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The Journal of Emergency Medicine, Vol. 32, No. 1, pp.

63– 69, 2007


Copyright © 2007 Elsevier Inc.
Printed in the USA. All rights reserved
0736-4679/07 $–see front matter

doi:10.1016/j.jemermed.2006.08.009

Selected Topics:
Toxicology

ARE ONE OR TWO DANGEROUS? METHYL SALICYLATE EXPOSURE


IN TODDLERS
Jonathan E. Davis, MD

Department of Emergency Medicine, Georgetown University Hospital and Washington Hospital Center, Washington, DC
Reprint Address: Jeffrey N. Love, MD, Department of Emergency Medicine, Georgetown University Hospital, 3800 Reservoir Road,
N.W., Washington, DC 20007

e Abstract—Serious toxicity can result from exposure to e Keywords—methyl salicylate; oil of wintergreen; pedi-
small amounts of methyl salicylate. Methyl salicylate is atrics; toxicity; poisoning
widely available as a component in many over-the-counter
brands of creams, ointments, lotions, liniments and medi-
cated oils intended for topical application to relieve mus- INTRODUCTION
culoskeletal aches and pains. Among the most potent forms
of methyl salicylate is oil of wintergreen (98% methyl sa- Aspirin and other salicylates have a long history of use
licylate). Other products with varying concentrations of
throughout the world as analgesics, antipyretics, anti-
methyl salicylate are ubiquitous throughout many parts of
the world, including a number of products marketed as
inflammatories, and inhibitors of platelet aggregation.
Asian herbal remedies. The toxic potential of all of these Their potential for serious, even fatal, toxicity has been
formulations is often underestimated by health care pro- appreciated for centuries. As a result of observed toxic-
viders and the general public. A comprehensive review of ity, the United States Food and Drug Administration
the existing medical literature on methyl salicylate poison- (FDA) mandated nearly four decades ago that aspirin
ing was performed, and data compiled over the past two tablets made especially for pediatric use be produced
decades by the American Association of Poison Control only in 81 mg strength, that retail packages contain no
Centers (AAPCC) was examined. Methyl salicylate contin- more than 36 tablets per bottle, and that tablets stronger
ues to be a relatively common source of pediatric exposures. than 81 mg be free of any sweeteners or flavorings (1). In
Persistent reports of life-threatening and fatal toxicity were addition, the Poison Prevention and Packaging Act of 1970
found. In children less than 6 years of age, a teaspoon
stipulates that the vast majority of aspirin-containing prod-
(5 mL) or less of oil of wintergreen has been implicated
in several well-documented deaths. More needs to be
ucts intended for oral use must be packaged in a child-
done to educate both health care providers and the gen- resistant fashion (2). Although these and similar mea-
eral public regarding the dangers of these widely avail- sures have undoubtedly contributed to the dramatic
able formulations. © 2007 Elsevier Inc. reduction in the incidence of death from the ingestion of
drugs by children in the past half-century, salicylates are
Series Editors: Jeffrey N. Love, MD, The Georgetown Uni- among the many poisons that continue to result in child-
versity Emergency Department, Washington, DC; Wendy hood morbidity and mortality (3).
Klein-Schwartz, PHARMD, MPH, The Maryland Poison Center, Non-aspirin salicylates, such as methyl salicylate, are
Baltimore, MD; Liesl Curtis, MD, The Georgetown University found in many over-the-counter brands of creams, oint-
Emergency Department, Washington, DC. ments, lotions, liniments and medicated oils intended for

Selected Topics: Toxicology is coordinated by Kenneth Kulig, MD, of Denver, Colorado


