RISK PROFILE

Methyl salicylate

CAS No.119 -36-8

Date of reporting 10.12.2012

Content of document

1. Identification of substance ...................................................................... p. 1

2. Uses and origin ................................................................................... p. 2
3. Regulation ................................................................................................ p. 4
4. Relevant toxicity studies ....................................................................... p. 4
5. Exposure estimates and critical NOAEL/NOEL .............................................. p. 9
6. Other sources of exposure than cosmetic products ................................. p. 11
7. Assessment ................................................................................................. p. 13
8. Conclusion ................................................................................................. p. 14
9. References ................................................................................................. p. 15
10. Annexes ................................................................................................. p. 18

1. Identification of substance
Chemical name (IUPAC): 2-Hydroxy-benzoic acid methyl ester

INCI Methyl salicylate

Synonyms Hydroxybenzoic acid, Oil of wintergreen (ca. 98% methyl salicylate)
CAS No. 119-36-8
EINECS No. 204-317-7
Molecular formula C8H8O3
Chemical structure

Molecular weight 152.15

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Contents (if relevant)
Physiochemical properties Appearance: colourless, yellowish or reddish oily liquid; characteristic
odour of wintergreen.
Boiling point (BP): 220 224 C
Melting point (MP): -8.6 C
LogKow: 2.55
Solubility: 0.74 g/l at 30C in water; also soluble in most common
organic solvents.
VP: The vapor pressure is 0.0343 mmHg at 25C

References: cited in Hansen et al., 2006; IUCLID, 2000)

2. Uses and origin

Uses Cosmetic products:

Functions according to

CosIng database:
- Denaturants, Fragrance (Methyl salicylate has the
characteristic odor of wintergreen, and is used in
perfumery).
Other:
- Easing and removing sore muscles and joints caused by
increased physical activity level (Hansen et al., 2006).
- Flavoring agent

Concentrations of Methyl salicylate being applied

Methyl salicylate is used in cosmetics as warming-up agent;

rubefacient in sport-massage products, at concentrations in the range
of 3 - 9% in the European (ES) market. It is used in perfumery as a
modifier in blossom fragrance and as a mild antiseptic in oral hygiene
products (Gerhartz, 1985, 2000); as a denaturant and flavouring
agent at concentrations in the range 0.0001% to 0.6% (25
formulations in the FDA voluntary file. CIR, 2003); as a flavouring
agent in toothpastes up till 1% (Storhagen et al., 2003). The prime
purpose of the sports cream/massage products is to alleviate certain
discomforts arising occasionally in connection with sports and
physical exercises. Although not claimed because this would have
placed these products under the medicinal products regulations, they
in fact remove aching in the muscles due to anti-inflammatory
properties. Saloons providing so-called aroma treatment (aroma-
therapy) also use wintergreen oil that contains methyl salicylate up till
1
98%. Wintergreen oil is an essential oil . According to their working
codex essential oils are blended with other base oils and the
concentrations are in the range 0.5 - 5%.

1
Essential is usually understood as something completely necessary or part of the basic nature of something;
e.g. is needed for life or health but not synthesized within the body, as an amino acid or vitamin that must be
consumed. Essential is also means containing, or having the properties of, a concentrated extract of a plant, drug,
food, etc.: an essential oil.

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 Frequency of use

The EWG Skin Deep [online] database lists 87 cosmetic products

containing methyl salicylate:
- pain relief (27 products)
- mouthwash (20 products)
- muscle/ joint soreness (17 products)
- wound treatment (7 products)
- anti-itch/ rash cream (7 products)

The German [Link] [online] database lists 724 products

containing Methyl salicylate.

Food

Flavouring agent: Methyl salicylate (MS) is used as a flavouring agent

in chewing gum, baked goods, syrups, candy, non-alcoholic
beverages and ice cream. Besides the compound occur naturally in a
series of vegetables and edible berries. According to JECFA the 95th
percentile 14-day average daily intake amounts to 0.09 mg/kg bw
(JECFA, 2002; Hall et al, 1999). In the age group 2 - 5 years the
estimate was 0.15 mg/kg bw. These were not worst-case intake
estimates.

JECFA has established an Acceptable Daily Intake (ADI) of 0.5 mg/kg

body weight.

Methyl salicylate has FDA-specified uses as indirect food additive

(CIR, 2003).

The Council of Europe publications Plants in Cosmetics Volume III

(2006) and Active ingredients in cosmetics: safety survey (2008)
present more details.

Medicinal products

Methyl salicylate has anti-inflammatory properties and is still used,

incorporated into liniments and ointments for joint and muscle pains
and for rheumatic conditions, but apart from this no plant extract with
salicylate is now available in western pharmacies. The French BIAM
database that shows an overview as to pharmaceutical products, lists
12 different methyl salicylate containing topical products meant to
help with muscle pain and that contain from 3% to 18% MS.

In the USA methyl salicylate has been present in OTC smoking

deterrent drugs, boil treatment, dandruff/ seborrhoea
dermatitis/psoriasis, fever blister and cold sore treatment, oral health
care and skin protectant-astringent drug products. However, currently
FDA has concluded that there are inadequate data to establish
general recognition of the safety and effectiveness of these
ingredients for the specified OTC uses.

Labelling: Any drug containing > 5% MS must bear a label that warns
that misdirected use may be dangerous and that the product should
be kept out of reach of children (CIR, 2003).

A FDA Advisory Review Panel (OTC products) has concluded that

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 methyl salicylate is safe for use up to a concentration of 0.4% in the
form of a mouthwash (US EPA, 1997 referring to an assessment
made by the FDA OTC panel 25 may 1982). Medicinal product or
cosmetics?

