology. At high concentrations methyl-
4 ppm (18 mg/m3). cyclohexane causes narcosis in animals, and it
is expected that severe exposure will produce
the same effect in humans.
REFERENCES
No effects have been reported in humans.
1. McGee WA, Oglesby FI, Raleigh RI, Fassett Rabbits did not survive exposure for 70
DW: The determination of a sensory response minutes to 15,227 ppm; conjunctival conges-
to alkyl 2-cyanoacrylate vapor in air. Am Ind tion, dyspnea, rapid narcosis, and severe con-
Hyg Assoc J 29:558561, 1968 vulsions preceded death.1 Exposure to 10,000
METHYLCYCLOHEXANOL 465
ppm 6 hours/day for a total of 10 days resulted Uses. Solvent for lacquers; blending agent in
in convulsions, narcosis, and death.1 There textile soaps; antioxidant in lubricants
were no signs of intoxication in rabbits exposed
to 2880 ppm for a total of 90 hours, but slight Exposure. Inhalation; skin absorption
cellular injury was observed in the liver and
kidneys.1 Toxicology. In animals methylcyclohexanol
The only effects seen after chronic expo- is a mild irritant of the eyes and mucous mem-
sure of rats, mice, hamsters, and dogs at 400 or branes, and at high concentrations it causes
2000 ppm for 1 year were weight depression in signs of narcosis. It is expected that severe
hamsters and male rats and progressive renal exposure will produce the same effects in
nephropathy in male rats.2 humans.
The liquid on the skin of a rabbit caused Headache and irritation of the ocular and
local irritation, thickening, and ulceration.3 upper respiratory membranes may result from
The 2003 ACGIH threshold limit value- prolonged exposure to excessive concentrations
time-weighted average (TLV-TWA) is 400 of the vapor.1
ppm (1610 mg/m3). Rabbits exposed 6 hours/day to 503 ppm
for 10 weeks had conjunctival irritation and
slight lethargy.2 There were no clinical signs of
REFERENCES intoxication at 232 ppm for a total exposure of
300 hours.
1. Treon JF, Crutcheld WE Jr, Kitzmiller KV: The minimal lethal dose for rabbits by oral
The physiological response of animals to administration was 1.252 g/kg; rapid narcosis
cyclohexane, methylcyclohexane, and certain and convulsive movements preceded death.3
derivatives of these compounds. II. Inhalation.
Sublethal doses caused narcosis with spasmodic
J Ind Hyg Toxicol 25:323347, 1943
head jerking; salivation and lacrimation were
2. Kinkead ER, Haun CC, Schneider MG, et al:
Chronic inhalation exposure of experimental also observed; hepatocellular degeneration was
animals to methylcyclohexane. Govt Reports apparent at autopsy.
Announcements & Index (GRA&I), Issue 21, Repeated cutaneous applications to rabbits
1985 of large doses of methylcyclohexanol caused
3. Treon JF, Crutcheld WE Jr, Kitzmiller KV: skin irritation and thickening, weakness,
The physiological response of rabbits to tremor, narcosis, and death.3
cyclohexane, methylcyclohexane and certain Methylcyclohexanol can be detected by its
derivatives of these compounds. I. Oral admin- odor at 500 ppm, a concentration capable of
istration and cutaneous application. J Ind Hyg causing upper respiratory irritation.1
Toxicol 25:199214, 1943
The 2003 ACGIH threshold limit value-
time-weighted average (TLV-TWA) is 50 ppm
(234 mg/m3).
METHYLCYCLOHEXANOL
CAS: 25639-42-3 REFERENCES
3. Treon JF, Crutcheld WE Jr, Kitzmiller KV: serious effects. Furthermore, lethal concen-
The physiological response of rabbits to trations of vapors are not expected at tem-
cyclohexane, methylcyclohexane, and certain peratures commonly encountered in the
derivatives of these compounds. I. Oral admin- workplace.1
istration and cutaneous application. J Ind Hyg The 2003 ACGIH threshold limit value-
Toxicol 25:199214, 1943
time-weighted average (TLV-TWA) is 50 ppm
(229 mg/m3) with a short-term excursion limit
(STEL)/ceiling level of 75 ppm (344 mg/m3)
and a notation for skin absorption.
o-METHYLCYCLOHEXANONE
CAS: 583-60-8 REFERENCES
differences.1 Dogs showed weakness, cyanosis, compared with the national death rate for
and methemoglobinemia after oral dosing. cancer of 139/100,000 population.
Acute effects have not been reported in In another report three noninvasive papil-
humans. Sprayed on the skin the liquid caused lary tumors of the bladder were identied in a
a burning sensation of the eyes and skin and screening of 540 MOCA workers; two tumors
nausea.2 occurred in men with completely normal urine
In chronic studies rats fed 1000 ppm screening who were under 30, had never
MOCA in a standard diet for 2 years developed smoked, and had no previous occupational
lung tumors; there were 25 adenomatoses and exposure to known bladder carcinogens.8
48 adenocarcinomas in 88 rats.3 Accompanying Exposure to MOCA was believed to be the
liver changes included hepatocytomegaly, cause of urinary frequency and mild hematuria
necrosis, bile duct proliferation, and brosis.2 in two of six exposed workers; however, a
In 88 control animals, there were two lung variety of other materials including toluene
adenomatoses. MOCA in a low-protein diet diisocyanate, polyester resins, polyether resins,
caused lung tumors in rats of both sexes, liver and isocyanate-containing resins also were
tumors in males, and malignant mammary present.9
tumors in females. The IARC has determined that there is
Repeated subcutaneous injection of inadequate evidence for carcinogenicity to
MOCA in 34 rats (total dose 25 g/kg for 620 humans and sufcient evidence for carcino-
days) resulted in nine liver cell carcinomas genicity to animals. However, on the basis
and seven lung carcinomas; 13 of 50 control of animal experiments it was concluded that
animals developed tumors, but no malignant MOCA probably is carcinogenic to humans,
tumors of the liver or the lungs were observed.4 and exposure by all routes should be monitored
MOCA was fed to male and female mice carefully.2
for 18 months at a dose of either 1 or 2 g/kg; MOCA is genotoxic in a wide variety of
in female mice, but not in males, a statistically assays. It also forms adducts with DNA both in
signicant incidence of hepatoma was vivo and in vitro.2
observed.5 In addition, a higher incidence The 2003 ACGIH threshold limit value-
of hemangiosarcomas and hemangiomas was time-weighted average (TLV-TWA) for 4,4-
observed in treated animals compared with methylene bis(2-chloroaniline) is 0.01 ppm
controls.5 Urinary bladder tumors (primarily (0.11 mg/m3) with an A2-suspected human
papillary transitional cell carcinomas) occurred carcinogen designation and a notation for skin
in dogs given 100 mg of MOCA by capsule for absorption.
up to 9.0 years.6
There was no evidence that MOCA was
tumorigenic in a study of 31 active workers REFERENCES
exposed from 6 months to 16 years.7 Quantita-
tive analysis of the workers urine conrmed 1. Dale EA, Fielder RJ: 4,4-Methylene bis(2-
exposure to the chemical. In addition, the chloroaniline) (MBOCA). HSE Toxicity Rev
records were reviewed for 178 employees who 8:19, 1983
at one time had worked with MOCA but who 2. IARC Monographs on the Evaluation of Carcino-
thereafter had had no further exposure for at genic Risks to Humans, Vol 57, Occupational
least 10 years. The general health of exposed exposures of hairdressers and barbers and
personal use of hair colourants; some hair
workers with respect to illness, absenteeism,
dyes, cosmetic colourants, industrial dyestuffs
and medical history was similar to that of the and aromatic amines. pp 271301. Lyon,
total plant population. Two deaths in this group International Agency for Research on Cancer,
due to malignancy had been diagnosed before 1993
any work with or exposure to MOCA.7 For the 3. Stula EF, Sherman H, Zapp JA Jr,
plant population in general, there were 115 Wesley-Clayton J Jr: Experimental neoplasia
cancer deaths/100,000 over a 15-year period in rats from oral administration of 3,3-
METHYLENE BIS-(4-HEXYLISOCYANATE) 469
1. Rye WA: Human response to isocyanate expo- Uses. Multipurpose solvent; paint remover;
sure. J Occup Med 15:306307, 1973 manufacture of photographic lm; aerosol pro-
2. Woolrich PF, Rye WA: Urethanes. J Occup pellants; urethane foam
Med 11:184190, 1969
3. National Institute for Occupational Safety and
Exposure. Inhalation; skin absorption
Health: Criteria for a Recommended Standard
. . . Occupational Exposure to Diisocyanates.
DHEW (NIOSH) Pub No 78-215. Washing- Toxicology. Methylene chloride is a central
ton, DC, US Government Printing Ofce, nervous system (CNS) depressant and an eye,
1978 skin, and respiratory tract irritant.
4. Tanser AR, Bourke MP, Blandford AG: Iso- Concentrations in excess of 50,000 ppm
cyanate asthma: respiratory symptoms caused are thought to be immediately life threatening.1
by diphenyl-methane-diisocyanate. Thorax 28: Four workers exposed to unmeasured but high
596600, 1973 levels of methylene chloride for 13 hours had
5. Johnson A, et al: Respiratory abnormalities eye and respiratory tract irritation and reduced
among workers in an iron and steel foundry.
hemoglobin and red blood cell counts; all
Br J Ind Med 42:94100, 1985
became comatose, and one died.2
6. Reuzel PGJ, Arts JHE, Lomax LG, et al:
Chronic inhalation toxicity and carcinogenic- A chemist repeatedly exposed to concen-
ity studies of respirable polymeric methylene trations ranging from 500 to 3600 ppm devel-
diphenyl diisocyanate (polymeric MDI) oped signs of toxic encephalopathy.3 A healthy
aerosol in rats. Fundam Appl Toxicol 22: young worker engaged in degreasing metal
195210, 1994 parts had a brief exposure to an undetermined
7. World Health Organization: Concise Interna- but very high concentration of vapor; he com-
tional Chemical Assessment Document(CICAD) plained of excessive fatigue, weakness, sleepi-
27 Diphenylmethane Diisocyanate (MDI), pp ness, light-headedness, chills, and nausea;
125. International Programme on Chemical pulmonary edema developed after several
Safety (IPCS), Geneva, 2001
hours, but all signs and symptoms had cleared
8. IARC Monographs on the Evaluation of the Car-
within 18 hours of terminating the exposure.4
cinogenic Risk of Chemicals to Humans, Vol 71,
Re-evaluation of some organic chemicals, In human experiments, inhalation of 500
hydrazine and hydrogen peroxide, pp 1049 1000 ppm for 1 or 2 hours resulted in light-
58. Lyon, International Agency for Research headedness.5
on Cancer, 1999 Volunteers exposed at 300800 ppm for at
9. Buschmann J, Koch W, Fuhst R, et al: least 40 minutes had altered responses to
472 METHYLENE CHLORIDE
various sensory and psychomotor tests.6 No individuals, those with a compromised cardio-
effects were seen in volunteers exposed to 250 vascular system may not be able to tolerate the
ppm for up to 7.5 hours.6 Although an excess added cardiovascular stress.6
in self-reported neurological symptoms was Contact with the liquid is irritating to the
found in workers repeatedly exposed at 75 skin, and prolonged contact may cause severe
100 ppm, no signicant deleterious effects burns.12 In a thumb immersion experiment, an
were observed on clinical examination, which intense burning sensation was noted within 2
included measurement of motor conduction minutes and mild erythema and exfoliation
velocity, electrocardiogram, and psychological were observed after 30 minutes of immersion;
tests.7 the erythema and paresthesia subsided within
Limited epidemiological studies initially an hour after exposure.13 Marked irritative
found no specic cause for excess deaths in conjunctivitis and lacrimation were noted at
workers chronically exposed to methylene concentrations sufcient to produce uncon-
chloride.6 There is no clear evidence of liver or sciousness.2 Splashed in the eye, it is painfully
kidney damage in humans despite many reports irritating but not likely to cause serious injury.1
of fatty degeneration in the liver and tubular Limited animal studies have suggested that
degeneration in the kidneys of exposed methylene chloride is slightly fetotoxic at doses
animals.8 A recent evaluation of workers that also produce maternal toxicity; in rats and
exposed to high levels of methylene chloride mice exposed at 1250 ppm on days 615 of ges-
averaging 475 ppm for 10 years found no tation, delayed ossication of sternabrae and
adverse health effects as determined by selected increased incidence of extra sternabrae were
liver, cardiac, and neurological tests.9 In noted, respectively.14
another report, no rm evidence of CNS A number of long-term animal studies
effects was found in retired mechanics who have explored the carcinogenic potential of
had had long-term exposure to methylene methylene chloride. A 1986 NTP study with
chloride.10 B6C3F1 mice exposed at 2000 or 4000 ppm
Methylene chloride is metabolized by 6 hours per day, 5 days per week for 2 years
two pathways.11 One pathway produces carbon showed clear evidence of carcinogenicity as
monoxide via mixed-function oxidase enzymes, indicated by increased incidences of alveolar-
which results in the subsequent formation of bronchiolar and hepatocellular neoplasms.15
carboxyhemoglobin (COHb). Carbon dioxide There was also a signicant increase in benign
is produced from the pathway involving mammary gland neoplasms in similarly
glutathione transferase. The metabolism to exposed rats.
COHb is saturable, with disproportionately In humans methylene chloride exposure
less carboxyhemoglobin formed and more has been associated with a wide variety of
unchanged methylene chloride expired as cancers in a number of cohort and case control
exposure increases. CNS effects are thought to studies; pancreatic, prostate, lung, liver, cervi-
be due to methylene chloride itself or in com- cal, breast, and astrocytic brain tumors have
bination with other sources of COHb, but not been reported.16 Limitations in these studies
to the metabolism of methylene chloride to include small sample size, incomplete exposure
COHb alone. Serious poisonings from methyl- information, and concomitant exposure to
ene chloride have been reported in the absence other carcinogenic substances. The IARC has
of signicant elevation of COHb levels. Ele- stated that there is not a sufciently consistent
vated COHb levels may persist for several elevation of risk across studies to make a
hours after removal from exposure, as fat and causal interpretation credible. In a recent
other tissues continue to release accumulated study of 1473 workers, followed for nearly
amounts of methylene chloride.3 Although the 50 years, methylene chloride exposure level
elevated COHb levels associated with moder- was not related to mortality due to all causes,
ate methylene chloride exposure are not malignant neoplasms, or lung and pancreatic
expected to cause adverse effects in healthy cancers.17
METHYLENE CHLORIDE 473
16. IARC Monographs on the Evaluation of the Car- experimental animals and is considered a sus-
cinogenic Risk of Chemicals to Humans, Vol 71, pected human carcinogen.
Re-evaluation of some organic chemicals, Occupational exposure of 12 male workers,
hydrazine and hydrogen peroxide, pp 251 whose hands were in contact with MDA several
315. Lyon, International Agency for hours per day, caused toxic hepatitis.1 The
Research on Cancer, 1999
clinical pattern of the cases included right
17. Tomenson JA, Bonner SM, Heijne CG, et al:
Mortality of workers exposed to methylene upper quadrant pain, high fever, and chills with
chloride employed at a plant producing cel- subsequent jaundice. A skin rash was seen in
lulose triacetate lm base. Occup Environ Med ve of the cases. Percutaneous absorption was
54(7):4706, 1997 considered to be the major route of exposure
18. Andersen ME, Clewell HJ III, Gargas ML, et because workers in the same occupational
al: Physiologically based pharmacokinetics setting who did not have direct skin contact
and the risk assessment process for methyl- with MDA were not affected. All patients
ene chloride. Toxicol Appl Pharmacol 87: recovered within 7 weeks, and follow-up more
185205, 1987 than 5 years later showed no biochemical or
19. Reitz RH, Mendrala AL, Guengerich FP: In clinical evidence of chronic hepatic disease.
vitro metabolism of methylene chloride in
Over a 9-year period (196776), 11 cases
human and animal tissues: Use in physiolog-
ically based pharmacokinetic models. Toxicol of jaundice were reported from a company that
Appl Pharmacol 97:230246, 1989 mixed preground MDA with silicon dioxide.2
20. Ghittori S, Marraccini P, Franco G, et al: In one instance, transient signs of myocardial
Methylene chloride exposure in industrial damage in addition to transient signs of hepatic
workers. Am Ind Hyg Assoc J 54:2731, 1993 damage were observed after MDA exposure
from a defective lter system.3
The inadvertent ingestion of bread pre-
pared with MDA-contaminated our led to an
outbreak of 84 cases of jaundice in Epping,
UK.4 Liver biopsies from seven of the patients
4,4-METHYLENE DIANILINE showed partial inammation, eosinophil inl-
CAS: 101-77-9 tration, cholangitis, cholestasis, and varying
degrees of hepatocellular damage. All patients
C13H14N2 made a good clinical recovery with no evidence
of progressive liver damage.5
In another case, ingestion of MDA in
Synonyms: 4,4-Diaminodiphenylmethane; potassium carbonate and g-butyrolactone
DDM; MDA; 4-(4-aminobenzyl)aniline resulted in severe systemic toxicity and visual
dysfunction.6 Transient effects included ECG
Physical Form. Light brown crystalline solid abnormalities, bradycardia, and hypotension
suggesting myocardial involvementand gly-
Uses. Production of methylene diphenyl cosuria with normoglycemia, which indicated
diisocyanate (MDI), which is used to produce renal tubular dysfunction. Liver effects
polyurethanes; hardening agent for epoxy included slight hepatomegaly 6 weeks after
resins, anticorrosive materials, printed circuit ingestion, which quickly resolved, and disap-
parts, dyestuff intermediates, lament-wound pearance of jaundice 23 weeks later. Liver
pipe, and wire coatings biopsy 1 year after the poisoning showed
normal hepatocytes and a preservation of
Exposure. Skin absorption; inhalation; hepatic architecture, but disturbed liver func-
ingestion tion tests were still evident 18 months after the
incident. Most signicant, however, was the
Toxicology. 4,4-Methylene dianiline (MDA) development of toxic optic neuritis with severe
is a human hepatotoxin; it is carcinogenic in visual dysfunction. Investigation of the retina
4,4-METHYLENE DIANILINE 475
revealed gross malfunction of the retinal conrmed bladder cancer.12 Although not
pigment epithelium, reected clinically as statistically signicant, these cases are of inter-
impaired visual acuity with severe loss of est because of ndings of bladder tumors in
central visual eld, color discrimination, and animals and the structural similarity of MDA
dark adaptation. Eighteen months later there to known human bladder carcinogens such as
was little improvement, and all visual indices benzene.
remained subnormal with little likelihood for MDA is genotoxic in vitro and forms DNA
further recovery. adducts in vivo.13
Support for the role of MDA in causing The IARC has determined that there is
visual disturbances is found in animal studies.7 sufcient evidence for the carcinogenicity of
Oral doses of 2550 mg/kg in cats caused 4,4-methylene dianiline and its dihydrochlo-
retinal damage. The changes observed in the ride to experimental animals and that it is pos-
affected eyes consisted of severe granular sibly carcinogenic to humans.8
degeneration of the rods and cones and prolif- Reports of allergic sensitivity to MDA are
eration of the pigmented epithelial cells of confounded by mixed exposures to chemicals
the retina. The neuronal structures located such as epoxy resins and isocyanates, which
beyond the pigmented layer remained intact. make it difcult to relate specic cause with
No visual disturbances were induced by MDA effect. MDA does appear to cause an intense
in the rabbit, guinea pig, and rat. In another yellow staining reaction involving the skin
study, degeneration of the inner and outer seg- (especially ngers and palms), nails, and
ments of the photoreceptor cells and the pig- occasionally hair in exposed workers.14 The
mented epithelial cell layer of the retinas of staining should serve as a marker for potential
guinea pigs resulted from a total inhaled dose systemic exposure.
of 24 mg/kg. MDA has a faint amine odor, but the odor
Chronic oral exposure of rats and mice to is not offensive enough to be useful as a warn-
MDA and its dihydrochloride is carcinogenic.8 ing property.7
Treatment-related increases in the incidences Monitoring atmospheric levels of MDA
of thyroid follicular cell adenomas and hepato- may not be useful, as skin absorption may be a
cellular neoplasms were observed in mice after more signicant route of exposure. Concentra-
chronic ingestion of MDA in drinking water.9 tions of N-acetyl MDA, a major metabolite of
In rats, increases in the incidences of thyroid MDA, in the urine may be used to reect
follicular cell carcinoma and hepatic nodules overall exposure.15
were observed in males and thyroid follicular The 2003 ACGIH threshold limit value-
cell ademonas occurred in females. Although time-weighted average (TLV-TWA) for MDA
not statistically signicant, certain uncommon is 0.1 ppm (0.81 mg/m3) with an A3-conrmed
tumors such as bile duct adenomas, papillomas animal carcinogen with unknown relevance to
of the urinary bladder, and granulosa cell humans designation and a notation for skin
tumors of the ovary also were reported. These absorption.
tumors are of low incidence in historical con-
trols. In another report, MDA acted as a pro-
moter of thyroid tumors in rats.10 REFERENCES
An epidemiological study of workers
potentially exposed to MDA (and numerous 1. McGill DB, Motto JD: An industrial out-
break of toxic hepatitis due to methylenedi-
other agents) in the helicopter parts manufac-
aniline. N Engl J Med 291:278282, 1974
turing industry showed limited evidence of an
2. Dunn GW, Guirguis SS: Proceedings of the
association between MDA and bladder cancer, 19th International Congress on Occupational
colon cancer, lymphosarcoma, and reticulosar- Health, VI, ISS Chem Hazards, pp 639644.
coma.11 A follow-up of 10 workers who had sig- Geneva, International Commission on Occu-
nicant exposure to MDA between 1967 and pational Health, 1980
1976 revealed one case of a pathologically 3. Brooks LJ, Neale JM, Pieroni DR, et al:
476 METHYL ETHYL KETONE
tion over a 2-year period to solvents that con- through 15 of gestation produced litters with
tained 100% MEK.4 Symptoms disappeared an increased incidence of a minor skeletal vari-
after 1 month of cessation of exposure.4 ation and delay in ossication of fetal bones.16
Compared to controls, 41 MEK workers Similar effects, including reduced fetal weight
with an average of 14 years exposure exhibited and a low incidence of cleft palate, fused ribs,
signicantly lower motor nerve conduction missing vertebrae, and syndactyly, were
velocities in the median, ulnar, and peroneal reported in the offspring of mice exposed at
nerves; irritation of the eyes and upper respira- 3000 ppm on days 615 of gestation.17 Slight
tory tract and a neurotoxic syndrome charac- maternal toxicity in the form of increased rel-
terized by mood disorders, irritability, memory ative liver weight was also noted. In a recent
difculties, sleep disturbances, headache, and human case report, multiple congenital mal-
numbness were also more prevalent in the formations (cleft lip and palate, malformed
exposed workers.5 right ear, cervical meningoencephalocele,
Three cases of polyneuropathy occurred horseshoe kidney, and ventricular septum
in shoe factory workers exposed to combined defect) occurred in an infant who did not
MEK and acetone vapors, as well as MEK survive and whose mother had been exposed
and toluene vapors at concentrations below to MEK during pregnancy.18
200 ppm.6 Skin absorption also occurred. MEK was not genotoxic in a variety of in
Although not highly neurotoxic itself, MEK vivo and in vitro assays.8
may potentiate substances known to cause MEK can be recognized at 25 ppm by its
neuropathy. odor, which is similar to that of acetone but
An historical prospective mortality study more irritating; its warning properties should
of 446 male workers in two MEK dewaxing prevent inadvertent exposure to toxic levels.9
plants, with an average follow-up of 13.9 years, In determining worker exposure to MEK, end
found no increase in deaths from neoplasms.7 of shift urine levels appear to be the most
In animal studies death of rats and mice reliable biological indicator of occupational
occurred within a few hours at concentrations exposure.19
of 90,000 ppm and above.8 Guinea pigs exposed The 2003 ACGIH threshold limit value-
to 10,000 ppm had signs of eye and nose irrita- time-weighted average (TLV-TWA) for
tion that developed rapidly, and narcosis methyl ethyl ketone is 200 ppm (590 mg/m3)
occurred after 5 hours.9 Exposure of rats to with a short-term excursion limit (STEL) of
6000 ppm 8 hours/day, 7 days/week, did not 300 ppm (885 mg/m3).
result in any obvious motor impairment; all
animals died from bronchopneumonia during
the seventh week.10 REFERENCES
Animal studies have shown MEK to
enhance the development of or increase the 1. Nelson KW, Ege JF Jr, Ross M, et al: Sensory
severity of neurotoxic effects due to methyl n- response to certain industrial solvent vapors.
butyl ketone, ethyl butyl ketone, n-hexane, and J Ind Hyg Toxicol 25:282285, 1943
2,5-hexanedione.1114 MEK exposure did not, 2. Dick RB, Krieg EF Jr, Setzer J, et al: Neu-
however, potentiate the neurobehavioral test robehavioral effects from acute exposures
decrements produced by acetone.15 Exposure to methyl isobutyl ketone and methyl ethyl
to 200 ppm MEK or 100 ppm MEK plus ketone. Fundam Appl Toxicol 19:453473,
1992
125 ppm acetone for 4 hours did not produce
3. Smith AR, Mayers MR: Poisoning and re
any signicant effects in a variety of behavioral
hazards of butanone and acetone. Ind Hyg
performance tests, whereas exposure to 250 Bull 23:175176, 1944
ppm acetone caused some mild decrements. 4. Orti-Pareja M, Jimenez-Jimenez FJ, Miquel
The liver and kidney toxicity of haloalkane J, et al: Reversible myoclonus, tremor, and
solvents may also be potentiated by MEK.7 ataxia in a patient exposed to methyl ethyl
Rats exposed to 3000 ppm during days 6 ketone. Neurology 46(1):272, 1996
478 METHYL ETHYL KETONE PEROXIDE
5. Mitran E, Callender T, Orha B, et al: Neu- ethyl ketone in Swiss mice. Fundam Appl
rotoxicity associated with occupational expo- Toxicol 16:742748, 1991
sure to acetone, methyl ethyl ketone, and 18. Ten Berg K, Hoogeboom AJ, Wesby-van
cyclohexanone. Environ Res 73(1/2):1818, Swaaij E, et al: Maternal occupational
1997 methyl ethyl ketone exposure and multiple
6. Dyro FM: Methyl ethyl ketone polyneuropa- congenital anomalies. Teratology 65(6):326,
thy in shoe factory workers. Clin Toxicol 2002
13:371376, 1978 19. Ong CN, Sia GL, Ong HY, et al: Biological
7. World Health Organization: Environmental monitoring of occupational exposure to
Health Criteria 143 Methyl Ethyl Ketone. pp methyl ethyl ketone. Int Arch Occup Environ
1108. Geneva, International Programme on Health 63:319324, 1991
Chemical Safety (IPCS), 1993
8. Agency for Toxic Substances and Disease
Registry (ATSDR): Toxicological Prole for 2-
Butanone. TP-91/08, 118pp. US Department
of Health and Human Services, Public
Health Service, 1992 METHYL ETHYL KETONE PEROXIDE
9. Krasavage WJ, ODonoghue JL, DiVincenzo CAS: 1338-23-4
GD: Ketones. In Clayton GD and Clayton
FE (eds): Pattys Industrial Hygiene and Toxi- C18H16O4 or
cology, 3rd ed, Vol 2C, Toxicology, pp C18H18O4
47284733. New York, John Wiley and Sons,
1982
10. Altenkirch H, Stoltenburg G, Wagner H:
Synonyms: 2-Butanone peroxide; MEKP;
Experimental studies on hydrocarbon neu-
ropathies induced by methyl-ethyl-ketone MEK peroxide
(MEK). J Neurol 219:159170, 1978
11. Saida K, Mendell J, Weiss H: Peripheral Physical Form. Liquid
nerve changes induced by methyl n-butyl
ketone and potentiation by methyl ethyl Uses. Reactive free radical-generating
ketone. J Neuropathol Exp Neurol 35:207225, chemical used as a curing agent for unsaturated
1976 polyester resins; hardening agent for berglass-
12. ODonoghue J, Krasavage W, DiVincenzo G, reinforced plastics; manufacture of acrylic
et al: Further studies on ketone neurotoxicity resins
and interactions. Toxicol Appl Pharmacol
72:201209, 1984
Exposure. Inhalation
13. Altenkirch H, Wagner H, Stoltenburg-
Didinger G, et al: Potentiation of hexacarbon
neurotoxicity by methyl ethyl ketone. Neu- Toxicology. Methyl ethyl ketone peroxide
robehav Toxicol Teratol 4:623627, 1982 (MEKP) is a skin and eye irritant.
14. Ralston WH et al: Potentiation of 2,5- MEKP has caused irritant dermatitis
hexanedione neurotoxicity by methyl ethyl with direct contact; only rarely has it caused
ketone. Toxicol Appl Pharmacol 81:319327, allergic contact dermatitis from occupational
1985 exposure.1
15. Dick RB, Setzer JV, Taylor BJ, et al: Neu- Exposure of the eyes has resulted in mild
robehavioral effects of short duration expo- to severe injury.2 The severity of ocular injury
sures to acetone and methyl ethyl ketone. Br
was dependent on the length of time from
J Ind Med 46:111121, 1989
exposure to adequate lavage. Delayed keratitis
16. Deacon MM, Pilny MD, John JA, et al:
Embryo and fetotoxicity of inhaled methyl has also been reported.
ethyl ketone in rats. Toxicol Appl Pharmacol In a case of accidental ingestion massive
59:620622, 1981 peripheral zonal hepatic necrosis developed
17. Schwetz BA, Mast TJ, Weigel RJ, et al: in a 47-year old man.3 The clinical course
Developmental toxicity of inhaled methyl was characterized by temporary cardiac arrest,
METHYL FORMATE 479
branes, oppression in the chest, dyspnea, symp- Uses. Rocket fuel; solvent; chemical
toms of central nervous system depression, and intermediate
temporary visual disturbances; air concentra-
tions were not determined.1 No effects were
Exposure. Inhalation; skin absorption
noted from experimental human exposures to
1500 ppm for 1 minute.2
Exposure of guinea pigs to 10,000 ppm for Toxicology. Methyl hydrazine causes respi-
3 hours was fatal; effects were eye and nose irri- ratory irritation, methemoglobinemia, and
tation, incoordination, and narcosis; autopsy convulsions; it is carcinogenic in experimental
revealed pulmonary edema.2 Exposure to animals.
5000 ppm was considered the maximum con- Volunteers exposed to 90 ppm for 10
centration tolerable for 60 minutes without minutes had slight redness in the eyes and
serious consequences. experienced a tickling sensation of the nose.
Methyl formate was negative in bacterial The only clinical abnormality found during the
mutagenicity assays with or without metabolic 60-day follow-up period was the presence of
activation.3 Heinz bodies in 35% of the erythrocytes by
Methyl formate has a distinct and pleasant the seventh day.
odor, but an odor threshold has not been As a reducing agent, methyl hydrazine
reported.2 causes characteristic oxidative damage to
The 2003 ACGIH threshold limit value- human erythrocytes in vitro. Effects include
time-weighted average (TLV-TWA) is 100 formation of Heinz bodies and production of
ppm (246 mg/m3) with a short-term excursion methemoglobin.1
limit (STEL)/ceiling of 150 ppm (368 mg/m3). Exposure of dogs to 21 ppm for 4 hours
resulted in convulsions and some deaths; post-
mortem examination revealed no lesions attrib-
REFERENCES
utable primarily to methyl hydrazine, although
1. von Oettingen WF: The aliphatic acids and secondary manifestations, probably due to con-
their esterstoxicity and potential dangers. vulsions, included pulmonary hemorrhage and
AMA Arch Ind Health 20:517531, 1959 edema; convulsions but not death occurred
2. Schrenk HH, Yant WP, Chornyak J, Patty FA: at 15 ppm.2 In the dogs that survived exposure,
Acute response of guinea pigs to vapors of there was evidence of moderately severe
some new commercial organic compounds. intravascular hemolysis. The hemolytic effect
XIII. Methyl formate. Public Health Rep 51: was most pronounced 48 days after exposure,
13291337, 1936 and blood values returned to normal within
3. Zeiger E, Anderson B, Haworth S, et al: Sal- 3 weeks. In another study, additional signs,
monella mutagenicity tests. V. Results from the
including eye irritation, tremor, ataxia, diar-
testing of 311 chemicals. Environ Mol Mutagen
rhea, and cyanosis, were noted in dogs.3 Dogs
19(Suppl 21):2141, 1992
exposed at 5 ppm 6 hours/day for 6 months had
at least a twofold increase in methemoglobin
and reductions in numbers of erythyrocytes,
hemoglobin concentrations, and hematocrit
METHYL HYDRAZINE values; the effect was reversible and was not
CAS: 60-34-4 observed at the 1 ppm level.4
Applied to the shaved skin of dogs, the
CH3NHNH2 liquid was rapidly absorbed, producing toxic
signs; at the site of application the skin became
red and edematous.5
Synonyms: Monomethylhydrazine; MMH Administered intraperitoneally to rats on
days 6 through 15 of pregnancy, 10 mg/kg/day
Physical Form. Liquid caused slight maternal toxicity in the form of
METHYL IODIDE 481
reduced weight gains but was not selectively 5. Smith EB, Clark DA: The absorption of
embryotoxic or teratogenic.6 monomethylhydrazine through canine skin.
Mice administered 0.001% methyl Proc Soc Exp Biol Med 131:226232, 1969
hydrazine sulfate in drinking water for life 6. Keller WC et al: Teratogenic assessment of
showed an increase in lung tumors, whereas three methylated hydrazine derivatives in the
rat. J Toxicol Environ Health 13:125131, 1984
0.01% methyl hydrazine enhanced the devel-
7. Toth B: Hydrazine, methylhydrazine and
opment of lung tumors by shortening latent methylhydrazine sulfate carcinogenesis in
periods; control incidences were not clearly Swiss micefailure of ammonium hydroxide
dened in this study.7 In two other mice studies to interfere in the development of tumors. Int
that may not have allowed for a sufcient J Cancer 9:109118, 1972
latency period, no evidence of carcinogenicity 8. Kelly MG et al: Comparative carcinogenic-ity
was found.8,9 of n-isopropyl-a-(2-methylhydrazino)-p-tolu-
Chronic inhalation exposure by mice (up amide HCl (procarbazine hydrochloride), its
to 2 ppm, 6 hours/day, 5 days/week for 1 year) degradation products, other hydrazines, and
or hamsters (up to 5 ppm, 6 hours/day, 5 isonicotinic acid hydrazide. J Natl Cancer Inst
days/week for 1 year) caused a signicant 42:337344, 1969
9. Roe FJC et al: Carcinogenicity of hydrazine
increase in rare tumors of the upper respiratory
and 1,1-dimethylhydrazine for mouse lung.
system including papillomas, adenomas, and Nature 216:375376, 1967
osteomas.10 These benign tumors were thought 10. Keller WC: Toxicity assessment of hydrazine
to be the result of chronic insult to the system. fuels. Aviat Space Environ Med 59 (11 Suppl):
An increase in liver tumors (hemangioma, A100A106, 1988
hemangiosarcoma, adenoma, and carcinoma)
also occurred in mice.
The odor threshold is 13 ppm, and the
odor is described as ammonia-like or shy.1
The 2003 short-term excursion limit
(STEL)/ceiling limit for methyl hydrazine is METHYL IODIDE
0.2 ppm (0.38 mg/m3) with a notation for CAS: 74-88-4
skin and an A3-conrmed animal carcinogen
designation. CH3I
recovery occurs, neurological ndings recede in short-term genotoxic assays and does not
over several weeks and are followed by psychi- require activation.
atric disturbances such as paranoia, delusions, NIOSH has determined that there is suf-
and hallucination. cient evidence of carcinogenicity in animals to
A chemical worker accidentally exposed to indicate a potential for human carcinogencity.5
an unknown concentration of the vapor devel- The IARC states that there is limited evidence
oped giddiness, diarrhea, sleepiness, and for the carcinogenicity of methyl iodide to
irritability, with recovery in a week; when experimental animals and it is not classiable as
reexposed 3 months later, he experienced to its carcinogenicity to humans.10
drowsiness, vomiting, pallor, incoordination, The 2003 ACGIH threshold limit value-
slurred speech, muscular twitching, oliguria, time-weighted average for methyl iodide
coma, and death.2 At autopsy there were bron- (TLV-TWA) is 2 ppm (12 mg/m3) with an A2-
chopneumonia and pulmonary hemorrhages, suspected carcinogen designation and a nota-
with accumulation of combined iodine in the tion for skin absorption.
brain.
In a recent report, two workers developed
symptoms and signs of cerebellar lesions and REFERENCES
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Spinal cord lesions producing motor and R: Methyl iodide intoxicationa case report.
Ann Intern Med 82:534536, 1975
sensory disturbances were present in one, and
2. von Oettingen WF: The Halogenated
late psychiatric disorders were observed in
Aliphatic, Olenic, Cyclic, Aromatic, and Halo-
both. genated Insecticides, Their Toxicity and Potential
Experimental application of the liquid to Dangers. US Public Health Service Pub No
human skin produced a stinging sensation and 414, pp 3032. Washington, DC, US
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In rats, reported LC50 values are 1750, 900, Preliminary survey. Br J Ind Med 7:122124,
1950
and 232 ppm for 0.5-, 1-, and 4-hour exposures,
5. National Institute for Occupational Safety
respectively.46
and Health: Current Intelligence Bulletin 43,
Local sarcomas occurred in rats after sub- Monohalomethanes. DHHS (NIOSH) Pub No
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occurred between 500 and 700 days after the of Drugs and Chemicals, p 756. New York,
rst injection, and, in most cases, pulmonary Academic Press, 1969
metastases were observed.6 Repeated intraperi- 7. Preussman R: Direct alkylating agents as car-
toneal injection of 44 mg/kg in mice reduced cinogens. Food Cosmet Toxicol 6:576577, 1968
survival and caused an increased incidence of 8. Poirier LA, Stoner GD, Shimkin MB: Bioas-
lung tumors.8 say of alkyl halides and nucleotide base
analogs by pulmonary tumor response in
Methyl iodide is considered a potent
Strain A mice. Cancer Res 35(6):14111415,
methylating agent; it methylates hemoglobin
1975
in experimental animals and humans.9 In DNA 9. Bolt HM, Gansewendt B: Mechanisms of
binding studies in rats, adducts were found in carcinogenicity of methyl halides. CRC Rev
all organs examined, with the highest levels in Toxicol 23:237253, 1993
the stomach and forestomach, after both oral 10. IARC Monographs on the Evaluation of the
and inhalation administration.9 It is mutagenic Carcinogenic Risk of Chemicals to Humans,
METHYL ISOBUTYL CARBINOL 483
Vol 71, Some organic chemicals, hydrazine complete adjuvant; this is not considered com-
and hydrogen peroxide, p 1503. Lyon, pelling evidence of a sensitization potential.
International Agency for Research on The 2003 ACGIH threshold limit value-
Cancer, 1999 time-weighted average (TLV-TWA) is 50 ppm
(234 mg/m3).
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METHYL ISOAMYL KETONE
CAS: 110-12-3 1. Katz GV, Renner ER Jr, Terhaar CJ: Sub-
chronic inhalation toxicity of methyl isoamyl
CH3COCH(C2H5)2 ketone in rats. Fundam Appl Toxicol 6:498505,
1986
2. Krasavage WJ, ODonoghue JL, Divicenzo
GD: Ketones. In Clayton GD, Clayton FE
Synonyms: MIAK; 5-methyl-2-hexanone; 2- (eds): Pattys Industrial Hygiene and Toxicology,
methyl-5-hexanone 3rd ed, Vol 2C, Toxicology, pp 47594760.
New York, Wiley-Interscience, 1982
Physical Form. Liquid
single-dose oral toxicity for rats was 2.6 g/kg; ness, loss of appetite, headache, eye irritation,
the dermal LD50 in rabbits was 3.6 ml/kg.2 sore throat, and nausea.1 At 200 ppm the eyes
No mutagenic activity was seen in a variety of most persons were irritated, and 100 ppm
of in vitro assays.3 was the highest concentration most volunteers
The 2003 ACGIH threshold limit value- estimated to be acceptable for an 8-hour expo-
time-weighted average (TLV-TWA) for sure.2 Volunteers exposed to 50 ppm for 2 hours
methyl isobutyl carbinol is 25 ppm (104 mg/m3) showed no signicant effects on the perform-
with a short-term excursion limit (STEL) of ance of reaction time tasks or tests of mental
40 ppm (167 mg/m3) and a notation for skin arithmetic; irritation in the nose and throat was
absorption. reported by three of eight subjects at this level.3
Eye, throat, and nose irritation and headache
occurred in another group of volunteers
REFERENCES exposed at 20 or 40 ppm for 7 hours.4
Exposure of rats to 4000 ppm for 4 hours
1. Silverman L, Schulte HF, First MW: Further caused death; 2000 ppm for 4 hours was not
studies on sensory response to certain indus- fatal.5 A 2-week exposure of rats to 200 ppm
trial solvent vapors. J Ind Hyg Toxicol 28: produced toxic nephrosis of the proximal
262266, 1946
tubules and increased liver weights.6 A 90-day
2. Smyth HF Jr, Carpenter CP, Weil CS: Range-
continuous exposure at 100 ppm produced no
nding toxicity data: List IV. AMA Arch Ind
Hyg Occup Med 4:119122, 1951 signicant changes.7 In a more recent report of
3. BIBRA working group: Toxicity Prole of Methyl rats and mice exposed 6 hours/day for 2 weeks
Isobutyl Carbinol. Vol 190, pp 14. Carshalton, to 100, 500, or 2000 ppm, the only observed
UK, British Industrial Biological Research histologic changes were increases in regenera-
Association, 1994 tive tubular epithelia and hyalin droplets in
kidneys of male rats exposed at the two highest
levels.7 Exposure of both species to MIBK at
levels up to 1000 ppm for 14 weeks was without
signicant toxicological effect, except for an
METHYL ISOBUTYL KETONE increase in the incidence and extent of hyalin
CAS: 108-10-1 droplets in the kidneys of male rats. The rele-
vance of kidney tubular effects to humans is not
C6H12O known.
Studies in mice have shown that MIBK
can enhance the ethanol-induced loss of right-
Synonyms: Hexone; MIBK; 4-methyl-2- ing reex by reducing the elimination rate of
pentanone ethanol.8 Human response to ethanol may be
affected by MIBK, and simultaneous exposure
Physical Form. Colorless liquid to alcoholic beverages and MIBK should be
avoided.
Uses. In paints, glues, and cleaning agents; The liquid splashed in the eyes may cause
used in the plastic and petrol industries pain and irritation. Repeated or prolonged skin
contact may cause defatting of the skin with
Exposure. Inhalation primary irritation and desquamation.9
Results from a number of genotoxic assays
Toxicity. Methyl isobutyl ketone (MIBK) is show that MIBK exhibits very little, if any,
an irritant of the eyes, mucous membranes, and mutagenic activity.10 Existing studies also
skin; high concentrations cause narcosis in demonstrate that MIBK is not teratogenic.
animals, and it is expected that severe exposure In two-generation reproductive studies, rats
will cause the same effect in humans. exposed at up to 2000 ppm 6 hours/day had
Exposures to 80500 ppm produced weak- some central nervous system effects and
METHYL ISOCYANATE 485
increased liver and kidney weights (males), but 9. Hygienic Guide Series: Methyl isobutyl
reproductive parameters were not adversely ketone. Am Ind Hyg Assoc J 27:209211,
affected.11 1966
MIBK has a characteristic camphorlike 10. Strickland GD: Methyl ethyl ketone and
odor detectable at 100 ppm.1 methyl isobutyl ketone not carcinogenic.
Environ Health Perspect 101:566, 1993
The 2003 ACGIH threshold limit value-
11. Nemec MD, Topping DC, Tyler TR, et al:
time-weighted average (TLV-TWA) for Inhalation 2-generation reproductive toxicity
methyl isobutyl ketone is 50 ppm (205 mg/m3) study of methyl isobutyl ketone in rats. Toxi-
with a short-term excursion limit (TLV-STEL) cologist 60(1):250, 2001
of 75 ppm (307 mg/m3).
REFERENCES
METHYL ISOCYANATE
1. National Institute for Occupational Safety CAS: 624-83-9
and Health: Criteria for a Recommended
Standard . . . Occupational Exposure to Ketones. CH3CNO
DHEW (NIOSH) Pub No 78-173. Wash-
ington, DC, US Government Printing
Ofce, 1978 Synonyms: Isocyanic acid, methyl ester; MIC
2. Silverman L, Schulte HF, First MW: Further
studies on sensory response to certain indus-
Physical Form. Liquid; aerosol
trial solvent vapors. J Ind Hyg Toxicol 28:
262266, 1946
3. Hjelm EW, Hagberg M, Iregren A, et al: Uses. Production of polyurethane foams and
Exposure to methyl isobutyl ketone: toxico- plastics; chemical intermediate
kinetics and occurrence of irritative and CNS
symptoms in man. Int Arch Occup Environ Exposure. Inhalation; skin absorption
Health 62:1926, 1990
4. Gagnon P, Mergler D, Lapare S: Olfactory Toxicology. Methyl isocyanate (MIC) is an
adaptation, threshold shift and recovery at irritant of the eyes, mucous membranes, and
low levels of exposure to methyl isobutyl skin; at higher doses it is extremely toxic and
ketone (MIBK). Neurotoxicology 15(3):637 can cause death from pulmonary edema.
642, 1994
Isocyanates cause pulmonary sensitization
5. Smyth HF Jr, Carpenter CP, Weil CS:
in susceptible individuals; if this occurs, further
Range-nding toxicity data: List IV. AMA
Arch Ind Hyg Occup Med 4:119122, 1951 exposure should be avoided, because extremely
6. MacEwen JD et al: Effect of 90-Day Continu- low levels of exposure may trigger an asthmatic
ous Exposure to Methylisobutylketone on Dogs, episode; cross sensitization to unrelated mate-
Monkeys and Rats, p 23. NTIS AD 730 291. rials probably does not occur.1
Springeld, VA, National Technical Informa- Experimental exposure of four human
tion Service, US Department of Commerce, subjects to MIC for 15 minutes caused the
1971 following effects: 0.04 ppm, no effects; 2 ppm,
7. Phillips RD, Moran EJ, Dodd DE, et al: A lacrimation, irritation of the nose and throat;
14-week vapor inhalation toxicity study of 4 ppm, symptoms of irritation more marked;
methyl isobutyl ketone. Fundam Appl Toxicol
21 ppm, unbearable irritation of eyes, nose,
9:380388, 1987
and throat.2
8. Cunningham J, Sharkawi M, Plaa GL:
Pharmacological and metabolic interactions Long-term, low-level exposure [generally
between ethanol and methyl n-butyl ketone, below the 0.02 ppm threshold limit value
methyl isobutyl ketone, methyl ethyl ketone (TLV)] was not associated with any pulmonary
or acetone in mice. Fundam Appl Toxicol 13: impairment in workers at a chemical plant with
102109, 1989 MIC exposure.3
486 METHYL ISOPROPYL KETONE
Uses. Solvent for nitrocellulose lacquers Toxicology. Methyl mercaptan causes coma
at high levels; hematologic effects have also
Exposure. Inhalation been reported.
In a fatal human exposure, a worker
Toxicology. Methyl isopropyl ketone engaged in emptying metal gas cylinders of
(MIPK), by analogy to other aliphatic ketones, methyl mercaptan was found comatose at the
is expected to be an irritant of the eyes, mucous work site; he developed expiratory wheezes,
membranes, and skin; at high concentrations it elevated blood pressure, tachycardia, and
causes narcosis in animals, and it is expected marked rigidity of extremities.1 Methemoglo-
that severe exposure in humans will produce binemia and severe hemolytic anemia devel-
the same effect. oped with hematuria and proteinuria but were
In a range-nding study, exposure for 4 brief in duration; deep coma persisted until
hours to 5700 ppm was fatal to rats.1 The oral death due to pulmonary embolus 28 days after
LD50 for male rats and mice was 3200 mg/kg. exposure. It was determined that the individual
Signs of intoxication included weakness, pros- was decient in erythrocyte glucose-6-
tration, and ataxia. phosphate dehydrogenase, which was the
The 2003 ACGIH threshold limit likely cause of the hemolysis and formation of
value-time-weighted average (TLV-TWA) methemoglobin.
for methyl isopropyl ketone is 200 ppm In a nonfatal incident, a worker in a ren-
(705 mg/m3). ery inhaled methyl mercaptan and was coma-
tose for 9 hours. Although not dyspneic, the
individual was cyanotic and experienced con-
vulsions; recovery occurred by the fourth day.
REFERENCE
Ten days later the worker was treated success-
1. Carpenter CP, Weil CS, Smyth HF Jr: Range- fully for a lung abscess.
nding toxicity data: List VIII. Toxicol Appl Although details are lacking, one report
Pharmacol 28:313319, 1974 states that effects in animals exposed to methyl
mercaptan were restlessness and muscular
weakness, progressing to paralysis, convulsions,
respiratory depression, and cyanosis.1 Rats
exposed via inhalation to methyl mercaptan at
1400 ppm, but not 1200 ppm, for 15 minutes
became lethargic and comatose.2 Exposure of
METHYL MERCAPTAN rats to various concentrations for 4 hours
CAS: 74-93-1 allowed a determination of an LC50 of 675 ppm,
making it slightly less acutely toxic than hydro-
CH3SH gen sulde (LC50 444 ppm) A subchronic toxi-
city study in young male rats exposed at 2, 17,
and 57 ppm for 3 months showed a dose-
Synonyms: Methanethiol; mercaptomethane; related decreased weight gain (about 15% at
thiomethyl alcohol; methyl sulfhydrate 57 ppm) but no clear pathologic or biochemi-
cal test alterations. There were some minor
Physical Form. Flammable gas liquefying at microscopic hepatic alterations in the exposed
6C; odor of rotten cabbage animals, which were of questionable
signicance.
Uses. Intermediate in manufacturing of jet Irritation of the skin and eyes has been
fuels, pesticides, fungicides, plastics; synthesis reported by workers exposed to mercaptans in
of methionine; emission from paper pulp mills, general, although specic information is not
odoriferous additive to natural gas available pertaining to methyl mercaptan.4
There are no reports of developmental, repro-
Exposure. Inhalation ductive, or genotoxic effects.4
488 METHYL METHACRYLATE
1. Shults WT, Fountain EN, Lynch EC: Toxicology. Methyl methacrylate is an irri-
Methanethiol poisoning. JAMA 211: tant of eyes, skin, and mucous membranes.
21532154, 1970 The toxic effects are due to the monomer;
2. Zieve L, Doizaki WM, Zieve FJ: Synergism
the polymer appears inert. The severity of
between mercaptans and ammonia or fatty
effects is believed to be inversely proportional
acids in the production of coma: A possible
role for mercaptans in the pathogenesis of to the degree of polymerization.
hepatic coma. J Lab Clin Med 83:1628, Workers exposed to either 1133 mg/m3 or
1974 100200 mg/m3 had dose-dependent increases
3. Tansy M et al: Acute and subchronic toxicity in the incidences of neurasthenia, laryngitis,
studies of rats exposed to vapors of methyl and hypotension.1 In another study of 91
mercaptan and other reduced-sulfur com- exposed and 43 nonexposed workers at ve
pounds. J Toxicol Environ Health 8:7188, plants producing polymethyl methacrylate
1981 sheets, exposures ranged from 4 to 49 ppm and
4. Agency for Toxic Substances and Disease Reg- there were no detectable clinical signs or symp-
istry (ATSDR): Toxicological Prole for Methyl
toms.2 In a survey of 152 workers exposed to
Mercaptan. TP-91/20, pp 162. US Depart-
concentrations ranging from 0.5 to 50 ppm,
ment of Health and Human Services, Public
Health Service, 1992 78% reported a high incidence of headache,
5. Wilms J, Lub J, Wever R: Reactions of 30% pain in the extremities, 10% irritability,
mercaptans with cytochrome c oxidase and 20% loss of memory, and 21% excessive fatigue
cytochrome c. Biochim Biophys Acta 589: 324, and sleep disturbances.3
1980 Handlers of methyl methacrylate cement
have developed paresthesia of the ngers.4
Dental technicians who use bare hands to mold
methyl methacrylate putty had signicantly
slower distal sensory conduction velocities
from the digits, implicating mild axonal degen-
METHYL METHACRYLATE eration in the area of contact with methyl
CAS: 80-62-6 methacrylate.5 The toxic effect on the nervous
tissues may be due to diffusion into the nerve
C5H8O2 cells causing lysis of the membrane lipids and
destruction of the myelin sheath.
Humans have developed strong skin
Synonyms: Methacrylic acid, methyl ester; reactions when rechallenged with the liquid.6
methyl 2-methylpropenoic acid; methyl a- Allergic contact dermatitis has been reported
methyl acrylate; methyl methylacrylate; 2- in workers handling methacrylate sealants,
(methyoxycarbonyl)-1-propene including methyl methacrylate.7 In another
report, ve subjects were shown by bronchial
Physical Form. Colorless liquid; commercial provocation tests to have occupational asthma
form contains a small amount of hydroquinone due to methyl methacrylate or cyanoacrylates.8
METHYL METHACRYLATE 489
Acute inhalation exposure of dogs to The IARC has determined that there is
11,000 ppm led to central nervous system inadequate evidence in humans for the car-
depression, a drop in blood pressure, liver and cinogenicity of methyl methacrylate and that
kidney damage, and death due to respiratory there is evidence suggesting the lack of
arrest.9 Mice exposed to 1520 ppm for 2 hours carcinogenicity in experimental animals.1
twice daily for 10 days showed no signicant Methyl methacrylate is not genotoxic in
histologic changes in heart, liver, kidney, or bacterial systems, but it has induced mutation
lungs. In male rats exposed to methyl metha- and chromosomal aberrations in vitro.17
crylate vapor at 116 ppm 7 hours/day, 5 days/ Increases in chromosomal aberrations in bone
week for 5 months, the tracheal mucosa was marrow cells of rats have been observed after
denuded of cilia and the number of microvilli in vivo inhalation exposure.17
on the epithelium was reduced.10 Methanol concentrations in blood and
Exposure of pregnant ICR mice to urine have been found to correlate with methyl
1330 ppm for 2 hours twice daily during days methacrylate exposure.18 The lack of specicity
615 of pregnancy resulted in no developmen- of methanol to methyl methacrylate exposure
tal effects.11 At 2028 ppm for 6 hours/day limits its usefulness as a biological indicator.
during days 615 of gestation there was The 2003 ACGIH threshold limit value-
decreased maternal food consumption and time-weighted average (TLV-TWA) is 50 ppm
body weight gain in pregnant rats exposed by (205 mg/m3) and the short-term excursion limit
vapor inhalation but no embryo or fetal toxic- (TLV-STEL) is 100 ppm (410 mg/m3) with a
ity or malformations.12 notation for sensitization.
In a 2-year inhalation study, there was
no evidence of carcinogenicity of methyl
methacrylate for male rats exposed at 500 or REFERENCES
1000 ppm, for female rats exposed at 250 or
500 ppm, or for male and female mice exposed 1. IARC Monographs on the Evaluation of Car-
at 500 or 1000 ppm.13 There was inammation cinogenic Risks to Humans, Vol 60, Some indus-
of the nasal cavity and degeneration of the trial chemicals, pp 445474. International
olfactory sensory epithelium in rats and mice; Agency for Research on Cancer, Lyon,
epithelial hyperplasia of the nasal cavity was 1994
also observed in exposed mice. In another study 2. Cromer J, Kronoveter K: A Study of Methyl
no exposure-related tumors were seen in rats or Methacrylate Exposures and Employee Health.
DHEW (NIOSH) Pub No 77-119. US
hamsters exposed at 100 and 400 ppm for 24
Department of Health, Education, and
and 18 months, respectively.14
Welfare, National Institute of Occupational
A mortality study of three cohorts engaged Safety and Health, Cincinnati, OH.
in the manufacturing and polymerization of Washington, DC, US Government Printing
acrylate monomers revealed an excess colon Ofce, 1976
cancer rate among men employed extensively 3. Blagodatin VM, Golova IA, Bladokatkina
during the 1940s in jobs entailing the highest NK, et al: Establishing the maximum per-
exposures to vapor-phase ethyl acrylate and missible concentration of the methyl ester of
methyl acrylate monomer.15 The excess mor- methacrylic acid in the air of a work area. Gig
tality appeared only after the equivalent of Tr Prot Zabol 6:58, 1976
3 years employment followed by a latency 4. Kassis V et al: Contact dermatitis to
methyl methacrylate. Contact Derm 11:2628,
of 20 years. The two cohorts with later dates of
1984
hire showed no excess mortality.15 A mortality
5. Seppalainen A, Rajaniemi R: Local neurotox-
study of 2671 men exposed to methyl icity of methyl methacrylate among dental
methacrylate alone found a nonsignicantly technicians. Am J Ind Med 5:471477, 1984.
increased mortality from all cancers but no 6. Spealman CR, Main RJ, Haag HB, et al:
signicant risk at any particular site with Monomeric methyl methacrylate. Studies on
increasing dose.16 toxicity. J Ind Med 14:292, 1945
490 METHYL PARATHION
cramps, and diarrhea, appear within 15 minutes Aging is of clinical interest in the treatment of
to 2 hours. After skin absorption, localized poisoning because cholinesterase reactivators
sweating and muscular fasciculations in the such as pralidoxime (2-PAM, Protopam)
immediate area usually occur within 15 chloride are ineffective after aging has
minutes to 4 hours; skin absorption is some- occurred. Measurement of metabolites of
what greater at higher ambient tempera- methyl parathion, para-nitrophenol, and
tures and is increased by the presence of dimethylphosphate in the urine has been used
dermatitis.13 to monitor exposure to workers.6
With severe intoxication by all routes, an Methyl parathion administered intraperi-
excess of acetylcholine at the neuromuscular toneally at maternally lethal doses was terato-
junctions of skeletal muscle causes weakness genic to mice, producing cleft palate and rib
aggravated by exertion, involuntary twitchings, abnormalities. High-dose administration to
fasciculations, and eventually paralysis. The rats, sometimes producing maternal toxicity,
most serious consequence is paralysis of the resulted in evidence of embryo-fetotoxicity
respiratory muscles. Effects on the central with increased resorptions and growth
nervous system include giddiness, confusion, retardation.6
ataxia, slurred speech, CheyneStokes respira- A 2-year bioassay of methyl parathion
tion, convulsions, coma, and loss of reexes. in mice and rats did not demonstrate any
The blood pressure may fall to low levels, and increased incidence of tumors in dosed
cardiac irregularities including complete heart animals.7 The IARC has concluded that there
block may occur.2 is no evidence that methyl parathion is car-
Complete symptomatic recovery usually cinogenic to experimental animals.6
occurs within a week; increased susceptibility Methyl parathion is not strongly geno-
to the effects of anticholinesterase agents per- toxic; it has produced both positive and nega-
sists for up to several weeks after exposure.4 tive results in both eukaryotic and prokaryotic
Daily exposure to concentrations that are assays.8
insufcient to produce symptoms after a single There is no evidence that methyl parathion
exposure may result in the onset of symptoms. can induce delayed peripheral neuropathy in
Continued daily exposure may be followed by humans or experimental animals.6
increasingly severe effects. The 2003 ACGIH threshold limit value-
Deaths from occupational exposure have time-weighted average (TLV-TWA) for
been reported, usually after massive accidental methyl parathion is 0.2 mg/m3 with a notation
exposures.1 Data from human poisonings by for skin absorption.
methyl parathion are not sufciently detailed
to identify the range between the doses pro-
ducing rst symptoms and those producing REFERENCES
severe or fatal intoxication.4 The probable oral
lethal dose is 550 mg/kg. Most animal data 1. Hayes WJ Jr: Pesticides Studied in Man, pp 284
and limited human data indicate that methyl 435. Baltimore, MD, Williams & Wilkins,
parathion is somewhat less acutely toxic than 1982
parathion.4 2. Taylor P: Anticholinesterase agents. In Gilman
Methyl parathion itself is not a strong AG et al. (eds): Goodman and Gilmans The
Pharmacological Basis of Therapeutics, 7th ed, pp
cholinesterase inhibitor, but one of its metabo-
116129. New York, Macmillan Publishing,
lites, methyl paraoxon, is an active inhibitor.
1985
Methyl paraoxon inactivates cholinesterase 3. Koelle GB (ed.): Cholinesterases and anti-
by phosphorylation of the active site of the cholinesterase agents. Handbuch der Experi-
enzyme to form the dimethylphosphoryl mentellen Pharmakologie, Vol 15, pp 9891027.
enzyme. Over the following 2448 hours Berlin, Springer-Verlag, 1963
there is a process, called aging, of conversion 4. National Institute for Occupational Safety and
to the monomethylphosphoryl enzyme. Health: Criteria for a Recommended Standard
492 METHYL PROPYL KETONE
. . . Occupational Exposure to Methyl Parathion. tion of the eyes and nose.2 There have been
DHEW (NIOSH) Pub No 77-106, pp 3168. no reports of chronic or systemic effects in
Washington, DC, US Government Printing humans.
Ofce, 1976 In guinea pigs, exposure to 50,000 ppm for
5. Namba T, Nolte CT, Jackrel J, Grob D: Poi-
50 minutes or 13,000 ppm for 300 minutes
soning due to organophosphate insecticides.
Am J Med 50:475492, 1971 was fatal.3 Animals survived 810 minutes at
6. IARC Monographs on the Evaluation of the Car- 5000 ppm, but narcosis occurred in 460
cinogenic Risk of Chemicals to Humans, Vol. 30, 710 minutes.2 Although methyl propyl ketone
Miscellaneous pesticides, pp 131152. Lyon, has not been reported to be nephro- or hepa-
International Agency for Research on Cancer, totoxic in rats, it has been shown to potentiate
1983 kidney and liver injury produced by chloro-
7. National Cancer Institute: Bioassay of Methyl form.4 Applied to the skin of rabbits, the undi-
Parathion for Possible Carcinogenicity, TR- luted liquid was only slightly irritating within
157. DHEW (NIH) Pub No 79-1713. 24 hours.5
Washington, DC, US Government Printing The 2003 ACGIH threshold limit value-
Ofce, 1979
time-weighted average (TLV-TWA) for
8. Agency for Toxic Substances and Disease Reg-
istry (ATSDR): Toxicological Prole for Methyl methyl propyl ketone is 200 pm (705 mg/m3)
Parathion. pp 1226. US Department of with a short-term excursion limit (STEL) of
Health and Human Services, Public Health 250 ppm (881 mg/m3).
Service, 2001
REFERENCES
(CHO3)4Si
REFERENCES
30 ppm exhibited irritation of the upper respi- 200 ppm the odor was objectionable; at 100
ratory tract and bronchiolar inammation. No ppm the odor was strong but tolerated without
adverse effects were noted at 10 ppm. excessive discomfort.1
Human experience indicates that methyl Guinea pigs and rats exposed 7 hours/day
silicate exposure has a delayed action on the to 3000 ppm for 34 days died; at 800 ppm for
eyes, causing slight or no immediate effect 27 days there were slight changes in liver and
that is followed, after a latent period of several kidney weight and some reduction in growth.1
hours, by potentially serious injury to the eyes.3 Exposure 7 hours/day to 200 ppm for 139 days
The 2003 ACGIH threshold limit value- caused no adverse effects in several species. In
time-weighted average (TLV-TWA) for a recent study, concentrations of 600, 800, or
methyl silicate is 1 ppm (6 mg/m3). 1000 ppm were lethal to some mice after 6
hours; animals surviving 12 exposures had sig-
nicantly increased liver weights and relative
REFERENCES spleen weights were signicantly decreased.2
No microscopic treatment-related lesions were
1. Smyth Jr HF, Carpenter CP, Weil CS: Range- observed. Exposure of male and female F344
nding toxicity data: List IV. Arch Ind Hyg rats and male NBR rats to 250 or 500 ppm 6
Occup Med 4:119122, 1951 hours/day for 9 days resulted in increased accu-
2. Kolesar GB, Siddiqui WH, Geil RG, et al:
mulation of hyalin droplets in the renal tubules
Subchronic inhalation toxicity of tetram-
of male F344 rats.
ethoxysilane in rats. Fundam Appl Toxicol 13:
285295, 1989 The liquid dropped in the eyes of rabbits
3. Grant WM: Toxicology of the Eye, 3rd ed, p 627. caused slight conjunctival irritation; applied to
Springeld, IL, Charles C. Thomas, 1986 rabbit skin, it produced erythema.1
a-methyl styrene induced sister chromatid
exchanges in human whole blood lymphocyte
cultures, but it was not mutagenic in bacterial
assays with or without metabolic activation.3,4
The odor of a-methyl styrene is detectable
a-METHYL STYRENE at 50 ppm; the odor and irritant properties
CAS: 98-83-9 provide good warning of toxic levels.
The 2003 ACGIH threshold limit value-
C9H10 time-weighted average (TLV-TWA) is 50 ppm
(242 mg/m3) with a short-term excursion level
(STEL) of 100 ppm (483 mg/m3).
Synonyms: 1-Methyl-1-phenyl ethylene; iso-
propenylbenzene; b-phenylpropylene
REFERENCES
Physical Form. Colorless liquid
1. Wolf MA, Rowe VK, McCollister DD, et al:
Uses. In the formulation of polymers and Toxicological studies of certain alkylated
resins benzenes and benzene. Arch Ind Health
14:387398, 1956
Exposure. Inhalation 2. Morgan DL, Mahler JF, Kirkpatrick DT, et al:
Characterization of inhaled a-methylstyrene
vapor toxicity for B6C3F1 mice and F344 rats.
Toxicology. a-Methyl styrene is an irritant
Toxicol Sci 47(2):187194, 1999
of the eyes and mucous membranes; severe 3. Norppa H, Vainio H: Induction of sister-
exposure may result in central nervous system chromatid exchanges by styrene analogues
depression. in cultured human lymphocytes. Mutat Res
Humans briey exposed to 600 ppm 116(34):379387, 1983
experienced strong eye and nasal irritation; at 4. Zeiger E, Anderson B, Haworth S, et al: Sal-
496 MEVINPHOS
monella mutagenicity tests. V. Results from the to 2 hours. After skin absorption, localized
testing of 311 chemicals. Environ Mol Mutagen sweating and muscular fasciculations in
19(suppl 21):2141, 1992 the immediate area occur usually within 15
minutes to 4 hours; skin absorption is some-
what greater at higher ambient tempera-
tures and is increased by the presence of
dermatitis.13
With severe intoxication by all routes, an
MEVINPHOS excess of acetylcholine at the neuromuscular
CAS: 7786-34-7 junctions of skeletal muscle causes weakness,
aggravated by exertion, involuntary twitchings,
C7H13O6P fasciculations, and eventually paralysis. The
most serious consequence is paralysis of the
respiratory muscles. Effects on the central
Synonym: 2-Methoxycarbonyl-1-methylvinyl nervous system include giddiness, confusion,
dimethylphosphate ataxia, slurred speech, CheyneStokes respira-
tion, convulsions, coma, and loss of reexes.
Physical Form. Light yellow to orange The blood pressure may fall to low levels, and
liquid cardiac irregularities, including complete heart
block, may occur. Complete symptomatic
Use. Insecticide recovery usually occurs within 1 week;
increased susceptibility to the effects of anti-
Exposure. Skin absorption; inhalation; cholinesterase agents persists for up to several
ingestion weeks after exposure. Daily exposure to con-
centrations that are insufcient to produce
Toxicology. Mevinphos is an anticholinest- symptoms after a single exposure may result in
erase agent. the onset of symptoms. Continued daily expo-
Signs and symptoms of overexposure are sure may be followed by increasingly severe
caused by the inactivation of the enzyme effects.
cholinesterase, which results in the accumula- A group of 31 farm workers who inadver-
tion of acetylcholine at synapses in the nervous tently entered a eld only 2 hours after it was
system, skeletal and smooth muscle, and secre- sprayed with mevinphos developed a variety
tory glands. The sequence of the development of initial symptoms, including eye irritation,
of systemic effects varies with the route of headache, visual disturbances, dizziness,
entry. The onset of signs and symptoms is nausea, vomiting, chest pain, shortness of
usually prompt, but may be delayed up to 12 breath, pruritis, eyelid and arm fasciculations,
hours.13 After inhalation, respiratory and excessive sweating, and diarrhea.4 Headache,
ocular effects are the rst to appear, often dizziness, visual disturbances, and nausea per-
within a few minutes after exposure. Respira- sisted for 58 weeks or more in a signicant
tory effects include tightness in the chest number of eld workers after cessation of expo-
and wheezing due to bronchoconstriction and sure. Despite symptoms suggesting moderate
excessive bronchial secretion. Laryngeal organophosphate intoxication, mean plasma
spasms and excessive salivation may add to the and red blood cell cholinesterase depression
respiratory distress; cyanosis may also occur. were only 16%, and 6%, respectively, when
Ocular effects include miosis, blurring of compared against a presumed baseline
distant vision, tearing, rhinorrhea, and frontal obtained in these workers long after the expo-
headache. sure.4 Another study of 16 cauliower workers
After ingestion, gastrointestinal effects, poisoned by residues of mevinphos and phos-
such as anorexia, nausea, vomiting, abdominal phamidon (a less potent organophospate)
cramps, and diarrhea appear within 15 minutes demonstrated persistent headaches, blurred
MICA 497
vision, and weakness in a number of workers mentellen Pharmakologie, Vol 15, pp 9891027.
59 weeks or more after the exposure.5 Berlin, Springer-Verlag, 1963
In many of these occupational cases, the 2. Taylor P: Anticholinesterase agents. In Gilman
dermal route of exposure may predominate.6 In AG et al. (eds): Goodman and Gilmans The
one report, it was found that when greenhouse Pharmacological Basis of Therapeutics, 7th ed, pp
110129. New York, MacMillan Publishing,
workers wore long-sleeved shirts, approxi-
1985
mately 6% of the pesticide reached the skin, 3. Hayes WJ Jr: Organic phosphorus pesticides.
compared with 38% for workers wearing short Pesticides Studied in Man, pp 284435. Balti-
sleeves.6 more, MD, Williams & Wilkins, 1982
In two cases of moderate intoxication from 4. Coye MJ, Barnett PG, Midtling JE, et al:
mevinphos, urinary excretion of dimethylphos- Clinical conrmation of organophosphate
phate (a metabolite of mevinphos) was almost poisoning of agricultural workers. Am J Ind
complete 50 hours after exposure.7 Although a Med 10:399409, 1986
number of other organophosphorus pesticides 5. Midtling JE, Barnett PG, Coye MJ: Clinical
also yield dimethyl phosphate, the presence of management of eld worker organosphos-
signicant amounts of this metabolite in the phate poisoning. West J Med 142:514518,
1985
urine may be useful in estimating the absorp-
6. Kangas J, Laitinen S, Jauhiainen A, et al: Expo-
tion of mevinphos. sure of sprayers and plant handlers to mevin-
Mevinphos inactivates cholinesterase by phos in Finnish greenhouses. AMA Ind Hyg
phosphorylation of the active site of the Assoc J 54:150157, 1993
enzyme to form the dimethylphosphoryl 7. Holmes JHG, Starr HG Jr, Hanisch RC, von
enzyme. Over the following 2448 hours, Kaulla KN: Short-term toxicity of mevinphos
there is a process, called aging, of conversion in man. Arch Environ Health 29:8489,
to the monomethylphosphoryl enzyme. 1974
Aging is of clinical interest in the treatment of 8. World Health Organization: 919. Mevinphos
poisoning because cholinesterase reactivators (Pesticide Residues in Food: 1996 Evaluations Part
such as pralidoxime (2-PAM, Protopam) chlo- II. Toxicological), pp 120. Geneva, Interna-
tional Programme on Chemical Safety (IPCS),
ride are ineffective after aging has occurred.
1996
There was no evidence of carcinogenicity
in an 18-month feeding study in mice (up to
25 ppm in the diet) or in a 2-year gavage study
in rats (0.025, 0.35, or 0.70 mg/kg body weight
per day).8 No fetotoxic or teratogenic effects
were observed in rats exposed on days 6
through 15 of gestation at doses of 1.0 mg/kg, MICA
which caused maternal toxicity in the form of CAS: 12001-26-2
tremors.8 There was some evidence of geno-
toxic potential in vitro but not in vivo.8 Formula unspecied
The 2003 ACGIH threshold limit value-
time-weighted average (TLV-TWA) for
mevinphos is 0.01 ppm (0.092 mg/m3) with a Synonyms: Mica is a nonbrous silicate occur-
short-term excursion limit (STEL) of 0.03 ppm ring in plate form and includes nine different
(0.27 mg/m3) and a notation for skin species; muscovite is a hydrated aluminum
absorption. potassium silicate also called white mica; phlo-
gopite is an aluminum potassium magnesium
silicate also called amber mica; other forms are
REFERENCES biotite, lepidolite, zinnwaldite, and roscoelite
1. Koelle GB (ed): Cholinesterases and anti- Physical Form. Light gray to dark-colored
cholinesterase agents. Handbuch der Experi- akes or particles
498 MOLYBDENUM (and Compounds)
Uses. Insulation in electrical equipment; 2. Vestal TF, Winstead JA, Joliet PV: Pneumo-
manufacture of roong shingles and wallpaper; coniosis among mica and pegmatite workers.
in oil rening; in rubber manufacture Ind Med 12:1114, 1943
3. Landas SK, Schwartz DA: Mica-associated
Exposure. Inhalation pulmonary interstitial brosis. Am Rev Respir
Dis 144:718721, 1991
Toxicology. Mica dust causes
pneumoconiosis.
In a study of 57 workers exposed to mica
dust, 5 of six workers exposed to concentrations
in excess of 25 million particles per cubic foot MOLYBDENUM (and Compounds)
(mppcf ) for more than 10 years had pneumo- CAS: 7439-98-7
coniosis.1 The most characteristic nding by
chest X ray was ne granulation of uneven Mo
density; there was a tendency, in some cases, to
a coalescence of shadows. The symptoms most
frequently reported were chronic cough and Synonyms: Soluble compounds include
dyspnea; complaints of weakness and weight molybdenum trioxide, ammonium molybdate,
loss were less frequent.1 Only one of six and sodium molybdate; insoluble compounds
workers exposed more than 10 years at con- include molybdenum disulde and molybde-
centrations in excess of 25 mppcf failed to show num dioxide
evidence of pneumoconiosis.
A group of mica miners were said to show a Physical Form. Silverish metal or dark
higher incidence of pneumoconiosis than miners powder
of other minerals, but some quartz was present
in the dust to which they were all exposed.2 Uses. Manufacture of special-purpose steel;
In one case report, a 63-year-old male with in ceramic glazes, enamels, and pigments;
a long history of extensive exposure to mica lubricant; corrosion inhibitor; additive to
presented (30 years after initial exposure) with fertilizer
complaints of progressive shortness of breath
and a chronic nonproductive cough. Pul- Toxicology. Molybdenum and its com-
monary function tests revealed restrictive lung pounds are considered to be of relatively low
function and a mild reduction in total lung toxicity; chronic inhalation of molybdenum
capacity. Chest radiographs and lung biopsy trioxide by animals causes inammation and
showed extensive interstitial brosis with heavy neoplastic changes to the lung.
mica deposition. The presence of mica was Workers at a molybdenum-roasting plant
conrmed spectroscopically but asbestos and with time-weighted average (TWA) exposures
other silicates were not identied, suggesting of approximately 9.5 mg Mo/m3 to soluble
that mica was the brogenic agent in this case. dusts had increased plasma and urine levels of
The authors note that the long latency and molybdenum; the only adverse biochemical
chronic exposure associated with the disease ndings were large elevations in serum cerulo-
indicate that mica is not as brogenic as other plasmin levels and some increase in serum uric
pneumoconiotic agents. acid levels.1
The 2003 threshold limit value (TLV) is No evidence of systemic disease or der-
3 mg/m3, respirable dust. matitis attributable to molybdenum (especially
molybdenum disulde) was seen by a plant
REFERENCES physician reporting on 50 years of operation.1
In a report from Russia, an increased
1. Dreessen WC et al: Pneumoconiosis among incidence of nonspecic symptoms, including
mica and pegmatite workers. Public Health Bull weakness, fatigue, anorexia, headaches, and
250:174, 1940 joint and muscle pains, was reported among
MOLYBDENUM (and Compounds) 499
mining and metallurgy workers exposed to reduction in activity of sulde oxidase in the
60600 mg/m3 molybdenum.2 Signs of gout liver.6 The reduced activity of this enzyme leads
and elevated uric acid concentrations have to accumulation of sulde in the tissues and
been observed among inhabitants of areas of subsequent formation of highly undissociated
Armenia, where the soil is rich in molybdenum. copper sulde, thus removing copper from
This effect apparently results from the induc- metabolic activity. This is a possible explana-
tion of the enzyme xanthine oxidase, for which tion for the induction of copper deciency by
molybdenum is a cofactor. molybdate.