RECEIVED: 22 December 2004; FINAL SUBMISSION RECEIVED: 31 August 2005;
ACCEPTED: 11 April 2006
63
64 J. E. Davis

topical application to relieve musculoskeletal aches and aches, pains or the common cold, contain potentially
pains. Owing to its potential for serious toxicity, al- dangerous concentrations of methyl salicylate, the most
though paling in comparison to the restrictions imposed potent of which is Koong Yick Hung Far Oil (KYHFO,
on aspirin, FDA regulations mandate that the label of any or Red Flower Oil), which contains about 67% methyl
drug containing more than 5% methyl salicylate bear a salicylate (Table 1) (7–10). Use of these methyl-
conspicuous warning against its use other than as di- salicylate-containing formulations is widespread, and
rected (i.e., for topical use only), and a warning to keep many patients and parents erroneously assume that they
the product safely out of the reach of children (1). must be safe, simply by virtue of their ubiquitous over-
Among the most potentially devastating forms of the-counter availability (11). As a result, patients may
methyl salicylate is oil of wintergreen, which is approx- not even think to report a history of their use, or think to
imately 98% methyl salicylate. It is a highly potent report them as a potential source of home pediatric
liquid, as just 1 mL of oil of wintergreen is equivalent to ingestion. In Hong Kong, medicated oils containing
1400 mg of aspirin (4). In other terms, one teaspoon methyl salicylate account for nearly 50% of acute salic-
(5 mL) of oil of wintergreen contains the equivalent of ylate poisonings treated at a major teaching hospital
approximately 7000 mg of aspirin. Given that a routine (8,10). In Africa, both topical and orally administered
adult tablet contains 325 mg of aspirin, a mere teaspoon methyl salicylate have been used as home remedies for
of this potent toxin is toxicologically similar to ingesting the treatment of acute respiratory infections in children
nearly 22 adult aspirin tablets (5). To place this in con- (12). Salicylate poisoning has also been reported after
text, the potentially acute toxic ingested dose of aspirin is ingestion of oil of wintergreen sold as a flavoring for
150 mg/kg, with serious toxicity possible in the 300 to homemade candy (13). In addition, salicylate toxicity has
500 mg/kg range (or roughly one adult aspirin tablet per been observed through percutaneous absorption after use
kilogram) (6). Thus, a teaspoon of oil of wintergreen of salicylate-containing topical preparations (14 –17).
(equivalent to 7000 mg of aspirin) can be inferred to The widespread over-the-counter availability,
possibly result in serious toxicity in children weighing pleasant odor, and palatability of methyl salicylate
less than about 23 kg (7000 mg divided by 23 kg equals often lead to a gross underestimation of its potential
for serious, even fatal, toxicity. The purpose of this
approximately 300 mg/kg), the weight of an average
article is to evaluate the existing medical literature as
6-year-old.
well as data from the American Association of Poison
Numerous commercially available methyl-salicylate-
Control Centers Toxic Exposure Surveillance System
containing compounds are available on the market (Table
(AAPCC-TESS) to determine the current risk of tox-
1). In addition, many readily available Asian herbal reme-
icity when children under 6 years of age are exposed
dies, sold as topical self-treatments for musculoskeletal
to small amounts of methyl salicylate.

Table 1. Examples of Some Non-prescription Methyl-


Salicylate-Containing Medications and Remedies CLINICAL MANIFESTATIONS

Product % Methyl Salicylate After oral ingestion, methyl salicylate is readily metab-
Oil of wintergreen 98 olized to salicylic acid. As such, the clinical features of
Topical creams* methyl salicylate poisoning are identical to those ob-
Icy Hot® Extra Strength Cream 30 served after poisoning with other salicylates (18). Salic-
Bayer® Muscle Joint Pain Relief Cream 30
Muscle Rub® Extra Strength Cream 30 ylate toxicity is dependent upon the ingested formulation
Ben-Gay® Extra Strength Cream 30 and dosage, patient age, and the acuity of ingestion, with
Tiger Balm® Liniment 28 those at the extremes of age and with chronic intoxica-
Ben-Gay® Original Cream 18.3
Pain Bust-R II® Ointment 17 tions at greatest risk.
Thera-Gesic® Cream 15 The pathophysiology of salicylate toxicity relates both
Banalg® Hospital Strength Lotion 4.9 to the direct stimulation of the central nervous system
Asian herbal remedies†
Hung Far Oil (Red Flower Oil) 67 (CNS) respiratory center, resulting in hyperventilation
Pak Far Oil (White Flower Medicine Oil) 40 and respiratory alkalosis, and the uncoupling of mito-
Tiger Oil 38 chondrial oxidative phosphorylation, resulting in an in-
Kwan Loong Medicated Oil 15
creased anion gap metabolic acidosis. These effects lead
* From information found online (www.americanrx.com; www. to the classic mixed acid-base disturbance characteristic
vitaminshoppe.com). of salicylate toxicity: a primary respiratory alkalosis and
† From (14): Chan TY. Potential dangers from topical prepara-
tions containing methyl salicylate. Hum Exp Toxicol 1996; a primary metabolic acidosis. In children, metabolic ac-
15:748. idosis with acidemia may predominate (19,20).
Methyl Salicylate 65