Other products

Origin Sources of natural origin:

Natural (exo /endo) Information is presented in the monograph on methyl salicylate in the
Synthetic Council of Europe publications Plants in Cosmetics Volume III
(2006) and Active ingredients in cosmetics: safety survey (2008).

Sources of synthetic origin:

Structurally, methyl salicylate is the methyl ester of salicylic acid,
produced e.g. from the condensation reaction of salicylic acid and
methanol.

1 ml of oil of wintergreen is equivalent to 1400 mg aspirin; i.e. one

teaspoon (5 ml) contains the equivalent of approx. 7000 mg of
aspirin. A routine adult aspirin tablet contains 325 mg aspirin.

3. Regulation

Norway Maximum allowed levels: skin cream (1%); mouth wash (0.05%).
Regulation to be lifted 11 July 2013
EU No regulation
Rest of the world Japanese regulation of methyl salicylate with a maximum limit of
2
0.1% in any cosmetics

4. Relevant toxicity studies

Absorption
Skin Human data from experiments conducted with methyl salicylate, indicate
GI tractus that the dermal bioavailability is in the range of 11.8 30.7%. For the
assessment of potential oral exposure to salicylates, bioavailability is
assumed to be 100% (Belsito et al., 2007).

Below is a shortened version of relevant toxicity studies contained within

monograph of methyl salicylate reported in the Council of Europe
publications Plants in Cosmetics Volume III (2006) and Active
ingredients in cosmetics: safety survey (2008).

Absorption (Skin penetration abilities):

The use of methyl salicylate as a topical medical product is subject to a

2
In Japan, methyl salicylate which conforms to the standards of the Japanese Standards of Cosmetic Ingredients
(JSCI) has precedent for use at a maximum concentration of 0.1% in all Comprehensive Licensing Standards of
Cosmetics (CLS) categories - except eyeliner preparations, in which it is not used. Methyl (and Ethylhexyl)
salicylates are restricted in that the total percentage of UV absorbers in a formulation shall not exceed 10%.

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 series of studies showing that the substance has a pronounced ability to
penetrate the skin upon dermal administration (Cross et al,. 1997;
Megwa et al., 1995; Morra et al., 1996; Yano, 1991; Pratzel et al., 1990;
Pratzel, 1987; Danon et al., 1986).

Part 2:
Humans:
Morra et al. (1996) carried out a study involving 12 healthy volunteers,
ages 21-44 years, who applied 5 g of an ointment containing 12.5%
methyl salicylate twice daily for 4 days. The recovery in the urine in the
first 24 h after application was 15.5%. When being used in sports
massage creams methyl salicylate is often applied together with a
vehicle like for example menthol or camphor - which enhances its skin
penetration ability (Yano et al., 1991). In humans approximately 12 to
20% of topically applied methyl salicylate is systemically absorbed within
10 hours of application (EMEA, 1999). CIR (2003) points out that the
available data describe the following percutaneous absorption patterns:
rate of penetration is proportional to concentration applied; absorption is
dependent on the vehicle (e.g., ethanol > water); absorption varies as a
function of pH; and absorption is greater through damaged skin
compared to normal skin.

An in vivo study indicated that l-menthol and dl-camphor enhances the

skin penetration of methyl salicylate and slows down the hydrolysis of it
markedly (Yano et al., 1991).

Aqueous chlorhexidine (Aq-C, 0.1% w/v) and alcoholic chlorhexidine (Al-

C, 0.5% w/v) have in Thoroughbred geldings shown to increase the
penetration of methyl salicylate and its analyte, salicylate. Compared with
control skin, significantly more methyl salicylate penetrated through skin
prepared with Al-C or Aq-C, and significantly more salicylate was
recovered in the receptor phase from skin prepared with Aq-C and Al-C
(Mills et Cross, 2006).

Distribution After absorption, salicylate is distributed throughout most body tissues

and most transcellular fluids, primarily by pH dependent passive
processes. Salicylate is actively transported by a low-capacity, saturable
system out of the CSF (cerebrospinal fluid?) across the choroid plexus.
The salicylate readily crosses the placental barrier. The plasma half-life
for salicylate is 2 to 3h in low doses and about 12h at usual anti-
inflammatory doses. The half-life of salicylate may be as long as 15 to 30
h at high therapeutic doses or when there is intoxication (Gilman et al.,
1990).
Metabolism Orally administered methyl salicylate is nearly completely hydrolysed to
salicylic acid/salicylate within 1 hour in rats and dogs. Salicylate levels in
plasma and brain reached about the same level as the one obtained
when administrating salicylic acid. In 6 healthy adults 21% of the intact
ester was found in plasma 90 min after oral exposure (Davidson C et al.,
1961).

For small doses 80% of the hepatic metabolism results from conjugation
with glycine to form salicyluric acid and with glucuronic acid to form
salicyl acyl and phenolic glucuronide. The two parallel pathways (glycine,
glucuronide conjugation) have limited capacity and saturate easily above
therapeutic doses (Ellenhorn et al., 1988).

The biotransformation of salicylates takes place in many tissues, but

particularly in the hepatic endoplasmic reticulum and mitochondria. The

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 three main metabolic products are salicyluric acid (the glycine
conjugate), the ether or phenolic glucuronide, and the ester or acyl
glucuronide. In addition, a small fraction is oxidized to gentisic acid (2,5-
dihydroxybenzoic acid) and to 2,3-dihydroxybenzoic and 2,3,5-
trihydroxybenzoic acids; gentisuric acid, the glycine conjugate of gentisic
acid, is also formed (Gilman et al., 1990).

