Documente Academic
Documente Profesional
Documente Cultură
D a t a s e t
Existing Chemical
CAS No.
EINECS Name
EINECS No.
Molecular Formula
Creation date:
18FEB2000
Number of Pages:
44
Chapters:
all
Edition:
Flags:
nonconfidential
date: 18FEB2000
1. General Information
Substance ID: 15687271
______________________________________________________________________________
organic
solid
1.1.1 Spectra
1.2 Synonyms
2(4Isobutylphenyl)propionic acid
Source:
ALBEMARLE S.A. Brussels
2(4isobutylphenyl) propanoic acid
Source:
Boots Chemicals, The Boots Company PLC
Knoll Pharmaceuticals Nottingham
Nottingham
4isobutylhydratropic acid
Source:
Boots Chemicals, The Boots Company PLC
Knoll Pharmaceuticals Nottingham
Nottingham
Nottingham
ibuprofen
Source:
pisobutylhydratropic acid
Source:
ALBEMARLE S.A.
Brussels
1.3 Impurities
1.4 Additives
1/44
Nottingham
date: 18FEB2000
1. General Information
Substance ID: 15687271
______________________________________________________________________________
1.5 Quantity
Quantity
10 000
50 000 tonnes
1.6.1 Labelling
1.6.2 Classification
type
Non dispersive use
Type:
Category:
type
Wide dispersive use
Type:
Category:
industrial
Chemical industry: used in synthesis
Type:
Category:
industrial
Personal and domestic use
Type:
Category:
use
Pharmaceuticals
other
5 mg/m3
15 mg/m3
15 minute(s)
3 times
ALBEMARLE S.A.
Brussels
2/44
date: 18FEB2000
1. General Information
Substance ID: 15687271
______________________________________________________________________________
Type of limit:
Limit value:
Short term expos.
Limit value:
Schedule:
Frequency:
Remark:
Source:
Type of limit:
Limit value:
Short term expos.
Limit value:
Schedule:
Frequency:
Remark:
Source:
other
5 mg/m3
15 mg/m3
15 minute(s)
3 times
Personal protective equipment:
Respiratory protectionapproved particulate respirator
Hand protectionPVC or rubber gloves
Eye protectionchemical safety goggles
Skin protectionoverall or disposable coverall
Type of occupational exposure limitin house workplace
exposure level.
Boots Chemicals, The Boots Company PLC Nottingham
other
5 mg/m3
15 mg/m3
15 minute(s)
3 times
Personal protective equipment:
Respiratory protectionapproved particulate respirator
Hand protectionPVC or rubber gloves
Eye protectionchemical safety goggles
Skin protectionoverall or disposable coverall
Type of occupational exposure limitin house workplace
exposure level.
Knoll Pharmaceuticals Nottingham
Production Process
Isobutylbenzene is acetylated with acetyl chloride in the
presence of aluminium chloride and in carbon tetrachloride
solvent.After quenching into dilute hydrochloric acid, the
organic layer is washed with water, stripped of its
solvent with steam, and 2(4isobutylphenyl) ethanone
isolated by vacuum distillation. Sodium isopropoxide
solution, made by dissolving sodium in refluxing isopropyl
alcohol, is mixed with the 2(4isobutylphenyl) ethanone
and isopropyl chloroacetate. After distilling off the
isopropyl alcohol the residue is hydrolysed by heating
with diluted caustic soda solution. Aqueous isopropyl
alcohol is then removed by steam distillation. The organic
layer is separated, and may be combined with a toluene
wash of the aqueous phase.Toluene is removed and
2(4isobutylphenyl) propanal isolated by vacuum
distillation. 2(4isobutylphenyl) propanal is converted
to its oxime by reaction with an aqueous solution of
hydroxylamine sulphate and caustic soda solution, in the
presence of acetic acid.After separating off the aqueous
layer, the oxime is rearranged and hydrolysed with a
solution of caustic soda in water or sodium chloride
solution.Some of the water is distilled off and the
3/44
date: 18FEB2000
1. General Information
Substance ID: 15687271
______________________________________________________________________________
Source:
1.11 Packaging
4/44
date: 18FEB2000
1. General Information
Substance ID: 15687271
______________________________________________________________________________
Source:
1.17 Reviews
5/44
date: 18FEB2000
2. Physicochemical Data
Substance ID: 15687271
______________________________________________________________________________
75 77.5 degree C
no data
Boots Chemicals, The Boots Company PLC
Knoll Pharmaceuticals Nottingham
Nottingham
(1)
Value:
Decomposition:
Sublimation:
Method:
GLP:
Source:
75 78 degree C
no
no
other: in house study using Mettler FP80 Central Processor and
FP81 MBC cell
no
Boots Chemicals, The Boots Company PLC Nottingham
Knoll Pharmaceuticals Nottingham
2.3 Density
Type:
Value:
Method:
GLP:
Remark:
Source:
Test condition:
bulk density
.2 .6 g/cm3
other: see TC
no data
Method: In house
Testcylinders raised and fall back under gravity
Boots Chemicals, The Boots Company PLC Nottingham
Knoll Pharmaceuticals Nottingham
Test believed to have been carried out at ambient
temperature
2.3.1 Granulometry
6/44
date: 18FEB2000
2. Physicochemical Data
Substance ID: 15687271
______________________________________________________________________________
Source:
Test condition:
log Pow:
Method:
Year:
GLP:
Source:
no data
Boots Chemicals, The Boots Company PLC
Knoll Pharmaceuticals Nottingham
Nottingham
(3)
log Pow:
Method:
Year:
GLP:
Remark:
Source:
= 3.94
no data
Value given in the average of 3 experiments
Boots Chemicals, The Boots Company PLC Nottingham
Knoll Pharmaceuticals Nottingham
(4)
Nottingham
(5)
7/44
date: 18FEB2000
2. Physicochemical Data
Substance ID: 15687271
______________________________________________________________________________
Qualitative:
Source:
not soluble
Boots Chemicals, The Boots Company PLC
Knoll Pharmaceuticals Nottingham
Nottingham
(6)
pKa:
pH:
Method:
GLP:
Source:
Test condition:
4.54 at 25 degree C
= 4.4 at 40 other: ug/ml
other: in house test
no data
Boots Chemicals, The Boots Company PLC
Knoll Pharmaceuticals Nottingham
pKa value temperature not known
Nottingham
2.9 Flammability
Result:
Remark:
Source:
non flammable
Stable at normal temperature. Will burn if exposed to heat
or flame.