Insoluble molybdenite, MoS2, was practi- The 2003 ACGIH threshold limit value-
cally nontoxic in animal studies; guinea pigs time-weighted average (TLV-TWA) is
with exposure to 230 mg Mo/m3 for 25 days 0.5 mg/m3 respirable particulate for the soluble
only showed increases in respiration rate; rats molybdates; TLV-TWAs of 10 mg/m3 (inhal-
ingesting as much as 500 mg/day for 44 days able particulate) and 3 mg/m3 (respirable par-
showed no toxic signs. ticulate) are recommended for occupational
More soluble and more active molybde- exposure to elemental molybdenum and its
num compounds, including calcium molybdate insoluble compounds.
and molybdenum trioxide, were fatal at oral
daily doses of over 100 mg/day.1
Guinea pigs exposed to molybdenum tri- REFERENCES
oxide dust at a concentration of 200 mg molyb-
denum/m3 for 1 hour daily for 5 days developed 1. Stokinger HE: The metals. In Clayton GD,
nasal irritation, diarrhea, weight loss, and inco- Clayton FE (eds): Pattys Industrial Hygiene
ordination.3 In 2-year inhalation studies at con- and Toxicology, 3rd ed, Vol 2, Toxicology,
pp 8071819. New York, Wiley-Interscience,
centrations of up to 100 mg/m3 molybdenum
1981
trioxide there was no evidence of carcinogenic
2. Lener J, Bibr B: Effects of molybdenum on the
activity in female rats, but there was equivocal organism (a review). J Hyg Epidemiol Microbiol
evidence in males based on a marginally sig- Immunol 29:405419, 1984
nicant positive trend of alveolar/bronchiolar 3. Browning E: Toxicity of Industrial Materials,
adenoma or carcinoma (combined). There was 2nd ed, pp 243248. London, Butterworths,
some evidence of carcinogenic activity in mice 1969
based on increased incidences of alveolar/bron- 4. National Toxicology Program: Toxicology and
chiolar adenoma and carcinomas (combined).4 Carcinogenesis Studies of Molybdenum Trioxide
Other exposure-related effects in exposed (CAS No. 1313-27-5) in F344/N Rats and
animals included alveolar inammation, squa- B6C3F1 Mice (Inhalation Studies). Technical
Report Series No. 462, NIH Publication No.
mous metaplasia of the epiglottis and hyaline
97-338, pp 1263. US Department of Health
degeneration of the respiratory and olfactory
and Human Services, 1997
epithelium. Molybdenum trioxide was not 5. Friberg L, Lener J: Molybdenum. In Friberg
mutagenic in bacterial assays, nor did it induce L et al. (eds): Handbook on the Toxicology of
sister chromatid exchanges or chromosomal Metals, Vol. II. Specic Metals, pp 445461.
aberrations in vitro.4 Amsterdam, Elsevier, 1986
In livestock, chronic molybdenum poison- 6. Halverson AW, Phifer JH, Monty KJ: A mech-
ing, known as teart disease, is caused by a anism for the copper-molybdenum interrela-
diet high in molybdenum and low in copper. tionship. J Nutr 71:79100, 1960
Symptoms include anemia, gastrointestinal dis-
turbances, bone disorders, and growth retarda-
tion.5
The metabolism of molybdenum is closely
associated with that of copper; molybdenum
toxicity in animals can be alleviated by the
administration of copper. High intake of
molybdenum in rats resulted in a substantial
500 MORPHOLINE
trial Hygiene and Toxicology, 3rd ed, rev, Vol 2A, only through the early 1970s, several other
Toxicology, pp 26932696. New York, Wiley- countries currently maintain large stockpiles
Interscience, 1981 that present an imminent danger from acci-
2. Shea TE: The acute and subacute toxicity dental or intentional exposure.1 Also used in
of morpholine. J Ind Hyg Toxicol 21:236245, small quantities as a model compound in bio-
1939
logical studies on alkylating agents.
3. Conaway CC, Coate WB, Voelker RW: Sub-
chronic inhalation toxicity of morpholine in
rats. Fundam Appl Toxicol 4:465472, 1984. Exposure. Inhalation; skin contact
4. Grant WM: Toxicology of the Eye, 2nd ed, pp
722723. Springeld, IL, Charles C. Thomas, Toxicology. Mustard gas causes skin and eye
1974 injury; after inhalation, pulmonary damage
5. Mirvish SS, Salmasi S, Cohen SM, et al: Liver may occur. Chronic exposure has been associ-
and forestomach tumors and other forestom- ated with an increased risk of respiratory cancer
ach lesions in rats treated with morpholine and in humans.
sodium nitrite, with and without sodium ascor- Mustard gas is primarily a vesicant, with
bate. J Natl Cancer Inst 71:8184, 1983 blisters being formed by either liquid or vapor
6. Shank RC, Newberne PM: Dose-response
contact.2 It attacks the eyes and lungs and is a
study of the carcinogenicity of dietary sodium
nitrite and morpholine in rats and hamsters. systemic poison, so that protection of the entire
Food Cosmet Toxicol 14:18, 1976 body must be provided. Insidious in its action,
7. Harbison RD, Marino DJ, Conaway CC, there is no pain at the time of exposure, and the
et al: Chronic morpholine exposure of rats. rst symptoms typically appear in 46 hours.
Fundam Appl Toxicol 12:491507, 1989 The higher the concentration, the shorter the
8. IARC Monographs on the Evaluation of interval of time between exposure to the agent
Carcinogenic Risks to Humans, Vol 71, Re- and the rst symptoms. After several hours, the
evaluation of some organic chemicals, gross biological evidences of injury begin to
hydrazine and hydrogen peroxide, pp appear as edema, hyperemia, and irritation. In
15111514. Lyon, International Agency for the eye, the corneal epithelium becomes
Research on Cancer, 1999
edematous, the lids and conjunctiva become
9. World Health Organization: Morpholine.
Environmental Health Criteria 179, pp 1163. red and swollen, and the patient experiences
Geneva, International Programme on Chemi- burning discomfort and photophobia, includ-
cal Safety (IPCS), 1996 ing tearing and blepharospasm.3 Areas of con-
taminated skin become inamed and blistered.
Burns caused by mustard gas are severe and
require long healing periods. After inhalation
of the agent, pulmonary edema and long-term
MUSTARD GAS dyspnea may occur.4 Follow-up of 197 Iranians
CAS: 505-60-2 who were exposed to a large single inhalation
episode in 1986 revealed chronic destructive
C4H8Cl2S pulmonary sequelae including asthma in 21
subjects, chronic bronchitis in 116 and pul-
monary brosis in 24.5
Synonyms: Sulfur mustard; bis-2-chloroethyl The toxic effects of mustard gas are pri-
sulde; di-2-chloroethyl sulde; 1,1-thiobis(2- marily related to its alkylating ability.6 In an
chloroethane); chemical agent symbol: HD aqueous environment, mustard gas rearranges
and loses one or two molecules of hydrogen
Physical Form. Colorless, odorless, oily chloride; then, mustard gas, minus its chlo-
liquid rides, becomes rmly attached through one or
both of its b-carbon atoms to tissue compo-
Uses. As a vesicant in chemical warfare. nents, altering their functional and physio-
Although US stockpiles were thought to exist chemical properties. Cytotoxic effects have
502 MUSTARD GAS
specically been related to a double alkylation cell wall skeleton (N-CWS) was found to sig-
reaction, in which the two reactive ends of nicantly suppress the development of cancer
the mustard gas molecule attach to strands of (7 in treated workers vs. 17 in untreated).
DNA, forming cross-links that prevent cell A study of 3354 British workers employed
replication. in the manufacture of mustard gas during
Exposure to mustard gas was considered to World War II (19391945) and traced for mor-
be a possible cause of cancer in humans, in light tality to the end of 1984, found large and highly
of its strong alkylating ability. Two types of signicant excesses, compared with national
exposures have been studied in particular: acute death rates, from cancer of the larynx (11
exposure resulting from the use of the gas in observed vs. 4 expected), pharynx (15 observed
war and chronic exposure in the course of its vs. 2.73 expected), and all other buccal cavity
manufacture. and upper respiratory sites combined (lip,
The mortality of British and American vet- tongue, salivary gland, mouth, and nose: 12
erans of World War I (19141918) who were observed vs. 4.29 expected).13 For lung cancer
acutely exposed to mustard gas has been inves- deaths, there were 200 observed cases, com-
tigated. British soldiers who received a pension pared with 138 expected. Signicant excesses
for mustard gas poisoning were found to have were also observed for deaths from acute and
a high mortality from chronic bronchitis (217 chronic nonmalignant respiratory disease. The
vs. 21 expected) and increased mortality from relative risk of both lung cancer and nonmalig-
cancer of the lung and pleura (29 vs. 14 nant respiratory disease was substantially
expected).7 However, most of the exposed men reduced. However, if comparison rates for
also had chronic bronchitis, and a similar excess the nearest urban area were used rather than
of lung and pleural cancers was found in national rates, the risk for cancer of the
pensioners with bronchitis who had not been pharynx and lung was signicantly related to
exposed to the gas. US veterans with mustard duration of employment. Furthermore, the risk
gas injury had signicantly increased mortality of respiratory cancer was not localized to indi-
from pneumonia and tuberculosis. There was viduals employed in process areas where expo-
some increased risk of respiratory cancer in the sures occurred to high levels of short duration,
exposed group, but the extent of the increase suggesting that the risk of cancer was due more
was not large.8 A further study involving an to lower-level ambient exposure of longer
additional 10 years of follow-up produced duration. Signicant excess mortality was also
similar results.9 observed for cancers of the esophagus and
Studies of the effects of occupational expo- stomach, but there was no consistent relation
sure to mustard gas have provided a stronger with time since rst exposure or duration of
association between exposure and respiratory exposure. The authors conclude that the results
cancer. Among 495 Japanese workers engaged provide strong evidence that exposure to
in the manufacture of mustard gas between mustard gas can cause cancers of the upper res-
1929 and 1945, 33 died from cancers of the res- piratory tract and some evidence that it can
piratory tract, compared to 0.9 expected.10 In cause lung cancer and nonmalignant respira-
an earlier report of this same cohort, it was tory disease.
stated that the working environment attained Mustard gas has been tested for carcino-
mustard gas concentrations of 0.550.07 mg/l genicity in mice, producing lung tumors after
and that protective measures were neither fully inhalation or intravenous injection and local
effective nor generally applied.11 Follow-up of sarcomas after subcutaneous injection.14
the Japanese factory workers through 1992 The IARC has determined that there is
found that workers who had engaged in the sufcient evidence for carcinogenicity to
production of mustard gas for more than 5 humans and limited evidence in animals.14
years had a standardized mortality ratio (SMR) Mustard gas is highly genotoxic.15 In vitro
of 7.35 for lung cancer.12 Treatment of 146 of assays in both prokaryotic and eukaryotic
these former gas workers with Nocardia rubra systems support a mechanism of DNA alkyla-
NALED 503
C10H9N
REFERENCES
(average time since rst exposure 39.4 years) 2. IARC Monographs on the Evaluation of Car-
revealed a signicant increase for bladder car- cinogenic Risks to Humans. Suppl 7, Overall
cinoma [standardized mortality ratio (SMR) evaluations of carcinogenicity: An updating
= 48.4] for BNA manufacturers but not for of IARC Monographs, Vols 1 to 42, pp
malignant neoplasms of other organs.7 261262. Lyon, International Agency for
Research on Cancer, 1987
Dyestuff workers exposed to BNA and
3. Case RAM: Tumours of the urinary tract
benzidine before 1972 showed alterations in as an occupational disease in several in-
some T lymphocyte subpopulations some 20 dustries. Ann R Coll Surg Engl 39:213235,
years later.8 Specically, there was a decreased 1966
number of circulating CD4+ T lymphocytes in 4. Goldwater LJ, Rossa AJ, Kleinfeld M:
exposed workers. Measurement of this T lym- Bladder tumors in a coal tar dye plant. Arch
phocyte subpopulation may provide a useful Environ Health 11:814817, 1965
biological marker of past exposure to aromatic 5. Schulte PA, Ringen K, Hemstreet GP, et al:
amines. Risk assessment of a cohort exposed to aro-
Bladder tumors were induced in 24 of 34 matic amines. Initial results. J Occup Med 27:
dogs that were fed 6.2550 mg/kg/day for 626 115121, 1985
6. Stern FB, Murthy LI, Beaumont JJ, et al:
months; carcinomas were present in 9 of 11
Notication and risk assessment for bladder
dogs that received 100200 g of BNA, whereas cancer of a cohort exposed to aromatic
6 of 22 carcinomas occurred in dogs receiving amines. III. Mortality among workers
total doses less than 100 g.9 All dogs treated exposed to aromatic amines in the last b-
with the carcinogen had multiple tumors. naphthylamine manufacturing facility in the
In monkeys, intragastric administration United States. J Occup Med 27:495500, 1985
of 372400 mg/kg/week for up to 250 weeks 7. Naito S, Tanaka K, Koga H, et al: Cancer
caused nine transitional cell carcinomas of the occurrence among dyestuff workers exposed
bladder and three papillary adenomas.10 to aromatic amines. A long term follow-up
In genotoxic assays BNA induced unsched- study. Cancer 76(8):144552, 1995
uled DNA synthesis in human cells in vitro 8. Araki S, Tanigawa T, Ishizu S, et al: Decrease
of CD4-positive T lymphocytes in workers
and chromosomal aberrations, sister chromatid
exposed to benzidine and b-naphthylamine.
exchanges, DNA strand breaks, and unsched- Arch Environ Health 48:205208, 1993
uled DNA synthesis in rodent cells in vitro; in 9. Conzelman GM Jr, Moulton JE: Dose-
vivo it formed DNA adducts in bladder and response relationships of the bladder tumori-
liver cells of dogs.2 gen 2-naphthylamine: A study in beagle dogs.
The IARC has determined that there is J Natl Cancer Inst 49:193205, 1972
sufcient evidence of carcinogenicity of BNA 10. Conzelman GM Jr et al: Induction of
in humans and animals.2 Because of demon- transitional cell carcinomas of the urinary
strated high carcinogenicity, exposure by any bladder in monkeys fed 2-naphthylamine. J
route should be avoided. Natl Cancer Inst 42:825836, 1969
ACGIH classies b-naphthylamine as A1,
a conrmed human carcinogen, and as such,
there is no threshold limit value (TLV).
72-2) in F344/N Rats and B6C3F1 Mice profound weakness; gastrointestinal symptoms
(Inhalation Studies). NTP-TRS No. 453, US may also occur. The temperature seldom
Department of Health and Human Services, rises above 101F, and leukocytosis above
Public Health Service, 1996 12,000/cm3 is infrequent. Physical signs are
15. IARC Monographs on the Evaluation of Car- compatible with pneumonitis or bronchopneu-
cinogenic Risks to Humans. Vol 49, Chromium,
monia. Except for the pronounced weakness
nickel and welding, pp 257445. Lyon, Inter-
national Agency for Research on Cancer, and hyperpnea, the physical ndings and symp-
1990 toms resemble those of a viral pneumonia.2,3
16. Chashschin VP, Artunina GP, Norseth T: Terminally, delirium and convulsions fre-
Congenital defects, abortion and other health quently occur; death has occurred from 3 to 13
effects in nickel renery workers. Sci Total days after exposure to nickel carbonyl. In sub-
Environ 148:28791, 1994 jects who recover from nickel carbonyl intoxi-
cation, convalescence is usually protracted (2
3 months) and is characterized by excessive
fatigue on slight exertion.
A close correlation exists between the clin-
NICKEL CARBONYL ical severity of acute nickel carbonyl intoxica-
CAS: 13463-39-3 tion and the urinary concentration of nickel
during the rst 3 days after exposure; hospital-
Ni(CO)4 ization should be considered in all cases where
the urinary nickel content exceeds 0.5 mg/liter
of urine.2
Synonyms: Nickel tetracarbonyl Long-term exposure to low levels of nickel
carbonyl have been associated with impaired
Physical Form. Colorless liquid lung function characterized by obstructive
pattern and small airway dysfunction.4
Uses. Purication intermediate in rening Controversy as to whether nickel carbonyl
nickel; catalyst in the petroleum, plastic, and causes cancer arose from observation of
rubber industries increased incidence of cancer of the paranasal
sinuses and lungs of workers in nickel rener-
Exposure. Inhalation ies. Suspicion of carcinogenicity focused
primarily on nickel carbonyl vapor, although
Toxicology. Nickel carbonyl is a severe there were concurrent exposures to respirable
pulmonary irritant. particles of nickel, nickel subsulde, and
The initial effects of acute exposure nickel oxide.1 Subsequent studies have shown
involve irritation of the respiratory tract an increased risk of lung and sinus cancer in
and nonspecic symptoms including frontal nickel reneries where nickel carbonyl was not
headache, vertigo, nausea, vomiting, and some- used in the process.5 Furthermore, the inci-
times substernal and epigastric pain; generally dence of respiratory cancer decreased greatly
these early effects disappear when the individ- by 1930 despite continued exposure of workers
ual is removed to fresh air.1,2 It is estimated that to the same levels of nickel carbonyl through
exposure to 30 ppm for 30 minutes may be 1957.
lethal to humans.2 Administration of nickel carbonyl to rats
There may be an asymptomatic interval by repeated intravenous injection was associ-
between recovery from initial symptoms and ated with an increased incidence of various
the onset of delayed symptoms, which tend to malignant tumors.6 Inhalation exposure of rats
develop 1236 hours after exposure. Constric- was associated with a few pulmonary malig-
tive pain in the chest is characteristic of the nancies not reaching statistical signicance.
delayed onset of pulmonary effects, followed The IARC has determined that there is
by cough, hyperpnea, and cyanosis, leading to limited evidence for the carcinogenicity of
512 NICOTINE
Exposure. Inhalation
REFERENCES
Toxicology. Nitric acid causes corrosion
1. Friedman PA: Poisoning and its management. of the skin and other tissues from topical
In Petersdorf RG et al. (eds): Harrisons Prin- contact and acute pulmonary edema or chronic
ciples of Internal Medicine, 10th ed, p 1271. New obstructive pulmonary disease from inhalation.
York, McGraw-Hill, 1983
When nitric acid is exposed to air or comes
2. Taylor P: Ganglionic stimulating and block-
ing agents. In Gilman AG et al. (eds): Goodman
in contact with organic matter, it decomposes
and Gilmans The Pharmacological Basis of Ther- to yield a mixture of oxides of nitrogen, includ-
apeutics, 7th ed, pp 217218. New York, ing nitric oxide and nitrogen dioxide, the latter
Macmillan, 1985 being more hazardous than nitric acid.1 Expo-
3. Gosselin RE, Smith RP, Hodge HC: Clinical sure to high concentrations of nitric acid vapor
Toxicology of Commercial Products, Section III, and nitrogen oxides causes pneumonitis and
5th ed, pp 311314. Baltimore, MD, Williams pulmonary edema, which may be fatal; onset of
& Wilkins, 1984 symptoms, such as dryness of the throat and
4. ACGIH: Nicotine. Documentation of the nose, cough, chest pain, and dyspnea, may or
Threshold Limit Values and Biological Exposure may not be delayed.2
Indices, 7th ed, pp 4. Cincinnati, OH, Ameri-
Three pulp mill workers died after inhala-
can Conference of Governmental Hygienists,
2001
tion of fumes for approximately 1015 minutes
5. Doolittle DJ, Winegar R, Lee CK, et al: The from a nitric acid tank explosion (concentra-
genotoxic potential of nicotine and its major tions not available).3 No signicant respiratory
metabolites. Mutat Res 344(34):95102, 1995 complaints were apparent during initial exam-
6. Nishimura H, Nakai K: Developmental anom- ination. However, 46 hours later they became
alies in offspring of pregnant mice treated with cyanotic with frothy uid escaping from the
nicotine. Science 127:877878, 1958 nose and mouth. All died in less than 24 hours.
7. Pauly JR, Mactutus CF, Sparks JA, et al: Per- Necropsy showed bronchiolar epithelial necro-
sistent behavioral and biochemical alterations sis, marked capillary engorgement, and slight
following in utero nicotine exposure. J Invest interstitial edema of alveoli; the lungs were ve
Med 48(1):152A, 2000
times heavier than normal and released abun-
dant frothy uid from all lobes. The delayed
manifestations of lung injury were consistent
514 NITRIC OXIDE
PNA is mildly irritating to the eyes and The 2003 ACGIH threshold limit value-
may cause some corneal damage.2 time-weighted average (TLV-TWA) is 3 mg/m3
Ingestion of alcohol aggravates the toxic with a notation for skin absorption.
effects of PNA.2
In general, higher ambient temperatures
increase susceptibility to cyanosis from expo- REFERENCES
sure to methemoglobin-forming agents.3
Exposure of rats to aerosol/vapor of PNA 1. Beard RR and Noe JT: Aromatic nitro and
at 30 mg/m3 for 4 weeks produced a signicant amino compounds. In Clayton GD, Clayton
increase in methemoglobin levels.4 FE (eds): Pattys Industrial Hygiene and Toxicol-
ogy, 3rd ed, Vol 2A, Toxicology, pp 24132489.
In subchronic studies, administration of
New York, Wiley-Interscience, 1981
PNA at 3, 10, or 30 mg/kg/day for 90 days pro-
2. MCA, Inc.: Chemical Safety Data Sheet SD-94,
duced a dose-related increase in methemog- para-Nitroaniline. pp 56, 1113. Washington,
lobin; decreases in hematocrit, hemoglobin, DC, MCA, Inc, 1966
and/or red blood cell count were indicative of 3. Linch AL: Biological monitoring for industrial
anemia; histopathologic changes in the spleen exposure to cyanogenic aromatic nitro and
included congestion, hemosiderosis, and exces- amino compounds. Am Ind Hyg Assoc J 35:
sive extramedullary hematopoiesis.5 Chronic 426432, 1974
studies in male rats administered 0, 0.25, 1.5, 4. Nair RS, Johannsen FR, Levinskas GJ, et al:
or 9.0 mg/kg/day by gavage for a period of 2 Subchronic inhalation toxicity of p-nitroani-
years yielded similar results: Blood methemo- line and p-nitrochlorobenzene in rats. Fundam
Appl Toxicol 6:618627, 1986
globin levels were elevated in the middle- and
5. Houser RM, Stout LD, Ribelin WE: The sub-
high-dose groups, and anemia and increased
chronic toxicity of p-nitroaniline administered
spleen weights were observed in the high-dose to male and female Sprague-Dawley rats for 90
groups.6 No treatment-related increase in days. Toxicologist 3:128, 1983
tumor incidence occurred at these PNA levels. 6. Nair RS, Auletta CS, Schroeder RE, et al:
In contrast to rats, there was equivocal evi- Chronic toxicity, oncogenic potential, and
dence of carcinogenic activity in male mice reproductive toxicity of p-nitroaniline in rats.
administered doses of 3, 30, or 100 mg/kg body Fundam Appl Toxicol 15:607621, 1990
weight/day 5 days/week for 2 years based on 7. National Toxicology Program: Toxicology and
the increased incidences of hemangiosarcoma carcinogenesis studies of p-nitroaniline (CAS No.
of the liver and hemangioma or hemangiosar- 100-01-6) in B6C3F1 Mice (Gavage Studies).
Technical Report Series 418, NIH Pub No
coma (combined) at all sites.7 There was no
93-3149, pp 1206. US Department of Health
evidence of carcinogenicity in female mice.
and Human Services, Public Health Service,
Methemoglobin concentrations were signi- National Institutes of Health, 1993
cantly higher in all 30 or 100 mg/kg mice and
erythrocyte counts were signicantly lower
in the high-dose animals. Treatment-related
lesions included increases in the incidence or
severity of splenic congestion, hematopoiesis,
pigment accumulation, and bone marrow
hyperplasia.7 NITROBENZENE
PNA was mutagenic in vitro in some CAS: 98-95-3
bacterial strains and in chromosomal aberra-
tion studies.7 C6H5NO2
In a reproductive study, doses of up to
9.0 mg/kg/day were administered to male and
female rats before and during mating and Synonyms: Nitrobenzol; oil of mirbane
during gestation and lactation to the F0 and F1
generations.6 No signicant effects were seen Physical Form. Almost water-white oily
in mating, pregnancy, or fertility indices. liquid, turning yellow with exposure to air
NITROBENZENE 517
Uses. Chemical intermediate for the produc- hematopoiesis and proliferative capsular
tion of aniline and other products lesions).5,6
In a 2-year inhalation study, nitrobenzene
Exposure. Inhalation; skin absorption was carcinogenic in mice and rats with differ-
ing target organs based on species, sex, and
Toxicology. Nitrobenzene causes anoxia due strain.7 Male B6C3F1 mice exposed at concen-
to the formation of methemoglobin; in experi- trations up to 50 ppm had increased incidences
mental animals chronic exposure has been of pulmonary alveolar/bronchiolar and thyroid
associated with lesions of the liver, spleen, and follicular cell neoplasms, whereas females had
kidney and testicular atrophy; it is carcinogenic mammary gland neoplasms. In rats, exposures
to mice and rats. up to 25 ppm resulted in hepatocellular and
Exposure of workers to 40 ppm for 6 renal neoplasms (male F344 rats), endometrial
months resulted in some cases of intoxication stromal neoplasms (female F344), and hepato-
and anemia; concentrations ranging from 3 to cellular neoplasms (male CD rats).
6 ppm caused headache and vertigo in 2 of 39 Nitrobenzene was not genotoxic in vivo or
workers; increased methemoglobin and sulfhe- in bacterial or mammalian assays in vitro.8 The
moglobin levels and Heinz bodies were IARC has determined that there is inadequate
observed in the blood.1 evidence in humans and sufcient evidence in
Signs and symptoms of overexposure are experimental animals for the carcinogenicity of
due to the loss of oxygen-carrying capacity of nitrobenzene and that, overall, nitrobenzene is
the blood. The onset of symptoms of methe- possibly carcinogenic to humans.8
moglobinemia is often insidious and may be Nonneoplastic effects in rodents from
delayed up to 4 hours; headache is commonly chronic exposure included methemoglobine-
the rst symptom and may become quite mia, anemia, lesions of the olfactory epithe-
intense as the severity of methemoglobinemia lium, and, in the CD males, an increased
progresses.2 Cyanosis develops early in the incidence of testicular atrophy.7 Degenerative
course of intoxication, characterized by blue- testicular lesions have also occurred in rats
ness of the lips, nose, and earlobes, usually rec- exposed to single oral doses of 50450 mg/kg.9
ognized rst by fellow workers, and occurring Male rats repeatedly administered up to 100
when the methemoglobin level is 15% or more. mg/kg body weight by gavage daily showed
The individual usually feels well, has no atrophy of the seminiferous tubules of the
complaints, and will insist that nothing is testis, but male fertility was not affected.10
wrong until the methemoglobin concentration No evidence of teratogenesis or adverse
approaches 40%. At methemoglobin concen- fetal effects was apparent in the offspring of
trations ranging from 40% to 70%, there is rats exposed at concentrations of 40 ppm for 6
headache, weakness, dizziness, ataxia, dyspnea hours/day from day 6 to day 15 of pregnancy.9
on mild exertion, tachycardia, nausea, vomit- In a two-generation reproduction study in rats,
ing, and drowsiness.2,3 Coma may ensue with a decrease in the fertility index of the F0 and F1
methemoglobin levels above 70%, and the generations occurred.
lethal level is estimated to be 8590%.3 Ingestion of alcohol aggravates the toxic
Hepatotoxicity, manifested by alterations effects of nitrobenzene.3 In general, higher
in liver function, including hyperbilirubinemia, ambient temperatures increase susceptibility to
and decreased prothrombin activity, is asso- cyanosis from exposure to methemoglobin-
ciated with exposure in both animals and forming agents.11 p-Nitrophenol and p-
humans.4 aminophenol are metabolites of nitrobenzene,
Inhalation exposure of rats and mice and their presence in the urine is an indication
(1025 ppm over 2 weeks or 550 ppm over of exposure.12
13 weeks) caused methemoglobinemia, ence- Nitrobenzene is mildly irritating to the
phalopathy, and lesions in the liver (hepatocyte eyes; it may produce dermatitis due to primary
necrosis and hepatomegaly), kidney (hyalin irritation or sensitization.3
nephrosis), and spleen (extramedullary The 2003 ACGIH threshold limit value-
518 p-NITROBIPHENYL
The case for the carcinogenicity of PNB Numerous cases of cyanosis in workers
is supported by (1) the induction of urinary exposed to ONCB and related compounds
bladder cancer in dogs after administration of occurred in the period 19351965.1
PNB; (2) the evidence that PNB is metabolized Signs and symptoms of overexposure are
in vivo to 4-aminobiphenyl (a potent carcino- caused by the loss of oxygen-carrying capacity
gen); and (3) the possibility that the cases of of the blood. The onset of symptoms of methe-
human urinary bladder cancer attributed to 4- moglobinemia is often insidious and may be
aminobiphenyl may also have been induced by delayed up to 4 hours; headache is commonly
exposure to PNB.1 the rst symptom and may become quite
There is no threshold limit value (TLV) intense as the severity of methemoglobine-
for PNB. It is classied as a conrmed human mia progresses.1 Cyanosis develops early in
carcinogen and exposure by any route the course of intoxication; it is characterized
respiratory, oral, or skinshould be avoided. by blueness of the lips, nose, and earlobes,
usually recognized rst by fellow workers, and
occurs when the methemoglobin concentration
REFERENCES
approaches 40%. At methemoglobin concen-
1. IARC Monographs on the Evaluation of the trations ranging from 15% to 70%, there is
Carcinogenic Risk of Chemicals to Man, Vol 4, headache, weakness, dizziness, ataxia, dyspnea
Some aromatic amines, hydrazine and related on mild exertion, tachycardia, nausea, vomit-
substances, N-nitroso compounds and miscel- ing, and drowsiness. Coma may ensue with
laneous alkylating agents, pp 113117. Lyon, methemoglobin levels of about 70%, and the
International Agency for Research on Cancer, lethal level is estimated to be 8590%.
1974 In general, higher ambient temperatures
2. Deichmann WB et al: Para-nitrobiphenyla increase susceptibility to cyanosis from expo-
new bladder carcinogen in the dog. Ind Med sure to methemoglobin-forming agents.1
Surg 27:634637, 1958
The acute oral LD50 of ONCB in rats is
560 mg/kg, whereas the dermal LD50 in rabbits
is 400 mg/kg.2 In subchronic inhalation studies,
rats were exposed to 10, 30, or 60 mg/m3
o-NITROCHLOROBENZENE 6 hours/day, 5 days/week for 4 weeks.
CAS: 88-73-3 Animals exposed to the midlevel and high
concentrations showed a signicant increase
NO2C6H4Cl in blood methemoglobin and a signicant
decrease in hemoglobin, hematocrit, and red
blood cell counts. Spleen and liver weights
Synonyms: 2-chloronitrobenzene; 1-chloro-2- were also signicantly increased for these
nitrobenzene; 2-CNB; ONCB two groups; microscopic changes, observed
only in the spleen, included an increased
Physical Form. Yellow solid degree of extramedullary hematopoiesis and
hemosiderosis.
Uses. Chemical intermediate in manufacture Thirteen-week inhalation exposure to
of dyes, picric acid, lumber preservatives, and ONCB in mice at doses ranging from 1.1 to 18
diaminophenol hydrochloride (a photographic ppm caused hyperplasia of the forestomach,
developer) hepatocellular necrosis, secondary effects of
methemoglobin formation on the spleen, liver,
Exposure. Inhalation; skin absorption and bone marrow, and, at the highest dose,
death.3 Rats similarly exposed had hyperplasia
Toxicology. o-Nitrochlorobenzene (ONCB) of the nasal cavity and, at the lowest dose
absorption causes anoxia owing to formation of tested, methemoglobinemia.
methemoglobin. In carcinogenicity bioassays, it was found
520 p-NITROCHLOROBENZENE
that ONCB produced an increase in the inci- Thirteen-week inhalation toxicity of 2- and
dence of multiple tumors in male rats at the low 4-chloronitrobenzene in F344 rats and
dose (1000 mg/kg diet for 6 months, followed B6C3F1 mice. Fundam Appl Toxicol 30(1):75
by 500 mg/kg diet for 12 months and control 92, 1996
diets for an additional 6 months) but not at the 4. Weisburger EK, Russeld AB, Homburger F,
et al: Testing of 21 environmental aromatic
high dose (2000 mg/kg diet for 6 months, fol-
amines or derivatives for long-term toxicity or
lowed by 100 mg/kg diet for 12 months and carcinogenicity. J Environ Pathol Toxicol 2:325,
control diets for 6 months).4 ONCB produced 1978
an increase in hepatocellular carcinomas in 5. IARC Monographs on the Evaluation of the Car-
female mice at high (6000 mg/kg diet) and low cinogenic Risk of Chemicals to Humans, Vol 65,
(3000 mg/kg diet) dose levels and in male mice Printing processes and printing inks, carbon
at low but not high dose levels. Because of the black and some nitro compounds, pp 26396.
inconsistency of the dose-response effects, the Lyon, International Agency for Research on
high doses used, and the long latent periods Cancer, 1996
before tumor development, ONCB was not 6. o-Chlornitrobenzol. Toxikologische Bewertung.
regarded as a very potent carcinogen under Heidelberg, Berufsgenossenschaft der chemis-
chen Industrie 73:168, 2000 (German)
the conditions of the test. The IARC has
determined that the studies were inadequate
for an evaluation of the carcinogenicity of
ONCB.5
In a continuous breeding study in mice
reproductive and fertility parameters were not
affected by gavage administration of ONCB p-NITROCHLOROBENZENE
even in the presence of systemic toxicity (sig- CAS: 100-00-5
nicant methemoglobinemia and increased
spleen and liver weights).5,6 Decreased sper- NO2C6H4Cl
matogenesis has been reported after inhalation
exposure in rats and mice.
ONCB has given positive and negative Synonyms: PNCB; p-Chloronitrobenzene; 4-
results in a variety of genotoxic assays: In mam- CNB
malian cells in vitro it has induced sister chro-
matid exchange and chromosomal aberrations, Physical Form. Yellowish crystals
and in vivo it has caused DNA damage in mice;
it was not mutagenic in insects in bacterial Uses. Manufacture of dyes, rubber, and agri-
assays without metabolic activation.5,6 cultural chemicals
There is no threshold limit value (TLV)
established for the ortho isomer of Exposure. Inhalation; skin absorption
nitrochlorobenzene.
Toxicology. Absorption of p-nitro-
chlorobenzene (PNCB) causes anoxia due to
REFERENCES the formation of methemoglobin.
Signs and symptoms of overexposure are
1. Linch AL: Biological monitoring for industrial due to the loss of oxygen-carrying capacity of
exposure to cyanogenic aromatic nitro and
the blood. The onset of symptoms of methe-
amino compounds. Am Ind Hyg Assoc J 35:426,
moglobinemia is often insidious and may be
1974
2. Nair RS, Johannsen FR, Levinskas GJ, et al: delayed for up to 4 hours; headache is com-
Assessment of toxicity of o-nitrochlorobenzene monly the rst symptom and may become quite
in rats following a 4 week inhalation exposure. intense as the severity of methemoglobinemia
Fundam Appl Toxicol 7:609614, 1986 progresses.1 Cyanosis develops early in the
3. Travlos GS, Mahler J, Ragan HA, et al: course of intoxication; blueness occurs rst in
p-NITROCHLOROBENZENE 521
the lips, nose, and earlobes and is usually was noted in mice in a continuous breeding
recognized by fellow workers. Cyanosis study.7
occurs when the methemoglobin concentration Applied to the skin or eyes of rabbits,
is 15% or more. The subject usually feels PNCB did not cause irritation; it was absorbed,
well, has no complaints, and is insistent that producing methemoglobinemia, Heinz bodies
nothing is wrong until the methemoglobin in erythrocytes, anemia, hematuria, and hemo-
concentration approaches approximately globinuria.3 The acute dermal LD50 for rabbits
40%. At methemoglobin concentrations over was 3400 mg/kg.
40%, there is weakness and dizziness; closer to In genotoxic assays PNCB induced reverse
70% concentration, there may be ataxia, mutations but not primary damage in bacteria.7
dyspnea on mild exertion, tachycardia, nausea, At toxic doses, it induced chromosomal
vomiting, and drowsiness. The ingestion of aberrations, sister chromatid exchange, and
alcohol aggravates the toxic effects of PNCB. repairable DNA breaks in cultured mammalian
In general, higher ambient temperatures cells. In vivo it induced DNA damage in mice.7
increase susceptibility to cyanosis from expo- PNCB has a pleasant, aromatic odor.
sure to methemoglobin-forming agents. The 2003 ACGIH threshold limit value-
Four workers exposed to an unmeasured time-weighted average (TLV-TWA) is 0.1 ppm
concentration of the vapor for a period of 24 (0.64 mg/m3) with a notation for skin absorption.
days developed methemoglobinemia; in these
cases there was an initial collapse, a slate gray
appearance, dyspnea, and a mild anemia 1 week
after exposure.2 REFERENCES
The acute oral LD50 in rats was 530 mg/ 1. Hamblin DO: Aromatic nitro and amino com-
kg.3 In a 4-week inhalation study, exposure to pounds. In Patty FA (ed): Industrial Hygiene
0.82, 2.5, or 7.5 ppm (5, 15, or 45 mg/m3) 6 and Toxicology, 2nd ed, Vol 2, Toxicology, pp
hours/day, 5 days/week caused a dose-related 21052119, 21302131. New York, Wiley-
increase in methemoglobin levels and decreases Interscience, 1963
in hemoglobin, hematocrit, and red blood cell 2. Renshaw A, Ashcroft GV: Four cases of poi-
counts.4 Microscopic changes in the spleen soning by mononitrochlorobenzene and one
included congestion, increased extramedullary by acetanilide occurring in a chemical works:
hematopoiesis, and hemosiderosis. In more With an explanation of the toxic symptoms
recent 13-week inhalation studies of PNCB in produced. J Ind Hyg 8:6773, 1926
3. ACGIH: p-Nitrochlorobenzene. Documenta-
mice and rats 1.524 ppm caused methemoglo-
tion of the Threshold Limit Values and Biological
bin formation and oxidative damage to red
Exposure Indices, 7th ed, pp 3, Cincinnati, OH,
blood cells and anemia. Male rats also had renal American Conference of Governmental
hyalin droplet accumulation and testicular Industrial Hygienists, 2001
atrophy.5 4. Nair RS, Johannsen FR, Levinskas GJ, et al:
No increase in tumor incidence was seen Subchronic inhalation toxicity of p-nitroani-
in rats fed up to 1000 ppm in the diet for 2 line and p-nitrochlorobenzene in rats. Fundam
years; in mice, results were equivocal, with Appl Toxicol 6:618627, 1986
high-dose animals showing an increase in vas- 5. Travlos GS, Mahler J, Ragan HA, et al:
cular tumors and low-dose males showing an Thirteen-week inhalation toxicity of 2- and 4-
increase in liver tumors.6 The IARC has deter- chloronitrobenzene in F344 rats and B6C3F1
mice. Fundam Appl Toxicol 30(1):7592, 1996
mined that there is inadequate evidence in
6. Weisburger EK, Russeld AB, Homburger F,
experimental animals and humans for the car-
et al: Testing of twenty-one environmental
cinogenicity of chlorobenzenes.7 aromatic amines or derivatives for long-term
When PNCB was administered to preg- toxicity or carcinogenicity. J Environ Toxicol
nant rabbits or rats, fetal effects were observed 2:325356, 1978
only at doses that produced severe maternal 7. IARC Monographs on the Evaluation of the
toxicity.8 A progressive decrease in fertility Carcinogenic Risk of Chemicals to Humans, Vol
522 NITROETHANE
65, Printing processes and printing inks, suggests a possible metabolism of nitroethane
carbon black and some nitrocompounds, pp to a more toxic nitrite compound that may
26396. Lyon, International Agency for in turn be responsible for the induction of
Research on Cancer, 1996 methemoglobin.1
8. Nair RS, Johannsen FR, Schroeder RE: Eval- Rabbits died from exposure to 5000 ppm
uation of teratogenic potential of p-nitroani-
for 3 hours but survived 3 hours at 2500 ppm.2,3
line and p-nitrochlorobenzene in rats and
rabbits. In Rickert DE (ed): Chemical Industry Exposure to the higher concentrations caused
Institute of Toxicology Series. Toxicity of Nitroaro- irritation of mucous membranes, lacrima-
matic Compounds, pp 6186. Washington, DC, tion, dyspnea, pulmonary rales, and, in a few
Hemisphere Publishing, 1985 animals, pulmonary edema; convulsions were
rare and of brief duration.2 Autopsy of animals
exposed to lethal concentrations showed mild
to severe liver damage and nonspecic changes
in the kidneys. Nitroethane was not hepato-
NITROETHANE toxic after administration of 9 mmol/kg to
CAS: 79-24-3 mice.4
Rats exposed to 1000 ppm 6 hours/day, 5
C2H5NO2 days/week for up to 90 days showed decreased
body weight gain, elevated methemoglobin
levels with cyanosis, increased reticulocytes,
Synonyms: None Heinz bodies, and associated splenic conges-
tion and hematopoiesis.5 Other target organs
Physical Form. Colorless, oily liquid included olfactory epithelium, liver, renal
epithelium, and salivary glands. Similarly
Uses. Common industrial solvent; more exposed mice showed slight effects on methe-
recently a commercial articial nail remover moglobin, salivary glands, liver, and olfactory
epithelium, along with multinucleated
Exposure. Inhalation spermatids.5
Nitromethane was not genotoxic in
Toxicology. In animals, nitroethane is a res- Salmonella typhimurium tester strains.4
piratory irritant and, at high concentrations, it The liquid is a mild skin irritant due to
causes narcosis and liver damage; methemo- solvent action.
globin has been reported after ingestion by The odor of nitroethane is detectable
humans. at 163 ppm; the odor and irritant properties
Accidental ingestion of less than 1 ounce do not provide sufcient warning of toxic
of an articial ngernail remover containing concentrations.2,3
100% nitroethane resulted in life-threatening The 2003 ACGIH threshold limit value-
methemoglobinemia in a 20-month-old child.1 time-weighted average (TLV-TWA) for
The child was initially asymptomatic, but on nitroethane is 100 ppm (307 mg/m3).
hospital admission 10 hours later, he was short
of breath and visibly cyanotic. Methemoglo-
bin concentrations reached 40.1%. The patient REFERENCES
received 15 mg of methylene blue intra-
1. Hornfeldt CS, Rabe WH: Nitroethane poi-
venously with resolution of cyanosis. One hour
soning from an articial ngernail remover.
later the childs methemoglobin concentration
Clin Toxicol 32:321324, 1994
dropped to 5.7% and other laboratory ndings 2. Machle W, Scott EW, Treon J: The physio-
and vital signs were within normal limits. logical response of animals to some simple
He was discharged 1 day later with a methe- mononitroparafns and to certain derivatives
moglobin concentration of 1.5%. The delayed of these compounds. J Ind Hyg Toxicol 22:
onset of symptoms (10 hours in this case) 315332, 1940
NITROGEN DIOXIDE 523
3. Hygienic Guide Series: Nitroethane. Akron, OH, or second stage of the disease; a severe second
Am Ind Hyg Assoc, 1978 stage may follow a relatively mild initial stage.
4. Dayal R, Gescher A, Harpur ES, et al: Com- The subject who survives the second stage
parison of the hepatotoxicity in mice and the usually recovers over 23 weeks; however,
mutagenicity of three nitroalkanes. Fundam some cases do not return to normal but expe-
Appl Toxicol 13:341348, 1989
rience varying degrees of impaired pulmonary
5. Anonymous: Nitroethane: A 4-Day and 13-Week
Inhalation Study in Rats and Mice. EPA/OTS: function.
Doc No. 86890001191, NTIS/OTS0520703, The radiographic features in the acute
Environmental Protection Agency, 2000 initial stage vary from normal to those of
typical pulmonary edema; most reports
mention a pattern of nodular shadows on the
chest lm at the outset.1,2 The roentgenogram
may then clear, only to show miliary mottling
as the second stage commences, progressing to
NITROGEN DIOXIDE the development of a conuent pattern. Results
CAS: 10102-44-0 of pulmonary function tests in the acute stage
show reduction in lung volume and diffusing
NO2 capacity; similar ndings are recorded in the
second stage.
Pathologic examination of the acute lesion
Synonyms: None shows extensive mucosal edema and inamma-
tory cell exudation. The delayed lesion shows
Physical Form. Gas the histologic appearance of bronchiolitis
obliterans; small bronchi and bronchioles
Uses/Sources. Intermediate in nitric and contain an inammatory exudate that tends
sulfuric acid production; nitration of organic to undergo brinous organization, eventually
compounds and explosives; found in vehicle obliterating the lumen.
emissions and fossil fuel combustion Humans exposed to nitrogen dioxide for
60 minutes can expect the following effects:
Exposure. Inhalation 100 ppm, pulmonary edema and death; 50 ppm,
pulmonary edema with possible subacute or
Toxicology. Nitrogen dioxide is a respiratory chronic lesions in the lungs; and 25 ppm, res-
irritant; at high concentrations it causes pul- piratory irritation and chest pain.3 A concen-
monary edema and, rarely among survivors, tration of 50 ppm is moderately irritating to the
bronchiolitis obliterans. eyes and nose; 25 ppm is irritating to some
Brief exposure of humans to concentra- people.1 Exposure of healthy and asthmatic
tions of about 250 ppm causes cough, pro- volunteers at 4 ppm for 75 minutes caused a
duction of mucoid or frothy sputum, and small but signicant decrease in systolic blood
increasing dyspnea.1,2 Within 12 hours, the pressure; there were no signicant effects on
person may develop pulmonary edema with airway resistance symptoms, heart rate, skin
tachypnea, cyanosis, ne crackles and wheezes conductance, or self-reported emotional state.4
through the lungs, and tachycardia. Alterna- However, in an earlier study, human volunteers
tively, there may be only increasing dyspnea exposed to 5 ppm for 15 minutes and 2.5 ppm
and cough over several hours, with symptoms for 2 hours showed increased airway
then gradually subsiding over a 2- to 3-week resistance.5
period. The condition may then enter a second Most reported cases of severe illness from
stage of abruptly increasing severity; fever nitrogen dioxide have been accidental expo-
and chills precede a relapse, with increasing sures to explosion or combustion of nitroex-
dyspnea, cyanosis, and recurring pulmonary plosives, or from the intermittent process of arc
edema. Death may occur in either the initial or gas welding (especially in a conned space),
524 NITROGEN DIOXIDE
or the entry into an agricultural silo that was time-weighted average (TLV-TWA) for nitro-
not vented.1,6 gen dioxide is 3 ppm (5.6 mg/m3) with a
Less severe respiratory complaints have short-term exposure limit (STEL) of 5 ppm
been reported in 116 individuals exposed to (9.4 mg/m3).
nitrogen dioxide during two hockey games
in an indoor ice arena.7 The gas was emitted
from the malfunctioning engine of an ice resur- REFERENCES
facer. Air concentrations were not recorded,
although air sampling under simulated condi- 1. National Institute for Occupational Safety
tions detected 4 ppm nitrogen dioxide; levels and Health: Criteria for a Recommended
Standard . . . Occupational Exposure to Oxides of
were probably higher during the games. Of
Nitrogen (Nitrogen Dioxide and Nitric Oxide).
interest was the occurrence of cough, dyspnea,
DHEW (NIOSH) Pub No 76149, pp
chest pain, and mild hemoptysis, principally 7685. Washington, DC, US Government
among the hockey players and cheerleaders, Printing Ofce, 1976
who were actively exercising and therefore had 2. Morgan WKC, Seaton A: Occupational Lung
a higher minute ventilation and greater lung Diseases, pp 330335, 344345. Philadelphia,
tissue exposure than spectators. PA, W. B. Saunders, 1975
In experimental animals, nitrogen dioxide 3. Anon: Emergency exposure limits: Nitrogen
induces several types of pulmonary toxicity.8 dioxide. Am Ind Hyg Assoc J 25: 580582,
Decreased pulmonary function occurs in mice 1964
after chronic exposure to 0.2 ppm with daily 4. Linn WS, Solomon JC, Trim SC, et al:
Effects of exposure to 4 ppm nitrogen dioxide
excursions to 0.8 ppm. Effects on lung
in healthy and asthmatic volunteers. Arch
morphology were seen in rats exposed to 10
Environ Health 40:234239, 1985
ppm for 36 hours and included cilia loss and 5. Kerr HD et al: Effects of nitrogen dioxide
hypertrophy of the bronchiolar epithelium. In on pulmonary function in human subjects: An
guinea pigs acute exposure to 4 ppm caused environmental chamber study. Environ Res
increased airway hyperresponsiveness toward 19:392404, 1979
histamine. 6. Scott EG, Hunt WB Jr: Silo llers disease.
Animal experimentation has also indicated Chest 63:701706, 1973
that in, addition to irritation and patholo- 7. Hedberg K et al: An outbreak of nitrogen
gic changes, nitrogen dioxide exposure may dioxide-induced respiratory illness among
decrease host resistance to infection.8,9 An ice hockey players. JAMA 262:30143017,
1989
increased mortality in mice infected with pneu-
8. Moldeus P: Toxicity induced by nitrogen
monia-causing organisms was found subse-
dioxide in experimental animals and isolated
quent to exposure at 0.5 ppm for 7 days and cell systems. Scand J Work Environ Health 19
longer.10 Nitrogen dioxide can adversely effect (S2):2834, 1993
lung defense mechanisms by reducing the ef- 9. State of California Air Resources Board:
cacy of mucociliary clearance, the alveolar Short-Term Ambient Air Quality Standard for
macrophage, and the immune system.11 Nitrogen Dioxide. Sacramento, CA, 1985
Individuals with a history of asthma or 10. Gardner DE et al: Inuence of exposure of
chronic obstructive airway disease are more node on the toxicity of NO2. Environ Health
susceptible to symptoms arising out of expo- Perspect 30:2329, 1979
sure to low levels of nitrogen dioxide.12,13 11. Samet JM, Utell MJ: The risk of nitrogen
dioxide: What have we learned from epi-
Nitrogen dioxide does not appear to be
demiological and clinical studies? Toxicol Ind
directly carcinogenic, and evidence regarding
Health 6:247262, 1990
its tumor-promoting or -enhancing capabilities 12. Bauer MA, Utell MJ, Morrow PE, et al:
is limited and conicting.13 Inhalation of 0.30 ppm nitrogen dioxide
The odor threshold is of the order of potentiates exercise-induced bronchospasm
0.12 ppm. in asthmatics. Am Rev Respir Dis 134:1203
The 2003 ACGIH threshold limit value- 1208, 1986
NITROGEN MUSTARDS (Blister Agents) 525
13. World Health Organization: Environmental Toxicology. Nitrogen mustards are vesicants
Health Criteria 188 Nitrogen Oxides (2nd ed), and alkylating agents that damage the respira-
pp 1434. Geneva, International Programme tory airways and cause skin and eye burns.
on Chemical Safety, 1997 Because nitrogen mustard agents are alky-
lating compounds, they destroy individual cells
by reaction with cellular proteins, enzymes,
RNA, and DNA.1 Once begun, tissue reaction
is irreversible. When nitrogen mustards are
absorbed by the body, they cause damage to
NITROGEN MUSTARDS (Blister Agents) bone marrow and the immune system. Expo-
CAS: HN-1: 538-07-8 sure to high levels causes death. Vesicant
HN-2: 51-75-2 agents are also capable of generating delayed
HN-3: 555-77-1 effects such as chronic bronchitis, carcinogen-
esis, or keratitis/keratopathy of the eye under
appropriate conditions of exposure and dose.
These effects may not become manifest until
years after exposure. It is unlikely that the
Synonyms: HN-1: C6H13Cl2; N-ethylbis(2- general public or workers will be exposed to
chloroethyl)amine; 2,2-dichlorotriethylamine; nitrogen mustard agents HN-1, HN-2, and
2-chloro-N-(2-chloroethyl)-N-ethyleth- HN-3, except in a terrorist attack or during
anamine; bis(2-chloroethyl)ethylamine; ethyl- war.
bis(2-chloroethyl)amine Inhalation will cause nasal and sinus pain
HN-2: C5H11Cl2N; Mechlorethana- or discomfort, pharyngitis, laryngitis, cough,
mine; chlormethine; N,N-bis(2-chloroethyl) and shortness of breath. Damage to cells lining
methylamine; 2-chloro-N-(2-chloroethyl)- airways will begin within hours and progress
N-methylethanamine; bis(2-chloroethyl) over the next several days. Skin contact with
methylamine; bis(b-chloroethyl) methyla- nitrogen mustard vapors or liquid will cause
mine; Caryolysine; 2,2-dichloro-N- initial swelling and rash followed by blistering.
methyldiethylamine; Dichloren; MBA Contact with high levels of nitrogen mustards
HN-3; C6H12Cl3N; tris(2-chloroethyl) can result in second- and third-degree burns. If
amine; 2,2,2-trichlorotriethylamine; tris(2- nitrogen mustards contact the eyes there
chloroethyl)amine; HN-3; 2-chloro-N, will be inammation, pain, swelling, corneal
N-bis(2-chloroethyl)ethanamine; N-methyl damage, burns, and even blindness. In the
lost unlikely event of ingestion, there will be
burning of the mouth, esophagus, and stomach.
Physical Form. Colorless to yellow oily The IARC has classied nitrogen mustard
liquids that evaporate very slowly. HN-1 has a HN-2 as probably carcinogenic to humans
faint shy or musty odor. HN-2 has a soapy based on evidence that it causes leukemia in
odor at low concentrations and a fruity odor at humans and cancers of the lung, liver, uterus,
higher concentrations. HN-3 may smell like and large intestine in animals.2
bitter almond. HN-2 nitrogen mustard, administered
mainly as the hydrochloride, has been tested
Uses. Although nitrogen mustards could be for carcinogenicity in mice and rats by sub-
used in chemical warfare, there are presently no cutaneous, intravenous, and intraperitoneal
records of such use. HN-1 has been used to administration and by skin painting. It pro-
remove warts in the past, and HN-2 has been duced mainly lung tumors and lymphomas
used sparingly in chemotherapy. in mice after subcutaneous, intravenous, and
intraperitoneal administration. Intravenous
Exposure. Skin contact and absorption; injection of nitrogen mustard to rats induced
inhalation tumors in different organs3. Application by skin
526 NITROGEN TRIFLUORIDE
painting produced local tumors in mice in a intoxication from nitrogen triuoride, the
dose-dependent manner.4,5 initial effects of methemoglobinemia include
cyanosis (especially in the lips, nose, and
earlobes), weakness, dizziness and severe
REFERENCES headache.1 At higher methemoglobin concen-
trations up to 70% there may be ataxia,
1. Greeneld RA et al: Microbiological, biologi- dyspnea on mild exertion, and tachycardia.
cal, and chemical weapons of warfare and ter- Coma may ensue with methemoglobin levels of
rorism. Am J Med Sci 323:326, 2002 about 70%, and the lethal level in humans is
2. IARC Monographs on the Evaluation of the Car-
estimated to be 8590%.
cinogenic Risk of Chemicals to Humans. Suppl. 7,
Rats died from exposure to 10,000 ppm for
Overall evaluations of carcinogenicity. An
updating of IARC Monographs Volumes 142. 6070 minutes; the methemoglobin concentra-
p 269. Lyon, International Agency for Cancer, tions at the time of death were equivalent to
1987 6070% of available hemoglobin.2 Animals
3. IARC Monographs on the Evaluation of the exposed to nearly lethal concentrations suf-
carcinogenic risk of Chemicals to humans, Vol 9, fered severe respiratory distress and cyanosis
Some aziridines, N-, S- and O-mustards and due to methemoglobinemia; severely affected
selenium, p 193. Lyon, International Agency animals showed incoordination, collapse, and
for Research on Cancer, 1975 convulsions. Rats repeatedly exposed to 100
4. Zackheim HS, Smuckler EA: Tumorigenic ppm for 4.5 months appeared normal, but
effect of topical mechlorethamine, BCNU and
autopsy ndings indicated injury to the liver
CCNU in mice. Experientia 36:12111212,
and kidneys.3 Dogs surviving exposure to 9600
1980
5. Epstein JH: Nitrogen mustard (mech- ppm for 60 minutes exhibited Heinz body
lorethamine) and UVB photocarcinogenesis: a anemia, decreased hematocrit levels, decreased
dose response effect. J Invest Dermatol hemoglobin levels, reduced red blood cell
83:320322, 1984 count, and clinical signs consistent with anoxia
from methemoglobin formation; some eye
irritation was observed during exposure.4
Nitrogen triuoride provides no odor-
warning properties at potentially dangerous
NITROGEN TRIFLUORIDE levels.
CAS: 7783-54-2 The 2003 ACGIH threshold limit value-
time-weighted average (TLV-TWA) is 10 ppm
NF3 (29 mg/m3).
Physical Form. Colorless gas 1. Hamblin DO: Aromatic nitro and amino com-
pounds. In Patty FA (ed): Industrial Hygiene and
Uses. Oxidizing agent in fuel combustion; as Toxicology, 2nd ed, Vol 2, Toxicology, pp
a uorine source in the electronics industry; in 21052119. New York, Interscience, 1963
high-power chemical lasers 2. Dost FN, Reed DJ, Wang CH: Toxicology of
nitrogen triuoride. Toxicol Appl Pharmacol
17:585595, 1970
Exposure. Inhalation
3. Torkelson TR, Oyen F, Sadek SE, Rowe VK:
Preliminary toxicologic studies on nitrogen
Toxicology. Nitrogen triuoride causes triuoride. Toxicol Appl Pharmacol 4:770781,
anoxia in animals due to the formation of 1962
methemoglobin. 4. Vernot EH, Haun CC, MacEwen JD, Egan
Although there are no reports of human GF: Acute inhalation toxicology and pro-
NITROGLYCERIN 527
posed emergency exposure limits of nitrogen symptoms, including headache, are indicative
triuoride. Toxicol Appl Pharmacol 26:113, of a shift in blood volume from the central to
1973 the peripheral circulatory system, initiated by
dilation of the blood vessels.
After 24 days of repeated NG exposure,
tolerance to the vasodilatory activity occurs,
probably as a result of compensatory vasocon-
NITROGLYCERIN striction. Tolerance may be lost during periods
CAS: 55-63-0 without NG exposure, such as weekends
and holidays.3 Recent studies have suggested
CH2NO3CHNO3CH2NO3 that tolerance may be mediated by a mito-
chondrial aldehyde dehydrogenase that cat-
alyzes the formation of 1,2-glyceryl dinitrate
Synonyms: 1,2,3-Propanetriol trinitrate; glyc- and nitrite from NG, leading to production of
erol trinitrate; nitroglycerol; NG; trinitroglyc- cGMP and relaxation of vascular smooth
erol; NTG; trinitrin muscle.4
Chronic, repeated exposures to NG and
Physical Form. Oily liquid at room temper- NG mixtures have also been associated with
ature; colorless in pure form and pale yellow or more serious cardiovascular effects, including
brown in commercial form angina pectoris and sudden death.
Signs and symptoms of ischemic heart
Uses. Manufacture of dynamite, gun powder disease were observed in nine munitions
and rocket propellants, and as a therapeutic workers involved in handling a nitroglycerin-
agent primarily to alleviate angina pectoris. cellulose mixture.5 Within 14 years of initial
Note: Workers engaged in the production or exposure, these workers developed nonexer-
use of dynamite are potentially exposed to tional chest pain that was relieved either by
mixed vapors of nitroglycerin (NG) and ethyl- therapeutic nitroglycerin or by returning to
ene glycol dinitrate (EGDN). work after the weekend. Coronary angiography
performed in ve of the patients showed no
Exposure. Inhalation; skin absorption obstructive lesions. In one patient, observed
while in the withdrawal state, coronary artery
Toxicology. NG is a vasodilator and has spasm was demonstrated and readily reversed
been associated with acute episodes of angina by sublingual nitroglycerin.
pectoris, myocardial infarction, and sudden Like the attacks of angina pectoris, sudden
death. deaths occurred most frequently during brief
Initial exposure to NG (or NG:EGDN periods away from work and in particular on
mixtures where exposures are considered Sunday nights or Monday mornings.6 In most
additive) characteristically results in an cases, there were no premonitory signs or
intense, throbbing headache that begins in the symptoms, although some subjects had anginal
forehead and moves to the occipital region.1 episodes during brief periods away from
Volunteers developed mild headaches when work. Atherosclerotic plaques, with or without
exposed to NG:EGDN vapor at concen- thrombosis, have been found in the coronary
trations of 0.5 mg/m3 for 25 minutes.2 It has arteries of workers at autopsy, but their coro-
been suggested that at least some workers may nary arteries were generally not occluded to the
develop headaches at concentrations as low as same extent as those of unexposed workers who
0.1 mg/m3.1 had died suddenly.1
Other signs and symptoms associated with The pathogenesis of the sudden death
initial exposure include dizziness, nausea, pal- syndrome has been postulated to be due to
pitations, and decreases in systolic, diastolic, withdrawal of coronary vasodilators (e.g., NG),
and pulse pressures.1 These initial signs and resulting in vasoconstriction with acute hyper-
528 NITROGLYCERIN
tension, or with myocardial ischemia in was found in explosives workers with over 20
workers adapted to and dependent on NG to years experience; most of the deaths occurred
maintain a minimum level of coronary ow.3 A months or years after exposure had ceased.12
second contributing mechanism for coronary It is generally recognized that workers
artery toxicity due to NG may relate to the so- exposed to either NG or EGDN have reduced
called aging of the vessels due to repeated tolerance for alcohol.1 Animal studies suggest
dilation.7 Other theories suggest that sudden that NG may decrease the activity of alcohol
deaths may be related to peripheral vasodila- dehydrogenase, thereby decreasing the rate of
tion consequent to reexposure to NG.6 alcohol metabolism.1
Estimates of exposure levels associated NIOSH-recommended exposure limits for
with sudden death have not been made because NG, EGDN, or a mixture of the two were set
workers typically absorb considerable amounts at a level to prevent signicant changes in the
of NG through the skin in addition to inhala- diameter of cerebral blood vessels during initial
tion.1 Skin contact may also cause an irritant exposure, as indicated by the occurrence of
dermatitis resembling poison ivy, and, occa- headache or by decrease in blood pressure,
sionally, allergic contact dermatitis has been thereby preventing the development of com-
reported.8 pensatory vasoconstrictive mechanisms that
Epidemiological studies have suggested may eventually result in more serious effects.1
that the effects of long-term workplace expo- Individuals with preexisting ischemic heart
sure to NG may not be completely reversed disease should not be assigned to work where
after exposure is terminated. Former workers signicant exposure to NG may occur.13
may be at increased risk for cardiovascular The 2003 ACGIH threshold limit value-
mortality for months to years after exposure time-weighted average (TLV-TWA) is 0.05
has ceased. ppm (0.46 mg/m3) with a notation for skin
A cohort study of 5668 NG-exposed absorption.
workers found an increased standardized mor-
tality ratio for deaths from ischemic heart
disease.9 The increase was more pronounced REFERENCES
for those with 10 or more years of exposure and
was statistically signicant for the 40- to 49- 1. National Institute for Occupational Safety
year age group, whereas a decit of cardiovas- and Health, US Department of Health,
cular mortality had been anticipated because of Education and Welfare: Criteria for a Recom-
mended Standard . . . Occupational Exposure to
preplacement and annual medical examinations
Nitroglycerin and Ethylene Glycol Dinitrate.
designed to exclude persons with cardiovas-
DHEW (NIOSH) Pub No 78167, 215pp.
cular abnormalities. These results were con- Washington DC, US Government Printing
rmed in a retrospective cohort mortality Ofce, 1978
study that found a signicant excess of ischemic 2. Trainor DC, Jones RC: Headaches in explo-
heart disease mortality among workers actively sive magazine workers. Arch Environ Health
exposed to NG and under the age of 45.10 12:231234, 1966
(Note: this study failed to detect a chronic 3. Sivertsen E: Glyceryltrinitrate as a problem
cardiovascular effect as excess risk was only in industry. J Clin Lab Invest 44(Suppl 173):
associated with workers actively exposed to 8184, 1984
NG.) 4. Chen Z, Zhang J, Stamler JS: Identication
of the enzymatic mechanism of nitroglycerin
An excess of deaths from acute myocardial
bioactivation. Proc Natl Acad Sci USA 99:
infarction was also conrmed in a younger
830611, 2002
group of workers exposed to NG and EGDN 5. Lange RL et al: Nonatheromatous ischemic
in a Scottish explosives factory and followed for heart disease following withdrawal from
16 years.11 chronic industrial nitroglycerin exposure.
In a case-control study in Sweden, a 2.5 Circulation 46:66678, 1972
relative risk of cardiocerebrovascular disease 6. Carmichael P, Lieben J: Sudden death in
NITROMETHANE 529
explosives workers. Arch Environ Health 7: The human oral lethal dose is estimated
424439, 1963 between 0.5 and 5.0 g/kg.1 Occupational expo-
7. Klaassen CD et al (eds): Casarett and Doulls sure to nitromethane was suspected as the
Toxicology. The Basic Science of Poisons, 3rd ed, cause of severe peripheral neuropathy in two
p 399. New York, Macmillan Publishing, workers exposed for 12 months.2
1986
Rabbits died from exposure to 10,000 ppm
8. Kanerva L, Laine R, Jolanki R, et al: Occu-
pational allergic contact dermatitis caused for 6 hours; initial effects were weakness, ataxia,
by nitroglycerin. Contact Derm 24:356362, and muscular incoordination followed by con-
1991 vulsions.3,4 The same concentration for 3 hours
9. Reeve G et al: Cardiovascular disease among was not fatal. Autopsy of animals exposed to
nitroglycerin-exposed workers. Am J Epi- lethal concentrations showed focal necrosis in
demiol 118:418, 1983 the liver and moderate kidney damage. Lower
10. Stayner LT, Dannenberg AL, Thun M, et al: concentrations produced slight irritation of the
Cardiovascular mortality among munitions respiratory tract, followed by mild narcosis,
workers exposed to nitroglycerin and dini- weakness, and salivation, but no evidence of eye
trotoluene. Scand J Work Environ Health 18: irritation.
3443, 1992
In a subchronic inhalation study, rabbits
11. Craig R et al: Sixteen year follow-up of
workers in an explosives factory. J Soc Occup exposed to 98 ppm 7 hours/day, 5 days/week for
Med 35:107110, 1985 6 months showed hemoglobin depression with
12. Hogstedt C, Axelson O: Nitroglycerin- some methemoglobin, elevated serum car-
nitroglycol exposure and mortality in cardio- bamyl transferase, and thyroxin depression.5
cerebrovascular diseases among dynamite For rats similarly exposed at 745 ppm, there
workers. J Occup Med 19:675678, 1977 was altered hematocrit, hemoglobin, and ery-
13. Rosenman KD: Cardiovascular disease and throcyte counts, altered prothrombin time, and
environmental exposure. Br J Ind Med 36: increased thyroid weight.
8597, 1979 Findings in rats exposed at 750 or 1500
ppm for 13 weeks included hind limb paralysis,
anemia, olfactory epithelial degeneration, and
minimal to mild degeneration of the sciatic
NITROMETHANE nerve and the lumbar spinal cord.6
CAS: 75-52-5 Two-year inhalation studies (6 hours/day,
5 days/week for 103 weeks) in rodents
CH3NO2 showed clear evidence of carcinogenicity. Mice
exposed at 375 and 750 ppm had increased
incidences of harderian gland adenomas and
Synonyms: Nitrocarbol carcinomas; female mice exposed at 188 and
750 ppm had increased liver neoplasms; female
Physical Form. Colorless oily liquid rats in the 188 and 375 ppm-exposed groups
had increased incidences of mammary gland
Uses. Solvent; chemical synthesis; fuel for broadenomas and carcinomas.6 Other treat-
professional and model racing cars; in explosive ment-related effects were an increase in nasal
mixtures lesions and degeneration of the respiratory
epithelium in mice.
Exposure. Inhalation Nitromethane was not mutagenic in a
variety of in vitro and in vivo assays.6
Toxicology. Nitromethane, in animals, The IARC has determined that there is
affects the central nervous system, causing con- sufcient evidence for the carcinogenicity of
vulsions and narcosis at high doses; it is also a nitromethane in experimental animals and that
mild pulmonary irritant and may cause liver it is possibly carcinogenic to humans.7
damage. The 2003 ACGIH threshold limit value-
530 1-NITROPROPANE
time-weighted average (TLV-TWA) is 20 ppm Uses. Solvent for organic materials; propel-
(50 mg/m3). lant fuel; gasoline additive
Exposure. Inhalation
REFERENCES
Toxicology. 1-Nitropropane vapor is an irri-
1. National Toxicology Program: Nitromethane. tant of the eyes; in animals it also causes liver
National Toxicology Program executive sum- damage and mild respiratory tract irritation.1
maries, pp 112, 1983 There are no reports of systemic effects from
2. Page EH, Pajeau AK, Arnold TC, et al:
industrial exposures.
Peripheral neuropathy in workers exposed to
Rabbits died from exposure to 5000 ppm
nitromethane. Am J Ind Med 40(1):10713,
2001 for 3 hours, but 10,000 ppm for 1 hour was not
3. Stokinger HE: Aliphatic nitro compounds, lethal.2 Effects were conjunctival irritation,
nitrates, nitrites. In Clayton DG, Clayton FE lacrimation, slow respiration with some rales,
(eds): Pattys Industrial Hygiene and Toxicology, incoordination, ataxia, and weakness.2 Autopsy
3rd ed, rev, Vol 2C, Toxicology, pp 41534155. of animals exposed to lethal concentrations
New York, Wiley-Interscience, 1982 revealed severe fatty inltration of the liver and
4. Machle W, Scott EW, Treon J: Physiological moderate kidney damage.2
response of animals to some simple mononi- Rats exposed 7 hours/day, 5 days/week at
troparafns and to certain derivatives of these 100 ppm for up to 21 months showed no effects
compounds. J Ind Hyg Toxicol 22:315332,
on appearance and behavior, serum chemistry,
1940
or hematology, and body and organ weights
5. Lewis TR, Ulrich CE, Busey WM: Sub-
chronic inhalation toxicity of nitromethane were unchanged.3 There were no histopatho-
and 2-nitropropane. J Environ Pathol Toxicol logic effects on the liver and, in particular, no
2:233249, 1979 induction of hepatocarcinomas. This contrasts
6. National Toxicology Program: Toxicology and with similar exposures to 2-nitropropane,
Carcinogenesis Studies of Nitromethane (CAS which produce severe hepatotoxicity and hepa-
No. 75 52 5) in F344/N Rats and B6C3F1 Mice tocellular carcinomas at this level. Further
(Inhalation Studies). NTP TR 461, NIH Pub studies have suggested that the lack of a car-
No 973377, US Department of Health and cinogenic effect of 1-nitropropane may be
Human Services, 1997 associated with the fact that it does not induce
7. IARC Monographs on the Evaluation of the
cell proliferation in the liver, whereas the
Carcinogenic Risk of Chemicals to Humans, Vol
carcinogenic isomer 2-nitropropane induces
77, Some industrial chemicals, pp 487501.
Lyon, International Agency for Research on marked and rapid induction of cell prolifera-
Cancer, 2000 tion in this organ.4
1-Nitropropane is mutagenic in V79 cells
and can induce unscheduled DNA synthesis
in rat hepatocytes, but it was not mutagenic
in Salmonella assays, nor did it produce sister
chromatid exchanges or chromosomal aberra-
tions in vitro.
1-NITROPROPANE The 2003 ACGIH threshold limit value-
CAS: 108-03-2 time-weighted average (TLV-TWA) for 1-
nitropropane is 25 ppm (91 mg/m3).
CH3CH2CH2NO2
REFERENCES
Synonym: 1-NP
1. Silverman L, Schulte HF, First MW: Further
Physical Form. Liquid studies on sensory response to certain indus-
2-NITROPROPANE 531
trial solvent vapors. J Ind Hyg Toxicol 28:262, propane.3,4 The deaths all involved application
1946 of paint coatings in poorly ventilated areas. In
2. Machle W, Scott EW, Treon JF: The physio- all cases, liver failure was the primary cause
logical response of animals to some simple of death, and postmortem ndings showed
mononitroparafns and to certain derivatives massive hepatocellular destruction. Descrip-
of these compounds. J Ind Hyg Toxicol 22:315,
tions of prodromal symptoms have included
1940
3. Grifn TB, Stein AA, Coulston F: Inhalation typical central nervous system effects of solvent
exposure of rats to vapors of 1-nitropropane exposure, including headache, nausea, and
at 100 ppm. Ecotox Environ Saf 6:268282, vomiting. In the most recently reported cases,
1982 two construction workers became ill after
4. Cunningham ML, Matthews HB: Relation- applying an epoxy resin coating containing 2-
ship of hepatocarcinogenicity and hepato- nitropropane in an enclosed area.4 One man
cellular proliferation induced by mutagenic died 10 days later from fulminant hepatic
noncarcinogens vs carcinogens. Toxicol Appl failure; the second man survived but has had
Pharmacol 110:505513, 1991 persistently elevated serum aminotransferase
activity. The serum concentration of 2-nitro-
propane on admission of the man who died was
13 mg/l vs. 8.5 mg/l for his coworker. Extrapo-
lating from animal pharmacokinetic studies,
2-NITROPROPANE the serum concentrations would be consistent
CAS: 79-46-9 with 6 hours of inhalation in the 600 ppm
range.
CH3CHNO2CH3 Chronic health effects in humans from
exposure to 2-nitropropane have not been ade-
quately determined, although a retrospective
Synonyms: Isonitropropane; nitroisopropane; mortality study of 1481 employees and former
dimethylnitromethane; 2-NP; NiPar S-20; employees of a 2-nitropropane production
NiPar S-30 facility with up to 27 years of exposure found
no increase in cancer of the liver or other
Physical Form. Liquid organs and no unusual disease mortality
pattern.5
Uses. Industrial solvent; chemical intermedi- Rabbits died from exposure to a concen-
ate; component in inks and paints tration near 2400 ppm for 4.5 hours, but
1400 ppm was not lethal.6 High concentrations
Exposure. Inhalation caused lethargy, weakness, difcult breathing,
cyanosis, prostration, and occasional convul-
Toxicology. 2-Nitropropane is a pulmonary sions; low levels of methemoglobin and the
irritant and hepatotoxin. Inhalation of vapor formation of Heinz bodies in erythrocytes were
produces hepatocellular carcinomas in rats, and observed. Autopsy of animals exposed to lethal
it is a suspected human carcinogen. concentrations revealed pulmonary edema and
Workers exposed to hot vapor containing hemorrhage and liver damage.6 The 6-hour
an unspecied concentration of xylene and 20 LC50 in the male rat is 400 ppm.7
45 ppm of 2-nitropropane developed occipital Rats exposed to 207 ppm daily for 6
headache, anorexia, nausea, vomiting, and, in months developed hepatic neoplasms; hepato-
some cases, diarrhea.1 Substitution of methyl cellular hyperplasia and necrosis occurred after
ethyl ketone for 2-nitropropane eliminated the 3 months of exposure at this concentration.7 In
problem. Workers exposed to 30300 ppm of another series of inhalation experiments on
2-nitropropane complained of irritation of the rats, 200 ppm produced hepatocellular carcino-
respiratory tract.2 A number of fatalities have mas in both sexes; 100 ppm resulted in liver
been reported in association with 2-nitro- tumors in males after 12 months of exposure
532 N-NITROSODIMETHYLAMINE
and in females after 18 months. At 25 ppm for 4. Harrison R, Letz G, Pasternak G, et al:
up to 22 months of exposure, no tumors or Fulminant hepatic failure after occupational
other hepatic lesions were produced.8 The exposure to 2-nitropropane. Ann Int Med
authors further suggested that damage to the 107:466468
liver parenchymal cells is an essential precursor 5. Bolender FL: 2-NP Mortality Epidemiology
Study of the Sterlington, LA Employees: An
to the induction of hepatocarcinoma in the rat.
Update Report to the International Minerals &
Hepatocellular carcinomas occur only when Chemical Corp, Northbrook, IL, 1983
the degree of exposure is sufcient to cause 6. Treon JF, Dutra FR: Physiological response
severe hepatotoxicity followed by hyperregen- of experimental animals to the vapor of 2-
eration, with some of the newly regenerated nitropropane. AMA Arch Ind Hyg Occup Med
cells becoming autonomous, leading to 5:5261, 1952
neoplasia. 7. Lewis TR, Ulrich CE, Busey WM: Sub-
More recent studies have shown that chronic inhalation toxicity of nitromethane
10-day gavage treatment of rats with up to and 2-nitropropane. J Environ Pathol Toxicol
2 mmol/kg 2-nitropropane caused an increased 2:233249, 1979
incidence of cell proliferation; similar treat- 8. US Environmental Protection Agency:
Integrated Risk Information System (IRIS)
ment with the noncarcinogenic isomer 1-
2-Nitropropane. 03/01/1991, URL.
nitropropane did not cause an increase in cell http://www.epa.gov/iris/subst/0519.htm
proliferation.9 9. Cunningham ML, Matthews HB: Relation-
The IARC has determined that there is ship of hepatocarcinogenicity and hepatocel-
sufcient evidence for carcinogenicity of 2- lular proliferation induced by mutagenic
nitropropane in experimental animals and that noncarcinogens vs carcinogens. Toxicol Appl
it is possibly carcinogenic to humans.10 Pharmacol 110:505513, 1991
2-Nitropropane is genotoxic in a variety of 10. IARC Monograph on the Evaluation of the
assays including the Ames/Salmonella assay, in Carcinogenic Risk of Chemicals to Humans, Vol
vitro sister chromatid exchange, and chromo- 71, Re-evaluation of some organic chemicals,
some aberrations and unscheduled DNA syn- hydrazine and hydrogen peroxide, pp 1079
94. Lyon, International Agency for Research
thesis assay.9
on Cancer, 1999
Although the early literature stated that 11. Crawford GN, Garrison RP, McFee DR:
the odor threshold was above 80 ppm and Odor threshold determination for 2-n
therefore not capable of providing adequate itropropane. Am Ind Hyg Assoc J 45:B-B7-8,
warning of exposure, a more recent study has 1984
determined that a lower threshold of approxi-
mately 5 ppm exists that should provide some
warning of exposure, especially if workers are
familiarized with the odor.11
The 2003 ACGIH threshold limit value-
time-weighted average (TLV-TWA) for 2- N-NITROSODIMETHYLAMINE
nitropropane is 10 ppm (36 mg/m3) with an CAS: 62-75-9
A2-suspected human carcinogen designation.