Methyl salicylate was extensively metabolised to salicylic acid in the

dermal and sc tissues after topical application (Cross et al., 1997;
Pratzel, 1987).

Excretion Salicylates are excreted in the urine as free salicylic acid (10%),
salicyluric acid (75%), salicylic phenolic (10%) and acyl (5%)
glucuronides, and gentisic acid (less than 1%). However, excretion of
free salicylate is extremely variable and depends upon both the dose and
the urinary pH. In alkaline urine, more than 30% of the ingested drug
may be eliminated as free salicylate, whereas in acidic urine this may be
as low as 2% (Gilman, 1990).

Local toxic effects

Irritation Skin irritation:
Sensitivity Methyl salicylate has skin-irritating properties of the primary irritation type
(Arts et al., 1997). When applied at a concentration as low as 1%
(vehicle being 70% ethanol + emollient), it is a moderate irritant and may
elicit necrosis and intradermal and subcutaneous haemorrhage. When in
propylene glycol methyl salicylate produced no or little irritation up to 6%
(Yankell, 1972). When applied in a closed patch test at a concentration of
8% in petrolatum, it has been found to be non-irritant at 48 hours.
(Opdyke, 1978). Application of sweet birch oil - that consists almost
wholly of methyl salicylate undiluted to the skin of rabbits, mice and pig
show methyl salicylate to be an irritant. However, at a concentration of
4% in petrolatum it was proven to be non-irritant when applied to human
skin (Opdyke, 1979). In 20 patients with eczema or contact dermatitis,
methyl salicylate at 67% is reported to cause irritation in 8 subjects; at
40%, 2 subjects; and at 38%, 15% and 3.75%, no irritation in any subject
(ref in CIR, 2003).

Mucous membranes irritation:

Severe irritant to guinea pig skin and eyes (Opdyke, 1978).

Skin sensitivity:

Animals:
Murine local lymph node assay of methyl salicylate at higher
concentrations (> or = 50%) show a dose-response relationship and
clearly positive results (Montelius et al., 1998).

Humans:
No sensitisation could be demonstrated in 25 volunteers subjected to a
maximisation test with 4% sweet birch oil in petrolatum (Opdyke, 1979).
Patch tests with 2% methyl salicylate produced 3 positive reactions in
183 eczema patients (Rudner, 1977).
Systemic toxic effects
Acute Acute toxicity:
Salicylates uncouple oxidative phosphorylation (ref. in for example
Beynen et al., 1982) and as regards methyl salicylate there is evidence
of high acute toxicity in man but only moderate acute toxicity in most
experimental animals.

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 K:
LD50 values (mg/kg bw): Rat (oral): 887; rabbit (oral): 2 800; guinea pig
(oral): 1 060; dog (oral): 2 100; guinea pig (dermal): 700 (Clayton et
Clayton, 1981). According to the IUCLID database, oral toxicity is 880 to
2100 mg/kg for various types of animals. For dermal toxicity, LD50 is
from 700 to more than 5000 mg/kg (IUCLID, 2000; Hansen et al., 2006).

Humans:
LD50 values in mg/kg bw: Man; adult (oral): 500; child (oral) 170 (LDlow)
(Clayton et Clayton, 1981).
Probable oral lethal dose in human: 50 500 (Gosselin et al., 1984).
The average lethal dose of methyl salicylate for children is 10 ml (Clayton
et al., 1981). As little as 4 ml (4 700 mg) taken orally may be fatal
(Gilman et al., 1990).

Repeated dose Short term toxicity:

Animals:
Rat feeding studies (10-12 weeks) showed development of
increased bone density. The no effect level (NOAEL) was high; 450
mg/kg bw (Harrison et al., 1963). In a sub-acute 13-day toxicity study in
rats, methyl salicylate induced alterations of microbodies in hepatocytes
at dietary level of approximately 50 mg/kg bw (EMEA, 1999).

A 6-month feeding study involving beagle dogs revealed a no effect level

(NOEL) of 170mg/kg bw/day, pertaining to the influence on liver and
kidney weight (Abbott et Harrison, 1978).

When methyl salicylate was administered topically to rabbits for 90 days

(0.5, 1, 2 and 4ml/kg bw/day), early deaths and kidney damage were
observed at all doses tested. As only summary information was available
no NOAEL could be established (EMEA, 1999). Conversion ml to (mg/kg
3
bw).

NOAEL
A NOAEL 50mg/kg bw has been established on the basis of long-term
studies only. Considering the safety of methyl salicylate in food (oral
intake), JECFA made use of the NOAEL 50 mg/kg bw observed by Webb
et Hansen (1963) and a conventional safety factor of 100 which implies
an acceptable daily intake (ADI) of 0.50 mg/kg bw. Already in 1967
JECFA set this ADI value. It was not changed when JECFA evaluated
the safety of use in the year 2002.

Mutagenicity/genotoxicity:
In vitro tests :
Methyl salicylate tested negative in the Salmonella/microsome
preincubation assay, when using the standard protocol approved by the
National Toxicology Program (NTP) (Mortelmans et al., 1986). Also other
authors reported negative reverse mutation tests (Ames) confer
overview given by JECFA (2002) they referring to tests performed by
Ishidate et al., (1984) and Kawachi et al., (1980). However, another
Ames test study demonstrated mutagenicity when applying the TA98
strain upon addition of hamster S-9 mixture. Weak mutagenicity was also
found using the TA100 strain with hamster S-9 mixture for methyl
salicylate (Kuboyama et Fujii, 1992 a study not mentioned in the
JECFA overview).