Boots Chemicals, The Boots Company PLC Nottingham
Knoll Pharmaceuticals Nottingham
8/44
Nottingham
date: 18FEB2000
3. Environmental Fate and Pathways
Substance ID: 15687271
______________________________________________________________________________
3.1.1 Photodegradation
3.3.2 Distribution
3.5 Biodegradation
Type:
Inoculum:
Concentration:
Degradation:
Result:
Method:
Year:
Test substance:
Source:
Test condition:
aerobic
activated sludge
20 mg/l related to Test substance
= 10 60 % after 28 day
other
OECD Guideline 301 B "Ready Biodegradability: Modified Sturm
Test (CO2 evolution)"
GLP: no data
as prescribed by 1.1 1.4
Knoll Pharmaceuticals Nottingham
The test carried out was the Sturm Test (OECD 301B). The
test substance at approximately 20 mg/l in an inorganic
medium was inoculated with 100000 1000000 per ml
microorganisms in the form of activated sluge from a
water reclamation works and aerated at 2025 degrees C.
The amount of carbon dioxide produced was compared to the
theoretical yield calculated from the carbon content of the
test substance. A standard, Dglucose, was also included.
The test substance is considered to have passed the Sturm
Test if >60% theoretical carbon dioxide is evolved in 28
days providing that this occurs within 10 days of the
sample liberating 10% carbon dioxide.
The standard, Dglucose, met the criteria of the test. The
test substcne, ibuprofen, showed >10% but <60% carbon
dioxide evolution over the 28 day test period. This
indicates that the test substance did not meet the criteria
9/44
date: 18FEB2000
3. Environmental Fate and Pathways
Substance ID: 15687271
______________________________________________________________________________
28 day
= 31.1 %
OECD Guideline 301 D "Ready Biodegradability: Closed Bottle
Test"
GLP: yes
no data
The closed bottle test gave an approximate 30%
biodegredation
Boots Chemicals, The Boots Company PLC Nottingham
Knoll Pharmaceuticals Nottingham
MethodClosed bottle test
inherently biodegradable
other: no data
GLP: no data
no data
Boots Chemicals, The Boots Company PLC Nottingham
Knoll Pharmaceuticals Nottingham
(7)
3.7 Bioaccumulation
10/44
date: 18FEB2000
4. Ecotoxicity
Substance ID: 15687271
______________________________________________________________________________
AQUATIC ORGANISMS
4.1 Acute/Prolonged Toxicity to Fish
Type:
Species:
Exposure period:
Unit:
NOEC:
LC50:
Method:
Year:
Test substance:
Remark:
Source:
Type:
Species:
Exposure period:
Unit:
NOEC:
LC50:
Method:
Year:
Test substance:
Remark:
Source:
static
Cyprinodon variegatus (Fish, estuary, marine)
96 hour(s)
mg/l
Analytical monitoring: no data
= 300
> 300
other: 96 hour static toxicity test
GLP: no data
no data
Due to apparent presence of undissolved test material in
the containers at 100 and 300 mg/L the actual LC50 may be
less than 300 mg/L and closer to 100 mg/L
Boots Chemicals, The Boots Company PLC Nottingham
Knoll Pharmaceuticals Nottingham
static
Lepomis macrochirus (Fish, fresh water)
96 hour(s)
mg/l
Analytical monitoring: no data
= 10
= 173
other: 96 hour static toxicity test
GLP: no data
no data
LC50 calculated with 95% confidence limits of 117 and 257
mg/l
Boots Chemicals, The Boots Company PLC Nottingham
Knoll Pharmaceuticals Nottingham
11/44
date: 18FEB2000
4. Ecotoxicity
Substance ID: 15687271
______________________________________________________________________________
Species:
Exposure period:
Unit:
NOEC:
LC50 :
Method:
Year:
Test substance:
Remark:
Source:
Species:
Exposure period:
Unit:
NOEC:
LC50 :
Method:
Year:
Test substance:
Source:
Source:
Test condition:
12/44
date: 18FEB2000
4. Ecotoxicity
Substance ID: 15687271
______________________________________________________________________________
Species:
Endpoint:
Exposure period:
Unit:
IC50 :
Method:
Year:
Test substance:
Remark:
Source:
Test condition:
Species:
Endpoint:
Exposure period:
Unit:
NOEC:
EC50:
Method:
Year:
Test substance:
Source:
Test condition:
Skeletonema costatum
other: see RM
96 hour(s)
mg/l
= 7.1
other: see TC
(Algae)
GLP: no data
no data
Endpoint was determined from cell density by direct
counts using a haemocytometer counting chamber and a
compound microscope
IC50 calculated with 95% confidence limits of 3.0 and 10.0
mg/l
Boots Chemicals, The Boots Company PLC Nottingham
Knoll Pharmaceuticals Nottingham
96 hour static toxicity test
Skeletonema costatum
5 day
mg/l
= 20.5
= 39.9
other: see TC
(Algae)
GLP: yes
no data
Boots Chemicals, The Boots Company PLC Nottingham
Knoll Pharmaceuticals Nottingham
Static test, 5 days exposure and 9 days recovery
aquatic
Photobacterium phosphoreum (Bacteria)
5 minute(s)
mg/l
Analytical monitoring: no
= 12.3
other
GLP: no
as prescribed by 1.1 1.4
Knoll Pharmaceuticals Nottingham
MICROTOX TOXICITY TEST
The test sample was dissolved in a suitable solvent at
suitable test concentrations and inoculated with the test
culture, Photobacterium phosphorium. A control consisting
of the test system without the test substance was also
included. After the required incubation times the amount
of bioluminescence of the control and test substance were
measured, and the EC50 values calculated by the system
software.