(CH3)N2O
REFERENCES
Synonyms: Dimethylnitrosamine; DMNA;
1. Skinner JB: The toxicity of 2-nitropropane.
DMN; NDMA
Ind Med 16:441443, 1947
2. Hygienic Guide Series: Nitropropane. Am
Ind Hyg Assoc 1978 Physical Form. Yellow liquid
3. Hine CH, Pasi A, Stephens BG: Fatalities
following exposure to 2-nitropropane. J Uses/Sources. No longer used industrially
Occup Med 20:333337, 1978 or commercially in the US; may occur as a by-
N-NITROSODIMETHYLAMINE 533
product from the manufacture of pesticides, attributed to DMN because such tumors are
rubber tires, alkylamines, and dyes extremely rare in mice.8
Chronic exposure to hepatotoxic doses of
Exposure. Inhalation; skin absorption DMN has also been found to suppress humoral
and cellular immunity in mice.9 DMN is geno-
Toxicology. N-nitrosodimethylamine toxic in a wide variety of assays inducing DNA
(DMN) is a liver toxin and is carcinogenic in synthesis, chromosomal aberrations, sister
many species of test animals. chromatid exchange, and bacterial mutations.10
Two men accidentally exposed to DMN The formation of DNA adducts by metabolites
developed toxic hepatitis.1 There are no reports of DMN may play a critical role in the car-
of chronic effects from human exposure.2 cinogenic process.11
The LC50 for rats exposed to DMN vapor The IARC has determined that there is
for 4 hours (and observed for 14 days) was 78 sufcient evidence of carcinogencity to animals
ppm; for similarly exposed mice the LC50 was and that, although no data are available for
57 ppm.3 Dogs exposed for 4 hours to 16 humans, the agent is probably carcinogenic to
144 ppm developed vomiting, polydipsia, and humans.
anorexia; most exposed dogs died, but one The ACGIH has classied N-nitrosodi-
survivor showed residual liver damage 7 methylamine as an A3-conrmed animal car-
months after exposure.3 cinogen with unknown relevance to humans;
DMN is clearly carcinogenic, producing there is a notation for skin absorption and no
tumors in a number of animal species at assigned threshold limit value (TLV).
relatively low doses. Swiss mice fed a diet con-
taining 0.005% DMN for 1 week developed
tumors of the kidney and lung.4 Hamsters fed
a diet containing 0.0025% for 11 weeks devel- REFERENCES
oped liver tumors.5 A consistent observation
after oral administration of DMN in rats has 1. Freund HA: Clinical manifestation and
been that long-term treatment with doses com- studies in parenchymatous hepatitis. Ann Int
patible with a favorable survival rate leads to Med 10:11441155, 1937
liver tumors, whereas short-term treatment 2. IARC Monographs on the Evaluation of the
with high doses produces renal tumors.2 Carcinogenic Risk of Chemicals to Man, Vol 17,
Hamsters receiving weekly subcutaneous Some N-nitroso compounds, pp 125175.
Lyon, International Agency for Research on
injections of DMN for life developed tumors;
Cancer, 1978
3 of 10 females receiving weekly injections
3. Jacobson KH, Wheelwright HJ Jr, Clem JH,
of 4.3 mg/kg developed liver tumors; at Shannon RN: Studies on the toxicology of N-
21.5 mg/kg/week, there were 8 liver tumors nitrosodimethylamine vapor. AMA Arch Ind
and 5 kidney tumors; in 10 male animals receiv- Health 12:617622, 1955
ing 2.8 mg/kg/week, there were 5 liver tumors 4. Terracini B, Palestro G, Gigliardi RM,
and 1 kidney tumor.6 Montesano R: Carcinogenicity of dimethyl-
Intraperitoneal injection of 6 mg/kg once nitrosamine in Swiss mice. Br J Cancer 20:
weekly for 10 weeks in mice resulted in a sta- 871876, 1966
tistically signicant increase of vascular tumors, 5. Tomatis L, Magee PN, Shubik P: Induction
mainly in the retroperitoneum in females. of liver tumors in the Syrian golden hamster
by feeding dimethylnitrosamine. J Natl
There was a low incidence of hepatic vascular
Cancer Inst 33:341345, 1964
tumors in both sexes.7 Pregnant mice treated
6. Mohr U, Haas H, Hilfrich J: The carcino-
with the maximum nonfetotoxic dose of DMN genic effects of dimethylnitrosamine and
on gestation day 16 or 19 had signicant nitrosomethylurea in European hamsters
transplacental carcinogenic effects, causing an (Cricetus cricetus L). Br J Cancer 29:359364,
increase in hepatocellular carcinomas and 1974
sarcomas.8 One intracranial schwannoma was 7. Cardesa A, Pour P, Althoff J, Mohr U:
534 N-NITROSODIPHENYLAMINE
Vascular tumors in female Swiss mice after Early carcinogenic studies in rats and mice
intraperitoneal injection of dimethylni- in which NDPhA was administered orally or by
trosamine. J Natl Cancer Inst 51:201205, intraperitoneal injection showed no evidence
1973 of carcinogenicity.26 However, a more recent
8. Andeson LM, Hagiwara A, Kovatch RM, study demonstrated carcinogenesis in rats.7,8
et al: Transplacental initiation of liver, lung,
NDPhA was administered in the diet to rats
neurogenic and connective tissue tumors by
N-nitroso compounds in mice. Fundam Appl and mice at the maximum tolerated dose for
Toxicol 12:604620, 1989 each species and at one-half that amount. A sig-
9. Desjardins R, Fournier M, Denizeau F, et al: nicant incidence of bladder tumors occurred
Immunosuppression by chronic exposure to in male (40%) and female (90%) rats at 240 and
N-nitrosodimethylamine (NDMA) in mice. 320 mg/kg, respectively. Few bladder tumors
J Toxicol Environ Health 37:351361, 1992 were seen in the mice.
10. Agency for Toxic Substances and Disease Primarily negative results have been found
Registry (ATSDR): Toxicological Prole for in in vitro and in vivo gene mutation and chro-
N-Nitrosodimethylamine, 119pp. US Depart- mosome assays.1
ment of Health and Human Services, Public The IARC has determined that there is
Health Service, 1989
limited evidence for carcinogenicity in experi-
11. World Health Organization: Concise Interna-
tional Chemical Assessment Document (CICAD) mental animals and that no evaluation of the
38. N-Nitrosodimethylamine, 39pp. Geneva, carcinogenicity to humans can be made.9
International Programme on Chemical ACGIH has not established a threshold
Safety (IPCS), 2002 limit value (TLV) for N-nitrosodiphenylamine.
REFERENCES
N-NITROSODIPHENYLAMINE 1. Agency for Toxic Substances and Disease
CAS: 86-30-6 Registry (ATSDR): Toxicological Prole for N-
nitrosodiphenylamine. pp 179. US Department
(C6H5)2N2O of Health and Human Services, Public Health
Service, 1993
2. Argus MF, Hoch-Ligeti C: Comparative study
Synonyms: NDPhA; diphenyl nitrosamine of the carcinogenic activity of nitrosamines.
J Natl Cancer Inst 27:695709, 1961
3. Boyland E, Carter RL, Gorrod JW, Roe FJC:
Physical Form. Yellow to brown or orange
Carcinogenic properties of certain rubber
powder or akes additives. Eur J Cancer 4:233239, 1968
4. National Cancer Institute: Evaluation of Car-
Uses. Formerly used as a vulcanization cinogenic, Teratogenic, and Mutagenic Activities of
retarder in the rubber industry Selected Pesticides and Industrial Chemicals, Vol I.
Carcinogenic Study, 1968
Exposure. Inhalation 5. Innes JRM et al: Bioassay of pesticides and
industrial chemicals for tumorigenicity in
Toxicology. N-nitrosodiphenylamine mice: A preliminary note. J Natl Cancer Inst
(NDPhA) is an animal carcinogen and causes 42(6):11011106, 1969
6. Druckrey H, Preussmann R, Ivankovic S,
bladder tumors in male and female rats.
Schmahl D: Organotrope carcinogene
No acute or chronic effects have been
Wirkungen bei 65 Verschiedenen N-nitroso-
reported from human exposure.1 Limited verbindungen an BD-Ratten. Z Krebsforsch 69:
animal data suggest that the respiratory system 103201, 1967
is the target of inhalation exposure.1 The 7. National Cancer Institute: Bioassay of N-
urinary bladder is considered the target organ Nitrosodiphenylamine for Possible Carcinogenicity.
after oral administration. DHEW (NIH) Pub No 79-1720. Washington,
N-NITROSODI-n-PROPYLAMINE 535
5. Reznik G, Mohr U, Kruger FW: Carcinogenic dependent increase in the total number of pre-
effects of di-n-propylnitrosamine, b-hydrox- neoplastic foci of altered hepatocytes and in the
ypropyl-n-propylnitrosamine and methyl-n- incidence of hepatocellular adenomas and
propylnitrosamine on Sprague-Dawley rats. J carcinomas.2 The induction of liver tumors by
Natl Cancer Inst 54(4):937943, 1975 NMOR has been conrmed in several strains
6. Pour P, Kruger FW, Cardesa A, et al:
of rats.1 Epithelial kidney tumors were
Carcinogenic effect of di-n-propylnitrosamine
in Syrian golden hamsters. J Natl Cancer Inst observed in 47 of 69 rats in which NMOR had
51(3):10191027, 1973 been administered in the drinking water at 120
7. Adamson RH, Sieber SM: Chemical Carcino- or 500 mg/l for 314 weeks. NMOR is also
genesis Studies in Nonhuman Primates. EPA- carcinogenic in hamsters after subcutaneous
600/9-83-008. NTIS PB 83-220137, 1983 injection, producing tumors of the respiratory
8. IARC Monographs on the Evaluation of the Car- system (mainly nasal cavity and trachea). The
cinogenic Risk of Chemicals to Humans, Suppl 7, IARC has determined that there is sufcient
Overall evaluations of carcinogenicity: An evidence for carcinogenicity of NMOR to
updating of IARC Monographs Volumes 142, experimental animals.1
p 68. Lyon, International Agency for Research NMOR is mutagenic in bacterial assays
on Cancer, 1987
in the presence of activated liver microsomal
fractions. However, NMOR did not induce
DNA damage in either human or rat kidney
cells in vitro as determined by DNA strand
breakage.3
N-NITROSOMORPHOLINE The ACGIH has not established a thresh-
CAS: 59-89-2 old limit value (TLV) for N-nitrosomorpho-
line.
C4H8N2O2
REFERENCES
Synonyms: NMOR; NNM; 4-nitrosomor-
pholine 1. IARC Monographs on the Evaluation of the
Carcinogenic Risk of Chemicals to Humans, Vol.
Physical Form. Yellow crystals 17, Some N-nitroso compounds, pp 263275.
Lyon, International Agency for Research on
Cancer, 1978
Uses. Solvent for polyacrylonitrile; present
2. Weber E, Bannasch P: Dose and time depend-
during rubber manufacturing ence of the cellular phenotype in rat hepatic
preneoplasia and neoplasia induced by contin-
Exposure. Inhalation; skin absorption uous oral exposure to N-nitrosomorpholine.
Carcinogenesis 15:123542, 1994
Toxicology. N-nitrosomorpholine (NMOR) 3. Robbiano L, Mereto E, Corbu C, et al: DNA
is carcinogenic in animals. damage induced by seven N-nitroso com-
There is no information available con- pounds in primary cultures of human and rat
cerning toxic effects in humans. kidney cells. Mutat Res 368(1):417, 1996
The LD50 of NMOR in rats by oral and
intraperitoneal routes was 320 mg/kg.
NMOR causes centrilobular hepatic
necrosis in rats.1 Hepatocellular carcinomas
were observed in 14 of 16 rats administered
NMOR in the drinking water at doses of
8 mg/kg body weight/day for life. Continuous
oral exposure of Sprague-Dawley rats to 6, 12,
or 24 mg/kg body weight resulted in a dose-
NITROTOLUENE 537
There was equivocal evidence of carcinogenic 3. Dunnick JK, Elwell MR, Bucher JR: Com-
activity in male and female mice based on parative toxicities of o-, m-, and p-nitrotoluene
increased incidences of hemangiosarcoma, car- in 13-week feed studies in F344 rats and
cinoma of the intestine (cecum), and hepato- B6C3F1 mice. Fundam Appl Toxicol 22:411
cellular neoplasms (females only). There was 421, 1994
4. Ciss M et al: Toxicological study of nitro-
equivocal evidence of carcinogenic activity of
toluenes: Long-term toxicity. Dakar Med 25:
p-nitrotoluene in male rats based on increased 293, 1980
incidences of subcutaneous skin neoplasms, 5. National Toxicology Program: NTP Technical
and there was some evidence of carcinogenic Report on the Toxicology and Carcinogenesis
activity in females based on increased inci- Studies of o-Nitrotoluene (CAS NO. 88-72-2) in
dences of clitoral gland neoplasms. There was F344/N Rats and B6C3F1 Mice (Feed Studies).
equivocal evidence of carcinogenic activity in NTP TR 504, NIH Publication No. 02-4438.
male mice based on increased incidences of US Department of Health and Human
alveolar/bronchiolar neoplasms, and there was Services, Public Health Service, National
no evidence of carcinogenic activity in female Institutes of Health, 2002
mice exposed to 1250, 2500, or 5000 ppm in the 6. National Toxicology Program: NTP Technical
Report on the Toxicology and Carcinogenesis
diet.
Studies of p-Nitrotoluene (CAS No 99-99-0) in
Metabolism and genetic toxicity have been F344/N Rats and B6C3F1 Mice (Feed Studies).
reported to differ with the isomer of nitro- NTP TR 498, NIH Pub No. 02-4432. US
toluene. p-Nitrotoluene was not mutagenic in Department of Health and Human Services,
bacterial assays, but it did increase sister chro- Public Health Service, National Institutes of
matid exchange frequencies and chromosomal Health, 2002
aberrations in vitro; in vivo it did not increase 7. Doolittle DJ et al: The inuence of intestinal
the frequency of micronuclei in bone marrow bacteria, sex of the animal, and position of
of treated rodents.6 Similar ndings were the nitro group on the hepatic genotoxicity of
reported for the ortho isomer, except that it did nitrotoluene isomers in vivo. Cancer Res 43:
not induce chromosomal aberrations in vitro.5 28362842, 1983
8. Rickert DE et al: Hepatic macromolecular
Only the ortho isomer induces DNA excision
covalent binding of mononitrotoluenes in
repair in the in vivo-in vitro hepatocyte Fischer-344 rats. Chem Biol Interact 52:131
unscheduled DNA synthesis assay.7 Further- 139, 1984
more, ortho-nitrotoluene binds to hepatic DNA
to a much greater extent than meta- or para-
nitrotoluene, and investigators suggest that it
may act similarly to the rodent hepatocarcino-
gen 2,6-dinitrotoluene.8
The 2003 ACGIH threshold limit value- NITROUS OXIDE
time-weighted average (TLV-TWA) for nitro- CAS: 10024-97-2
toluene is 2 ppm (11 mg/m3) with a notation for
skin absorption. N2O
laterality), but only after exposure on day 8 of 3. Cook TL, Smith M, Starkweather JA, et al:
gestation. Increases in skeletal malformations Behavioural effects of trace and subanesthetic
and hydrocephalus occurred after exposure on halothane and nitrous oxide in man. Anesthe-
day 9 of gestation. An increase in fetal deaths siology 49:419424, 1978
occurred from exposure on days 8 and 11.9 4. Allinson RH, Shirley AW, Smith G: Thresh-
old concentration of nitrous oxide affecting
There were no signicant changes in
psychomotor performance. Br J Anesth 51:
sperm count or in sperm morphology in a 177180, 1979
group of male anesthesiologists exposed to 5. Bruce DL, Bach MJ: Effects of trace anes-
nitrous oxide compared with a nonexposed thetic gases on behavioural performance of
group.11 Concentrations were estimated to volunteers. Br J Anesth 48:871876, 1976
range from 5 to 300 ppm, which is substantially 6. Venables H, Cherry N, Waldron HA, et al:
lower than the concentrations that have been Effects of trace levels of nitrous oxide on psy-
shown to have a deleterious effect on sperm in chomotor performance. Scand J Work Environ
experimental animals.10 Health 9:391396, 1983
Nitrous oxide exerts a variety of its adverse 7. Cohen EN, Brown BW, Wu ML, et al: Occu-
effects by oxidizing vitamin B12 and rendering pational disease in dentistry and chronic
exposure to trace anesthetic gases. J Am Dent
it inactive as a coenzyme in many essen-
Assoc 101:2131, 1980
tial metabolic processes.12 One vitamin B12- 8. American Society of Anesthesiologists: Occu-
dependent enzyme in particular, methionine pational disease among operating room per-
synthetase, is involved in cell division and is sonnel: A national study. Report of an ad hoc
necessary for DNA production. Adverse repro- committee on the effect of trace anesthetics
ductive and hematologic effects caused by on operating room personnel. Anesthesiology
nitrous oxide are thought to be due to inacti- 41:321340, 1980
vation or dysfunction of methionine synthetase 9. Fujinaga M, Baden JM, Mazze RI: Suscep-
resulting in impairment of cell division. tible periods of nitrous oxide teratogenicity
The possible carcinogenicity of nitrous in Sprague-Dawley rats. Teratology 40:439
oxide has been studied in dentists and chairside 444, 1989
10. Mazze RI, Wilson AI, Rice SA, et al: Repro-
assistants with occupational exposures. No
duction and fetal development in rats exposed
effect was observed in male dentists, but a 2.4- to nitrous oxide. Teratology 30:259265, 1984
fold increase in cancer of the cervix in heavily 11. Wyrobek AJ, Brodsky J, Gordon L, et al:
exposed female assistants was reported.7 Other Sperm studies in anesthesiologists. Anesthesi-
epidemiological reports of workers exposed to ology 55:527532, 1981
waste anesthetic gases have been negative.1 12. Nunn JF, Chanarin I: Nitrous oxide inacti-
Carcinogenic bioassays in animals have yielded vates methionine synthetase. In Eger EI (ed):
negative results. Nitrous oxide was not geno- Nitrous Oxide. pp 211233. New York, Else-
toxic in a variety of assays.1 vier, 1985
The 2003 ACGIH threshold limit value-
time-weighted average (TLV-TWA) for
nitrous oxide is 50 ppm (90 mg/m3).
REFERENCES NONANE
CAS: 111-84-2
1. ACGIH: Nitrous oxide. Documentation of the
Threshold Limit Values and Biological Exposure
Indices, 7th ed, pp 6. Cincinnati, OH, Amer-
CH3(CH2)7CH3
ican Conference of Governmental Industrial
Hygienists, 2001
2. Eger EI, Gaskey NJ: A review of the present Synonyms: n-Nonane
status of nitrous oxide. J Assoc Nurs Anesth
54:936, 1986 Physical Form. Liquid
NONYLPHENOL 541
Uses. Solvent; organic synthesis; distillation Physical Form. Clear, straw-colored liquid;
chaser; major ingredient of such petroleum technical grade is a mixture of isomers, pre-
fractions as VM&P naphtha, 140 ash, Stod- dominantly para-substituted
dard solvent, and gasoline
Uses. Principal use as an intermediate in the
Exposure. Inhalation production of nonionic ethoxylated surfactants;
as an intermediate in the manufacture of phos-
Toxicology. Nonane is an irritant of the eyes phite antioxidants used for the plastics and
and skin; at extremely high concentrations it rubber industries
causes central nervous system depression.
The 4-hour LC50 in rats was 3200 ppm.1
Exposure. Inhalation
Rats exposed for 6 hours/day for 7 days to 1500
ppm had mild tremor, slight incoordination,
and slight irritation of eyes and extremities. Toxicology. Nonylphenol is a severe irritant
A no-adverse-effect level for 65 days, 6 hours/ of the eyes and skin.
day, 5 days/week, was 590 ppm in rats. Reports of the oral LD50 in rats for the
Nonane could be expected to dry and defat mixed isomers have ranged from 580 to
skin, resulting in irritation and dermatitis, by 1537 mg/kg; the dermal LD50 in rabbits was
analogy to other liquid parafn hydrocarbons. between 2000 and 3160 mg/kg.14 Nonylphenol
Aspiration into the lung could be expected to is considered to be a corrosive agent that
cause chemical pneumonitis. may cause burns and blistering of the skin.3
Nonane was not mutagenic in bacterial When the liquid was applied to the shaved
assays with or without metabolic activation.2 skin of a rabbit and left in place for 4 hours,
The 2003 ACGIH threshold limit value- there was skin necrosis 48 hours after the
time-weighted average (TLV-TWA) is 200 application.5 No skin sensitization occurred in
ppm (1050 mg/m3). tests with guinea pigs.6 When tested on black
guinea pigs and black mice, irritation was
observed but nonylphenol did not induce
REFERENCES depigmentation.7
The liquid in the eye of the rabbit as a 1%
1. Carpenter CP et al: Petroleum hydrocarbon solution caused severe corneal damage.1,2
toxicity studies. XVII: animal response to Leukoderma was reported in two women
nonane. Toxicol Appl Pharmacol 44:53, 1978 engaged in degreasing metal parts with syn-
2. Zeiger E, Anderson B, Haworth S, et al:
thetic detergents containing polyoxyethylene
Salmonella mutagenicity tests. V. Results from
(316), nonyl- or octylphenylether. Analysis
the testing of 311 chemicals. Environ Mol
Mutagen 19(suppl 21):2141, 1992 revealed contamination with free alkylphe-
nol, possibly octylphenol, or nonylphenol.
Although a relationship between the cases of
leukoderma and octyl- and nonylphenol expo-
sure was suggested, it could not be conrmed.8
NONYLPHENOL Nonylphenol has recently been shown to
CAS: 25154-52-3 (mixed isomers) have estrogenic properties, triggering mitotic
136-83-4 (2-nonylphenol) activity in rat endometrium and cell prolifera-
104-40-5 (4-nonylphenol) tion in estrogen-sensitive tumor cells.9 Poten-
tial toxicity to humans who may be exposed to
C9H19(C6H4)OH nonylphenol through leaching of plastics has
not been determined.
In a multigenerational study of rats
Synonyms: 2-nonylphenol; o-nonylphenol; 4- treated at 200, 650, and 2000 ppm 4-
nonylphenol; p-nonylphenol nonyklphenol in the diet, there were dose-
542 NUISANCE PARTICULATES
REFERENCES
skin cleansing procedures necessary for their Exposure of workers by inhalation or skin
removal.1 absorption to lower-chlorinated naphthalenes
Animal studies have found that subchronic (penta- and hexachloro) causes a severe acne-
exposure to nuisance dusts at levels equal to the form dermatitis, chloracne.13 Surprisingly, on
threshold limit value have induced mild inam- human volunteers, octachloronaphthalene was
matory response in the lung and sufcient entirely nonacneigenic.2 Octachloronaphtha-
accumulation of particles to slow lung clear- lene (20 mg, 5 times/week for 2 weeks) did not
ance.2 The investigators suggest that exposure induce gross or histologic changes in skin of
to nuisance dust at a level that will impair pul- hairless mice.4
monary clearance should be avoided to prevent There is no information on systemic
excessive accumulation of dust in the lung. effects in humans. In animals, systemic toxicity
The 2003 ACGIH threshold limit from chlorinated naphthalenes appears to be
value-time weighted average (TLV-TWA) is limited to liver injury characterized as acute
10 mg/m3, total dust, containing no asbestos yellow atrophy.13 In general the tri- to hexa-
and <1% crystalline silica. chlorinated range shows the highest toxicity,
with octachlorinated naphthalene signicantly
less toxic than the others, presumably reect-
REFERENCES ing poor uptake of octachloronaphthalene by
organisms.3
1. ACGIH: Particulates not otherwise classied The 2003 ACGIH threshold limit value-
(PNOC). Documentation of TLVs and BEIs, time-weighted average (TLV-TWA) for
6th ed, p 116667. Cincinnati, OH, American octachloronaphthalene is 0.1 mg/m3 with a
Conference of Governmental Industrial
short-term excursion limit (STEL) of
Hygienists (ACGIH), 1991
0.3 mg/m3 and a notation for skin absorption.
2. Henderson RF, Barr EB, Cheng YS, et al: The
effect of exposure pattern on the accumulation
of particles and the response of the lung to
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367374, 1992
1. Deichmann WB: Halogenated cyclic hydro-
carbons. In Clayton GD, Clayton FE (eds):
Pattys Industrial Hygiene and Toxicology, 3rd ed,
Vol 2B, Toxicology, pp 36693675. New York,
OCTACHLORONAPHTHALENE Wiley-Interscience, 1981
CAS: 2234-13-1 2. Shelley WB, Kligman AM: The experimental
production of acne by penta- and hexa-
C10C18 chloronaphthalenes. Arch Dermatol 75:689
695, 1957
3. World Health Organization: Concise Interna-
tional Chemical Assessment Document (CICAD)
Synonym: Halowax 1051 34, Chlorinated Napthalenes. pp 140, Geneva,
2001
Physical Form. Waxy solid 4. Puhvel SM, Sakamoto M, Ertl DC, Reisner
RM: Hairless mice as models for chloracne:
Uses. In electric cable insulation; additive to A study of cutaneous changes induced by
lubricants topical application of established chloracne-
gens. Toxicol Appl Pharmacol 64(3):492503,
Exposure. Inhalation; skin absorption 1982
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OCTANE
CAS: 111-65-9 1. Low LK, Meeks JR, Mackerer CR: n-Octane.
In Snyder R (ed): Ethel Brownings Toxicity and
CH3(CH2)6CH3 Metabolism of Industrial Solvents, 2nd ed, Vol I,
Hydrocarbons, pp 307311. New York,
Elsevier, 1987
Synonyms: None 2. Swann HE Jr, Kwon BK, Hogan GK,
Snellings WM: Acute inhalation toxicology of
Physical Form. Colorless liquid; n-octane volatile hydrocarbons. Am Ind Hyg Assoc J
has 17 isomers with similar properties 35:511, 1974
employed for many years.3 Similar results were mineral oil mist is 5 mg/m3 with a short-term
found in a 5-year study of 460 printer pressmen excursion level (STEL) of 10 mg/m3.
exposed to a respirable concentration of less
than 5 mg/m3.4,5 An increased prevalence of
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uted to contaminants such as polycyclic aro- 3. Ely TS, Pedley SF, Hearne FT, Stille WT: A
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6. Skyberg K, Ronneberg A, Kamoy JI, et al:
there is inadequate evidence that the fully
Pulmonary brosis in cable plant workers
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studies.11 The IARCs determination that there 7. Skyberg K, Skaug V, Gylseth B, et al:
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tries associated with cancer in humans
present no hazard because of rening tech-
(IARC monographs, Vol 1 to 29), pp
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More recently there has been some leum hydrocarbons. A critical review of the
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lymph nodes of F344 rats after subchronic oral 10. Jarvolm B et al: Cancer morbidity among
ingestion of rened white mineral oils.13,14 The men exposed to oil mist in the metal indus-
histopathologic changes appear to be species- try. J Occup Med 23:333337, 1981
and strain specic as results have not been 11. IARC Monographs on the Evaluation of the Car-
cinogenic Risk of Chemicals to Humans, Suppl 7,
replicated in other rat strains or in dogs.15 The
Overall evaluations of carcinogenicity: An
toxicological signicance of the histopatho-
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not appear to impact signs of clinical toxicity Research on Cancer, 1987
or animal life span.16 12. Kane ML et al: Toxicological characteristics
The 2003 ACGIH threshold limit of renery streams used to manufacture
value-time-weighted average (TLV-TWA) for lubricating oils. J Ind Med 5:183200, 1984
546 OSMIUM TETROXIDE
13. Baldwin MK, Berry PH, Esdaile DJ, et al: Rabbits exposed for 30 minutes to vapor
Feeding studies in rats with mineral hydro- at estimated concentrations of 130 mg/m3
carbon food grade white oils. Toxicol Pathol developed irritation of mucous membranes
20(3):42635, 1992 and labored breathing; at autopsy there was
14. Smith JH, Mallett AK, Priston RA, et al: bronchopneumonia, as well as slight kidney
Ninety-day feeding study in Fischer-344 rats
damage.1 A 4-hour exposure at 400 mg/m3 was
of highly rened petroleum-derived food-
grade white oils and waxes. Toxicol Pathol lethal to rats.3
24(2):21430, 1996 Application of a drop of 1% solution of
15. Smith JH, Bird MG, Lewis SC, et al: Sub- osmium tetroxide to a rabbit eye caused severe
chronic feeding study of four white mineral corneal damage, permanent opacity, and super-
oils in dogs and rats. Drug Chem Toxicol:18(1): cial vascularization.4 Osmium compounds
83103, 1995 have a caustic action on the skin, resulting in
16. Nash JF, Gettings SD, Diembeck W, et al: eczema and dermatitis.2
A toxicological review of topical exposure to The 2003 ACGIH threshold limit value-
white mineral oils. Food Chem Toxicol 34(2): time-weighted average (TLV-TWA) is 0.0002
213225, 1996 ppm (0.0016 mg/m3) as Os with a short-term
excursion limit (STEL)/ceiling of 0.0006 ppm
(0.0047 mg/m3) as Os.
OSMIUM TETROXIDE
CAS: 20816-12-0 REFERENCES
selected pulmonary function measurements common lesion was transverse white bands of
in subjects exposed to ozone. Int Arch Occup discoloration, but other lesions were loss of
Environ Health 53:345358, 1984 nail surface, transverse ridging and gross defor-
10. Kulle TJ et al: Pulmonary function adapta- mity of the nail plate, and, in some cases, loss
tion to ozone in subjects with chronic bron- of the nail.2
chitis. Environ Res 34:5563, 1984
Paraquat is commonly combined in com-
11. Hackney JD et al: Adaptation to short-term
respiratory effects of ozone in men exposed mercial herbicides with diquat, a related com-
repeatedly. J Appl Physiol 43:8285, 1977 pound; in several instances, the commercial
12. Stokinger HE, Scheel LD: Ozone toxicity: preparations splashed in the eyes have caused
Immunochemical and tolerance-producing serious injury.3,4 Effects have been loss of
aspects. Arch Environ Health 4:327334, 1962 corneal and conjunctival epithelium, mild iritis,
13. National Toxicology Program: Toxicology and residual corneal scarring. In contrast, in
and Carcinogenesis Studies of Ozone and the eye of a rabbit, one drop of a 50% aqueous
Ozone/NNK in F344/N Rats and B6C3F1 solution of pure paraquat caused slow develop-
Mice. Technical Report Series 440, pp 307. ment of mild conjunctival inammation and
Research Triangle Park, NC, 1994 pure diquat proved even less irritating.5 Pre-
14. ACGIH: Ozone. Documentation of the Thresh-
sumably, the surfactants present in the com-
old Limit Values and Biological Exposure Indices,
7th ed, pp 19. Cincinnati, OH, American mercial preparations are responsible for the
Conference of Governmental Industrial severe eye injuries to humans.4
Hygienists, 2001 In a survey of 36 paraquat formulation
workers, acute skin rashes and burns from a
delayed caustic effect, eye injuries with con-
junctivitis from splash injuries, nail damage,
and minor epistaxis were common clinical
complaints.6 Despite a mean exposure period
PARAQUAT of 5 years, there was no evidence of chronic
CAS: 4685-14-7 effects on skin, mucous membranes, or general
health. Comparison of a group of 27 Malaysian
C12H14N2 plantation spray men, with a mean of 5.3 years
of heavy paraquat use, to unexposed groups did
not demonstrate any signicant differences in
Synonyms: 1,1-Dimethyl-4,4-bipyridinium pulmonary, renal, liver, or hematologic func-
dichloride; gramoxone; methylviologen tions.7 No abnormalities were attributable
to paraquat exposure.7 More recently, farm
Physical Form. Yellow solid workers exposed to paraquat have shown some
evidence of respiratory disease. South African
Uses. Herbicide farm workers had a dose-dependent association
with exposure and abnormal exercise physiol-
Exposure. Inhalation; ingestion ogy based on arterial oxygen desaturation but
no effects on chest radiograph or spirometry or
Toxicology. Paraquat is an irritant of the self-reported symptoms.8 Increased wheeze was
eyes, mucous membranes, and skin; ingestion noted among exposed Nicaraguan banana
causes broblastic proliferation in the lungs. workers.9
In a study of 30 workers engaged in spray- In rats exposed to aerosols of paraquat,
ing paraquat over a 12-week period, approxi- the LC50 for 6 hours was 1 mg/m3; death was
mately 50% of them had minor irritation of delayed and resulted from pulmonary hemor-
the eyes or nose; one worker had an episode rhage and edema.10 In practice, the large
of epistaxis.1 Of 296 spray operators with skin particle size of agricultural sprays probably
exposure described as gross and prolonged, mitigates against this occurring in exposed
55 had damaged ngernails. The most workers.11
PARAQUAT 551
The results from ingestion by humans or damage.11 Such episodes occurred with pro-
injection in animals are in marked contrast longed skin contact during spraying and expo-
to the irritant effects usually encountered sure to concentrated solutions or exposure to
in industrial exposure. There are numerous areas of preexisting dermatitis; all could have
reports of fatal accidental and suicidal ingestion been prevented with use of recommended work
by humans.1113 In two cases, one person practices.
ingested about 114 ml of a 20% solution and Workers involved in the manufacture of
the other person was believed to have taken paraquat were found to have a high prevalence
only a mouthful of the liquid, most of which of hyperpigmented macules and hyperkerato-
was rejected immediately. The former person sis, both of which may be premalignant skin
died after 7 days; the latter died after 15 days.12 lesions. Analysis of the data suggested that
Initial symptoms included burning in the exposure to bipyridine precursors along with
mouth and throat, nausea, vomiting, and sunlight, rather than paraquat itself, was
abdominal pain with diarrhea. After 23 days, responsible.14
signs of liver and kidney toxicity developed, A mouse bioassay involving dietary expo-
including jaundice, oliguria, and albuminuria; sure to 25, 50, and 75 mg/kg/day for 80 weeks
electrocardiogram changes were suggestive of yielded no evidence of carcinogenicity, despite
toxic myocarditis with conduction defects. the occurrence of some deaths from respiratory
Shortly before death, respiratory distress disease.11 A 2-year bioassay in rats exposed to
occurred; at autopsy, ndings in the lung paraquat in drinking water at 1.3 and 2.6 mg
included hemorrhage, edema, and massive similarly resulted in lung pathology but no
solid areas that were airless owing to broblas- increased tumor incidence.11 In general, para-
tic proliferation in the alveolar walls and else- quat was not genotoxic in a variety of in vitro
where.12 Early deaths from massive poisonings and in vivo assays.15
usually result from a combination of acute pul- Embryotoxicity has only been observed at
monary edema, acute oliguric renal failure, and doses that also cause signicant maternal toxi-
hepatic failure. Deaths from less massive poi- city in rats, mice, and rabbits.15
sonings typically result from pulmonary bro- The 2003 ACGIH threshold limit value-
sis, developing 13 weeks after ingestion.11 time-weighted average (TLV-TWA) for
Intraperitoneal injection or oral adminis- paraquat is 0.5 mg/m3 for total dust and
tration to rats at doses that caused delayed 0.1 mg/m3 for the respirable fraction.
death resulted in the same proliferative lesion
in the lung; ndings were alveolar, perivascu-
lar, and peribronchial edema, with cellular pro- REFERENCES
liferation into the alveolar walls resulting
in large solid areas of the lung with no air- 1. Swan AAB: Exposure of spray operators to
containing cavities.5 paraquat. Br J Ind Med 26:322329, 1969
There is no evidence that inhalation expo- 2. Hearn CED, Keir W: Nail damage in spray
sures in occupational settings cause the rapid operators exposed to paraquat. Br J Ind Med
progressive pulmonary brosis and injury to 28:399403, 1971
the heart, liver, and kidneys that occur after 3. Cant JS, Lewis DRH: Ocular damage due to
ingestion. Because of the low vapor pressure, paraquat and diquat. Br Med J 2:224, 1968
there is little inhalation hazard. Spray droplets 4. Grant WM: Toxicology of the Eye, 3rd ed,
pp 699700. Springeld, IL, Charles C.
are usually too large to reach the alveoli. If
Thomas, 1986
exposure is excessive, droplets may be inhaled 5. Clark DG, McElligott TF, Hurst EW: The
into the upper respiratory tract and cause nose- toxicity of paraquat. Br J Ind Med 23:126
bleed, sore throat, headache, and coughing 132, 1966
from local irritant action. Rarely, dermal expo- 6. Howard JK: A clinical survey of paraquat for-
sure to paraquat has resulted in systemic poi- mulation workers. Br J Ind Med 36:220223,
sonings and deaths with renal and pulmonary 1979
552 PARATHION
7. Howard JK, Sabapathy NN, Whitehead PA: Physical Form. Brown or yellowish liquid
A study of the health of Malaysian plantation
workers with particular reference to paraquat Uses. Acaracide; insecticide
spraymen. Br J Ind Med 38:110116, 1981
8. Dalvie MA, White N, Raine R, et al: Exposure. Inhalation; skin absorption;
Long-term respiratory health effects of the
ingestion
herbicide, paraquat, among workers in the
Western Cape. Occup Environ Med 56:391
396, 1999 Toxicology. Parathion is a highly toxic anti-
9. Castro-Gutierrez N, McConnell R, Anders- cholinesterase agent.
son K, et al: Respiratory symptoms, spiro- Hundreds of deaths associated with
metry and chronic occupational paraquat parathion exposure have been reported. These
exposure. Scand J Work Environ Health 23: deaths have resulted from accidental, suicidal,
421427, 1997 and homicidal poisonings. It has been the cause
10. Gage JC: Toxicity of paraquat and diquat of most crop worker poisonings in the United
aerosols generated by a size-selective cyclone: States.1 Fatal human poisonings have resulted
Effect of particle size distribution. Br J Ind from ingestion, skin exposure, and inhalation
Med 25:304314, 1968
(with varying degrees of skin exposure).
11. World Health Organization: Environmental
Health Criteria 39-Paraquat and Diquat, pp Signs and symptoms of overexposure are
13128. Geneva, International Programme caused by the inactivation of the enzyme
on Chemical Safety (IPCS), 1984 cholinesterase, which results in the accumula-
12. Bullivant CM: Accidental poisoning by tion of acetylcholine at synapses in the nervous
paraquat: Report of two cases in man. Br Med system, skeletal and smooth muscle, and secre-
J 1:12721273, 1966 tory glands. The sequence of the development
13. Toner PG, Vetters JM, Spilg WGS, et al: of systemic effects varies with the route of
Fine structure of the lung lesion in a case of entry. The onset of signs and symptoms is
paraquat poisoning. J Pathol 102:182185, usually prompt but may be delayed up to 12
1970 hours.14 After inhalation, respiratory and
14. Wang JD, Li WE, Hu FC, et al: Occupa-
ocular effects are the rst to appear, often
tional risk and the development of prema-
lignant skin lesions among paraquat within a few minutes after exposure. Respira-
manufacturers. Br J Ind Med 44:196200, tory effects include tightness in the chest
1987 and wheezing due to bronchoconstriction and
15. Trochimowicz HJ, et al: Heterocyclic and excessive bronchial secretion; laryngeal spasms
miscellaneous nitrogen compounds. In and excessive salivation may add to the respi-
Clayton GD, Clayton FE (eds): Pattys Indus- ratory distress; cyanosis may also occur. Ocular
trial Hygiene and Toxicology, 4th ed, Vol II, effects include miosis, blurring of distant
Part E, Toxicology, pp 33903394. New vision, tearing, rhinorrhea, and frontal
York, John Wiley and Sons, 1994 headache.
After ingestion, gastrointestinal effects
such as anorexia, nausea, vomiting, abdominal
cramps, and diarrhea appear within 15 minutes
to 2 hours. After skin absorption, localized
PARATHION sweating and muscular fasciculations in the
CAS: 56-38-2 immediate area occur usually within 15
minutes to 4 hours; skin absorption is some-
C10H14NO5PS what greater at higher ambient temperatures
and is increased by the presence of dermatitis.3
With severe intoxication by all routes, an
Synonyms: O,O-diethyl O-p-nitrophenyl excess of acetylcholine at the neuromuscular
phosphorothioate; Akron; Niran; Amer. Cyan. junctions of skeletal muscle causes weakness
3422; BAY E-605; Bladan; Folidol E605 aggravated by exertion, involuntary twitchings,
PARATHION 553
7. Arterberry JD, Durham WF, Elliott JW, Wolfe importance in relating ambient air concentra-
HR: Exposure to parathionmeasurement by tions to population morbidity and mortality.
blood cholinesterase level and urinary p-nitro- Routing ambient air monitoring studies before
phenol excretion. Arch Environ Health 3:476 1999 generally measured thoracic PM,
485, 1961 namely, PM10 (upper size limited by a 50% cut
8. Spear RC, et al: Worker poisonings due to
at 10-mm aerodynamic diameter). Research
paraoxon residues. J Occup Med 19:411414,
1977 and monitoring studies since 1999 have
9. IARC Monographs on the Evaluation of the Car- measured other fractions, but one of consider-
cinogenic Risk of Chemicals to Humans, Vol 30, able signicance is termed ne PM, namely,
Miscellaneous pesticides, pp 153181. Lyon, PM2.5 (upper size limited by a 50% cut point
International Agency for Research on Cancer, at 2.5-mm aerodynamic diameter.) An emerging
1983 measurement of importance is ultrane
particles, namely, PM0.1 (upper size limited
by a 50% cut point at 0.1-mm aerodynamic
diameter).
atrophy and ventricular dilation. Institutional- persons exposed to pentaborane. Clin Toxicol
ization was required. Eight of 14 individuals 23:519536, 198586
with mild exposure to pentaborane from the 6. Hart RP, et al: Neuropsychological function
same accident were judged to have mild following mild exposure to pentaborane. Am J
cognitive decits as determined by various Ind Med 6:3744, 1984
7. Emergency Exposure Limits: Pentaborane-9.
neuropsychological tests 2 months after
Am Ind Hyg Assoc J 27(2):193195, 1966
exposure.6 8. Hughes RL, Smith IC, Lawless EW: III.
The concentrations of vapor and duration Pentaborane (9) and derivatives. In
of exposures that cause mild, moderate, or Holzmann RT (ed): Production of the Boranes
severe intoxication are not documented. It has and Related Research, pp 294489. New York,
been estimated, on the basis of animal studies, Academic Press, 1967
that exposure for 60 minutes will cause slight
signs of toxicity at 8 ppm, convulsions at
15 ppm, and death at 30 ppm. It was the clini-
cal impression of one investigator that in
humans a transient wafting odor did not PENTACHLOROETHANE
produce symptoms (median odor threshold is 1 CAS: 76-01-7
ppm), but a strong whiff, producing a pene-
trating feeling in the nose, usually produced C2HCl5
symptoms.1,7 Olfactory fatigue also occurs,
and dangerous levels of pentaborane may not
be readily detected.1 Synonyms: Ethane pentachloride; pentalin
Severe irritation and corneal opacity of the
eyes of test animals occurred from exposure Physical Form. Dense, colorless liquid with
to the vapor; the liquid on the skin of animals a chloroform-like odor
caused acute inammation, with the formation
of blisters, redness, and swelling.8 Because the Uses. May occur as an intermediate in the
liquid may ignite spontaneously, re and con- production of chlorinated ethylenes; formerly
sequent burn damage may be a greater hazard used as a solvent for cellulose ethers, resins, and
than toxicity on contact with the liquid.4 gums, for dry cleaning, coal purication, as a
The 2003 ACGIH threshold limit soil sterilizing agent, and as a chemical inter-
value-time-weighted average (TLV-TWA) is mediate in the production of dichloroacetic
0.005 ppm (0.013 mg/m3) with a short-term acid
excursion limit (STEL)/ceiling of 0.015 ppm
(0.039 mg/m3). Exposure. Inhalation
lethargy and weight gain decrements in the inadequate to produce the high incidence of
survivors of the 500 mg/kg/day dose group. tumors found in the pentachloroethane studies.
Neither gross nor histopathologic examina- Pentachloroethane was not mutagenic in
tions revealed lesions that could be attributed Salmonella typhimurium strains with or without
to the chemical. Mice survived 2 weeks at metabolic activation.1
1000 mg/kg/day but lost weight during the The IARC determined that there is limited
experiment.2,3 evidence for the carcinogenicity of pentach-
Male rats administered 0.62 or loroethane to experimental animals and that it
1.24 mmol/kg per day by gavage for 21 days is not classiable as to its carcinogenicity to
showed hyalin droplet nephropathy.4 humans.5
Dose levels of 75 and 150 mg/kg/day were The ACGIH has not established a thresh-
administered to rats by gavage during chronic old limit value (TLV) for pentachloroethane
(41103 week) studies.2,3 A signicant dose- exposure.
related increase in the incidence of chronic
renal inammation and a dose-related trend in
the incidence of tubular cell adenomas of the REFERENCES
kidneys in males was noted, although the sur-
vival of the high-dose group was signicantly 1. IARC Monographs on the Evaluation of Carcino-
reduced compared with controls. The kidney genic Risk of Chemicals to Humans, Vol 41, Some
lesions were distinguishable from the nephro- halogenated hydrocarbons and pesticide expo-
sures, pp 99111. Lyon, International Agency
pathy normally seen in aging rats, and some
for Research on Cancer, 1986
of the dosed animals had both types of
2. National Toxicology Program: Carcinogenesis
changes. Bioassay of Pentachloroethane (CAS No 76-01-7)
Mice were administered 250 or 500 mg/ in F344/N Rats and B6C3F1 Mice (Gavage
kg/day pentachloroethane by gavage for Study). NTP-TR-232, NIH Pub No 83-1788,
life. The hepatic carcinogenicity of pen- pp 1149. Research Triangle Park, NC, US
tachloroethane was clearly established despite Department of Health and Human Services,
reduced survival rates. The incidence of 1983
hepatocellular carcinomas was signicantly 3. Mennear JH, Haseman JK, Sullivan DJ, et al:
increased in low-dose males and in treated Studies on the carcinogenicity of pen-
females; there also was a signicant dose- tachloroethane in rats and mice. Fundam Appl
Toxicol 2:8287, 1982
related increase in the incidence of hepatocel-
4. National Toxicology Program: NTP Technical
lular adenomas in treated females.2,3
Report on Renal Toxicity Studies of Selected Halo-
It has been suggested that the mechanism genated Ethanes Administered by Gavage to
of action of pentachloroethane may be similar F344/N Rats. Technical Report Series No. 45,
to that of other chlorohydrocarbons that also NIH Pub No 96-3935, pp 152. Research Tri-
induce a high incidence of hepatocellular car- angle Park, NC, US Department of Health
cinoma in mice and have little or no carcino- and Human Services, 1996
genic effect in rats. The carcinogenic potential 5. IARC Monographs on the Evaluation of the Car-
may be mediated through the active metabolic cinogenic Risk of Chemicals to Humans, Vol 71,
intermediates trichloroethylene and tetra- Re-evaluation of some organic chemicals,
chloroethylene, which are formed in some hydrazine and hydrogen peroxide, pp
15191523. Lyon, International Agency for
species but not in others.
Research on Cancer, 1999
It has also been noted that hexa-
chloroethane is a major contaminant of the
pentachloroethane used in the chronic studies.
This compound also has been shown to induce
hepatocellular carcinoma in mice but not rats,
although the low levels of hexachloroethane
present in the pentachloroethane samples seem
558 PENTACHLORONAPHTHALENE
Animal studies have shown that the Case reports and case control studies in
immune system is sensitive to exposure.9 Mice humans have suggested a possible association
fed diets containing 50 or 500 ppm technical- between cancer, including soft tissue sarcoma,
grade pentachlorophenol showed greatly acute leukemia, Hodgkin disease, and non-
reduced immunocompetence in the form of Hodgkin lymphoma, and occupational exposure
increased susceptibility to the growth of to pentachlorophenol. However, in all cases
transplanted tumors. Oral and intraperitoneal concomitant exposure to other toxic substances
administration to animals causes adverse effects may have contributed to the effects seen.1,11
on thyroid homeostasis and on the thyroid The IARC has determined that there is
gland. Competition for serum protein thyrox- limited evidence for carcinogenicity in humans
ine binding sites may account for the antithy- and sufcient evidence of carcinogenicity in
roid effects of pentachlorophenol.1 experimental animals.11
Given orally to pregnant rats at doses Occupational exposure of 20 workers
ranging from 5 to 50 mg/kg body weight/day, to pentachlorophenol at concentrations that
puried pentachlorophenol produced dose- ranged from 1.2 to 180 mg /m3 for 334 years
related signs of fetotoxicity, including resorp- did not result in any increased incidence of
tions, subcutaneous edema, dilated ureters, and sister chromatid exchanges or chromosomal
anomalies of the skull, ribs, and vertebrae.10 aberrations.14 In another report, signicant
Although early animal studies found no increases in the incidence of dicentric chromo-
sufcient evidence of carcinogenicity, a 2-year somes and acentric fragments were detected
NTP report found clear evidence of carcino- in the peripheral lymphocytes of exposed
genicity in mice for two technical-grade pen- workers; the frequency of sister chromatid
tachlorophenol mixtures.11,12 Male B6C3F1 exchanges was not increased.15
mice fed diets containing 100 or 200 ppm tech- The 2003 ACGIH threshold limit value-
nical-grade pentachlorophenol had increased time-weighted average (TLV-TWA) for pen-
incidences of adrenal medullary and hepato- tachlorophenol is 0.5 mg/m3 with a notation for
cellular neoplasms; there was some evidence skin absorption.
of carcinogenicity in female mice similarly
exposed, as shown by increased incidences
of hemangiosarcomas and hepatocellular neo- REFERENCES
plasms. For male and female mice given up to
600 ppm EC-7 pentachlorophenol, there were
1. Agency for Toxic Substances and Disease
increased incidences of adrenal medullary
Registry (ASTDR): Toxicological Prole for
and hepatocellular neoplasms (females also had Pentachlorophenol (Update). pp 1269. US
hemangiosarcomas of the liver and spleen). It Department of Health and Human Services,
was concluded that pentachlorophenol was Public Health Service, 2001
primarily responsible for the carcinogenic 2. Jorens PG, Schepens PJC: Human pen-
response in mice, but that impurities may pos- tachlorophenol poisoning. Hum Exp Toxicol
sibly play a role in the neoplastic process.12 12:479495, 1993
A more recent 2-year study found no 3. Wood S, Rom WN, White GL, et al: Pen-
evidence of carcinogenic activity for pen- tachlorophenol poisoning. J Occup Med
tachlorophenol in male or female F344/N rats 25:527530, 1983
4. Williams PL: Pentachlorophenol, an assess-
fed diets containing 200, 400, or 600 ppm.13
ment of the occupational hazard. Am Ind Hyg
There was some evidence of carcinogenic
Assoc J 43:799810, 1982
activity in male F344/N rats given feed con- 5. Gray RE, Gilliland RD, Smith EE: Pen-
taining 1,000 ppm for 1 year followed by tachlorophenol intoxication: Report of a fatal
control feed for 1 year (stop-exposure study), case, with comments on the clinical course
based on increased incidences of mesothelioma and pathologic anatomy. Arch Environ Health
and nasal squamous cell carcinoma. 40:161164, 1985
PENTAERYTHRITOL 561
opmental toxicity study of pentane by inhala- second and sixth weeks of exposure.3,4 Death
tion in the rat. Food Chem Toxicol 37(5): was attributed to brain lesions consisting of
565567, 1999 degenerative changes in the deep cerebellar
and vestibular nuclei and the corpora striata.
Gliosis and malacia were observed in the same
brain regions in approximately half of the
surviving animals. Other changes included
2,4-PENTANEDIONE minimal squamous metaplasia in the nasal
CAS: 123-54-6 mucosa, decreased body and organ weights,
lymphocytosis, and minor alterations in serum
CH3COCH2COCH3 and urine chemistries. No spinal cord or
peripheral lesions were found in any rats. No
clinical signs or neuropathies were seen in rats
Synonyms: Acetylacetone, diacetyl methane, treated at 101 or 307 ppm for 14 weeks, sug-
acetyl 2-propanone, 2,4-PD gesting a well-dened threshold for effects.
Central neuropathologic lesions have also
Physical Form. Clear liquid with a rancid been described after gavage administration.1
odor Rats developed weakness, ataxia, tremors,
paresis, and rolling movements of the head
Uses. Chemical intermediate, metal chelator, after 100150 mg/kg twice daily for periods
and lubricant additive from 3 to 61 days. Histologic changes induced
by the shorter dosing schedules were periv-
Exposure. Inhalation; skin absorption ascular edema, hemorrhage into the
VirchowRobin spaces, and endothelial
Toxicology. 2,4-Pentanedione is moderately swelling, all primarily localized in the cerebel-
irritating to the skin and eyes; repeated expo- lum and brain stem. Chronic central nervous
sure to high concentrations causes dyspnea, system lesions were bilateral, symmetrical areas
central nervous system damage, and death. of malacia and gliosis centered on the cerebel-
Information on human exposures is lar peduncles, olivary nuclei, and lower brain
limited. Exposure to levels ranging from 2 to stem.
14 ppm have been reported to produce nausea The central neuropathologic effects fol-
and headache.1 lowing inhalation exposure in rats appear to
For male and female rats the combined require a critical number of repeated exposures
LC50 for a 4-hour exposure was 1224 ppm.2 to high (>650 ppm) concentrations.3 Thus
Signs of toxicity before death included perio- central neuropathologic effects did not occur
cular, perinasal, and perioral wetness and after acute exposure to potentially lethal con-
encrustation, mouth and abdominal breathing, centrations or after subchronic exposures at
tremors, ataxia, and negative tail and toe pinch 307 ppm. The steep slope of the concentration-
reexes. Necropsy of animals that died showed response relationship and the sharply dened
dark red lungs, mottled livers, and gas-lled exposure conditions for inducing central
gastrointestinal tracts. Survivors did not show nervous system damage suggest that the mech-
any gross pathology. At 919 ppm for 4 hours anism of neurotoxicity may involve depletion
there was decreased motor activity with recov- of a biochemical pathway. Specically, the sim-
ery by the rst postexposure day, and there ilarity between the morphologic damage
were no signs of toxicity at 628 ppm. produced by 2,4-pentanedione and acute
Repeated exposure of rats to 650 ppm 6 vitamin B deciency and the ability of 2,4-
hours/day, 5 days/week for 14 weeks caused pentanedione to inactivate lysyl residues
hypoactivity, incoordination, ataxia, paresis, suggest that the toxicity of 2,4-pentanedione is
and slowed righting reexes; death occurred due to its ability to produce deciencies of thi-
in all females and 10 of 30 males between the amine, folic acid, and/or pyridoxine.1
564 PERCHLOROETHYLENE
Pregnant Fischer 344 rats were exposed inhalation studies in Fischer-344 rats. Fundam
to 2,4-pentanedione at 53, 202, or 398 ppm Appl Toxicol 7:329339, 1986
6 hours/day on gestational days 615.5 At the 4. Garman RH, Dodd DE, Ballantyne B: Central
highest dose there was maternal toxicity in the neurotoxicity induced by subchronic exposure
form of reduced body weight gain and fetotox- to 2,4-pentanedione vapour. Hum Exp Toxicol
14(8):662671, 1995
icity as reduced fetal body weight and a consis-
5. Tyl RW, Ballantyne B, Pritts IM, et al: An
tent pattern of reduced skeletal ossication; at evaluation of the developmental toxicity of
202 ppm there was reduced fetal body weight 2,4-pentanedione in the Fischer 344 rat by
gain. Embryotoxicity and teratogenicity were vapour exposure. Toxicol Ind Health 6:461474,
not observed at any concentration. 1990
The percutaneous LD50 values for 24-hour 6. Slesinski RS, Guzzie PJ, Ballantyne B: An in
occluded contact on the skin of rabbits were vitro and in vivo evaluation of the genotoxic
1.41 ml/kg for males and 0.81 for females.2 potential of 2,4-pentanedione. Environ
Times of death ranged from 45 minutes to Mutagen 9 (suppl 8):4449, 1987
1 day. Signs of toxicity were dilated pupils
within 1530 min, convulsions in one animal,
and excess, blood-stained saliva. Local signs
of inammation were erythema, edema, and
necrosis. In survivors, inammation persisted PERCHLOROETHYLENE
for up to 7 days with scab formation by 2 weeks. CAS: 127-18-4
Instilled in the eye of rabbits, the liquid pro-
duced mild conjunctivitis without corneal C2Cl4
injury.
Although irritant effects do not appear
until high concentrations are reached, it is Synonyms: Tetrachloroethylene; ethylene
expected that the low odor threshold tetrachloride; tetrachloroethene; 1,1,2,2-
(0.01 ppm) could provide adequate warning of tetrachloroethylene; PCE
exposure to 2,4-pentanedione.2
2,4-Pentanedione caused sister chromatid Physical Form. Colorless liquid
exchange increases in Chinese hamster ovary
(CHO) cells and an increase in the incidence of Uses. Solvent for dry cleaning and textile
micronuclei in peripheral blood erythrocytes processing; chemical intermediate; metal
of mice.6 It was not mutagenic in a Salmonella degreasing
typhimurium assay.
A threshold limit value (TLV) has not been Exposure. Inhalation
established for 2,4-pentanedione.
Toxicology. Perchloroethylene causes
central nervous system depression and liver
REFERENCES damage. Chronic exposure has caused periph-
eral neuropathy, and it is carcinogenic in exper-
1. Krasavage WJ, ODonoghue JL, Divincenzo imental animals.
GD: 2,4-Pentanedione. In Clayton GD, Occupational exposure has caused signs
Clayton FE (eds): Pattys Industrial Hygiene and and symptoms of central nervous system depre-
Toxicology, Vol 2C, Toxicology, pp 47734776. ssion, including dizziness, light-headedness,
New York, Wiley, 1982
inebriation, and difculty in walking.1
2. Ballantyne B, Dodd DE, Myers RC, et al: The
acute toxicity and primary irritancy of 2,4- Four human subjects exposed to 5000 ppm
pentanedione. Drug Chem Toxicol 9:133146, left a chamber after 6 minutes to avoid being
1986 overcome; they experienced vertigo, nausea,
3. Dodd DE, Garman RH, Pritts IM, et al: and mental confusion during the 10 minutes
2,4-Pentanedione:9-day and 14-week vapor after cessation of exposure.2 In an industrial
PERCHLOROETHYLENE 565
and that, overall, perchloroethylene is probably Health Criteria 31. Tetrachlorothylene, 48pp.
carcinogenic to humans.16 Geneva, International Programme on
Both positive and negative results have Chemical Safety (IPCS), 1984
been reported in a variety of genotoxic studies. 8. Reinhardt CF, Mullin LS, Maxeld ME:
Many studies have been done with commercial Epinephrine-induced cardiac arrhythmia
potential of some common industrial sol-
grades of perchloroethylene, which suggests
vents. J Occup Med 15:953955, 1973
that contaminants may be involved when 9. Schwetz BA, Leong BKJ, Gehring PJ: The
effects are seen. Furthermore, there is evidence effect of maternally inhaled trichloroethyl-
that the mutagenic properties may depend on ene, perchloroethylene, methyl chloroform,
a glutathione-mediated metabolic pathway that and methylene chloride on embryonal and
is more prominent in rats than in humans.18 fetal development in mice and rats. Toxicol
The 2003 ACGIH threshold limit value- Appl Pharmacol 32:8496, 1975
time-weighted average (TLV-TWA) for per- 10. van der Gulden JWJ, Zielhuis GA: Repro-
chloroethylene is 25 ppm (170 mg/m3) with a ductive hazards related to perchloroethylene.
short-term exposure limit (STEL) of 100 ppm Int Arch Occup Environ Health 61:235242,
(685 mg/m3) and an A3-animal carcinogen 1989
11. Kyyronen P, Taskinen H, Lindbohm M, et al:
designation.
Spontaneous abortions and congenital mal-
formations among women exposed to tetra-
chloroethylene in dry cleaning. J Epidemiol
REFERENCES Community Health 43:346351, 1989
12. Ahlborg G Jr: Pregnancy outcome among
1. National Institute for Occupational Safety women working in laundries and dry clean-
and Health: Criteria for a Recommended ing shops using tetrachloroethylene. Am J
Standard . . . Occupational Exposure to Tetra- Ind Med 17:567575, 1990
chloroethylene (Perchloroethylene). DHEW 13. Olsen J, Hemminki K, Ahlborg G, et al: Low
(NIOSH) Pub No 76-185, pp 1765. Wash- birthweight, congenital malformations, and
ington, DC, US Government Printing spontaneous abortions among dry cleaning
Ofce, 1976 workers in Scandinavia. Scand J Work Environ
2. Hygienic Guide Series: Tetrachloroethylene Health 16:163168, 1990
(perchloroethylene). Am Ind Hyg Assoc J 26: 14. National Cancer Institute: Bioassay of Tetra-
640643, 1965 chloroethylene for Possible Carcinogenicity.
3. Stewart RD, Erley DS, Schaffer AW, Gay DHEW (NIH) Pub No 77-813. Washington
HH: Accidental vapor exposure to anesthetic DC, US Government Printing Ofce, 1977
concentrations of a solvent containing tetra- 15. National Toxicology Program: Toxicology and
chloroethylene. Ind Med Surg 30:327330, Carcinogenesis Studies of Tetrachloroethylene
1961 (Perchloroethylene) (CAS No 127-18-4) in
4. Stewart RD: Acute tetrachloroethylene F344/N Rats and B6C3F1 Mice(Inhalation
intoxication. JAMA 208:14901492, 1969 Studies). DHHS (NTP) TR-311 pp 1197.
5. von Oettingen WF: The Halogenated Washington, DC, US Government Printing
Aliphatic, Olenic, Cyclic, Aromatic, and Ofce, August 1986
Aliphatic-Aromatic Hydrocarbons Including 16. IARC Monographs on the Evaluation of the Car-
the Halogenated Insecticides, Their Toxicity and cinogenic Risks of Chemicals to Humans, Vol 63,
Potential Dangers. US Public Health Service Dry cleaning, some chlorinated solvents
Publication Pub No 414, pp 227235. and other industrial chemicals, pp 159221.
Washington DC, US Government Printing Lyon, International Agency for Research on
Ofce, 1955 Cancer, 1995
6. Stewart RD, Baretta ED, Dodd HC, 17. Ruder AM, Ward EM, Brown DP: Mortality
Torkelson TR: Experimental human expo- in dry-cleaning workers: An update. Am J Ind
sure to tetrachloroethylene. Arch Environ Med 39(2):12132, 2001
Health 20:224229, 1970 18. Agency for Toxic Substances and Disease
7. World Health Organization: Environmental Registry (ASTDR): Toxicological Prole for
PERCHLORYL FLUORIDE 567
Tetrachloroethylene, 278pp. US Department of edema; the LC50 for mice was 9 ppm for 3
Health and Human Services, Public Health hours; repeated exposures over 3 months at
Service, 1997 1 ppm resulted in the death of some of the mice
tested.1,2 Rats exposed at 1 ppm 6 hours/day, 5
days/week for 2 weeks had labored breathing,
tremors, and nasal irritation; pulmonary edema
was evident at autopsy.3 No effects were seen at
0.13 ppm for the same exposure period.
PERCHLOROMETHYL MERCAPTAN The 2003 ACGIH threshold limit
CAS: 594-42-3 value-time-weighted average (TLV-TWA)
for perchloromethyl mercaptan is 0.1 ppm
CCl3SCl (0.76 mg/m3).
vapor readily penetrates the skin, with an burns.1 Erythema, edema, tissue necrosis, and
absorption efciency equal to that for inhala- gangrene have been reported, and prolonged
tion. Skin absorption can occur at low vapor contact with dilute solutions may result in
concentrations, apparently without discomfort. deposition of dark pigment in the skin
Signs and symptoms can develop rapidly, with (ochronosis).1 After severe chemical burns,
serious consequences, including shock, col- progressive areas of depigmentation may also
lapse, coma, convulsions, cyanosis, respiratory develop.
arrest, and death. Rats and mice given doses of up to
A worker who accidentally fell into a 120 mg/kg and 280 mg/kg, respectively, by
shallow vat containing 40% phenol for a few gavage on days 615 of gestation showed dose-
seconds subsequently collapsed and suffered related signs of fetotoxicity with no evidence of
50% body surface burns; he developed nausea teratogenic effects.4 A Russian study demon-
and vomiting and was diagnosed as suffering strated increased preimplantation loss and early
from acute renal tubular necrosis.2 After a postnatal death in the offspring of rats exposed
number of days, respiratory distress also devel- to 0.13 and 1.3 ppm throughout pregnancy.4 In
oped. Kidney function improved after 6 weeks, two-generation studies in rats, reduced litter
but the patient still showed marginal polyuria survival was seen at doses of 5000 ppm in the
1 year later. drinking water, which also caused signicant
A laboratory technician repeatedly exposed reductions in food and water consumption of
to the vapor (unknown concentration) and the parental generation.8
to the liquid spilled on the skin developed Mice were treated twice weekly for 42
anorexia, weight loss, weakness, muscle pain, weeks by application of one drop of a 10%
and dark urine.3 During several months of non- solution of phenol in benzene to the shaved
exposure, there was gradual improvement in dorsal skin; after 52 weeks, there were papillo-
his condition, but, after brief reexposure, he mas in 5 of 14 mice, and a single brosarcoma
suffered an immediate worsening of symptoms, appeared at 72 weeks.9 Phenol, as a nonspecic
with prompt darkening of the urine and tender irritant, may promote development of tumors
enlargement of the liver. when applied repeatedly to the skin in large
Brief intermittent industrial exposures to amounts.1
vapor concentrations of 48 ppm of phenol Phenol was not considered carcinogenic to
(accompanied by 8 ppm of formaldehyde) caused rats or mice receiving 25005000 ppm in drink-
marked irritation of eyes, nose, and throat.1 ing water for 103 weeks, although an increased
Workers at the same plant who were continu- incidence of leukemia and lymphomas was
ously exposed to an average concentration of detected in the low-dose male rats.10 Two-stage
4 ppm experienced no respiratory irritation. carcinogenicity studies showed that phenol,
Ingestion of lethal amounts causes severe applied repeatedly to mouse skin, has promot-
burns of the mouth and throat, marked abdom- ing activity.
inal pain, cyanosis, muscular weakness, col- In a case-control study of workers in
lapse, coma, and death. Tremor, convulsions, various wood industries, an increased risk for
and muscle twitching have also occurred.1,4 tumors of the mouth and respiratory tract was
The minimal lethal oral dose in humans associated with phenol exposure; however, the
has been estimated to be approximately small number of cases and confounding expo-
140 mg/kg.5,6 sures were inadequately controlled.11,12 The
Concentrated phenol solutions are IARC has determined that there is inadequate
severely irritating to the human eye and cause evidence for carcinogenicity of phenol in
conjunctival swelling; the cornea becomes humans and experimental animals and that it is
white and hypesthetic. Loss of vision has not classiable as to its carcinogenicity to
occurred in some cases.7 humans.12
In addition to systemic effects, contact After in vivo administration, phenol
with the solid or liquid can produce chemical induced micronuclei in mice and chromosomal
570 p-PHENYLENEDIAMINE
aberrations in rats.12 In vitro, it caused muta- promoting action of phenol and related
tions and sister chromatid exchanges in compounds for mouse skin. Cancer Res
mammalian cells but was not mutagenic in bac- 19:413424, 1959
teria.12 Although phenol is a major metabolite 10. National Cancer Institute: Bioassay of Phenol
for Possible Carcinogenicity. CAS No 108-95-2,
of the leukemogen benzene, it does not exhibit
NCI-CG-TR-203, NTP-80-15. DHHS
any potential for myeloclastogenicity in animal (NIH) Pub No 80-1759, 123pp. Washington,
tests.13 DC, US Government Printing Ofce,
Phenol is detectable by odor at a threshold August 1980.
of 0.05 ppm.14 11. Kauppinen TP, Partanen TJ, Nurminen
The 2003 ACGIH threshold limit value- MM, et al: Respiratory cancers and chemical
time-weighted average (TLV-TWA) for phenol exposures in the wood industry: A nested
is 5 ppm (19 mg/m3) with a notation for skin case-control study. Br J Ind Med 43:8490,
absorption. 1986
12. IARC Monographs on the Evaluation of
Carcinogenic Risks to Humans, Vol 71, Re-
REFERENCES evaluation of some organic chemicals,
hydrazine and hydrogen peroxide, pp 749
1. National Institute for Occupational Safety 68. Lyon, International Agency for Research
and Health: Criteria for a Recommended on Cancer, 1999
Standard . . . Occupational Exposure to Phenol. 13. Gad-ed-Karim MM, et al: Benzene myelo-
DHEW (NIOSH) Pub No 76-1967, pp clastogenicity: A function of its metabolism.
2369. Washington, DC, US Government Am J Ind Med 7:475484, 1985
Printing Ofce, 1976 14. Leonardos G, et al: Odor threshold determi-
2. Foxall PJD, Bending MR, Gartland KPR, et nation of 53 odorant chemicals. J Air Pollu-
al: Acute renal failure following accidental tant Control Assoc 19:9195, 1969
cutaneous absorption of phenol: Application
of NMR urinalysis to monitor the disease
process. Hum Toxicol 9:491496, 1989
3. Merliss RR: Phenol marasmus. J Occup Med
14:5556, 1972 p-PHENYLENEDIAMINE
4. US Environmental Protection Agency (EPA): CAS: 106-50-3
Summary Review of the Health Effects Associated
with Phenol: Health Issue Assessment, 37pp. C6H4(NH2)2
Washington, DC, US Government Printing
Ofce, January 1986
5. Bruce RM, Santodonato J, Neal MW:
Summary review of the health effects asso- Synonyms: p-Diaminobenzene; 1,4-benzene-
ciated with phenol. Toxicol Ind Health 3:535 diamine
568, 1987
6. Agency for Toxic Substances and Disease Physical Form. Colorless crystalline solid;
Registry (ASTDR): Toxicological Prole for with exposure to air, it turns red, brown, and
Phenol. pp 1111. US Department of Health nally black
and Human Services, Public Health Service,
1989 Uses. Dyeing of furs; hair dye formulations;
7. Grant WM: Toxicology of the Eye, 3rd ed,
in photographic developers; in antioxidants
pp 720721. Springeld, IL, Charles C.
Thomas, 1986
8. Ryan BM, Selby R, Gingell R, et al: Two gen- Exposure. Inhalation; skin absorption
eration oral (drinking water) reproductive
toxicity study of phenol in rats. Toxicologist Toxicology. p-Phenylenediamine is a sensi-
54(1):367, 2000 tizer of the skin and respiratory tract and may
9. Boutwell RK, Bosch DK: The tumor- produce bronchial asthma.
2-PHENYLETHANOL 571
Frequent inammation of the pharynx and 4. Ashraf W, Dawling S, Farrow LJ: Systemic
larynx has been reported in exposed workers.1 paraphenylenediamine (PPD) poisoning: A
Very small quantities of the dust have caused case report and review. Hum Exp Toxicol
asthmatic attacks in workers after periods of 13(3):167170,1994
exposure ranging from 3 months to 10 years. 5. Re TA, Loehr RF, Rodwell DE, et al: The
absence of teratogenic hazard potential of
Sensitization dermatitis has been reported
p-phenylenediamine in Sprague-Dawley rats.
from its use in the fur dyeing industry. In this Fundam Appl Toxicol 1:421425, 1981
process, oxidation products of p-phenylenedi- 6. IARC Monographs on the Evaluation of the
amine are generated that are also strong skin Carcinogenic Risk of Chemicals to Man, Vol.
sensitizers. Many instances of inammation 16, Some aromatic amines and related nitro
and damage of periocular and ocular tissue compoundshair dyes, colouring agents
have been reported from contact with hair dyes and miscellaneous industrial chemicals, pp
containing p-phenylenediamine, presumably in 125142. Lyon, International Agency for
sensitized individuals.2,3 Research on Cancer, 1978
Although unlikely in an occupational 7. National Cancer Institute: Bioassay of p-
setting, ingestion of p-phenylenediamine (espe- Phenylenediamine Dihydrochloride for Possible
Carcinogenicity. TR-174, DHEW (NIH)
cially hair dyes) has resulted in fatalities.4 The
9-1730, 1979.
primary systemic effect is rhabdomyolysis with 8. Chung KT, Murdock CA, Stevens SE Jr, et al:
subsequent renal failure. Mutagenicity and toxicity studies of p-
Developmental or teratogenic effects were phenylenediamine and its derivatives. Toxicol
not observed in rats, even at doses that were Lett 81(1):2332, 1995
severely maternally toxic.5
p-Phenylenediamine was tested for car-
cinogenicity in mice by skin application and in
rats by oral and subcutaneous administration,
however, the IARC has determined that these 2-PHENYLETHANOL
studies were not adequate to evaluate carcino- CAS: 60-12-8
genicity.6 The dihydrochloride was not car-
cinogenic in 2-year feeding studies with mice C6H5CH2CH2OH
and rats.7
p-Phenylenediamine was weakly muta-
genic in some bacterial strains and caused a Synonyms: Benzyl carbinol; PEA; phenylethyl
dose-dependent increase in chromosomal aber- alcohol
rations in Chinese hamster ovary (CHO) cells
in vitro.8 Physical Form. Colorless, viscous liquid
The 2003 ACGIH threshold limit
value-time-weighted average (TLV-TWA) for Uses. In fragrance; antimicrobial agent; in
p-phenylenediamine is 0.1 mg/m3. organic synthesis; preservative, food additive
Exposure. Inhalation
REFERENCES
Toxicology. Phenylethanol is an irritant of
1. Goldblatt MW: Research in industrial health
the eyes and a teratogen in rats.
in the chemical industry. Br J Ind Med 12:120,
1955
An 8-hour exposure of rats to an essentially
2. Grant WM: Toxicology of the Eye, 2nd ed, saturated atmosphere failed to cause any
pp 696698. Springeld, IL, Charles C. deaths.1 The acute oral LD50 for rats ranged
Thomas, 1974 from 2.5 to 3.1 ml/kg.2 The dermal LD50 values
3. Baer RL et al: The most common contact for rabbits and guinea pigs were 0.8 and 5 g/kg,
allergens. Arch Dermatol 108:7478, 1973 respectively.2
572 PHENYL ETHER
2. Kirwin CJ Jr, Sandmeyer EE: Ethers. In predominant effect was central nervous system
Clayton GD, Clayton FE (eds): Pattys depression, and death was due to paralysis of
Industrial Hygiene and Toxicology, 3rd ed, the respiratory muscles. Surviving animals
Vol 2A, Toxicology, pp 25412543. New York, exhibited a reversal of the depressant effect,
Wiley-Interscience, 1981 with increased central nervous system activity
3. Haworth S, Lawlor T, Mortelmans K et al:
manifested by hypersensitivity to sound,
Salmonella mutagenicity test results for 250
chemicals. Environ Mutagen 5(suppl 1):3142, muscle twitching, and tremor.
1983 No deaths were produced in mice exposed
4 hours, or rats exposed 8 hours, to saturated
vapors at room temperature.