In vivo tests are not available and apparently have not been performed

3
Conversion: 4 ml methyl salicylate equals 4 700 mg

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 (JECFA, 2002).

Mutagenicity /genotoxicity EMEA concluded that salicylic acid and methyl salicylate can be
considered not to possess genotoxic properties (EMEA, 1999).

No studies have been performed with the primary purpose of determining

the carcinogenicity of methyl salicylate. Chronic exposure studies with
two-year exposure durations that included extensive pathology did not
indicate any dose dependent increases in incidences of benign or
malignant tumors.

Carcinogenicity Also corroborating the view that methyl salicylate is devoid of

carcinogenic properties is the finding that acetyl salicylic acid apparently
does not possess such a property. Carcinogenicity studies have been
performed to assess the carcinogenic potential of acetyl salicylic acid in
mice at 1 and 5% and in rats at 0.25% and 2% in drinking water. The
results were negative in both studies. Considering these results, salicylic
acid, a metabolite of acetyl salicylic acid (and of methyl salicylate), was
considered to be devoid of such a potential (SCCNFP, 2002).

Reprotoxicity / Animals:
teratogenicy Drug-induced renal abnormality is apparent in offspring of rats exposed
to methyl salicylate on days 10 and 11 of gestation. It also caused
retarded renal development in fetuses (Gibson, 1976). Methyl salicylate
was administered topically to pregnant hamsters (days 7 9) and the
teratogenic results were compared with those obtained following oral
treatment with the same compound. A daily dose of 1 750mg/kg bw was
applied in both the dermal (dose on the skin) and oral study. Both
treatments produced the same defect in embryos recovered at day 9:
failure of fusion of the neural tube, especially in the area of the
developing brain. Analysis of serum salicylate levels following both
treatments produced similar curves and indicated that teratogenic levels
of salicylate can reach the maternal circulation after topical exposure
(Overman, 1983).

In two 3-generation studies in rats at 25, 50, 150 and 250 mg/kg bw no
adverse effects were observed at 50 mg/kg bw (NOAEL). Salicylate, but
not its metabolites, was found to be primarily or solely responsible for the
teratogenetic effects in rats (EMEA, 1999).

Methyl salicylate is teratogenic in animals and can be absorbed in toxic

quantities by the dermal route. Consequently, the dermal absorption and
teratogenic potential of a petroleum-based grease (PBG) manufactured
using methyl salicylate (3%) was assessed. The test material (petroleum
based grease/methyl salicylate) was dermally applied at doses of either
0, 1, 3, or 6 g/kg/day to groups of pregnant rats on gestational days 6-15.
The maternal and developmental No-Observable-Adverse-Effect-Level
for petroleum based grease/methyl salicylate was greater than 6
g/kg/day (Infurna R et al, Teratology 41 (5): 566, 1990, cited in Hansen et
al., 2006).

Humans:
There is no evidence that moderate therapeutic doses of salicylates
cause foetal damage in human beings; however, babies born to women
who ingest salicylates for long periods may have significantly reduced
weights at birth. In addition, there is an increase in perinatal mortality,
anemia, antepartum and postpartum haemorrhage, prolonged gestation,
and complicated deliveries (Gilman et al., 1990).
Other effects

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 Other toxicity:
Human dermal toxicity according to the case literature: severe urticaria
and angioedema with methyl salicylate exposure (ref in CIR, 2003).

Phototoxic effects:
The phototoxic properties of methyl salicylate seem not to have been
investigated. One should observe, however, that the UV absorption
maximum of a methanol solution of methyl salicylate is 305nm, which
indicates that methyl salicylate can undergo direct photolysis. One
photolysis study was performed which yielded a half-life of methyl
salicylate in solution of about 48min (Kondo, 1978). The degradation
products may possibly be harmful to skin causing irritation and or other
toxic effects. CIR (2003) concluded that salicylic acid is not a photo
sensitizer, nor is it phototoxic.

SCCNFP (2002), on the other hand, states that no information is

available concerning the phototoxicity or photo allergenic potential of
salicylic acid in animals.

Interactions:
Methyl salicylate, like other salicylates, interferes with vitamin K
metabolism thereby decreasing the blood clothing ability.

5. Exposure estimate and critical NOAEL / NOEL

NOAEL/NOEL critical For risk assessment of methyl salicylate in cosmetic products, we
have used the NOAEL value of 50 mg/kg bw/day for salicylates
identified in sub-chronic and chronic toxicity studies (Belsito et al.,
4
2007) . Cf. also Cosmetic Ingredient review of various salicylates,
including methyl salicylate (CIR, 2003).

Exposure cosmetic Although a global exposure scenario cannot be performed because of

products lack of data, among cosmetic products giving rise to highest systemic
exposure of methyl salicylate are probably sport massage products
(see e.g. Hansen et al., 2006).

Sport massage products (lower limbs)

Alt 1: (according to Council of Europe, 2008)

Premises:
2
Skin surface treated - legs: 3240 cm (18% of total body area; use the
rule of 9 principle see References).
2
Amount of product per area (cm ): 1.0 (default; SCCNFP guidelines)
5
Concentration of methyl salicylate in product: 9.0%
6
Skin penetration rate: 20% (worst case scenario).
Body weight: 60 kg (default female; SCCNFP guidelines)

SED (single use): 3240 x 1 x 0.09 x 0.20 /60 = 0.97 mg /kg bw/day.
SED (corrected; footnote 5) = 1.5 mg/kg bw/day

Alt 2:
Premises:

4
The RIFM Expert Panel, 2007.
5
Letter from Norwegian Medicines Agency to distributor of a cosmetic product containing 9% methyl salicylate,
which exceeds the current limit of 1% set by SNT/MT as the maximum safe level of this ingredient (SLV, 2000).
6
Human data indicate dermal bioavailability of methyl salicylate in the range of 12 30.7% (Belsito et al., 2007).