13/44
date: 18FEB2000
4. Ecotoxicity
Substance ID: 15687271
______________________________________________________________________________
Type:
Species:
Exposure period:
Unit:
EC50:
Method:
Year:
Test substance:
Source:
Test condition:
aquatic
Photobacterium phosphoreum (Bacteria)
15 minute(s)
mg/l
Analytical monitoring: no
= 13.12
other
GLP: no
as prescribed by 1.1 1.4
Knoll Pharmaceuticals Nottingham
MICROTOX TOXICITY TEST
Test as for 5 minute incubation time
Type:
Species:
Exposure period:
Unit:
EC50:
Method:
Year:
Test substance:
Source:
Test condition:
aquatic
Photobacterium phosphoreum (Bacteria)
30 minute(s)
mg/l
Analytical monitoring: no
= 13.82
other
GLP: no
as prescribed by 1.1 1.4
Knoll Pharmaceuticals Nottingham
MICROTOX TOXICITY TEST
Test as for 5 minutes incubation time
14/44
date: 18FEB2000
4. Ecotoxicity
Substance ID: 15687271
______________________________________________________________________________
TERRESTRIAL ORGANISMS
4.6.1 Toxicity to Soil Dwelling Organisms
15/44
date: 18FEB2000
5. Toxicity
Substance ID: 15687271
______________________________________________________________________________
Source:
Test substance:
Type:
Species:
Sex:
Number of
Animals:
Vehicle:
Value:
Method:
Year:
Test substance:
Source:
LD50
rat
= 969 mg/kg bw
other: no detail given
GLP: no data
other TS: ibuprofen ester with guaiacol
Boots Chemicals, The Boots Company PLC Nottingham
Knoll Pharmaceuticals Nottingham
(9)
Type:
Species:
Sex:
Number of
Animals:
Vehicle:
Value:
Method:
Year:
Test substance:
Remark:
other
rat
= 400 mg/kg bw
other: see RM
GLP: yes
no data
Method
5 male and 5 female rats were given single oral doses of
ibuprofen at 400, 800, 1200 and 1600 mg/kg. 15 male and 15
female controls received the vehicle, 0.4% aqueous
Cellosize solution. The rats were observed for a 14 day
16/44
date: 18FEB2000
5. Toxicity
Substance ID: 15687271
______________________________________________________________________________
period.
Source:
Type:
Species:
Sex:
Number of
Animals:
Vehicle:
Value:
Method:
Year:
Test substance:
Remark:
Source:
Test substance:
Type:
Species:
Sex:
Number of
Animals:
Vehicle:
Value:
Method:
Year:
Test substance:
Source:
Results
The animals given 400mg/kg ibuprofen showed no overt signs
of toxicity.Animals given 800mg/kg or more lost condition,
had a wasted appearance and distened abdomen. There were
no deaths after 400mg/kg treatment. Six rats given
800mg/kg ibuprofen and all the animals given 1200 and
1600mg/kg became moribund and were killed between one and
five days. Gastrointestinal irritation and adhesions, and
pale livers, kidneys and spleens were seen in the treated
groups, except for the 400mg/kg group where no treatment
related findings were made.
Type of test NOEL
Boots Chemicals, The Boots Company PLC Nottingham
Knoll Pharmaceuticals Nottingham
LD50
mouse
= 897 mg/kg bw
other: no detail given
GLP: no data
other TS: ibuprofen ester with guaiacol
Boots Chemicals, The Boots Company PLC Nottingham
Knoll Pharmaceuticals Nottingham
(9)
17/44
date: 18FEB2000
5. Toxicity
Substance ID: 15687271
______________________________________________________________________________
Type:
Species:
Sex:
Number of
Animals:
Vehicle:
Value:
Method:
Year:
Test substance:
Remark:
Source:
Type:
Species:
Sex:
Number of
Animals:
Vehicle:
Value:
Method:
Year:
Test substance:
Remark:
other
dog
other: see RM
GLP: no data
other TS: ibuprofen in gelatin capsules
Method
Single oral doses of 20 to 320 mg/kg were given after
overnight fasting.Examination of blood, urine and faeces
was carried out before and after dosing. Some of the dogs
were killed after 1 day, others after 7 days.
Results
Doses of 20 and 50 mg/kg were non toxic. Doses of 125, 200
and 320 mg/kg all caused gastric damage, feacal blood loss
and albuminuria. The maximun no effect level was between
50 and 125 mg/kg.
Study conducted prior to GLP requirements
Type of test in house test, effect of single oral dose
Boots Chemicals, The Boots Company PLC Nottingham
Knoll Pharmaceuticals Nottingham
other: see RM
primate
other: see RM
GLP: no data
no data
Method
One male and one female baboon were each given a single
oral dose of 100 mg/kg of ibuprofen. Signs of toxicity,
food consumption and water intake were recorded daily.
Comprehensive haematology, blood biochemistry and
urinalysis were carried out at least once before dosing
and 24 hours and 6 days after dosing. Faecal examination
for occult blood was carried out daily before and after
dosing. Both baboons were killed one week after dosing,
organ weights determined and organs examined
histologically.
Results
A single dose of 100 mg/kg of ibuprofen had no adverse
effect in the baboon
Both animals had minor fluctuations in body weight after
dosing and were slightly below initial weight when killed.
Food and water intake was unaffected.
Haematological and blood biochenical values were not
altered significantly.
Urine analysis normal.
Trace of blood detected in faeces of male 6 days after
18/44
date: 18FEB2000
5. Toxicity
Substance ID: 15687271
______________________________________________________________________________
Source:
dosing.
All organ weights were within normal limits and on gross
and microscopic examination there were no findings
attributable to dosing.
Study conducted prior to GLP requirements
Type of Test investigation of effect of single oral dose
of 100 mg/kg on baboons.