Rats exposed for 7 hours/day for 50 days
to about 10 ppm showed no overt signs of tox-
PHENYL GLYCIDYL ETHER icity and no deaths, although a few animals,
CAS: 122-60-1 when euthanized, had mild pulmonary inam-
mation and nonspecic cellular changes in
C6H5OCH2CHOCH2 the liver.1,2 Exposure to 5 and 12 ppm PGE
30 hours/week for 13 weeks caused hair loss in
rats attributed to direct irritation of the skin
Synonyms: PGE; Phenoxypropenoxide; 2,3- rather than to systemic toxicity.3
epoxypropyl phenyl ether Chronic exposure of rats to 1 or 12 ppm
6 hours/day, 5 days/week for 2 years caused an
Physical Form. Colorless liquid increased incidence of rhinitis, squamous meta-
plasia, and epidermal carcinomas of the nasal
Uses. Chemical intermediate with high sol- cavity.4 The IARC has determined that there is
vency for halogenated materials sufcient evidence for the carcinogenicity of
PGE in animals and that it is possibly carcino-
Exposure. Inhalation genic to humans.5
Exposure of pregnant rats to 11.5 ppm
Toxicology. Phenyl glycidyl ether (PGE) is 6 hours/day on days 415 of gestation did not
an irritant of mucous membranes and skin and cause effects in mothers or their offspring.2
causes sensitization; it has caused nasal tumors Localized degeneration of the seminiferous
in experimental animals. tubules has been reported in some male rats
Of 20 workers exposed to PGE, 13 had exposed at this level.2,6
acute skin changes, including second-degree Direct application of PGE into rabbit eyes
burns, vesicular rash, papules, and edema.1 In produced irritation ranging from mild to severe
another study of 15 workers with PGE-induced without permanent damage.2
dermatitis, there was erythema with papules PGE was mutagenic in Salmonella
and vesicles.2 Of these 15 workers, 8 reacted typhimurium assays.
positively to patch tests. In addition to skin The 2003 ACGIH threshold limit value-
sensitization PGE can also cause cross- time-weighted average (TLV-TWA) for phenyl
sensitization with other glycidyl ethers. glycidyl ether is 0.1 ppm (0.6 mg/m3) with an
During animal exposure studies, techni- A3-animal carcinogen designation.
cians experienced irritation of the eyes, nose,
and respiratory tract.1,2
There are no reports describing systemic
REFERENCES
effects in humans, and the low vapor pressure
should limit the risk of acute inhalation 1. Hine CH, Kodama JK, Wellington JS, et al:
exposure.2 The toxicology of glycidol and some glycidyl
Intragastric LD50 values were 1.40 and ethers. AMA Arch Ind Health 14:250264,
3.85 g/kg, respectively, for mice and rats.1 The 1956
574 PHENYLHYDRAZINE
increased mortality, lower weight gain, liver were exposed to b-naphthylamine (a known
enlargement, and kidney lesions were found in carcinogen); 23 bladder tumors were observed
rats and mice receiving up to 40,000 ppm. vs. 10.3 expected, between 1946 and 1970,
Other effects in rats included hematopoietic among 2081 men exposed to material that con-
hypoplasia or atrophy of the femoral bone tained b-naphthylamine.1
marrow, testicular hypospermatogenesis, lym- An increased risk of death from bladder
phoid degeneration of the thymus, and lym- cancer (33 vs. 22.7 expected) was reported in
phoid depletion of the spleen. 40,000 rubber and cable workers who had
PBNA has been tested for carcinogenicity mixed exposures to many rubber additives,
in a number of species without conclusive including PBNA, but not to known carcino-
results. There was no evidence of carcinogenic gens.6 In contrast to this study, no signicant
activity in male or female rats or in male mice increases in overall or site-specic cancer was
fed 2500 or 5000 ppm in the diet for 2 years.2 detected in a cohort of 2410 rubber chemical
The lack of carcinogenicity in rats may be manufacturing workers, who were employed at
related to an inability to metabolize PBNA to a factory in north Wales, United Kingdom,
the known animal and human urinary bladder between 1955 and 1984.7
carcinogen b-naphthylamine. There was Additional concern has been afforded
equivocal evidence for carcinogenicity in PBNA because commercial PBNA contains
female mice, as indicated by the occurrence of 2030 ppm of b-naphthylamine.8 Furthermore,
two rare kidney tumors. Chemical-related non- experimental evidence from human volunteers
neoplastic lesions, including nephropathy, ingesting PBNA and workers inhaling PBNA
karyomegaly, and hyperplasia, occurred in the dust indicates that b-naphthylamine is a
kidneys of both species. metabolite of PBNA. Specically, 34 mg of b-
In a limited dog study, no bladder tumors naphthylamine was found in 24-hour samples
were observed in three animals fed 540 mg 5 of urine obtained from two volunteers who
days/week for a period of 4.5 years.3 ingested 50 mg PBNA containing 0.7 mg of b-
An increased incidence of carcinogenicity naphthylamine.9
has been observed in other studies. In one The IARC has concluded that there is
strain of male mice given 464 mg/kg/day by limited evidence for carcinogenicity to animals
stomach tube for 3 weeks followed by a diet of and inadequate evidence for humans.10 ACGIH
1206 mg/kg for 78 weeks, there was an considers PBNA to be a suspected human
increased frequency of tumor-bearing animals carcinogen because b-naphthylamine is both an
(7/17 vs. 0/16 for controls), with the increase impurity and a human metabolite of PBNA.8
being primarily due to hepatomas (5/17 vs. A numerical threshold limit value (TLV) is
0/16 for controls).4 A single subcutaneous not recommended for occupational exposure to
injection of 464 mg/kg PBNA to one strain of PBNA.
female mice on the 28th day of life increased
the total tumor incidence (5/18 vs. 9/154
for controls).4 Repeated subcutaneous injection
of 16 mg three times/week for 9 weeks REFERENCES
caused an increased incidence of carcinomas
of the lungs in treated mice (4/19 vs. 0/18 for 1. IARC Monographs on the Evaluation of Car-
controls).5 cinogenic Risk of Chemicals to Man, Vol 16,
No excess of bladder tumors was found in Some aromatic amines and related nitro
compounds, pp 325341. Lyon, International
men with known exposures to PBNA at a
Agency for Research on Cancer, 1978
rubber tire factory.6 From 1946 to 1970, there
2. National Toxicology Program: NTP Technical
were 9 cases of bladder cancer among 4177 Report on the Toxicology and Carcinogenesis
men vs. 10.0 expected; of these 4177 workers, Studies of N-Phenyl-2-Naphthylamine (CAS No
3301 had known exposures to PBNA. These 135-88-6) in F344/N Rats and B6C3F1 Mice
results contrast with those involving exposures (Feed Studies), NTP TR 333, NIH Pub No
before 1949, when workers at the factory also 88-2589, pp 161. Research Triangle Park,
578 PHENYLPHOSPHINE
respiratory disease. No evidence of increased 7. Polednak AP: Mortality among men occupa-
lung cancer mortality was found, but the small tionally exposed to phosgene in 19431945.
sample size was noted. Environ Res 22:357367, 1980
No chronic lung problems were found in 8. Cameron GR, Courtice FC, Foss GL, et al:
326 workers exposed to concentrations ranging First Report on Phosgene Poisoning: Part II. Min-
istry of Defence, UK Porton Report 2349,
from nondetectable to greater than 0.13 ppm.5
April 1942
Forty-one percent of animals exposed to
0.2 ppm 5 hours/day for 5 consecutive days
developed pulmonary edema.8 At 1 ppm,
lung lesions that would be likely to cause
serious clinical symptoms in humans were PHOSPHINE
observed.8 Splashes of liqueed phosgene in CAS: 7803-51-2
the eye may produce severe irritation.3 Skin
contact with the liqueed material may cause PH3
severe burns.3
The irritant properties of phosgene are not
sufcient to give warning of hazardous con- Synonyms: Hydrogen phosphide; phosphoret-
centrations. A trained observer can recognize ted hydrogen; phosphorus trihydride
0.5 ppm as being sweet, and, at about 1 ppm,
the odor becomes typical of the musty or new- Physical Form. Colorless gas
mown hay smell usually ascribed to phosgene.
Workers exposed to phosgene can lose their Uses. Insecticide used for fumigation; prepa-
ability to detect low concentrations through ration of phosphonium halides; doping agent in
olfactory fatigue. semiconductor manufacture
The 2003 ACGIH threshold limit value-
time-weighted average (TLV-TWA) for phos- Exposure. Inhalation
gene is 0.1 ppm (0.40 mg/m3).
Toxicology. Phosphine is a severe pul-
monary irritant.
REFERENCES Workers exposed intermittently to con-
centrations up to 35 ppm, but averaging below
1. Cucinell SA: Review of the toxicity of long- 10 ppm, complained of nausea, vomiting, diar-
term phosgene exposure. Arch Environ Health rhea, chest tightness and cough, headache, and
28:272275, 1974
dizziness; no evidence of cumulative effects was
2. Diller WF: Medical phosgene problems and
their possible solution. J Occup Med 20: noted.1 Single severe exposures cause similar
189193, 1978 signs and symptoms, as well as excessive thirst,
3. Hygienic Guide Series: Phosgene. Am Ind Hyg muscle pain, chills, sensation of pressure in the
Assoc J 29:308311, 1968 chest, dyspnea, syncope, and stupor.2 In a few
4. World Health Organization: Environmental cases of exposure, dizziness and staggering gait
Health Criteria 193: Phosgene, pp 15. Geneva, have also occurred.1 From 1900 to 1958 there
International Programme on Chemical Safety were 59 reported cases of phosphine poisoning
(IPCS), 1997 with 26 deaths; the effect most frequently
5. National Institute for Occupational Safety and reported was marked pulmonary edema.2 The
Health: Criteria for a Recommended Standard acute lethal effects of phosphine are associated
. . . Occupational Exposure to Phosgene. DHEW
with its ability to inhibit electron transport and
(NIOSH) Pub No 76-137, pp 43, 55.
Washington, DC, US Government Printing combine with heme iron in the presence of
Ofce, 1976 oxygen.3
6. Diller WF: Late sequelae after phosgene poi- Inhalation of phosphine released after
soning: A literature review. Toxicol Ind Health fumigation with aluminum phosphide on a
1:129136, 1985 grain freighter resulted in acute illnesses
PHOSPHORIC ACID 581
skin; the dust is especially irritating to skin in Phosphoric acid was not mutagenic in
the presence of moisture.1 bacterial assays.2
The hazards associated with occupational The 2003 threshold limit value-time-
exposure to phosphoric acid depend on its weighted average (TLV-TWA) for phosphoric
acidic nature.2 Concentrated phosphoric acid is acid is 1 mg/m3 with a short-term excursion
corrosive to exposed tissue, and lower concen- limit (STEL) of 3 mg/m3.
trations are irritating to the skin, eyes, and
mucous membranes. Phosphoric acid has a low
vapor pressure at room temperature and is
unlikely to present an inhalation hazard unless REFERENCES
introduced into the atmosphere as a spray or 1. Hygienic Guide Series: Phosphoric Acid. Am
mist.2 Unacclimated workers could not endure Ind Hyg Assoc Q 18:175176, 1957
exposure to fumes of phosphorus pentoxide 2. Commission of the European Communities
(the anhydride of phosphoric acid) at a Environmental Resources Limited: Occupa-
concentration of 100 mg/m3; exposure to tional Exposure Limits. Criteria Document for
concentrations between 3.6 and 11.3 mg/m3 Phosphoric Acid. pp 184. Ofce for Ofcial
produced cough, whereas concentrations of Publications of the European Communities,
0.85.4 mg/m3 were noticeable but not Luxembourg, Grand Duchy of Luxembourg,
uncomfortable.3 1992
It has been noted that phosphorus pentox- 3. ACGIH: Phosphoric acid. Documentation of
the TLVs and BEIs, 6th ed, pp 12501251.
ide is a powerful dehydrating agent that com-
Cincinnati, OH, American Conference of
bines with moisture in the respiratory tract
Governmental Industrial Hygienists, 1991
to produce phosphoric acid in an exothermic 4. MCA, Inc.: Chemical Safety Data Sheet SD-70,
reaction; because this reaction generates heat Phosphoric Acid, pp 56, 1213. Washington,
and desiccates tissues it contacts, it is likely to DC, MCA, Inc, 1958
cause more tissue damage than preformed 5. Checkoway H, et al: Mortality among workers
phosphoric acid.2 There is no evidence that in the Florida phosphate industry. II. Cause-
phosphorus poisoning can result from contact specic mortality relationships with work
with phosphoric acid.4 The risk of pulmonary areas and exposures. J Occup Med 27:
edema resulting from the inhalation of mist or 893896, 1985
spray is remote.4 A subcohort of workers from 6. Von Burg R: Toxicology update: Phosphoric
acid/phosphates. J Appl Toxicol 12:301303,
16 phosphate companies who were occupa-
1992
tionally exposed to unspecied amounts of
7. Grant WM: Toxicology of the Eye, 3rd ed,
phosphoric acid had no signicant increase in pp 733734. Springeld, IL, Charles C.
cause-specic mortality.5 Thomas, 1986
Ingestion of concentrated solutions can
produce nausea, vomiting, abdominal pain,
hematemesis, bloody diarrhea, and burns of the
mouth, esophagus, and stomach.6 In one case,
death occurred 19 days after ingestion as a
result of recurrent internal hemorrhage; at PHOSPHORUS (Yellow)
autopsy there was necrosis of the upper and CAS: 7723-14-0
lower digestive tract and of the pancreas.3 In
some cases signs of obstruction and scarring P4
may occur weeks to months after initial
exposure.6
A dilute solution buffered to pH 2.5 caused Synonyms: Phosphorus (white)
a moderate brief stinging sensation but no
injury when dropped in the human eye.7 A 75% Physical Form. Yellowish or colorless trans-
solution will cause severe skin burns.1 parent crystals that darken on exposure to light
PHOSPHORUS (Yellow) 583
P2S5
Toxicology. Phosphorus trichloride vapor is 1. MCA, Inc.: Chemical Safety Data Sheet SD-27,
a severe irritant of the eyes, mucous mem- Phosphorus Trichloride, pp 119. Washington,
branes, and skin. DC, MCA, Inc, 1972
2. Weeks MH: Acute vapor toxicity of phospho-
The irritant effects of phosphorus trichlo-
rus oxychloride, phosphorus trichloride and
ride result primarily from the action of the
methyl phosphonic dichloride. Am Ind Hyg
strong acids (hydrochloric acid and acids of Assoc J 25:470475, 1964
phosphorus) formed on contact with water.1 3. Wason S, Gomolin I, Gross P, et al: Phospho-
Inhalation by humans could be expected to rus trichloride toxicity, preliminary report. Am
cause injury ranging from mild bronchial J Med 77:10391042, 1984
spasm to severe pulmonary edema; the onset of
severe respiratory symptoms may be delayed
for 26 hours, and, after moderate exposure,
the onset may not occur until 1224 hours
later.1 Prolonged or repeated exposure to low
concentrations may induce chronic cough and PHTHALIC ANHYDRIDE
wheezing; pulmonary changes are nonbrotic CAS: 85-44-9
and nonprogressive.
Phosphorus trichloride causes severe burns C6H4(CO)2O
in contact with the eyes, skin, or mucous mem-
branes.1 Although ingestion is unlikely to occur
in industrial use, it will cause burns of the Synonyms: Phthalic acid anhydride; phthalan-
mouth, throat, esophagus, and stomach.2 dione; 1,3-isobenzofurandione
Seventeen people exposed to phosphorus
trichloride liquid and its hydration products Physical Form. White crystalline solid
after a tanker accident were evaluated.3 Those
closest to the spill experienced burning of Uses. Production of plasticizers for vinyl,
the eyes, lacrimation, nausea, vomiting, epoxy, and acetate resins; in alkyd resins;
dyspnea, and cough. Six patients had transient manufacture of dyes
elevation of lactic dehydrogenase. Chest roen-
tgenograms were normal. Pulmonary function Exposure. Inhalation
tests showed statistically signicant decreases
in vital capacity and FEV1 in direct correlation Toxicology. Phthalic anhydride is an irritant
with distance from the accident and duration of of the eyes, skin, and respiratory tract; it may
exposure. Of the 17 patients examined 1 also act as a sensitizer.
month later, pulmonary function tests In workers, air concentrations of 30 mg/m3
showed improvement, suggesting that acute (5 ppm) caused conjunctivitis; at 25 mg/m3
effects were due to phosphorus trichloride (4 ppm), there were signs of mucous membrane
toxicity.3 irritation.1 Workers exposed to undetermined
In rats, the LC50 was 104 ppm for 4 hours; concentrations of mixed vapors of phthalic acid
at autopsy, the chief nding was nephrosis; pul- and phthalic anhydride developed, in addition
monary damage was negligible.2 to conjunctivitis, bloody nasal discharge,
The 2003 ACGIH threshold limit value- atrophy of the nasal mucosa, hoarseness,
time-weighted average TLV-TWA for phos- cough, occasional bloody sputum, bronchitis,
phorus trichloride is 0.2 ppm (1.1 mg/m3) with and emphysema.2 Several cases of bronchial
m-PHTHALODINITRILE 587
2. Sunderman FW, Weidman FD, Batson OV: antagonism.1 Death in animals from chronic
Studies of the effects of ammonium picrate on exposure is due to multiple internal
man and certain experimental animals. J Ind hemorrhage.
Hyg Toxicol 27:241248, 1945 The 2003 ACGIH threshold limit value-
3. von Oettingen WF: The Halogenated Aliphatic,
time-weighted average (TLV-TWA) for
Olenic, Cyclic, Aromatic, and Aliphatic-
Aromatic Hydrocarbons Including the Halogenated pindone is 0.1 mg/m3.
Insecticides, Their Toxicity and Potential Dangers,
US Public Health Service Pub No 414, pp
150154. Washington, DC, US Government REFERENCE
Printing Ofce, 1941
4. Harris AH, Binkley OF, Chenoweth BM Jr: 1. US Department of Health, Education and
Hematuria due to picric acid poisoning at a Welfare: Operational Memoranda on Economic
naval anchorage in Japan. Am J Public Health, Poisons, Public Health Service, pp 8184.
36:727733, 1946 Atlanta, GA, Communicable Disease Center,
5. Grant WM: Toxicology of the Eye, 3rd ed. 1956
Springeld, IL, Charles C. Thomas, 1986
6. Wyman JF, Serve MP, Hobson DW, et al:
Acute toxicity, distribution, and metabolism of
2,4,6-trinitrophenol (picric acid) in Fischer
344 rats. J Toxicol Environ Health 37:313327,
1992 PIPERAZINE DIHYDROCHLORIDE
7. Kawai A, Goto S, Matsumoto Y, et al: Muta- CAS: 142-64-3
genicity of aliphatic and aromatic nitro com-
pounds. Sangyo Igaku 29(1):3455, 1987 C4H12N2Cl2
where the average concentration was 0.3 mg/ platinate and ammonium tetrachloroplatinate,
m3. It is unclear whether the total dose or the but not elemental platinum, may cause skin
brief high exposure was critical to asthma sensitization and a progressive allergic reaction
induction. that may lead to pronounced asthmatic
The systemic toxicity appears to be symptoms.
low; the oral LD50 for rats was approximately The signs and symptoms of hypersensitiv-
4.9 g/kg. ity include urticaria, contact dermatitis of the
The 2003 ACGIH threshold limit value- skin, and respiratory disorders ranging from
time-weighted average (TLV-TWA) for sneezing, shortness of breath, and cyanosis to
piperazine dihydrochloride is 5 mg/m3. severe asthma.1 The latency period from the
rst contact with platinum to the occurrence of
the rst symptoms varies from a few weeks to
REFERENCES several years.1
A syndrome characterized by runny nose,
1. ACGIH: Piperazine dihydrochloride. Docu- sneezing, tightness of the chest, shortness of
mentation of the TLVs and BEIs, 6th ed, pp
breath, cyanosis, wheezing, and cough has been
12761277. Cincinnati, OH, American
Conference of Governmental Industrial described after exposure to soluble complex
Hygienists, 1991 platinum salts and is referred to variously as
2. Criteria group for occupational standards: platinum allergy, platinum asthma, and plati-
Arbete och Hlsa 32:2241, 1985 (in Swedish) nosis.2,3 Of 91 men employed in four platinum
reneries and exposed to the dust or spray of
the complex platinum salts, 52 experienced
these symptoms.2 The severity of response was
greatest in workers crushing platinum salts,
PLATINUM (and Soluble Salts) where airborne levels reached 1.7 mg/m3. Thir-
CAS: 7440-06-4 teen of the men also complained of dermatitis.
Contact dermatitis has also been said to occur
Pt from exposure to platinum oxides and chlo-
rides.4 Removal from platinum salt exposure
results in almost immediate relief of asthma; the
Compounds: Ammonium chloroplatinate; dermatitis usually clears in 12 days but may be
sodium chloroplatinate; platinic chloride; plat- persistent.4 However, if long-duration exposure
inum chloride; sodium tetrachloroplatinate; occurs after sensitization, individuals may never
potassium tetrachloroplatinate; ammonium become completely free of symptoms.1
tetrachloroplatinate; sodium hexachloroplati- Smokers have been found to be at
nate; potassium hexachloroplatinate; ammo- increased risk of sensitization by platinum
nium hexachloroplatinate salts.5 An historical perspective cohort study of
91 platinum renery workers showed a four- to
Physical Form. Crystalline solids vefold risk of developing a positive skin test
to platinum salts in smokers. The risk of
Uses. Jewelry; oxygen sensor in internal smokers developing symptoms was approxi-
combustion engines; chemical and electrical mately twofold, and, among recent employees,
industries; dentistry; windings of high- the rate of development of a positive skin test
temperature furnaces; electroplating; photog- result was faster in smokers versus nonsmokers.
raphy; cancer chemotherapeutic agents Smoking is thought to act by increasing the
serum levels of IgE. In another report, 78
Exposure. Inhalation newly hired renery workers were followed for
24 months; platinum salt sensitivity developed
Toxicology. Exposure to the complex salts of in 41% of the new hires.6 Smoking was found
platinum, especially ammonium hexachloro- to increase the risk of platinum salt sensitivity
POLYBROMINATED BIPHENYLS 591
eightfold compared with not smoking and 4. Beliles RP: The metals. In Clayton GD,
being exposed to platinum salts above the Clayton FE (eds): Pattys Industrial Hygiene
threshold limit value (TLV) increased the risk and Toxicology, 4th ed, Toxicology, pp 219094.
by sixfold compared with exposures below the New York, Wiley-Interscience, 1991
TLV. 5. Venables KM, Dally MB, Nunn AF, et al:
Smoking and occupational allergy in workers
The assumption that platinosis is due to an
in a platinum renery. Br Med J 299:939942,
allergic response rather than to toxic or irritant 1989
effects is suggested by the following: (1) the 6. Calverley AE, Rees D, Dowdeswell RJ, et al:
appearance of sensitivity after previous expo- Platinum salt sensitivity in renery workers:
sure without apparent effect; (2) only a fraction incidence and effects of smoking and exposure.
of exposed persons exhibit a response; and Occup Environ Med 52(10):6616, 1995
(3) affected subjects show increasingly high 7. National Research Council: Platinum Group
degrees of sensitivity to small amounts.7 The Metals. Medical and Biologic Effects of Envi-
potent allergenicity of the divalent and tetrava- ronmental Pollutants, 232pp. Washington, DC,
lent platinum compounds is thought to occur National Academy of Sciences, 1977
by conjugation with sulfhydryl-containing 8. Murdoch RD et al: IgE antibody responses to
platinum group metals: A large scale renery
groups within proteins, thus forming immu-
survey. Br J Ind Med 43:3743, 1986
nogenic complexes.8 Complexes where there 9. Grant WM: Toxicology of the Eye, 3rd ed, p 748.
are no halogen ligands coordinated to plat- Springeld, IL, Charles C. Thomas, 1986
inum (nonhalogenated complexes), such as
K2[Pt(NO2)4], [Pt(NH3)4]C12, and [Pt(NH2)2
CS4]C12, and neutral complexes such as cis-
[PtC12(NH3)2], are not allergenic, because they
probably do not react with proteins to form a
complete antigen.1 POLYBROMINATED BIPHENYLS
Solid platinum wire or foil is considered to Hexabromobiphenyl: C12H4Br6
be biologically inert.1 Technical grades:
In the eyes, the dusts cause a burning FireMaster BP-6 (CAS: 59536-65-1)
sensation, lacrimation, and conjunctival hyper- FireMaster FF-1 (CAS: 67774-32-7)
emia, sometimes associated with photophobia.9
Several platinum compounds have been Octabromobiphenyl C12H2Br8
found to be mutagenic in bacterial assays.1 Technical grade:
The 2003 ACGIH threshold limit Bromkal 80 (CAS: 61288-13-9)
value-time-weighted average (TLV-TWA) is
1.0 mg/m3 for the metal dust and 0.002 mg/m3 Decabromobiphenyl C12Br10
for the soluble salts as Pt. Technical grade:
Flammex B-10 (CAS: 13654-09-6)
REFERENCES
Physical Form. Solids
1. World Health Organization: Environmental
Health Criteria(125) Platinum, 167pp. Geneva, Uses. Polybrominated biphenyls (PBBs) are
International Programme on Chemical Safety, compounds that were formerly used as ame
(IPCS) 1991 retardants in electrical products and in business
2. Hunter D, Milton R, Perry KMA: Asthma
machines and motor housings. There are 209
caused by the complex salts of platinum. Br J
Ind Med 2:9298, 1945 possible bromobiphenyl congeners, although
3. Parrot JL, Herbert R, Saindelle A, Ruff F: only a small number have been synthesized and
Platinum and platinosis, allergy and histamine used. All of the commercial products contained
release due to some platinum salts. Arch a mixture of several individual PBBs. Com-
Environ Health 19:685691, 1969 mercial production ceased in 1977.
592 POLYBROMINATED BIPHENYLS
Exposure. Inhalation; ingestion; skin absorp- neoplastic nodules of the liver in rats of both
tion sexes.5
In general, PBBs have been negative in
Toxicology. PBBs are animal carcinogens, genotoxic assays both in vivo and in vitro.4
with the liver being the main organ affected. The IARC considers that there is suf-
The majority of the human toxicity data of cient evidence that PBB is carcinogenic to
PBBs stem from studies carried out after experimental animals.6
accidental addition of PBBs to farm feed in Adverse effects on endocrine function and
Michigan in 1973, resulting in exposure of reproductive organs have been found in animal
large numbers of the rural population of studies, including blockage of implantation
Michigan by ingestion of PBB-contaminated when administered to rats on gestation days
food. Higher rates of dermatological, neuro- 014.4 Follow-up of a cohort of daughters born
logical, and musculoskeletal disorders were to mothers enrolled in the Michigan PBB
reported in a group of 933 Michigan farmers Exposure Registry found age at menarche was
and residents than in 229 unexposed Wiscon- approximately 6 months earlier for girls who
sin farmers considered as controls.1 These were in the upper decile of PBB exposure in
included rashes, acne, darkening or thickening utero and had been breast-fed compared with
of the skin, erythema, and hair loss. girls whose in utero exposure was less than or
A high prevalence of abnormal liver func- equal to 1 ppb.7
tions tests (SGOT and SGPT) was observed A threshold limit value-time-weighted
among 614 Michigan adults compared with average (TLV-TWA) for polybrominated
141 Wisconsin adults considered as controls.2 biphenyls has not been assigned.
A group of 55 workers who had been
employed in the Michigan plant producing REFERENCES
FireMaster BP-6 from 1970 to 1974 were
examined, and all were found to have serum 1. Anderson HS, Lilis R, Selikoff IJ, et al: Unan-
levels of PBBs greater than 1 mg/l.3 An ticipated prevalence of symptoms among dairy
increased prevalence of respiratory symptoms farmers in Michigan and Wisconsin. Environ
and skin disorders was seen in this group com- Health Perspect 23:217226, 1978
pared with the available data on PBB-exposed 2. Anderson HA, Holstein EC, Daum SM, et al:
farmers 1in Michigan. Liver function tests among Michigan and Wis-
Animal studies have shown that oral expo- consin dairy farmers. Environ Health Perspect
sure to FireMaster PBB causes a wasting syn- 23:333339, 1978
3. Anderson HA, Wolff MS, Fischbein A,
drome characterized by progressive decreased
Selikoff IJ: Investigation of the health status
weight gain, with immediate moderate to severe
of Michigan Chemical Corporation employ-
body weight loss generally preceding death.4 ees. Environ Health Perspect 23:187191, 1978
The thyroid gland is a target organ in 4. Agency for Toxic Substances and Disease
animals, although strong evidence for an effect Registry (ATSDR): Toxicological Prole for
in humans is lacking.4 In rats exposed for acute Polybrominated Biphenyls and Polybrominated
and intermediate durations, effects have been Diphenyls, pp 1448. Atlanta, GA, US Depart-
decreases in serum levels of thyroxine and tri- ment of Health and Human Services, Public
iodothyronine along with histologic and ultra- Health Service, 2002
structural changes in the thyroid. Hematologic 5. National Toxicology Program: Toxicology and
changes indicative of anemia have also been Carcinogenesis Studies of a Polybrominated
Biphenyl Mixture (Firemaster FF-1) in F344/N
reported as well as effects on the liver, skin, and
Rats and B6C3F1 Mice (Gavage Studies). Tech-
stomach.
nical Report Series No. 244. Springeld, VA,
When administered by oral gavage for 6 National Technical Information Service, US
months at 10 mg/kg, technical-grade hexabro- Department of Commerce, 1983
mobiphenyl (FireMaster FF-1) induced 6. IARC Monographs on the Evaluation of the Car-
hepatocellular carcinomas in mice and rats of cinogenic Risk of Chemicals to Humans, Vol 41,
both sexes and cholangiocarcinomas and Some halogenated hydrocarbons and pesticide
POLYTETRAFLUOROETHYLENE DECOMPOSITION PRODUCTS 593
REFERENCES
POTASSIUM HYDROXIDE
CAS: 1310-58-3 1. National Institute for Occupational Safety and
Health: Criteria for a Recommended Standard
KOH . . . Occupational Exposure to Sodium Hydroxide.
DHEW (NIOSH) Pub No 76-105, pp 2350.
Washington, DC, US Government Printing
Synonyms: Caustic potash; KOH Ofce, 1975
2. Grant WM: Toxicology of the Eye, 3rd ed, p 756.
Physical Form. White solid, usually as Springeld, IL, Charles C. Thomas, 1986
lumps, rods, or pellets 3. Criteria group for occupational standards:
Scientic basis for Swedish occupational
Uses. Strong alkali; manufacture of soft and standards XXI. Consensus report for potassium
liquid soaps; manufacture of potassium car- hydroxide. Arbete och Hlsa 22:1517, 2000
bonate for use in manufacture of glass
Exposure. Inhalation
10,000 ppm for 10 minutes or after exposure to literature. Forensic Sci Int 82(3):193200,
1,000 ppm 8 hours/day for 9 days. 1996
Intentional inhalation of 95% propane for 7. Moore AF: Final report of the safety assess-
approximately 1 minute produced feelings of ment of isobutane, isopentane, n-butane
euphoria, ataxia, and light-headedness; death, and propane. J Am Coll Toxicol 1:127142,
1982
possibly due to hypoxemia secondary to
8. Sandmeyer EE: Aliphatic hydrocarbons. In
propane inhalation, has been reported.4,5 A Clayton GD, Clayton FE (eds): Pattys Indus-
recent study has also suggested that propane trial Hygiene and Toxicology, 3rd ed, Vol 2B,
may have direct toxic effects (besides asphyxia Toxicology, pp 31813182. New York, Wiley-
from hypoxia) that may lead to death in some Interscience, 1981
cases.6 Specically, when some oxygen contin-
ues to be available during prolonged exposure
unconsciousness may be induced by direct
central nervous system suppressive effects of PROPANE SULTONE
propane. CAS: 1120-71-4
Guinea pigs exposed at 47,00055,000
ppm had tremors within 5 minutes and nausea, C3H6O3S
retching, and stupor after 30120 minutes. No
effects were observed in monkeys exposed to
approximately 750 ppm for 90 days.7 Synonyms: 1,3-Propane sultone; 3-hydroxy-1-
Direct contact with the liqueed product propanesulfonic acid sultone; 1,2-oxathrolane
causes burns and frostbite.8 2,2-dioxide
Propane is odorless, and atmospheres de-
cient in oxygen do not provide adequate Physical Form. White crystals or colorless
warning.1 liquid
The 2003 ACGIH threshold limit value-
time weighted average (TLV-TWA) for Uses. Chemical intermediate to confer water
propane is 2500 ppm (4508 mg/m3) solubility and anionic properties
Exposure. Inhalation
18 treated rats. A single intravenous dose Physical Form. Clear to slightly straw-
of 150 mg/kg in 32 rats caused the death of 1 colored liquid
rat with a brain tumor after 235 days and death
of 9 others with malignant tumors of a variety Uses. To prevent the hydrogen embrit-
of sites within 459 days. A single intravenous tlement of steel; as a corrosion inhibitor,
dose of 20 mg/kg given to pregnant rats on day solvent stabilizer, soil fumigant, and chemical
15 of gestation produced malignant neurogenic intermediate
tumors in some of the offspring.
Propane sultone is genotoxic in a wide Exposure. Inhalation; skin absorption
variety of in vitro assays; it also induces DNA
strand breaks in vivo in rodents.1 Toxicology. Propargyl alcohol is an irritant
The IARC has determined that there is of the eyes and the skin; atmospheric con-
sufcient evidence for carcinogenicity of centrations of the chemical, readily attain-
propane sultone in experimental animals and able under room conditions, are dangerous to
that it is possibly carcinogenic to humans.1 life even with exposures of short duration;
A 2003 ACGIH threshold limit value it is highly toxic when ingested and is easily
(TLV) has not been established. absorbed through the skin in toxic amounts.
No reports of adverse effects in humans are
available.
REFERENCES Two of three rats died after a 6-minute
exposure to an essentially saturated atmos-
1. IARC Monographs on the Evaluation of the Car- phere, whereas a 12-minute exposure was fatal
cinogenic Risk of Chemicals to Humans, Vol 71,
to all exposed animals.1 A 2-hour LC50 of 850
Re-evaluation of some organic chemicals,
hydrazine and hydrogen peroxide, pp 1095 ppm has been reported for both rats and mice.2
1102. Lyon, International Agency for Research Rats exposed to 80 ppm for 7 hours initially
on Cancer, 1999 appeared to have eye irritation and to be
2. Druckery H, et al: Carcerogene alkylierende lethargic.1 Repeated exposures to this con-
Substanzen. IV. 1,3-Propanesultone und 1,4- centration for 5 days/week over a period of
Butansulton. Z Krebsforsch 75:6984, 1970 3 months resulted in slight liver and kidney
3. Ulland B, et al: Carcinogenicity of the indus- changes. Males had increased liver weights, and
trial chemicals propylene imine and propane females had increases in both kidney and liver
sultone. Nature 230:460461, 1971 weights. Histopathologic examination showed
4. Van Durren BL, et al: Carcinogenicity degenerative changes in these organs, with
of isoesters of epoxides and lactones: Aziridine
females showing the most injury.
ethanol, propane sultone and related com-
pounds. J Natl Cancer Inst 46:143149, 1971 Oral LD50 values of 50 mg/kg for the
5. Druckery H, Kruse H, Preussman R: Propane mouse, 60 mg/kg for the guinea pig, and
sultone, a potent carcinogen. Nautrwiessen- 70 mg/kg for the rat have been reported.1
schaften 55:449, 1968 Hepatocytic megalocytosis and karyomegaly of
the renal tubular epithelial cells was observed
in rats dosed orally with 15 or 50 mg/kg for 13
weeks; some treatment-related mortality was
PROPARGYL ALCOHOL also reported in the high-dose group.3 Daily
CAS: 107-19-7 administration of 5 mg/kg for 13 weeks pro-
duced no apparent treatment-related effects.
C3H4O Applied to the skin of rabbits, propargyl
alcohol causes hyperemia, edema, and some
supercial necrosis.1 It is rapidly absorbed
Synonyms: Ethynol carbinol; acetylene through a skin of rabbits in lethal amounts,
carbinol; propiolic alcohol; 2-propyn-1-ol; with a LD50 of approximately 16 mg/kg. A
2-propynyl alcohol 10% solution is slightly irritating and may
PROPENE 599
Limited information is available on the trial Hygiene and Toxicology, 3rd ed, Vol 2B,
effects of chronic propene exposure. In mice, Toxicology, pp 31993201. New York, Wiley-
chronic exposure to minimal narcotic concen- Interscience, 1982
trations caused moderate to very slight fatty 2. Gibson GG, Clarke SE, Farrar D, et al:
degeneration of the liver.1,2 Propene. In Snyder R (ed): Ethel Brownings
Toxicity and Metabolism of Industrial Solvents,
No signicant evidence for propene car-
2nd ed, Vol I, Hydrocarbons, pp 354361.
cinogenicity was found in rats or mice exposed Amsterdam, Elsevier, 1987
by inhalation to 500010,000 ppm 6 hours/day 3. Reinhardt CF, Azar A, Maxeld ME, et al:
for 103 weeks.4 However, signs of nasal cavity Cardiac arrhythmias and aerosol snifng.
pathology were observed in rats, including an Arch Environ Health 22:265279, 1971
increased incidence of nonneoplastic lesions 4. Quest JA, Tomaszewski JE, Haseman JK, et al:
consisting of epithelial hyperplasia and squa- Two year inhalation study of propylene in
mous metaplasia. In addition, inammatory F344/N rats and B6C4F1 mice. Toxicol Appl
changes were noted, characterized by an inux Pharmacol 76:288295, 1984
of lymphocytes, macrophages, and granulo- 5. Maltoni C, Ciliberti A, Cerretti D: Experi-
cytes into the submucosa. A slight increase in mental contributions in identifying brain
potential carcinogens in the petrochemical
the incidence of vascular tumors was observed
industry. Ann NY Acad Sci 381:216249, 1982
in female mice. Other more limited animal 6. IARC Monographs on the Evaluation of Carcino-
studies also have failed to nd a carcinogenic genic Risks to Humans, Vol 60, Some industrial
response to propene.5 chemicals, pp 161180. Lyon, International
The IARC has determined that there is Agency for Research on Cancer, 1994
inadequate evidence in humans and in experi- 7. Criteria group for occupational standards:
mental animals for the carcinogenicity of Scientic basis for Swedish occupational
propene.6 Overall, propene is not classiable as standards XVII. Consensus report for
to its carcinogenicity to humans.6 propene. Arbete och Hlsa 25:716, 1996
Propene has been reported to be nonmu-
tagenic to both Escherichia coli and Salmonella
typhimurium, either with or without metabolic
activation; interestingly, the purported reactive b-PROPIOLACTONE
metabolite of propene, propene oxide, is widely CAS: 57-57-8
accepted as a mutagen.2,6 Furthermore,
propene oxide forms hemoglobin adducts in C3H4O2
exposed animals.6
Propene gas is not an irritant to the skin or
eyes, but direct contact with the liquid may Synonyms: BPL; 2-oxetanone; hydracrylic
cause frostbite.7 acid; b-lactone
An important factor in the use of propene
is the fact that explosive concentrations of the Physical Form. Colorless liquid
gas are reached well before any physiological
changes occur, and the gas or compressed Uses. Vapor sterilant and disinfectant; inter-
liquid should be handled according to strict mediate in the production of acrylic acid and
safety precautions. esters
According to the ACGIH propene is
classied as a simple asphyxiant. Exposure. Inhalation; skin absorption
cause permanent corneal opacication. In rats, Because of high acute toxicity and demon-
the 30-minute LC50 was 250 ppm whereas for strated skin tumor production in animals,
6 hours the LC50 was 25 ppm.2 Oral or intra- human contact by all routes should be avoided.1
peritoneal administration caused muscular The 2003 ACGIH threshold limit value-
spasms, respiratory difculty, convulsions, and time-weighted average (TLV-TWA) for b-pro-
death in rodents.1 Intravenous injection caused piolactone is 0.5 ppm (1.5 mg/m3) with an
kidney tubule and liver damage.1 A2-suspected human carcinogen designation.
BPL applied to mouse skin one to seven
times (over a period of 2 weeks) as undiluted
REFERENCES
BPL or in solutions of corn oil or acetone at
doses of 0.8100 mg caused skin irritation; the 1. US Department of Health and Human Ser-
effects ranged from erythema to hair loss and vices (NIOSH): Occupational safety and health
scarring.3 Lifetime painting (3 times/week) guidelines for chemical hazardsSupplement II
with acetone and corn oil solutions showed that OHG (Pub No. 89-104), pp 16. Occupational
BPL produced both papillomas and cancer of safety and health guideline for b propiolactone
the mouse skin; 0.25 mg in acetone caused potential human carcinogen. Cincinnati, OH,
papillomas in 12 of 30 animals and cancers in 1988
3, whereas 5 mg produced tumors in 21 of 30 2. ACGIH: b-Propiolactone. Documentation of
animals and cancers in 11. In corn oil, 0.8 mg TLVs and BEIs, 6th ed, pp 12921293. Cincin-
nati, OH, American Conference of Govern-
caused tumors in 27 of 30 mice; 12 of the
mental Industrial Hygienists, 1991
tumors were malignant.3 Papillomas developed
3. Palmes ED, Orris L, Nelson N: Skin irritation
in 11 of 90 and 14 of 80 of the acetone and corn and skin tumor production by b-propiolactone
oil control groups, respectively.3 (BPL). Am Ind Hyg J 23:257264, 1962
After weekly subcutaneous injection of 4. Van Duuren BL, et al: Carcinogenicity of
0.73 mg BPL in tricaprylin for 503 days, 89 epoxides, lactones, and peroxy compounds. IV.
mice developed brosarcomas, 3 adenocarci- Tumor response in epithelial and connective
nomas, 7 squamous cell carcinomas, and 3 tissue in mice and rats. J Natl Cancer Inst
squamous papillomas, all at the injection site. 37:825834, 1966
The number of months to the rst tumor was 5. Dickens F, Jones HEH: Carcinogenic activity
7, and no local tumors developed in 110 con- of a series of reactive lactones and related sub-
stances. Br J Cancer 15:85100, 1961
trols treated with tricaprylin alone for up to
6. IARC Monographs on the Evaluation of the Car-
581 days.4
cinogenic Risk of Chemicals to Humans, Vol 71,
All of 10 rats injected biweekly for 44 Re-evaluation of some organic chemicals,
weeks with 1 mg of BPL in arachis oil devel- hydrazine and hydrogen peroxide, pp
oped injection-site sarcomas; no local sarcomas 11031118. Lyon, International Agency for
were observed in 7 controls given repeated Research on Cancer, 1999
injections of 0.5 mg of arachis oil for 54 weeks.5
Repeated gastric administration of 10 mg
BPL/0.5 ml tricaprylin/week for 70 weeks
caused squamous cell carcinomas of the PROPIONIC ACID
forestomach in three of ve rats; there were CAS: 79-09-4
no tumors in controls treated with tricaprylin
alone.4 CH3CH2COOH
BPL is a direct-acting alkylating agent and
forms DNA adducts. It is mutagenic in a wide
variety of in vitro and in vivo systems, both in Synonyms: Methylacetic acid; ethylformic
somatic and germ cells.6 The IARC has deter- acid; ethanecarboxylic acid; propanoic acid
mined that BPL is carcinogenic in experimen-
tal animals and that it is possibly carcinogenic Physical Form. Colorless oily liquid with
to humans.6 pungent odor
602 n-PROPYL ACETATE
some animals within 4 days after exposure.1 produce mild irritation of the eyes, nose, and
Exposure for 5 hours caused narcosis and some throat.2
deaths in cats at 7400 ppm. Moderate irritation Mice exposed to 3250 ppm developed
and salivation were observed at 5300 ppm for ataxia in 90120 minutes, and prostration was
6 hours/day. evident in 165180 minutes; deep narcosis was
n-Propyl acetate has a pearlike odor, but manifest in 240 minutes at 4100 ppm.2 Expo-
the odor threshold has not been determined. sure to 13,120 ppm for 160 minutes or 19,680
The 2003 ACGIH threshold limit value- ppm for 120 minutes was lethal to mice.2 Expo-
time-weighted average (TLV-TWA) for n- sure of rats to 20,000 ppm for 1 hour resulted
propyl acetate is 200 ppm (835 mg/m3) with a in no mortalities during a 14-day postexposure
short-term excursion limit (STEL)/ceiling of observation period.2 n-Propyl alcohol is not
250 ppm (1040 mg/m3). appreciably irritating to the skin of rabbits even
after prolonged contact, but it can be absorbed
in signicant amounts if conned to the skin.
REFERENCE Application of 38 ml/kg/day for 30 days
resulted in death of one-third of the rabbits.2
1. Sandmeyer EE, Kirwin CJ: Esters. In Clayton Instilled in rabbit eyes, 0.1 ml produced
GD, Clayton FE (eds): Pattys Industrial Hygiene marked conjunctivitis, corneal opacities, and
and Toxicology, 3rd ed, Vol 2A, Toxicology, pp ulcerations.2
22732277. New York, Wiley-Interscience, In a limited study, lifetime administration
1981 of n-propyl alcohol by intubation or subcuta-
neous injection caused severe liver injury,
hematopoietic effects, and a number of malig-
nant tumors not found in controls.1 It was not
carcinogenic to mice in a skin painting assay.3
n-PROPYL ALCOHOL n-Propyl alcohol was not mutagenic in
CAS: 71-23-8 bacterial assays, nor did it induce micronuclei
or sister chromatid exchanges in cultured cells.3
CH3CH2CH2OH Administered to pregnant rats on days 1
19 of gestation for 7 hours/day concentrations
in excess of 5000 ppm produced congenital
Synonyms: 1-Propanol; n-propanol; propyl malformations in offspring and maternal toxi-
alcohol; ethyl carbinol city in dams.4
The odor threshold (40 ppm) and irritant
Physical Form. Clear liquid properties of n-propyl alcohol are expected to
prevent inadvertent exposure to hazardous
Uses. Solvent; organic syntheses concentrations.2
The 2003 ACGIH threshold limit value-
Exposure. Inhalation; minor skin absorption time-weighted average (TLV-TWA) for n-propyl
alcohol is 200ppm (492mg/m3) with a short-
Toxicology. n-Propyl alcohol is an irritant of term excursion limit (STEL)/ceiling of 250ppm
the eyes and mucous membranes. At high con- (614mg/m3) and a notation for skin absorption.
centrations it causes narcosis in animals, and it
is expected that severe exposure in humans will
produce the same effect.
REFERENCES
On the basis of acute animal studies, n-
propyl alcohol appears to be slightly more toxic 1. Gosselin RE, et al: Clinical Toxicology of Com-
than isopropyl alcohol. No chronic effects have mercial Products, 5th ed, p 218. Baltimore, MD,
been reported in humans, although a human Williams & Wilkins, 1984
fatality has been ascribed to ingestion.1 Expo- 2. Rowe VK, McCollister SB: Alcohols. In
sure to 400 ppm for 35 minutes will reportedly Clayton GD, Clayton FE (eds): Pattys Indus-
604 PROPYLENE DICHLORIDE
trial Hygiene and Toxicology, 3rd ed, Vol 2C, determined by laboratory tests (AST, ALT,
Toxicology, pp 45574561. New York, Wiley- total bilirubin, prothrombin); the patient re-
Interscience, 1982 covered after 3 weeks of hospitalization.1
3. Anonymous: 1-Propanol (April 1996). Berater- Guinea pigs repeatedly exposed to 2200
gremium fuer umweltrelevante Altstoffe (BUA) ppm for 7 hours developed severe conjunctival
190:1197, 1998
swelling, as well as signs of respiratory irrita-
4. Nelson BK, Brightwell WS, Krieg EF Jr:
Developmental toxicology of industrial alco- tion and incoordination; 11 of 16 animals died
hols: A summary of 13 alcohols administered after daily exposure and had severe liver injury
by inhalation to rats. Int J Occup Med Immun and some kidney injury.2 Rats dying from
Toxicol 5(1):2942, 1996 repeated inhalation of 1000 ppm showed weak-
ness, general debility, and signs of respiratory
irritation a few days before death; mice died
after a few hours of exposure to 1000 ppm.
In general, animals that survived 35 or more
PROPYLENE DICHLORIDE 7-hour exposures to 10002200 ppm showed
CAS: 78-87-5 no signicant lesions at autopsy.
At 400 ppm, rats, guinea pigs and dogs
C3H6Cl2 exposed for up to 140 daily 7-hour exposures
showed no adverse effects.3 There was a high
percentage of mortality among mice repeatedly
Synonyms: 1,2-Dichloropropane; propylene exposed to 400 ppm. In mice of a susceptible
chloride strain, hepatomas were found that were similar
histologically to those induced by carbon tetra-
Physical Form. Colorless liquid chloride. Oral administration of 100, 250, 500,
or 1000 mg/kg to rats for up to 10 days caused
Uses. Solvent; stain remover; chemical body weight loss and central nervous system
intermediate; fumigant depression.4 Morphologic changes in the liver
were apparent in the two highest-dosed groups.
Exposure. Inhalation Resistance to propylene dichloride hepatotoxi-
city over the 10 days of exposure was reected
Toxicology. Propylene dichloride is an eye by progressively lower serum enzyme levels
and respiratory irritant; at very high concen- and by decreases in the severity and incidence
trations it is a central nervous system depres- of toxic hepatitis and periportal vacuolization.
sant and may cause liver injury. Female rats given 250 mg/kg/day by
Ingestion or inhalation of high levels gavage for 103 weeks had a marginal, but
caused severe liver damage, acute renal failure, statistically signicant, increased incidence of
hemolytic anemia, and disseminated intra- adenomas of the mammary gland.5 A dose-
vascular coagulation in three reported cases.1 related increase in liver adenomas for both
Symptoms from inhalation included anorexia, male and female mice was observed with treat-
abdominal pain, vomiting, ecchymoses, and ment with 125 or 250 mg/kg/day for 103 weeks.
hematuria. In all cases, more than 24 hours The NTP concluded that there was equivocal
elapsed between exposure and onset of symp- evidence of carcinogenicity in female rats and
toms. Because 8090% of propylene dichloride some evidence of carcinogenicity in male and
and its metabolites are eliminated within 24 female mice.5
hours, analysis of blood, urine, and feces for Propylene dichloride was mutagenic in
solvent is useless once symptoms appear.1 various strains of Salmonella and in mouse
Workers tolerated short-term exposures to lymphoma cells, and it induced chromosomal
400500 ppm without apparent adverse effects. aberrations in Chinese hamster cells.6
Inhalation of a 98% solution over the course of No indication of teratogenic effects was
an evening resulted in acute liver damage, as observed in rats or rabbits administered propy-
PROPYLENE GLYCOL DINITRATE 605
lene dichloride by gavage during periods of 6. Agency for Toxic substances and Disease
major organogenesis.7 Developmental effects Registry (ATSDR): Toxicological Prole for
(delayed ossication of skull bones) were con- 1,2-Dichloropropane. 119pp. US Public Health
sidered to be secondary to maternal toxicity. Service, 1989
Administered in drinking water of rats for two 7. Kirk HD, Berdasco NM, Breslin WJ, et al:
Developmental toxicity of 1,2-dichloro-
generations, propylene dichloride did not
propane (PDC) in rats and rabbits following
effect fertility.8 It was not mutagenic in the oral gavage. Fundam Appl Toxicol 28(1):1826,
dominant lethal assay. 1995
Some skin absorption may occur; the 8. Hanley TR, Kirk HD, Johnson KA, et al:
dermal LD50 for rabbits was 8.75 ml/kg.1 The Propylene dichloride (PDC): A two-genera-
liquid is moderately irritating to the eye but tion reproductive toxicity and dominant lethal
does not cause serious or permanent injury.9 mutagenicity study in rats. Toxicologist
Repeated or prolonged skin contact with 12(1):200, 1992
propylene dichloride may result in skin irrita- 9. Hygienic Guide Series: Propylene dichloride.
tion due to defatting.9 Am Ind Hyg Assoc J 28:294296, 1967
The liquid has a characteristic unpleasant,
chloroform-like odor; human subjects
described the odor as strong at 130190 ppm
and not noticeable at 1523 ppm.9
The 2003 ACGIH threshold limit value- PROPYLENE GLYCOL DINITRATE
time-weighted average (TLV-TWA) for propy- CAS: 6423-43-4
lene dichloride is 75 ppm (347 mg/m3) with a
short-term excursion limit (STEL) of 110 ppm C3H6N2O6
(508 mg/m3).
level two of nine subjects reported mild disease on angiography, a nding suggestive of
headaches; seven of nine had headaches at vasoplastic etiology associated with PGDN
0.2 ppm that decreased dramatically with exposure in these cases.
repeat exposures. At this level most subjects Pregnancy outcomes in women munitions
could detect the odor for just 5 minutes. Pro- workers were investigated between 1980 and
gressive throbbing headaches were noted in 1983.5 Spontaneous abortions among all female
seven of nine volunteers exposed at 0.5 ppm, torpedo munitions workers were the same or
and after 6 hours one subject was dizzy and lower compared with hospital employees
nauseous. By 8 hours, three subjects had abnor- (enlisted female health care workers) or all
mal Romberg and heel-to-toe neurological other Navy women. There were no sponta-
tests and narrowed pulse pressures with an neous abortions among the few PGDN-
increase in diastolic pressure. Alteration in exposed pregnant women.
visual evoked response was the only other effect Acute LD50 values have been reported in
noted. At 1.5 ppm all eight subjects could various animal species.6 The oral LD50 in
detect odor, had eye irritations within 40 female rats was 1190 mg/kg; subcutaneous
minutes of exposure, and developed headaches. LD50 values in milligrams per kilogram were
The headaches were so severe that exposure 463 for female rats, 524 for male rats, 1208, for
was stopped at 3 hours. All symptoms resolved female mice, and 200300 for female cats. The
within the subsequent 8 hours. There was no LD50 in rats resulted in almost complete con-
biochemical or hematologic evidence of organ version of hemoglobin to methemoglobin, with
damage in the studied exposure range. lower conversion rates at lower doses. Death
A study of 87 naval employees chronically was due to anoxia. Methemoglobin levels were
exposed to PGDN noted acute headaches and not measured in the mice or cats, but premor-
nasal congestion of presumed vascular origin bid signs were consistent with methemoglo-
but no chronic cardiovascular or neurotoxic binemia in these species as well.
disorders.3 Twenty-nine subjects from this Blood pressure effects were recorded from
study group were tested before and immedi- cannulized femoral arteries in anesthetized rats
ately after PGDN exposure during torpedo after subcutaneous injection.6 Maximal falls in
maintenance procedure or turnaround. Signi- blood pressure occurred within 30 minutes
cant changes in oculomotor function tests of injection. Small responses were seen at the
were observed although peak airborne concen- 5 mg/kg level, but as the dose was increased
trations were below 0.2 ppm. Although changes marked hypotension occurred.
in these test scores were noted, there was no Continuous 90-day exposure studies were
correlation between exposure levels and bio- conducted in rats, guinea pigs, dogs, and
logical effects. The authors concluded that monkeys.7 At 10 ppm, dogs had hemosiderin
PGDN could exert acute neurophysiological deposits in the liver and similar pigment was
effects, but at this exposure level they were not found in the proximal convoluted tubules of the
functionally signicant. kidney. Guinea pigs showed foci of pulmonary
A cohort of 1352 male Navy torpedo muni- hemorrhage at 15 ppm, whereas monkeys had
tion workers exposed to PGDN between 1970 increased serum urea nitrogen and decreased
and 1979 had elevated rates and signicantly alkaline phosphatase, suggesting the possibility
elevated risks of angina pectoris and myocardial of renal damage at this level. At 35 ppm hemo-
infarction.4 The age-adjusted incidence rate for siderin deposits were found in the liver, spleen,
myocardial infarction was 18/10,000 in PGDN- and kidneys of dogs, female rats and four of
exposed workers vs. 8/10,000 for a group of nine monkeys. Methemoglobin values peaked
nonexposed torpedomen; for angina pectoris at week 2 with values of 20% in dogs and
incidence rates were 9.8/10,000 in exposed monkeys. No changes in behavior patterns
workers vs. 2.6/10,000 in nonexposed muni- were observed in monkeys trained to perform
tions workers. It was noted that two of the a visual discrimination test and exposed con-
angina cases had no coronary atheromatous tinuously to 35 ppm for 90 days.
PROPYLENE GLYCOL MONOMETHYL ETHER 607
Rabbit skin applications were made daily 5. Forman SA: A review of propylene glycol dini-
for a 20-day subacute study.7 At 1 g/kg there trate toxicology and epidemiology. Toxicol Lett
was reversible erythema and no signs of sys- 43:5165, 1988
temic effect. At 2 g/kg the rabbits appeared 6. Clark DG, Lichteld MH: The toxicology,
weak and slightly cyanotic and had rapid, metabolism, and pharmacological properties
of propylene glycol 1,2-dinitrate. Toxicol Appl
shallow breathing. At 4 g/kg, 13 of 14 animals
Pharmacol 15:175184, 1969
were dead by the fth application. Methemo- 7. Jones RA, Strickland JA, Siegal J: Toxicity of
globin was measured at 35% at death. Autop- propylene glycol 1,2-dinitrate in experimental
sies showed overall weight loss and dark, animals. Toxicol Appl Pharmacol 22:128137,
blue-gray internal organs, and the urinary 1972
bladder was markedly distended. The hemo-
globin and hematocrit values were depressed,
and urinary nitrates accounted for approxi-
mately 7% of the PGDN given at the 4 g/kg
level. PROPYLENE GLYCOL MONOMETHYL
Applied to rabbit eyes, 0.1 ml was only ETHER
slightly irritating and the irritation disappeared CAS: 107-98-2
within 24 hours.7
Negative results were reported in various C4H10O2
mutagenic assays including the Ames Salmo-
nella assay (with or without microsomal activa-
tion), sister chromatid exchange assay in mouse Synonyms: Propylene glycol methyl ether;
lymphoma cells, mouse bone marrow cyto- PGME; 1-methoxy-2-propanol; Dowanol PM
genic analysis, and mouse dominant lethal Glycol Ether; Propasol Solvent M; Poly-solv
assay.5 MPM Solvent
The 2003 ACGIH threshold limit value-
time-weighted average (TLV-TWA) for propy- Physical Form. Colorless liquid
lene glycol dinitrate is 0.05 ppm (0.34 mg/m3)
with a notation for skin absorption. Uses. Solvent
Exposure. Inhalation
REFERENCES
Toxicology. Propylene glycol monomethyl
1. Agency for Toxic Substances and Disease
ether (PGME) is low in systemic toxicity but
Registry (ATSDR): Toxicological Prole for Otto
Fuel II and Its Components. pp 1166, US causes irritation of the eyes, nose, and throat,
Department of Health and Human Services, with discomfort from the objectionable odor.
Public Health Service, 1995 In human studies, 100 ppm was reported
2. Stewart RD, Peterson JE, Newton PE, et al: as having a transient objectionable odor. At
Experimental human exposure to propylene 1000 ppm, there was irritation of the eyes, nose,
glycol dinitrate. Toxicol Appl Pharmacol 30:377 and throat and signs of central nervous system
395, 1974 impairment.1
3. Horvath EP, Ilka RA, Boyd J, et al: Evaluation The LC50 in rats was 10,000 ppm for 56
of the neurophysiologic effects of 1,2-propy- hours, with death caused by central nervous
lene glycol dinitrate by quantitative ataxia and
system depression.2 Rats and monkeys exposed
oculomotor function tests. Am J Ind Med 2:
for 132 daily exposures to 800 ppm over a
365378, 1981
4. Forman SA, Helmkamp JC, Bone CM: period of 186 days showed no evidence of
Cardiac morbidity and mortality associated adverse effects.
with occupational exposure to 1,2-propylene Exposure of rats to 3000 ppm 6 hours/day
glycol dinitrate. J Occup Med 29:445450, for a total of 9 days over an 11-day interval
1987 caused central nervous system depression that
608 PROPYLENEIMINE
C3H7N
REFERENCES
1. Stewart RD, Baretta ED, Dodd HC, Torkel- Synonyms: 2-Methylaziridine; 1,2-propy-
son TR: Experimental human exposure to leneimine; 2-methylethylenimine
PROPYLENE OXIDE 609
Physical Form. Flammable liquid 2. Carpenter CP, et al: The acute toxicity of
ethylene imine to small animals. J Ind Hyg
Uses. Intermediate in production of poly- Toxicol 30:26, 1948
mers, coatings, adhesives, textiles, and paper 3. Ulland B, et al: Carcinogenicity of industrial
nishes chemicals propylene imine and propane
sultone. Nature 230:460461, 1971
Exposure. Inhalation; skin absorption 4. Anonymous: CEC. The Toxicology of Chemicals.
1. Carcinogenicity Vol 1:153154, 1989.
Toxicology. Propyleneimine vapor is an eye 5. IARC Monographs on the Evaluation of the Car-
and respiratory tract irritant. It was carcino- cinogenic Risk of Chemicals to Humans, Vol 71,
genic to rats, the only species tested. Re-evaluation of some organic chemicals,
Inhalation may cause vomiting, breathing hydrazine and hydrogen peroxide. p 1497.
difculty, and irritation of eyes, nose, and Lyon, International Agency for Research on
throat; on prolonged exposure, vapors tend to Cancer, 1999
redden the whites of the eyes.1
Exposure of rats at 500 ppm for 4 hours
was fatal, but inhalation for 2 hours resulted in
no deaths.2 Rats given 20 mg/kg by gavage
twice weekly suffered from advanced accid PROPYLENE OXIDE
paralysis after 18 weeks, and the mortality rate CAS: 75-56-9
was high.3 At 10 mg/kg, paralysis occurred to a
lesser extent after 30 weeks. Granulocytic CH3CHOCH2
leukemia, squamous cell carcinoma of the ear
duct, and brain tumors (glioma) were observed
in the rats after 60 weeks at the 10 mg/kg dose; Synonyms: 1,2-Epoxypropane; propene oxide;
females showed mammary adenocarcinomas, a methyloxirane; propylene epoxide
number of which metastasized to the lung.3
Propyleneimine is DNA damaging and muta- Physical Form. Colorless liquid
genic to bacteria. In cultured mammalian cells
it induces cell transformations.4 Uses. Primarily as a chemical intermediate
No information is available to assess the to produce polyether polyols, propylene
carcinogenic risk to humans.5 The IARC has glycols and propylene glycol ethers; fumigant;
determined that there is sufcient evidence preservative
of carcinogenicity in animals and that propy-
leneimine is possibly carcinogenic to humans. Exposure. Inhalation
Instilled in the eye of a rabbit, a 5%
aqueous solution produced corneal damage.2 Toxicology. Propylene oxide is an irritant of
Contact with the liquid on the skin causes the eyes, mucous membranes, and skin. At high
burns, and burns of the mouth and stomach concentrations it causes narcosis in animals,
would be expected with ingestion.1 and it is expected that severe exposure will
The 2003 ACGIH threshold limit value- produce the same effect in humans. It is car-
time-weighted average (TLV-TWA) for cinogenic in experimental animals.
propyleneimine is 2 ppm (4.7 mg/m3) with an In direct contact with the skin or mucous
A2-suspected human carcinogen classication. membranes propylene oxide has an irritant or
corrosive effect, depending on the concentra-
tion; allergic contact dermatitis has been
REFERENCES reported, and corneal burns from the vapor
have also been described.1
1. Anonymous: 2-Methylaziridine. Dangerous The LC50 for rats exposed for 4 hours was
Properties of Industrial Materials Report, pp 4000 ppm; for mice, it was 1740 ppm.2 Rats and
8590. July/Aug 1987 guinea pigs exhibited irritation, dyspnea,
610 PROPYLENE OXIDE
drowsiness, weakness, and some incoordination ity at this dose, as indicated by increased inci-
at concentrations of 2000 ppm or more.3 Dogs dence of hemangiomas and hemangiosarcomas
exposed to 2030 ppm for 4 hours showed of the nasal turbinates. In the respiratory
lacrimation, salivation, nasal discharge, and epithelium of the nasal turbinates, propylene
vomiting, and there were some deaths.2 oxide also caused suppurative inammation,
Rats, guinea pigs, rabbits, and a monkey hyperplasia, and squamous metaplasia in rats
were given repeated (79 or more) 7-hour expo- and inammation in mice. The IARC has
sures to 457 ppm. Irritation of the eyes and determined that there is sufcient evidence for
respiratory passages was noted in the rats and carcinogenicity to animals.9
guinea pigs; rats had increased mortality due to One case-control study in humans found
pneumonia.3 There were no adverse effects on no signicant associations between exposure
the monkey or the rabbits.3 Rats exposed at and various cancers; no information was given
1500 ppm 6 hours/day, 5 days/week for 7 weeks on exposure levels or possible confounding
developed ataxia in the hind legs. The main effects of other exposures.9 The IARC has
pathologic change was axonal degeneration of determined that there is inadequate evidence in
the myelinated bers in both the hind leg nerve humans for the carcinogenicity of propylene
and the fasciculus gracilis.4 oxide but that it is possibly carcinogenic to
No signicant neurophysiological effects humans.9
(as determined by nerve conduction velocity Propylene oxide was mutagenic to yeast,
and neuropathology) were found in monkeys fungi, and bacteria. In mammalian cells in vitro
exposed at 100 or 300 ppm 7 hours/day, 5 it also induced DNA damage and gene muta-
days/week for 24 months.5 tion as well as sister chromatid exchange and
Rats exposed to 500 ppm 7 hours/day for 15 chromosomal aberrations.9 Propylene oxide
days 3 weeks before breeding and during gesta- forms adducts with proteins such as hemoglo-
tion had a signicant reduction in the numbers bin in a variety of species including humans.
of corpora lutea, implants, and live fetuses.6 For In mice the concentration of the N-terminal
pregnant rats exposed on gestation days 615, valine adduct of propylene oxide in hemo-
there were no exposure-related effects, except globin is linearly related to administered dose.
for an increased frequency of seventh cervical Aqueous solutions of 10% and 20% propy-
ribs in fetuses at the maternally toxic exposure lene oxide applied to the skin of rabbits caused
level of 500 ppm.7 In another report, inhalation hyperemia and edema when the duration of
exposure at levels up to 300 ppm over two gen- skin contact was 6 minutes or longer; severe
erations did not produce any adverse effects on exposures resulted in scar formation.3
reproductive function.8 Fetotoxicity was limited The odor has been described as sweet,
to minor skeletal abnormalities for exposed alcoholic, and similar to natural gas, ether, or
litters. Propylene oxide did not cause sperm benzene. The median detectable concentration
abnormalities in mice treated 7 hours/day for 5 is 200 ppm, which does not provide sufcient
days by inhalation.9 warning for prolonged or repeated exposures.2
Repeated subcutaneous administration of The 2003 ACGIH threshold limit value-
up to 2.5 mg/week for 95 weeks caused local time-weighted average (TLV-TWA) for propy-
sarcomas in mice.10 Administered by oral lene oxide is 20 ppm (48 mg/m3).
gavage to rats twice a week for 2 years, propy-
lene oxide caused a dose-dependent increase in
forestomach tumors, which were mainly
REFERENCES
squamous cell carcinomas.11
In inhalation studies, there was some evi- 1. International Labour Ofce: Encyclopaedia of
dence of carcinogenicity in rats exposed at 400 Occupational Health and Safety. 4th ed.
ppm, as indicated by an increased incidence of Volumes 14, p 104, Geneva, 1998.
papillary adenomas of the nasal turbinates.12 In 2. Jacobson KH, Hackley EB, Feinsilver L: The
mice, there was clear evidence of carcinogenic- toxicity of inhaled ethylene oxide and propy-
n-PROPYL NITRATE 611
In one anecdotal case a fatality was associ- Uses. Solvent; organic syntheses, especially
ated with pyrethrin inhalation.4 Death was agricultural chemicals
attributed to sudden irreversible bron-
chospasm. Exposure. Inhalation; skin absorption
Dogs fed pyrethrins at a dietary level of
5000 ppm for 90 days showed tremor, ataxia, Toxicology. Pyridine is an irritant and a
labored respiration, and salivation during central nervous system depressant; ingestion
the rst month of exposure.1 Rats given up to may cause liver and kidney damage.
5000 ppm in their diets for 2 years suffered no Chemical plant workers chronically
signicant effects on growth or survival but exposed to 612 ppm developed headache,
had slight liver damage.1 A daily gavage dose of vertigo, nervousness, sleeplessness, nausea, and
50, 100, or 150 mg/kg on days 615 of preg- vomiting.1 Similar symptoms have occurred in
nancy caused an increased incidence of resorp- workers repeatedly exposed to 125 ppm; in some
tions in rats compared with controls.4 cases, lower abdominal or back discomfort with
The 2003 ACGIH threshold limit value- urinary frequency was observed without associ-
time-weighted average (TLV-TWA) for ated evidence of liver or kidney damage.2
pyrethrum is 5 mg/m3. Serious liver and kidney injury has been
reported after oral administration of 1.82.5 ml
of pyridine daily for 2 months in the treatment
REFERENCES of epilepsy.3 Skin irritation may result from pro-
longed or repeated contact with the chemical.
1. Hayes WJ Jr: Pesticides Studied in Man, pp Exposure of rats to 23,000 ppm was lethal
7580. Baltimore, MD, Williams & Wilkins, in 1.5 hours, and exposure to 3600 ppm for 6
1982 hours was fatal to two of three rats tested.2 The
2. Hayes WJ Jr: Clinical Handbook on Economic
oral LD50 for rats was 1.58 g/kg; the dermal
Poisons. Emergency Information for Treating Poi-
LD50 was 12 ml/kg in guinea pigs.2 In the eye
soning. US Public Health Service Pub No 476,
pp 7476. Washington, DC, US Government of a rabbit, a 40% solution caused corneal
Printing Ofce, 1963 necrosis. In animals, inhalation of pyridine can
3. Casida JE (ed): PyrethrumThe Natural Insec- cause necrotic damage of the nasal epithelium
ticide, pp 123142. New York, Academic Press, and repeated feeding results in kidney and liver
1973 injury.2
4. Wax PM, Hoffman RS: Fatality associated In 2-year drinking water studies mice
with inhalation of a pyrethrin shampoo. J showed increased incidences of hepatocellular
Toxicol Clin Toxicol 32(4):457460, 1994 carcinomas and hepatoblastomas; male Fischer
5. Khera KS, Whalen C, Angers G: Teratogenic- 344 rats had increased incidences of renal
ity study on pyrethrum and rotenone (natural
tubule adenomas, and male Wistar rats showed
origin) and ronnel in pregnant rats. J Toxicol
evidence of interstitial cell adenoma of the
Environ Health 10:111119, 1982
testis.5 No increase in tumor incidence at any
site was observed in rats after chronic subcuta-
neous injection.6 The IARC has determined
that there is limited evidence in experimental
animals for the carcinogenicity of pyridine and
PYRIDINE that it is not classiable as to its carcinogenic-
CAS: 110-86-1 ity to humans.6 Pyridine was not genotoxic in
a variety of assays.6
NC5H5 Pyridine has an unpleasant odor detectable
at 1 ppm; the odor is objectionable to unaccli-
matized individuals at 10 ppm but does not
Synonyms: Azabenzene; azine provide sufcient warning of hazardous con-
centrations because olfactory fatigue occurs
Physical Form. Colorless liquid quickly.4
614 QUINONE
The 2003 ACGIH threshold limit value- Toxicology. Quinone affects the eyes.
time-weighted average (TLV-TWA) for Acute exposure causes conjunctival irrita-
pyridine is 5 ppm (16 mg/m3). tion and, in some cases, corneal edema, ulcer-
ation, and scarring; transient eye irritation may
be noted above 0.1 ppm and becomes marked
REFERENCES at 12 ppm.1 Chronic exposure causes the
gradual development of changes characterized
1. Teisinger J: Mild chronic intoxication with as 1) brownish discoloration of the conjunctiva
pyridine. J Ind Hyg Toxicol 30:58, 1948 and cornea conned to the intrapalpebral
2. Reinhardt CF, Brittelli MR: Heterocyclic
ssure, 2) small opacities of the cornea, and 3)
and miscellaneous nitrogen compounds. In
structural corneal changes that result in loss of
Clayton GD, Clayton FE (eds): Pattys Indus-
trial Hygiene and Toxicology, 3rd ed rev, Vol 2A, visual acuity.2,3 The pigmentary changes are
Toxicology, pp 27272731. New York, Wiley- reversible, but the more slowly developing
Interscience, 1981 structural changes in the cornea may progress.
3. Pollack LJ, Finkelman I, Arieff AJ: Toxicity of Although pigmentation may occur with less
pyridine in man. Arch Intern Med 71:95106, than 5 years of exposure, this is uncommon and
1943 usually is not associated with serious injury.
4. Santodonato J et al: Monograph on Human Skin contact may cause discoloration, ery-
Exposure to Chemicals in the Workplace: Pyridine. thema, swelling, and the formation of papules
Washington, DC, National Cancer Institute, and vesicles; prolonged contact may lead to
1985
necrosis. Systemic effects from industrial expo-
5. National Toxicology Program: Toxicology and
sure have not been reported.
Carcinogensis Studies of Pyridine(CAS 110-86-1)
in F344/N Rats, Wistar Rats, and B6C3F1 Mice Administration of large doses of quinone
(Drinking Water Studies) Technical Report to experimental animals caused local irritation,
Series 470, pp 1327, 2000 clonic convulsions, respiratory difculties,
6. IARC Monographs on the Evaluation of the Car- drop in blood pressure, and death due to
cinogenic Risk of Chemicals to Humans, Vol 77, paralysis of the medullary centers. In chronic
Some industrial chemicals, pp 503528. Lyon, studies, quinone has been tested in mice by skin
International Agency for Research on Cancer, application and inhalation and in rats by sub-
2000 cutaneous injection.4 The IARC has deter-
mined that there is inadequate evidence in
experimental animals for carcinogenicity of
quinone and that it is not classiable as to its
carcinogenicity to humans.5
QUINONE The odor and irritant properties do not
CAS: 106-51-4 provide adequate protection from levels capable
of producing chronic eye injury.1
C6H4O2 The 2003 ACGIH threshold limit value-
time-weighted average (TLV-TWA) for
quinone is 0.1 ppm (0.44 mg/m3).
Synonyms: p-Benzoquinone; 1,4-cyclohexadi-
endione; p-quinone
3. Anderson B, Oglesby F: Corneal changes from two neutrons), which are highly effective in
quinone hydroquinone exposure. AMA Arch damaging lung tissues. The decay rate of
Ophthalmol 59:495501, 1958 radioactive elements has traditionally been
4. IARC Monographs on the Evaluation of the Car- specied in curies (Ci). The curie is approxi-
cinogenic Risk of Chemicals to Man, Vol 15, Some mately 37 billion disintegrations (37 109 dis-
fumigants, the herbicides 2,4-D and 2,4,5-T,
integrations) per second. In discussing radon,
chlorinated dibenzodioxins and miscellaneous
industrial chemicals, pp 255261. Lyon, Inter- the picocurie (pCi) is used, where 1 pCi is equal
national Agency for Research on Cancer, 1977 to 1 10-12 Ci.
5. IARC Monographs on the Evaluation of the Car-
cinogenic Risk of Chemicals to Humans, Vol 71, Exposure. Inhalation (radon daughters
Re-evaluation of some organic chemicals, attach to lung tissue and decay, resulting in the
hydrazine and hydrogen peroxide, pp deposition of radiation, in the form of alpha
12451250. Lyon, International Agency for particles, in the lung tissue); ingestion of
Research on Cancer, 1999 radon-containing groundwater.
REFERENCES
Synonyms: Cyclonite; hexahydro-1,3,5-trini-
1. Agency for Toxic Substances and Disease Reg- tro-1,3,5-triazine; hexogen
istry (ATSDR). Toxicological Prole for Radon.
Atlanta, GA, US Department of Health and Physical Form. Colorless crystals
RESORCINOL 617
were exposed to 34 mg/m3 6 hours/day for 2 industrial toxicology and current industrial
weeks, no toxic effects were observed.1 exposure limits. Am Ind Hyg Assoc J 37:596
Repeated gavage doses ranging from 606, 1976
55 mg/kg/day to 450 mg/kg/day, 5 days/week, 2. Strakosch EA: Studies on ointments: Oint-
ments containing resorcinol. Arch Dermatol
for 2 weeks caused tachypnea and hyperex-
Syph 48:393, 1943
citability within 30 minutes of dosing to 3. Deichmann WB, Keplinger ML: Phenols
F344/N rats.4 In 13-week studies rats given 65 and phenolic compounds. In Clayton GD,
mg/kg/day or more had increased liver weights, Clayton FE (eds): Pattys Industrial Hygiene and
whereas mice had signicantly reduced adrenal Toxicology, 3rd ed, rev, Vol 2A, Toxicology, pp
weights when administered 28 mg/kg/day or 25862589. New York, Wiley-Interscience,
more for the same period.4 There was no evi- 1981
dence of carcinogenicity in rats or mice receiv- 4. National Toxicology Program: Toxicology and
ing up to 225 mg/kg/day, 5 days/week, for 2 Carcinogenesis Studies of Resorcinol (CAS No.
years.4 In a dermal oncogenicity study, three 108-46-3) in F344/N Rats and B6C3F1 Mice
groups of female Swiss mice were treated with (Gavage Studies). NTP Technical Rep No. 403,
Pub No. 92-2858. Research Triangle Park,
0.02 ml of 5%, 25%, and 50% solutions of
NC, US Department of Health and Human
resorcinol in acetone twice weekly for 100 Services, Public Health Service, National
weeks.5 The percentage of tumor-bearing Institutes of Health, National Toxicology
animals was similar in the resorcinol-treated, Program, 1992
untreated, and acetone-treated groups. Under 5. Stenback F, Shubik P: Lack of toxicity and car-
the conditions of the test, resorcinol was con- cinogenicity of some commonly used cuta-
sidered noncarcinogenic. neous agents. Toxicol Appl Pharmacol 30:713,
The IARC has determined that there is 1974
inadequate evidence for the carcinogenicity of 6. IARC Monographs on the Evaluation of the Car-
resorcinol in animals and that it is not classi- cinogenic Risk of Chemicals to Humans, Vol 71,
able as to its carcinogenicity in humans.6 Re-evaluation of some organic chemicals,
hydrazine and hydrogen peroxide, pp 1119
Resorcinol was not genotoxic in bacterial
1125. Lyon, International Agency for Research
assays or in in vivo mammalian assays; it did on Cancer, 1999
cause chromosomal aberrations in human lym- 7. Estable JJ: The ocular effect of several irritant
phocytes in vitro but not in cultured human drugs applied directly to the conjunctiva. Am
broblasts.6 J Ophthalmol 31:837, 1948
A 10% solution in rabbit eyes has caused 8. DiNardo JC, Picciano JC, Schnetzinger RW,
pain, conjunctivitis, and corneal vasculariza- et al: Teratological assessment of ve oxidative
tion.7 Dry, powdered resorcinol applied to hair dyes in the rat. Toxicol Appl Pharmacol
rabbit eyes has caused necrosis and corneal per- 78:163166, 1985
foration.
No evidence of teratogenicity was found in
rats receiving up to 250 mg/kg/day on days
615 of gestation.8 This dose was maternally
toxic, causing reduced body weight.
The 2003 ACGIH threshold limit value- RHODIUM (and Compounds)
time-weighted average (TLV-TWA) for resor- CAS: 7440-16-6
cinol is 10 ppm (45 mg/m3) with a short-term
excursion limit (STEL) of 20 ppm (90 mg/m3). Rh
Synonym: O, O-Dimethyl-O-(2,4,5-trichlo-
rophenyl) phosphorothioate; Fenchlorfos
REFERENCES
Physical Form. White, crystalline powder 1. McCollister DD, Oyen F, Rowe VK: Toxico-
logical studies of O,O-dimethyl-O-(2,4,5-
Uses. Systemic insecticide in livestock trichlorophenyl) phosphorothioate (ronnel) in
laboratory animals. J Agric Food Chem 7:689
693, 1959
Exposure. Inhalation; ingestion 2. Worden AN et al: Effect of ronnel after
chronic feeding to dogs. Toxicol Appl Pharma-
col 23:19, 1972
Toxicology. Ronnel is a weak cholinesterase
3. Khera KS, Whalen C, Angers G: Teratogenic-
inhibitor and has low toxicity. ity study on pyrethrum and rotenone (natural
On both single and repeated doses, ronnel origin) and ronnel in pregnant rats. J Toxic
affects the pseudoesterase of the plasma rather Environ Health 10:111119, 1982
than the true acetylcholinesterase of the red
blood cells.1
In an experiment on humans to evaluate
the primary skin irritating and skin sensitizing
potential of ronnel, 50 subjects received three ROTENONE
applications/week for 3 weeks of gauze satu- CAS: 83-79-4
rated with a 10% suspension of ronnel in
sesame oil; there were no signicant effects on C23H22O6
the skin.1
In male rats, the oral LD50 was 1.7 g/kg;
effects were salivation, tremor, diarrhea, Synonyms: Derrin; nicouline, tubatoxin
miosis, and respiratory distressall attributed
to the anticholinesterase effect of ronnel.1 Rats Physical Form. Colorless crystals
fed 50 mg/kg body weight in the diet for 105
days developed slight liver and kidney damage. Uses. Insecticide; lotion for chiggers;
Dogs fed 10 mg/kg/day for 2 years showed emulsion for scabies
no overt clinical signs or evidence of any effect
on urinalysis, hematologic analysis, organ Exposure. Inhalation; ingestion
weight measurement, or histologic evaluation
of the tissues; depression of plasma choline- Toxicology. Rotenone is an irritant and af-
sterase was the only signicant nding.2 fects the nervous system, causing convulsions.