Effects of salicylate toxicity include nausea and vom- at any given point in time (31). That is to say that a
iting (by stimulation of the CNS chemoreceptor trigger patient’s serum salicylate concentration may be declin-
zone), fever (paradoxical effect of an antipyretic pro- ing, however, their clinical condition may continue to
duced by uncoupling of oxidative phosphorylation, with deteriorate due to the ongoing cascade of events at the
excessive heat generation resulting from a heightened cellular level in the target organs, despite falsely reas-
rate of anaerobic metabolism), dehydration and electro- suring blood laboratory results. Indeed, plasma salicylate
lyte disturbances (fluid losses from hyperpnea, emesis concentration is not the sole indicator of morbidity or
and renal wasting), tinnitus (vasoconstriction of the au- fatal outcome (32).
ditory microvasculature), hematologic disturbances (ef-
fects on platelets and, rarely, on hepatic synthetic func-
tion), and in severe cases, non-cardiogenic pulmonary TREATMENT
edema (increased permeability of pulmonary vasculature)
(21,22). The earliest manifestations of acute toxicity include The first priorities in the treatment of any poisoned
mild gastrointestinal (GI) symptoms, diaphoresis, fever and patient are fundamental, beginning with attention to a
tinnitus. As toxicity progresses, multisystem organ dysfunc- secure airway, maintenance of oxygenation, ventilation
tion, including seizures, coma, non-cardiogenic pulmonary and adequate perfusion of vital organs. Once these pri-
edema, and cardiovascular collapse may ensue. orities have been achieved, attention then focuses on the
Movement of salicylic acid into tissues is facilitated specific toxins involved. In the majority of poisoned
by the increased volume of distribution seen in overdose, patients, treatment is largely supportive in nature. How-
and with a pKa of 3.5, by the increased fraction of ever, certain toxins have specific antidotes and other treat-
non-ionized (lipophilic) drug yielded as progressive ment modalities that have been shown to reduce their harm-
acidemia ensues. This allows access to the crucial ful effects. Such is the case with salicylate toxicity, where
tissues of the brain (resulting in encephalopathy, sei- treatments such as gastrointestinal decontamination, hy-
zures and coma), lung (resulting in noncardiogenic pul- dration, urinary alkalinization, and hemodialysis have
monary edema) and heart (resulting in cardiovascular been successfully employed.
collapse) (23–25). The target of the lethal effects of Initial therapy for salicylate toxicity includes early GI
salicylates is most often the CNS. Patients who die as a decontamination with activated charcoal. Fluid resusci-
result of salicylate toxicity often die a brain death (26). In tation should be early and aggressive, ensuring adequate
addition, dysrhythmia resulting from hypokalemia (pri- tissue perfusion and urinary output. In addition, alkalin-
marily through vomiting and renal losses) and hypoxia ization by intravenous sodium bicarbonate administra-
resulting from pulmonary edema may also contribute to tion is advocated to correct acidemia, tempering the shift
mortality. of non-ionized salicylate into target tissues, and hasten-
Laboratory evaluation for salicylate toxicity, includ- ing urinary elimination by trapping ionized salicylate in
ing methyl salicylate, includes the qualitative ferric chlo- the proximal tubule. In fact, urine alkalinization is con-
ride test and the quantitative serum salicylate concentra- sidered the first line treatment for patients with moder-
tion (27). The advantages of the ferric chloride test ately severe salicylate poisoning who do not meet criteria
include the ability to perform it rapidly and at the bed- for extracorporeal elimination (33). Potassium supple-
side, potentially averting a needlestick in low-risk chil- mentation is also an important aspect of management, as
dren, especially where it is not clear that ingestion has patients may become severely depleted. Extracorporeal
even occurred. A positive result is indicated by a purple methods of elimination are indicated if a patient has very
or brown color change when adding a few drops of ferric high serum salicylate concentrations, exhibits progres-
chloride solution to urine. The disadvantages include sive clinical deterioration despite adequate hydration and
qualitative information only, and an appreciable false- alkalinization, or is otherwise unable to eliminate salicy-
positive rate (28). Overall, this test is rarely used these lates, as in the case of renal failure (34). Hemodialysis,
days, as serum quantitative tests are so rapidly available hemoperfusion, and peritoneal dialysis have been em-
and reliable. Quantitative serum salicylate concentrations ployed, with hemodialysis having the added advantage of
are obtained both on presentation as a baseline and at correcting acid-base and electrolyte disturbances in ad-
least every 2 h until clearly decreasing (29). Given a dition to clearing salicylate from plasma (35). Exchange
number of limitations, the Done nomogram is no longer transfusion also has been reported as a viable alternative
advocated to predict the severity of salicylate toxicity to hemodialysis in infants with severe salicylate toxicity,
(30). The clinical severity of single-dose acute salicylate given the challenges in obtaining suitable vascular access
ingestion correlates better with the highest overall serum in this population and the need for specialized dialysis
concentration attained during the patient’s course, as equipment and highly experienced personnel (36). Prep-
opposed to the measured serum salicylate concentration aration for hemodialysis may be initiated in the Emer-
66 J. E. Davis