Boots Chemicals, The Boots Company PLC Nottingham
Knoll Pharmaceuticals Nottingham
Source:
LD50
mouse
i.p.
ca. 320 mg/kg bw
in house method
GLP: no data
other TS: ibuprofen in 10% acacia
Results
Toxic doses caused depression of the central nervous
system.
Death resulted from gastric ulceration.
Maximum noeffect level = 100 mg/kg
Lowest dose causing overt signs = 200 mg/kg
Highest nonlethal dose = 100 mg/kg
Lowest dose causing death = 200 mg/kg
Highest dose with survivors = 800 mg/kg
Study conducted prior to GLP requirements
Boots Chemicals, The Boots Company PLC Nottingham
Knoll Pharmaceuticals Nottingham
(11)
19/44
date: 18FEB2000
5. Toxicity
Substance ID: 15687271
______________________________________________________________________________
Type:
Species:
Sex:
Number of
Animals:
Vehicle:
Route of admin.:
Value:
Method:
Year:
Test substance:
Remark:
Source:
LD50
rat
s.c.
ca. 1300 mg/kg bw
in house method
GLP: no data
other TS: ibuprofen in 10% acacia
Results
Toxic doses caused depression of the central nervous
system.
Death resulted from perforation of the lower intestine.
Maximum noeffect level = 800 mg/kg
Lowset dose causing overt signs = 1600 mg/kg
Highest nonlethal dose = 800 mg/kg
Lowest dose causing death = 1600 mg/kg
Highest dose with survivors = 1600 mg/kg
Study conducted prior to GLP requirements
Boots Chemicals, The Boots Company PLC Nottingham
Knoll Pharmaceuticals Nottingham
(11)
Source:
GLP:
Recorded on the company Safety Data Sheet as "May be
irritating to skin". This is based on worker anecdotal
evidence which suggests that any potential for skin
irritancy may be slight.
Boots Chemicals, The Boots Company PLC Nottingham
Knoll Pharmaceuticals Nottingham
20/44
date: 18FEB2000
5. Toxicity
Substance ID: 15687271
______________________________________________________________________________
GLP:
Recorded on the company Safety Data Sheet as "Irritating
to eyes". This is based on worker anecdotal evidence.
Boots Chemicals, The Boots Company PLC Nottingham
Knoll Pharmaceuticals Nottingham
5.3 Sensitization
Type:
Species:
Number of
Animals:
Vehicle:
Result:
Classification:
Method:
Year:
Test substance:
Source:
not sensitizing
OECD Guideline 406 "Skin Sensitization"
1981
GLP: yes
other TS: 10% ibuprofen gel
Boots Chemicals, The Boots Company PLC Nottingham
Knoll Pharmaceuticals Nottingham
21/44
date: 18FEB2000
5. Toxicity
Substance ID: 15687271
______________________________________________________________________________
Result:
Source:
Species:
Strain:
Route of admin.:
Exposure period:
Frequency of
treatment:
Post. obs.
period:
Doses:
Control Group:
Method:
Year:
Test substance:
Remark:
Result:
rat
other: AshWistar
oral feed
2 years
Sex: male/female
0, 20, 60, and 120 mg/kg/day, 80 rats per dose level (40 male
and 40 female)
yes, concurrent no treatment
other: see RM
GLP: no data
no data
Method In house study conducted 1975
Detailed macroscopic and microscopic examination was
carried out on animals which died or were killed.
See also section 5.7. as the studies in that section are
combined carcinogenicity and chronic toxicity studies.
Study conducted prior to GLP requirements
The only pathological findings considered to be related to
treatment were RENAL PAPILLARY changes in the groups given
60 or 120 g/kg/day and GASTROINTESTINAL DAMAGE that was
most prevalant in animals receiving the highest dose.
No evidence of CARCINOGENICITY was seen.
INCREASED URINE FLOW rate at the highest dose. PULMONARY
and LIVER LESIONS were prevalant at 120 mg/kg/day which
were probably stress related.
Boots Chemicals, The Boots Company PLC Nottingham
Knoll Pharmaceuticals Nottingham
rat
Wistar
other: oral intubation
13 weeks
Sex: male/female
date: 18FEB2000
5. Toxicity
Substance ID: 15687271
______________________________________________________________________________
Source:
Species:
Strain:
Route of admin.:
Exposure period:
Frequency of
treatment:
Post. obs.
period:
Doses:
Control Group:
NOAEL:
Method:
Year:
Test substance:
Remark:
Result:
Source:
rat
Wistar
other: oral intubation
6 months
Sex: male/female
daily
23/44
date: 18FEB2000
5. Toxicity
Substance ID: 15687271
______________________________________________________________________________
Species:
Strain:
Route of admin.:
Exposure period:
Frequency of
treatment:
Post. obs.
period:
Doses:
Control Group:
Method:
Year:
Test substance:
Remark:
Result:
Source:
Species:
Strain:
Route of admin.:
Exposure period:
Frequency of
treatment:
Post. obs.
period:
Doses:
Control Group:
NOAEL:
Method:
Year:
Test substance:
Remark:
Result:
rat
Wistar
other: oral intubation
28 days
Sex: male
daily
Non reported
25, 50 and 100 mg/kg/day (5 male rats per dose level)
yes
other: see RM
GLP: no data
other TS: ibuprofen in 10% acacia
Method this was a preliminary test only.
Groups of 5 male rats were given 0, 25, 50 and 100
mg/kg/day ibuprofen in 10% acacia for 28 days. The rats
were killed and examined for gross damage. Histopathology
tests were not carried out.
Study conducted prior to GLP requirements
No DEATHS were observed in any of the groups and the
WEIGHT GAINS of the dosed groups were similar to those of
the controls.
At autopsy NO GROSS ABNORMALITIES were observed in any of
the animals.