When a small amount of ronnel powder The lethal oral dose in humans is estimated
was placed in the eye of a rabbit, effects were to be 0.30.5 g/kg.1 Symptoms of inhalation,
slight discomfort and transient conjunctival absorption, or ingestion in humans (inferred
irritation, which subsided within 48 hours.1 mostly from animal studies) may include
Daily oral administration of 600 or 800 numbness of oral mucous membranes, nausea,
mg/kg ronnel to dams on days 6 through 15 of vomiting, abdominal pain, muscle tremor,
gestation caused a signicant dose-related incoordination, clonic convulsions, and
increase in fetuses with an extra rib.3 stupor.1 Local effects from the dust include
ROTENONE 621
inadequately leached products. These gloves Physical Form. Elemental selenium occurs
contained unprecedented concentrations of as gray to black crystals; many compounds are
protein allergens, which sensitized thousands. solids, although hydrogen selenide is a color-
During the late 1980s, an oversupply of gloves less gas.
occurred, prices plummeted, and many new
manufacturers went out of business. However, Uses. In electronics; selenium rectiers and
a newly sensitized population continues to have photocells; used to coat the metal cylinders
problems even with high-quality products. from which a photographic image is transferred
in xerography; glass and ceramics manufacture
(exposure also may occur during smelting and
REFERENCES rening of ores containing selenium)
recoveries. There have been no reports of and liver tumors in female mice.12 Mutagenic
disabling chronic disease or death from indus- and antimutagenic effects of selenium also have
trial exposure. been reported.11,13
An accidental spray of selenium dioxide (See separate entries on selenium hexau-
into the eyes of a chemist caused supercial oride and hydrogen selenide.)
burns of the skin and immediate irritation of The 2003 ACGIH threshold limit value-
the eyes. Within 16 hours, the subjects vision time-weighted average (TLV-TWA) for sele-
was blurred and the lower portions of both nium and compounds is 0.2 mg/m3, as Se.
corneas appeared dulled. Sixteen days after the
accident, the corneas were normal.6
Elemental selenium is not particularly irri- REFERENCES
tating, but various compounds such as selenium
oxychloride and selenium dioxide are strong 1. Barceloux DG: Selenium. J Toxicol Clin Toxicol
vesicants.7 Skin contact with the fume of heated 37(2):14572, 1999
selenium dioxide caused an acute, weeping 2. Clinton M Jr: Selenium fume exposure. J Ind
Hyg Toxicol 29:225226, 1947
dermatitis, with the development of hypersen-
3. Wilson HM: Selenium oxide poisoning.
sitivity in some cases.8 Selenium dioxide forms
JAMA 180(8):173174, 1962
selenious acid when in contact with water; if 4. Glover JR: Selenium and its industrial toxi-
allowed to penetrate beneath the ngernails, cology. Ind Med Surg 39:5054, 1970
it causes an especially painful inammatory 5. Yang G, Wang S, Zhou R, et al: Endemic
reaction.8 selenium intoxication of humans in China.
In livestock, selenium has been found to be Am J Clin Nutr 37:872881, 1983
the cause of blind staggers and alkali disease. 6. Middleton JM: Selenium burn of the eye.
Blind staggers occurs as a result of acute inges- AMA Arch Ophthalmol 38:806811, 1947
tion of seleniferous plants and is characterized 7. Wilber CG: Toxicology of selenium: A
by impaired vision, depressed appetite, a ten- review. Clin Toxicol 17:171230, 1980
8. Committee on Medical and Biological Effects
dency to wander in circles, paralysis, and death
of Environmental Pollutants, National
from respiratory failure.9 A more chronic syn-
Research Council: Selenium. pp 116118.
drome described in horses and livestock is Washington, DC, National Academy of
alkali disease, which also is associated with con- Sciences, 1976
sumption of grains or plants containing sele- 9. Hogberg J, Alexander J: Selenium. In Friberg
nium. The disease is characterized by lack of L et al (eds): Handbook on the Toxicology of
vitality, loss of appetite, emaciation, deformed Metals, 2nd ed, Vol II, Specic metals, pp
hoofs, loss of hair, erosion of the joints of long 482520. Amsterdam, Elsevier, 1986
bones, anemia, cirrhosis, and cardiac atrophy.9 10. Domingo JL: Metal-induced developmental
In a number of reproductive studies in toxicity in mammals: a review. J Toxicol
mammals, using a variety of selenium com- Environ Health 42:123141, 1994
11. Agency for Toxic Substances and Disease
pounds, adverse effects have only been seen
Registry (ATSDR): Toxicological Prole for
at doses that are associated with maternal
Selenium, 389pp. US Department of Health
toxicity10,11 and Human Services, Public Health Service,
Epidemiological studies in humans do not 2001
suggest an association between excess exposure 12. National Cancer Institute: Bioassay of Sele-
to selenium and cancer.11 Low levels of intake, nium Sulde (Gavage) for Possible Carcinogenic-
however, have been associated with an ity, DHHS (NIH) Pub No 80-1750, 130pp.
increased risk of developing many kinds of Washington, DC, US Governmental Print-
cancers. With the exception of selenium ing Ofce, 1980
sulde, most animal studies have shown that 13. Shamberger RJ: The genotoxicity of sele-
selenium compounds inhibit tumorigenesis.11 nium. Mutat Res 154:2948, 1985
High doses of selenium sulde administered by
gavage caused liver tumors in rats and lung
SILICA, AMORPHOUSDIATOMACEOUS EARTH 625
quartz, which is reduced to silicon monoxide, ray. Over a period of 26 years after rst diag-
escaping from the furnace and oxidized by air nosis, 22 cases remained static, regressed, or
to silicon dioxide. This condenses to form returned to normal; 8 cases progressed with
spherical particles. For the production of fer- increased brosis and nodulation by X ray.46
rosilicon, iron metal is added to the charge; Autopsy of cases of alleged silicosis in
during charging there is also exposure to Swedish ferrosilicon workers revealed no
crystalline silica.1 silicosis, and it was postulated that pulmonary
conditions that had been recognized by X
Uses. None; produced only as a by-product. ray may have been due to unspecied infec-
tious changes.7 This study also concluded that
Exposure. Inhalation exposure to fumes and dust particles, for the
most part amorphous SiO2, in ferrosilicon alloy
Toxicology. Amorphous silica fume expo- melting works, does not seem to give rise to a
sure is associated with recurrent fever, similar serious risk of silicosis although the additional
to metal fume fever, and nonprogressive pul- handling of quartz in this industry certainly
monary changes. constitutes a grave risk of silicosis.
Adverse effects on the lungs of workers More recently, the importance of silica
exposed to the fumes of ferrosilicon furnaces fume particle size on toxicity has been noted.8
have been recognized since 1937. Subsequent Specically, particles of the ultrane size range
clinical studies of workers exposed to amor- may be expected to have higher toxicity com-
phous silica fume in silicon and ferrosilicon pared with particles of larger size.
plants reported pulmonary symptoms and The 2003 ACGIH threshold limit value-
X-ray ndings difcult to differentiate from time-weighted average (TLV-TWA) for amor-
classic silicosis due to crystalline silica, es- phous silica fume is 2 mg/m3 for the respirable
pecially because there is often concurrent fraction of dust.
exposure to quartz dust during furnace
operations.14
The disease process in workers exposed to REFERENCES
silica fume was originally described as silicosis
or acute silicosis, but it is now recognized that 1. ACGIH: Silica, amorphousfume. Documen-
the X-ray pattern and symptom complex are tation of the Threshold Limit Values and Biologi-
different from both, the severity of the symp- cal Exposure Indices, 7th ed, p 4. Cincinnati,
OH, American Conference of Governmental
toms is less, and there is apparently no pro-
Industrial Hygienists, 2001
gression. It has been postulated that heavy
2. Princi F, Miller LH, Davier A, Cholak J: Pul-
exposure to freshly formed silica fume causes monary disease of ferroalloy workers. J Occup
an acute reaction similar to metal fume fever. Med 4:301310, 1962
Continued or repeated exposure causes the 3. Vitums VC, Edwards MJ, Niles NR, Borman
ferroalloy disease, which has been JO: Pulmonary brosis from amorphous silica
described.1,2,5 This is characterized by recurrent dust. A product of silica vapor. Arch Environ
fever over a period of 312 weeks, with the Health 32:6268, 1977
appearance of X-ray markings similar to silico- 4. Davis JCA: Inhalation hazards in the manu-
sis. The development of classic silicosis may facture of silicon alloys. Cent Afr J Med 20(7):
be the result of long, continued exposure to 140, 1974
5. Taylor DM, Davies JCA: Ferro-alloy workers
amorphous silica fume, or possibly concurrent
disease. A report of a recent case against the
exposure to crystalline silica.1,5
background of twelve years experience. Cent
Of 900 African production workers in a Afr J Med 23:28, 1977
ferroalloy plant, 35 cases of ferroalloy worker 6. Bowie DS: Ferro-alloy workers disease. Cent
disease were identied over a 10-year period. Afr J Med 24(5):81, 1978
These were either acute episodes of metal fume 7. Swenson A, Kvarnstrom K, Bruce T, et al:
fever or pulmonary brosis recognized by X Pneumoconiosis in ferrosilicon workersA
628 SILICA, CRYSTALLINEQUARTZ
follow-up study. J Occup Med 13:427432, Histologically, the silicotic nodule consists
1971 of a relatively acellular, avascular core of
8. Cunningham EA, Todd JJ, Jablonski W: Was hyalinized reticulin bers arranged concentri-
there sufcient justication for the 10-fold cally and blending with collagen bers
increase in the TLV for silica fume? A critical toward the periphery, which has well-dened
review. Am J Ind Med 33(3):21223, 1998
borders.3
The clinical signs and symptoms of silico-
sis tend to be progressive with continued expo-
sure to quantities of dust containing free silica,
with advancing age, and with continued
SILICA, CRYSTALLINEQUARTZ smoking habits.1 Symptoms may also be exac-
CAS: 14808-60-7 erbated by pulmonary infections and cardiac
decompensation. Symptoms include cough,
SiO2 dyspnea, wheezing, and repeated nonspecic
chest illnesses. Impairment of pulmonary func-
tion may also be progressive. In individual
Synonyms: Silicon dioxide; silicic anhydride cases, there may be little or no decrement when
simple discrete nodular silicosis is present, but
Physical Form. Colorless crystals when nodulations become larger or when con-
glomeration occurs, recognizable cardiopul-
Uses. Manufacture of glass, porcelain, and monary impairment tends to occur.
pottery; metal casting; sandblasting; granite The progression of symptoms may con-
cutting; manufacture of refractory, grinding, tinue after dust exposure ceases. Although
and scouring compounds there may be a factor of individual susceptibil-
ity to a given exposure to silica dust, the risk of
Exposure. Inhalation onset and the rate of progression of the pul-
monary lesion are clearly related to the char-
Toxicology. Crystalline silica causes silicosis acter of the exposure (dust concentration and
and is associated with an increased risk of lung duration).1 The disease tends to occur after an
cancer. exposure measured in years rather than in
Silicosis is a form of disabling, progressive, months. It is generally accepted that silicosis
and sometimes fatal pulmonary brosis charac- predisposes to active tuberculosis and that
terized by the presence of typical nodulation the combined disease tends to be more rapidly
in the lungs.1 The earliest lesions are seen in progressive than uncomplicated silicosis.
the region of the respiratory bronchioles. Lym- The earliest radiographic evidence of
phatics become obliterated by inltration nodular silicosis consists of small, discrete
with dust-laden macrophages and granulation opacities of 1- to 3-mm diameter appearing in
tissue. Morphologically, the typical lesion of the upper lung elds. As the disease advances,
silicosis is a rm nodule composed of concen- discrete opacities increase in number and size
trically arranged bundles of collagen; these and are seen in the lower as well as the other
nodules usually measure between 1 and 10 mm zones of the lung elds. Small conglomerations
in diameter and appear around blood vessels may then appear, subsequently developing into
and beneath the pleura, as well as in mediasti- large, irregular, and sometimes massive opaci-
nal lymph nodes. There may be conglomera- ties occupying the greater part of both lung
tion of nodules as the disease progresses, elds. Bullae may be seen in the vicinity of
leading to massive brosis.1 The pulmonary conglomerations.2
pleura is usually thickened due to brosis and A group of 972 granite shed workers were
is often adherent to the parietal pleura, espe- studied to relate exposure levels to incidence of
cially over the upper lobes and in the vicinity silicosis.4 The workers were grouped according
of underlying conglomerate lesions.2 to four average exposure levels: 1) 3760, 2)
SILICA, CRYSTALLINEQUARTZ 629
2744, 3) 20, and 4) 39 mppcf. Those with the cant numbers of excess deaths or cases of renal
highest dust exposure showed development of disease or subclinical renal changes.8
early silicosis in 40% of the workers after 2 A large number of studies have been con-
years and 100% after 4 years of exposure. The ducted in an effort to assess the role of silica
development of silicosis in the remaining exposure in the pathogenesis of lung cancer.810
workers appeared to be proportional to the Some studies of mining, quarry, tunnel, and
dust exposure. At the second-highest exposure foundry workers have shown moderately raised
level (2744 mppcf ), early stages of silicosis standardized mortality ratio (SMRs) for lung
appeared after 4 years of exposure and more cancer, ranging from 127 to 156.11 However,
advanced stages developed by the seventh year. the role of smoking or other contributing
In the group exposed at an average of 20 mm, factors, such as radon exposure, cannot be
there was little indication of severe effects excluded, and other large cohort studies
on the health of the workers. In the lowest- have not found any increased risk for lung
exposure group, where the average dust con- cancer.
centration was 6 mm (range 39 mppcf), there Cohort and case control studies on regis-
was no indication of any untoward effects of tered silicotics reported excess lung cancer
dust exposure on workers. risks, with relative risks ranging from 1.5 to
Exposures to relatively low concentrations 6.0.9 Excesses were seen across countries,
of silica for a prolonged period may be capable industries, and time periods, and a number of
of causing hilar node brosis, impairing the studies reported exposure-response gradients,
clearance of any silica inhaled subsequently. In using varying indicators of exposure. Meta-
one case, 30 years of exposure to <0.1 mg/m3 analyses of the epidemiological studies of silica
led to hilar node brosis and calcication in an exposure and lung cancer reported a moderate
exposed stonemason; subsequent exposure for summary risk of 1.3 for silica-exposed workers
5 years to about 2 mg/m3 led to rapid, progres- and higher summary relative risks of 2.22.3
sive silicosis that proved fatal. Estimates of for studies of silicotic workers.8
exposure tallied with postmortem measure- In animal studies, signicant increases in
ment of lung burden, suggesting retention of adenocarcinomas and squamous cell carcino-
all dust deposited in the lungs over his nal mas of the lung have occurred in rats after
period of work.5 inhalation or intratracheal instillation in rats,
In some occupations, such as sandblasting but not in hamsters.9 Increasing in vitro and in
and production of silica our, exposure to high vivo evidence suggests that the rat lung tumor
concentrations of silica over only a few years response to crystalline silica exposure is a result
has produced a more rapidly progressive form of marked and persistent inammation and
of the disease termed accelerated silicosis. The epithelial proliferation. However, other path-
symptoms are those of the more chronic ways such as a role for crystalline silica surface-
disease, but clinical and radiological progres- generated oxidants or a direct genotoxic effect
sion is rapid.6 An acute form of silicosis has cannot be ruled out.
occurred in a few workers exposed to very high Silica was not mutagenic in bacterial
concentrations of silica over periods of as little assays; both positive and negative results have
as a few weeks. The history is one of progres- been reported in a wide variety of in vivo and
sive dyspnea, fever, cough, weight loss, and, in in vitro genotoxic assays.8
severe cases, death with a year or two. In acute The IARC has determined that there is
silicosis the nodular pattern is absent, the lungs sufcient evidence for the carcinogenicity of
showing a diffuse ground-glass appearance, crystalline silica to experimental animals and to
similar to pulmonary edema.6 humans.9
Exposure of silica has also been related to The 2003 ACGIH threshold limit value-
chronic airow limitation without radiographic time-weighted average (TLV-TWA) for
changes.7 Epidemiological studies of quartz- crystalline quartz silica is 0.1 mg/m3 for the
exposed workers reported statistically signi- respirable fraction of dust.
630 SILICON
REFERENCES
SILICON
1. National Institute for Occupational Safety CAS: 7440-21-3
and Health: Criteria for a Recommended Stan-
dard . . . Occupational Exposure to Crystalline Si
Silica. DHEW (NIOSH) Pub No 75-120.
Washington, DC, US Government Printing
Ofce, 1974 Synonyms: None
2. Parkes WR: Occupational Lung Disorders, 2nd
ed, pp 142, 147148. London, Butterworths, Physical Form. Black to gray needlelike
1982
crystals
3. Levy SA: Occupational pulmonary diseases.
In Zenz C (ed): Occupational MedicinePrin-
ciples and Practical Applications, pp 117, 129 Uses. In manufacture of transistors, silicon
134. Chicago, Year Book Medical Publishers, diodes, and similar semiconductors; for making
1975 alloys such as ferrosilicon and silicon copper
4. Russell AE, Britten RH, Thompson LR,
Bloomeld JJ: The Health of Workers in Dusty Exposure. Inhalation
TradesII. Exposure to Siliceous Dust (Granite
Industry.) US Public Health Service Bulletin Toxicology. Silicon appears to be a biologi-
No 187. Washington, DC, US Government cally inert material.
Printing Ofce, 1929 Little information is available on the toxi-
5. Seaton A, Cherrie JW: Quartz exposures and
cology of pure elemental silicon, which is an
severe silicosis: A role for the hilar nodes.
Occup Environ Med 55(6):3836, 1998 inert material that appears to lack the property
6. Seaton A. In Morgan WKC, Seaton A: Occu- of causing brosis in lung tissue.1 Silicon dust
pational Lung Diseases, 2nd ed. Philadelphia, gave an inert response on intraperitoneal injec-
W. B. Saunders, 1984 tion into guinea pigs and rats.2 Another study,
7. Neukirch F, Cooreman J, Korobaeff M, et al: however, reported minimal pulmonary lesions
Silica exposure and chronic airow limitation in rabbits after the intratracheal injection of
in pottery workers. Arch Environ Health 49: silicon dust at a high level of 25 mg.3
459464, 1994 The 2003 ACGIH threshold limit
8. World Health Organization: Concise Inter- value-time-weighted average (TLV-TWA) is
national Chemical Assessment Document No. 24. 10 mg/m3, for total dust containing no asbestos
Crystalline Silica, Quartz. Geneva, Interna-
and <1% crystalline silica.
tional Programme on Chemical Safety
(IPCS), 2000
9. IARC Monographs on the Evaluation of Car-
cinogenic Risk of Chemicals to Humans, Vol 68, REFERENCES
Silica and some silicates, coal dust and para-
aramid brils, p 41. Lyon, International 1. ACGIH: Silicon. Documentation of the TLVs
Agency for Research on Cancer, 1997 and BEIs, 6th ed, pp 138788. Cincinnati, OH,
10. Holland LM: Crystalline silica and lung American Conference of Governmental
cancer: A review of recent experimental evi- Industrial Hygienists, 1991
dence. Regul Toxicol Pharmacol 12:224237, 2. McCord CP, Fredrick WG, Stolz S: The tox-
1990 icity of silicon. J Lab Clin Med 23:2789, 1937
11. McDonald JC: Silica, silicosis and lung 3. Schepers GWH: Lung tumors of primates and
cancer. Br J Ind Med 46:289291, 1989 rodents. Ind Med Surg 40:4853, 1971
SILICON CARBIDE 631
et al: Cohort study of silicon carbide produc- mucosa.5 No other changes were noted after
tion workers. Am J Epidemiol 140(11): hematologic, biochemical, or histopathologic
100915, 1994 examination. In the Ames assay silicon tetrahy-
8. Lapin CA, Craig DK, Valerio MG, et al: A dride was mutagenic in some strains of bacte-
subchronic inhalation toxicity study in rats ria with or without metabolic activation.6
exposed to silicon carbide whiskers. Fundam
The potential for explosion, re, and
Appl Toxicol 16:128146, 1991
9. Davis JMG, Brown DM, Cullen RT, et al:
oxygen-decient atmospheres constitutes the
A comparison of methods of determining major hazard with silicon tetrahydride.
and predicting the pathogenicity of mineral The 2003 ACGIH threshold limit value-
bers. Inhal Toxicol 8(8):74770, 1996 time-weighted average (TLV-TWA) is 5 ppm
10. Vaughan GL, Trently SA: The toxicity of (6.6 mg/m3).
silicon carbide whiskers, a review. J Environ
Sci Health A: Environ Sci Eng Toxic Hazard
Subst Control 31(8):203354, 1996
REFERENCES
Physical Form. Elemental silver is a lus- Massive exposure to heated vapor of metal-
trous, white solid metal. lic silver for 4 hours by a workman caused lung
damage with pulmonary edema.4 Ingestion of
Uses. Photographic materials; electrical and 10 g of silver nitrate is usually fatal. Large oral
electronics products; alloys and solders; in doses of the compound cause abdominal pain
jewelry, mirrors, atware, and coinage and rigidity, vomiting, convulsions, and shock.5
Patients dying after intravenous administration
Exposure. Inhalation; oral; dermal of Collargol (silver plus silver oxide) showed
necrosis and hemorrhage in the bone marrow,
Toxicology. The primary effect of silver liver, and kidney.6
exposure is argyria, a gray-blue discoloration There is no historical information in
of the skin, eyes, nails, mucous membranes, humans to suggest that silver affects reproduc-
and/or internal organs. tion.2 In an early animal study, there was no
Argyrosis (deposition of silver in the eyes) reduction in fertility or observable changes in
appears to be the critical effect and is observed spermatozoa after 2 years of exposure to 89 mg
in workers exposed to silver compounds at con- silver/kg/day as silver nitrate or silver chloride
centrations in the range of 0.0050.38 mg/m3.1 in the drinking water.
Disturbances with night vision and lens Although brosarcomas have been re-
changes without visual impairment have been ported in animals after subcutaneous imbed-
associated with argyrosis.1 ding of silver foil, normal routes of exposure
Argyria may occur in an area of repeated have not provided indications of carcinogenic-
or abrasive dermal contact with silver or silver ity in animals or humans, and silver is not
compounds, or more extensively over wide- expected to be carcinogenic in humans.2
spread areas of skin and the conjunctiva of the In genotoxic assays, the silver ion caused
eyes after long-term oral or inhalation expo- DNA strand breaks in vitro but silver com-
sure.2 Localized argyria occurs in the skin and pounds were not mutagenic in several bacterial
eyes, where gray-blue patches of pigmentation assays.1,2
are formed without evidence of tissue reaction.3 The 2003 ACGIH threshold limit
Generalized argyria is recognized by the wide- value-time-weighted average (TLV-TWA) is
spread pigmentation of the skin; the tissue dis- 0.01 mg/m3 for soluble compounds, as Ag, and
coloration is due to the deposition of silver 0.1 mg/m3 for metal dust and fume.
complexes and to a silver-induced increase in
melanin and is more pronounced in the sun-
REFERENCES
light-exposed parts of the skin.1 Argyria of the
respiratory tract has been described in two 1. Jongeneelen FJ, Jongerius O: Criteria Docu-
workers involved in the manufacture of silver ment for Metallic Silver. Occupational Exposure
nitrate. Their only symptom was mild chronic Limits. pp 130. Ofce for Ofcial Publica-
bronchitis. Bronchoscopy revealed tracheo- tions of the European Communities, 2985
bronchial pigmentation. Biopsy of the nasal Luxembourg, Grand Duchy of Luxembourg,
mucous membrane showed silver deposition in 1992
the subepithelial area.3 It has been estimated 2. Agency for Toxic substances and Disease Reg-
that gradually accumulated intake of from 1 to istry (ATSDR): Toxicological Prole for Silver.
5 g of silver will lead to generalized argyria.3 TP-9024. 145pp. US Department of Health
and Human Services, Public Health Service,
Upper respiratory tract irritation has been
1990
observed in humans at estimated exposure
3. Browning E: Toxicity of Industrial Metals, 2nd
levels of between 0.04 and 0.4 mg silver/m3 for ed, pp 296301. London, Butterworths, 1969
less than 1 to greater than 10 years.2 Irritant 4. Forycki Z, Zegarski W, Bardzik J, et al: Acute
effects are considered to be related to the silver poisoning through inhalation. Bull
caustic properties of the various silver com- Inst Maritime Trop Med Gydnia 34:199202,
pounds, rather than the silver itself. 1983
634 SOAPSTONE
REFERENCES
Synonyms: Steatite; massive talc
1. Spiegel RM: Medical aspects of talc. In
Physical Form. Talclike material of varying Goodwin A (ed): Proceedings of the Symposium
composition, but generally grayish-white, ne, on Talc, Bureau of Mines Report No 8639, pp
odorless power. It is noncombustible and 97102. Washington, DC, US Government
Printing Ofce, 1973
insoluble in water.
2. Kleinfeld M, Messite J, Kooyman O, Zaki
MH: Mortality among talc miners and millers
Uses. Pigment in paint, varnishes; ller for in New York State. Arch Environ Health 14:
paper, rubber, soap; lubricating molds and 663667, 1967
machinery; heat insulator 3. Dreessen WC, DallaValle JM: The effects of
exposure to dust in two Georgia talc mills and
Exposure. Inhalation mines. Pub Health Rep 50:131143, 1935
4. Blejer HP, Arlon R: Talc: A possible occupa-
Toxicology. The brous talc in soapstone tional and environmental carcinogen. J Occup
dust causes brotic pneumoconiosis; an in- Med 15:9297, 1973
creased incidence of cancer of the lungs and 5. Kleinfeld M, Messite J, Zaki MH: Mortality
experiences among talc workers: A follow-up
pleura has been reported.
study. J Occup Med 16:345349, 1974
In the development of talc pneumocon-
iosis or talcosis, the subject initially is symp-
tom-free, but cough and dyspnea develop as the
disease progresses; cyanosis, digital clubbing,
and cor pulmonale occur in advanced cases.
The disease progresses slowly, even in the
absence of continued exposure; occasionally, SODIUM FLUOROACETATE
the disease may progress rapidly, with death CAS: 62-74-8
occurring within a few years of a very heavy
exposure.1,2 CH2FCOONa
In an early report of 66 workers handling
soapstone, no cases of pneumoconiosis were
found in workers with an average dust exposure Synonyms: Compound 1080; uoroacetic
of 2.8 mg/m3 but exposures ranging from 22 to acid, sodium salt; Fratol; sodium monouo-
50 mg/m3 caused severe cases.3 roacetate
SODIUM FLUOROACETATE 635
Physical Form. Fine white powder epithelium and with milder hepatic, neurolog-
ical, and thyroid dysfunctions.8
Uses. Rodenticide (restricted use) In developmental studies in rats
0.75 mg/kg/day administered by gavage on
Exposure. Inhalation; ingestion days 617 of gestation caused signicant reduc-
tions in maternal and fetal body weight gains,
Toxicology. Sodium uoroacetate is highly but no external fetal abnormalities were noted.9
toxic and causes convulsions and ventricular The 2003 ACGIH threshold limit value-
brillation. time-weighted average (TLV-TWA) for
Fluoroacetate produces its toxic action by sodium uoroacetate is 0.05 mg/m3 with a
inhibiting the citric acid cycle.1 The uorine- notation for skin.
substituted acetate is metabolized to uoroci-
trate that inhibits the conversion of citrate to
isocitrate. There is an accumulation of large REFERENCES
quantities of citrate in the tissue, and the cycle
is blocked. The heart and central nervous 1. Murphy SD: Toxic effects of pesticides. In
system are the most critical tissues involved in Klaassen CD et al. (eds): Casarett and Doulls
poisoning by a general inhibition of oxidative Toxicology, The Basic Science of Poisons, 3rd ed,
energy metabolism.1 p 565. New York, Macmillan, 1986
Onset of symptoms after ingestion is 2. Harrisson JWE et al: Acute poisoning with
frequently delayed for 30 minutes to 2 hours; sodium uoroacetate (compound 1080).
JAMA 149:15201522, 1952
effects are vomiting, apprehension, auditory
3. Hayes WJ Jr: Clinical Handbook on Economic
hallucinations, nystagmus, a tingling sensation
Poisons. Emergency Information for Treating
of the nose, numbness of the face, facial twitch- Poisoning. US Public Health Service Pub
ing, and epileptiform convulsions.2,3 After a No 476, pp 7982. Washington, DC, US
period of several hours, there may be pulsus Government Printing Ofce, 1963
alterans, long sequences of ectopic heartbeats 4. Gosselin RE et al: Clinical Toxicology of Com-
(often multifocal), tachycardia, ventricular b- mercial Products, Section III, 5th ed, pp 193
rillation, and death.3,4 The lethal oral dose in 196. Baltimore, MD, Williams and Wilkins,
humans is estimated to be approximately 5.0 1984
mg/kg.4,5 In a fatal case of ingestion, autopsy 5. Harrisson JWE, Ambrus JL, Ambrus CM:
ndings included hemorrhagic pulmonary Fluoroacetate (1080) poisoning. Ind Med Surg
21:440442, 1952
edema and degeneration of renal tubules.5
6. Chi CH, Chen KW, Chan SH, et al: Clinical
A retrospective study of 38 cases of sodium
presentation and prognostic factors in sodium
uoroacetate poisoning (including 7 deaths) monouoroacetate intoxication. J Toxicol Clin
concluded that hypotension and early-onset Toxicol 34(6):70712, 1996
metabolic acidosis and increased serum creati- 7. LaGoy PK, Bohrer RL, Halvorsen FH:
nine were most often associated with poor The development of cleanup criteria for an
short-term survival.6 acutely toxic pesticide at a contaminated
Applied as a 0.1% mixture in sh meal, and industrial facility. Am Ind Hyg Assoc J 53:
widely dispersed throughout a workplace as a 298302, 1992
rat poison, sodium uoroacetate caused several 8. Parkin PJ: Chronic sodium monouoroacetate
employees to become seriously ill (details not (compound 1080) intoxication in a rabbiter.
NZ Med J 85:9399, 1977
given).7 Exposure is thought to have occurred
9. Turck PA, Eason CT, Wickstrom M: Assess-
from airborne contamination, although acci-
ment of the developmental toxicity of sodium
dental ingestion cannot be ruled out. monouoroacetate (1080) in rats. Toxicologist
In the only alleged case of chronic human 42(1-S):2589, 1998
poisoning, an exterminator repeatedly exposed
over a period of 10 years presented with severe
and progressive lesions of the renal tubular
636 SODIUM HYDROXIDE
3. Patty FA: Alkaline materials. In Fassett DW, recovered to baseline after 30 or 40 minutes.
Irish DD (eds): Pattys Industrial Hygiene and Neither enhanced sensitivity to subsequent his-
Toxicology, 2nd ed, Vol 2, Toxicology, pp tamine inhalation nor refractoriness to subse-
867868. New York, Wiley-Interscience, 1963 quent sodium metabisulte inhalation was
4. Criteria group for occupational standards: found. None of the nonasthmatic, nonatopic
Scientic basis for Swedish occupational
subjects responded to sodium metabisulte,
standards XXI. Consensus report for sodium
hydroxide. Arbete och Halsa 22:727, 2000 but inhalation of high doses may cause mild
5. Rubin AE, Bentur L, Bentur Y: Obstructive bronchoconstriction in these individuals.
airway disease associated with occupational The mechanism of action of may involve
sodium hydroxide inhalation. Br J Ind Med 49: the liberation of sulfur dioxide gas from sodium
213214, 1992 metabisulte that in turn acts on the parasym-
pathetic nerves in the lung.2
In mice exposed to aerosols of sodium
metabisulte there was sensory irritation of the
upper respiratory tract.3
A low order of systemic toxicity was found
SODIUM METABISULFITE in chronic feeding studies with rats. Adminis-
CAS: 7681-57-4 tered in the diet for 2 years 0.215% sodium
metabisulte caused no adverse effects.4 Re-
Na2S2O5 productive parameters were not affected in
three-generation feeding studies in rats at con-
centrations up to 13 mmol/kg/day.4
Synonyms: Disodium disulte; sodium Sodium metabisulte was genotoxic in
pyrosulte mice in vivo as determined by chromosomal
aberration, micronucleus, and sperm shape
Physical Form. White powder or crystal assays.5 It was not mutagenic in bacterial
with the odor of sulfur dioxide assays.6
The 2003 ACGIH threshold limit value-
Uses. As a preservative in food and wine; as time-weighted average (TLV-TWA) for sodium
an antioxidant in pharmaceuticals. metabisulte is 5 mg/m3.
by mammalian in vivo bioassays. Cytologia within a few days by profound anemia.5 Stibine
57(4):455461, 1992 is also a pulmonary irritant in animals, causing
6. Fujita H, Aoki N, Sasaki M: Mutagenicity test pulmonary congestion and edema and, ulti-
of food additives with Salmonella typhimurium mately, death in cats and dogs after a 1-hour
TA97 and TA102. IX. Tokyo-Toritsu Eisei
exposure at 4045 ppm.5
Kenkyusho Kenkyu Nenpo 45:1919, 1994
The 2003 ACGIH threshold limit value-
time-weighted average (TLV-TWA) for stibine
is 0.1 ppm (0.51 mg/m3).
STIBINE
CAS: 7803-52-3 REFERENCES
Exposure. Inhalation
nantly C9 to C11 hydrocarbons of which The odor threshold is 0.9 ppm; the odor
3050% are straight- and branched-chain and irritative properties probably do not
parafns, 3040% naphthenes, and 1020% provide adequate warning of dangerous
aromatic hydrocarbons.1 Although uses may concentrations.2
differ, Stoddard solvent is chemically similar to The 2003 ACGIH threshold limit value-
mineral spirits and the terms have been used time-weighted average TLV-TWA for
interchangeably.1 Stoddard solvent is 100 ppm (525 mg/m3).
One of six volunteers exposed to 150 ppm
of Stoddard solvent for 15 minutes had transi-
tory eye irritation; at 470 ppm (2700 mg/m3) all REFERENCES
subjects had eye irritation and two had slight
dizziness.2 Eight volunteers exposed at 4000 1. National Institute for Occupational Safety and
mg/m3 for 50 minutes had some changes in Health: Criteria for a Recommended Standard
simple reaction time tests but not in perceptual . . . Occupational Exposure to Rened Petroleum
Solvents. DHEW (NIOSH) Pub No 77-192.
speed, short-term memory, or manual dexter-
Washington, DC, US Government Printing
ity compared with pre- and postexposure self
Ofce, 1977
controls.3 2. Carpenter CP et al: Petroleum hydrocarbon
Studies involving painters with long-term toxicity studies. III. Animal and human
exposure to Stoddard solvent have found in- response to vapors of Stoddard solvent. Toxicol
creased incidences of memory impairment, Appl Pharmacol 32:282297, 1975
fatigue, impaired concentration, irritability, 3. Gamberale F, Annwall G, Hultengren M:
dizziness, headache, and reduced cognitive Exposure to white spirit: II. Psychological
function.4 functions. Scand J Work Environ Health 1:31
Reports of Stoddard solvent as an etiologic 39. 1975
agent in the development of aplastic anemia are 4. World Health Organization: Environmental
Health Criteria 187. White Spirit (Stoddard
of questionable validity.1 Skin exposure may
Solvent), pp 1166. International Programme
cause dermatitis and sensitization.1
on Chemical Safety (IPCS). Geneva, 1996
Rats exposed to Stoddard solvent at a level 5. Agency for Toxic Substances and Disease Reg-
of 1400 ppm for 8 hours exhibited eye irrita- istry (ASTDR): Toxicological Prole for Stoddard
tion, bloody exudate around the nostrils, and Solvent. 135pp. US Department of Health and
slight loss of coordination. Exposure of a dog Human Services, Public Health Service, 1995
resulted in increased salivation at 3 hours,
tremor at 4 hours, and clonic spasms after 5
hours; 1700 ppm caused tremors, convulsions,
and nally death in cats after 2.57.5 hours.2 STRYCHNINE
No signicant effects were observed in dogs CAS: 57-24-9
exposed 6 hours/day for 65 days to 330 ppm;
there was elevated blood urea nitrogen levels C21H22N2O2
and marked tubular regeneration in the kidneys
of rats similarly exposed.2 Renal effects noted
in rats are consistent with a mechanism that Synonym: Stricnina
appears to be unique to male rats (i.e., interac-
tions with a2u-globulin), and it is not known Physical Form. White crystalline powder
whether Stoddard solvent would cause similar
effects in humans.5 Use. Rodenticide
Stodddard solvent was not genotoxic
in a variety of assays including Salmonella Exposure. Inhalation; ingestion
typhimurium, a mouse lymphoma mutation
assay, rodent bone marrow cytogenic tests, and Toxicology. Strychnine is a potent
rodent dominant lethal tests.4,5 convulsant.
640 STYRENE, MONOMER
Strychnine poisoning occurs from acciden- time-weighted average (TLV-TWA) for stry-
tal and intentional ingestion and from misuse chnine is 0.15 mg/m3.
as a therapeutic agent.1 Doses of 57 mg cause
muscle tightness, especially in the neck and
jaws, and twitching of individual muscles, espe- REFERENCES
cially in the little ngers.1
The lethal oral dose in humans is probably 1. Hayes WJ Jr, Laws ER Jr: Handbook of Pesticide
around 100, but doses as low as 16 mg have Toxicology, Vol 2 Classes of Pesticides. pp 615
reportedly been fatal whereas doses of 2000 mg 619. New York, Academic Press, 1991
2. Gosselin RE et al: Clinical Toxicology of Com-
have been survived.1,2 After ingestion, effects
mercial Products, Section III, 5th ed, pp 375
usually occur within 1030 minutes and include
379. Baltimore, MD, Williams and Wilkins,
stiffness of the face and neck muscles and 1984
increased reex excitability.3 Strychnine acts by 3. Franz DN: Central nervous system stimulants.
altering nerve impulses in the spinal cord, In Goodman LS, Gilman A (eds): The Phar-
resulting in a decreased threshold for stimula- macological Basis of Therapeutics, 7th ed, pp 582
tion, and, hence, a hyperexcitable state. Any 584. New York, Macmillan, 1985
sensory stimulus may produce a violent motor 4. Greene R, Meatherall R: Dermal exposure to
response that, in the early stages of intoxica- strychnine. J Anal Toxicol 25(5):344347, 2001
tion, tends to be a coordinated extensor thrust
and, in later stages, may be a tetanic convulsion
with opisthotonos; anoxia and cyanosis develop
rapidly. Between convulsions, muscular relax-
ation is complete, breathing is resumed, and STYRENE, MONOMER
cyanosis lessens.1 Because sensation is un- CAS: 100-42-5
affected, the convulsions are painful and lead
to overwhelming fear. As many as 10 convul- C6H5CHCH2
sions separated by intervals of 1015 minutes
may be experienced, but death often occurs
after the second to fth convulsion, and even Synonyms: Vinylbenzene; phenylethylene;
the rst convulsion may be fatal if sustained; styrene monomer; cinnamene
death is commonly due to asphyxia.2,3 If recov-
ery occurs, it is remarkably prompt and com- Physical Form. Colorless to yellowish oily
plete despite the violence of the illness; muscle liquid
soreness may persist for a number of days.1
In fatal cases, the pathologic ndings are Uses. Solvent for synthetic rubber and
entirely nonspecic. They usually consist of resins; intermediate in chemical synthesis;
petechial hemorrhages and congestion of the manufacture of polymerized synthetic
organs, indicating combined action of severe materials
convulsions and anoxia.1 Compression frac-
tures and related injury may be found in cases Exposure. Inhalation; skin absorption
with violent tetany.1
Strychnine poisoning may also occur from Toxicology. Styrene is an irritant of the
dermal exposure. In one recent case report a skin, eyes, and mucous membranes and is
women experienced marked pain in the lower neurotoxic.
limbs, dermal sensitivity, and stiffness in her Humans exposed to 376 ppm experienced
jaw 24 hours after cleaning up a strychnine eye and nasal irritation within 15 minutes;
spill. Strychnine was conrmed in the plasma after 1 hour at 376 ppm, effects were headache,
and urine by gas chromatography-mass nausea, decreased dexterity and coordination,
spectrometry.4 and other signs of transient neurological
The 2003 ACGIH threshold limit value- impairment.1 Subjective complaints, including
STYRENE, MONOMER 641
4. Pahwa R, Kalra J: A critical review of the Physical Form. Colorless to pale straw
neurotoxicity of styrene in humans. Vet colored liquid
Human Toxicol 35:516519, 1993
5. Dutkiewicz T, Tyras H: Skin absorption of Uses. Used as an intermediate in the pro-
toluene, styrene, and xylene by man. Br J Ind duction of styrene glycol and its derivatives; as
Med 25:243, 1968
a reactive dilutent in the epoxy resin industry;
6. Bond JA: Review of the toxicology of styrene.
CRC Crit Rev Toxicol 19:227249, 1989 as a chemical intermediate for making b-
7. Sandmeyer EE: The aromatic hydrocarbons. phenethyl alcohol, a fragrance material
In Clayton GD, Clayton FE (eds): Pattys
Industrial Hygiene and Toxicology, 3rd ed, Vol Exposure. Inhalation; skin
2A, Toxicology, pp 33123319. New York,
Wiley-Interscience, 1981 Toxicology. Styrene oxide is a skin and eye
8. Harkonen H, Lehtniewi A, Aitio A: Styrene irritant and may produce skin sensitization; it
exposure and the liver. Scand J Work Environ is carcinogenic in experimental animals.
Health 10:5961,1984 Tests with human subjects indicate that
9. Hodgson J, Jones R: Mortality of styrene styrene oxide is capable of causing moderate
production, polymerization and processing
skin irritation and skin sensitization.1 These
workers of a site in northwest England. Scand
J Work Environ Health 11:347352, 1985 effects may result from single or repeated con-
10. Okun A et al: Mortality patterns among tact with the undiluted liquid and with solu-
styrene-exposed boatbuilders. Am J Ind Med tions as dilute as 1%. Experience indicates that
8:193205, 1985 persons who have become sensitized may react
11. Ott MG, Kolsear RC, Scharnweber HC, et severely to contact with the vapor as well as
al: A mortality survey of employees engaged with the liquid material.
in the development or manufacture of In rats, exposure to 1000 ppm was lethal to
styrene-based products. J Occup Med two of six animals within 4 hours.2 Repeated 7-
22:445460, 1980 hour exposures at 300 ppm were rapidly fatal to
12. IARC Monographs on the Evaluation of Car- 40% of female rats, and extensive mortality
cinogenic Risks to Humans, Vol 82, Traditional
occurred in rats receiving prolonged exposure
herbal medicines, some mycotoxins, naph-
thalene and styrene, pp 437550. Lyon, to 100 ppm.3 Toxicity also was marked in
International Agency for Research on the rabbit, with prolonged and repeated ex-
Cancer, 2002 posures at 1550 ppm producing mortality.3
13. Lemasters GK, Samuels SJ, Morrison JA, Histopathologic changes in rats and rabbits
et al: Reproductive outcomes of pregnant included metaplasia and hyperplasia of the
workers employed at 36 reinforced plastics lungs.
companies. II. Lowered birth weight. J Occup Inhalation exposure during gestation by
Med 31:115120, 1989 rats and rabbits produced reproductive and
developmental toxicity as well as maternal tox-
icity.3 Exposure to 15 or 50 ppm for 7
hours/day on days 124 of gestation resulted
in maternal toxicity (increased mortality,
decreased food consumption, and weight gain)
STYRENE OXIDE and increased the frequency of resorptions in
CAS: 96-09-3 rabbits. Exposure of rats to 100 ppm on days
119 of gestation decreased fecundity by
C8H8O signicantly increasing preimplantation loss.
Fetal size, including crown-rump length and
weight, also tended to be decreased by expo-
Synonyms: Epoxyethylbenzene; epoxystyrene; sure in both species. It has not been established
phenylethylene oxide; phenyloxirane; styrene- whether the developmental effects are direct
7,8-oxide effects or are the result of maternal toxicity.
SULFOLANE 643
The liquid is slowly absorbed by the skin 2. Weil CS, Condra N, Haun C, et al: Experi-
and may reach toxic levels in rabbits over a 24- mental carcinogenicity and acute toxicity of
hour period with an LD50 of 2.8 g/kg.1 representative epoxides. Am Ind Hyg Assoc J
Intraperitoneal injection has been associ- 24:305325, 1963
ated with hepatic damage in rats, causing a 3. Sikov MR, Cannon WC, Carr DB, et al:
Reproductive toxicology of inhaled styrene
decrease in the activities of mixed function
oxide in rats and rabbits. J Appl Toxicol 6:155
oxidases and in cytochrome P-450 content.4 164, 1986
In a long-term bioassay, styrene oxide 4. Parkki MG, Marniemi J, Vainio H: Action of
administered to rats by gavage (250 or styrene and its metabolites styrene oxide and
50 mg/kg daily for 1 year) produced a high styrene glycol on activities of xenobiotic bio-
incidence of tumors in the forestomach transformation enzymes in rat liver in vivo.
(papillomas, acanthomas, and in situ and inva- Toxicol Appl Pharmacol 38:5970, 1976
sive squamous cell carcinomas).5 Styrene oxide 5. Conti B, Maltoni C, Perion G, et al: Long-
also increased the incidence of squamous cell term carcinogenicity bioassays on styrene
papillomas and carcinomas of the forestomach administered by inhalation, ingestion and
in mice when administered by gavage at doses injection and styrene oxide administered by
ingestion on Sprague-Dawley rats, and para-
of 375 or 750 mg/kg for 2 years.6
methylstyrene administered by ingestion in
Prenatal exposure followed by postnatal Sprague-Dawley rats and Swiss mice. Ann NY
oral administration of 96 weekly doses of Acad Sci 534:203234, 1988
100150 mg/kg also produced a signicantly 6. Lijinsky W: Rat and mouse forestomach
increased incidence of forestomach tumors, tumors induced by chronic oral administration
including papillomas and carcinomas in rats.7 of styrene oxide. J Natl Cancer Inst 77:
No increase in the incidence of skin 471476, 1986
tumors was observed in two mice studies after 7. Ponomarkov V, Cabral JRP, Wahrendorg J,
topical application.2,8 et al: A carcinogenicity study of styrene-7,8-
Both positive and negative ndings have oxide in rats. Cancer Lett 24:95101, 1984
been reported in genotoxic assays of styrene 8. Van Duuren BL, Nelson H, Orris L, et al:
Carcinogenicity of epoxides, lactones, and
oxide. It has induced gene mutations in bacte-
peroxy compounds. J Natl Cancer Inst 31:
ria and rodent cells in vitro and caused chro- 4155, 1963
mosomal aberrations and sister chromatid 9. IARC Monographs on the Evaluation of Carcino-
exchange both in vivo and in vitro.9 genic Risks to Humans, Vol 60, Some industrial
Styrene oxide forms covalent adducts with chemicals, pp 321346. Lyon, International
DNA in humans, rats, and mice. Agency for Research on Cancer, 1994
The IARC has determined that there is
sufcient evidence for the carcinogenicity of
styrene oxide to experimental animals and that,
although there is inadequate evidence for
the carcinogenicity to humans, it should be
regarded as probably carcinogenic to humans.9
The ACGIH has not determined a thresh- SULFOLANE
old limit value (TLV) for styrene oxide. CAS: 126-33-0
C4H8SO2
REFERENCES
1. Hine CH, Rowe, VK, White ER, et al: Epoxy Synonyms: 1,1-Dioxidetetrahydrothiofuran;
compounds. In Clayton GD, Clayton FE (eds): 1,1-dioxothiolan; cyclotetramethylene sulfone;
Pattys Industrial Hygiene and Toxicology, 3rd ed, dioxothiolan; sulfoxaline; tetrahydrothiophene
rev, Vol 2B, Toxicology, pp 21922194. New 1,1-dioxide; tetramethylene sulfone; thiocy-
York, Wiley-Interscience, 1981 clopentane dioxide; thiophane dioxide
644 SULFUR DIOXIDE
3. Elkins HB: The Chemistry of Industrial Toxicol- Physical Form. Colorless gas with odor
ogy, 2nd ed, p 81. New York, John Wiley and similar to sulfur dioxide
Sons, 1959
Uses and Sources. As a uorinating agent in
the production of water- and oil-repellant
materials and lubricity improvers; found as a
degradation product of sulfur hexauoride
SULFUR PENTAFLUORIDE
CAS: 5714-22-77 Exposure. Inhalation
smaller size.6 For 8-hour exposures, the LC50 at 10% whereas others report no effects at
was 30 mg/m3 for mists of 0.8 mm and was this concentration.1 Although ingestion of the
greater than 109 mg/m3 for 0.4-mm mists.6 liquid is unlikely in ordinary industrial use, the
Animals that died from exposure to the larger highly corrosive nature of the substance will
mists had hyperinated lungs, whereas those produce serious burns of the mouth and the
that died from the smaller mists also had hem- esophagus.4
orrhage and transudation. Changes in pul- A number of studies have indicated that
monary function, however, were more severe exposures to sulfuric acid or to acid mist
for aerosols of smaller diameter.7 The concen- in general are associated with laryngeal
tration producing a 50% increase in pulmonary cancer.1013 In a nested case-referent study, a
ow resistance was 0.3 mg/m3 for 0.3-mm par- 13-fold excess risk of laryngeal cancer was
ticles, 0.7 mg/m3 for 1 mm, 6 mg/m3 for 3.4 mm, found among chemical renery workers with
and 30 mg/m3 for 7 mm. Long-term exposure of the highest levels of sulfuric acid exposure
monkeys at concentrations between 0.1 and compared with those least exposed; a fourfold
1 mg/m3, regardless of particle size, produced risk for moderately exposed workers versus
slight but increasingly severe microscopic pul- those least exposed also was found.10 Fourteen
monary lesions.8 Impairment of pulmonary cases of laryngeal cancer were identied (vs.
ventilation occurred above 2.5 mg/m3. 6.4 expected) in 1031 steelworkers exposed to
The corrosive effects of sulfuric acid on acid mists for an average of 9.2 years, with an
teeth with chronic exposure are well estab- average rst year of exposure of 1949.11 Expo-
lished.4 The damage, etching of dental enamel sure levels averaged about 0.2 mg/m3, and
followed by erosion of enamel and dentine with the average duration of exposure was 9.5 years.
loss of tooth substance, is limited to the parts Excess risks for laryngeal cancer were also
of the teeth that are exposed to direct impinge- found in a Swedish study of a cohort of workers
ment of acid mist upon the surface. Although in steel pickling.12 In a population-based case-
etching typically occurs after years of occupa- referent report from Canada, there was an
tional exposure, in one case exposure to an association between exposure to sulfuric acid in
average of 0.23 mg/m3 for 4 months was suf- the workplace, particularly at higher concen-
cient to initiate erosion.3 trations and over longer periods of time, and
Splashed in the eye, the concentrated acid the development of laryngeal cancer.13 More
causes extremely severe damage, often leading recently, sulfuric acid mist exposure has also
to blindness, whereas dilute acid produces been associated with gastric cardia cancer and
more transient effects, from which recovery nasopharyngeal carcinoma.14, 15
may be complete.9 Chemical burns are the It has been postulated that sulfuric acid
most commonly encountered occupational may produce tumors by direct genotoxic effects
hazard. Initially, the zone of contact is bleached of lowered pH or may promote carcinogenesis
and turns brown before the formation of a by inducing chronic tissue irritation.1 IARC has
clearly dened ulcer on a light red background. determined that there is sufcient evidence
The wounds are long in healing, and scarring that occupational exposure to strong inorganic
may result in functional inhibition. Severe acid mists containing sulfuric acid is carcino-
burns have been fatal. A worker sprayed in the genic to humans.16
face with liquid fuming sulfuric acid suffered Signicant increases in the incidences
skin burns of the face and body, as well as pul- of sister chromatid exchange, micronucleus
monary edema from inhalation.4 Sequelae were formation, and chromosomal aberrations in
pulmonary brosis, residual bronchitis, and peripheral lymphocytes were observed in a
pulmonary emphysema; in addition, necrosis of single study of workers engaged in the manu-
the skin resulted in marked scarring.4 The facture of sulfuric acid.16
threshold sulfuric acid concentrations resulting Sulfuric acid mist was not teratogenic in
in skin and eye irritation are unclear, with some mice or rabbits exposed 7 hours/day to 20 mg/m3
studies reporting severe ocular and skin effects during the period of major organogenesis.17
650 SULFURYL FLUORIDE
The 2003 ACGIH threshold limit value- 12. Ahlborg G, Hogstedt C, Sundell L, et al:
time-weighted average (TLV-TWA) for sulfu- Laryngeal cancer and pickling house vapors.
ric acid is 1 mg/m3 with a short-term excursion Scand J Work Environ Health 7:239240, 1981
level (STEL/ceiling) of 3 mg/m3. 13. Soskolne CL, Jhangri GS, Siemiatycki J, et al:
Occupational exposure to sulfuric acid in
southern Ontario, Canada, in association
with laryngeal cancer. Scand J Work Environ
REFERENCES
Health 18:225232, 1992
14. Cocco P, Ward MH, Dosemeci M: Occupa-
1. Agency for Toxic Substances and Disease
tional risk factors for cancer of the gastric
Registry (ATSDR): Toxicological Prole for
cardia. J Occup Environ Med 40(10):855861,
Sulfur Trioxide and Sulfuric Acid, 189pp. US
1998
Department of Health and Human Services.
15. Ho CK, Lo WC, Huang PH, et al:
Public Health Service, 1998
Suspected nasopharyngeal carcinoma in
2. Amdur MO, Silverman L, Drinker P: Inhala-
three workers with long-term exposure to
tion of sulfuric acid mist by human subjects.
sulphuric acid vapour. Occup Environ Med
AMA Arch Ind Hyg Occup Med 6:305313,
56(6):4268, 1999
1952
16. IARC Monographs on the Evaluation of Car-
3. Gamble J, et al: Epidemiological-environ-
cinogenic Risks to Humans, Vol 54, Occupa-
mental study of lead acid battery workers. III.
tional exposures to mists and vapours from
Chronic effects of sulfuric acid on the respi-
strong inorganic acids; and other industrial
ratory system and teeth. Environ Res 35:
chemicals, pp 41130. Lyon, International
3052, 1984
Agency for Research on Cancer, 1992
4. National Institute for Occupational Safety
17. Murray FJ, et al: Embryotoxicity of inhaled
and Health: Criteria for a Recommended Stan-
sulfuric acid aerosol in mice and rabbits.
dard . . . Occupational Exposure to Sulfuric Acid.
J Environ Sci Health 13:251266, 1979
DHEW (NIOSH) Pub No 74128, pp
1949. Washington, DC, US Government
Printing Ofce, 1974
5. US EPA: Health Effects Assessment for Sulfuric
Acid. Report No EPA/540/186/031, p 33.
Washington, DC, US Environmental Pro- SULFURYL FLUORIDE
tection Agency, Environmental Criteria and CAS: 2699-79-8
Assessment Ofce, 1984
6. Wolff RK, et al: Toxicity of 0.4- and 0.8- SO2F2
microm sulfuric acid aerosols in the guinea
pig. J Toxicol Environ Health 5:10371047,
1979
7. Amdur MO, et al: Respiratory response of Synonyms: Sulfuric oxyuoride; sulfuryl diu-
guinea pigs to low levels of sulfuric acid. oride; Vikane
Environ Res 5:418423, 1978
8. Alarie YC et al: Long-term exposure to sulfur Physical Form. Colorless gas
dioxide, sulfuric acid mist, y ash, and their
mixturesresults of studies in monkeys and Uses. Insect fumigant
guinea pigs. Arch Environ Health 30:
254263, 1975 Exposure. Inhalation
9. Grant WM: Toxicology of the Eye, 3rd ed,
pp 866868. Springeld, IL, Charles C. Toxicology. Sulfuryl uoride is a central
Thomas, 1986
nervous system depressant and a pulmonary
10. Soskolne CL, et al: Laryngeal cancer and
occupational exposure to sulfuric acid. Am J irritant in animals.
Epidemiol 120:358369, 1984 A worker exposed to an undetermined
11. Steenland K: Laryngeal cancer incidence concentration of a mixture of sulfuryl uoride
among workers exposed to acid mists (United and 1% chloropicrin for 4 hours developed
States). Cancer Causes Control 8(1):348, 1997 nausea, vomiting, abdominal pain, and pruritis;
TALC (Nonasbestos Form) 651
usually crystalline, exible, and soft. The purity ease (COLD) compared with 189 nonexposed
and physical form of any sample of talc depend workers.7 The increase in COLD and wheez-
on the source of the talc and on the minerals ing occurred only among smokers. Those talc
found in the ore body from which it is rened. workers with more than 10 years of exposure
had signicantly decreased FEV1; none of the
Uses. For clarifying liquid by ltration; talc workers had chest X rays denitely con-
pigment; for lubricating molds and machinery; sistent with classic talc pneumoconiosis.7
electric and heat insulator; in cosmetics Exposure had been to talc of industrial grade
with less than 1% silica and less than two bers
Exposure. Inhalation of asbestos/ml at levels of 0.513.55 mg/m3,
with most of the workers being exposed to less
Toxicology. The nonasbestos form of talc, than 1 mg/m3 (or 2 mppcf).
also termed nonbrous or pure talc, has not A mortality study of 392 miners and millers
been proven to cause the effects produced by of nonasbestos talc in Vermont showed an
exposure to brous talc, namely, brotic pneu- excess of deaths due to nonmalignant respira-
moconiosis and an increased incidence of tory disease among millers and an excess of
cancer of the lungs and pleura. lung cancer mortality among miners.8 The
Although there are a number of contra- fact that the excess lung cancer mortality was
dictory reports regarding the effects of talc, observed for miners and not millers, despite
the contradiction has been ascribed to the dif- probable higher dust exposure, led the investi-
ferences in mineral composition of the various gators to conclude that other etiologic agents
talcs, which include pure talc, talc associated either alone or in combination with talc dust
with silica and other nonasbestiform minerals, affected the miners.8
and talc containing asbestiform bers such as Another historical cohort study of 655
tremolite and anthophyllite.1 workers in a New York talc mine and mill
In a study of 20 workers exposed for 10 revealed no signicant differences in death
36 years to talc described as pure, at levels rates from all causes, from cancer of the respi-
ranging from 15 to 35 mppcf, no evidence of ratory system, or from nonmalignant respira-
pneumoconiosis was found.2,3 In another study tory disease for the period from 1948 to 1978.9
that compared the pulmonary function of However, workers with previous occupational
workers exposed to either brous or nonbrous histories were found to have excessive mortal-
talc, it was concluded that although the brous ity from lung cancer and from nonmalignant
form was the more pathogenic type, both talcs respiratory tract disease, again suggesting
produced pulmonary brosis; no data were pre- another etiologic agent. No excess cancer risk
sented to document the types of talc involved.4 or cause-specic mortality was found in a
A study of 260 workers with 15 or more cohort mortality study of 94 talc miners and
years of exposure to commercial talc dust (con- 295 talc millers from Norway who were
taining not only talc, but also tremolite, antho- exposed to a nonasbestiform talc with low
phyllite, carbonate dusts, and a small amount quartz content.10
of free silica) revealed a 40-fold greater than A 1-year follow-up of 103 miners and
expected proportional mortality from cancer of millers of talc ore free from asbestos and silica
the lungs and pleura. In addition, a major cause showed an association between exposure and
of death was cor pulmonale, a result of the small opacities on chest radiographs; the
pneumoconiosis; the effects were likely due to annual loss in FEV1 and FVC was greater than
the asbestos-form contaminants.5,6 The role of expected and could not be wholly attributed to
nonbrous talc in these disease states could not cigarette smoking.11 However, effects on pul-
be assessed. monary function in nonsmokers was not asso-
In a study of 80 talc workers, there was ciated with lifetime or current talc exposure.11
an excess prevalence of productive cough and In inhalation studies with hamsters
of criteria of chronic obstructive lung dis- exposed to 8 mg/m3 at a cumulative dust dose
TALC (Nonasbestos Form) 653
Environment. Park Forest South, IL, bronchi and bronchioles. Doses as high as
Pathotox Publishers, 1979 8000 mg/kg given orally produced no untoward
14. IARC Monographs on the Evaluation of the Car- effects in rats.3
cinogenic Risk of Chemical to Humans, Vol 42, There was no mutagenic enhancement
Silica and some silicates, pp 185224. Lyon, detected in the sera of animals implanted with
International Agency for Research on
tantalum pellets.4
Cancer, 1987
15. National Toxicology Program: NTP Technical The 2003 threshold limit value-time-
Report on the Toxicology and Carcinogenesis weighted average (TLV-TWA) for tantalum
Studies of Talc in F344/N Rats and B6C3F Mice. metal and oxide dusts, as Ta, is 5 mg/m3.
NIH Publication No. 923152. Bethesda,
MD, National Institutes of Health, 1992
REFERENCES
16. Davies R, Skidmore JW, Grifths DM, et al:
Cytotoxicity of talc for macrophages in vitro.
1. Stokinger HE: The metals. In Clayton GD,
Food Chem Toxicol 21:201207, 1983
Clayton FE (eds): Pattys Industrial Hygiene and
Toxicology, 3rd ed, rev, Vol 2A, Toxicology, pp
14922060. New York, Wiley-Interscience,
1981
2. Schepers GWH: The biologic action of tanta-
lum oxide. AMA Arch Ind Health 12:121123,
TANTALUM 1955
CAS: 7440-25-7 3. Cochran KW et al: Acute toxicity of zir-
conium, columbium, strontium, lanthanum,
cesium, tantalum and yttrium. Arch Ind Hyg
Ta
Occup Med 1:637650, 1950
4. Miller AC, Fuciarelli AF, Jackson WE, et al:
Urinary and serum mutagenicity studies with
Synonyms: None rats implanted with depleted uranium or tan-
talum pellets. Mutagenesis 13(6):6438, 1998
Physical Form. Solid (powder)
C2Cl4F2
REFERENCES
Synonyms: TCDF; Refrigerant 112 1. Greenberg LA, Lester D: Toxicity of the tetra-
chlorodiuoroethanes. Arch Ind Hyg Occup
Physical Form. Colorless solid or liquid Med 2:345347, 1950
2. Clayton JW Jr, Sherman H, Morrison SD,
et al: Toxicity studies on 1,1,2,2-tetrachloro-
Uses. As a refrigerant; solvent extractant; as 1,2-diuoroethane and 1,1,1,2-tetrachloro-
a blowing or foaming agent 2,2-diuoroethane. Am Ind Hyg Assoc J
27(4):332340, 1966
Exposure. Inhalation 3. Bucher JR: NTP Technical Report on Renal
Toxicity Studies of Selected Halogenated Ethanes
Toxicology. At high concentrations, 1,1,2,2- Administered by Gavage to F344 Rats. Toxicity
tetrachloro-1,2-diuoroethane affects the ner- Report Series No. 45, NIH Publication No.
963935, pp 163. Research Triangle Park,
vous system and causes pulmonary edema in
NC, National Toxicology Program, 1996
animals; it is expected that severe exposure in
humans will produce the same effects.
There are no reports of adverse effects in
humans.
Rats exposed to 30,000 ppm died within 1,1,2,2-TETRACHLOROETHANE
1 hour after onset of exposure with severe CAS: 79-34-5
pulmonary hemorrhage.1 At 15,000 ppm, rats
exhibited excitability, incoordination, coma, CHCl2CHCl2
rapid respiration, tremor, and convulsions;
three of four died in 3 hours with pulmonary
edema and hyperemia of the lungs and liver.2 Synonyms: Acetylene tetrachloride; sym-
Exposure at 5000 ppm for 18 hours caused tetrachloroethane; 1,1-dichloro-2,2-dichloro-
coma, pulmonary damage, and death.1 Rats sur- ethane
vived 10 exposures of 4 hours each at 3000 ppm
with rapid, shallow respiration, hyperrespon- Physical Form. Heavy, clear liquid
siveness, and slight incoordination; recovery
was immediate after exposure.2 Decreased Uses. Intermediate in the production of
leukocyte count occurred in female rats exposed trichloroethylene, tetrachloroethylene, and
to 1000 ppm 6 hours/day for 31 days.2 1,2-dichloroethylene; previously used as a
Gavage administration of 0.62 or 1.24 solvent, insecticide and fumigant
mmol/kg/day to rats for 21 days did not cause
clinical signs of toxicity or microscopic effects Exposure. Inhalation; skin absorption
in either the liver or kidney.3 The inability to
produce hyalin droplet nephropathy suggests Toxicology. 1,1,2,2-Tetrachloroethane is
that kidney neoplasms would not occur in rats toxic to the liver and causes central nervous
in 2-year studies.3 system depression and gastrointestinal effects.
1,1,2,2-Tetrachloro-1,2-difluoroethane Reports of industrial experience indicate
was mildly irritating to rabbit eyes and guinea that cases of intoxication most commonly have
pig skin. presented symptoms of gastrointestinal irri-
658 1,1,2,2-TETRACHLOROETHANE
tation (nausea, vomiting, abdominal pain, and other confounding factors may have been
anorexia) and liver involvement (enlarged and present, so that no denite conclusions could
tender liver, jaundice, bilirubinuria).1,2 Jaundice be drawn from the study.9 The IARC has
sometimes progressed to cirrhosis and was determined that there is limited evidence of
often accompanied by delirium, convulsions, carcinogenicity for 1,1,2,2-tetrachloroethane
coma, and death. Other cases have primarily in experimental animals and that it is not clas-
been characterized by central nervous system siable as to its carcinogenicity to humans.10
effects (dizziness, headache, irritability, nerv- In in vivo genetic assays tetrachloroethane
ousness, insomnia, paresthesia, and tremors).1,2 bound covalently to mice DNA.10 It induced
In one study, exposure of two men at sister chromatid exchanges and cell transfor-
116 ppm for 20 minutes caused dizziness and mation, but not chromosomal aberrations or
mild vomiting; at 146 ppm, dizziness occurred unscheduled DNA synthesis, in rodent cells in
after 10 minutes, mucosal irritation at 12 min- vitro.
utes, and fatigue within 20 minutes.2 Concen- Tetrachloroethane has a mild, sweetish
trations up to 335 ppm produced the same odor detectable at 3 ppm that may not provide
symptoms with shorter exposure times. Occu- sufcient warning of dangerous levels because
pational exposure to concentrations ranging of olfactory fatigue.
from 1.5 to 247 ppm caused signs of liver injury The 2003 ACGIH threshold limit
such as hepatomegaly and increased serum value-time-weighted average (TLV-TWA) for
bilirubin. These signs were still found after air 1,1,2,2-tetrachloroethane is 1 ppm (6.9 mg/m3)
concentrations had been reduced below 36 with a notation for skin absorption.
ppm.2 Among a group of workers in India
exposed to 2065 ppm, effects were nausea,
vomiting, and abdominal pain and a high inci- REFERENCES
dence of tremor of the ngers.3
Oral ingestion of 3 ml caused coma or im- 1. von Oettingen WF: The Halogenated
paired consciousness in eight adult patients Aliphatic, Olenic, Aromatic, and Aliphatic-
mistakenly administered tetrachlorethane.2 Aromatic Hydrocarbons Including the Halogen-
Dermal absorption has been suspected in ated Insecticides, Their Toxicity and Potential
some poisoning cases.2 Skin exposure may also Dangers. US Public Health Service Publica-
produce dermatitis due to defatting action; in tion Pub No 414, pp 158164. Washington,
rare cases, the dermatitis may be caused by DC, US Government Printing Ofce, 1955
2. National Institute for Occupational Safety
hypersensitivity to the substance.4
and Health: Criteria for a Recommended
Treatment of mice during gestation caused
Standard . . . Occupational Exposure to 1,1,2,2-
embryotoxic effects and a low incidence of Tetrachloroethane. DHEW (NIOSH) Pub No
malformations.5 Administration of 3.2 mg/ 77121, 143pp. Washington, DC, US Gov-
kg/day to rats for 27 weeks caused irreversible ernment Printing Ofce, 1976
histopathologic changes in the testes.6 3. Lobo-Mendonca R: Tetrachloroethanea
In short-term renal toxicity studies in survey. Br J Ind Med 20:5056, 1963
rats gavage administration of 1,1,2,2-tetra- 4. MCA, Inc.: Chemical Safety Data Sheet SD-34,
chloroethane caused renal toxicity as evidenced Tetrachloroethane, 12pp. Washington, DC,
by an increased renal tubule cell labeling index, MCA, Inc, 1949
indicating replicative DNA synthesis.7 In 2- 5. IARC Monographs on the Evaluation of the
Carcinogenic Risk of Chemicals to Humans,
year studies 1,1,2,2-tetrachloroethane adminis-
Vol 20, Some Halogenated Hydrocarbons,
tered by gavage produced an increased
pp 477489. Lyon, International Agency for
incidence of hepatocellular carcinomas in mice Research on Cancer, 1979
but not in rats.8 In one epidemiological study 6. Agency for Toxic Substances and Disease
of exposed army workers there was a slight Registry (ATSDR): Toxicological Prole for
increase in deaths due to genital cancer and 1,1,2,2-Tetrachloroethane (Update), 184pp. US
leukemia.8 Exposure levels were not available, Public Health Service, 1996
TETRAETHYL LEAD 659
7. National Toxicology Program: NTP Technical months, denite liver injury and some mortal-
Report On Renal Toxicity Studies Of Selected ity occurred.2
Halogenated Ethanes Administered By Gavage Tetrachloronaphthalene was not muta-
To F344/N Rats. Toxicity Report Series genic in the Salmonella Ames test.3
Number 45. NIH Pub 963935, pp 152. US The 2003 ACGIH threshold limit value-
Department of Health and Human Services,
time-weighted average (TLV-TWA) for tetra-
Public Health Service, NIH, 1996
8. National Cancer Institute: Bioassay of 1,1,2,2- chloronaphthalene is 2 mg/m3.
Tetrachloroethane for Possible Carcinogenicity.
DHEW (NIOSH) Pub No 78827. Wash-
ington, DC, US Department of Health, REFERENCES
Education and Welfare, 1978
9. Norman JE Jr, Robinette CD, Fraumeni JF 1. Shelley WB, Kligman AM: The experimental
Jr: The mortality experience of Army World production of acne by penta- and hexa-
War II chemical processing companies. J chloronaphthalenes. Arch Dermatol 75:689
Occup Med 23:818822, 1981 695, 1957
10. IARC Monographs on the Evaluation of the Car- 2. Deichmann WB: Halogenated cyclic hydro-
cinogenic Risk of Chemicals to Humans, Vol 71, carbons. In Clayton GD, Clayton, FE (eds):
Re-evaluation of some organic chemicals, Pattys Industrial Hygiene and Toxicology, 3rd ed,
hydrazine and hydrogen peroxide, pp 817 rev, Vol 2B, Toxicology, pp 36693675. New
27. Lyon, International Agency for Research York, Wiley-Interscience, 1981
on Cancer, 1999 3. World Health Organization: Concise Interna-
tional Chemical Assessment Document (CICAD):
Chlorinated Naphthalenes. Vol 34:140, Geneva,
International Programme on Chemical Safety
(IPCS), 2001
TETRACHLORONAPHTHALENE
CAS: 1335-88-2
to early production methods, to cleaning of lead is rarely more than 50 mg/100 g of blood.2,3
leaded gasoline storage tanks without protec- There is also a total absence of morphologic or
tive equipment, and to suicidal or accidental chemical abnormalities in the erythrocytesin
ingestion.1 Milder cases of intoxication have sharp contrast to intoxication caused by inor-
been caused by exposures to leaded gasoline in ganic lead.2
the workplace.1 A cohort of gasoline depot workers
The absorption by humans of a sufcient exposed to a mean external TEL concentration
quantity of TEL, either briey at a high rate of 84.8 mg/m3 (as Pb) had a statistically
(100 mg/m3 for 1 hour) or for prolonged increased frequency of appearance of tremor
periods at a lower rate, causes intoxication.2 and sinus bradycardia (vs. controls).4 No clini-
The interval between exposure and the onset cal neurological or neurobehavioral ndings
of symptoms varies inversely with dose and were found after long-term exposure at a
may last 1 hour to several days.1 This clinical chemical manufacturing plant where TEL
latency is related to the time it takes for TEL exposures ranged from 0.6 to 43.1 mg/m3 (as
to be absorbed, distributed, and metabolized to Pb).5
triethyl lead before toxic action develops.1 In a mortality study of 592 workers, the
The signs and symptoms of TEL intoxica- mean exposure time to TEL was 17.9 years and
tion differ in many respects from those of inor- urinary lead levels during this period did not
ganic lead intoxication and are often vague exceed 180 mg/liter. The incidence of death in
and easily missed. The initial or prodromal this group and in a control group of employees
symptoms are nonspecic and include asthenia, was less than that expected in the general
weakness, fatigue, headache, nausea, vomiting, population, and there were no peculiarities in
diarrhea, and anorexia.1 Insomnia is usually the specic causes of death in either group.6 In
present, and any sleep is light, usually with a similar study of a different cohort of these
nightmares. Signs of nervous system involve- exposed workers, there were no signicant
ment may then develop (ataxia, tremor, hypo- health differences compared with a control
tonia) as well as bradycardia and hypothermia, group.7 A recent case-control study of TEL
referred to as the TEL triad.1 manufacturing workers found an increased
More severe intoxication causes recurrent incidence of rectal cancer (odds ratio = 3.7) and
or nearly continuous episodes of disorienta- sigmoid colon cancer (odds ratio = 3.5).8 With
tion, hallucinations, facial contortions, and both of these cancers, an exposure-response
intense hyperactivity, which requires that the relationship was observed; odds ratios showed
individual be restrained. Such episodes may a nearly fourfold increase at the high to very
convert abruptly into maniacal or violent con- high cumulative exposure level.
vulsive seizures, which may terminate in coma Of 41 female Swiss mice that survived for
and death.2 Autopsy reports from humans 36 weeks after a single subcutaneous injection
who succumbed to TEL poisoning conrm of 0.6 mg, 5 developed malignant lymphomas
that the brain is the critical target organ, and during the next 15 weeks; the signicance of
both focal and generalized damage have been the study cannot be evaluated, because this
described. For survivors of TEL poisoning, tumor occurs spontaneously with a variable
recovery may take many weeks or months.1 incidence in the mouse strain used.9,10
There is some question as to whether or not all TEL is not an irritant, and no unpleasant
changes are reversible after heavy or long-term sensations are related to skin contact or inha-
exposures.1 lation.1 The ability to penetrate skin makes
During intoxication, there is a striking ele- reliance on airborne concentrations imprac-
vation of the rate of excretion of lead in the tical.2 Teratogenic effects have not been
urine, but only a negligible or slight eleva- observed after exposure to maximally tolerated
tion of the concentration of lead in the blood.2,3 doses in mice or rats.1 Rodent embryos may
In severe intoxication, the urine lead is rarely serve as a poor model for human fetuses
less than 350 mg/l of urine, whereas the blood because the hepatic microsomal metabolizing
TETRAETHYL PYROPHOSPHATE 661
cation of articles for packaging, transporting, at 1800 and 5000 ppm as indicated by a reduc-
and storing of foods tion in the number of live fetuses per litter
(95% resorptions in the 5000 ppm group).6
Exposure. Inhalation These doses were also maternally toxic, pro-
ducing narcosis in dams at 1800 ppm and sig-
Toxicology. Tetrahydrofuran (THF) is an nicant lethality at 5000 ppm. There were no
upper respiratory tract irritant; at high concen- statistically signicant differences in the inci-
trations it is a central nervous system depres- dences of malformations or variations. In
sant; it causes liver tumors in female mice. rats similarly exposed, maternal and fetal
Two workers, who had been exposed to body weights were signicantly reduced at the
glue containing THF for up to 8 hours in a 5000 ppm exposure level.
conned space, had nausea, headache, dizzi- THF showed little evidence of mutagenic
ness, dyspnea, and chest pain.1 Clinical exami- activity in a variety of in vitro and in vivo
nation disclosed conjunctival irritation and assays.5
alteration in liver enzymes. Symptoms dis- Studies have suggested that measurement
appeared within a few hours after exposure of THF concentration in the urine may be
ceased, and liver enzymes returned to normal a useful biological indicator of occupational
within 2 weeks. exposure to THF, whereas exhaled breath and
Administered to mice, 49,000 ppm for 51 blood analyses may be less suitable.7
minutes resulted in narcosis, muscular hypo- The liquid has an ethereal odor similar to
tonia, disappearance of corneal reexes, then acetone and a pungent taste.
coma followed by death.2 The LC50 was esti- The 2003 ACGIH time-weighted average-
mated to be 21,000 ppm in rats exposed for 3 threshold limit value (TWA-TLV) for tetra-
hours.3 Repeated exposure of rats to concen- hydrofuran is 200 ppm (590 mg/m3) with a
trations ranging from 100 to 5000 ppm for short-term exposure limit (STEL) of 250 ppm
12 weeks caused a dose-related increase in ir- (737 mg/m3).
ritation of the mucous membranes. At the
5000 ppm level there was marked edema or
opacity of the cornea, salivation, and discharge REFERENCES
or bleeding in the nasal mucosa.