gency Department in certain circumstances, including the late, however, is a relatively common pediatric exposure
presence of coma, seizures, pulmonary edema, severe acid- in its own right. The 2003 annual AAPCC-TESS data
base disturbances, or rapidly deteriorating clinical condition reports nearly 10,000 exposures to methyl salicylate, of
despite initiation of more conservative treatments. which the majority (77%) occurred in children under 6
years of age (41). These numbers have been relatively
stable over the past several years (40,42– 47). Likewise,
LITERATURE REVIEW children under the age of 6 years have made up the
majority of methyl salicylate exposures reported in the
Although it has been reported and referenced that mini- last two decades.
mal doses of oil of wintergreen can be fatal to a child, we A medical literature search found many case reports
reviewed the existing medical literature on this topic to and a few case series involving methyl salicylate intox-
see what evidence exists to support this widely purported ication, yet failed to reveal any clinical studies. Table 2
claim (37–39). Literature on methyl salicylate exposure summarizes the lowest doses of methyl salicylate that
was identified by a Medline search using the key words resulted in life-threatening toxicity (48 – 61). As avail-
“methyl salicylate” or “oil of wintergreen,” focusing on able treatment regimens have been refined with a grow-
articles pertinent to the pediatric population. Textbooks ing knowledge of the underlying mechanisms of toxicity
in Emergency Medicine, Toxicology, Pediatrics and in salicylate poisoning in general, we have focused on
other disciplines were also reviewed in search of perti- methyl salicylate cases reported in the past half-century.
nent publications. References from all of the articles and However, several cases from antiquity are included in
chapters were reviewed to extend the search. Further- addition to the more contemporary cases, as they are
more, data from the AAPCC-TESS yearly reports from illustrative of the potential dangers of methyl salicylate.
1983 to the present time were reviewed to identify epi- The seminal case series that defined methyl salicylate
demiologic information and current trends. as a poison was published in 1937 by Stevenson (48). Of
The available information on serious aspirin toxicity the 43 exposures tabulated in this case series, Stevenson
in children is more frequently encountered in the medical reported on 20 pediatric exposures (ages 1 month to 4
literature as compared with non-aspirin salicylates, ow- years), of which only 5 patients survived (75% fatality
ing to the comparatively increased incidence of aspirin rate). The lowest reported doses producing fatalities in
poisonings (40). As a result, many of the references to this series were 4 mL in two cases (17 months old and 2
the fatal effects of methyl salicylate are extrapolated years old) and 5 mL in two additional cases (1 month old
from a calculated “aspirin-equivalency.” Methyl salicy- and 2 years old). Also of note is that the smallest lethal