Boots Chemicals, The Boots Company PLC Nottingham
Knoll Pharmaceuticals Nottingham
mouse
other
oral feed
13 weeks
Sex: male/female
daily
Source:
24/44
date: 18FEB2000
5. Toxicity
Substance ID: 15687271
______________________________________________________________________________
Species:
Strain:
Route of admin.:
Exposure period:
Frequency of
treatment:
Post. obs.
period:
Doses:
Control Group:
NOAEL:
Method:
Year:
Test substance:
Remark:
Result:
Source:
Species:
Strain:
Route of admin.:
Exposure period:
Frequency of
treatment:
Post. obs.
period:
Doses:
Control Group:
NOAEL:
Method:
Year:
Test substance:
Remark:
Result:
Source:
cat
no data
other: see RM
30days
Sex: no data
daily
Sex: male/female
Daily
25/44
date: 18FEB2000
5. Toxicity
Substance ID: 15687271
______________________________________________________________________________
Species:
Strain:
Route of admin.:
Exposure period:
Frequency of
treatment:
Post. obs.
period:
Doses:
Control Group:
NOAEL:
Method:
Year:
Test substance:
Remark:
Result:
Source:
Species:
Strain:
Route of admin.:
Exposure period:
Frequency of
treatment:
Post. obs.
period:
Doses:
Control Group:
Method:
Year:
Test substance:
Remark:
Result:
Source:
dog
Beagle
other: see RM
26 weeks
Sex: male/female
Daily
Sex: male
daily
none
4 mg/kg/day for 2 weeks, then 4 mg/kg twice daily for a
further 13 weeks.
no data specified
other: 3 dogs treated as above , the drug being administered
in gelatin capsules. Faeces regularly tested for occult blood,
blood and urine analyses carried out and histological
examination of various tissues after death
GLP: no data
other TS: ibuprofen in gelatin capsules
Study conducted prior to GLP requirements
With the dose of 4 mg/kg/day for 2 weeks there was NO SIGN
of GASTRIC DAMAGE.After increasing the dose to 4 mg/kg
twice daily OCCASIONAL FAECAL BLOOD LOSS was observed and
one dog developed PELVIC PERITONITIS.
Boots Chemicals, The Boots Company PLC Nottingham
Knoll Pharmaceuticals Nottingham
26/44
date: 18FEB2000
5. Toxicity
Substance ID: 15687271
______________________________________________________________________________
Species:
Strain:
Route of admin.:
Exposure period:
Frequency of
treatment:
Post. obs.
period:
Doses:
Control Group:
Method:
Year:
Test substance:
Remark:
Result:
Source:
Species:
Strain:
Route of admin.:
Exposure period:
Frequency of
treatment:
Post. obs.
period:
Doses:
Control Group:
NOAEL:
LOAEL:
Method:
Year:
Test substance:
Remark:
primate
Sex: male/female
other: baboon
other: ibuprofen in gelatin capsules given orally
30 days
Twice daily
date: 18FEB2000
5. Toxicity
Substance ID: 15687271
______________________________________________________________________________
Result:
Source:
28/44
date: 18FEB2000
5. Toxicity
Substance ID: 15687271
______________________________________________________________________________
Species:
Strain:
Route of admin.:
Exposure period:
Frequency of
treatment:
Post. obs.
period:
Doses:
Control Group:
Method:
Year:
Test substance:
Remark:
Result:
Source:
primate
other: baboon
oral unspecified
37 days
Sex: male/female
Twice daily
None recorded
16, 40 and 100 mg/kg/day (2 baboons per dose level, one male
and one female)
other: given lactose only
other
GLP: no data
other TS: ibuprofen in gelatin capsules
Method
Groups of one male and one female baboons were given twice
daily (at 10.00 and 16.00 hours) doses of ibuprofen in
gelatin capsules. Total doses per day were 16, 40 and 100
mg/kg.The control group, one male and one female received
lactose only.
Study conducted prior to GLP requirements
No OVERT REACTIONS to treatment were observed.
HAEMATOLOGY, BLOOD BIOCHEMISTRY, URINE ANALYSIS and FAECAL
BLOOD LOSS were not adversely affected by treatment.
At 100 mg/kg/day SUPERFICIAL EROSIONS in the GASTRIC
ANTRUM and the UPPER DUODENUM were observed.
Boots Chemicals, The Boots Company PLC Nottingham
Knoll Pharmaceuticals Nottingham
Ames test
Salmonella typhimurium strains TA98, TA100, TA1535, TA1537 and
TA1538
1, 10, 100, 500, 750 and 1000 ug per plate
with and without
negative
other: see RM
GLP: no data
no data
Method similar to OECD 471, although there appears to be
no replication of the test.
Boots Chemicals, The Boots Company PLC Nottingham
Knoll Pharmaceuticals Nottingham
(13)
29/44
date: 18FEB2000
5. Toxicity
Substance ID: 15687271
______________________________________________________________________________
Result:
Method:
Year:
Test substance:
Remark:
Result:
Source:
Cytogenetic assay
human
Sex: no data
no data
unspecified
Not specified
Daily dose of 0.8 to 1.2 g in adults, and 0.2 to 0.6 g in
children, overall course doses of 5 to 32.4 and 5.6 to 16.8 g
respectively
other: see RM
GLP: no data
no data
Method
11 adults and 10 children receiving antirheumatic therapy
were given daily doses of Brufen. Chromosome sets in the
lymphoid cells of peripheral blood were analysed
using the methodology of Hungerford, D.A. Stain
Technology 40, 333 (1965)
Results
The use of Brufen in both adults and children resulted in
no significant increases in the numbers of chromosomal
aberrations.
Boots Chemicals, The Boots Company PLC Nottingham
Knoll Pharmaceuticals Nottingham
(14)
Type:
Species:
Strain:
Route of admin.:
Exposure period:
Doses:
Result:
Method:
Year:
Test substance:
Remark:
Result:
Source:
Sex: male/female
other: see RM
GLP: no data
other TS: BrufenR
Method
4 male and 3 female, non smoking patients aged 34 to 61,
all with degenerative rheumatic diseases received 1200
mg/day BrufenR. There was a control group of 34 females,
aged 22 to 30, who were healthy, non smoking and
untreated.All investigations were carried out in two
separate tests. Sister chromatid exchange rates were
carried out with reference to the methods of Perry, P.
and Wolfe, S. (1974), New Giemsa Method for Differential
Staining of Sister Chromatids, Nature (London) 251,
156158.