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 The exposure scenarios are from Hansen et al. (2006). The maximum
content of methyl salicylate was 76 mg per gram product (i.e. 7.6%).

- Concentration of methyl salicylate in product: 7.6% (illustrative

example; Hansen et al., 2006) = 0.076
- Calculated relative daily exposure of product: 123.20 * 0.20 = 24.64
7
mg/kg bw/day
- Dermal absorption: 31% = 0.31 (worst case, experimental data).

SED = A (mg/kg bw/day) x C(%)/100 x Dap (%)/100

= 24.64 mg/kg bw/day x 0.076 x 0.31 = 0.5 mg/kg bw/day

SED (corrected): 0.5 * 3.2 = 1.6 mg/kg bw/day

Mouthwash

0.2% methyl salicylate (mouth wash) as illustrative example -

maximum amount used according to FDA (CIR, 2003).

Calculated relative daily exposure of product: 32.54 mg/kg bw/day

Concentration of ingredient in product: 0.2% = 0.002
Dermal absorption (SCCS default value): 100% = 1

SED = A (mg/kg bw/day) x C(%)/100 x Dap (%)/100

= 32.54 mg/kg bw/day x 0.002 x 1 = 0.07 mg/kg bw/day

Face cream

2.0% methyl salicylate (face cream) as illustrative example

Calculated relative daily exposure of product: 24.14 mg/kg bw/day
Concentration of ingredient in product: 2.0% = 0.02
Dermal absorption (experimental value): 31% = 0.31 (worst case)

SED = A (mg/kg bw/day) x C(%)/100 x Dap (%)/100

= 24.14 mg/kg bw/day x 0.02 x 0.31 = 0.15 mg/kg bw/day

Hand cream

2.0% methyl salicylate (hand cream) as illustrative example

Calculated relative daily exposure of product: 32.70 mg/kg bw/day
Concentration of ingredient in product: 2.0% = 0.02
Dermal absorption (SCCS default value): 100%% = 1

SED = A (mg/kg bw/day) x C(%)/100 x Dap (%)/100

= 32.70 mg/kg bw/day x 0.02 x 0.31 = 0.20 mg/kg bw/day

Total systemic exposure (cosmetics): overall use of sport massage

products + mouthwash + face cream + hand cream:

7
Application of sport massage product was estimated to be 7.82 g daily for total body area (- face) (SCCS, 2010).
2 2
The ratio of area two legs (3240 cm ) / total body lotion area (15670 cm ): 0.20. Theoretically this amounts to
daily application of 7.82 * 0.20 = 1.564 g sports cream. Because experimental data determined that 5 g cream
was applied per day (Hansen et al., 2006), as opposed to 1.564 g according to SCCS default value, the estimated
2
exposure is multiplied with a correction factor of 3.2 (5/1.564). Alt1: amount of applied product: 1 mg/cm * 3240
2
cm = 3200 mg = 3.2 g. Assuming that 5g sport massage cream is applied, the correction factor is 5/3.2 = 1.5;
SED (corrected) = 0.97 * 1.5 = 1.5 mg/kg bw/day.

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 SED (total) 1.60 + 0.07 + 0.15 + 0.20 = 2.02 mg /kg bw/day

Margin of Safety (MoS) MoS (NOAEL / SED):

MoS for sport massage cream (limbs):

SED = 1.6 mg/kg bw/day
MoS = 50/1.6 = 31.25

MoS for mouthwash:

SED = 0.07 mg/kg bw/day
MoS = 50 / 0.07 = 714

MoS for face cream:

SED = 0.15 mg/kg bw/day
MoS = 50 / 0.15 = 333
MoS for hand cream:
SED = 0.20 mg/kg bw/day
MoS = 50 / 0.20 = 250

MoS for overall use of cosmetics:

SED = 2.02 mg/kg bw/day
MoS = 50 / 2.02 = 25.0

6. Other sources of exposure than cosmetic products

Food stuffs The (oral) dietary intake of methyl salicylate as a flavouring ingredient
th
amounts to 0.09mg/kg bw/day (95 percentile; average over a period
of 14 days), see Council of Europe reports (2006 and 2008).

A NOAEL of 0.1% methyl salicylate in the diet, equivalent to 50 mg/kg

bw/day, has been identified (Tobacco information [online]). JECFA
used the NOAEL 50 mg/kg bw observed by Webb et Hansen (1963)
and a conventional safety factor of 100 to establish an acceptable
daily intake (ADI) of 0.50 mg/kg bw/day.
Pharmaceuticals The Procter and Gamble Company (1999a) developed a risk
assessment of facial cosmetic products containing 2% Salicylic Acid
using oral studies on acetyl salicylic acid ASA (aspirin).

Using the premise that oral intake of a low-dose regimen (81 mg)
baby aspirin by a 58-kg female would result in an exposure of 1.4
mg/kg/day and that this exposure level is not considered to present
any reproductive or developmental toxicity risk, the CIR Expert Panel
considered that a representative exposure to a cosmetic product
containing Salicylic Acid could result in exposure to 0.4 - 0.5
mg/kg/day and would not present a risk of developmental or
reproductive toxicity (CIR, 2003).
Other sources
Adverse side effects - from Prominent features of poisoning by methyl salicylate similar to those
uses other than cosmetics described for aspirin (acetylsalicylate): central excitation, intense
hyperpnea, and hyperpyrexia (Gilman et al., 1990).