Table 2. Lowest Doses of Oil of Wintergreen (Methyl Salicylate) Found to Cause Life-Threatening Toxicity and Death in
Children: Summary of Notable Cases

Estimated Death (D)/


Source (reference) Age* Exposure† Treatment CNS Toxicity Recovery (R)

Stevenson (48) 17 M 4 Induced emesis Yes D


Stevenson (48) 2Y 4 Unspecified Yes D
Cann (49) 2.5 Y 5 Unspecified Yes D
Adams (50) 20 M 5 Exchange transfusion Yes R
Eimas (51) 22 M 5 i.v. Fluids Yes D
Stevenson (48) 1M 5 Home remedies Yes D
Stevenson (48) 2Y 5 GI decontamination Yes D
Litovitz (52) 2Y 10 Hemodialysis Yes D
Litovitz (53) 2Y 15 GI decontamination Yes D
Cann (49) 2.5 Y 15 Unspecified Yes D
Cann (49) 2Y 15 Unspecified Yes D
Martin (54) 2.5 Y 15 i.v. Fluids Yes D
Stevenson (48) 2Y 15 Blood transfusion Yes R
Done (55) 2Y 20 Exchange transfusion Yes R
Jacobziner (56) 18 M 22.5 Gastric lavage Yes D
Feldman (57) 20 M 30 Exchange transfusion Yes D
Kloss (58) 3Y 30 Peritoneal dialysis Yes R
Millar (59) 3Y 30 Exchange transfusion Yes R
Halle (60) 3.5 Y 60 Peritoneal dialysis Yes R
Diamond (61) 2Y 60 Exchange transfusion Yes R

* Age in months (M) or years (Y).


† Milliliters (mL) of oil of wintergreen (98% methyl salicylate).
Methyl Salicylate 67