No significant alteration in the Sister Chromatid Exchange
Rates was observed in lymphocytes under in vivo conditions
at this dosage over a 2 week period.
Boots Chemicals, The Boots Company PLC Nottingham
Knoll Pharmaceuticals Nottingham
(15)
30/44
date: 18FEB2000
5. Toxicity
Substance ID: 15687271
______________________________________________________________________________
5.7 Carcinogenicity
Species:
Strain:
Route of admin.:
Exposure period:
Frequency of
treatment:
Post. obs.
period:
Doses:
Result:
Control Group:
Method:
Year:
Test substance:
Remark:
Result:
Source:
Species:
Strain:
Route of admin.:
Exposure period:
Frequency of
treatment:
Post. obs.
period:
Doses:
Result:
Control Group:
Method:
Year:
Test substance:
Remark:
rat
other: AshWistar
oral feed
2 years
Sex: male/female
daily
20, 60 and 120 mg/kg (80 animals per dose level, 40 male and
40 female. Control group same number of animals and sex
distribution)
yes, concurrent no treatment
other: in house test
GLP: no data
no data
Study conducted prior to GLP requirements
This was a combined carcinogenicity and chronic toxicity
study and the data are therefore also relevant to section
5.4.
The only specific pathological effect observed in treated
animals was an increased incidence of RENAL PAPILLARY
LESIONS, i.e.NECROBIOSIS in rats of both sexes given 60
and 120 mg/kg daily and PAPILLARY NECROSIS in one rat
given 60 mg/kg daily and in five rats given 120 mg/kg
daily.There was a variable degree of GASTROINTESTINAL
DAMAGE that was more in evidence in the high dose group.
Distribution, type and time of appearance of tumours in
treated and control animals were similar, and there was no
significant difference in the incidence of animals bearing
tumours whether malignant or of all types.
It is concluded that ibuprofen was NOT CARCINOGENIC in the
AshWistar rat.
Boots Chemicals, The Boots Company PLC Nottingham
Knoll Pharmaceuticals Nottingham
rat
Wistar
oral feed
2 years
Sex: male/female
daily
None reported
180 mg/kg/day for the first 55 weeks, then 60 mg/kg/day
thereafter. 30 male and 30 female rats treated.
yes, concurrent no treatment
other: in house test
GLP: no data
no data
Study conducted prior to GLP requirements
This was a combined carcinogenicity and chronic toxicity
study and the data are therefore also relevant to section
5.4.
31/44
date: 18FEB2000
5. Toxicity
Substance ID: 15687271
______________________________________________________________________________
Result:
Source:
Species:
Strain:
Route of admin.:
Exposure period:
Frequency of
treatment:
Post. obs.
period:
Doses:
Result:
Control Group:
Method:
Year:
Test substance:
Remark:
Result:
Source:
Sex: male/female
daily
300 mg/kg daily for first 43 weeks, then 100mg/kg daily for
the remainder of experiment. 100 animals per dose level (50
male and 50 female). Same number of animals and sex
distribution in control group.
yes, concurrent no treatment
other: in house test
GLP: no data
no data
Strain of mouse was Schofield
Study conducted prior to GLP requirements
This was a combined carcinogenicity and chronic toxicity
study and the data are therefore also relevant to section
5.4.
In treated mice GROWTH was DEPRESSED but FOOD CONSUMPTION
was NOT ADVERSELY AFFECTED. The only specific pathological
effect observed was GASTROINTESTINAL DAMAGE, the males
appearing more susceptible than the females before
adjustment in dose level. A VARIETY of TUMOURS developed
which were similar in disribution pattern, incidence and
time of appearance to that occurring in undosed control
mice, with one exception. MAMMARY TUMOURS were less common
among the mice on ibuprofen.
It is concluded that ibuprofen is NOT CARCINOGENIC in the
mouse.
Boots Chemicals, The Boots Company PLC Nottingham
Knoll Pharmaceuticals Nottingham
32/44
date: 18FEB2000
5. Toxicity
Substance ID: 15687271
______________________________________________________________________________
Frequency of
treatment:
once daily by oral intubation
Premating Exposure Period
male:
at least 63 days
female:
14 days
Duration of test:
Doses:
120 or 20 mg/kg once daily, 12 male and 24 female rats per
dose level
Control Group:
yes, concurrent vehicle
Method:
other: see RM
Year:
GLP: no data
Test substance:
no data
Remark:
Method
Using the protocol recommended by the FDA
Groups of 12 male and 24 female BootsWistar rats were
33/44
date: 18FEB2000
5. Toxicity
Substance ID: 15687271
______________________________________________________________________________
Result:
Source:
Type:
other: general effect on reproduction
Species:
rat
Sex: female
Strain:
no data
Route of admin.: oral unspecified
Exposure Period: from day 6 of pregnancy
Frequency of
treatment:
daily
Premating Exposure Period
male:
none
female:
none
Duration of test: see RM
Doses:
5, 20 and 100 mg/kg/day (40 rats per dose level)
Control Group:
yes
Method:
other: see RM
Year:
GLP: no data
Test substance:
no data
Remark:
Method
Groups of 40 rats were dosed with 5, 20 and 100 mg/kg/day
ibuprofen from day 6 of pregnancy. 20 rats per dose level
were killed at day 19 of pregnanacy, the remainder
continuing to term. The control group consisted of 80
animals.
Study conducted prior to GLP requirements
This was a combined reproductive and teratogenic study and
the results are therfore also relevant to section 5.9.
Result:
LITTER SIZE, FOETAL WEIGHT and FOETAL VIABILITY were not
34/44
date: 18FEB2000
5. Toxicity
Substance ID: 15687271
______________________________________________________________________________
Source:
affected.