Generally, ingestion of salicylates at doses larger than 150mg/kg bw

can produce toxic symptoms such as tinnitus, nausea, and vomiting.
Salicylates have been linked with Reyes syndrome in children and
can cause retention of salt and water as well as acute reduction of
renal function in-patients with congestive heart failure or hypovolemia
(Gilman et al., 1990).

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 Serious toxicity in humans at doses greater than 400 mg/kg bw, with
severe vomiting, hyperventilation, hyperthermia, confusion, coma,
convulsions, hyper- or hypoglycemia, and acid-base disturbances e.g.
respiratory alkalosis or metabolic acidosis (Amdur et al., 1991).

One death incident has been related to excessive use of a sports

8
cream containing high amounts of methyl salicylate . Associated
Press reported June 13, 2007, that a 17 years old girl from New York
died because of an overdose of methyl salicylate caused by long term
use of sport cream BenGay producted by Johnson & Johnsen. The
cause of the death was established by health authorities in New York.

8
[Link]
[Link]

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7. Assessment
As stated in the monograph of methyl salicylate in the Council of Europe publication Plants in
Cosmetics Volume III (2006): Taking into account data on hepatotoxicity, the toxic effect on
reproduction, the ability to cause severe malformation in the unborn, the ability to irritate skin and
mucous membranes and the skin penetration, the concentration of methyl salicylate should not exceed
2% in finished cosmetic products. Due to irritation potential when combined with ethanol the maximum
authorized concentration in products high in that vehicle should not exceed 0.4%. Methyl salicylate
should be forbidden in products near the eyes. Further data on mutagenicity (in vivo) and photo
toxicity should be provided.

General toxicity:
In the period after publication of the two Council of Europe monographs on methyl salicylate (2006,
2008), no further evidence for mutagenic or carcinogenic effects of the ingredient has been found. In
the present updated report, the Council of Europe monographs have been extended by estimating
MoS of methyl salicylate in cosmetics (see below).

Cosmetics:
Systemic:
Among cosmetic products, sport massage products contribute most to the systemic exposure dose
(SED) of methyl salicylate. The following premises were used to estimate SED: sports massage
cream containing maximum 7.6% (Hansen et al., 2006) or 9% methyl salicylate (worst case), dermal
bioavailability of 20% (Council of Europe reports, 2006, 2008) or 31% (present risk profile), and
2
application of 5g sport massage product to both legs (corresponding to an area of 3240 cm ). A
NOAEL value of 50 mg/kg bw/day is based on oral intake of methyl salicylate (CIR, 2003; Belsito et al,
2007). Critical effect: kidneys

Thus, the estimated margin of safety (MOS) for sports massage creams and other products types
9
(illustrative concentrations of ingredient) amounts to:
MoS (sport massage cream): SED = 1.6 mg/kg bw/day; MoS = 50/1.6 = 31.25
MoS (mouthwash): SED = 0.07 mg/kg bw/day; MoS = 50 / 0.07 = 714
MoS (face cream): SED = 0.15 mg/kg bw/day; MoS = 50 / 0.15 = 333
MoS (hand cream): SED = 0.20 mg/kg bw/day; MoS = 50 / 0.20 = 250
MoS (overall use of cosmetics): SED = 2.02 mg/kg bw/day; MoS = 50 / 2.02 = 25.0

Local:
MoS is not used for describing sensitizing effects as these effects do not have a lower concentration
limit. Methyl salicylate has skin-irritating properties at concentrations greater than 50% (CIR, 2003).
When applied at a concentration as low as 1% with a 70% ethanol + emollient) it is a moderate irritant,
but produces little or no irritation at methyl salicylate concentrations up to 6%.

Food:
The average daily intake of methyl salicylate as a flavouring substance amounts to 0.09 mg/kg
bw/day, whereas safe long-term use in food is established by an ADI of 0.5 mg/kg bw/day.

Medicinal products:
- Pharmacological effects (pain relief; analgesic) of methyl salicylate have been reported at
concentrations in the range of 15-20 mg/kg bw/day. However, the exposure of this ingredient from
drugs is generally short-term, and smaller than expected from cosmetics and dietary products.

Total exposure:
The systemic dose resulting from the usage of methyl salicylate in cosmetics come on top of the daily
background dose due to dietary intake (0,5 + 0.09 = approx. 0.6 mg/kg bw/day), i.e. 30% (0.6/2) of
the total exposure from cosmetics.

9
Fragrances: at concentrations of salicylates typically used in fragrances (perfume), MoS = 125 - 2500000,
based on an oral NOAEL of 50 mg/kg/day (The RIFM Expert Panel, 2007). Thus, all use of methyl salicylate in
fragrances is considered safe. Typical use levels of fragrances: 0.5% .

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8. Conclusion
Maximum use levels of methyl salicylate according to current regulations/practice: Norway: maximum
10
1%; other EU (ES) countries: 3 9%. In Norway, methyl salicylate is allowed only in specified
cosmetic product categories at the following maximum concentrations:

Skin creams: 1%
Mouth water: 0.05%

In the present updated risk profile, the following maximum usage limits (%) were calculated for methyl
salicylate, corresponding to an acceptable margin of safety (MoS) of 100 (based on animal data):
11
- Sport massage products: (7.6% x 31.25) /100 = 2.4%
- Mouth wash: (0.2% x 714) / 100 = 1.5%
- Face cream: (2% x 333) / 100 =6.7%
- Hand cream: (2% x 250) / 100 = 5.0%
12
- Overall exposure to methyl salicylate from cosmetics): (7.6% x 25) / 100 = 1.9%

Other product categories (e.g. body lotion) not assessed.