In subchronic studies mice and rats were 1. Garnier R, Rosenberg N, Puissant JM, et al:
exposed at 0, 66, 200, 600, 1800, and 5000 ppm Tetrahydrofuran poisoning after occupational
exposure. Br J Ind Med 46:677678, 1989
6 hours/day, 5 days/week for 13 weeks.4 Rats
2. Sax NI: Hazardous Chemicals Information
were ataxic at the high dose, and mice exposed
Annual. Vol 1, pp 640644. New York, Van
to 1800 or 5000 ppm appeared to be in a state Nostrand Reinhold Information Services,
of narcosis. A minimal to mild centrilobular 1986
hepatocytomegaly also occured in the mice 3. Katahira T, Teramoto K, Horiguchi S: Ex-
exposed at 5000 ppm. Stomach lesions, limited perimental studies on the acute toxicity of
to the rats, were thought to occur from direct tetrahydrofuran in animals. Jpn J Ind Health
contact of THF ingested during the inhalation 24:373378, 1982
exposure period. 4. Chhabra RS, Elwell MR, Chou B, et al: Sub-
In 2-year inhalation studies (0, 200, 600 or chronic toxicity of tetrahydrofuran vapors in
1800 ppm) there was some evidence of carcino- rats and mice. Fundam Appl Toxicol 14:338345,
1990
genicity in male rats based on increased inci-
5. National Toxicology Program: Toxicology and
dences of renal tubule adenoma or carcinoma
Carcinogenesis Studies of Tetrahydrofuran (CAS
and clear evidence of carcinogenicity in female No. 109-99-9) in F344 Rats and B6C3F1 Mice
mice based on increased incidences of hepato- (Inhalation Studies). NTP Technical Report
cellular neoplasms.5 475, pp 1244, 1998
Exposure of pregnant CD-1 mice 6 hours/ 6. Mast TJ, Weigel RJ, Westerberg RB, et al:
day on days 617 of gestation was embryotoxic Evaluation of the potential for developmental
664 TETRALIN
toxicity in rats and mice following inhalation phosphatase, lactic dehydrogenase, and glu-
exposure to tetrahydrofuran. Fundam Appl tamic oxaloacetic transaminase. All signs and
Toxicol 18:255265, 1992 symptoms returned to normal within 2 weeks.
7. Ong CN, Chia SE, Phoon WH, et al: Bio- Exposure to tetralin-saturated vapor for
logical monitoring of occupational exposure to 8 hours was lethal to rats.3 Nephrotoxicity,
tetrahydrofuran. Br J Ind Med 48:616621,
evidenced as increased cytoplasmic hyalin
1991
droplets in proximal convoluted tubular
epithelial cells, occurred in male but not female
rats exposed intragastrically for 2 weeks.4
Acute intoxication of guinea pigs, exposed
orally (0.25 ml/day), percutaneously (by appli-
TETRALIN cation to 6 cm2 of shaved skin), or by inhalation
CAS: 119-64-2 (1.42 mg/l for 8 hours/day), produced loss of
weight, tremors, paralysis of the hindquarters,
C10H12 and difcult respiration.3
Tetralin has caused cataracts in guinea pigs
and rabbits but not rats after oral or inhalation
Synonyms: 1,2,3,4-tetrahydronaphthalene; exposure; differences in the susceptibility of
tetraline; tetranap; benzocyclohexane different species to cataractogenic effects have
been attributed to differences in their metabo-
Physical Form. Colorless liquid lism of the compound.5
Applied to the skin of guinea pigs, the
Uses. As a solvent for fats and oils and as an liquid caused erythema, drying, and defatting.
alternative to turpentine in polishes and paint; In rabbits, the irritant dermal and ocular
insecticide dose was 500 mg and the dermal LD50 was
17.3 g/kg.3
Exposure. Inhalation An ACGIH threshold limit value-time-
weighted average (TLV-TWA) has not been
Toxicology. Tetralin is an irritant to the skin, established for tetralin.
eyes, and mucous membranes and may cause
neurological disturbances at high concentra-
tions.
The hallmark for tetralin exposure in
REFERENCES
humans is the production of green urine.1 Two
painters who used tetralin-containing varnishes 1. Longacre SL: Tetralin. In Snyder R (ed): Ethel
in a poorly ventilated area had intense irrita- Brownings Toxicity and Metabolism of Industrial
tion of the mucous membranes, profuse Solvents, 2nd ed, Vol I, Hydrocarbons, pp
lacrimation, headache, stupor, and the charac- 143152. Amsterdam, Elsevier, 1987
teristic green urine. Hospital patients on a ward 2. Drayer DE, Reidenberg MM: Metabolism of
whose oor had been waxed with a tetralin- tetralin and toxicity of Cuprex in man. Drug
based polish experienced similar symptoms Metab Dispos 1:577579, 1973
including eye irritation, headache, nausea, 3. Smyth HF, Carpenter CP, Weil CS: Range-
diarrhea, and green urine. Asthenia also was nding toxicity data: List IV. AMA Arch Ind
observed in subjects who had slept in rooms Hyg Occup Med 4:119122, 1951
4. Serve MP, Llewelyn BM, Yu KO, et al:
waxed with a tetralin-based polish.
Metabolism and nephrotoxicity of tetralin in
In a human case involving ingestion of male Fischer 344 Rats. J Toxicol Environ Health
approximately 11.5 mg/kg, effects consisted of 26(3):267-75, 1989
nausea, vomiting, and green-gray urine.2 Clin- 5. Hayes WJ Jr, ER Laws Jr (eds): Handbook of
ical changes included proteinuria and elevated Pesticide Toxicology. Vol. 2. Classes of Pesticides.
serum levels of bilirubin, creatine, alkaline p 642. New York, Academic Press, 1991
TETRAMETHYL LEAD 665
detecting presence of double bonds in organic The IARC has determined that there is
compounds sufcient evidence for the carcinogenicity of
tetranitromethane in experimental animals and
Exposure. Inhalation that it is possibly carcinogenic to humans.7
The 2003 ACGIH threshold limit value-
Toxicology. Tetranitromethane vapor is a time-weighted average (TLV-TWA) for tetran-
severe irritant of the eyes and respiratory tract; itromethane is 0.005 ppm (0.04 mg/m3) with an
it can cause mild methemoglobinemia. A2-suspected human carcinogen designation.
In workers, various studies showed that
exposure caused irritation of the eyes, nose,
and throat; dizziness; headache; chest pain; REFERENCES
dyspnea; and, rarely, skin irritation.1
Severe exposure may be expected to cause 1. Horn HJ: Inhalation toxicology of tetrani-
the formation of methemoglobin and resultant tromethane. AMA Arch Ind Hyg Occup Med
anoxia with cyanosis (especially evident in the 10:213222, 1954
lips, nose, and earlobes); other effects are weak- 2. Hygienic Guide Series: Tetranitromethane.
ness, dizziness, and severe headache.24 Am Ind Hyg Assoc J 25:513515, 1964
3. Hager KF: Tetranitromethane. Ind Eng Chem
Concentrations in excess of 1 ppm cause
41:21682172, 1949
lacrimation and upper respiratory irritation,
4. Rieder RF: Methemoglobinemia and sul-
whereas 0.4 ppm may cause mild irritation.2 methemoglobinemia. In Wyngaarden JB,
The liquid on the skin may cause mild burns.2 Smith LH (eds): Cecil Textbook of Medicine, 16th
The LC50 for rats was 1230 ppm for 36 ed, p 896. Philadelphia, PA, W. B.
minutes; effects included lacrimation, rhinor- Saunders, 1982
rhea, gasping, and cyanosis. Pulmonary edema 5. Bucher JR, Huff JE, Jokinen MP, et al: Inhala-
was present at autopsy.1 At 300 ppm, all rats tion of tetranitromethane causes nasal passage
died within 4090 minutes, whereas exposure irritation and pulmonary carcinogenesis in
to 33 ppm caused deaths in 310 hours.1 Expo- rodents. Cancer Lett 57:95101, 1991
sure to 6.35 ppm 6 hours/day, 5 days/week, for 6. National Toxicology Program: Toxicology and
Carcinogenesis Studies of Tetranitromethane (CAS
6 months resulted in death of 11 of 19 rats;
No. 509-14-8) in F344/N Rats and B6C3F1
similar exposure in dogs caused mild symptoms
Mice (Inhalation Studies). NTP No. 386.
the rst 2 days, followed by complete recovery.1 NTIS Pub No. PB-91-113-373. Springeld,
In three species of animals, intravenous in- VA, National Technical Information Service,
jection caused methemoglobinema, anemia, 1990
damage to the central nervous system, and 7. IARC Monographs on the Evaluation of Carcino-
pulmonary edema.1 genic Risk to Humans, Vol 65, Printing
Rats and mice were exposed 6 hours/day, processes and printing inks, carbon black
5 days/week for 2 years at 2 or 5 ppm or 0.5 or and some nitrocompounds. pp 4378.
2 ppm, respectively.5,6 Tetranitromethane was Lyon, International Agency for Research on
found to cause mild irritation and hyperplastic Cancer, 1996
lesions in the nasal passages. Nearly all animals
exposed at the higher dose levels developed
alveolar/bronchiolar adenoma or carcinoma;
squamous cell neoplasms of the lung also
occurred in exposed rats. The carcinogenic TETRASODIUM PYROPHOSPHATE
activity of tetranitromethane appears to be the CAS: 7722-88-5
result of chronic epithelial irritation mitotic
stimulation and ensuing hyperplastic response.6 Na4P2O7
Tetranitromethane was genotoxic in a
number of assays inducing chromosomal
aberrations and sister chromatid exchanges in Synonyms: Sodium pyrophosphate; tetra-
Chinese hamster ovary cells.6 sodium diphosphate; TSPP
668 TETRYL
Physical Form. White crystalline powder Uses. Once widely used as a military explo-
sive but no longer manufactured or used in the
Uses. As a water softener; as a metal cleaner; United States
as a dispersing and emulsifying agent
Exposure. Inhalation; skin absorption
Exposure. Inhalation
Toxicology. Tetryl causes contact and sensi-
Toxicology. Tetrasodium pyrophosphate tization dermatitis and irritation of the upper
(TSPP) is of low toxicity, but the dust may be respiratory tract.
irritating to the eyes, upper respiratory tract, Contact with tetryl causes a bright yellow
and skin. staining, most often seen on the palms, face, and
Mild to moderate skin and eye irritation neck and in the hair.1 The irritant effects on the
have occurred with acute exposure to the dust. upper respiratory tract are variously localized
In rats the oral LD50 ranges between 1 and from the nostrils to the bronchi and cause
3 g/kg.1 Applied to rabbit eyes it can cause burning, itching, sneezing, nasal discharge,
severe irritation and corneal injury. There were epistaxis, and cough. The symptoms may begin
no adverse effects in rats fed 50 mg/kg/day for the rst day of exposure or as late as the third
1 year. month; on removal from exposure the symp-
Injected into chick embryos TSPP pro- toms typically regress over 24 weeks.1
duced terata.2 Dermatitis in workers may appear as early
The 2003 ACGIH threshold limit value- as the rst week of exposure to the dust, with
time-weighted average (TLV-TWA) for tetra- itching of and around the eyes; there is a pro-
sodium pyrophosphate is 5 mg/m3. gression to erythema and edema occurring
most often on the nasal folds, cheeks, and neck;
papules and vesicles may develop; the remain-
REFERENCES der of the body is rarely affected.1 The sever-
est forms show massive generalized edema with
1. ACGIH: Tetrasodium pyrophosphate. Docu- partial obstruction of the trachea due to swell-
mentation of TLVs and BEIs, 6th ed, pp
ing of the tongue and require hospitalization;
15291530. Cincinnati, OH, American
exfoliation usually occurs after the edema sub-
Conference of Governmental Industrialist
Hygienists, 1991 sides.1 The majority of these effects occur
2. Verrett MJ, Scott WF, Reynaldo EF, et al: between the 10th and 20th days of exposure; on
Toxicity and teratogenicity of food additive cessation of exposure, there is rapid abatement
chemicals in the developing chicken embryo. of the mild symptoms and, after 310 days, dis-
Toxicol Appl Pharmacol 56:265273, 1980 appearance of physical signs.1
Some individuals have become sensitized
to tetryl and developed a rash in response to
recontact with even small amounts of the
substance.2
TETRYL Other effects reported in tetryl workers
CAS: 479-45-8 are irritability, fatigue, malaise, headache, las-
situde, insomnia, nausea, and vomiting.1
C7H5N5O8 Anemia, of either the marrow depression or
deciency type, has been observed among
tetryl workers.1 Conjunctivitis may be caused
Synonyms: 2,4,6-Trinitrophenylmethyl- by rubbing the eyes with contaminated hands
nitramine; tetralite; nitramine; N-methyl-N- or by airborne dust; keratitis and iridocyclitis
2,4,6-tetranitroaniline have occurred.3 Tetryl has been reported to
cause irreversible liver damage and death after
Physical Form. Yellow crystals chronic heavy exposure.4 However, complicat-
THALLIUM 669
ing medical conditions and/or coexposure to Toxicology. Thallium is one of the most
other toxic chemicals could be contributing toxic of the heavy metals; it primarily affects
factors in the deaths.2 the nervous system and gastrointestinal tract
A number of in vitro genotoxic assays in and causes hair loss.
bacteria and fungi suggest that tetryl is a direct- The lethal oral dose of thallium acetate for
acting genotoxin.2 humans is estimated to be about 12 mg/kg body
The 2003 ACGIH threshold limit value- weight.1 Although symptoms may be nonspe-
time-weighted average (TLV-TWA) for tetryl cic owing to multiorgan toxicity, gastroen-
is 1.5 mg/m3. teritis, polyneuropathy, and hair loss are the
dominant clinical features of poisoning.2 In
fatal cases, however, death has been regularly
REFERENCES attributed to cardiac or respiratory failure,
which may overshadow the characteristic man-
1. Bergman BB: Tetryl toxicity: A summary of ten
ifestation of neuropathy.3 A latent period of
years experience. AMA Arch Ind Hyg Occup
hours to 12 days may follow acute exposure.2
Med 5:1020, 1952
2. Agency for Toxic Substances and Disease Nausea, vomiting, diarrhea, abdominal pain,
Registry (ATSDR): Toxicological Prole for and gastrointestinal hemorrhage are common
Tetryl (2,4,6 Trinitrophenyl-N-Methylnitramine) initial complaints. These symptoms are fol-
pp 1100. US Department of Health and lowed or accompanied by ptosis and strabis-
Human Services, Public Health Service, 1995 mus; peripheral neuritis; pain, weakness, and
3. Troup HE: Clinical effects of tetryl (CE paresthesias in the legs; tremor; and retroster-
powder). Br J Ind Med 3:2023, 1946 nal tightness and chest pain.1,4 Severe and
4. Hardy HL, Maloof CC: Evidence of systemic abrupt alopecia is pathognomonic of the toxic
effect of tetryl, with summary of available effects of thallium and usually, but not always,
literature. AMA Arch Ind Hyg Occup Med
occurs after 23 weeks.4,5
1:545555, 1950
Severe intoxication has resulted in prostra-
tion, tachycardia, blood pressure uctuations,
convulsive seizures, choreiform movements, and
psychosis. Recovery may be complete, but
THALLIUM permanent residual effects such as ataxia, optic
CAS: 7440-28-0 atrophy, tremor, mental abnormalities, and
footdrop have been reported.4 In cases of fatal
Tl intoxication, typical autopsy ndings include pul-
monary edema, necrosis of the liver, nephritis,
and degenerative changes in peripheral axons.1
Compounds. Thallium acetate; thallium Prolonged ingestion of thallium produces
chloride a variable clinical picture, which includes stom-
atitis, tremor, cachexia, polyneuropathy, alope-
Physical Form. Bluish-white, very soft, cia, and emotional disturbance.4 Alopecia may
inelastic, easily fusible heavy metal be the best known effect of chronic poisoning,
with epilation beginning about 10 days after
Uses. In the semiconductor industry for the ingestion and complete hair loss occurring in
production of switches and closures; the phar- about 1 month.2
maceutical industry for cardiac imaging; man- In a study of 15 workers who had handled
ufacture of optical glass; formerly used as a solutions of organic thallium salts over a 7.5-
rodenticide and insecticide until banned in the year period, 6 workers suffered thallium intox-
US in 1972. ication. Chief complaints were abdominal pain,
fatigue, weight loss, pain in the legs, and
Exposure. Inhalation; skin absorption; nervous irritability; three of the workers had
ingestion albuminuria, and one had hematuria.6
670 THALLIUM
Physical Form. Fine white to gray powder Two-year studies of rats administered up
to 2500 ppm and mice administered up to
Uses. As an antioxidant in the rubber and 1000 ppm in the diet was associated with
plastics industry; as a stabilizer in polyethylene Kupffer cell hypertrophy, cytoplasmic vac-
and polyolen packaging materials for food- uolization, and mixed cell foci in the liver of
stuffs rats but no signicant pathologic ndings in
Exposure. Ingestion; inhalation mice. There was no evidence of carcinogenic
activity in either species.
Toxicology. 4,4-Thiobis(6-tert-butyl-m- TBBC was not mutagenic in Salmonella
cresol) (TBBC) is of low systemic toxicity in typhimurium strains with or without metabolic
animals; allergic contact dermatitis has been activation. In Chinese hamster ovary cells,
reported in humans. TBBC induced an increase in sister chromatid
Allergic contact dermatitis developed on exchanges but there were no increases in chro-
the hands and face of two patients after expo- mosomal aberrations.
sure to latex examination gloves.1 Both patients The 2003 ACGIH threshold limit value-
were patch test negative to the usual rubber time-weighted average (TLV-TWA) for 4,4-
allergens, but both had a positive test reaction thiobis(6-tert-butyl-m-cresol) is 10 mg/m3.
to TBBC.
In 15-day feeding studies, groups of rats
and mice were fed diets containing 1000, REFERENCES
2500, 5000, 10,000, or 25,000 ppm TBBC.2 All
25,000 and some 10,000 ppm rats died; rats in 1. Rich P, Belozer ML, Norris P, et al: Allergic
the 5000 and 10,000 ppm group consumed less contact dermatitis to two antioxidants in latex
food than controls and had signicant weight gloves: 4,4-Thiobis(6-tert-butyl-meta-cresol)
(Lowinox 44536) and butylhydroxyanisole.
loss and diarrhea. Renal papillary and tubule
Allergen alternatives for glove allergic
necroses were the principle lesions attributed
patients. J Am Acad Dermatol 24:3743, 1991
to TBBC exposure in the 10,000 ppm group. 2. National Toxicology Program: NTP Technical
Focal necrosis of the glandular stomach also Report on the Toxicology and Carcinogenesis
occurred in some 10,000 ppm rats. Some Studies of 4,4-Thiobis(6-t-Butyl-m-Cresol) (CAS
mice did not survive exposure at 5000 and No. 96-69-5) in F344 Rats and B6C3F1 Mice
10,000 ppm, and 25,000 ppm was lethal to all. (Feed Studies), NTP TR 435, NIH Pub No 93-
Weight loss, diarrhea, and renal tubule necro- 3166, US Department of Health and Human
sis were similar to that observed in rats. Services, Public Health Service, National
Histopathologic ndings in rats fed 2500 Institutes of Health, 1994
or 5000 ppm for 13 weeks included hypertro-
phy of Kupffer cells, bile duct hyperplasia, and
individual cell necrosis of hepatocytes; pig-
mentation and degeneration of the renal corti- THIOGLYCOLIC ACID
cal tubule epithelial cells was also present.2 In CAS: 68-11-1
male rats exposed at 1000 ppm and above
hematocrit and hemoglobin concentrations C2H4O2S
and mean erythrocyte volume were signi-
cantly lower than controls. Mice survived expo-
sures up to 2500 ppm in their diets for 13 Synonyms: Mercaptoacetic acid; thiovanic
weeks. Body weights were signicantly lower in acid; thioglycollic acid
the high-dose groups and corresponded with
reduced feed consumption. Kupffer cell hyper- Physical Form. Colorless liquid
trophy, bile duct hyperplasia, increased spleen
weights, and an increase in size and number of Uses. In the formulations of permanent wave
macrophages in mesenteric lymph nodes were solutions and depilatories; in pharmaceutical
present in the 2500 ppm-treated mice. manufacture; as a stabilizer in vinyl plastics
674 THIONYL CHLORIDE
Exposure. Inhalation; skin absorption 2. Fassett DW: Organic Acids and Related Com-
pounds. In Fassett DW, Irish DD (eds): Indus-
Toxicology. Thioglycolic acid is corrosive to trial Hygiene and Toxicology, 2nd ed, rev, Vol 2,
the skin, eyes, and mucous membranes on pp 180708. New York, John Wiley & Sons,
contact. 1963
In one reported case, thioglycolic acid acci- 3. Huntingdon Res Ctr Ltd: Initial Submission:
dentally splashed onto the eyes, face, legs, and Thioglycolic Acid Acute Inhalation Toxicity
arms caused second-degree burns of the skin.1 Study in Rats 4-Hour Exposure, with cover
Within 2 hours the corneas became clouded letter dated 09/15/94. EPA/OTS Doc #
88-940000230
and the conjunctivae was edematous. Over the
4. Zeiger E, Anderson B, Haworth S. et al:
course of several months the cornea cleared and Salmonella mutagenicity tests: III. Results
necrotic conjunctiva regenerated and vascular- from the testing of 255 chemicals. Environ Mol
ized, leaving slightly impaired vision. Mutagen 9(suppl 9):1110, 1987
In rats the oral LD50 is less than 50 mg/kg.2
Applied to the skin of guinea pigs, 5 ml/kg of a
10% solution caused weakness, gasping, con-
vulsions, and death.
Whole body exposure of rats for 4 hours THIONYL CHLORIDE
to 0.172 or 0.338 mg/l resulted in some mor- CAS: 7719-09-7
tality; clinical signs of irritative respiratory tox-
icity during exposures included wetness about SOCl2
the eyes and mouth, abnormal respiration,
restlessness, and hunched posture.3 Abnormal
respiration, brown-stained snout, sensitivity Synonyms: Sulfurous oxychloride; thionyl
to touch, and reduced food and water dichloride
consumption were noted during the 14-day
observation period. Microscopic evaluation Physical Form. Colorless to pale yellow
of decedent rats and rats surviving 2-week liquid with a suffocating odor
recovery found lung congestion among study
lethalities only.3 Uses and Sources. In the manufacture of
Two drops of a 10% solution instilled in lithium batteries; in the synthesis of herbicides,
rabbit eyes caused immediate pain, and the surfactants, drugs, vitamins, and dyestuffs
epithelium turned gray within seconds; the
conjunctivae were hyperemic with moderate Exposure. Inhalation
discharge and corneas were opaque at 2 days.2
Corneal clouding gradually, but not com- Toxicology. Thionyl chloride may cause
pletely, cleared with in 6 weeks. severe irritation of the skin, eyes, and mucous
Thioglycolic acid was not mutagenic in a membranes as well as potentially serious lung
number of Salmonella typhimurium strains with injury.
or without metabolic activation.4 Two cases of accidental thionyl chloride
The 2003 ACGIH threshold limit value- exposure resulting in lung injury that varied
time-weighted average (TLV-TWA) for thio- from relatively mild and reversible interstitial
glycolic acid is 1 ppm (3.8 mg/m3) with a lung disease to a severe form of bronchiolitis
notation for skin absorption. obliterans have recently been reported.1 In the
rst case a 30-year-old worker was exposed
REFERENCES when a thionyl chloride tank burst in an open
space. The worker was asymptomatic until
1. Grant WM: Toxicology of the Eye, 3rd ed, dyspnea gradually developed 2 weeks after his
p 905. Springeld, Illinois, Charles C Thomas, exposure. The patient was mildly dyspneic with
1986 22 respirations per minute, and lung function
THIRAM 675
Physical Form. White or yellow crystals 25 mg/kg/day for 90 days produced a signi-
cant increase in relative testes weight and mild
Uses. Agricultural fungicide; rubber acceler- pathomorphological changes indicative of tes-
ator ticular dysfunction.7 A signicant increase in
the frequency of abnormal sperm was found in
Exposure. Inhalation mice after a single subcutaneous dose of 1000
mg/kg or ve repeated doses at 250 mg/kg
Toxicology. Thiram is an irritant of the eyes, body weight.8
mucous membranes, and skin and causes sensi- Thiram was teratogenic at maternally toxic
tization dermatitis; adverse reproductive effects doses, causing primarily skeletal malformations
have been reported in experimental animals. in hamsters given a single oral dose of 250
Thiram is the methyl analog of disulram mg/kg during the period of organogenesis and
or Antabuse, a drug used to establish a con- in mice given oral doses of 530 mg per animal
ditioned reex of fear of alcohol in the treat- daily between days 6 and 17 of pregnancy.9,10
ment of alcoholism.1 Ingestion of even a small A dietary level of 1000 ppm for 2 years pro-
amount of alcohol while undergoing Antabuse duced weakness, ataxia, and varying degrees of
therapy is followed by distressing and occa- paralysis of the hind legs of rats.2
sionally dangerous symptoms including, ush- In a chronic feeding study, rats were
ing, palpitations, headache, nausea, vomiting, administered 3, 30, or 300 ppm in the diets for
and dyspnea. The systemic Antabuse-alcohol up to 2 years and dogs were given 0.4, 4, or
syndrome is apparently rare in thiram-exposed 40 mg/day for up to 2 years.11 Rats of the
workers, but it has been reported.2 In one case, high-dose group had retarded growth and
a man became ill and died 4 days after treating females had anemia, regressive changes of the
seed with thiram. Although he received sub- sciatic nerve, and atrophy of the calf muscle.
stantial exposure over 10 hours, it is unclear Dogs in the high-dose group had severe toxic
whether he received enough thiram to produce signs, including vomiting, salivation, and clonic
death without associated alcohol ingestion.2 A convulsions and did not survive the rst year of
skin reaction, without other systemic effects, is treatment. Ophthalmological changes included
said to occur in chronically exposed workers fundal hemorrhage, miosis, and desquamation
after ingestion of alcohol. The response of the of the retina. At the mid-dose range dogs had
skin is rapid and takes the form of ushing, ery- liver failure and females also had kidney
thema, pruritis and urticaria.1 Thiram without damage. There were no increased incidences of
alcohol can produce dermatitis but only in a any tumors.
few susceptible people. Sensitization dermatitis Thiram also was not carcinogenic in rats
in the form of eczema has occurred on the by gavage or in mice by single subcutaneous
hands, forearms, and feet.1,3 injection.2,5 In skin painting studies in mice
In mice and male rats, the oral LD50 was thiram had tumor-initiating and -promoting
approximately 4 g/kg; symptoms of toxicity activity but was not a complete carcinogen.12
were ataxia and hyperactivity followed by inac- The IARC has noted, however, that thiram
tivity, loss of muscular tone, labored breathing, can react with nitrite under mildly acidic
clonic convulsions, and death within 27 days.4 conditions, simulating those in the human
Daily administration of 132 mg/kg body stomach, to form N-nitrosodimethylamine,
weight in the diet for 13 weeks decreased the which is carcinogenic in a number of species.5
fertility of CD rats; 14 days at 96 mg/kg altered Dietary administration of 500 ppm thiram plus
the estrous cycle of females.5 In female rats 50 2000 ppm sodium nitrite for 2 years caused a
mg/kg injected intraperitoneally on the day of high incidence of nasal cavity tumors in rats vs.
proestrus delayed ovulation and resulted in a no tumors in controls or in animals given only
lower fertility rate, a reduction of live fetuses, one compound.13
an increase in resorptions, and a slower rate of The IARC has determined that there is
fetal development.6 Gavage doses in rats of inadequate evidence in experimental animals
TIN (Inorganic Compounds) 677
and in humans for the carcinogenicity of small laboratory animals. Toxicol Appl Phar-
thiram. macol 15:152173, 1969
Thiram was genotoxic to insects, plants, 10. Roll R: Teratologische Untersuchungen mit
fungi, and bacteria: it induced sister chromatid Thiram (TMTD) an zwei Mausestammen.
exchange and unscheduled DNA synthesis in Arch Toxicol 27:163186, 1971
11. Maita K, Tsuda S, Shirasu Y: Chronic studies
cultured human cells. Despite established
with thiram in wistar rats and beagle dogs.
genotoxicity in vitro, it showed no clastogenic Fundam Appl Toxicol 16:667686, 1991
and/or aneugenic activity in vivo after oral 12. Shukla Y, Baqar SM, Mehrotra NK: Car-
administration to mice at the maximum toler- cinogenic and co-carcinogenic studies of
ated dose.14 thiram on mouse skin. Food Chem Toxicol
The 2003 ACGIH threshold limit value- 34(3):2839, 1996
time-weighted average (TLV-TWA) for thiram 13. Lijinsky W: Induction of tumors of the nasal
is 1 mg/m3. cavity in rats by concurrent feeding of thiram
and sodium nitrite. J Toxicol Environ Health
13:609614, 1984
14. Villani P, Andreoli C, Crebelli R, et al:
Analysis of micronuclei and DNA single-
REFERENCES
strand breaks in mouse splenocytes and
peripheral lymphocytes after oral administra-
1. Shelley WB: Golf-course dermatitis due to
tion of tetramethylthiuram disulde (thiram).
thiram fungicide. JAMA 188:415417, 1964
Food Chem Toxicol 36(3):15564, 1998
2. Hayes WJ Jr: Pesticides Studied in Man,
pp 603606. Baltimore, MD, Williams &
Wilkins, 1982
3. Fogh A, Pock-Steen B: Contact sensitivity
to thiram in wooden shoes. Contact Derm
27:348, 1992 TIN (Inorganic Compounds)
4. Lee CC et al: Oral toxicity of ferric CAS: 7440-31-5
dimethyldithiocarbamate (ferbam) and
tetramethyl-thiram disulde (thiram) in Sn
rodents. J Toxicol Environ Health 4:93106,
1978
5. IARC Monographs on the Evaluation of Car- Compounds: Stannic oxide; tin tetrachloride;
cinogenic Risk to Humans, Vol 53, Occupa- stannic chloride; stannous chloride; stannous
tional exposures in insecticide application, sulfate; sodium stannate; potassium stannate
and some pesticides, pp 403420. Lyon,
International Agency for Research on
Cancer, 1991 Physical Form. Solid
6. Stoker TE, Cooper RL, Goldman JM, et al:
Characterization of pregnancy outcome fol- Uses. Protective coatings and alloys; glass
lowing thiram-induced ovulatory delay in the bottle manufacture
female rat. Neurotoxicol Teratol 18(3):27782,
1996 Exposure. Inhalation
7. Mishra VK, Srivastava MK, Raizada RB: Tes-
ticular toxicity of thiram in rat: Morphologi- Toxicology. Inorganic tin salts are irritants
cal and biochemical evaluations. Ind Health of the eyes and skin.
31:5967, 1993 No systemic effects have been reported
8. Hemavathi E, Rahiman MA: Toxicological
from industrial exposure. Some inorganic tin
effects of ziram, thiram, and dithane m-45
assessed by sperm shaped abnormalities in compounds can cause skin or eye irritation
mice. J Toxicol Environ Health 38:393398, because of acid or alkaline reaction produced
1993 with water. Tin tetrachloride, stannous chlo-
9. Robens JF: Teratologic studies of carbaryl, ride, and stannous sulfate are strong acids;
diazinon, norea, disulram, and thiram in sodium and potassium stannate are strong
678 TIN (Organic Compounds)
alkalies.1 Glass bottle makers exposed to a hot tially hazardous substances. J Occup Med 27:
mist of stannic chloride (0.100.18 mg/m3) 277282, 1985
and hydrogen chloride (5 ppm) had an excess 3. Dundon CE, Hughes JP: Stannic oxide pneu-
of symptoms of respiratory irritation over moconiosis. Am J Roentgen 63:797812, 1950
workers exposed predominantly to hydrogen 4. Schafer SG, Femfurt U: Tina toxic heavy
metal? A review of the literature. Regul Toxicol
chloride in the same plant.2 Exposure to dust
Pharmacol 4:5769, 1984
and fume of tin oxide results in stannosis, a rare 5. Barnes JM, Stoner HB: The toxicology of tin
benign pneumoconiosis.3 compounds. Pharmacol Rev 11:214216, 1959
Ingested inorganic tin exhibits only mod- 6. Agency for Toxic Substances and Disease Reg-
erate toxicity, probably because of poor absorp- istry (ATSDR): Toxicological Prole for Tin. TP-
tion and rapid tissue turnover. However, 91/27, 148pp. US Department of Health and
consumption of food and fruit juices heavily Human Services, Public Health Service, 1992
contaminated with tin compounds in the range
of 1400 ppm or more results in symptoms of
gastrointestinal irritation, including nausea,
abdominal cramps, vomiting, and diarrhea.4
In animals, high doses of soluble tin salts TIN (Organic Compounds)
induce neurological disturbances.4 Subcuta- CAS: 7440-31-5
neous injection of animals with sodium stan-
nous tartrate at a daily dose of 12.5 mg/kg was Sn
fatal. Death was preceded by vomiting, diar-
rhea, and paralysis with twitching of the limbs.5
Daily administration to a dog of stannous chlo- Synonyms: Triethyltin iodide; dibutyltin
ride in milk at a level of 500 mg/kg produced chloride; tributyltin chloride; triphenyltin
paralysis after 14 months.1 acetate; bis(tributyltin) oxide; triphenyltin
Administration of 1 and 3 mg Sn/kg body chloride
weight to rats resulted in inhibition of various
enzymes, including hepatic succinate dehydro- Physical Form. Solids and liquids
genase and the acid phosphatase of the femoral
epiphysis. Tin also appears to interact with the Uses. Stabilizers in polymers; biocides, cata-
absorption and metabolism of biological essen- lysts
tial metals such as copper, zinc, and iron and to
inuence heme metabolism.4 Exposure. Inhalation; skin absorption
Limited animal testing with stannous chlo-
ride has not revealed evidence of carcinogenic Toxicology. Organotin compounds cause
potential.6 Mixed results have been observed in irritation of the eyes, mucous membranes, and
genotoxic assays. skin; some produce cerebral edema and others
The 2003 ACGIH threshold limit value- cause hepatic necrosis.
time-weighted average (TLV-TWA) for tin The most toxic of the organotin
(metal, oxide, and inorganic compounds except compounds are the trialkyltins, followed by
SnH4) is 2 mg/m3. the dialkyltins and monoalkyltins.1 The
tetraalkyltins are metabolized to their tri-
alkyltin homologs; their effects are those of the
trialkyltins, with severity of effects dependent
REFERENCES on the rate of metabolic conversion. In each
major organotin group, the ethyl derivative is
1. Stauden A (ed): Kirk-Othmer Encyclopedia of
Chemical Technology, 2nd ed, Vol 20, pp the most toxic.1
323325. New York, Interscience, 1972
2. Levy BS, Davis F, Johnson B: Respiratory Triethyltin: Oral administration of a French
symptoms among glass bottle makers exposed medication (Stalinon, containing diethyltin
to stannic chloride solution and other poten- diiodide and isolinoleic esters) for treatment of
TITANIUM DIOXIDE 679
Uses. Widely used in paints, paper, plastics, the biological relevance of these tumors to
ceramics, rubber, and inks; in sunscreens and humans.7 There was no evidence that titanium
cosmetics dioxide-coated mica produced either toxico-
logical or carcinogenic results when adminis-
Exposure. Inhalation tered in the diet of F344 rats for 130 weeks at
concentrations as high as 5%.8
Toxicology. Titanium dioxide is a mild pul- Titanium dioxide was not mutagenic in
monary irritant and is generally regarded as a bacterial assays, but it did increase the fre-
nuisance dust. quency of sister chromatid exchanges and
Three of 15 workers who had been micronuclei in Chinese hamster ovary cells.8,9
exposed to titanium dioxide dust, three showed In another report titanium dioxide was not
radiographic signs in the lungs resembling genotoxic in a number of in vitro assays, but
slight brosis, but disabling injury did not irradiation with UV/visible light caused signif-
occur. The magnitude and duration of expo- icant photogenotoxicity in a single-cell gel
sure were not specied.1,2 In the lungs of three assay and a chromosomal aberration assay.10
workers involved in processing titanium The 2003 ACGIH threshold limit value-
dioxide pigments, deposits of the dust in the time-weighted average (TLV-TWA) for tita-
pulmonary interstitium were associated with nium dioxide is 10 mg/m3.
cell destruction and slight brosis; the ndings
indicated that titanium dioxide is a mild pul-
monary irritant.3
Cohort and case control analyses of 1576 REFERENCES
workers found no statistically signicant asso- 1. Browning E: Toxicity of Industrial Metals, 2nd
ciations between titanium dioxide exposure and ed, pp 331335. London, Butterworths, 1969
risk of lung cancer, chronic respiratory disease, 2. AIHA: AIHA Hygienic Guide Series: Titanium
and chest roentgenogram abnormalities.4 No Dioxide. Akron, OH, American Industrial
cases of pulmonary brosis were observed Hygiene Association, 1978
among titanium dioxide-exposed employees. 3. Elo R, Maatta K, Uksila E, Arstila AU: Pul-
Rats exposed 6 hours/day for 5 days to monary deposits of titanium dioxide in man.
50 mg/m3 and examined at various intervals Arch Pathol 94:417424, 1972
after exposure showed no pulmonary response 4. Chen JL, Fayerweather WE: Epidemiologic
to titanium dioxide as determined by study of workers exposed to titanium dioxide.
J Occup Med 30(12):93742, 1988
bronchoalveolar lavage uid parameters or
5. Driscoll KE, Lindenschmidt RC, Maurer JK,
histopathology.5 Repeated exposure of rats to
et al: Pulmonary response to inhaled silica or
concentrations of 10328 mppcf of air for as titanium dioxide. Toxicol Appl Pharmacol 111:
long as 13 months caused small focal areas of 201210, 1991
emphysema, which were attributed to large 6. Christie H, Mackay RJ, Fisher AM: Pul-
deposits of dust. There was no evidence of any monary effects of inhalation of titanium
specic lesion being produced by titanium dioxide by rats. Am Ind Hyg Assoc J 24:4246,
dioxide.6 1963
In a 2-year inhalation bioassay exposure to 7. Lee K et al: Pulmonary response of rats
250 mg/m3 titanium dioxide resulted in the exposed to titanium dioxide (TiO2) by inhala-
development of squamous cell carcinomas in tion for two years. Toxicol Appl Pharmacol 79:
179192, 1985
13 of 74 female rats and in 1 of 77 male rats,
8. Bernard BK, Osheroff MR, Hofmann A,
as well as an increase in bronchioloalveolar
et al: Toxicology and carcinogenesis studies
adenomas. No excess tumor incidence was of dietary titanium dioxide-coated mica in
observed at 50 mg/m3.7 Given the extremely male and female Fischer 344 rats. J Toxicol
high concentration exposures, the unusual his- Environ Health 29:417429, 1990
tology and location of the tumors, and the 9. Lu PJ, Ho IC, Lee TC: Induction of sister
absence of metastases, the authors questioned chromatid exchanges and micronuclei by tita-
TOLUENE 681
nium dioxide in Chinese hamster ovary-K1 been described after long-term inhalational
cells. Mutat Res 414(13):1520, 1998 abuse of toluene among glue sniffers exposed
10. Nakagawa Y, Wakuri S, Sakamoto K, et al: to very high concentrations. Several studies
The photogenotoxicity of titanium dioxide of workers repeatedly exposed to toluene or
particles. Mutat Res 394(13):12532, 1997 mixtures of toluene and other solvents have
suggested minor abnormalities on neuropsy-
chological testing or differences in perform-
ance on such testing compared with unexposed
controls, hearing loss, changes in visual-evoked
TOLUENE brain stem potentials and color vision impair-
CAS: 108-88-3 ment.6 In contrast, a study of 43 rotogravure
printers exposed to estimated mean levels of
C6H5CH3 117 ppm for a mean of 22 years failed to
demonstrate signicant clinical neuroradiolog-
ical, neurophysiological, or neuropsychological
Synonyms: Toluol; methylbenzene; phenyl- differences when compared with a control
methane group of 31 unexposed printers.7
Severe but reversible liver and kidney
Physical Form. Colorless liquid injury occurred in a person who was a glue
sniffer for 3 years. The chief component of the
Uses. Manufacturing of benzene and other inhaled solvent was toluene (80% vol/vol);
chemicals; solvent for pains and coatings; com- other ingredients were not listed.3 In workers
ponent of gasoline exposed for many years to concentrations in
the range of 80300 ppm, there was no
Exposure. Inhalation; skin absorption clinical or laboratory evidence of altered liver
function.3
Toxicology. Toluene causes central nervous Toluene exposure does not result in the
system depression. hematopoietic effects caused by benzene. The
Exposure to extremely high concentra- myelotoxic effects previously attributed to
tions of toluene (500030,000 ppm) may cause toluene are judged by more recent investiga-
mental confusion, loss of coordination, and tions to be the result of concurrent exposure
unconsciouness within a few minutes. Con- to benzene present as a contaminant in
trolled exposure of human subjects to 200 ppm toluene solutions.3 Most of the toluene
for 8 hours produced mild fatigue, weakness, absorbed from inhalation is metabolized to
confusion, lacrimation, and paresthesias of the benzoic acid, conjugated with glycine in the
skin. At 600 ppm for 8 hours other effects liver to form hippuric acid, and excreted in
included euphoria, headache, dizziness, dilated the urine. The average amount of hippuric
pupils, and nausea. At 800 ppm for 8 hours, acid excreted in the urine by persons not
symptoms were more pronounced and afteref- exposed to toluene is approximately 0.7
fects included nervousness, muscular fatigue, 1.0 g/l of urine.3
and insomnia persisting for several days.14 There are a number of reports that women
Subjects exposed to 100 ppm of toluene for exposed to toluene have an increased risk of
6 hours complained of eye and nose irritation spontaneous abortions; however, a causal rela-
and, in some cases, headache, dizziness, and a tionship is difcult to establish because of con-
feeling of intoxication. However, no signicant founding exposures, lack of exposure data, and
difference in performance on a variety of neu- small sample sizes.6
robehavioral tests were noted. No symptoms Chronic maternal inhalation abuse of
were noted at 10 or 40 ppm.5 toluene during pregnancy has been associated
Chronic organic brain dysfunction, associ- with teratogenic effects in a number of case
ated with cerebral and cerebellar atrophy, has reports. Manifestations include microcephaly,
682 TOLUENE
central nervous system dysfunction, attentional longed skin contact with liquid toluene has a
decits, developmental delay with language defatting action, causing drying, ssuring, and
impairment, and growth retardation.8 Pheno- dermatitis.
typic abnormalities may include a small The 2003 ACGIH threshold limit value-
midface, short palpebral ssures with deep-set time-weighted average (TLV-TWA) for
eyes, low-set ears, at nasal bridge with a small toluene is 50 ppm (188 mg/m3) with a notation
nose, micrognathia, and blunt ngertips. Inter- for skin absorption.
pretation of these human results may be con-
founded by the contribution of multiple
chemical exposures.9 Furthermore, it has been
noted that only excessively high doses, possibly REFERENCES
on the order of 30,000 ppm, that produce 1. Department of Labor: Occupational expo-
maternal toxicity have been associated with sure to toluene. Fed Reg 40:4620646219,
developmental effects. 1975
Results from a number of animal studies 2. von Oettingen WF, Neal PA, Donahue DD:
indicate that exposure to levels of toluene that The toxicity and potential dangers of
begin to produce maternal toxicity can cause toluenePreliminary report. JAMA 113:
fetal effects, including reduced fetal survival 578584, 1942
and retardation of growth and skeletal devel- 3. National Institute for Occupational Safety
opment toxicity.6 Rat studies also suggest that and Health: Criteria for a Recommended Stan-
exposure in utero can impair behavioral devel- dard . . . Occupational Exposure to Toluene.
DHEW (NIOSH) Pub No (HSM) 7311023,
opment.6 Exposure to 2000 ppm 6 hours/day,
pp 1445. Washington, DC, US Government
for 80 days before mating and through lacta-
Printing Ofce, 1973
tion, produced no signicant maternal toxicity 4. Low LK, Meeks JR, Mackerer CR: Health
but caused retardation of both fetal and post- effects of the alkylbenzenes. I. Toluene.
natal development in rats.9 Toxicol Ind Health 4:4975, 1988
A chronic inhalation study found no evi- 5. Anderson I et al: Human response to con-
dence of carcinogenic activity in rats exposed trolled levels of toluene in six-hour expo-
at concentrations of 600 ppm or 1200 ppm for sures. Scand J Work Environ Health
2 years, or in mice exposed at 120, 600, or 1200 9:405418, 1983
ppm for the same duration.10 Epidemiological 6. Agency for Toxic Substances and Disease
ndings of various cancer (stomach, lung, and Registry (ATSDR): Toxicological Prole for
Toluene, 312pp. US Department of Health
colorectal) increases with toluene exposure are
and Human Services, Public Health Service,
not strong enough to conclude an association
2000
because of multiple exposure circumstances 7. Juntunen J et al: Nervous system effects of
and weak consistency of ndings.11 long-term occupational exposure to toluene.
The IARC has determined that there is Acta Neurol Scand 75: 512517, 1985
evidence for the lack of carcinogenicity of 8. Hersh JH: Toluene embryopathy: Two new
toluene in experimental animals and that there cases. J Med Genet 26:333337, 1987
is inadequate evidence for carcinogenicity in 9. Donald JM, Hooper K, Hopenhayn-Richc:
humans.11 Results of in vitro assays generally Reproductive and developmental toxicity of
indicate that toluene is not genotoxic.6 Reports toluene: A review. Environ Health Perspect 94:
of increased incidences of sister chromatid 237244, 1991
10. National Toxicology Program: NTP Technical
exchanges and chromatid breaks in exposed
Report on the Toxicology and Carcinogenesis
workers are confounded by concurrent expo-
Studies of Toluene (CAS No 108-88-3) in
sure to other organic chemicals.6 F344/N Rats and B6C3F1 Mice, NTR TR 371,
The liquid splashed in the eyes of two NIH Pub No 892826, 1989
workers caused transient corneal damage and 11. IARC Monographs on the Evaluation of
conjunctival irritation; complete recovery Carcinogenic Risks to Humans, Vol 71, Re-
occurred within 48 hours.3 Repeated or pro- evaluation of some organic chemicals, hy-
TOLUENE-2,4-DIISOCYANATE 683
0.02 ppm and as low as 0.003 ppm). The annual induced asthma had positive responses to spe-
declines were two- to threefold greater than cic bronchial provocation testing with low
expected, appeared to be dose related, and concentrations of TDI (up to 0.02 ppm) at a
correlated with observed cross-shift declines. mean of 4.5 years after cessation of exposure.
Workers, in general, exhibited no acute or These persons had persistent respiratory symp-
chronic symptoms related to these exposures or toms requiring daily treatment for asthma
pulmonary function decrements.9,10 and persistent airway hyperreactivity.16 Once
The diagnosis of TDI-induced asthma sensitized, it is clear that patients can react to
relies primarily on the clinical history in a concentrations of 0.005 ppm or less.7
worker with known exposure, recognizing that Bronchial biopsies of subjects with occu-
symptoms (wheezing, dyspnea, cough) may pational asthma induced by TDI revealed
develop at night long after the end of the shift. pathologic features such as increased number
Serial measurement of peak ow rates by the of inammatory cells in the airway mucosa and
worker may aid in making the diagnosis.11 thickening of subepithelial collagen.18
Nonspecic bronchial hyperreactivity to hista- Splashes of TDI liquid in the eye cause
mine or methacholine is frequently, but not severe conjunctival irritation and lacrimation.
invariably, present in patients with TDI- On the skin, the liquid produces a marked
induced asthma. Its absence may reect that inammatory reaction. Sensitization of the skin
the asthma is quiescent owing to no recent occurs but is uncommon because of proper
exposure and re-exposure may lead to hyperre- work practices. There seems to be little rela-
activity. Failure to demonstrate nonspecic tion between skin sensitivity and respiratory
hyperreactivity on a single test does not exclude sensitivity to TDI.1
the diagnosis of TDI-induced asthma.12 RAST Commercial-grade TDI consisting of 80%
testing for IgE antibodies against p-tolyl 2,4-TDI and 20% 2,6-TDI was administered
monoisocyanate antigens is probably not by gavage to female rats and mice at doses of
useful because of the occurrence of false- 60 or 120 mg/kg, whereas male rats received
positive (in exposed but asymptomatic workers) 30 or 60 mg/kg and male mice received 120 or
and false-negative results.13 Specic bron- 240 mg/kg.19 The major nonneoplastic lesions
choprovocation challenge with TDI is a den- observed in rats were dose-related increases in
itive way to make the diagnosis but is often not acute bronchopneumonia, and in mice there
practical because of the need for prolonged was cytomegaly of the renal tubular epithelium
observation for late reactions and the risk of in males. Despite early mortality in all groups,
severe reactions. TDI was carcinogenic to both species, causing
After removal from exposure, some pancreatic acinar cell adenomas in male rats,
patients have had resolution of symptoms. The pancreatic islet cell adenomas, neoplastic
early detection of TDI-induced occupational nodules of the liver, and mammary gland
asthma and the prompt removal of sensitized tumors in female rats and subcutaneous bro-
workers from exposure may increase the mas and brosarcomas in both sexes. In female
chances of remission.14 However, there is evi- mice there was an increase in hemangiomas and
dence from several studies that individuals hepatocellular adenomas. The pattern of mul-
with TDI-induced asthma may continue to tiple tumor sites was similar to that found with
have symptoms of dyspnea and wheezing and 2,4-diaminotoluene. Metabolic studies have
bronchial hyperreactivity for 2 or more years shown that common metabolites are produced
after cessation of exposure.1517 In one study, from the 2,4-TDI isomer and from 2,4-
patients with TDI-induced asthma who con- diaminotoluene, suggesting that the 2,4-isomer
tinued to have exposure to TDI for 2 more in the commercial-grade TDI was responsible
years had, as a rule, marked abnormal decreases for the carcinogenic activity. No strong associ-
in spirometric parameters and increases in non- ation or consistent pattern of carcinogenicity
specic hyperreactivity.15 In another study, 6 of has emerged in limited human epidemiological
12 workers with a convincing history of TDI- studies involving isocyanate exposure.20
TOLUENE-2,4-DIISOCYANATE 685
The IARC has determined that there is 8. Belin L, Wass U, Audunsson G, et al:
inadequate evidence for the carcinogenicity of Amines: Possible causative agents in the
toluene diisocyanates in humans and sufcient development of bronchial hyperreactivity in
evidence in experimental animals.20 workers manufacturing polyurethanes from
In genotoxic assays, TDI has produced isocyanates. Br J Ind Med 40:251257, 1983
9. Diem JE, Jones RN, Hendrick DJ, et al:
chromosomal aberrations, base pair substitu-
Five-year longitudinal study of workers
tion, frameshift mutations, and DNA stand employed in a new toluene diisocyanate
breaks of human white blood cells in vitro.21 It manufacturing plant. Am Rev Respir Dis 126:
induced gene mutation and sister chromatid 420428, 1982
exchanges but not DNA damage or chromoso- 10. Wegman D Musk AW, Main DM, et al:
mal aberrations in cultured rodent cells.20 It did Accelerated loss of FEV-1 in polyurethane
not induce micronuclei in mammalian erythro- production workers: A four-year prospective
cytes in vivo. study. Am J Ind Med 3:209215, 1982
Biological monitoring of TDI exposure 11. Burge P, OBrien I, Harries M: Peak ow
levels has been accomplished with postshift rate record in the diagnosis of occupational
analysis of urinary toluene.22 asthma due to isocyanates. Thorax 34:317,
1979
The 2003 ACGIH threshold limit
12. Burge P: Nonspecic bronchial hyperreac-
value-time-weighted average (TLV-TWA) tivity in workers exposed to toluene diiso-
for toluene-2,4-diisocyanate is 0.005 ppm cyanate, diphenylmethane diisocyanate and
(0.036 mg/m3) with a short-term excursion colophony. Eur J Respir Dis 63(suppl 123):
limit (STEL) of 0.02 ppm (0.14 mg/m3). 9196, 1982
13. Butcher B, ONeil CE, Reed MA, et al:
Radioallergosorbent testing with p-tolyl
REFERENCES monoisocyanate in toluene diisocyanate
workers. Clin Aller 13:3134, 1983
1. National Institute for Occupational Safety 14. Park H-S, Nahm D-H: Prognostic factors for
and Health: Criteria for a Recommended Stan- toluene diisocyanate-induced occupational
dard . . . Occupational Exposure to Toluene Diiso- asthma after removal from exposure. Clin Exp
cyanate. DHEW (NIOSH) Pub No (HSM) Aller 27(10):11451150, 1997
73-11022. Washington, DC, US Govern- 15. Paggiaro P, Loi AM, Rossi O, et al: Follow-
ment Printing Ofce, 1973 up study of patient with respiratory disease
2. Elkins HB, McCarl GW, Brugsch HG, Fahy due to toluene di-isocyanate (TDI). Clin Aller
JP: Massachusetts experience with toluene 14:463469, 1984
diisocyanate. Am Ind Hyg Assoc J 23:265272, 16. Moller DR, Brooks SM, McKay RT, et al:
1962 Chronic asthma due to toluene diisocyanate.
3. Rye WA: Human responses to isocyanate Chest 90:494499, 1986
exposure. J Occup Med 15:306307, 1973 17. Luo CJ, Nelson KG, Fishbein A: Persistent
4. OBrien I, Harris M, Burge P, Pepys J: reactive airway dysfunction syndrome after
Toluene diisocyanate-induced asthma. Clin exposure to toluene diisocyanate. Br J Ind
Aller 9:1, 1979 Med 47:239241, 1990
5. Chester E, Martinez-Catinchi FL, Schwartz 18. Saetta M, Di Stefano A, Maestrelli P, et al:
HJ, et al: Patterns of airway reactivity to Airway mucosal inammation in occupational
asthma produced by exposure to toluene asthma induced by toluene diisocyanate. Am
diisocyanate. Chest 75:229, 1979 Rev Respir Dis 145:160168, 1992
6. Bernstein I: Isocyanate-induced pulmonary 19. Dieter MP, Boorman GA, Jameson CW, et al:
diseases: A current perspective. J Allergy Clin The carcinogenic activity of commercial
Immun 70:2431, 1982. grade toluene diisocyanate in rats and mice
7. ACGIH: Toluene-2,4-Diisocyanate. Documen- in relation to the metabolism of the 2,4-
tation of the Threshold Limit Values and and 2,6-TDI isomers. Toxicol Ind Health
Biological Exposure Indices, 7th ed, 6pp. Cincin- 6:599621, 1990
nati, OH, American Conference of Govern- 20. IARC Monographs on the Evaluation of the Car-
mental Industrial Hygienists, 2001 cinogenic Risk of Chemicals to Humans, Vol 71,
686 TOLUIDINE
cases of bladder cancer were observed (vs. 3.61 5. Smyth HF Jr, et al: Range-nding toxicity
expected) among 1749 chemical workers data: List VI. Am Ind Hyg Assoc J 23:9596,
exposed to o-toluidine and aniline.12 Increased 103, 1962
risk of bladder cancer was strongly associated 6. Henderson Y, Haggard HW: Noxious Gases,
with duration of employment in the depart- 2nd ed, p 288. New York, Reinhold, 1943
7. Beard RR, Noe JT: Aromatic and nitro com-
ment where o-toluidine and aniline were used.
pounds. In Clayton GD and Clayton FE
The investigators suggested that because o- (eds): Pattys Industrial Hygiene and Toxicology
toluidine was a more potent animal bladder 3rd ed rev, Vol 2A Toxicology pp 24832484.
carcinogen than aniline, it was more likely New York, Wiley-Interscience, 1981
to be the etiologic agent responsible for the 8. National Cancer Institute: Bioassay of o-
bladder cancer excesses in this plant. Toluidine Hydrochloride for Possible Carcino-
The IARC has determined that there is genicity, TR-153. DHEW (NIH) Pub No 79-
sufcient evidence for carcinogenicity of o- 1709, Washington, DC, US Government
toluidine hydrochloride in animals and that it Printing Ofce, 1979
should be regarded as though it presents a car- 9. Weisburger EK et al: Testing of twenty-one
cinogenic risk to humans.11,13 environmental aromatic amines or derivatives
for long term toxicity or carcinogenicity.
In genotoxic assays o-toluidine induced
J Environ Pathol Toxicol 2:325356, 1978
sister chromatid exchanges and chro- 10. Hecht SS et al: Comparative carcinogenicity
mosomal aberrations in vitro, and in vivo it of o-toluidine hydrochloride and nitroso-
enhanced sister chromatid exchanges but gave toluene in F-344 Rats. Cancer Lett 16:
equivocal results for micronuclei and sperm 103108, 1982
morphology.11 11. IARC Monographs on the Evaluation of
Skin absorption of toluidines is considered Carcinogenic Risks to Humans, Vol 77, Some
to be a potential hazard. Recent estimations of industrial chemicals, pp 267322. Lyon,
workplace exposures have included individual International Agency for Research on
dermal badges and surface wipes in addition to Cancer, 2000
airborne monitoring.14 12. Ward E, Carpenter A, Markowitz S, et al:
Excess number of bladder cancers in workers
The 2003 ACGIH threshold limit value-
exposed to ortho-toluidine and aniline. J Natl
time-weighted average (TLV-TWA) for the Cancer Inst 83:501506, 1991
toluidines is 2 ppm (8.8 mg/m3) with a notation 13. IARC Monographs on the Evaluation of the Car-
for skin absorption; the ortho and para isomers cinogenic Risk of Chemicals to Humans, Vol 27,
have an A2-suspected human carcinogen Some aromatic amines, anthraquinones and
designation. nitroso compounds, and inorganic uorides
used in drinking water and dental prepara-
tions, pp 155175. Lyon, International
Agency for Research on Cancer, 1982
REFERENCES 14. Pendergrass SM: An approach for estimating
workplace exposure to o-toluidine, aniline,
1. MCA Inc.: Chemical Safety Data Sheet SD-82, and nitrobenzene. Am Ind Hyg Assoc J 55:
Toluidine, pp 1314. Washington, DC, MCA, 733737, 1994
Inc, 1961
2. Goldblatt MW: Research in industrial health
in the chemical industry. Br J Ind Med
12:120, 1955
3. Hamblin DO: Aromatic nitro and amino TOXAPHENE
compounds. In Patty FA (ed): Industrial CAS: 8001-35-2
Hygiene and Toxicology. 2nd ed, Vol 2, Toxi-
cology, pp 2123, 2155. New York, Wiley-
Interscience, 1963 C10H10Cl8 (approximate)
4. Linch AL: Biological monitoring for indus-
trial exposure to cyanogenic aromatic nitro
and aminocompounds. Am Ind Hyg Assoc J Synonyms: Chlorinated camphene; poly-
35:426432, 1974 chlorocamphene; octachlorocamphene
688 TOXAPHENE
Physical Form. Yellow waxy solid In subchronic animal studies, rats fed diets
containing 4, 20, 100, or 500 ppm of the com-
Use. Formerly used as an insecticide pound showed no clinical signs of toxicity;
dose-dependent histologic changes were ob-
Exposure. Inhalation; skin absorption; served in the kidney, thyroid, and liver.8 For
ingestion dogs administered 0.2, 2.0, and 5.0 mg/kg/day
for 13 weeks by capsule, there were mild to
Toxicology. Toxaphene is a central nervous moderate dose-dependent histologic changes
system stimulant; it is carcinogenic in experi- in the liver and thyroid, but no clinical signs of
mental animals. toxicity were observed.8
Toxaphene is a mixture of at least 670 chlo- Toxaphene is less toxic when applied to the
rinated camphenes; differences in toxicity have skin as compared with oral administration.1
been observed for various toxaphene fractions Dermal LD50 values ranging from 7.8 to
or components.1 45 g/kg have been obtained in laboratory
Most fatal cases of poisoning have been animals. Applied to rabbit skin for 4 hours toxa-
due to accidental ingestion, resulting in con- phene was mildly irritating; a 0.5% solution
vulsions and death due to respiratory arrest.14 was nonirritating to the forearms and faces
The lethal oral dose for humans is estimated to of volunteers.
be 27 g.2 No fetal anatomic defects were observed
Symptoms of acute intoxication are saliva- in rats and mice at doses ranging from 0.05 to
tion, hyperexcitability, behavioral changes, and 75 mg/kg/day.1 Adverse developmental effects,
in severe cases convulsions and death.1 Con- such as impaired righting reexes, have been
vulsions may be preceded by nausea, vomiting, observed in rats at doses below those required
and muscle spasms or may begin without to produce maternal toxicity.9
antecedent symptoms.2 Onset of symptoms There was no evidence that toxaphene
occurs within 4 hours, with death occurring interfered with fertility or pup survival and
from 4 to 24 hours after exposure. Nonfatal growth when male and female rats were fed
poisoning has been characterized by nausea, toxaphene in their diet at concentrations as
mental confusion, jerking of the arms and legs, high as 25 mg/kg/day and then mated.10
and convulsions.3,4 Toxaphene caused a dose-related increase
One proposed mechanism for toxaphene- of hepatocellular carcinomas in mice fed 98 or
induced neurotoxicity is that it acts as a non- 198 ppm for 80 weeks. In rats, there was a sig-
competitive g-aminobutyric acid (GABA) nicantly increased incidence of neoplastic
antagonist at the chloride channel in brain thyroid lesions at the high dose.11 The IARC
synaptosomes. Substances that bind to the has determined that there is sufcient evidence
GABA-regulated chloride channel induce in experimental animals for the carcinogenicity
convulsions by inhibiting chloride ux of toxaphene and that it is possibly carcino-
thus allowing brain cells to depolarize and re genic to humans.12
spontaneously.1,5 Toxaphene has been found to be genotoxic
Few cases of intoxication due to occupa- in a number of assays.1 It was mutagenic in Sal-
tional exposure have been reported, and, of monella typhimurium, and increased the fre-
these, two cases of pneumonitis in insecticide quency of sister chromatid exchanges in cell
sprayers are of dubious validity.6 In one culture. In one study toxaphene-exposed indi-
acute study, 25 volunteers were exposed to viduals had a higher incidence of chromosomal
500 mg/m3 for 30 minutes for 10 days.7 After a aberrations in lymphocytes than controls.
3-week respite, the exposure was repeated for However, in vivo toxaphene did not bind to
3 days. Each subject was thought to have DNA or produce dominant lethal mutations.12
absorbed 1 mg/kg/day. Physical examination The 2003 ACGIH threshold limit value-
and blood and urine tests revealed no toxic time-weighted average (TLV-TWA) for
manifestations. toxaphene is 0.5 mg/m3 with a short-term
TRIBUTYL PHOSPHATE 689
excursion limit (STEL) of 1 mg/m3 and a nota- International Agency for Research on
tion for skin absorption. Cancer, 2001
REFERENCES
over 2 weeks, the damage is not considered char- 2A, Toxicology, pp 2370, 2379. New York,
acteristic of delayed neuropathy. Wiley-Interscience, 1981
Administered by gavage to rats 5 3. Carrington CD, Lapadula DM, Othman M,
days/week for 18 weeks, doses of 0.20 g and et al: Assessment of the delayed neurotoxic-
above caused diffuse hyperplasia of the urinary ity of tributyl phosphate, tributoxyethyl
phosphate, and dibutylphenyl phosphate.
bladder epithelium.4 After chronic administra-
Toxicol Ind Health 6:415423, 1989
tion of TBP at levels of 200, 700, and 3000 ppm 4. Latham L, Long G, Broxup B: Induction of
in the feed of rats for 2 years there was a dose- urinary bladder hyperplasia in Sprague-
related increase in the severity of urinary Dawley rats orally administered tri-n-butyl
bladder hyperplasia and the incidence of phosphate. Arch Environ Health 40:310306,
urinary bladder papillomas in the two highest 1985
groups; transitional cell carcinomas were 5. Auletta CS, Weiner ML, Richter WR: A
present in 6 of 49 males in the 3000 ppm dietary toxicity/oncogenicity study of tributyl
group.5 In a parallel study in mice receiving phosphate in the rat. Toxicology 128(2):
150, 1000, and 3500 ppm in feed, increased rel- 125134, 1998
ative and absolute liver weights were observed 6. Auletta CS, Kotkoslie LA, Saulog T, et al: A
dietary oncogenicity study of tributyl phos-
in the mid- and high-dose groups; hepatocel-
phate in the CD-1 mouse. Toxicology 128(2):
lular adenomas were increased in the high-dose 135141, 1998
males.6 TBP was not genotoxic in a variety of 7. Batt KJ, Healy CE, Kneiss JJ, et al: Geno-
in vivo and in vitro assays.7 It has been suggested toxicity testing of tributyl phosphate. Environ
that the carcinogenic effects of TBP are Mol Mutagen 19(20):5, 1992
species- and organ specic. The necrotic 8. Anonymous: Tributyphosphat. Toxikologis-
actions of TBP (or a metabolite) on rat urinary che Bewertung. Heidelberg, Berufsgenossen-
bladder epithelium may induce chronic repair schaft der chemischen industrie, vol 170:175,
processes that cause the normal epithelium to 2000
be transformed into its metaplastic and neo- 9. Schroeder RE, Gerhart JM, Kneiss J: Devel-
plastic forms.8 opmental toxicity studies of tributyl phos-
phate (TBP) in the rat and rabbit. Teratology
TBP was not teratogenic when adminis-
43(5):455, 1991
tered to rats and rabbits during gestation; 10. Tyl RW, Gerhart JM, Myers CB, et al: Two
fetotoxic effects (delayed ossication and re- generation reproductive toxicity study of
duced fetal body weights) occurred in rats at dietary tributyl phosphate in CD rats.
doses that caused severe maternal toxicity.9 Fundam Appl Toxicol 40(1):90100, 1997
There was no evidence of reproductive toxic-
ity or reproductive organ pathology in two-
generation studies in rats fed TBP in the diet.10
The liquid has a mildly irritating effect on
the rabbit eye and skin.8
The 2003 ACGIH threshold limit value- TRICHLOROACETIC ACID
time-weighted average (TLV-TWA) is 0.2 ppm CAS: 76-03-9
(2.2 mg/m3).
CCl3COOH
REFERENCES
Synonyms: TCA; trichloroethanoic acid
1. ACGIH: Tributyl phosphate. Documentation
of the TLVs and BEIs, 6th ed, pp 16001601.
Physical Form. Crystals
Cincinnati, OH, American Conference
of Governmental Industrial Hygienists,
1991 Uses. As a reagent for albumin detection; in
2. Sandmeyer EE, Kirwin CJ Jr: Ethers. In making herbicides. It is found as a by-product
Clayton GD, Clayton FE (ed.): Pattys Indus- after chlorination of water containing humic
trial Hygiene and Toxicology, 3rd ed, rev, Vol materials.
TRICHLOROACETIC ACID 691
extraction solvent; aerosol propellant; dry and 1000 ppm for 3 months had increased glial
cleaning solvent brillary acid protein, which is considered to be
a marker for astrogliosis and is associated with
Exposure. Inhalation; skin absorption brain injury.8
An epidemiological study of 151 matched
Toxicology. 1,1,1-Trichloroethane causes pairs of exposed textile workers revealed no
central nervous system depression. evidence of cardiovascular, hepatic, renal, or
Human deaths after inhalation exposure other effects as a function of exposure; for some
have been attributed to respiratory failure sec- workers, exposures exceeded 200 ppm, and
ondary to central nervous system depression duration of exposure ranged from several
and to cardiac arrhythmias.1,2 Lethal arrhyth- months to 6 years.9
mias may result from sensitization of the heart A few scattered reports have indicated mild
to epinephrine. kidney and liver injury in humans from
Based on effects caused in monkeys and severe exposure; animal experiments have con-
rats, the following are expected in humans: rmed the potential for liver, but not kidney,
20,000 ppm for 60 minutes, coma and possibly injury.1,10
death; 10,000 ppm for 30 minutes, marked The liquid is mildly irritating when applied
incoordination; 2000 ppm for 5 minutes, dis- to the skin or instilled directly into the eyes.2
turbance of equilibrium.3 Human subjects In a carcinogenicity study, rats and mice
exposed to 9001000 ppm for 20 minutes expe- were given the liquid orally at two different
rienced light-headedness, incoordination, and dose levels, 5 days a week for 78 weeks.11 Both
impaired equilibrium; transient eye irritation female and male test animals exhibited early
has also been reported at similar concentra- mortality compared with untreated controls,
tions.1 Impairments in psychomotor task per- and a variety of neoplasms were found in both
formance such as reaction time, perceptual treated animals and controls. Although rats of
speed, and manual dexterity have been demon- both sexes demonstrated a positive dose-
strated at levels around 350 ppm.4,5 Other related trend, no relationship was established
studies at similar exposure levels have failed to between the dosage groups and the species, sex,
show any impairment, but the type of task type of neoplasm, or sites of occurrence. The
chosen to test behavioral effects and the times IARC concluded that an evaluation of the car-
at which behavioral measures were sampled cinogenicity of 1,1,1-trichloroethane could not
during the course of exposure may explain the be made.12 In a subsequent study, rats exposed
variations from study to study.4 at 1500 ppm 6 hours/day, 5 days/week for 2
Some case reports have associated chronic years showed no oncogenic effects.13
long-term exposure with peripheral sensory Inhalation exposure of female rats before
neuropathy and toxic encephalitis.6,7 In one mating and during pregnancy at 2100 ppm
instance, a woman with daily exposure to 1,1,1- caused an increased incidence of skeletal and
trichloroethane and considerable potential of soft tissue variation in the offspring, indicative
dermal exposure developed perioral tingling of developmental delay; no persistent detri-
accompanied by discomfort in her hands and mental effects were found in the offspring at 12
feet; the oral and hand symptoms disappeared months of age.14
after removal from exposure.6 In another The genotoxic data are largely negative,
report, a group of 28 workers with long- although 1,1,1-trichloroethane was mutagenic
term repetitive high exposures to 1,1,1- in some Salmonella assays and induced chro-
trichloroethane had signicant decits in mosomal aberrations in Chinese hamster ovary
memory, intermediate memory, rhythm, and cells and cell transformation in mammalian
speed as determined by a neuropsychological systems.2
battery of tests.7 Evidence of long-term central The odor threshold has been described
nervous system damage has also been suggested by various investigators as ranging from 16 to
from animal studies. Gerbils exposed at 210 400 ppm.1
694 1,1,2-TRICHLOROETHANE
The 2003 ACGIH threshold limit value- 12. IARC Monographs on the Evaluation of the Car-
time weighted average (TLV-TWA) is 350 ppm cinogenic Risk of Chemicals to Humans, Vol 20,
(1910 mg/m3) with a short-term excursion level Some halogenated hydrocarbons, pp 515
(STEL) of 450 ppm (2460 mg/m3). 531. Lyon, International Agency for Research
on Cancer, 1979
13. Quast JF, Calhoun LL: Chlorothene VG: A
Chronic Inhalation Toxicity and Oncogenicity
REFERENCES
Study in Rats and Mice. Part II. Results in Rats.
Final Report, Feb 5, 1986, pp 1165. Midland,
1. National Institute for Occupational Safety
MI, Mammalian and Environmental Toxicol-
and Health: Criteria for a Recommended Stan-
ogy Research Laboratory, Dow Chemical,
dard . . . Occupational Exposure to 1,1,1-
1986
Trichloroethane (Methyl Chloroform). DHEW
14. York RG, Sowry BM, Hastings L, et al: Eval-
(NIOSH) Pub No 76-184, pp 1696. Wash-
uation of teratogenicity and neurotoxicity
ington, DC, US Government Printing
with maternal inhalation exposures to methyl
Ofce, 1976
chloroform. J Toxicol Environ Health 9:
2. Agency for Toxic Substances and Disease
251266, 1982
Registry (ATSDR): Toxicological Prole for
1,1,1-Trichloroethane, 277pp. US Department
of Health and Human Services, Public
Health Service, 1995
3. 1,1,1-TrichloroethaneEmergency expo- 1,1,2-TRICHLOROETHANE
sure limits. Am Ind Hyg Assoc J 25:585, 1964 CAS: 79-00-5
4. Mackay CJ et al: Behavioral changes during
exposure to 1,1,1-trichloroethane: Time- C2H3Cl3
course and relationship to blood solvent
levels. Am J Ind Med 11:223239, 1987
5. Gamberale F, Hultengren M: Methylchloro- Synonyms: Vinyl trichloride; ethane trichlo-
form exposure. II. Psychophysiological func-
ride; b-trichloroethane; TCE
tions. Work Environ Health 10:8292, 1973
6. House RA, Liss GM, Wills MC: Peripheral
sensory neuropathy associated with 1,1,1- Physical Form. Colorless liquid
trichloroethane. Arch Environ Health 49:
196199, 1994 Uses. Intermediate in the production of
7. Kelafant GA, Berg RA, Schleenbaker R: vinylidene chloride; solvent
Toxic encephalopathy due to 1,1,1-
trichloroethane exposure. Am J Ind Med Exposure. Inhalation; skin absorption
25:439446, 1994
8. Rosengren LE, Aurell A, Kjellstrand P, et al:
Astrogliosis in the cerebral cortex of ger- Toxicology. In animals, 1,1,2-trichloroe-
bils after long-term exposure to 1,1,1- thane is a central nervous system depressant
trichloroethane. Scand J Work Environ Health and causes liver and kidney damage; it is
11:447455, 1985 expected that severe exposure will produce the
9. Kramer C et al: Health of workers exposed to same effects in humans.
1,1,1-trichloroethane: A matched-pair study. No cases of human intoxication or sys-
Arch Environ Health 33:331342, 1978 temic effects from industrial exposure have
10. Cohen C, Frank AL: Liver disease follow- been reported.1
ing occupational exposure to 1,1,1- The lethal concentration for rats was
trichloroethane: A case report. Am J Ind Med
2000 ppm for 4 hours, with the deaths occur-
26:237241, 1994
11. National Cancer Institute: Bioassay of 1,1,1- ring during a 14-day observation period.2 An 8-
Trichloroethane for Possible Carcinogenicity, hour exposure to 500 ppm was also lethal to
Technical Report Series No 3. DHEW about half of the exposed rats.3 Rats exposed to
(NIOSH) Pub No 77-803. Washington DC, 250 ppm for 4 hours survived but showed liver
US Government Printing Ofce, 1977 and kidney necrosis.4 Repeated exposure to
1,1,2-TRICHLOROETHANE 695
30 ppm resulted in minor liver changes in damage and micronuclei in human lympho-
female rats. cytes in vitro. It showed some evidence of
Application of 0.5 ml to the skin of guinea mutagenicity in bacteria.11
pigs was lethal to all animals within 3 days, The 2003 ACGIH threshold limit value-
whereas 0.25 ml was fatal to 5 of 20 animals.5 time-weighted average (TLV-TWA) for 1,1,2-
No effects were observed with repeated trichloroethane is 10 ppm (55 mg/m3) with a
application of 0.1 ml to the forearm of a volun- notation for skin absorption.
teer. However, the liquid caused stinging,
burning, and whitening of the skin when placed
under occlusion for 5 min.6 The liquid is con- REFERENCES
sidered a slight eye irritant when instilled in
1. National Institute for Occupational Safety
rabbit eyes.
and Health: Current Intelligence Bulletin 27,
Mice treated by intraperitoneal injection Chloroethanes: Review of Toxicity. DHEW
with anesthetic doses showed moderate hepatic (NIOSH) Pub No 78-181, p 22, 1978
and renal dysfunction. At autopsy, ndings 2. Carpenter CP, Smyth HF Jr, Pozzani UC:
were centrilobular necrosis of the liver and The assay of acute vapor toxicity, and the
tubular necrosis of the kidneys; the 24-hour grading and interpretation of results on 96
LD50 for intraperitoneal injection was 0.35 mg/ chemical compounds. J Ind Hyg Toxicol 31:
kg.7 The LC50 values for 1,1,2-trichloroethane 343346, 1949
administered by a single gavage dose to 3. Smyth HF Jr, Carpenter CP, Weil CS, et al:
male and female mice were 378 and 491 mg/ Range-nding toxicity data: List VII. Am Ind
Hyg Assoc J 30:470476, 1969
kg, respectively.8 Above 450 mg/kg, animals
4. Torkelson TR, Rowe VK: Halogenated
became sedated within an hour, and deaths
aliphatic hydrocarbons. In Clayton GD,
from central nervous system depression Clayton FE (eds): Pattys Industrial Hygiene
occurred within 24 hours. Necropsies showed and Toxicology, 3rd ed, rev, Vol 2B, Toxicology,
irritation of the upper gastrointestinal tract, pp 35103513. New York, Interscience, 1981
pale liver, and some lung damage. Dose- 5. Wahlberg JE: Percutaneous toxicity of sol-
dependent alterations in hepatic microsomal vents. A comparative investigation in the
enzyme activities and serum enzyme levels guinea pig with benzene, toluene, and 1,1,2-
were found in mice given 1,1,2-trichloroethane trichloroethane. Ann Occup Hyg 19:226229,
in their drinking water for 90 days.8 1976
Administered orally to pregnant mice, 6. Agency for Toxic Substances and Disease
Registry (ATSDR): Toxicological Prole for
1,1,2-trichloroethane caused no reduction in
1,1,2-Trichloroethane, 109pp. US Public
neonate survival or in neonatal weight at doses
Health Service, 1989
that were maternally toxic.9 7. Klassen CD, Plaa GL: Relative effects of
A signicant increase in hepatocellular various chlorinated hydrocarbons on liver
carcinomas occurred in mice given 195 or and kidney function in mice. Toxicol Appl
390 mg/kg/day by gavage for 78 weeks.10 Pharmacol 9:139151, 1966
Adrenal pheochromocytomas were also in- 8. White KL Jr, Sanders VM, Barnes DW, et al:
creased for the high-dose female mice. No Toxicology of 1,1,2-trichloroethane in the
neoplasms were observed at statistically mouse. Drug Chem Toxicol 8:333335, 1985
signicant incidences in rats given up to 9. Seidenberg JM, Anderson DG, Becker RA:
92 mg/kg/day. Validation of an in vivo developmental toxic-
ity screen in the mouse. Teratog Carcinog
The IARC has determined that there is
Mutagen 6:361374, 1986
limited evidence that 1,1,2-trichloroethane is
10. National Cancer Institute: Carcinogenesis
carcinogenic in experimental animals and that Technical Report Series No 74. Bioassay of 1,1,2-
1,1,2-trichloroethane is not classiable as to its Trichloroethane for Possible Carcinogenicity.
carcinogenicity to humans.11 NCI-CG-TR-74. Washington, DC, US
1,1,2-Trichloroethane bound to DNA, Department of Health, Education and
RNA, and protein in vivo and induced DNA Welfare, 1978
696 TRICHLOROETHYLENE
11. IARC Monographs on the Evaluation of Car- effects. Prolonged exposure at toxic levels may
cinogenic Risks to Humans, Vol 71, Re-evalua- also result in hearing defects.
tion of some organic chemicals, hydrazine Workers exposed to average levels of TCE
and hydrogen peroxide, pp 11531161. Lyon, estimated to be 100200 ppm have reported
International Agency for Research on increased incidence of fatigue, vertigo, dizzi-
Cancer, 1999
ness, headaches, memory loss, and impaired
ability to concentrate. Other effects noted at
about 100 ppm and above include pares-
thesia, muscular pains, and gastrointestinal
TRICHLOROETHYLENE disturbances.