dose reported among adults occurred in a 21-year-old significant toxicity resulting from percutaneous or trans-
man who died after consuming only 6 mL of oil of mucosal absorption after topical or intraoral application,
wintergreen, giving further credence to the lethality of respectively, of salicylate-containing compounds, but
this agent (62). The author concludes that because only 4 none specifically involving methyl salicylate in children
to 5 mL of methyl salicylate had been lethal in four (16,17,68,69). In 1959, Burt referenced a fatality pro-
toddlers, and only 6 mL lethal in an adult, the drug duced by a topically applied methyl salicylate product;
should be labeled “poisonous if used internally.” Another however, he failed to provide any specifics regarding the
pediatric fatality caused by ingestion of a minimal case, including the decedent’s age or the source of the
amount of methyl salicylate was reported by Eimas in information (70).
1938 (51). He reported on the clinical and post-mortem
findings observed in a 22-month-old boy who ingested
5 mL (one teaspoonful) of oil of wintergreen. EVALUATION RECOMMENDATIONS
Since the AAPCC started publishing its annual reports
in 1983, only five fatalities have been reported in chil- Over a half century of clinical experience suggests that
dren younger than 6 years as a result of methyl salicylate small doses of oil of wintergreen are toxic, especially in
poisoning (52,63– 66). For cases where specific ingested a child under 6 years of age. Several well-documented
doses of oil of wintergreen were included in the AAPCC cases suggest that doses of 5 to 15 mL (or less) may
data, the fatal doses were up to 10 mL in a 2-year-old, cause serious toxicity and even death. This, coupled with
and 15 mL in another 2-year-old. Although such fatali- the difficulty in accurately assessing the amount of liquid
ties are sparsely reported in the literature, methyl salic- that has been ingested by a toddler, supports the recom-
ylate toxicity seems to be an ongoing risk to the pediatric mendation that any child who ingests any amount of oil
patient given the number of annual exposures reported to of wintergreen should be immediately assessed by an
the AAPCC and the outcomes observed. For instance, a experienced pediatric provider skilled in acute care, with
published comparison of pediatric poisoning hazards input from a toxicologist or poison control specialist.
from examination of the AAPCC data during an 8-year This recommendation also holds true for liquid Asian
period from 1983–1990 revealed four deaths from methyl herbal preparations containing a high concentration of
salicylate, compared with only two deaths reported from methyl salicylate (Red Flower Oil, for example).
aspirin during the same period (67). However, the more frequently encountered situation
The cases in Table 2 all document serious toxicity involves ingestion of methyl salicylate in a cream, oint-
from doses of 2 ounces (60 mL) or less. These doses are ment, lotion or liniment formulation, which necessitates
largely based on parental estimates of volumes ingested. different recommendations. The consistency of these
At least some signs of serious CNS toxicity, including formulations makes ingestion of a large volume of the
some degree of alteration in level of consciousness with product difficult. This, combined with their relatively
or without seizures, were noted in all, and 13 children low methyl salicylate concentration, makes significant
died. On initial review of our data, it paradoxically seems toxicity unlikely. These patients should be managed by
as though the majority of patients who recovered from calculating an “aspirin equivalent ingested dose” by use
methyl salicylate intoxication ingested comparatively of the methyl salicylate conversion factor of 1.4, and
larger volumes of the liquid. However, on close exami- then applying the aspirin guidelines to determine the
nation it becomes apparent that the vast majority of those potential severity of the ingestion (71). For example, a
who survived were evaluated in more recent times (last 15-kg child who ingests 5 mL of 18.3% Ben-Gay® Orig-
half century), and were rescued with treatment modali- inal Cream: 18.3% is equivalent to 183 mg/mL, therefore, 5
ties that are now appreciated as effective, such as ex- mL ingested volume multiplied by 183 mg/mL results in
change transfusion, dialysis, or intravenous bicarbonate 915 mg of methyl salicylate ingested. With use of the
administration. Stevenson, on the other hand, reported a methyl salicylate conversion factor, 915 mg multiplied
2-year-old who in 1927 fully recovered after ingestion of by 1.4 is equivalent to 1281 mg of aspirin. The aspirin
15 mL of oil of wintergreen after treatment with blood equivalent dose of 1281 mg divided by the child’s weight
transfusions, among other modalities (48). of 15 kg yields a weight-based ingested dose of 85
The cases of life-threatening toxicity or death found mg/kg. Applying the guidelines used for aspirin inges-
on our review of the literature all involved oil of win- tion, 85 mg/kg falls well below 150 mg/kg, the poten-
tergreen or Asian herbal oils. To our knowledge, there tially toxic dose from acute aspirin ingestion (6).
are no modern reports of significant toxicity resulting Because patients who progressed to life-threatening
from the oral ingestion of methyl-salicylate-containing toxicity nearly uniformly experienced emesis within sev-
creams, ointments, lotions or liniments (such as Ben- eral minutes to a few hours of ingestion, followed by
Gay® and others; Table 1). There are several reports of signs of at least some degree of CNS toxicity (drowsi-
68 J. E. Davis

ness, lethargy, seizures), observation for clinical symp- 3. Shannon M. Ingestion of toxic substances in children. New Engl
J Med 2000;342:186 –91.
toms should occur for a minimum of several hours post 4. Johnson PN, Welch DW. Methyl salicylate/aspirin (salicylate)
ingestion. We recommend at least 6 h of observation in equivalence: who do you trust? Vet Hum Toxicol 1984;26:317– 8.
a facility fully equipped with advanced pediatric airway 5. Wolowich WR, Hadley CM, Kelley MT, Walson PD, Casavant
and critical care capabilities. Treatment should be initi- MJ. Plasma salicylate from methyl salicylate cream compared to
oil of wintergreen. J Toxicol Clin Toxicol 2003;41:355– 8.
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Emerg Med 1998;31:793– 4.
further decision-making always remains in the continual 8. Chan TY. Medicated oils and severe salicylate poisoning: quanti-
reassessment of a patient’s global clinical picture, with fying the risk based on methyl salicylate content and bottle size.
special attention to findings of CNS toxicity. On the Vet Hum Toxicol 1996;38:133– 4.
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other hand, patients who remain entirely asymptomatic
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Methyl Salicylate 69

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