Thus, the following upper use levels are recommended for methyl salicylate, when only exposure from
13
cosmetic products is considered:

Sport massage products, face cream and hand cream 2%

Mouth water 0.2%
Not allowed in products near the eyes

Remarks:
Due to irritation potential when combined with ethanol, the maximum allowed concentration of methyl
salicylate in products high (70%?) in ethanol should not exceed 0.4%.

Interactions: Patients must be aware of the potential hazard of using topical methyl salicylate in
combination with warfarin.

10
N: Authorised up to 0.05% in oral care products and up to 1% in skin creams (methyl salicylate as such).
CH: Max. 3.0% of essential oils and its main ingredient in products which remain on the skin.
S: Sport-massage products only acceptable claims are warming or cooling.
Although there is no maximal concentration set up of how much methyl salicylate cosmetic and hygienic products
can contain in Sweden, a content of 8% methyl salicylate is with margin far too much compared with well-
established practice.
A: Maximum 0.5% as fragrance
D: Recommendation: maximum 1% in leave on products; max. 2.5% in rinse off products.
11
C2 (%) [SED2] = (C1 (%) [SED1] x MoS1) / MoS2
12
With the premise that the cosmetic product contains 7.6% methyl salicylate; i.e. the maximum amount of the
ingredient found by Hansen et al (2006) in a Danish survey of sports cream products.
13
The recommendation is largely in agreement with a previous risk assessment of salicylic by SCCNFP acid
concluding that: The SCCNFP considers that salicylic acid is safe for other uses than as a preservative, at a
concentration up to 2.0 % for the leave-on and rinse-off cosmetic products ... (REF: SCCNFP opinion 4 June
2001), and two previous monographs on methyl salicylate published by the Council of Europe (September 2006,
March 2008): ISBN-19: 92-871-5912-2 and ISBN 978-92-871-6298-4.

Risk profile Methyl salicylate Page 14 of 19

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9. References
Abbott DD, Harrisson JWE (1978): Methyl salicylate: Studies of osseous changes in the rat,
reproduction in the rat and mouse, and liver and kidney effects in the dog. Unpublished
communication to the Flavor and Extract Manufacturers Association. (JECFA 2002 referred to this
study in detail).
th
Amdur MO, Doull J, Klaasen CD (eds), Casarett and Doulls Toxicology. 4 ed. New York, NY:
Pergamon Press: 940.

Anderson, F.A. (2003). CIR 2003: Cosmetics Ingredient Review (CIR): Safety assessment of salicylic
acid, butyloctyl salicylate, calcium salicylate, C12-15 alkyl salicylate, capryoyl salicylic acid,
hexyldodecyl salicylate, isocetyl salicylate, isodecyl salicylate, magnesium salicylate, MEA-salicylate,
ethylhexyl salicylate, potassium salicylate, methyl salicylate, myristyl salicylate, sodium salicylate,
TEA-salicylate, and tridecyl salicylate. Int. J. Toxicol. 22 (Suppl. 3), 1-108.

Arts JH, Droege SC, Spanhaak S, Bloksma N, Penninks AH, Kuper CF (1997): Local lymph node
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salicylate, Toxicology. 24(1): 33-43.

Buccellato, Ylang Survey, Perfume. Flav, 1982. 7(4): 9-12.

[CIR 2003: Cosmetics Ingredient Review (CIR) final report: Safety Assessment of Salicylic Acid,
Butyloctyl Salicylate, Calcium Salicylate, C12-15 Alkyl Salicylate, Capryloyl Salicylic Acid,
Hexyldodecyl Salicylate, Isocetyl Salicylate, Isodecyl Salicylate, Magnesium Salicylate, MEA-
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referanse som Andersen, FA (2003)

Clayton GD and Clayton FE (eds.) (1981-82), Pattys Industrial Hygiene and Toxicology, Volume 2A,
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Poisoning, New York, NY: Elsevier Science Publishing Co., Inc. 563.

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Evaluation Unit, summary report: Salicylic acid, Sodium salicylate, Aluminium salicylate, basic and
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[Link]
th
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Gilman AG, Rall TW, Nies AS, Taylor P (eds.) (1990): Goodman and Gilmans The Pharmacological
Basis of Therapeutics. 8th ed. New York, NY. Pergamon Press, 649, 653.

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Baltimore: Williams and Wilkins. II-205.

Hall RL and Ford RA (1999): Comparison of Two Methods to Assess the Intake of Flavouring
Substances. Food Addit Contam., Nov; 16(11): 481-95.

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mutagenicity screening of food additives currently used in Japan, Food Chem. Toxicol, 22: 623636.

JECFA 1967: Joint FAO/WHO Expert Committee on Food Additives (JECFA) monograph on
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Series, No. 44; Wld Hlth Org. techn. Rep. Ser., 1968, 383 Monograph can be reached on the
Internet at: [Link]

JECFA 2002: Joint FAO/WHO Expert Committee on Food Additives (JECFA) article called Safety
evaluation of certain food additives and contaminants hydroxyl- and alkoxy-substututed benzyl
derivatives, and that includes also Methyl salicylate. It was prepared by the 57th JECFA meeting
and is included in the WHO FOOD ADDITIVES SERIES: 48 (WHO, Geneva, 2002). Authors: Mattia,
A, Renwick, AG, Sipes, IG, DiNovi, M. Available at:
[Link] and also
at: [Link] as far as concerns intake data for
use as a flavouring agent.