NO MALFORMATIONS or CONSTITUTIONAL ABNORMALITIES occurred
in either the young or the foetuses.
It was concluded that ibuprofen has NO EXPERIMENTAL
TERATOGENIC ACTIVITY.
Boots Chemicals, The Boots Company PLC Nottingham
Knoll Pharmaceuticals Nottingham
Type:
other: general effect on reproduction
Species:
mouse
Sex: female
Strain:
no data
Route of admin.: oral unspecified
Exposure Period: from day 6 of pregnancy
Frequency of
treatment:
daily
Premating Exposure Period
male:
none
female:
none
Duration of test: see RM
Doses:
5, 20 and 100 mg/kg/day (50 mice per dose level)
Control Group:
yes
Method:
other: see RM
Year:
GLP: no data
Test substance:
no data
Remark:
Method
Groups of 50 mice were treated with 5, 20 and 100
mg/kg/day ibuprofen from the 6th day of pregnancy. 20 mice
from each group were killed at day 17, and the remainder
went to term.The control group consisted of 150 mice.
Study conducted prior to GLP requirements
This was a combined reproductive and teratogenic study and
therefore the results are also relevant to section 5.9.
Result:
LITTER SIZE, FOETAL WEIGHT and FOETAL VIABILITY were not
affected.
No MALFORMATIONS or CONSTITUTIONAL ABNORMALITIES occurred
in either the YOUNG or the FOETUSES.
It was concluded that ibuprofen has NO EXPERIMENTAL
TERATOGENIC ACTIVITY.
Source:
Boots Chemicals, The Boots Company PLC Nottingham
Knoll Pharmaceuticals Nottingham
35/44
date: 18FEB2000
5. Toxicity
Substance ID: 15687271
______________________________________________________________________________
Type:
other: general effect on reproduction
Species:
rabbit
Sex: female
Strain:
no data
Route of admin.: oral unspecified
Exposure Period:
Frequency of
treatment:
from day 6 of pregnanacy
Premating Exposure Period
male:
none
female:
none
Duration of test: see RM
Doses:
5, 15 and 50 mg/kg/day ( 30 rabbits per dose level)
Control Group:
yes
Method:
other: see RM
Year:
GLP: no data
Test substance:
no data
Remark:
Method
Groups of 30 rabbits were dosed with 5, 15 and 50
mg/kg/day ibuprofen from day 6 of pregnancy. 12 rabbits
at the lowest dose and 10 at the two highest doses were
killed at day 29 of pregnancy. The control group contained
60 animals.
Study conducted prior to GLP requirements
This was a combined reproductive and teratogenic study and
the data are therefore also relevant to section 5.9.
Result:
LITTER SIZE, FOETAL WEIGHT and FOETAL VIABILITY were not
affected.
NO MALFORMATIONS or CONSTITUTIONAL ABNORMALITIES occurred
in either the young or the foetuses.
It was concluded that ibuprofen has NO EXPERIMENTAL
TERATOGENIC ACTIVITY.
Source:
Boots Chemicals, The Boots Company PLC Nottingham
Knoll Pharmaceuticals Nottingham
36/44
date: 18FEB2000
5. Toxicity
Substance ID: 15687271
______________________________________________________________________________
rabbit
Sex: female
New Zealand white
gavage
days 1 to 29 of pregnancy, where day 0 was the day of mating
Daily
females killed on day 30 of pregnancy (day 0 was the day of
mating) and uterine contents examined
Doses:
60, 20 and 7.5 mg/kg/day (17, 19 and 22 animals per group
respectively). Control group contained 23 animals
Control Group:
yes, concurrent vehicle
NOAEL Maternalt.: < 7.5 mg/kg bw
NOAEL Teratogen.: > 60 mg/kg bw
Method:
other
Year:
GLP: no data
Test substance:
other TS: aqueous solution of the sodium salt of ibuprofen
Remark:
Method
Newly mated female rabbits were given ibuprofen in doses
of 60, 20 and 7.5 mg/kg/day from day 1 to 29 of
pregnancy.Control females received 1 ml/kg daily of
water.All females were killed on day 30 of pregnancy and
their uterine contents examined.
Study conducted prior to GLP requirements
This was a combined reproductive and teratogenic study and
the data are therefore also relevant to section 5.8.
Result:
LESS GROWTH than controls plus STOMACH ULCERS observed in
females given 60 mg/kg/day. A few also had PNEUMONIA and
a mild degree of FOCAL HEPATITIS.
Females given 20 mg/kg/day were similarily though less
affected.
Females given 7.5 mg/kg/day GREW NORMALLY, but had some
GASTRIC ULCERS or EROSIONS
Minimal GASTRIC DAMAGE was observed in 2/23 controls
PREMATURE BIRTHS on days 26 and 28 of pregnancy observed
(NORMAL YOUNG) in 2/17 females given 60 mg/kg/day
In females given 60 mg/kg/day there was a REDUCTION IN
THE NUMBER OF LIVE FOETUSES per litter plus a
corresponding REDUCTION IN THE RATIO OF IMPLANTS TO
CORPORA LUTEA
In females given 20 and 7.5 mg/kg/day LITTER SIZE was
UNAFFECTED
There was no significant differences between the groups
in the numbers of dead and resorbed foetuses
Average FOETAL WEIGHT normal in all groups
CONGENITAL MALFORMATIONS of various kinds occurred in the
foetuses of treated and control animals.
Source:
37/44
date: 18FEB2000
5. Toxicity
Substance ID: 15687271
______________________________________________________________________________
Species:
Strain:
Route of admin.:
Exposure period:
Frequency of
treatment:
Duration of test:
Doses:
Control Group:
Method:
Year:
Test substance:
Remark:
Result:
rabbit
Sex: female
New Zealand white
gavage
days 1 to 28 of gestation where day 0 was the day of mating
daily
females killed on day 29 of pregnancy (day o was day of
mating) , litter values determined and foetuses examined for
structural abnormalities
60, 20 and 7.5 mg/kg/day (21 animals per level)
yes
other
GLP: no data
other TS: aqueous solution of ibuprofen
Method
Animals killed on day 29, litter values determined and
foetuses subsequently examined for structural
abnormalities of the skeleton and viscera.