CAS: 79-01-6 Intolerance to alcohol, presenting as a
transient redness affecting mainly the face and
C2HCl3 neck (trichloroethylene ush) has frequently
been observed after repeated exposure to TCE
and alcohol ingestion. It has been suggested
Synonyms: TCE; 1,1,2-Trichloroethylene; that ingestion of alcohol may potentiate the
trichloroethene, 1,1-dichloro-2-chloroethyl- effect of TCE intoxication.2
ene; acetylene trichloride; ethylene trichloride TCE is mildly irritating to the skin;
repeated contact may cause chapping and ery-
Physical Form. Colorless liquid thema due to defatting.1 Direct eye contact
produces injury to the corneal epithelium;
Uses. Degreasing solvent; dry cleaning and recovery usually occurs within a few days.1
extraction; chemical intermediate; limited use Breath analysis for TCE has provided a
as an anesthetic and analgesic more accurate index of exposure than the meas-
urement of metabolites (trichloroethanol and
Exposure. Inhalation trichloroacetic acid) in the urine.3
Technical-grade TCE (later shown to be
Toxicology. Trichloroethylene (TCE) is pri- contaminated with other chemicals) has been
marily a central nervous system (CNS) depres- found to cause liver cancer in B6C3F1 mice but
sant. Although it is carcinogenic at high doses not in Osborne-Mendel rats in an NCI study.4
in experimental animals, it is not considered to Intragastric administration of 2.4 g/kg, ve
be a human carcinogen at low exposure levels. times per week for 78 weeks resulted in hepa-
Inhalation of concentrations in the range tocellular carcinomas in 31 of 48 male mice. At
of 500020,000 ppm have been used to produce 1.2 g/kg, 26 of 50 males were affected, whereas
light anesthesia.1 Recovery from unconscious- male controls had a 5% liver cancer rate.
ness is usually uneventful, but ventricular Among female mice, 11 of 47 developed liver
arrhythmias and death from cardiac arrest have hepatocellular carcinomas, whereas only 1 of
occurred rarely. Exposure of volunteers to 80 control animals did.4 In a second gavage
5001000 ppm has resulted in some symptoms bioassay using epichlorohydrin-free reagent-
of CNS disturbance such as dizziness, light- grade TCE, results paralleled the NCI study;
headedness, lethargy, and impairment in visual- signicantly elevated incidences of hepatocel-
motor response tests. In general, no signicant lular adenomas and carcinomas occurred in
signs of toxicity or impaired performance have mice administered 1.0 g/kg for 2 years.5 An
been noted in subjects acutely exposed to increase in renal adenocarcinomas was also
300 ppm or less. found in male rats.5
Prenarcotic symptoms, including visual Mice, rats, and hamsters inhaling up to
disturbances and feelings of inebriation, oc- 500 ppm 6 hours/day 5 days/week for 18
curred in workers exposed to mean levels of months showed no increase in tumor formation
200300 ppm. Some evidence of mild liver dys- except for an increased incidence of malignant
function has occurred in workers exposed to lymphomas in female MRI mice.6 This strain
levels sufcient to produce marked CNS normally has a high spontaneous incidence of
TRICHLOROETHYLENE 697
lymphomas, and the signicance of TCE expo- mental toxicity.13 In humans, there is no evi-
sure is unclear. ICR mice exposed at 150 and dence of an increased incidence of adverse
450 ppm for 107 weeks developed a 16% and effects in the offspring of female TCE-exposed
15% incidence of adenocarcinomas of the workers. An increased incidence of menstrual
lungs vs. 2% for controls.7 Rats did not show a disorders in women workers and decreased
higher incidence at any site. libido in males has been reported in workers
Although a number of epidemiological exposed to levels sufcient to produce marked
studies have been reported, limitations have CNS disturbances.1 Chronic TCE exposure
included short latency period, young age of was signicantly and negatively correlated with
cohort, no direct data on exposure levels, expo- testosterone levels in male electronics factory
sure to other chemicals, and possible inclusion workers.14
of unexposed workers. However, in 1995 the The 2003 ACGIH threshold limit value-
IARC considered three cohort studies particu- time-weighted average (TLV-TWA) for
larly relevant for the evaluation of TCE car- trichloroethylene is 50 ppm (269 mg/m3) with a
cinogenicity.8 Overall, the most important short-term excursion level (STEL) of 100 ppm
observations were the elevated risk for cancer (537 mg/m3).
of the liver and biliary tract (23 observed cases
vs. 12.87 expected) and the modestly elevated
risk for non-Hodgkin lymphoma (27 observed REFERENCES
vs. 18.9 expected) in all three of the most
informative cohort studies. A more recent 1. Fielder RJ, et al: Toxicity Review 6.
analysis of the epidemiological studies suggests Trichloroethylene. Health and Safety Execu-
tive, pp 170. London, Her Majestys Sta-
a stronger association of TCE exposure with
tionery Ofce, 1982
kidney and liver cancers and some support for 2. National Institute for Occupational Safety
Hodgkin disease and non-Hodgkin lym- and Health: Criteria for a Recommended Stan-
phoma.9 There is also a possible association of dard . . . Occupational Exposure to Trichloroeth-
cervical cancer. ylene. DHEW (NIOSH) Pub No (HSM)
The IARC has stated that there is sufcient 73-11025, pp 1540. Washington, DC, US
evidence in experimental animals and limited Government Printing Ofce, 1976
evidence in humans for the carcinogenicity of 3. Stewart RD, Hake CL, Peterson JE: Use of
TCE and that it is possibly carcinogenic to breath analysis to monitor trichloroethylene
humans.8 exposures. Arch Environ Health 29:613, 1974
TCE carcinogenesis may require exposure 4. National Cancer Institute: Carcinogenesis
Bioassay of Trichloroethylene. TR-2. DHEW
to high doses sufcient to cause cellular necro-
(NIH) Pub No 76-802. Washington, DC, US
sis.10 Repeated cycles of necrosis and regener- Department of Health, Education, and
ation would occur with the emergence of Welfare, 1976
hyperplasia and then neoplasia. Low exposures 5. Kimbrough RD, et al: Trichlorethylene: An
commonly encountered in human studies are update. J Toxicol Environ Health 15:369383,
not sufcient to initiate the carcinogenic 1985
process. 6. Henschler D, Romer W, Elasser HM, et al:
Results from genotoxic studies suggest that Carcinogenicity study of trichloroethylene
TCE is a very weak indirect mutagen.11 by long-term inhalation in three animal
No evidence of teratogenic effects have species. Arch Toxicol 43:237248, 1980
been seen in rodent assays.1 At 1800 ppm, 6 7. Fukuda K, Takemoto K, Tsuruta H: Inhala-
tion carcinogenicity of trichloroethylene
hours/day on days 020 of gestation, there
in mice and rats. Ind Health 21:243254,
were some fetotoxic effects, including incom- 1983
plete ossication of the sternum in rats.12 Rats 8. IARC Monographs on the Evaluation of Car-
administered 600 ppm by inhalation on days cinogenic Risks to Humans, Vol 63, Dry clean-
620 of gestation showed maternal toxicity as ing, some chlorinated solvents and other
evidenced by signicant decreased body weight industrial chemicals, p 75. Lyon, Interna-
gain, but there were no indications of develop- tional Agency for Research on Cancer, 1995
698 TRICHLOROFLUOROMETHANE
carcinogenic to mice; results from rats are Physical Form. White solid
inconclusive because of poor survival rates.8 It
was not genotoxic in a number of in vitro Uses. Electric wire insulation; lubricants
assays.2
The 2003 ACGIH TLV-ceiling limit Exposure. Inhalation; skin absorption
for trichlorouoromethane is 1000 ppm
(5620 mg/m3). Toxicology. Trichloronaphthalene is moder-
ately toxic to the liver.
Industrial exposure to trichloronaphtha-
REFERENCES lene (usually mixed with tetrachloronaphtha-
lene) has been relatively free of untoward
1. Stewart RD, Newton PE, Baretta ED, et al: effects compared with the more highly chlori-
Physiological response to aerosol propellants. nated naphthalenes.1 No fatal cases of liver
J Environ Health Perspect 26:275285, 1978 injury have been reported, but one instance of
2. World Health Organization (WHO): Environ- toxic hepatitis supposedly resulted from expo-
mental Health Criteria 113: Fully Halogenated
sure to 3 mg/m3.2 Although there are several
Chlorouorocarbons pp 1164, Geneva, 1990
reports of chloracne from exposure to
3. Reinhardt CF, Azar A, Maxeld ME, et al:
Cardiac arrhythmias and aerosol snifng. trichloronaphthalene, they do not stand up well
Arch Environ Health 22:265279, 1971 to critical analysis.1 Experiments on human
4. Lester D, Greenburg LA: Acute and chronic volunteers showed that the mist was entirely
toxicity of some halogenated derivatives of nonacneigenic as opposed to the penta- and
methane and ethane. Arch Ind Hyg Occup Med hexachloro derivatives, which produce severe
2:335344, 1950 chloracne.3
5. Jenkins LJ Jr, Jones RA, Coon RA, et al: Rats exposed to 11 mg/m3 of trichloron-
Repeated and continuous exposures of labora- aphthalene, containing some tetrachloronaph-
tory animals to trichlorouoromethane. Toxicol thalene, 16 hours/day for 2.5 months showed
Appl Pharmacol 16:133142, 1970
slightly swollen liver cells with granular
6. Belej MA, Smith DG, Aviado DM: Toxicity
cytoplasm.4
of aerosol propellants in the respiratory and
circulatory systems. IV. Cardiotoxicity in the The higher-chlorinated naphthalenes
monkey. Toxicology 2:381395, 1974 show a much greater toxicity.1
7. Clark DG, Tinston DJ: Acute inhalation The 2003 ACGIH threshold limit value-
toxicity of some halogenated and non- time-weighted average (TLV-TWA) for trich-
halogenated hydrocarbons. Hum Toxicol 1:239 loronaphthalene is 5 mg/m3 with a notation for
247, 1982 skin absorption.
8. National Cancer Institute: Bioassay of Trich-
lorouoromethane for Possible Carcinogenicity.
CAS No 75-69-4. MCI-CGTR-106, p 46. US
Department of Health, Education, and
Welfare, 1978
REFERENCES
4. Drinker CK, Warren MF, Bennett GA: The offspring of treated males and untreated
problem of possible systemic effects from females.4,5 Reduced mean litter size was
certain chlorinated hydrocarbons. J Ind Hyg observed in rats after exposure to 42 mg/kg/day
Toxicol 19:283311, 1937 in drinking water, but not at 4.2 mg/kg/day.5
Reproductive function and litter size were
not affected in rats administered as much as
1000 mg/kg/day by gavage.4
A statistically signicant increase in mono-
2,4,6-TRICHLOROPHENOL cytic leukemia was observed in male rats chron-
CAS: 88-06-2 ically administered either 250 or 650 mg/
kg/day.3 In addition, there was a statistically
C6H3Cl3O signicant increase in hepatocellular tumors in
male (both dose levels) and female (high dose
only) mice. Although there is limited evidence
Synonyms: Dowicide 2S, Omal, Phenachlor supporting the carcinogenicity of chlorophe-
nols as a general class of chemicals to humans,
Physical Form. Yellow akes there are no data from which to evaluate the
possible carcinogenicity of 2,4,6-trichlorophe-
Uses. Wood preservative; disinfectant; fungi- nol, specically, in humans.6 The EPA has
cide, herbicide, defoliant classied 2,4,6-trichlorophenol as a probable
human carcinogen based on the animal data.7
Exposure. Inhalation, skin absorption 2,4,6-Trichlorophenol has been evaluated
for genotoxicity in a variety of in vivo and in
Toxicology. In experimental animals, 2,4,6- vitro assays, and results are inconclusive.7
trichlorophenol causes toxic effects to the liver Although a majority of the studies reported
and hematologic system and cancer. There is negative results, some positive results in bacte-
no reliable information regarding exposure and ria, yeast, and mammalian cells suggest that
toxic effects in humans. 2,4,6-trichlorophenol may have some geno-
The acute intraperitoneal LD50 in rats is toxic potential.7 In contrast to earlier studies,
276 mg/kg.1 Signs of toxicity before death 2,4,6-trichlorophenol was found to induce
included sluggishness, hypotonia, elevated chromosome aberrations in Chinese hamster
body temperature, labored breathing, altered ovary (CHO) and V79 cells; variations in pro-
respiratory rate, and central nervous system tocol were thought to account for the contra-
effects, including convulsions, tremors, coma, dictory ndings.8
excited behavior, and incoordination.2 It has An ACGIH threshold limit value-time-
been suggested that 2,4,6-trichlorophenol acts weighted average (TLV-TWA) has not been
by interfering with mitochondrial oxidative established for 2,4,6-trichlorophenol.
phosphorylation and inhibition of cytochrome
P450-dependent mixed function oxidases.1
Hepatic and splenic lesions were observed REFERENCES
after subchronic oral studies in rodents.3 Rats
exposed to 2300 mg/kg/day in the diet for 7 1. IARC Monographs on the Evaluation of the Car-
weeks experienced a moderate to marked cinogenic Risk of Chemicals to Humans, Vol. 20,
increase in splenic hematopoiesis.3 A high inci- Some halogenated hydrocarbons, p 360. Lyon,
International Agency for Research on Cancer,
dence of bone marrow hyperplasia and leuko-
1979
cytosis occurred in rats after chronic exposure 2. Farquaharson ME, Gage JC, Northover J:
to about 1300 mg/kg/day in the diet. The biological action of chlorophenols. Br J
No developmental effects were noted in Pharmacol 13:2024, 1958
offspring of female rats exposed to 2,4,6- 3. National Cancer Institute: Bioassay of 2,4,6-
trichlorophenol throughout gestation or in the Trichlorophenol for Possible Carcinogenicity.
2,4,5-TRICHLOROPHENOXYACETIC ACID 701
DHEW (NIH) Publ. No. 79-1711. Bethesda, nation to produce birth defects and cancer,
MD, National Institutes of Health, 1979 despite the lack of rm evidence that 2,4,5-T
4. Blackburn K et al: Evaluation of the repro- alone had contributed to teratogenesis or car-
ductive toxicology of 2,4,6-trichlorophenol in cinogenesis in humans.1
male and female rats. Fundam Appl Toxicol
6:233239, 1986
Exposure. Inhalation
5. Exon JH, Koller LD: Toxicity of 2-chlorophe-
nol, 2,4-dichlorophenol and 2,4,6-
trichlorophenol. In Jolley RL et al. (eds): Water Toxicology. 2,4,5-T is of low-order acute
Chlorination, Vol. 5, Chemistry, environmental toxicity; at high doses, it is teratogenic in exper-
impact and health effects. Chelsea, MI, Lewis imental animals.
Publishers, 1985 Eleven men in two separate experiments
6. IARC Monographs on the Evaluation of Carcino- experienced no clinical effects after ingestion of
genic Risks to Humans, Suppl 7, Overall evalu- 5 mg/kg 2,4,5-T. Most did report a metallic
ations of carcinogenicity: An updating of taste lasting 12 hours after ingestion.1
IARC Monographs Volumes 1 to 42, pp Most, if not all, occupational illnesses asso-
154156. Lyon, International Agency for ciated with 2,4,5-T (such as chloracne) have
Research on Cancer, 1987
been found to be the result of product con-
7. Agency for Toxic Substances and Disease
Registry (ATSDR): Toxicological Prole for tamination with TCDD.2 TCDD is extremely
2,4,6-Trichlorophenol. TP-90-28, 119pp. US toxic to animals, and exposure has also been
Department of Health and Human Services, associated with liver function impairment,
Public Health Service, 1990 peripheral neuropathy, personality changes,
8. Armstrong MJ, Galloway SM, Ashby J: 2,4,6- porphyria cutanea, hypertrichosis, and hyper-
Trichlorophenol (TCP) induces chromosome pigmentation in humans.3 TCDD is a chlori-
breakage and aneuploidy in vitro. Mutat Res nated dioxin, one of a large number of related
303(3):101108, 1993 compounds referred to as dioxins; it has no
functional use and is not intentionally pro-
duced. It has been identied as the responsible
toxic agent in several industrial disasters, such
2,4,5-TRICHLOROPHENOXYACETIC as accidental releases at Nitro, WV in 1949,
ACID and at Seveso, Italy in 1976.3,4 The role of
CAS: 93-76-5 dioxin contaminants must also be considered in
the discussion of 2,4,5-T toxicology.
C8H5Cl3O A study of 204 workers exposed for from 1
month to 20 years to 2,4,5-T and its contami-
nants (concentrations unspecied) showed no
Synonym: 2,4,5-T evidence of increased risk for cardiovascular
disease, hepatic disease, renal damage, central
Physical Form. Solid or peripheral nervous system effects, reproduc-
tive problems, or birth defects.3 Clinical evi-
Uses. Formerly used as an herbicide in brush dence of chloracne persisted in 55.7%, and an
control. Production was terminated in the association between exposure and history of
United States in 1979 when the Environ- upper gastrointestinal tract ulcer was found.
mental Protection Agency, in an emergency The oral LD50 for dogs was in the range of
action, suspended all uses because of contami- 100 mg/kg; effects were limited to a slight or
nation with 2,3,7,8-tetrachlorodibenzo- moderate stiffness in the hind legs with devel-
p-dioxin (TCDD). In October 1983, all opment of ataxia.5 Dogs survived 10 mg/kg/day
registrations for use of 2,4,5-trichlorophenoxy- for 90 days without illness. In rats fed diets con-
acetic acid (2,4,5-T) were cancelled by the taining 2000 ppm 2,4,5-T (<0.05% TCDD),
US Department of Agriculture because of the minimal cumulative fatal dose was approx-
concerns over the potential of dioxin contami- imately 900 mg/kg.6
702 2,4,5-TRICHLOROPHENOXYACETIC ACID
Concern about the toxicology of 2,4,5-T chlorophenoxy herbicides are possibly carcino-
has centered on its teratogenic action in exper- genic to humans.13
imental animals.2 Although the rst studies 2,4,5-T was not mutagenic in bacterial
were carried out with 2,4,5-T contaminated by assays, and it did not induce aneuploidy or
30 ppm TCDD, subsequent experiments using somatic mutation in vitro. In vivo it did not
analytical-grade 2,4,5-T (<0.05% TCDD) cause micronuclei in mice or dominant lethal
showed that 100 mg/kg/day administered sub- mutations in mice or rats.13
cutaneously to mice on days 6 through 15 of The 2003 ACGIH threshold limit value-
gestation caused an increased incidence of cleft time-weighted average (TLV-TWA) for 2,4,5-
palates.7 Administered by gavage on gestational trichlorophenoxyacetic acid is 10 mg/m3.
days 6 through 14 to various stocks and strains
of mice, 2,4,5-T caused developmental toxicity
at doses below those producing discernible REFERENCES
maternal toxicity.8 The most signicant prena-
tal effects were cleft palate, embryolethality, 1. Hayes WJ Jr: Pesticides Studied in Man, pp
and intrauterine growth retardation. The 526533. Baltimore, MD, Williams &
number of viable fetuses per litter and mean Wilkins, 1982
fetal weight decreased with increasing dose and 2. Murphy SD: Toxic effects of pesticides. In
embryolethality increased.8 2,4,5-T containing Klaasen CD et al. (eds): Casarett and Doulls
no detectable TCDD was feticidal and terato- Toxicology. The Basic Science of Poisons, 3rd ed,
genic to hamsters when administered orally pp 554555. New York, Macmillan, 1986
3. Suskind RR, Hertzberg VS: Human health
on days 610 of gestation at a dosage of
effects of 2,4,5-T and its toxic contaminants.
100 mg/kg/day.9 At 80 mg/kg/day, there was a
JAMA 251:23722380, 1984
reduction in the number of pups per litter, 5. Drill VA, Hiratzka T: Toxicity of 2,4-
in fetal weight, and in survival.9 Rats, dichlorophenoxyacetic acid and 2,4,5-
rabbits, and monkeys have appeared relatively trichlorophenoxyacetic acid. AMA Arch Ind
resistant to teratogenic effects in a number of Hyg Occup Med 7:6167, 1953
studies.1,2 6. Chang H et al: Effects of phenoxyacetic acids
An epidemiological investigation of New on rat liver tissues. J Agric Food Chem
Zealand chemical applicators using 2,4,5-T 22:6265, 1974
found no signicant differences in the rate of 7. Moore JA, Courtney KD: Teratology studies
congenital defects, stillbirths, or miscarriages with the trichlorophenoxy acid herbicides,
2,4,5-T and silvex. Teratology 4(abstr):36,1971
compared with controls.10
8. Holson JF, Gaines TB, Nelson CJ, et al:
Several epidemiological studies in Sweden
Developmental toxicity of 2,4,5-
suggested an association between exposure to trichlorophenoxyacetic acid (2,4,5-T).
phenoxyherbicides (and/or their contaminants) Fundam Appl Toxicol 19:286297, 1992
and soft tissue sarcomas.11 There has also been 9. Collins TFX, Williams CH: Teratogenic
widespread concern among Vietnam veterans studies with 2,4,5-T and 2,4-D in the ham-
that exposure to the defoliant Agent Orange, ster. Bull Environ Contam Toxicol 6:559567,
which contains equal quantities of 2,4-D and 1971
2,4,5-T (with its contaminant TCDD), might 10. Smith AH et al: Preliminary report of repro-
increase their risk of adverse health effects, ductive outcomes among pesticide applica-
particularly various forms of cancer.2 Animal tors using 2,4,5-T. NZ Med J 93:177179,
1981
studies do not support the notion that 2,4,5-T
11. Johnson ES: Review. Association between
itself is carcinogenic.12 Chronic feeding studies
soft tissue sarcomas, malignant lymphomas,
in rats did not produce an increased tumor inci- and phenoxy herbicides/chlorophenols: Evi-
dence, even at doses of 30 mg/kg/day, which dence from occupational cohort studies.
produced toxic effects.12 The IARC has deter- Fundam Appl Toxicol 14:219234, 1990
mined that there is inadequate evidence for car- 12. Kociba RJ et al: Results of a two-year
cinogenicity of 2,4,5-T in animals and that chronic toxicity and oncogenic study of
1,2,3-TRICHLOROPROPANE 703
rats ingesting diets containing 2,4,5- nervous system damage have included pilo-
trichlorophenoxyacetic acid (2,4,5-T). Food erection, salivation, ataxia, and coma; hemor-
Cosmet Toxicol 17:205221, 1979 rhagic damage to the liver and kidneys was also
13. IARC Monographs on the Evaluation of the Car- observed. Repeated gavage administration of
cinogenic Risk of Chemicals to Humans, Suppl 7, 250 mg/kg caused hepatic and renal necrosis
Overall evaluations of carcinogenicity: An
severe enough to cause death within 2 weeks in
updating of IARC Monographs Volumes 1 to
42, p 156. Lyon, International Agency for both mice and rats.5 Increased liver weights and
Research on Cancer, 1987 altered enzyme levels were found in rats at
doses as low as 16 mg/kg/day for 17 weeks,
whereas 32 mg/kg/day for the same period
caused increased kidney weights and
slight inammation. In another report, suba-
1,2,3-TRICHLOROPROPANE cute gavage exposure of rats with 0.80 mmol/
CAS: 96-18-4 kg/day for 10 days caused myocardial degen-
eration and necrosis in addition to mild
C3H5Cl3 hepatotoxicity.6
Oral exposures in the near-lethal range
also produced pathologic changes in the nasal
Synonyms: Glycerol trichlorohydrin; allyl turbinates of both mice and rats.5 Effects
trichloride; trichlorohydrine included inammation and necrotic alterations
in the dorsal posterior of the nasal passages.
Physical Form. Colorless liquid Other effects in rats after repeated gavage
administration were hyperkeratosis and/or
Uses. Intermediate in the manufacture of acanthosis of the esophagus and stomach (doses
pesticides and polysulde rubbers; formerly greater than 63 mg/kg/day) and nonregenera-
used as a solvent and extractive agent tive anemia as indicated by decreased hemat-
ocrit, hemoglobin, and erythrocyte counts
Exposure. Inhalation; skin absorption (doses of 16 mg/kg day).
1,2,3-Trichloropropane was carcinogenic
Toxicology. 1,2,3-Trichloropropane is an in Fischer-344 rats and B6C3F1 mice when
irritant of the eyes and mucous membranes; in administered for 2 years by gavage.5 Rats given
experimental animals it has caused hepatic, 3 mg/kg/day or more and mice given 6 mg/
renal, hematologic, and central nervous system kg/day or more had increased incidences of
effects; it is carcinogenic to rodents exposed squamous cell papillomas and/or carcinomas
orally. in the oral mucosa and/or the forestomach.
Human subjects exposed to 100 ppm for 15 Increased incidences of other tumors included
minutes noted eye and throat irritation and pancreatic acinar adenoma, renal tubule
objected to the unpleasant odor.1 Ingestion of adenoma, and adenoma and carcinoma of the
3 g caused drowsiness, headache, unsteady gait, preputial gland in male rats; clitoral gland
and lumbar pain.2 adenoma and carcinoma and mammary gland
In rats, 1000 ppm caused death in ve of six adenocarcinoma in female rats; hepatocellular
animals after 4 hours of exposure.3 Eight of 15 adenoma and carcinoma and Harderian gland
mice did not survive exposure to 5000 ppm for adenoma in male and female mice; and uterine
20 minutes; liver damage accounted for four neoplasms in female mice.
additional deaths after 710 days.2 Daily 10- The carcinogenicity of 1,2,3-trichloro-
minute exposures to 2500 ppm for 10 days propane is consistent with positive genotoxic
resulted in the death of 7 of 10 mice tested.2 ndings that have included mutagenicity in
Oral LD50 values ranging from 150 to Salmonella typhimurium and induction of sister
450 mg/kg have been determined in rats.4 chromatid exchanges in cultured hamster cells.5
Before death, signs suggestive of central It forms DNA adducts in vivo in mice and rats.6
704 1,1,2-TRICHLORO-1,2,2-TRIFLUOROETHANE
Intraperitoneal doses causing maternal 7. La DK, Lilly PD, Anderegg RJ, et al: DNA
toxicity in rats were not fetotoxic or terato- adduct formation in B6C3F1 mice and
genic.8 Male rats administered 80 mg/kg/day Fischer-344 rats exposed to 1,2,3-trichloro-
by gavage for 5 days and then mated with an propane. Carcinogenesis 16(6):14191424, 1995
untreated female did not have any meaningful 8. Hardin BD, Bond GP, Sikov MR, et al: Testing
of selected workplace chemicals for terato-
changes in indices such as numbers of implants
genic potential. Scand Work Environ Health 7
and number of live embryos compared with (suppl 4):6675, 1981
controls.9 Oral administration for up to 4 9. Saito-Suzuki R, Teramoto S, Shirasu Y: Dom-
months at near-lethal levels caused decreased inant lethal studies in rats with 1,2-dibromo-
testes and epididymis weights in rats and mice 3-chloropropane and its structurally related
but no effects on testicular histology, sperm compounds. Mutat Res 191:321327, 1982
counts, or sperm morphology.4
The liquid was irritating to the skin of
rabbits with prolonged or repeated exposure
and was also extremely irritating when instilled
in rabbit eyes.4 The dermal absorption LD50 1,1,2-TRICHLORO-1,2,2-
was 2.5 g/kg.3 TRIFLUOROETHANE
The 2003 ACGIH threshold limit value- CAS: 76-13-1
time-weighted average (TLV-TWA) for 1,2,3-
trichloropropane is 10 ppm (60 mg/m3) with a CCl3CF3
notation for skin absorption.
1. Silverman L, Schulte HF, First MW: Further Physical Form. Colorless gas; volatile liquid
studies on sensory response to certain indus-
trial solvent vapors. J Ind Hyg Toxicol 28: Uses. Solvent for cleaning electronic equip-
262266, 1946 ment and degreasing of machinery; refrigerant;
2. McOmie WA, Barnes TR: Acute and subacute dry cleaning agent
toxicity of 1,2,3-trichloropropane in mice and
rabbits. Fed Proc 8:319, 1948 Exposure. Inhalation
3. Smyth HF Jr, Carpenter CP, Weil CS, et al:
Range-nding toxicity data: List VI. Am Ind
Toxicology. 1,1,2-Trichloro-1,2,2-trifluo-
Hyg Assoc J 23:95107, 1962.
4. Agency for Toxic Substances and Disease Reg- roethane (TCTFE) is a central nervous system
istry (ATSDR): Toxicological Prole for 1,2,3- depressant, a cardiac sensitizer, and a mild
Trichloropropane. TP-91/28, 93pp. US mucous membrane irritant.
Department of Health and Human Services, Although TCTFE is not considered to be
Public Health Service, 1992 extremely toxic, several deaths have occurred
5. National Toxicology Program (NTP): Toxicol- when the chemical was used as a cleaning agent
ogy and Carcinogenesis Studies of 1,2,3-Trichloro- in small, closed, unventilated areas.1 The vapor
propane (CAS No. 96-18-4) in F344/N Rats and acts by displacing oxygen in the victims imme-
B6C3 F1 Mice (Gavage Studies). Technical diate breathing zone, resulting in asphyxia
report series No. 384, NIH pub 91-2839. followed by pulmonary edema and death.
Research Triangle Park, NC, Department of
Symptoms such as headache, light-headedness,
Health and Human Services, National Insti-
tute of Health, 1993 dizziness, or drowsiness may or may not
6. Merrick BA, Robinson M, Condie LW: Car- precede collapse.
diopathic effect of 1,2,3-trichloropropane after In experimental human studies, exposure
subacute and subchronic exposure in rats. J to 4500 ppm for 30100 minutes resulted in
Appl Toxicol 11:179187, 1991 signicant impairment in tests of manual dex-
1,1,2-TRICHLORO-1,2,2-TRIFLUOROETHANE 705
terity and vigilance. Subjects reported loss of were observed after 20 weeks of applications to
concentration and a tendency to somnolence, uncovered skin.7 The liquid produced no sig-
which disappeared 15 minutes after the expo- nicant irritation in a rabbit eye test.7
sure ended. At 1500 ppm, no effects were TCTFE is odorless, tasteless, and colorless
observed.2 More prolonged human exposures and provides no warning of overexposure.1
of 6 hours daily, 5 days/week for 2 weeks The 2003 ACGIH threshold limit value-
at concentrations of approximately 500 and time-weighted average (TLV-TWA) for 1,1,2-
1000 ppm caused mild throat irritation on the trichloro-1,2,2-triuoroethane is 1000 ppm
rst day; there was no decrement in perform- (7670 mg/m3) with a TLV-STEL (short term
ance of complex mental tasks.3 No signs or excursion limit) of 1250 ppm (9590 mg/m3).
symptoms of adverse effects were found among
50 workers exposed to levels ranging from 46 REFERENCES
to 4700 ppm for an average duration of 2.8
years.4 1. Voge VM: Freon: An unsuspected problem.
The liquid dissolves the natural oils of the Aviat Space Environ Med 60(10, suppl):
skin, and dermatitis may occur as a result of B27B28, 1989
repeated contact; one worker experienced 2. Stopps GJ, McLaughlin M: Psychophysio-
drying of the skin attributed to contact with logical testing of human subjects exposed to
TCTFE.4,5 solvent vapors. Am Ind Hyg Assoc J 28:4350,
Pharmacokinetic studies have not deter- 1967
mined whether TCTFE is metabolized by 3. Reinhardt CF et al: Human exposures to u-
orocarbon 113. Am Ind Hyg Assoc J 32:143
humans or eliminated unchanged.6
152, 1971
Animal studies have indicated low acute
4. Imbus HR, Adkins C: Physical examination
toxicity from inhaled TCTFE. The LC50 for of workers exposed to trichlorotriuo-
2-hour exposures ranged from 50,000 to roethane. Arch Environ Health 24:257261,
120,000 ppm for a number of species.7 Dogs 1972
exposed at 11,00013,000 ppm for 6 hours 5. Hygienic Guide Series: 1,1,2-Trichloro-
showed lethargy, nervousness, vomiting, and 1,2,2-triuoroethane. Am Ind Hyg Assoc J
tremorsall reversible within 15 minutes after 29:521525, 1968
exposure. Chronic exposure of rats and rabbits 6. Auton TR, Woollen BH: A physiologically
to 12,000 ppm for up to 2 years caused no based mathematical model for the human
adverse effects. Rats exposed by whole body inhalation pharmacokinetics of 1,1,2-
trichloro-1,2,2-triuoroethane. Int Arch
inhalation to 2000, 10,000 or 20,000 ppm 6
Occup Environ Health 63:133138, 1991
hours/day, 5 days/week for 24 months showed
7. ACGIH: 1,1,2-Tricholoro-1,2,2-triuoro-
no microscopic evidence of compound-related ethane. Documentation of the TLVs and BEIs,
toxicity or carcinogenicity.8 Observations of 6th ed, pp 16311634. Cincinnati, OH,
appearance, behavior, mortality, and clinical American Conference of Governmental
laboratory measurements were unremarkable, Industrial Hygienists, 1991
except for a 510% decrease in body weight 8. Trochimowicz HJ, Rusch GM, Chiu T, et al:
gains at the 10,000 and 20,000 ppm exposure Chronic inhalation toxicity/carcinogenicity
levels. study in rats exposed to uorocarbon 113
In dogs, cardiac sensitization to intra- (FC-113). Fundam Appl Toxicol 11:6875,
venously administered epinephrine occurred at 1988
9. Reinhardt CF, Mullin LS, Maxeld ME:
concentrations of 5,00010,000 ppm.9 Concen-
Cardiac sensitization potential of some
trations greater than 25,000 ppm were neces-
common industrial solvents. Ind Hyg News
sary to produce arrhythmias in animals under Rep 15:34, 1972
anesthesia.10 10. Aviado DM: Toxicity of aerosol propellants in
Occluded contact with rabbit skin of the respiratory and circulatory systems. X.
5 gm/kg/day for 5 days caused local necrosis of Proposed classication. Toxicology 3:321332,
skin and enlargement of liver cells; no effects 1975
706 TRIETHANOLAMINE
Mono-, Di-, and Triethanolamine, Carbode and subjects experienced heavy hazing of the visual
Carbon Chem Div, UCC Industrial Fellow- eld, an inability to distinguish outlines of
ship No 274-13 (Report 13-67), August 18, objects 100 m or more away, and bluish halos
1950 around lights. There was pronounced increase
7. Smyth HF Jr, et al: Range-nding toxicity in corneal thickness. The investigators suggest
data: List IV. AMA Arch Ind Hyg Occup Med
that the decrease in visual acuity at the end of
4:119, 1951
8. Hoshino H, Tanooka H: Carcinogenicity of work may be severe enough to cause accidents
triethanolamine in mice and its mutagenicity in the workplace or in trafc. Effects are
after reaction with sodium nitrite in bacteria. reversible, and it appears that even repeated
Cancer Res 38:3918, 1978 bouts of edema do not cause permanent
9. Konishi Y, Denda A, Uchida K, et al: damage to the cornea. In another report TEA
Chronic toxicity carcinogenicity studies of a concentration of 3.0 mg/m3 for 4 hours
triethanolamine in B6C3F1 mice. Fundam caused no effects whereas exposure to 6.5 mg/
Appl Toxicol 18:2529, 1992 m3 for the same period caused blurred vision
10. Maekawa A, Onodera H, Tanigawa H, et al: and a decrease in contrast sensitivity.2 Only
Lack of carcinogenicity of triethanolamine minor increases in corneal thickness were
in F344 rats. J Toxicol Environ Health 19:
noted, but there was marked edema in the
345357, 1986
11. National Toxicology Program: Toxicological corneal epithelium.
and Carcinogenesis Studies of Triethanolamine in Among 19 workers repeatedly exposed to
F344/N Rats and B6C3F1 Mice. NTP TR time-weighted average (TWA) levels of 3 ppm
449, pp 1295. Research Triangle Park, NC, with brief excursions to higher levels, 5 workers
US Department of Health and Human Ser- reported foggy vision, blue haze, and halo phe-
vices, 1999 nomena on 47 occasions over an 11-week
12. Beyer KH Jr, et al: Final report on the safety period.3 In another study, these same vision
assessment of triethanolamine, diethano- symptoms (blurriness, halos around lights, and
lamine, and monoethanolamine. J Am Coll blue, hazy vision) occurred more often in cur-
Toxicol 1:183235, 1983 rently exposed workers than those previously
or never exposed to TEA.4 There was no
corneal edema, but reported symptoms were
more common among those with the highest
TRIETHYLAMINE exposures (1020.3 mg/m3).
CAS: 121-44-8 Exposure of six rats to 1000 ppm for 4
hours was lethal to one.5 Rabbits survived expo-
(C2H5)3N sures to 100 ppm daily for 6 weeks but showed
pulmonary irritation, myocardial degeneration,
and cellular necrosis of liver and kidneys; at
Synonyms: TEA; N,N-diethylethanamine 50 ppm, the effects on lung, liver, and kidneys
were less severe, but there was also damage to
Physical Form. Colorless liquid the cornea.6 Rats appeared to be less sensitive
to the effects of TEA than rabbits.7 Exposure
Uses. In the manufacture of waterproong to 25 or 247 ppm 6 hours/day, 5 days/week for
agents; as a corrosion inhibitor; as a propellant up to 28 weeks caused no statistically signi-
cant treatment-related effects on body weight
Exposure. Inhalation gain, organ weights, hematology, clinical
chemistry, or electrocardiographic indices.7 No
Toxicology. Triethylamine (TEA) causes gross pathologic or histopathologic lesions
ocular effects in humans; in animals it is a skin attributable to exposure were noted at autopsy.
and mucous membrane irritant. In rabbits, skin application produced
Two volunteers exposed to approximately adverse effects ranging from irritation to cor-
4.5 ppm for 8 hours experienced slight subjec- rosion, depending on the amount and duration
tive visual disturbances.1 At 12 ppm for 1 hour, applied.8
708 TRIETHYLENE TETRAMINE
TEA was not mutagenic in bacterial assays, Physical Form. Slightly viscous yellow
but it did cause aneuploidy and chromosome liquid; commercially available form is 9598%
aberrations in rats.8 pure, and impurities include linear, branched,
The 2003 ACGIH threshold limit value- and cyclic isomers.
time-weighted average (TLV-TWA) for triethy-
lamine is 1 ppm (4.1 mg/m3) with a short-term Uses. Hardener/cross-linker for epoxy
excursion limit (STEL)/ceiling of 5 ppm (20.7 resins; metal chelator; constituent of wet-
mg/m3) and a notation for skin absorption. strength paper resins; copolymer with fatty
acids in metal spray coatings; constituent of
synthetic elastomer formulations
REFERENCES
Exposure. Inhalation
REFERENCES
Toxicology. Triuorobromomethane in
1. Spitz RD: Diamines and higher amines, animals causes sensitization of the myocardium
aliphatic. In Grayson M, Eckroth D (eds): to epinephrine and central nervous system
Kirk-Othmer Encyclopedia of Chemical Technol- effects.
ogy, 3rd ed. New York, Wiley-Interscience, Human exposure to 70,000 ppm for 3
1979 minutes caused no adverse effects.1 Light-
2. Beard RR, Noe JT: Aliphatic and alicyclic
headedness, paresthesia, and diminished per-
amines. In Pattys Industrial Hygiene and Toxi-
cology, Vol 2B, Toxicology, pp 32353273. New formance were reported during exposures up to
York, John Wiley & Sons, 1971 100,000 ppm; at 150,000 ppm, a feeling of
3. Eckardt RE, Hindin R: The health hazards of impending unconsciousness developed.2 Expo-
plastics. J Occup Med 15:808819, 1973 sure to 10,000 ppm (1%) for 24 hours produced
4. Eckardt RE: Occupational and environmental minor disturbances of central nervous system
health hazards in the plastics industry. Environ function as assessed by cognitive tasks.3
Health Perspect 17:103196, 1976 In dogs and rats repeatedly exposed to
5. Fawcett IW, Taylor AJN, Pepys J: Asthma due 23,000 ppm, there were no toxic signs or patho-
to inhaled chemical agentsEpoxy resin logic changes.2 Monkeys exposed to concentra-
systems containing phthalic acid anhydride, tions of 200,000 ppm were lethargic and
trimellitic acid anhydride and triethylene
suffered spontaneous cardiac arrhythmias
tetramine. Clin Allergy 7:114, 1977
6. Cohen NL, Keen CL, Lonnerdal B, Hurley within 540 seconds of exposure.3 Dogs
LS: Low tissue copper and teratogenesis in tri- exposed to 200,000 ppm or greater became agi-
ethylenetetramine-treated rats. Fed Proc tated within 12 minutes, and tremor occurred
41:944, 1982 within 3 minutes.4 Epileptiform convulsions
7. Tanaka H, Inomata K, Arima M: Teratogenic characterized by generalized rigidity, apnea,
effects of triethylene tetramine dihydrochlo- and cyanosis of the tongue were observed in
ride on the mouse brain. J Nutr Sci Vitamin about half of the dogs exposed to 500,000
39:177188, 1993 800,000 ppm. Intravenous injection of a pressor
8. Anonymous: Triethylenetetramine (June dose of epinephrine produced arrhythmias in
1992). Beratergremium fuer umweltrelevante all animals exposed to 400,000 ppm; larger
Altstoffe (BUA) 89:158, 1995
doses of epinephrine (510 mg/kg) caused ven-
tricular brillation with cardiac arrest in dogs
and spontaneous debrillation in monkeys.
The 2003 ACGIH threshold limit value-
time-weighted average (TLV-TWA) for triu-
orobromomethane is 1000 ppm (6090 mg/m3).
710 TRIMELLITIC ANHYDRIDE
headache, and skin irritation. Symptoms of The 2003 ACGIH threshold limit value-
chest pain and respiratory tract irritation have ceiling (TLV-CEILING) for trimellitic anhy-
been reported in workers exposed to levels in dride is 0.04 mg/m3.
the range of 0.110 mg/m3. In one study, inter-
mittent exposure to levels ranging up to
2.1 mg/m3 caused late respiratory systemic syn- REFERENCES
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1. McGrath KG, Zeiss R, Patterson R: Allergic
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reactions to industrial chemicals. Clin
to 0.03 mg/m3 coincided with symptomatic
Immunol Rev 2:158, 1983
improvement in the three workers with late 2. Zeiss, CR, Wolkonsky P, Pruzansky JJ,
respiratory systemic syndrome and a fall in Patterson R: Clinical and immunologic eval-
total antibody binding to trimellityl-human uation of trimellitic anhydride workers in
serum albumin. However, the continued low- multiple industrial settings. J Allergy Clin
level exposure was sufcient to elicit and main- Immunol 70:1518, 1982
tain a specic IgE immune response in a 3. Letz G, Wygofski L, Cone JE, et al: Trimel-
worker who eventually developed lacrimation litic anhydride exposure in a 55-gallon drum
and rhinorrhea. Further study of this same manufacturing plant: Clinical, immunologic,
population showed that workers exposed only and industrial hygiene evaluation. Am J Ind
Med 12:407417, 1987
after the low levels were in place developed no
4. National Institutes of Health: Occupa-
immunologic syndromes and had insignicant
tional asthma from a low-molecular-weight
antibody responses.6 organic chemical. JAMA 244:16671668,
A follow-up study of 29 workers with 1980
TMAN-induced immunologic lung disease who 5. Bernstein DI, Roach DE, McGrath K, et al:
had been moved to low-exposure jobs for more The relationship of airborne trimellitic
than 1 year revealed that workers with late anhydride-induced symptoms and immune
asthma or late respiratory systemic syndrome responses. J Allergy Clin Immunol 72:709
had improved symptoms, improved pulmonary 713, 1983
functions, and lower total antibody against 6. McGrath K, Roach D, Zeiss R, Patterson R:
TMAN-HSA.7 In contrast, 7 of 12 workers Four-year evaluation of workers exposed to
trimellitic anhydride. J Occup Med 26:671
with asthma rhinitis continued to have moderate
675, 1984
to severe symptoms, abnormal pulmonary func-
7. Grammer LC, Shaughnessy MA, Henderson
tions, and elevated IgE against TMAN-HSA. J, et al: A clinical and immunological study of
Elevated IgE against TMAN-HSA appears to be workers with trimellitic-anhydride-induced
a marker for the subpopulation of workers with immunologic lung disease after transfer to
asthma rhinitis that does not improve. low exposure jobs. Am Rev Respir Dis
In animal studies, TMAN had a low acute 148:5457, 1993
toxicity when administered by the oral or the 8. Health and Safety Executive: Toxicity Review
percutaneous route.8 Rats given 10,000 ppm in 8. Trimellitic Anhydride. London, Her
the diet for 90 days showed an increase in the Majestys Stationery Ofce, 1983
number of white blood cells. Inhalation of 9. World Health Organization: Health and
Safety Guide No. 71 Trimellitic Anhydride.
0.2 mg/m3 and above for 14 days was associated
Geneva, International Programme on Chem-
with hemorrhagic foci in the lungs.
ical Safety (IPCS), 1992
There are no reports of carcinogenicity 10. Ryan BM, Hatoum NS, Zeiss CR, Garvin PJ:
associated with TMAN exposure. It was not Immunoteratologic investigation of trimel-
mutagenic in bacterial assays with or without litic anhydride (TMA) in the rat and guinea
metabolic activation.9 No teratogenic effects pig. Teratology 39:477478, 1989 (abst)
or developmental toxicity was seen in rats
or guinea pigs exposed to 500 mg/m3 for
6 hours/day during their period of major
organogenesis.10
712 TRIMETHYLAMINE
REFERENCES
Synonyms: N,N-dimethylmethanamine; TMA
1. Grant WM: Toxicology of the Eye, 3rd ed, p 952.
Physical Form. Colorless gas Springeld, IL, Charles C. Thomas, 1986
2. Kinney LA, Burgess BA, Chen HC, et al:
Inhalation toxicology of trimethylamine
Uses. As an insect attractant, as a warning (TMA). Inhal Toxicol 2:4151, 1990
agent for natural gas, and in organic synthesis 3. Guest I, Varma DR: Teratogenic and macro-
molecular synthesis inhibitory effects of
Exposure. Inhalation trimethylamine on mouse embryos in culture.
J Toxicol Environ Health 36:2741, 1992
Toxicology. Trimethylamine is a skin, eye, 4. British Industrial Biological Research Associa-
and respiratory irritant. tion: BIBRA Toxicity Prole of Trimethylamine
and its Hydrochloride. Technical Report 432, pp
In an accidental exposure, a blast of vapor
15. Carshalton, UK, 1993
that struck the eye of a student caused the
epithelium to be lost from the cornea. There
was no edema of the corneal stroma, and the
eye was completely normal within 4 or 5 days;
the exposure was thought to be minimal. TRIMETHYL BENZENE
Tests of single drops of aqueous solutions CAS: 25551-13-7
applied to the eyes of animals have shown that
1% solution causes severe irritation, 5% causes Mesitylene 108-67-8
hemorrhagic conjunctivitis, and 16% causes Pseudocumene 95-63-6
severe reaction with conjunctival hemorrhages, Hemimellitene 526-73-8
corneal edema, and opacities, followed by some
clearing but much vascularization.1 (CH3)3C6H3
In rats, 3500 ppm for 4 hours was consid-
ered an approximate lethal concentration. Rats
exposed 6 hours/day for 10 days to 0, 75, 250, Synonyms: The three isomers of trimethyl
or 750 ppm had dose-dependent degenerative benzene are mesitylene (1,3,5-trimethylben-
changes in the olfactory and respiratory epithe- zene, sym-trimethylbenzene, 1,3,5-TMB),
lium.2 Degeneration of the tracheal mucosa pseudocumene (1,2,4-trimethylbenzene,
was also observed at the two higher doses. pseudocumol, 1,2,4-TMB), and hemimellitene
Administered to mouse embryo cultures in (1,2,3-trimethylbenzene, 1,2,3-TMB).
vitro, trimethylamine was teratogenic, causing
neural tube defects and inhibiting embryonic Physical Form. Colorless liquid
growth.3 Trimethylamine may exert these
effects by reducing macromolecular synthesis. Uses. As a raw material in chemical synthe-
Repeated intraperitoneal injections of tri- ses; as ultraviolet stabilizers in plastics; found
methylamine hydrochloride in pregnant mice in solvents and as a constituent of gasoline
caused fetotoxicity only at maternally toxic
doses.4 Exposure. Inhalation
Trimethylamine was not mutagenic in bac-
terial assays.4 Toxicology. Trimethyl benzene is an eye,
The 2003 ACGIH threshold limit value- nose, and respiratory irritant; at high concen-
TRIMETHYL PHOSPHITE 713
trations it causes central nervous system quency of sister chromatid exchanges in these
depression. cells.5
In one of the few reports of human expo- It is expected that repeated skin exposure
sure, 27 workers exposed for a number of years to the liquid will cause drying and cracking of
to a paint thinner containing primarily 1,2,4- the skin.
TMB (50%) and 1,3,5-TMB (30%), plus other The 2003 ACGIH threshold limit value-
alkylbenzenes in unspecied amounts, had time-weighted average (TLV-TWA) for
signs and symptoms of impairment of the res- trimethyl benzene is 25 ppm (123 mg/m3).
piratory, nervous, and hematopoietic systems.1
Approximately 70% of the workers complained
of headaches and drowsiness, with 51% suffer- REFERENCES
ing from anemia, 30% displaying signs of
asthmalike bronchitis, and 30% showing a 1. Snyder R (ed): Ethel Brownings Toxicity and
tendency to hemorrhage. The presence of Metabolism of Industrial Solvents, 2nd ed Vol I:
other hydrocarbons and unidentied additives Hydrocarbons. pp 121142. New York,
that accounted for 20% of the thinner sug- Elsevier, 1987
2. Sandmeyer EE: Aromatic hydrocarbons. In
gested that the blood disturbances were prob-
Clayton GD, Clayton FE (eds): Pattys Indus-
ably due to a contaminant.
trial Hygiene and Toxicology, 3rd rev ed, Vol 2B,
Mice exposed at 51007140 ppm 1,3,5- Toxicology, pp 33003302. New York, Wiley-
TMB for 2 hours suffered from a loss of right- Interscience, 1981
ing reex, and at 71409180 ppm for 2 hours 3. Gage JC: The subacute inhalation toxicity of
mice showed depression of the central nervous 109 industrial chemicals. Br J Ind Med 27:
system.1,2 Similar exposures to 1,2,4-TMB 118, 1970
produced similar results, with 8130 ppm for 4. Maltoni C, Ciliberti A, Pinto C, et al: Results
2 hours causing a loss of righting reex and of long-term experimental carcinogenicity
81309140 ppm causing a loss of reexes and studies of the effects of gasoline, correlated
depression of the central nervous system. fuels, and major gasoline aromatics on rats.
Ann NY Acad Sci 837:1552, 1997
In rats, exposure to 2400 ppm 1,3,5-TMB
5. Janik-Spiechowicz E, Wyszynska K,
for 24 hours caused death due to respiratory
Dziubaltowska E: Genotoxicity evaluation
failure and depression of the central nervous of trimethylbenzenes. Mutat Res 412(3):299
system in 4 of 10 animals; at 612 ppm for 24 305, 1998
hours there were no adverse effects.1 Rats
exposed at 600 ppm 6 hours/day, 6 days/week
for 5 weeks showed no hematologic or bio-
chemical changes. Experiments with 1,2,4-
TMB showed nose and eye irritation,
respiratory difculty, lethargy, tremors, and TRIMETHYL PHOSPHITE
reduced weight gain with 12 exposures to CAS: 121-45-9
2000 ppm for 16 hr each; at 1000 ppm there was
only slight eye and nose irritation.3 Inhalation C3H9O3P
of mixed trimethylbenzene by rats 4 hours/day
for 6 months at 200 ppm caused inhibition of
phagocytic activity of the leukocytes. Synonyms: Methyl phosphite; phosphorus
Rats administered 1,2,4-TMB by gavage acid trimethyl ester; TMP; trimethoxyphos-
for 2 years exhibited increased total malignant phine
tumors and head cancers.4 1,2,3-TMB (but not
1,2,4-TMB or 1,3,5-TMB) was mutagenic in Physical Form. Colorless liquid
bacterial assays; in vivo none of the isomers
increased the frequency of micronuclei in bone Uses. Used primarily in the synthesis of
marrow; however, all three increased the fre- organophosphate insecticides; also used in the
714 2,4,6-TRINITROTOLUENE
occurred after a latent period of 24 days and A study at two explosive manufacturing
were characterized by weakness, vertigo, facilities in China found an increased incidence
headache, nausea, paleness, enlarged liver and of malformed spermatozoa in TNT-exposed
spleen, dark urine, decreased hemoglobin workers.8
levels, and reticulocytosis.3 Although no simul- Rats administered 50 mg/kg/day in their
taneous measurements of atmospheric levels diets had anemia, splenic lesions, and liver
were available, measurement on other occa- and kidney damage.9 Testicular atrophy and
sions showed levels up to 3.0 mg/m3.3 atrophic seminiferous tubules have been
Above 1.0 mg/m3, the liver is unable to reported in rats after 13 weeks of treatment at
handle the increased amounts of red blood high doses.10 Hyperplasia and carcinoma of the
cell breakdown products and indirect biliru- urinary bladder were also observed in females
bin levels rise.2 Elevations of liver function exposed for 24 months. A statistically signi-
enzymes may occur, particularly in new cant incidence of leukemia and/or malignant
employees or those recently exposed to higher lymphoma of the spleen was present in female
levels. There are suggestions of marked indi- mice receiving 70 mg/kg/day for 24 months.10
vidual susceptibility to liver damage, with most The IARC has determined that there is inade-
not showing effects unless exposures consider- quate evidence in experimental animals and
ably exceed 1.0 mg/m3.2 humans for the carcinogenicity of TNT.11
A characteristic TNT cataract is report- In bacterial and mammalian in vitro cell
edly produced with exposures regularly exceed- systems TNT is a direct-acting mutagen.10
ing 1.0 mg/m3 for more than 5 years.2 In one However, inclusion of exogenous metabolic
study, 6 of 12 workers had bilateral peripheral activation appears to abolish the genotoxicity.
cataracts, visible only with maximum dilation.4 In vivo assays of TNT have not shown it to be
The opacities did not interfere with visual genotoxic, suggesting that TNT may be
acuity or visual elds. The induced cataracts reduced to nonmutagenic metabolic products
may not regress once exposure ceases, although in the whole animal.
progression is arrested. The 2003 ACGIH threshold limit value-
The vapor or dust can cause irritation of time-weighted average (TLV-TWA) for 2,4,6-
mucous membranes, resulting in sneezing, trinitrotoluene is 5 mg/m3 with a notation for
cough, and sore throat.5 Although intense or skin absorption.
prolonged exposure to TNT may cause some
cyanosis, it is not regarded as a strong producer
of methemoglobin.6 Other occasional effects REFERENCES
include leukocytosis or leukopenia, peripheral 1. Woollen BH, Hall Mg, Craig R, et al: Trini-
neuritis, muscular pains, cardiac irregularities, trotoluene: Assessment of occupational
and renal irritation.2 The skin, hair, and nails absorption during manufacture of explosives.
of exposed workers may be stained yellow.5 Br J Ind Med 43:465473, 1986
TNT is absorbed through skin fairly 2. Hathaway JA: Subclinical effects of trinitro-
rapidly, and reference to airborne levels of toluene: A review of epidemiology studies. In
vapor or dust may underestimate total systemic Richert DE (ed): Toxicity of Nitroaromatic
exposure if skin exposure also occurs.2 Appar- Compounds, pp 255274. New York, Hemi-
ent differences in dose-response relationships sphere Publishing, 1985
based only on airborne levels may be explained 3. Djerassi LS, Vitany L: Haemolytic episode in
G6-PD decient workers exposed to TNT.
by differences in dermal absorption.2 TNT
Br J Ind Med 32:5458, 1975
causes sensitization dermatitis; the hands,
4. Harkonen H, Karki M, Lahti A, et al: Early
wrist, and forearms are most commonly equatorial cataracts in workers exposed to
affected, but skin at friction points such as the trinitrotoluene. Am J Ophthalmol 95:807
collar line, belt line, and ankles is also often 810, 1983
involved. Erythema, papules, and an itchy 5. Hygienic Guide Series: 2,4,6-Trinitrotoluene
eczema can be severe.7 (TNT). Am Ind Hyg Assoc J 25:516519, 1964
716 TRIORTHOCRESYL PHOSPHATE
6. Goodwin JW: Twenty years handling TNT taminated foods and beverages.1 The most
in a shell loading plant. Am Ind Hyg Assoc J notable example was the consumption of an
33:4144, 1972 adulterated Jamaica ginger extract (Jake).2
7. Schwartz L: Dermatitis from explosives. However, reports of intoxication from occupa-
JAMA 125:186190, 1944. tional exposure are rare.1 Shortly after inges-
8. Liu HX, Qin WH, Wang GR, et al: Some
tion, there may be nausea, vomiting, diarrhea,
altered concentrations of elements in semen
of workers exposed to trinitrotoluene. Occup
and abdominal pain.1 After a symptom-free
Environ Med 52(12):842845, 1995 interval of 328 days, most patients complain
9. Levine BS, et al: Two-year chronic oral toxi- of sharp, cramplike pains in the calf muscles;
city/carcinogenicity study on the munitions some patients complained of numbness and
compound trinitrotoluene (TNT) in rats. tingling in the feet and sometimes the hands.1,3
Toxicologist 5:(abstr 697)175, 1985 Within a few hours, there is increasing weak-
10. Agency for Toxic Substances and Disease ness of the legs and feet, progressing to bilat-
Registry (ATSDR): Toxicological Prole for eral footdrop.3 After an interval of another 10
2,4,6-Trinitrotoluene, 186pp. US Department days, weakness of the ngers and wristdrop
of Health and Human Services, Public develop, but the paralysis is not usually as
Health Service, 1995
severe as that in the feet and legs. This process
11. IARC Monographs on the Evaluation of the Car-
cinogenic Risk of Chemicals to Humans, Vol 65,
does not extend above the elbows; the thigh
Printing processes and printing inks, carbon muscles are infrequently involved. Sensory
black and some nitrocompounds, pp 449 changes, if they occur, are minor.4,5
475. Lyon, International Agency for With severe intoxication, lesions of the
Research on Cancer, 1996 anterior horn cells and the pyramidal tracts
may also occur.5,6 Muscular weakness may
increase over a period of several weeks or
months; recovery may take months or years
and in 2530% of cases, permanent residual
TRIORTHOCRESYL PHOSPHATE effects remain, usually conned to the lower
CAS: 78-30-8 limbs.3,5 Gait impairment, characterized by
high steps and footdrop and permanent in
(CH3C6H4)3PO4 some, was called Jake Walk.2
Fatalities are rare and occur principally in
those who have taken large quantities in a short
Synonyms: TOCP; tri-o-tolyl phosphate; period of time; autopsy of six human cases
phosphoric acid, tri-o-tolyl ester revealed involvement of anterior horn cells and
demyelination of nerve cells.4 The lethal dose
Physical Form. Colorless or pale yellow for humans by ingestion is about 1.0 g/kg;
liquid severe paralysis has been produced by ingestion
of 67 mg/kg.4
Uses. Plasticizer in vinyl plastics, lacquers, In workers engaged in the manufacture of
and varnishes; ame retardant aryl phosphates (including up to 20% TOCP)
and exposed to concentrations of aryl phos-
Exposure. Inhalation; skin absorption; phates at 0.23.4 mg/m3, there was some
ingestion inhibition of plasma cholinesterase but no cor-
relation of this effect with degree of exposure
Toxicology. Triorthocresyl phosphate or with minor gastrointestinal or neuromuscu-
(TOCP) causes peripheral neuropathy with lar symptoms.7,8 No effects on the eyes or skin
accid paralysis of the distal muscles of the have been reported; TOCP is readily absorbed
upper and lower extremities, followed in some through the skin without local irritant effects.
cases by spastic paralysis. In affected cats and hens, extensive damage
Thousands of people have been poisoned is observed in the spinal cord and sciatic nerves;
by the accidental ingestion of TOCP in con- damage to the myelin sheath and Schwann cells
TRIPHENYL AMINE 717
(C6H5O)3PO4
REFERENCES
Synonyms: TPP; Celluex TP; Phosex TPP 1. Sutton WL, et al: Studies on the industrial
hygiene and toxicology of triphenyl phos-
Physical Form. Colorless crystalline powder phate. Arch Environ Health 1:4548, 1960
TRIPHENYL PHOSPHITE 719
2. Tabershaw IR, Kleinfeld M, Feiner B: Manu- later stage occurred several days after treat-
facture of tricresyl phosphate and other alkyl ment and was characterized by hyperexcitabil-
phenyl phosphates: An industrial hygiene ity, some spasticity, and incoordination,
study. I. Environmental factors. AMA Arch Ind followed by partial accid paralysis of the
Health 15:537540, 1957 extremities. The posterior extremities were
3. Tabershaw IR, Kleinfeld M, Feiner B: Manu-
usually more affected.
facture of tricresyl phosphate and other alkyl
phenyl phosphates: An industrial hygiene In the same study, cats received a one-time
study. II. Clinical effects of tricresyl phosphate. subcutaneous injection of 0.1, 0.2, 0.3, or
AMA Arch Ind Health 15:541544, 1957 0.5 mg/kg. At the lower doses, the compound
4. Camarasa JG, Serra-Baldrich E: Allergic produced ataxia and paresis of the extremities
contact dermatitis from triphenyl phosphate. after several days. The intermediate dose
Contact Derm 26:264265, 1992 (0.3 ml/kg) was eventually lethal in two animals
5. Welsh JJ, Collins TFX, Whitby KE, et al: and produced rapidly progressing ataxia on day
Teratogenic potential of triphenyl phosphate 6 followed in 12 days by extensor rigidity. The
in Sprague-Dawley (Spartan) rats. Toxicol Ind highest dose (0.5 ml/kg) produced death within
Health 3:357369, 1987 30 hours.
In a later report, rats were injected with
two 1.0 ml/kg (1184 mg/kg) subcutaneous
injections spaced 1 week apart and were euth-
anized after the second injection.2 Dysfunc-
TRIPHENYL PHOSPHITE tional changes, including tail rigidity, circling,
CAS: 101-02-0 and hind limb paralysis were noted. However,
the pattern of triphenyl phosphite-induced
P(O-C6H5)3 spinal cord damage in conjunction with mar-
ginal neurotoxic esterase inhibition suggested
that this toxic neuropathy differed from those
Synonyms: Phenyl phosphite; tripheno- previously described for organophosphorus-
xyphosphine; TPP induced delayed neuropathy (OPIDN).
Follow-up studies of the central nervous
Physical Form. Water-white to pale yellow, system of rats found widespread axonal and ter-
solid (below 22C) or oily liquid minal degeneration involving not only spinal
cord and brain stem, as is the case with other
Uses. Stabilizer/antioxidant for vinyl plastics organophosphorus compounds, but also the
and polyethylene, polypropylene, styrene midbrain, thalamus, and cerebral cortex.3 Sub-
copolymers, and rubber cutaneous injection of triphenyl phosphite in
the hen also produced patterns of severe and
Exposure. Inhalation widespread central nervous system neuro-
pathology including damage to the spinal cord,
Toxicology. Triphenyl phosphite (TPP) is a brain stem, and other higher-order centers
skin irritant and sensitizer in humans and is responsible for sensorimotor, visual, and
neurotoxic in laboratory animals. auditory information.4
Systemic effects have not been reported in Interperitoneal injection of rats at doses
humans. insufcient to produce clinical signs of neuro-
In an early study in rats, subcutaneous toxicity did cause reduction in T-maze spatial
injections of triphenyl phosphite caused two alternation scores. The authors concluded that
distinct stages of neurotoxic action.1 The early, acute TPP administration has a persistent
rapidly developing stage was characterized by effect on the neural systems required for spatial
ne or coarse tremor, usually involving the alternation learning in rats.5
large muscle groups. The tremor disappeared Applied to human skin in patch tests, triph-
in surviving animals within a few hours. The enyl phosphite diluted 1 : 3 with cold cream
720 TUNGSTEN (and Compounds)
of uranium are respiratory irritants, whereas has also been attributed to arsenic exposure
soluble compounds are also toxic to the that occurred in men who worked in both
kidneys. uranium and gold mines.6
Soluble Compounds: Animals repeatedly In a group of uranium mill workers, there
exposed to dusts of soluble uranium com- was an excess of deaths from malignant disease
pounds in concentrations from 3 to 20 mg/m3 of lymphatic and hematopoietic tissue; data
died of pulmonary and renal damage; both from animal experiments suggested that this
feeding and percutaneous toxicity studies on excess may have resulted from irradiation of
animals indicated that the more soluble com- lymph nodes by thorium-230, a disintegration
pounds are the most toxic.1 In animals, effects product of uranium.5 Some absorbed uranium
on the liver are a consequence of the acidosis is deposited in bone. A potential risk of
and azotemia induced by renal dysfunction.1 radiation effects on bone marrow has been
Animal studies indicate that the primary postulated, but extensive clinical studies on
toxic effect of uranium exposure is on the exposed workers have disclosed no hematologic
kidney, with particular damage to the pro- abnormalities.7,8
ximal tubules. Functionally, this may result in Accidental exposure of workers to a
increased excretion of glucose and amino acids. mixture of uranium hexauoride, uranyl uo-
Structurally the necrosis of tubular epithelium ride, hydrouoric acid, and live steam caused
leads to formation of cellular casts in the urine. lacrimation, conjunctivitis, shortness of breath,
If exposure is insufcient to cause death from paroxysmal cough, rales in the chest, nausea,
renal failure, the tubular lesion is reversible vomiting, skin burns, transitory albuminuria,
with epithelial regeneration. Although bone is and elevation of blood urea nitrogen.7 Two
the other major site of deposition, there is no deaths occurred among the most heavily
evidence of toxic or radiocarcinogenic effects exposed workers shortly after exposure. The
to bone or bone marrow from experimental persons having the greatest exposure showed
studies.2 the highest urinary uranium levels. In addition,
Insoluble Compounds: These compounds their urinary abnormalities were the most
are generally considered to be less toxic than severe, including albuminuria plus red blood
the soluble compounds.3 Repeated exposures of cells and casts in the urinary sediment, and
three animal species to uranium dioxide dust blood urea nitrogen remained elevated for
at a concentration of 5 mg uranium/m3 for several weeks. The injurious effects observed
periods up to 5 years resulted in no kidney on the skin, eyes, and respiratory tract were
injury. More than 90% of the uranium found apparently caused by the irritant action of the
in the body was in the lungs and tracheo- hydrouoric acid, whereas the uranium was
bronchial lymph nodes (TLN).2 Fibrotic believed to be responsible for the transient
changes suggestive of radiation injury was seen renal changes.
occasionally in the TLN of dogs and monkeys No evidence of chronic toxicity, either
and in the lungs of monkeys after exposure chemical or radiation, was observed for any
periods longer than 3 years; the estimated alpha uranium compound during the rst 6 years
dose to tissues was greater than 500 rads for of the atomic energy program; all exposed
lungs and 7000 rads for TLN.4 workers were under very close medical
Uranium: A number of studies document surveillance.1
no lung cancers solely from inhaled uranium- Several uranium compounds tested on the
bearing dust. It is generally accepted that lung eyes of animals caused severe eye damage as
cancers developed subsequent to inhalation of well as systemic poisoning. The anion and its
uranium-containing dusts were due to radon hydrolysis products determine the degree of
daughters and long-term cigarette smoking, injury.9,10 A hot nitric acid solution of uranyl
and not due to uranium metallotoxicity or nitrate spilled on the skin caused skin burns,
uranium radioactive emissions.3,5 In some nephritis, and heavy metal encephalopathy.9
mining cohorts part of the lung cancer excess Prolonged skin contact with uranium com-
724 USED MINERAL-BASED CRANKCASE OIL
pounds should be avoided because of potential 6. Kusiak RA, Ritchie AC, Muller J, et al: Mor-
radiation damage to basal cells. Dermatitis tality from lung cancer in Ontario uranium
has occurred as a result of handling uranium miners. Br J Ind Med 50:920928, 1993
hexauoride.9 7. Voegtlin C, Hodge HC: Pharmacology and
In genotoxic assays, signicant increases in Toxicology of Uranium Compounds, Vol 1, pp
413414. New York, McGraw-Hill, 1949
frequencies of chromosomal aberrations
8. Voegtlin C, Hodge HC: Pharmacology and
in peripheral lymphocytes have been reported Toxicology of Uranium Compounds, Vol 2, pp.
in uranium miners.3 This effect has been attrib- 687689, 9931017. New York, McGraw-
uted to radon daughter products and more Hill 1949
recently to mutagenic mycotoxins produced by 9. Hygienic Guide Series: Uranium (natural)
molds present in the uranium mines.11 and its compounds. Am Ind Hyg Assoc J
Oral administration of 3 mg uranium/ 30:313317, 1969
kg/day as uranyl acetate dihydrate to pregnant 10. Grant WM: Toxicology of the Eye, 2nd ed, p
mice on gestation days 615 caused an increase 1073. Springeld, IL, Charles C. Thomas,
in fetotoxicity (stunted fetuses, external and 1974
skeletal malformations, and developmental 11. Sram RJ, Dobias L, Rossner P, et al: Moni-
toring genotoxic exposure in uranium mines.
variations) and maternal toxicity.12 In reproduc-
Environ Health Perspect 101(suppl 3):155158,
tive studies, no adverse effects were observed in 1993
testicular function or spermatogenesis in male 12. Domingo JL, Paternain JL, Llobet JM, et al:
mice treated with up to 80 mg/kg/day uranyl The developmental toxicity of uranium
acetate dihydrate for 64 days.13 in mice. Arch Environ Health 44:395398,
The 2003 ACGIH threshold limit 1989
value-time-weighted average (TLV-TWA) for 13. Llobet JM, Sirvent JJ, Ortega A, et al: Inu-
uranium (soluble and insoluble compounds, ence of chronic exposure to uranium on male
as U) is 0.2 mg/m3 with a short-term excursion reproduction in mice. Fundam Appl Toxicol
limit (STEL) of 0.6 mg/m3. 16:821829, 1991
REFERENCES
USED MINERAL-BASED CRANKCASE OIL
1. Beliles RP: The metals. In Clayton GD,
Clayton FE (eds): Pattys Industrial Hygiene Synonyms: Used motor oil; used engine oil
and Toxicology, 4th ed, Vol IIC, Toxicology, pp
23002317. New York, Wiley-Interscience,
Physical Form. brown to black oily liquid;
1994
2. US Environmental Protection Agency: new mineral-based crankcase oil contains
Drinking Water Criteria Document for petrochemicals (straight-chain hydrocarbons,
Uranium. F-198. Washington, DC, Ofce of aromatic hydrocarbons, and polyaromatic
Drinking Water, 1985 hydrocarbons or PAH) plus stabilizers and
3. Agency for Toxic Substances and Disease detergents including zinc dithiophosphate, zinc
Registry (ATSDR): Toxicological Prole for diaryl or dialkyl dithiophosphates (ZTDP),
Uranium, 398pp. US Department of Health calcium alkyl phenates, magnesium, sodium,
and Human Services, Public Health Service, and calcium sulfonates, tricresyl phosphates,
1999 molybdenum disulde, heavy metal soaps,
4. Leach LJ, Maynard EA, Hodge CH, et al: cadmium, and zinc.1
A ve-year inhalation study with natural
In a crankcase-lubricated engine, the oil
uranium dioxide (UO2) dust. I. Retention and
biologic effect in the monkey, dog and rat. compartment acts as a sink for heavy mole-
Health Phys 18:599612, 1970 cular incomplete combustion products such as
5. Archer VE, Wagoner JK, Lundin FE Jr: PAH, which can be present at up to 1000 times
Cancer mortality among uranium mill original concentrations.2 The lubricating oil
workers. J Occup Med 15:1114, 1973 is altered by nitration, cracking of polymers,
USED MINERAL-BASED CRANKCASE OIL 725
11. Roy TA, Johnson SW, Blackburn GR, et al: An odor threshold of 0.028 ppm has been
Correlation of mutagenic and dermal car- reported.5
cinogenic activities of mineral oils with poly- The 2003 ACGIH threshold limit value-
cyclic aromatic content. Fundam Appl Toxicol time-weighted average (TLV-TWA) for n-
10(3):466476, 1988 valeraldehyde is 50 ppm (176 mg/m3).
12. Dautreband L, Capps R: Studies on aerosols.
IX. Enhancement of irritating effects of
various substances on the eye, nose, and
throat by particulate matter and liquid REFERENCES
aerosols in connection with pollution of
the atmosphere. Arch Int Pharmacodyn Ther 1. Smyth HF Jr, Carpenter CP, Weil CS, et al:
82:505, 1950 Range-nding toxicity data; list VII. Am Ind
Hyg Assoc J 30:470476, 1969
2. Salem H, Cullumbine H: Inhalation toxicities
of some aldehydes. Toxicol Appl Pharmacol
2:183187, 1960
3. Steinhagen WH, Barrow CS: Sensory irrita-
n-VALERALDEHYDE tion structureactivity study of inhaled alde-
CAS: 110-62-3 hydes in B6C3F1 and Swiss-Webster Mice.
Toxicol Appl Pharmacol 72:495503, 1984
C5H10O 4. British Industrial Biological Research Associa-
tion: BIBRA Toxicity Prole of Valeraldehyde. pp
14. Carshalton, UK, 1986
Synonyms: Amyl aldehyde; butyl formal; 5. Amoore JE, Hautala E: Odor as an aid to
pentanal; valeric aldehyde chemical safety: Odor thresholds compared
with threshold limit values and volatilities
for 214 industrial chemicals in air and water
Physical Form. Colorless liquid
dilution. J Appl Toxicol 3:272290, 1983
Uses. In food avorings and in the accelera-
tion of rubber vulcanization
particle size of fume, which allows more com- normal.5 Subjects exposed to a concentration of
plete penetration to the small airways of the 0.2 mg/m3 for 8 hours developed a loose cough
lungs. the following morning; other subjects exposed
Sixteen workers exposed to concentrations for 8 hours to 0.1 mg/m3 developed slight
of dust (and possibly some fume) in excess of cough with increased mucus, which lasted
0.5 mg/m3 with particle sizes ranging from 34 days.
0.1 m to 10 m developed conjunctivitis, Although some cases of emphysema have
nasopharyngitis, hacking cough, ne rales, and been observed among workers with exposure to
wheezing. In three workers exposed to the vanadium pentoxide, other possible causes,
highest concentrations, the onset of symptoms such as smoking, were not excluded. Cases of
occurred at the end of the rst workday.1 The asthma have occurred more frequently, sug-
bronchospastic element in the more seriously gesting that this may be an effect of chronic
ill persisted for 48 hours after removal from exposure.3
exposure; rales lasted for 37 days, and, in Animal studies in cynomolgus monkeys
several cases, cough lasted for up to 14 days.1 have not found evidence of increased pul-
Among those with acute intoxication, there was monary reactivity to vanadium pentoxide after
dramatically increased severity of symptoms repeated exposures; cytological/immunologic
from repeated exposures of lesser time and and skin test results also indicated the absence
intensity. of allergic sensitization.6
Absorbed vanadium is primarily excreted Exposure to the dust can cause eye irrita-
in the urine, and it was detectable in 12 of the tion, and skin rashes have been reported. Green
workers for periods of up to 2 weeks. Urinary discoloration of the tongue may occur as a
vanadium concentrations were elevated in result of direct deposition of vanadium.7
workers exposed to mean air concentrations of No adverse effects on fertility, reproduc-
0.10.28 mg/m3, but there was no correlation tion, or parturition were found when male and
between the air and urinary concentrations. female rats were treated with sodium meta-
Although most absorbed vanadium was vanadate by gavage and then mated.8
excreted within 1 day after cessation of expo- Male and female mice exposed at concen-
sure, increased excretion relative to unexposed trations up to 4 mg/m3 6 hours/day for 104
controls continued for more than 2 weeks weeks had clear evidence of carcinogenicity
among chronically exposed workers.2 based on increased incidences of alveolar/bron-
Workers exposed to a mixture of ammo- chiolar neoplasms.9 In rats similarly exposed at
nium metavanadate and vanadium pentoxide concentrations up to 2 mg/m3 there was some
at concentrations near 0.25 mg/m3 developed evidence of carcinogenicity in male rats and
green tongue, metallic taste, throat irritation, equivocal evidence in females based on the
and cough.3 Of 36 workers examined 8 years occurrence of alveolar/bronchiolar neoplasms.
after their original exposure to vanadium Exposure to vanadium pentoxide also caused a
pentoxide, there was no evidence of either spectrum of nonneoplastic lesions in the respi-
pneumoconiosis or emphysema, although 6 of ratory tract including alveolar and bronchiolar
the workers still had bronchitis with rhonchi epithelial hyperplasia, inammation, brosis,
resembling asthma and bouts of dyspnea.4 and alveolar histocytosis of the lung. Hyper-
Two volunteers exposed to a concentration plasia of the bronchial lymph node occurred in
of 1 mg/m3 for 8 hours developed a persistent female mice, and an unusual squamous meta-
cough, which lasted for 8 days; 21 days after the plasia of the lung occurred in rats.9
original exposure, reexposure for 5 minutes Vanadium pentoxide was not mutagenic
to a heavy cloud of vanadium pentoxide dust in Salmonella strains and did not increase the fre-
occurred and, within 16 hours, marked cough quency of micronucleated erythrocytes in mice.9
developed; the following day, rales and expira- In other studies vanadium compounds have pro-
tory wheezes were present throughout the duced clear evidence of aneuploidy in somatic
entire lung eld, but pulmonary function was cells after exposure by several different routes.10
728 VINYL ACETATE
REFERENCES
Synonyms: 1-Acetoxyethylene; acetic acid
1. Zenz C, Bartlett JP, Thiede WH: Acute vana- ethenyl ester; ethanoic acid; ethenyl ethanoate;
dium pentoxide intoxication. Arch Environ vinyl ethanoate
Health 5:542546, 1962
2. Kiviluoto M: Serum and urinary vanadium of Physical Form. Colorless liquid that poly-
workers processing vanadium pentoxide. Int merizes to a transparent solid on exposure to
Arch Occup Environ Health 48:251256, 1981
light
3. National Institute for Occupational Safety
and Health: Criteria for a Recommended Stan-
dard . . . Occupational Exposure to Vanadium. Uses. Production of vinyl acetate polymers
DHEW (NIOSH) Pub No 77-222, 142pp.
Washington, DC, US Government Printing Exposure. Inhalation
Ofce, 1977
4. Sjoberg SG: Follow-up investigation of Toxicology. Vinyl acetate is an irritant of the
workers at a vanadium factory. Acta Med eyes, nose, and throat; it is carcinogenic in
Scand 154:381, 1956
experimental animals at high doses.
5. Zenz C, Berg BA: Human responses to
controlled vanadium pentoxide exposure. Volunteers exposed to vinyl acetate showed
Arch Environ Health 14:709712, 1967 a wide variation in individual sensitivity to its
6. Knecht EA, Moorman WJ, Clark JC, et al: irritant effects; one of three had throat irrita-
Pulmonary reactivity to vanadium pentoxide tion at 20 ppm for 4 hours, whereas 72 ppm for
following subchronic inhalation exposure in 30 minutes produced eye irritation in three of
a non-human primate animal model. J Appl four participants.1 All subjects agreed that they
Toxicol 12: 427434, 1992 could not work at 72 ppm for 8 hours.
7. Agency for Toxic Substances and Disease From a study of 21 workers exposed for an
Registry (ATSDR): Toxicological Prole for average of 15 years at concentrations between
Vanadium. TP-91/29, 106pp. US Depart- 5 and 10 ppm (with occasional excursions above
ment of Health and Human Services, Public
300 ppm), vinyl acetate produced no serious
Health Service, 1992
8. Domingo JL, Paternain JL, Llobet JM, et al: chronic effects.2 Some subjects were sensitive
Effects of vanadium reproduction, gestation, at concentrations of about 6 ppm, and concen-
parturition, and lactation in rats upon oral trations above 20 ppm produced irritation in
administration. Life Sci 39:819824, 1986 most persons.
9. National Toxicology Program: NTP Technical Prolonged dermal contact, such as that
Report on the Toxicology and Carcinogenesis afforded by clothing wet with vinyl acetate,
Studies of Vanadium Pentoxide (CAS No. may result in severe irritation or blistering of
1314621) in F344/N Rats and B6C3F1 Mice the skin in some persons.1 Direct eye contact
(Inhalation Studies). NTP TR 507, NIH Pub with the liquid or vapor can cause irritation of
No 03-4441. US Department of Health and the eyes.3
Human Services, Public Health Service,
The LC50 for 4 hours in rats was
National Institutes of Health, 2002
10. World Health Organization: Vanadium pen- 14,000 mg/m3 (about 4667 ppm).4 Dogs ex-
toxide and other inorganic vanadium com- posed 6 hours daily for several weeks starting
pounds. Vol 29, Concise International Chemical at 91 ppm and ending after 11 weeks at 186 ppm
Assessment Document (CICAD), 47pp. Inter- exhibited eye irritation and lacrimation.5 Rats
national Programme on Chemical Safety exposed repeatedly to 100 ppm showed no
(IPCS), Geneva 2001 effects.6
VINYL ACETATE 729
Rats administered 0, 200, 1000, or 5000 ppm vinyl acetate in the drinking water
5000 ppm in the drinking water from the time over two generations did not show selective
of gestation up to 104 weeks showed no evi- reproductive effects.11
dence of systemic organ toxicity and/or car- Vinyl acetate was genotoxic in a number
cinogenicity.7 Decreased food consumption of mammalian system assays, inducing micro-
and concurrent body weight decrement was nuclei, chromosomal aberrations, sister chro-
observed in the high-dose group. In rats and matid exchange, and DNA cross-links.3 It has
mice exposed at 0, 50, 200, or 600 ppm by also been noted that the primary metabolite of
inhalation for 2 years, signicant histopatho- vinyl acetate, acetaldehyde, is genotoxic in a
logic changes were noted in the nasal cavity at wide range of assays.
the two highest dose levels.8 Epithelial atrophy, The IARC has determined that there is
basal cell hyperplasia, and regenerative effects limited evidence in experimental animals and
(squamous metaplasia and respiratory meta- inadequate evidence in humans for the car-
plasia of the olfactory epithelium) were cinogenicity of vinyl acetate.12
observed in both species. In rats the total tumor The ACGIH threshold limit value-time-
incidence in the high-exposure group was 9% weighted average (TLV-TWA) for vinyl acetate
and included papillomas, squamous cell carci- is 10 ppm (35 mg/m3) with a short-term excur-
noma, and carcinoma in situ in olfactory sion level (STEL) of 15 ppm (53 mg/m3)
regions and papillomas of the respiratory and an A3-conrmed animal carcinogen with
region. It has been noted that the unique unknown relevance to humans designation.
nature, both structurally and functionally, of
the rodent nasal cavity may make it an unsuit-
REFERENCES
able model for assessing human risk. More
recently, vinyl acetate monomer was shown to 1. National Institute for Occupational Safety
be a multipotential carcinogen in mice admin- and Health: Criteria for a Recommended
istered up to 5000 ppm in the drinking water Standard . . . Occupational Exposure to Vinyl
for 78 weeks; zymbal gland, lung, uterine, oral Acetate. DHEW (NIOSH) Pub No 78-205,
cavity, tongue, esophageal, and forestomach 78pp. Washington, DC, US Government
cancers were increased.9 Printing Ofce, 1978
One human study of workers in a US 2. Deese DE, Joyner RE: Vinyl acetatea study
synthetic chemical plant failed to nd any of chronic human exposure. Am Ind Hyg Assoc
specic association between exposure to vinyl J 30: 449, 1969
3. Agency for Toxic Substances and Disease
acetate and excess lung cancer.10
Registry (ATSDR): Toxicological Prole for
Vinyl acetate has been tested for terato-
Vinyl Acetate. TP-9130, 140pp. US. Depart-
genicity in inhalation and oral assays.3 Preg- ment of Health and Human Services, Public
nant rats exposed to levels as high as 1000 ppm Health Service, 1992
by inhalation or 5000 ppm in drinking water on 4. Carpenter CP et al: The assay of acute vapor
gestation days 615 had signicantly reduced toxicity, and the grading and interpretation of
weight gain during exposure. The fetuses of the results on 96 chemical compounds. J Ind Hyg
rats exposed via inhalation were also signi- Toxicol 31:343346, 1949
cantly smaller than control fetuses and had an 5. Haskell Laboratory: Report of Toxicity of Vinyl
increased incidence of minor skeletal defects. Acetate. Wilmington, DE, EI DuPont de
However, investigators thought that the fetal Nemours, January 1967
6. Gage JC: The subacute inhalation toxicity of
effects were a consequence of the maternal
109 industrial chemicals. Br J Ind Med 27:
growth retardation, and not of vinyl acetate
118, 1970
treatment. In the drinking water study, there 7. Bogdanffy MS, Tyler TR, Vinegar MB, et al:
were no signicant effects on the fetuses, and Chronic toxicity and oncogenicity study with
the investigators concluded that vinyl acetate vinyl acetate in the rat: in utero exposure in
did not elicit embryolethality, embryotoxicity, drinking water. Fundam Appl Toxicol 23:
or teratogenicity. Rats administered up to 206214, 1994
730 VINYL BROMIDE
8. Bogdanffy MS, Dreef-Van Der Meulen HC, A signicant decline in animal body
Beems RB, et al: Chronic toxicity and onco- weights was the only treatment-related effect
genicity inhalation study with vinyl acetate after exposure at 10,000 ppm, 7 hours/day for
in the rat and mouse. Fundam Appl Toxicol 4 weeks. In a 6-month inhalation study in a
23:215229, 1994 number of species, serum bromide levels
9. Maltoni C, Ciliberti A, Lefemine G, et al:
increased after exposure to 250 and 500 ppm.
Results of a long-term experimental study on
the carcinogenicity of vinyl acetate monomer In male and female rats exposed to 10, 50,
in mice. Ann NY Acad Sci 837:20938, 1997 250, or 1250 ppm vinyl bromide in a lifetime
10. Waxweiler RJ, Smith AH, Falk H, et al: inhalation study, there was a dose-related
Excess lung cancer risk in a synthetic chemi- increase in angiosarcomas of the liver in both
cals plant. Environ Health Perspect 41:159 sexes.2 A signicant increase in hepatocellular
165, 1981 neoplasms was also seen in male rats exposed
11. Mebus CA, Carpanini FMB, Rickard RW, at 250 ppm and in female rats exposed at 10, 50,
et al: A two-generation reproduction study and 250 ppm. The lack of increase in hepato-
in rats receiving drinking water containing cellular neoplasms in rats at the 1250 ppm level
vinyl acetate. Fundam Appl Toxicol 24(2): was probably due to their early mortality and
20616, 1995
termination at 72 weeks. In limited mice
12. IARC Monographs on the Evaluation of the
Carcinogenic Risk of Chemicals to Humans, Vol studies, no local tumors were produced by skin
63, Dry cleaning, some chlorinated solvents application or subcutaneous administration.3
and other industrial chemicals, pp 44366. Vinyl bromide is mutagenic in bacterial
Lyon, International Agency for Research on assays and Drosophila.3 It is activated via a P-
Cancer, 1995 450-dependent pathway to its epoxide that can
covalently bind to DNA.3
The IARC has determined that there is
sufcient evidence for the carcinogenicity of
vinyl bromide to experimental animals and that
VINYL BROMIDE it is probably carcinogenic to humans.3
CAS: 593-60-2 The liquid was moderately irritating to the
rabbit eye but essentially nonirritating to the
C2H3Br skin.
The 2003 ACGIH threshold limit value-
time-weighted average (TLV-TWA) for vinyl
Synonyms: Bromoethene; bromoethylene bromide is 0.5 ppm (2.2 mg/m3) with an A2-
suspected human carcinogen designation.
Physical Form. Gas
portal brosis and portal hypertension have have generally been observed at doses that
been attributed to vinyl chloride exposure.8 produce some maternal toxicity.1 Testicular
A large multicentric cohort study of Euro- damage and decreased male fertility have been
pean vinyl chloride workers revealed a nearly found in rats exposed by inhalation. Vinyl chlo-
threefold increase in liver cancer based on 24 ride workers have complained of impotence
observed deaths vs. 8.4 expected. The excess and decreased libido, and decreased androgen
was clearly related to time since rst exposure, levels have been measured.1
duration of employment, and estimated ranked The 2003 ACGIH threshold limit value-
and quantitative exposures.9 A cohort study of time-weighted average (TLV-TWA) for vinyl
10,173 US men who had worked at least 1 year chloride is 1 ppm (3 mg/m3) with an A1-
in jobs involving exposure to vinyl chloride conrmed human carcinogen designation.
conrmed a signicant mortality excess in
angiosarcoma (15 deaths), cancer of the liver
and bilary tract [standardized mortality ratio REFERENCES
(SMR) = 641], and cancer of central nervous
system (SMR = 180).10 A recent follow-up of 1. Agency for Toxic Substances and Disease
this cohort found that excess mortality risk Registry (ATSDR): Toxicological Prole for
from cancer of the liver and biliary tract, Vinyl Chloride (Update), 239pp. US Depart-
largely due to angiosarcoma, continued; risk of ment of health and Human Services, Public
mortality from brain cancer had attenuated; Health Service, 1997
and excess of deaths from cancer of connective 2. Lester D, Greenberg LA, Adams WR:
and soft tissue appeared for the rst time Effects of single and repeated exposures of
humans and rats to vinyl chloride. Am Ind
but was based on few cancers of assorted
Hyg Assoc J 24:265275, 1963
histology.11
3. Easter MD, Von Burg R, et al: Toxicology
The tumorigenic potential of vinyl chloride update: vinyl chloride. J Appl Toxicol 14:
has been conrmed in a number of animal 301307, 1994
studies. Zymbal gland carcinomas, nephroblas- 4. Dodson VN et al: Occupational acroosteoly-
tomas, and angiosarcomas were the prevailing sis. III. A clinical study. Arch Environ Health
tumors in treated rats. Results ranged from 22:8391, 1971
a 16% tumor incidence at an exposure level of 5. Marstellar HJ, Lelbach WK, Muller R, et al:
250 ppm to a 39% incidence at 10,000 ppm. Chronisch-toxische Leberschaden bei
In mice, liver angiosarcomas, pulmonary adeno- Arbeitern in der PVC Produktion. Dtsch Med
mas, and mammary carcinomas were observed Wschr 98: 23112314, 1973
6. Waxweiler RJ, Stringer W, Wagner JK, et al:
after exposures ranging from 50 to 10,000
Neoplastic risk among workers exposed to
ppm.12 The development of some tumors was
vinyl chloride. Ann NY Acad Sci 271:4048,
more dependent on duration of exposure than 1976
on concentration of vinyl chloride.12 7. Lloyd JW: Angiosarcoma of the liver in vinyl
Vinyl chloride was genotoxic in a variety of chloride/polyvinyl chloride workers. J Occup
in vitro assays.1 It is also reportedly mutagenic Med 17:333334, 1975
and clastogenic in humans. Increased frequen- 8. Falk H, Creech JL Jr, Heath CW Jr, et al:
cies of chromosomal aberrations, micronuclei, Hepatic disease among workers at a vinyl
and sister chromatid exchanges have been chloride polymerization plant. JAMA 230:
found in the peripheral blood lymphocytes 5963, 1974
of workers exposed to high levels of vinyl 9. Simonato L, LAbbe Ka, Anderson A, et al:
A collaborative study of cancer incidence
chloride.13
and mortality among vinyl chloride workers.
The IARC has determined that there
Scand J Work Environ Health 17:159169,
is sufcient evidence of carcinogenicity to 1991
humans and animals.14 10. Wong O, Whorton MD, Foliart DE, et al:
Developmental effects in animals, consist- An industry-wide epidemiologic study of
ing of resorptions, delayed development, and vinyl chloride workers, 19421982. Am J Ind
increased incidences of soft tissue anomalies, Med 20:317334, 1991
4-VINYLCYCLOHEXENE 733
11. Mundt KA, Dell LD, Austin RP, et al: impairment of pigment and carbohydrate
Historical cohort study of 10,109 men in metabolism.1 It is not clear what other con-
the North American vinyl chloride industry, founding chemical exposures may have been
194272: Update of cancer mortality to concurrent. It has also been noted that these
31 December 1995. Occup Environ Med exposure levels contrast signicantly with those
57(11):77481, 2000
found in the discharged off-gases to which
12. Maltoni C, Lefemine G: Carcinogenicity
bioassays of vinyl chloride. I. Research plan domestic rubber workers were exposed in the
and early results. Environ Res 7:387405, tire-curing process, which measured 118 ppb.2
1974 In rats the oral LD50 was 2.6 g/kg.3 Inhala-
13. World Health Organization: Environmental tion of 8000 ppm for 4 hours was lethal to four
Health Criteria 215. Vinyl Chloride. Geneva, of six rats.3 The liquid produced moderate irri-
International Programme on Chemical safety tation when applied to the skin of rabbits and
(IPCS), 1999 caused a small necrotic area on the cornea
14. IARC Monographs on the Evaluation of Car- when instilled into a rabbit eye.
cinogenic Risk to Humans, Suppl 7, Overall All rats and most mice died in 14-day
evaluations of carcinogenicity: An updating studies when administered VCH by gavage in
of IARC Monographs Vols 1 to 42, pp
corn oil at doses greater than or equal to
373376. Lyon, International Agency for
Research on Cancer, 1987 1250 mg/kg/day.1 Before death, tremors and
inactivity were observed in mice, whereas rats
showed central nervous system depression,
tremors, and gastrointestinal distress. No com-
pound-related gross pathologic or histopatho-
4-VINYLCYCLOHEXENE logic effects were observed.
CAS: 100-40-3 Subchronic inhalation exposure for 13
weeks (6 hours/day, 5 days/week) to 1000 ppm
C8H12 VCH caused mortality in mice but not in rats;
the most notable adverse histopathologic effect
was ovarian atrophy in exposed female mice.4
Synonyms: 4-Ethenylcyclohexene; 1-vinyl-3- Final body weights were reduced in 13-
cyclohexene; VCH week studies in male rats receiving oral doses
of 400 mg/kg/day or more, in female rats
Physical Form. Colorless liquid receiving 800 mg/kg/day, and in female mice
receiving 600 mg/kg/day.1 Compound-related
Uses/Sources. As an intermediate in the histopathologic effects included hyalin droplet
production of ame retardants, avors, fra- degeneration of the proximal convoluted
grances, and vinyl cyclohexene dioxide (which tubules of the kidney in male rats and a reduc-
itself is used in the manufacture of epoxy tion in the number of primary follicles and
resins); found in gases discharged during the mature graaan follicles in the ovaries of
process of curing rubber in tire manufacturing. female mice dosed at the 1200 mg/kg/day level.
No compound-related gross pathologic or
Exposure. Inhalation; skin absorption histopathologic effects were observed in female
rats or male mice in this study.
Toxicology. 4-Vinylcyclohexene (VCH) is a Administration of VCH by oral intubation
moderate skin irritant and causes ovarian toxi- to rats 5 days/week for 2 years at 0, 200, or
city in mice. It is carcinogenic in some animal 400 mg/kg/day was associated with slightly
species when metabolically activated. increased incidence of epithelial hyperplasia of
In one isolated report, Russian rubber the forestomach and squamous cell papillomas
workers exposed to concentrations averaging or carcinomas of the skin in high-dose males.1
271542 ppm with excursions to 677 ppm were Poor survival of the dosed animals may have
reported to suffer keratitis, rhinitis, headache, compromised the study. In mice similarly
leukopenia, neutrophilia, lymphocytosis, and dosed, the number of uncommon ovarian neo-
734 VINYL CYCLOHEXENE DIOXIDE
plasms and ovarian pathologies was signi- value-time-weighted average (TLV-TWA) for
cantly increased in the females and there was 4-vinylcyclohexene is 0.1 ppm (0.4 mg/m3)
some suggestion of increased numbers of with an A2-suspected human carcinogen
adrenal gland adenomas in the high-dose designation.
females. Among high-dosed male mice there
were scattered instances of lymphomas and
cancers of the lung, but, again, poor survival REFERENCES
confounded results.
Toxicological studies have suggested that 1. National Toxicology Program: Toxicology and
the species specicity for induction of ovarian Carcinogenesis Studies of 4-Vinylcyclohexene (CAS
tumors (produced in mice but not rats) occurs No. 100-40-3) in F344/N Rats and B6C3F1
Mice (Gavage Studies). NTP TR 303, NIH Pub
because the blood level of the ovotoxic VCH
No 86-2559, Research Triangle Park, NC,
metabolite VCH-1,2-epoxide is dramatically
1986
higher in VCH-treated female mice compared 2. Rappaport SM, Fraser DA: Air sampling and
with rats.5 VCH has been shown to be metab- analysis in a rubber vulcanization area. Am Ind
olized by the liver of mice to the ovotoxic Hyg Assoc J 38:205210, 1977
metabolite (VCH-1,2-epoxide), which circu- 3. Smyth HF Jr, Carpenter CP, Weil CS, et al:
lates in blood and is delivered to the ovary, Range-nding toxicity data. List VII. Am Ind
where it destroys small oocytes. This destruc- Hyg Assoc J 30:470476, 1969
tion of small oocytes is considered to be an 4. Bevan C, Stadler JC, Elliott GS, et al: Sub-
early event in carcinogenesis. Species differ- chronic toxicity of 4-vinylcyclohexene in rats
ence in epoxidation of VCH by hepatic micro- and mice by inhalation exposure. Fundam Appl
Toxicol 32(1):110, 1996
somes correlates well with the differences
5. Smith BJ, Mattison DR, Sipes IG: The role of
observed in the blood concentration of VCH-
epoxidation in 4-vinylcyclohexene-induced
1,2-epoxide and VCH ovarian toxicity. Further ovarian toxicity. Toxicol Appl Pharmacol 105:
in vitro studies have found that the rate of VCH 372381, 1990
epoxidation in humans by human hepatic 6. Smith BJ, Sipes IG: Epoxidation of 4-vinylcy-
microsomes was 13- and 2-fold lower than clohexene by human hepatic microsomes.
epoxidation by mouse and rat systems respec- Toxicol Appl Pharmacol 109:367371, 1991
tively.6 Therefore, if the rate of hepatic VCH 7. Grizzle TB, George JD, Fail PA, et al: Repro-
epoxidation is the main factor that determines ductive effects of 4-vinylcyclohexene in Swiss
the ovotoxicity of VCH, rats may be a more mice assessed by a continuous breeding proto-
appropriate animal model for humans. col. Fundam Appl Toxicol 22:122129, 1994
8. IARC Monographs on the Evaluation of Carcino-
In a reproductive study using the con-
genic Risks to Humans, Vol 60, Some industrial
tinuous breeding protocol, 500 mg/kg/day
chemicals, pp 347359. Lyon, International
administered by gavage to mice caused slight Agency for Research on Cancer, 1994
generalized toxicity and reduced the number of
oocytes by 33% in females and testicular sperm
count by 17% in males but did not adversely
affect the reproductive competence of F0 and
F1 generations.7
VCH was not mutagenic in Salmonella VINYL CYCLOHEXENE DIOXIDE
typhimurium; however, several of its metabo- CAS: 106-87-6
lites, including 4-vinylcyclohexene dioxide, are
genotoxic.1,8 C8H12O2
The IARC has determined that there is
inadequate evidence in humans, but sufcient
evidence in animals, for the carcinogenicity of Synonyms: 4-Vinylcyclohexene diepoxide;
VCH.8 1,2-epoxy-4-(epoxyethyl)cyclohexane; 1-
The 2003 ACGIH threshold limit epoxyethyl-3,4-epoxycyclohexane; VCD
VINYL CYCLOHEXENE DIOXIDE 735
Physical Form. Colorless or pale yellow testis and resulted in enlarged adrenal glands.4
liquid The leukocyte count fell more than 60%, and
the myeloid-to-erythroid ratio was increased.
Uses. As a chemical intermediate and as a In 14-day dermal studies, rats receiving
reactive diluent for diepoxides and epoxy 139 mg/rat or higher for males and 112 mg/rat
resins. or higher for females died before the end of
the treatment period.3 There was congestion
Exposure. Inhalation; skin absorption and/or hypoplasia of the bone marrow, and
most had acute nephrosis. Skin lesions included
Toxicology. Vinyl cyclohexene dioxide epidermal necrosis and ulceration, epidermal
(VCD) is an irritant to the skin, eyes, and res- hyperplasia, and hyperkeratosis. Male rats
piratory system. It is ovotoxic and carcinogenic receiving 68 mg/rat and females receiving
in experimental animals. 57 mg/rat had nal mean body weights lower
In humans VCD is considered to be a mild than those of control animals; skin lesions were
to moderate skin irritant, although occasional similar to those seen at the higher dose levels
instances of marked irritation have been but of less severity.
reported. In one case severe vesiculation of the VCD is ovotoxic, causing follicle destruc-
skin of both feet occurred when a worker wore tion in both rats and mice.5 After 30 days
shoes previously contaminated with VCD.1 A of intraperitoneal dosing with 80 mg/kg the
single case of allergic contact dermatitis has number of oocyte-containing primordial and
also been reported in a worker whose gloves primary follicles was reduced 80% in rats and
were permeable to VCD.2 Systemic illness in 92% in mice.
humans has not been reported in association All rats survived dermal doses of up to
with exposure.1 60 mg/rat administered over 13 weeks.3 Mean
In rats the inhalation LC50 is 800 ppm for body weights were up to 14% lower than
4 hours, and the oral LD50 is 2.1 g/kg.3 Dermal controls, and redness, scabs, and ulceration
application of the undiluted material to rabbits occurred at the application site. In mice, appli-
caused edema and redness equivalent to a mod- cations of up to 10 mg/mouse produced
erate rst-degree burn. The liquid can pene- increased liver and kidney weights. Com-
trate the skin and is more toxic when applied pound-related skin lesions included sebaceous
dermally than by other routes. The dermal gland hyperplasia and hyperplasia and hyperk-
LD50 in rabbits is 0.62 ml/kg body weight. eratosis of the stratied squamous epithelium
VCD is an alkylating agent and is selec- at the site of application; ovarian atrophy was
tively active against rapidly dividing cells, such also considered to be compound related.
as the blood-forming elements in the bone Two-year studies were conducted by
marrow, lymphoid tissues, and reproductive administering VCD in acetone by dermal
organs.4 Immunotoxic effects were observed in application 5 days per week for over 100 weeks
mice after 5-day dermal exposures at 10 mg/ to groups of rats of each sex at 0, 15, or
day.3 Hematologic studies indicated a signi- 30 mg/animal and to groups of mice at 0, 2.5,
cant decrease in the leukocyte count that was 5, or 10 mg/animal. Acanthosis and sebaceous
related to the decreased numbers of circulating gland hypertrophy of skin from the scapula
lymphocytes at this same dose. A decrease in were observed at increased incidences in both
the lymphoproliferative response to phyto- species. Squamous cell papillomas in male rats
hemagglutinin and concanavalin A and sup- and squamous cell carcinomas in males and
pression of the antibody plaque-forming cell females were observed in exposed rats at an
response indicated that VCD was immunosup- increased incidence. The combined incidence
pressive. of basal cell adenomas or carcinomas was also
Repeated intramuscular injections of increased in both sexes. Squamous cell carci-
400 mg/kg VCD to male rats for 7 days nomas were found in the exposed mice. Follic-
decreased the size of the spleen, thymus, and ular atrophy and tubular hyperplasia of the
736 VINYLIDENE CHLORIDE
ovary in female mice were increased with Cyclohexene Diepoxide (CAS No. 106-87-6) in
increasing dose, and the combined incidences F344/N Rats and B6C3F1 Mice (Dermal
of luteomas, granulosa cell tumors, benign Studies). Technical Report No. 362, NIH
mixed tumors, or malignant granulosa cell Pub 902817, Research Triangle Park, NC,
tumors in mid- and high-dose female mice 1989
4. Kodama JK, Guyman RJ, Dunlap MK, et al:
were increased. Increased incidences of lung
Some effects of epoxy compounds on the
neoplasms in females may also have been blood. Arch Environ Health 2:5657, 1961
related to chemical exposure. 5. Kao SW, Sipes IG, Hoyer PB: Early effects of
Under the conditions of the study, there ovotoxicity induced by 4-vinylcyclohexene
was clear evidence of carcinogenicity in rats as diepoxide in rats and mice. Reprod Toxicol
shown by squamous cell and basal cell neo- 13(1):6775, 1999
plasms of the skin and in mice as shown by 6. Hendry JA, Homer RF, Rose FL, et al: Cyto-
squamous cell carcinomas of the skin and toxic agents. II. Bis-epoxides and related com-
ovarian neoplasms in females. No information pounds. Br J Pharmacol 6:235255, 1951
has been reported on the carcinogenicity of 7. Kotin P, Falk HL: Organic peroxides, hydro-
VCD in humans. gen peroxide, epoxides and neoplasia. Radiat
Res 3(suppl):193211, 1963
A number of early studies also demon-
8. IARC Monographs on the Evaluation of Carcino-
strated the carcinogenicity of VCD in rodents. genic Risks to Humans, Vol 60, Some industrial
Dermal application of 16 mg, 5 days per week, chemicals, pp 347359. Lyon, International
for 12 months resulted in squamous cell carci- Agency for Research on Cancer, 1994
nomas or sarcomas in 9 of 20 exposed male
mice.6 One skin neoplasm and four malignant
lymphomas occurred in 16 of 20 mice surviving
a total dermal dose of 70 mg over 14 months.7
The IARC has determined that there is VINYLIDENE CHLORIDE
sufcient evidence in experimental animals and CAS: 75-35-4
inadequate evidence in humans for the car-
cinogenicity of VCD.8 C2H2Cl2
VCD has been found to be mutagenic in a
number of bacterial tester strains in the pres-
ence and absence of mammalian microsomal Synonyms: 1,1-Dichloroethylene; VDC;
metabolic activation. It induced direct sister asym-dichloroethylene; 1,1-dichloroethene;
chromatid exchange and chromosomal aberra- 1,1-DCE; vinylidene dichloride
tions in cultured Chinese hamster ovary cells.8
The 2003 ACGIH threshold limit value- Physical Form. Clear liquid that is highly
time-weighted average (TLV-TWA) for vinyl ammable and reactive and in the presence of
cyclohexene dioxide is 10 ppm (57 mg/m3) with air can form complex peroxides in the absence
an A2-suspected human carcinogen designation. of chemical inhibitors
Limited information is available on the dose-related changes in the liver but did not
human health effects of exposure to VDC.1 affect the reproductive capacity through three
Upper airway irritation consisting of inam- generations that produced six sets of litters.7
mation of mucous membranes has been Prenatal exposure to doses ranging from 15 to
reported after acute exposure, whereas CNS 450 ppm resulted in skeletal defects in rats,
toxicity has been associated with levels of rabbits, and mice and also caused maternal
4000 ppm.1 toxicity in the form of decreased body weight
In male rats, the 4-hour LC50 was and death.1
6350 ppm.2 The oral LD50 of VDC in corn oil In a carcinogenicity study, Swiss mice were
was 1500 mg/kg in male rats.3 Rats exposed exposed to 10 or 25 ppm 4 hours/day, 5 days/
6 hours/day for 20 days to 200 ppm exhibited week for 52 weeks.8,9 After 98 weeks, 25 ppm
only slight nasal irritation.4 had caused kidney adenocarcinomas in 24 of
Results from animal studies indicate that 150 males and 1 of 150 females whereas none
the liver is a primary target for VDC-induced were seen in the control group. Rats exposed
toxicity.1 Hepatotoxicity following both inhala- to 75 ppm 6 hours/day, 5/days week for 18
tion and oral exposures has ranged from months and then held until 24 months showed
biochemical changes, including increases in a reversible hepatocellular fatty change but no
serum enzyme markers of liver dysfunction increase in tumor incidence that could be
and induction of hepatic enzymes, to marked attributed to VDC exposure.10 Several other
histologic changes including centrilobular studies in other strains of mice, rats, and ham-
vacuolization, swelling, degeneration, and sters did not produce carcinogenic effects.5
necrosis. The effects appear to follow a dose- In one epidemiological study of 138
response relationship and may also be inu- exposed workers, no excess of cancer cases was
enced by duration of exposure. Mice exposed found, but follow-up was incomplete; nearly
to 50 ppm for 6 hours exhibit slight centrilob- 40% of the workers had less than 15 years
ular swelling, whereas hepatic degeneration latency since rst exposure, and only 5 deaths
was observed in mice exposed up to 200 ppm 6 were observed.11 The IARC has determined
hours/day, 5 days/week for 2 weeks. VDC also that there is inadequate evidence for carcino-
affects several liver enzymes: It decreases the genicity to humans and limited evidence for
activity of hepatic glucose-6-phosphatase and carcinogenicity to animals.5
the content of glutathione and increases serum VDC was genotoxic in a number of test
alanine a-ketoglutarate transaminase activity systems; it induced chromosome aberrations
and liver content of triglycerides.5 and sister chromatid exchanges in cultured
Renal toxicity including enzyme changes, mammalian cells and DNA damage in mice in
hemoglobinuria, and tubular swelling, degen- vivo; gene mutations were observed in vitro for
eration, and necrosis have been observed in bacteria, yeast, and plant cells after metabolic
experimental animals after VDC exposure.1 activation.1
Severe histologic lesions of the kidney were The liquid is moderately irritating to the
observed in mice after acute exposure to 10 eyes and irritating to the skin of rabbits.
50 ppm of VCD, whereas exposures of up to The 2003 ACGIH threshold limit
300 ppm were necessary to produce the same value-time-weighted average (TLV-TWA) for
effects in rats. vinylidene chloride is 5 ppm (20 mg/m3) with a
Studies in mice have shown that selective short-term excursion level (STEL) of 20 ppm
covalent binding of VDC occurs in the proxi- (79 mg/m3).
mal tubules, the liver lobules, and the mucosa
of the upper respiratory tract and corresponds
to sites of potential toxicity.6 Additional events REFERENCES
such as depletion of glutathione appear to be
necessary for VDC-induced cell death to occur. 1. Agency for Toxic Substances and Disease
In rats, ingestion of drinking water Registry (ASTDR): Toxicological Prole for
containing up to 200 ppm VDC caused mild, 1,1-Dichloroethene, 174pp. US Department of
738 VINYLTOLUENE
Health and Human Services, Public Health Physical Form. Colorless liquid
Service, 1994
2. Siegel J, Jones RA, Con RA, Lyon JP: Effects Uses. As a reactive monomer in the produc-
on experimental animals of acute, repeated tion of polymers and coatings
and continuous inhalation exposures to
dichloroactylene mixture. Toxicol Appl Phar-
Exposure. Inhalation
macol 18:168174, 1971
3. Jenkins LF Jr, Trabulus MJ, Murphy SD:
Biochemical effects of 1,1-dichloroethylene. Toxicology. Vinyltoluene is an irritant of the
Toxicol Appl Pharmacol 23(3):501510, 1972 eyes and mucous membranes; at high concen-
4. Gage JC: The subacute inhalation toxicity of trations it causes narcosis in animals, and it is
109 industrial chemicals. Br J Ind Med expected that severe exposure will produce the
27:118, 1970 same effect in humans.
5. IARC Monographs on the Evaluation of Commercial vinyltoluene is a mixture of
Carcinogenic Risks to Humans, Vol 71, Re- meta and para isomers with small amounts of
evaluation of some organic chemicals, ortho isomer.1
hydrazine and hydrogen peroxide, pp Human subjects exposed to 200 ppm
116380. Lyon, International Agency for
detected a strong odor, but excessive dis-
Research on Cancer, 1999
6. Brittebo EB, Darnerud PO, Eriksson C, comfort was not experienced; at 400 ppm, there
et al: Nephrotoxicity and covalent binding was strong eye and nasal irritation.2 Central
of 1,1-dichloroethylene in buthionine nervous system effects, such as depression,
sulphoximine-treated mice. Arch Toxicol 67: poor memory, and slow visuomotor per-
605612, 1993 formance, have been associated with heavy
7. Nitschke KD, Smith FA, Quast JF, et al: exposures.1
A three-generation rat reproductive toxicity Exposure of rats and guinea pigs to
study of vinylidene chloride in the drinking 1350 ppm 7 hours/day for 100 days caused the
water. Fundam Appl Toxicol 3:7579, 1983 death of some of the rats and slight liver
8. Maltoni C: Recent ndings on the carcino- damage in guinea pigs; there were no effects in
genicity of chlorinated olens. Environ Health
female monkeys at this concentration.2
Perspect 21:15, 1977
9. Maltoni C, Cotti G, Morisi L, Chieco P: Rats tolerated exposure to 300 ppm for
Carcinogenicity bioassays of vinylidene 60 hours without clinical symptoms, although
chloride. Research plans and early results. they appeared relatively inactive.3 At this con-
Med Lav 58:241262, 1977 centration, vinyltoluene was found to accumu-
10. Quast JF, McKenna MJ, Rampy LW, et al: late in perirenal fat and was more effective than
Chronic toxicity and oncogenicity study on styrene, xylene, or toluene in producing neu-
inhaled vinylidene chloride in rats. Fundam rochemical effects as determined by enzyme
Appl Toxicol 6:105144, 1986 assays.
11. Ott mg, Fishbeck WA, Townsend JC, et al: A Mice administered 0, 10, 50, or 250 mg/kg
health study of employees exposed to vinyli- and rats given 0, 10, 50, 250, or 500 mg/kg
dene chloride. J Occup Med 18:735738, 1976
by gastric intubation once a day for 83 and
107 weeks, respectively, showed no treatment-
related increases in malignant or benign
tumors.4 Chronic inhalation experiments in
VINYLTOLUENE B6C3F1 mice (10 or 25 ppm) and Fischer
CAS: 25013-15-4 344/N rats (100 or 300 ppm) produced hyper-
plasia of the respiratory epithelium of the nasal
C9H10 passages in both species, but there was no
evidence of treatment-related increases in
the incidences of any tumor.5
Synonyms: Ethenylmethylbenzene; methyl- The IARC has determined that there is
styrene; tolyethylene; methylvinylbenzene evidence suggesting the lack of carcinogenicity
VM&P NAPHTHA 739
dust concentration was found in German fur- a sensitized individual, exposure may produce
niture workers. Fourteen persons were exposed an immediate onset of symptoms and rapid
to a dust concentration below 5 mg/m3, 15 reversibility or a delayed onset of 58 hours
to 59 mg/m3, 26 to 1019 mg/m3, and 36 to with a more gradual reversibility.
20 mg/m3 or more.3 Immunologic ndings in individuals with
Middle ear symptoms occurred signi- wood dust-induced asthma also vary.1 In some
cantly more frequently among Danish furni- cases, a Type 1 allergic reaction is conrmed by
ture workers exposed to dust levels above the presence of IgE antibodies. Positive skin
5 mg/m3.4 Other illnesses, such as sinus inam- reactions and the presence of precipitating
mation, long-lasting colds, asthma, nosebleed, antibodies to wood dust or extracts may or may
and sneezing, also occurred more frequently in not occur.
the higher-exposure group. Extensive studies have been done on a
Impairment of mucociliary clearance, the clearly dened asthma syndrome produced by
rate at which mucus is transported from the exposure to western red cedar.810 Plicatic acid
nose to the pharynx, was found in a study of has been identied as the etiologic agent. The
68 Danish hardwood furniture workers.5 western red cedar asthma syndrome includes
Mucostasis (dened as a nasal transit time of rhinitis, conjunctivitis, wheezing, cough, and
40 or more minutes) increased in direct nocturnal attacks of breathlessness character-
proportion to the dust concentration; at ized by a precipitous decline in FEV1. There is
25.5 mg/m3, 63% had mucostasis vs. 11% at no apparent relation between skin sensitivity
2.2 mg/m3. and respiratory changes. No precipitating IgG
Obstructive lung disease, as measured by antibodies are found in the serum of sensitized
pulmonary function tests, has been associated individuals, and circulating IgE antibodies
with wood dust exposure. Vermont wood- are present in about one-third of affected
workers with hardwood or pine dust exposures individuals.
greater than 10 mg-years/m3 generally had It has been estimated that approximately
lower pulmonary function, as determined by 5% of exposed workers are affected.1 The
FEV1/FVC, than those with exposure indices asthmatic reaction is species specic; subjects
of 02 mg-years/m3.6 Higher exposures also who exhibit asthma with one type of wood dust
signicantly lowered values of the maximal show no reaction when challenged with
midexpiratory ow rate (MMEFR), compared another type.2
with theoretical values. Other syndromes are associated with expo-
Although no dose-response relationship sure to fungi present on wood.11 Organic dust
was established, a study of employees from ve toxic syndrome is characterized by generalized
plants with dust levels ranging from 0.46 to feelings of feverishness, often accompanied
8.3 mg/m3 found decreases in FEV1 and FVC by dry cough, fatigue, and shaking chills; it
of up to 0.19 l during the work shift for workers appears to be caused by high-dose exposures to
employed at the dustier furniture plant.7 fungal spores in moldy materials. Extrinsic
A hypersensitivity reaction leading to allergic alveolitis has been associated with
asthma (dened as reversible airway obstruc- fungi found in bark and wood our. Findings
tion) has been reported from exposure to a include abnormal X ray, reduced lung
number of wood dusts, including oak, volume and serum precipitating antibodies to
mahogany, and redwood, as well as more exotic fungal antigens. Lung biopsy studies have
woods, such as iroko cocobolo, zebrawood, and reported interstitial inltration with granuloma
abiruana.1,2 Connecting asthma to wood dust formation.
exposure has been difcult because, frequently, The association between nasal cancer and
the subject has worked with wood for years occupations involving exposure to wood dust
with no reaction.2 Sensitization typically begins has been established from case reports and epi-
as eye and nose irritation, followed by non- demiological studies.12 This relationship rst
productive cough and difculty in breathing. In was noted in the late 1960s in Great Britain,
WOOD DUST 743
where the incidence of nasal adenocarcinoma, dust exposure. Data are insufcient, inconclu-
a rare type of nasal cancer, among wood- sive, and lacking in consistency regarding the
workers in the furniture industry was found to relationship between occupational exposure
be 1020 times greater than among other to wood dust and cancers other than nasal
woodworkers and 100 times greater than in adenocarcinoma.1
the general population.1 In a 19-year follow-up The 2003 ACGIH threshold limit value-
study of 8141 Swedish furniture workers, nasal time-weighted average (TLV-TWA) is 1 mg/m3
adenocarcinoma was 62 times higher than for hardwoods with an A1 conrmed human
expected, whereas sinonasal adenocarcinoma carcinogen designation and 5 mg/m3 for soft-
and sinonasal carcinoma were 44 and 7 times woods with a short-term excursion limit
higher than expected, respectively.13 (STEL) of 10 mg/m3.
A study of deaths in furniture-making
counties of North Carolina found that 8 of 37
(21.6%) people dead from nasal cancer had REFERENCES
been employed in the furniture industry,
whereas only 5 of the 73 (6.8%) controls had 1. Tatken RL, et al: Health Effects of Exposure to
been so employed.14 Of 215 patients with nasal Wood Dust: A Summary of the Literature, pp
cancer in Connecticut, 2.8% probably had 1157. Cincinnati, OH, US Dept of Health
been occupationally exposed to wood dust vs. and Human Services, Public Health Service,
only 0.8% of 741 persons dying of other Centers for Disease Control, National Insti-
cancers with similar exposures.15 tute for Occupational Safety and Health,
1977
A pooled reanalysis of 12 case control
2. Meola A: Toxic effects of wood dust exposure.
studies conrmed as increasing risk of sino-
Prof Saf 2629, March 1984
/nasal adenocarcinoma with increasing esti- 3. IARC Monographs on the Evaluation of the Car-
mated levels of exposure to wood dust, but the cinogenic Risk of Chemicals to Humans, Vol 25,
evidence in regard to squamous cell carcinomas Wood, leather and some associated indus-
was ambiguous.16 Although estimates of the tries, pp 99138. Lyon, International Agency
relative risk of nasal adenocarcinoma vary con- for Research on Cancer, 1981
siderably because of differences in exposure 4. Solgaard J, Anderson I: Airway function and
levels, types of wood dust, latency periods, symptoms in woodworkers. Ugeskr Laeg 137:
selection of controls, and other confounding 25932599, 1975
factors, the IARC has concluded that wood 5. Anderson HC, et al: Nasal cancers, symptoms
and upper airway function in woodworkers.
dust is carcinogenic to humans.12 The carcino-
Br Med J 34:201207, 1977
genic agent(s) in wood dust have not been iden-
6. Whitehead LW, et al: Pulmonary function
tied, nor has the importance of particle size status of workers exposed to hardwood or
and shape been investigated.17 pine dust. Am Ind Hyg Assoc 42:178186, 1981
It has been postulated that wood dust 7. Zuhair YS, et al: Ventilatory function in
carcinoma results from a multistep process: workers exposed to tea and wood dust. Br J
Exposure causes loss of cilia and hyperplasia of Ind Med 38:339345, 1981
the goblet cells and initiation of cuboidal cell 8. Goldsmith DF, Shy CM: Respiratory health
metaplasia, followed (after a quiescent period) effects from occupational exposure to wood
by squamous cell metaplasia.8 Decades later, dusts. Scand J Work Environ Health 14:115,
cellular aplasia leads to nasal adenocarcinoma. 1988
9. Chan-Yeung M, et al: Occupational asthma
The time between rst occupational exposure
and rhinitis due to Western red cedar (Thuja
to wood dust and the development of nasal
plicata). Am Rev Respir Dis 108:10941102,
cavity adenocarcinoma averages 40 years.17 1973
Other cancers, including lung cancer, 10. Chan-Yeung M, et al: Follow-up study of
Hodgkin disease, multiple myeloma, stomach 232 patients with occupational asthma caused
cancer, and colorectal cancer and lymphosar- by Western red cedar (Thuja plicata). J Allergy
coma, have been mentioned in relation to wood Clin Immunol 79:792796, 1987
744 XYLENE
11. Enarson DA, Chan Yeung M: Characteriza- space of a fuel tank were overcome by xylene
tion of health effects of wood dust exposures. vapor estimated to be 10,000 ppm; they were
Am J Ind Med 17:3338, 1990 not found until 18.5 hours after entering the
12. IARC Monographs on the Evaluation of the tank, and one died from pulmonary edema
Carcinogenic Risks to Humans, Vol 62, Wood shortly thereafter. The other two workers
dust and formaldehyde, pp 35215. Lyon,
recovered completely in 2 days; both had
International Agency for Research on
Cancer, 1995 temporary hepatic impairment (inferred from
13. Gerhardsson MR, et al: Respiratory cancer in elevated serum transaminase levels), and one
furniture workers. Br J Ind Med 42:403405, had evidence of temporary renal impairment
1985 (increased blood urea and reduced creatinine
14. Brinton LA, et al: A death certicate analysis clearance).1
of nasal cancer among furniture workers in Giddiness, anorexia, and vomiting
North Carolina. Cancer Res 37:34733474, occurred in a worker exposed to a solvent con-
1977 taining 75% xylene at levels of 60350 ppm,
15. Wills JH: Nasal carcinoma in woodworkers: with possible higher excursions.2 In another
A review. J Occup Med 24:526530, 1982 report, eight painters exposed to a solvent con-
16. Demers PA, Kogevinas M, Boffetta P, et al:
sisting of 80% xylene and 20% methylglyco-
Wood dust and sino-nasal cancer: pooled
reanalysis of twelve case-control studies. Am lacetate experienced headache, vertigo, gastric
J Ind Med 28(2):15166, 1995 discomfort, dryness of the throat, and signs of
17. Nylander LA, Dement JM: Carcinogenic slight drunkenness.3
effects of wood dust: Review and discussion. Volunteers exposed to 460 ppm for 15
Am J Ind Med 24:619647, 1993 minutes had slight tearing and light-headed-
ness.4 A level of 230 ppm was not considered to
be objectionable to most of these subjects.
However, in an earlier study, the majority of
subjects found 200 ppm irritating to the eyes,
XYLENE nose and throat, and judged 100 ppm to be the
CAS: 1330-20-7 highest concentration subjectively satisfactory
for an 8-hour exposure.5
o-Xylene: 95-47-6 Before 1940, most reports on the possible
m-Xylene: 108-38-3 chronic toxicity of xylene also involved expo-
p-Xylene: 106-42-3 sure to solvents that also contained high
percentages of benzene or toluene as well as
C6H4(CH3)2 other compounds. Consequently, the effects
attributed to xylene in these reports are
questionable.6 Blood dyscrasias, such as those
Synonyms: Xylol; dimethylbenzene reportedly caused by benzene exposure, have
not been associated with the xylenes.6
Physical Form. Colorless liquid Both human and animal data suggest that
mixed xylene, m-xylene, o-xylene, and p-xylene
Uses. Solvent; manufacture of certain all produce similar effects, although the
organic compounds; cleaning agent; compo- potency with regard to a given effect may vary
nent of fuels with individual isomers.7 In mice the 6-hour
LC50 values for m-, o-, and p-xylene were deter-
Exposure. Inhalation; skin absorption mined to be 5267, 4595, and 3907 ppm, respec-
tively.7 The 4-hour LC50 value for mixed xylene
Toxicology. Xylene vapor is an irritant of the in rats ranged from 63506700 pm.
eyes, mucous membranes, and skin; at high Exposure of rats to 1600 ppm for 2 or 4
concentrations it causes narcosis. days produced mucous membrane irritation,
Three painters working in the conned incoordination, narcosis, weight loss, increased
XYLENE 745
erythrocyte count, and death. Exposure to The odor threshold has been reported as
980 ppm for 7 days caused leukopenia, kidney 1 ppm.6
congestion, and hyperplasia of the bone and The 2003 ACGIH threshold limit value-
spleen.5 time-weighted average (TLV-TWA) for xylene
Repeated exposure of rabbits to 1150 ppm (o-, m-, p-isomers) is 100 ppm (434 mg/m3)
of a mixture of isomers of xylene for 4055 days with a short-term excursion limit (STEL) of
caused a reversible decrease in red and white 150 ppm (651 mg/m3).
blood cell counts and an increase in thrombo-
cytes; exposure to 690 ppm for the same time
period caused only a slight decrease in the REFERENCES
white blood cell count.8
1. Morley R, Eccleston DW, Douglas CP, et al:
Fetotoxic effects have been reported after
Xylene poisoningA report on one fatal
inhalation exposure to xylenes and include case and two cases of recovery after pro-
altered enzyme activities in rat pups.9 Oral longed unconsciousness. Br Med J 3:442443,
treatment has resulted in prenatal mortality, 1970
growth inhibition, and malformations, prima- 2. Glass WI: A case of suspected xylol poison-
rily cleft palate, but only at maternally toxic ing. NZ Med J 60:113, 1961
doses. No reproductive effects were found in 3. Goldie I: Can xylene (xylol) provoke convul-
rats after inhalation of 500 ppm of xylene sive seizures? Ind Med Surg 29:3335, 1960
before mating and during gestation and lacta- 4. Carpenter CP, Kinkead ER, Geary DJ, et al:
tion.7 However, prenatal exposure at this level Petroleum hydrocarbon toxicity studies. V.
Animal and human responses to vapors of
impaired development of neuromotor ability
mixed xylenes. Toxicol Appl Pharmacol
and learning and memory in rats, with the
33:543558, 1975
effects more pronounced in females.10 After 5. National Institute for Occupational Safety and
intermediate and chronic exposures, there was Health: Criteria for a Recommended Standard . .
no histologic evidence of reproductive organ . Occupational Exposure to Xylene. DHEW
damage in mice administered 1000 mg/kg/day (NIOSH) Pub No 75-168. Washington, DC,
or rats given 800 mg/kg/day.11 US Government Printing Ofce, 1975
In 2-year gavage studies, there was no evi- 6. Von Burg R: Toxicology updates. Xylene. J
dence of carcinogenicity of mixed xylenes for Appl Toxicol 2:269271, 1982
male or female rats given 250 or 500 mg/ 7. Agency for Toxic Substances and Disease
kg/day, or for male or female mice given 500 Registry (ATSDR); Toxicological Prole for
Xylenes (Update), 270pp. US Department of
or 1000 mg/kg/day.11 Limited epidemiological
Health and Human Services, Public Health
studies have not established an association
Service, 1995
between xylene exposure and cancer due to 8. Fabre R, et al: Toxicological research on
multiple-exposure circumstances and weak replacement solvents for benzene. IV. Study
consistency of the ndings.12 of xylenes. Arch Mal Prof Med Trav Secur Soc
Mixed xylene and the individual xylene 21:301, 1960
isomers have tested negative in a wide variety 9. Hood RD, Ottley MS: Developmental effects
of genotoxic assays; they are considered to be associated with exposure to xylene. A review.
nonmutagenic.7 Drug Chem Toxicol 8:281297, 1985
The IARC has determined that there is 10. Hass U, Lund SP, Simonsen L, et al: Effects
inadequate evidence in humans and experimen- of prenatal exposure to xylene on postnatal
development and behavior in rats. Neurotox
tal animals for the carcinogenicity of xylenes.12
Teratol 17(3):341349, 1995
Repeated application of 95% xylene to
11. National Toxicology Program: Toxicology
rabbit skin caused erythema and slight and Carcinogenesis Studies of Xylenes (Mixed)
necrosis. Instilled in rabbit eyes, it produced in F344/N Rats and B6C3F Mice (Gavage
conjunctival irritation and temporary corneal Studies). NTP, TR 327, NIH Pub No 87-
injury. Exposure to the vapors produced 2583. US Department of Health and Human
reversible vacuoles in the corneas of cats. Services, 1986
746 XYLIDINE (Mixed Isomers)
12. IARC Monographs on the Evaluation of the respectively; all three isomers induced fatty
Carcinogenic Risk of Chemicals to Humans, degeneration of the liver, with the 2,6-isomer
Vol 71, Re-evaluation of some organic being the most toxic.4 In rats, doses up to
chemicals, hydrazine and hydrogen peroxide, 700 mg/kg for 4 weeks caused hepatomegaly,
pp 11891208. Lyon, International Agency for but liver histology was normal.
Research on Cancer, 1999
Chronic 2-year studies showed a signi-
cant increase in the incidences of adenomas and
carcinomas of the nasal cavity in high-dose rats
fed diets containing 3000 ppm of 2,6-xylidine.1
XYLIDINE (Mixed Isomers) The carcinomas were highly invasive and fre-
CAS: 1300-73-8 quently destroyed the nasal turbinates and
nasal septum. Rhabdomyosarcomas, a rare
C8H11N tumor of the nasal cavity were also observed in
the high-dose male and females. The nonneo-
plastic lesions observed in the nasal cavity
Synonyms: Aminodimethylbenzene; dim- included acute inammation, epithelial hyper-
ethylaniline plasia, and squamous metaplasia. In addition,
subcutaneous bromas and brosarcomas
Physical Form. Liquid, except o-4-xylidine occurred in both males and females and there
is a solid was an increased incidence of neoplastic
nodules in the livers of female rats.
Uses. Chemical intermediate in the manu- The IARC has determined that there is
facture of pesticides, dyes, antioxidants, phar- sufcient evidence for the carcinogenicity of
maceuticals, synthetic resins, and fragrances 2,6-xylidine in experimental animals and inad-
equate evidence in humans.5 Overall, 2,6-
Exposure. Inhalation xylidine is considered possibly carcinogenic to
humans.
Toxicology. Xylidine causes liver damage in In genotoxic assays, 2,6-xylidine induced
experimental animals and is a mild methemo- sister chromatid exchanges and chromosomal
globin former; it caused tumors of the nasal aberrations in cultured mammalian cells but
cavity in rats. did not induce micronuclei in the bone marrow
There are six isomeric forms of xylidenes of mice treated in vivo; conicting results have
with the commercial product consisting prima- been reported in the Salmonella typhimurium
rily of the 2,4- and 2,6-isomers.1 assay.5
The oral LD50 in rats ranged from 470 mg/ The 2003 ACGIH threshold limit value-
kg for 2,4-xylidine to 1300 mg/kg for 2,5- time-weighted average (TLV-TWA) for xyli-
xylidine.2 Although cyanosis has been observed dine (mixed isomers) is 0.5 ppm (2.5 mg/m3)
in severely intoxicated animals, methemoglo- with an A2-suspected human carcinogen
bin-induced hypoxia did not appear to be classication.
severe enough to be the cause of death.
The extent of methemoglobin formation
from xylidines appears to be species dependent,
with cats more susceptible than humans and REFERENCES
dogs less susceptible.3 Administered intra-
1. National Toxicology Program: NTP Technical
venously to cats, 0.28 mM/kg produced 10%
Report on the Toxicology and Carcinogenesis
methemoglobin in cats, whereas similar expo- Studies of 2,6-Xylidine (2,6-Dimethylaniline)
sure in dogs did not produce methemoglobin.3 (CAS No 87-62-7) in Charles River CD Rats
Oral doses of 2,4-, 2,5-, and 2,6-xylidine (Feed Studies). NTP TR 278, NIH Pub No 90-
administered to dogs for 4 weeks caused hepa- 2534, pp 1138. US Dept of Health and
totoxicity at doses of 2, 20, and 50 mg/kg/day, Human Services, 1990
YTTRIUM 747
2. Vernot, EH, MacEwen ID, Haun GG, of yttrium chloride in animals caused peritoni-
Kinkead ER: Acute toxicity and skin cor- tis with serous or hemorrhagic ascites.2 It was
rosion data for some organic and inorganic speculated that the development of ascites may
compounds and aqueous solutions. Toxicol Appl have been related to the acidity of the admin-
Pharmacol 42(2):417423, 1977 istered solution rather than to the yttrium.2 In
3. McLean S, Starmer GA, Thomas J:
a more recent report, the toxicity of intra-
Methaemoglobin formation by aromatic
amines. J Pharmacol 21(7):441450, 1969 tracheally administered yttrium chloride, as
4. Magnusson G, Majeed SK, Down WH, et al: determined by lactate dehydrogenase activity
Hepatic effects of xylidine isomers in rats. Tox- in bronchoalveolar lavage uid, was judged to
icology 12:6374, 1979 be higher than zinc oxide but lower than
5. IARC Monographs on the Evaluation of Carcino- cadmium compounds.3
genic Risks to Humans, Vol 57, Occupational Intravenous administration of 1 mg of
exposures of hairdressers and barbers and per- yttrium chloride to rats caused formation of
sonal use of hair colourants; some hair dyes, colloidal material in blood plasma, which accu-
cosmetic colourants, industrial dyestuffs and mulated primarily in the liver and spleen
aromatic amines, pp 323335. Lyon, Interna- causing injury to these organs.4
tional Agency for Research on Cancer, 1993
Application of a 0.1 M solution of yttrium
chloride to the eyes of rabbits caused no injury;
similar exposure of eyes from which the corneal
epithelium had been removed resulted in
immediate slight haziness of the cornea, which
YTTRIUM subsequently became opaque and vascularized.5
CAS: 7440-65-5 The 2003 ACGIH threshold limit value-
time-weighted average (TLV-TWA) for
Y yttrium and compounds is 1 mg/m3 as Y.
affected some reproductive parameters, result- ogy of Metals. Vol II, Specic metals, pp
ing in decreased implantation efciency, 664679. New York, Elsevier, 1986
reduced litter size, and abnormal nursing and 10. Agency for Toxic Substances and Disease
nesting behaviors.7 Registry (ATSDR): Toxicological Prole for
Injection of zinc chloride solution into the Zinc. 230pp. US Department of Health and
Human Services, Public Health Service, 1994
testes of 49 Syrian hamsters resulted in areas of
necrosis occupying about 25% of each testis;
two embryonal carcinomas of the testis were
found 10 weeks later at necropsy.8 There is no
evidence that zinc compounds are carcinogenic
after administration by any other route.9 ZINC DITHIOCARBAMATESRUBBER
In general exposure to zinc chloride does COMPONENTS
not increase mutation frequencies in bacterial CAS: Zinc diethyldithiocarbamate: 14324-55-1
or mammalian test systems.10 Zinc dibutyldithiocarbamate: 136-23-2
The 2003 ACGIH threshold limit value- Zinc dimethyldithiocarbamate:137-30-4
time-weighted average (TLV-TWA) for zinc
chloride fume is 1 mg/m3 with a short-term
excursion level (STEL) of 2 mg/m3.
Symptoms lasted 30 minutes after glove Uses. Metallic zinc in galvanizing, electroplat-
removal. Itching was intense, with resultant ing, dry cells, alloying; zinc oxide in pigments
scratching causing excoriations on arms. There
was no history of skin disease or atopy. Imme- Exposure. Inhalation
diate reactions were not observed in patch tests.
In scratch chamber tests, a small piece of Toxicology. Inhalation of zinc oxide fume
rubber gloves and ZDC produced a wheal causes an inuenza-like illness termed metal
greater than histamine control at 15 minutes. fume fever.
No urticaria appeared after switching to differ- During human exposure to zinc oxide
ent gloves. fume, effects are dryness and irritation of the
A study of the mutagenicity of ZDC used throat, a sweet or metallic taste, substernal
a battery of in vitro mutagenicity studies. tightness and constriction in the chest, and a
ZDMC and ZDEC were positive in both the dry cough.15 Several hours after exposure,
Ames Salmonella typhimurium assay and the the subject develops chills, lassitude, malaise,
human lymphocyte cell mutation assay but not fatigue, frontal headache, low back pain,
in the mouse lymphoma cell mutation assay.3 In muscle cramps, and occasionally blurred vision,
contrast, ZDBC was not positive in the assays. nausea, and vomiting. Physical signs include
The ACGIH has not established a thres- fever, perspiration, dyspnea, rales through the
hold limit value for ZDC. chest, and tachycardia; in some instances,
there has been a reversible reduction in pul-
monary vital capacity. There is usually leuko-
REFERENCES cytosis, which may reach 12,00016,000/cmm.2
The pathogenesis of the syndrome is not clear,
1. Helander I, Makela A; Contact urticaria to but an allergic response has been suggested,
zinc diethyldithiocarbamate (ZDC). Contact with zinc entering the blood circulation and
Derm 9:327, 1983 forming a sensitizing complex with plasma
2. Greim H (ed): Occupational Toxicants, Vol 15,
proteins.5
critical data evaluation for MAK values and
An attack usually subsides after 612 hours
classication of carcinogens, Commission for
the investigation of health hazards of chemical but may last for up to 24 hours; recovery is
compounds in the work area. Rubber compo- usually complete.3 Most workers develop an
nentsDithiocarbamates, p 147, New York, immunity to these attacks, but it is quickly lost;
VCH, 2001 attacks tend to be more severe on the rst day
3. Tinkler J, et al: Risk assessment of dithiocar- of the workweek.3 Despite the severity of the
bamate accelerator residues in latex-based acute subjective symptoms there appear to be
medical devices: Genotoxicity considerations. no consistent functional or pathological respi-
Food Chem Toxicol 36:9, 1998 ratory effects attributable to chronic exposure.1
The critical factor in the development of
the syndrome is the size of the ultrane zinc
oxide particles produced when zinc is heated to
temperatures approaching its boiling point in
ZINC OXIDE an oxidizing atmosphere.4 The particles must
CAS: 1314-13-2 be small enough (<1 mm) to reach the alveoli
when inhaled. The syndrome is not produced
ZnO when normal zinc oxide powder is either
inhaled or taken orally.2 Only freshly formed
fume causes the illness, presumably because
Synonyms: Calamine; zincite occulation occurs in the air with formation of
larger particles that are deposited in the upper
Physical Form. White to yellowish powder respiratory tract and do not penetrate deeply
that may exist as a fume or dust into the lungs.6
ZIRCONIUM COMPOUNDS 751
753
754 CAS NUMBER INDEX
761
762 INDEX
Carbon tetrachloride, vi, 18, 19, 126128, Chloroacetyl chloride, vi, 145, 146
228, 414, 473, 604 Chlorobenzene, vi, 146, 147, 168, 220223,
carbonyl chloride, 264, 579 271, 369371, 516, 519522, 692
Carbonyl uoride, 593 chlorobenzol, 146, 220, 369
carbophos, 430 Chlorobenzylidene malononitrile, vi, 147, 148
carborundum, 631 2-Chlorobenzylidene malononitrile, 1, 148
Caswell No. 392, 278 o-Chlorobenzylidene malononitrile, vi, 147,
Catechol, vi, 129, 130, 335, 407, 449, 618, 698 148
caustic, 112, 189, 191, 299, 546, 550, 596, Chlorobromomethane, vi, 91, 149
633, 636 chlorobutadiene, 166, 167
caustic ake, 636 2-chloro-1,3-butadiene, 166
caustic potash, 596 1-chloro-2-(b-chloroethoxy)-ethane, 229
caustic soda, 636 chloro(chloromethoxy)methane, 160
Cellosolve, 258, 300, 303, 304, 326, 327, 412, p-Chloro-m-cresol, vi, 150
445, 447 chlorocyanide, 193
Cellosolve acetate, 304, 447 chlorocyanogen, 193
Celluex TP, 718 Chlorodibromomethane, vi, 92, 94, 150152
Cellulose and compounds, vi Chlorodiuoromethane, vi, 152, 153, 164,
cesium chromate, 172 165, 225, 226
cesium hydrate, 131 Chlorodiphenyl, 42% chlorine, vi, 153, 157
Cesium hydroxide, vi, 131 Chlorodiphenyl, 54% chlorine, vi, 156
CD-68, 131 1-chloro-2,3-epoxypropane, 294
CHA, 198 3-chloro-1,2-epoxypropane, 294
chalk, 110 chloroethane, 227, 228, 314316, 501, 695
channel black, 118 2-chloroethanol, 317, 318, 611
Chemical Mace, 144 chlorethene, 731
Chemox PE, 278 b-chloroethyl alcohol, 317
chorallylene, 32 chloroethylene, 731
chlordan, 131 bis(2-chloroethyl)ether, 229
Chlordane, vi, 131133, 292, 366, 367 bis-2-chloroethyl sulde, 501
Chlordecone, vi, 126128, 133, 134 Chloroform, vi, 9294, 152, 158160, 230,
chlorex, 229 453, 473, 492, 556, 566, 605, 621, 694
chlorinated camphene, 687689 chloromethane, 462
Chlorinated diphenyl oxide, vi, 137, 138 (chloromethyl) benzene, 80
chlorinated phenyl ethers, 137 2-chloro-1-methylbenzene, 169
Chlorine, vi, 5, 126, 134142, 153, 155157, chloromethyl bromide, 149
159, 175, 193, 244, 292, 371, 388, 546, chloromethyl ether, 160163
567, 579 bis (Chloromethyl) ether, vi, 160162
chlorine cyanide, 193 (chloromethyl)ethylene oxide, 294
Chlorine dioxide, vi, 140142 Chloromethyl methyl ether, vi, 160163
chlorine uoride, 142, 567 chloromethyloxirane, 294
chlorine uoride oxide, 567 2-chloronitrobenzene, 519
chlorine oxide, 140 1-chloro-2-nitrobenzene, 519
chlorine oxyuoride, 567 p-chloronitrobenzene, 199, 520
chlorine peroxide, 140 1-Chloro-1-nitropropane, vi, 163, 164, 231
Chlorine triuoride, vi, 142 Chloropentauoroethane, vi, 153, 164, 165
Chloroacetaldehyde, vi, 142, 143 2-chloro-1-phenylethanone, 144
2-chloroacetaldehyde, 142, 143 Chloropicrin, vi, 165, 459, 650, 651
Chloroacetone, vi, 143, 144 b-Chloroprene, vi, 166, 167
a-Chloroacetophenone, vi, 144 3-chloroprene, 32
766 INDEX
HD, 103, 199, 501, 524, 605, 611, 651 HFA, 376, 377
HDI, 378, 379 HHDN(ISO), 30
heavy naphtha, 505 high-ash naphtha, 505
Hedonal, 233 HMDI, 378, 469
Helium, viii, 366 HMPA, 379, 380
hemimellitene, 712 HMPT, 379
HEOD, 243 HMX, viii, 383, 384
Heptachlor, viii, 131133, 292, 366368 HPA, 399, 473
Heptachlor epoxide, viii, 367, 368 HPT, 379
heptane, viii, 97, 368, 369, 381, 544, 562 hydrazobenzene, 284
n-Heptane, viii, 368, 369, 544 hydrated lime, 111
2-heptanone, 455 Hydrazine, viii, ix, 14, 15, 30, 34, 7981, 93,
3-heptanone, 310, 311, 314 94, 96, 101, 116, 128, 130, 152, 159161,
4-heptanone, 257, 285 163, 167, 196, 214, 220, 225, 230, 233,
heptan-4-one, 285 245, 255, 265, 266, 268, 279, 274, 283,
heptyl hydride, 368 295, 298, 308, 314, 316, 321, 323, 333,
Hexachlorobenzene, viii, 369371 355, 380, 384, 385, 393, 397, 414, 451,
hexachlorobenzol, 369 460, 463, 471, 474, 480, 481, 483, 501,
Hexachlorobutadiene, viii, 371373 519, 532, 557, 561, 570, 574, 575, 578,
hexachloro-1,3-butadiene, 371 601, 609, 615, 618, 659, 686, 696, 730,
1,2,3,4,5,6-hexachlorocyclohexane, 426 738, 746
Hexachlorocyclopentadiene, viii hydrazine anhydrous, 384
hexachlorodiphenyl oxide, 137 hydrazinobenzine, 574
Hexachloroethane, viii, 374, 375, 557, 749 hydrobromic acid, 386
Hexachloronaphthalene, viii, 375, 376, 543, hydrobromic ether, 312
558, 659, 699 hydrochloric acid, aqueous, 387
Hexauoroacetone, viii, 376, 377 hydrochloric ether, 314
hexahydroaniline, 198 hydrocyanic acid, 389, 390
hexahydrobenzenamine, 198 hydrouoric acid, 345, 347, 390392, 723
hexahydrobenzene, 193 hydrogen antimonide, 638
hexahydrocresol, 465 hydrogen arsenide, 58
hexahydromethylphenol, 465 hydrogenated MDI, 469
hexahydrophenol, 195 Hydrogenated terphenyls, viii, 386
hexahydrotoluene, 464 Hydrogen bromide, viii, 88, 386388
hexahydro-1,3,5-trinitro-1,3,5-triazine, 616 hydrogen carboxylic acid, 351
hexamethylene, viii, 193, 378, 379 Hydrogen chloride, viii, 5, 139, 387389, 501,
Hexamethylene diisocyanate, viii, 378, 379 585, 646, 675, 678, 752
Hexamethyl phosphoramide, viii, 379 hydrogen cyanamide, 111, 189
hexamethyl phosphoric triamide, 379 Hydrogen cyanide, viii, 191193, 389, 390
hexane, viii, 18, 97, 200, 329, 369, 380382, Hydrogen uoride, viii, 5, 89, 142, 347, 387,
461, 477, 544, 562 388, 390392
n-Hexane, viii, 18, 369, 380382, 461, 477, hydrogen nitrate, 513
544 Hydrogen peroxide (90%), viii, 392, 393
hexanon, 195 hydrogen phosphide, 580
2-hexanone, 460, 483 Hydrogen selenide, viii, 393, 394, 623, 624
hexogen, 616, 617 Hydrogen sulde, viii, 337, 394, 395
hexone, 484 hydroquinol, 395
sec-Hexyl acetate, viii, 382 Hydroquinone, viii, 100, 130, 334, 395397,
Hexylene glycol, viii, 382, 383 448, 449, 488, 614, 615, 618
774 INDEX
hydroquinone monomethyl ether, 448, 449, isobutyl carbinol, ix, 406, 483, 484
488 bis-(4-isocyanalocyclohexyl)-methane, 411
hydrosulfuric acid, 394 3-isocyanatomethyl-3,5,5-trimethyl
4-hydroxyaniline, 41 cyclohexylisocyanate, 411
4-hydroxyanisole, 448, 449 isocyanic acid, methyl ester, 485
hydroxybenzene, 41, 231, 395, 568 Isoforon, 410
p-hydroxybenzene, 395 Isol, 382
2-hydroxybutane, 102 isonitropropane, 531
Hydroxylamine, viii, 397, 398 isooctanol, 409
Hydroxylamine sulfate, 397, 398 Isooctyl alcohol, viii, 409, 410
hydroxyl ammonium, 397 isopentyl alcohol, 406
4-hydroxyl-4-methyl-2-pentanone, Isophorone, viii, 299, 410412, 441, 469
207 Isophorone diisocyanate, viii, 411, 412,
3-hydroxy-1-propanesulphonic acid 469
sultone, 597 isophthalonitrile, 168, 587
2-Hydroxypropyl acrylate, viii, 399 isopropanol, 413415
isoprene cyanide, 451
IGE, 300, 417, 418 isopropenylbenzene, 495
imidazolidinethione, 330, 332 isopropenylnitrile, 451
2-imidazoline-2-thiol, 330 2-Isopropoxyethanol, viii, 412
2,2-iminodiethanol, 245 2-isopropoxypropane, 417
Indene, viii, 75, 399 Isopropyl acetate, viii, 412, 413
indeneopyrene, 400 Isopropyl alcohol, viii, 127, 255, 413415,
Indenol (1,2,3-cd) pyrene, viii 599, 603
Indium and compounds, 401 Isopropylamine, viii, 415, 416
Indium antimonide, 400 N-isopropylaniline, viii, 415, 416
Indium arsenide, 400402 isopropylbenzene, 188
Indium nitrate, 400 isopropylcarbinol, 408
Indium sesquioxide, 400, 401 Isopropyl Cellosolve, 412
Indium trichloride, 400402 Isopropyl ether, viii, 417
Indonaphthene, 399 Isopropyl glycidyl ether, 300, 417
infusorial earth, 625 isopropyl glycol, 412
Iodine, viii, 43, 122, 126, 287, 402, 403 isopropylideneacetone, 440
Iodoform, viii, 403, 404 isopropylmethylbenzene, 201
iodomethane, 481 isopropyltoluene, 201
IP, 400 Isotron, 225
N-IPA, 415 Isovalerone, 257
IPDI, 411, 412, 469
IPE, 412 Jasmolin I or II, 612
iron carbonyl, 405 Jet fuel, viii, 352, 418, 419, 445, 487
Iron oxide fume, viii, 404 JP-4, 418, 419
Iron pentacarbonyl, viii, 405 JP-7, 418, 419
isoacetophorone, 410
Isoamyl acetate, viii, 49, 382, 405, 406 Kepone, 133, 134
Isoamyl alcohol, viii, 406, 407 Ketene, viii, 420
1,3-isobenzofurandione, 586 b-ketopropane, 17
isobrome, 457 2-keto-1,7,7,-trimethylnorcamphane,
Isobutane, viii, 98, 407, 408, 597 114
Isobutyl acetate, viii, 408 KOH, 596
Isobutyl alcohol, viii, 408, 409 Kwell, 426
INDEX 775
silicic acid, tetraiethyl ester, 338 Sulfur dioxide, xv, 112, 201, 554, 637,
silicic anhydride, 628 644648, 650, 675
Silicon, xv, 6, 91, 342, 390, 429, 474, sulfureted hydrogen, 394
626628, 630632, 725 sulfur uoride, 645
Silicon carbide, xv, 631, 632 Sulfur hexauoride, xv, 645647
silicon dioxide, 6, 342, 429, 474, 627, 628 Sulfuric acid, xv, 254, 255, 273, 389, 414, 514,
Silicon tetrahydride, xv, 632 523, 644, 648650
Silver (and compounds), 632 sulfuric acid diethyl ester, 254
silver chloride, 632, 633 sulfuric acid dimethyl ester, 273
silver nitrate, 632, 633 sulfuric ether, 333
silver sulde, 632 sulfuric oxyuoride, 650
slaked lime, 111 Sulfur monochloride, xv, 646
Soapstone, xv, 634 sulfur mustard, 501, 503
sodium borate, 87 sulfurous anhydride, 644
sodium chloroplatinate, 590 sulfurous oxide, 644
sodium cyanide, 190, 191 Sulfur pentauoride, xv, 647
Sodium uoroacetate, 634 sulfur subchloride, 646
sodium hexachloroplatinate, 590 Sulfur tetrauoride, 647
Sodium hydroxide, xv, 596, 636, 637 sulfurous oxychloride, 674
Sodium metabisulte, xv, 637 Sulfuryl uoride, xv, 650, 651
sodium molybdate, 498 sulphuric acid, 648, 650
sodium monouoroacetate, 634, 635 Systox, 206, 288
sodium pyroborate, 87
sodium pyrophosphate, xv, 667, 668 2,4,5-T, xvi, 130, 135, 136, 234, 615, 701703
sodium pyrosulte, 637 Talbot, 423
sodium selenate, 623 Talc, 300, 634, 651654
sodium selenite, 623 Tantalum, xv, 654
sodium stannate, 677 tar camphor, 506
sodium tetrachloroplatinate, 590 TBP, 689, 690
softwood, 741 TBT, 107, 679
Solvirex, 288 TCA, 690, 691
Soprabel, 423 TCDD, 136, 137, 701
spirit of turpentine, 721 TCDF, 657
stannic chloride, 677, 678 TCE, 694, 696, 697
stannic oxide, 677, 678 TCTFE, 704, 705
stannous chloride, 677, 678 TDI, 378, 379, 683685
stannous sulfate, 677 tear gas, 144, 147
Stibine, xv, 638 Tecquinol, 395
Stoddard solvent, 638 TECZA, 708
stricnina, 639 Teon, 593
strontium chromate, 172, 174 TEL, 659, 660, 665, 747
Strychnine, xv, 639, 640 Tellurium, 654
Styrene, monomer, xv, 640 Tellurium hexauoride, xv, 655, 656
Styrene oxide, xv, 298, 459, 611, 642, 643, Telone, 235, 237
739 Telone II, 235, 237
succinonitrile, tetramethyl, 666 TEP, 661
Sulfo Black B, 278 TEPP, 661, 662
Sulfolane, xv, 643, 644 m-terphenyl, 656
sulfur chloride, 646 o-terphenyl, 656
INDEX 783