Study conducted prior to GLP requirements
This was a combined reproductive and teratogenic study and
the data are therefore also relevant to section 5.8.
Treatment did not appear to adversely affect the
following:
1)Parent animals body weight change, pregnany rate and
macroscopic changes.
2)Litter values as assessed by number of implantations,
viable young, pre and post implantation loss, litter and
mean foetal weights.
3)Embryonic and foetal development incidences of major
malformations, minor visceral or skeletal anomalies and
skeletal variance.3 malformations of the same type
(umbilical hernia) at 60 mg/kg/day was considered likely to
be a coincidental event, albeit rare.
Source:
38/44
date: 18FEB2000
5. Toxicity
Substance ID: 15687271
______________________________________________________________________________
Species:
Strain:
Route of admin.:
Exposure period:
rat
Sex: female
Wistar
other: oral intubation
days 1 to 20 where presence of spermatozoa in vaginal smear
was taken as first day of pregnancy
Frequency of
treatment:
daily
Duration of test: uterine contents examined on day 21 of pregnancy (day 1 was
first day of pregnancy)
Doses:
180, 60, 20 and 7.5 mg/kg/day (4, 15, 13 and 11 animals
respectively per dose level). Control group contained 11
animals
Control Group:
yes, concurrent vehicle
NOAEL Maternalt.: = 7.5 mg/kg bw
NOAEL Teratogen.: > 180 mg/kg bw
Method:
other
Year:
GLP: no data
Test substance:
other TS: aqueous solution of the sodium salt of ibuprofen
Remark:
Method
Newly mated female rats were given ibuprofen in doses of
180, 60, 20 and 7.5 mg/kg/day from day 1 to day 20 of
pregnancy. Control females received 10 ml/kg of water
daily. The uterine contents were examined on day 21 of
pregnancy and the foetuses examined for external,
visceral and skeletal abnormalities.
Study conducted prior to GLP requirements
This was a combined reproductive and teratogenic study and
the data are therefore also relevant to section 5.8.
Result:
Females receiving 180, 60 or 20 mg/kg of ibuprofen on
days 1 to 20 of pregnancy were found to have
GASTROINTESTINAL LESIONS graded in severity according to
dose.
NO LESIONS observed in animals on 7.5 mg/kg/day or in the
controls.
Females on 180 mg/kg/day had a DIMINISHED RATE OF GROWTH.
LITTER SIZE NORMAL, FOETAL WEIGHT and SURVIVAL RATE NORMAL
in all groups.
It is concluded that ibuprofen is NOT TERATOGENIC in the
rat.
Source:
Boots Chemicals, The Boots Company PLC Nottingham
Knoll Pharmaceuticals Nottingham
(16)
39/44
date: 18FEB2000
5. Toxicity
Substance ID: 15687271
______________________________________________________________________________
Species:
Strain:
Route of admin.:
Exposure period:
rat
Sex: female
Wistar
other: oral intubation
days 1 to parturition, where presence of spermatozoa in
vaginal smear was taken as first day of pregnancy.
Frequency of
treatment:
daily
Duration of test: mothers and young killed when young were 21 days old.
Doses:
20 and 7.5 mg/kg/day (10 and 6 animals per dose level
respectively). Control group contained 15 animals.
Control Group:
yes
NOAEL Maternalt.: = 7.5 mg/kg bw
NOAEL Teratogen.: > 20 mg/kg bw
Method:
other
Year:
GLP: no data
Test substance:
no data
Remark:
Method
Newly mated female rats were given ibuprofen in doses of
0, 7.5 and 20 mg/kg/day from day 1 of pregnancy to
parturition. The rats were allowed to deliver and rear
their young normally until the young were 21 days old
when both mothers and young were killed and examined.
Study conducted prior to GLP requirements
This was a combined reproductive and teratogenic study and
the data are therefore also relevant to section 5.8.
Result:
Rats given 20 mg/kg/day GAINED LESS WEIGHT than the
controls during pregnancy.
All groups had UNEVENTFUL PREGNANCIES and the young were
DELIVERED WITHOUT DIFFICULTY.
In all groups there was no significant effect on the
NUMBER OF LIVE YOUNG PER LITTER, VIABILITY INDEX and
WEANING WEIGHT.
Source:
Source:
adsorption
Ibuprofen administered orally was rapidly absorbed in
rats, rabbits and dogs. Absorption in rats was shown to
occur mainly from the intestine and to a lesser, though
significant, extent from the stomach.Four metabolites of
ibuprofen were detected in rabbit plasma, 3 of these also
in rat plasma, but none in dog plasma. Distribution
studies with ibuprofen14C revealed that repreated oral
dosing of rats led to some accumulation of radioactivity
in the adrenals, ovaries, thyroid, skin and fat, without
structure or function being affected. Dogs, however had
high levels only in bile.
Boots Chemicals, The Boots Company PLC Nottingham
Knoll Pharmaceuticals Nottingham
(11)
40/44
date: 18FEB2000
5. Toxicity
Substance ID: 15687271
______________________________________________________________________________
Type:
Remark:
Source:
Distribution
See information under absorption (page 1)
Boots Chemicals, The Boots Company PLC Nottingham
Knoll Pharmaceuticals Nottingham
Type:
Remark:
Source:
Metabolism
See information under absorption (page 1)
Boots Chemicals, The Boots Company PLC Nottingham
Knoll Pharmaceuticals Nottingham
Source:
41/44
date: 18FEB2000
6. References
Substance ID: 15687271
______________________________________________________________________________
42/44
date: 18FEB2000
6. References
Substance ID: 15687271
______________________________________________________________________________
43/44
date: 18FEB2000
7. Risk Assessment
Substance ID: 15687271
______________________________________________________________________________
44/44