Kawachi T, Yahagi T, Kada T, Tazima Y, Ishidate M, Sasaki M, Sugiyama T (1980a): Results of recent
studies on the relevance of various short-term screening tests in Japan, In: Williams GM; Kroes R;
Waajiers HW; van de Poll KW, (eds.): The Predictive Value of Short-term Screening Tests in
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Holland Biomedical Press. 253267.

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Studies Environment Agency Japan.

Kuboyama N, Fujii A (1992): Mutagenicity of analgesics, their derivatives, and anti-inflammatory drugs
with S9 mix of several animal species, J Nihon Univ Sch Dent.. Volume 34(3): 183-9 (see also
Toxnet).

Megwa SA, Benson HA, Roberts MS (1995): Percutaneous absorption of salicylates from some
commercially available topical products containing methyl salicylate or salicylate salts in rats, J.
Pharm. Pharmacol. 47; Nov: 891-896.

Mills PC and Cross SE (2006): The effects of equine skin preparation on transdermal drug penetration
in vitro. Can J Vet Res; 70(4): p. 317320.

Montelius J, Wahlkvist H, Boman A, Wahlberg JE (1998): Murine local lymph node assay for predictive
testing of allergenicity: two irritants caused significant proliferation, Acta dermato-venereologica; 78, 6:
433-7.

Morra P, Bartle WR, Walker SE, Lee SN, Reeves RA (1996); Serum concentrations of salicylic acid
following topically applied salicylate derivatives, Ann. Pharmacother. Volume 30, Sep: 935-940.

Mortelmans K, Haworth S, Lawlor T, Speck W, Tainer B, Zeiger E (1986): Salmonella mutagenicity

tests: II. Results from the testing of 270 chemicals, Environ Mutagen; 8 Suppl 7: 1-119.

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NTP: National Toxicology Program (1984), Methyl salicylate: Reproduction and fertility assessment in
CD-1 mice when administered by gavage (NTP85-022). Washington DC, USA.

Opdyke DLJ (1979): Monographs on fragrance raw materials. Sweet birch oil. Food and Cosmetics
Toxicology 17: 907.

Opdyke DLJ (1978): Monographs on fragrance raw materials. Canadian snakeroot oil. Food and
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Overman DO, White JA (1983): Comparative teratogenic effects of methyl salicylate applied orally or
topically to hamsters, Teratology 28 (3): 421-6.

Pratzel HG (1987): , Zur perkutanen Resorption von Salicylsaeuremethylester aus Baedern.

(Percutaneous resorption of salicylic acid methylester from bathing solutions). Zeitschrift fur
rheumatologie; 46. 3: 143-50.

Pratzel HG, Schubert E, Muhanna N (1990): Pharmakokinetische Untersuchung zur perkutanen

Aufnahme von Salicylsaeure aus Baedern mit Salicylsaeuremethylester und Salicylsaeure,
(Pharmacokinetic study of percutaneous absorption of salicylic acid from baths with salicylate methyl
ester and salicylic acid). Z Rheumatol. Jul-Aug;49(4):185-91

Rudner EJ (1977): North American group results, Contact Dermatitis 3; 208.

Rule of 9: Estimating the Skin Surface Area (SSA) expected to be treated with the finished product, it
is precluded that the part of the body where the product is mainly applied is each lower limb front and
back. According to the (rough) so-called Wallaces Rule of nine, this skin surface amounts to 18%
of the whole body surface which according to the SCCNFP guidelines is 18 000 cm2.
Internet: [Link]

SCCNFP 2002: EU Commission Scientific Committee for Cosmetic Products and Non-food Products
(SCCNFP) 4 June 2002 adopted an opinion on Salicylic acid.

Sorensen G (1995). The Guide to Aromatherapy, Descriptions of Essential and Carrier Oils and some
uses. Internet: [Link] or, [Link]
Authors postal address is Graham Sorenson, 185 Meadow Rise, Brynna, Mid-Glamorgan, CF72 9TL,
Wales, U.K.

Stofberg J, Grundschober F (1987): Consumption ratio and food predominance of flavoring materials,
Perfumer Flavorist, 12: 27.

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at and made publicly available by the Department of pharmacology and pharmaterapy of the Institute
for clinical odontology at the University of Oslo.

US ENVIRONMENTAL PROTECTION AGENCY (US EPA 1997), Methyl Salicylate; Establishment of

an Exemption from Requirement of a Tolerance, Federal Register: November 19 (Volume 62, Number
223). This concerns the establishment of an exemption from the requirement of a tolerance
for residues of the insecticide methyl salicylate in or on food, when used as an insect repellent in food
packaging and animal feed packaging at an application rate that does not exceed 0.2 mg of methyl
salicylate per square inch of packaging materials.
[Link]/fedrgstr/EPA-PEST/1997/November/Day-19/[Link]
EPA refers to the assessment of the FDA OTC panel 25 May 1982 that methyl salicylate can be safely
used on mucous membranes up till 0.4%

USDA stands for the Phytochemical database of the American Department of Agriculture.
Internet address [Link]

Webb WK and Hansen WH (1963): Chronic and subacute toxicology and pathology of methyl
salicylate in dogs, rats and rabbits. Toxicol Appl Pharmacol., Sep; 33: 576-87.

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Yankell SL (1972): The effects of various vehicles on absorption rates in skin, Adv. Biol. Skin 12, 511

Yano T, Kanetake T, Saita M, Noda K (1991): Effects of l-menthol and dl-camphor on the penetration
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References in addition to the Council of Europe monograph:

Belsito D, Bickers D, Bruze M, Calow P, Greim H, Hanifin JM, Rogers AE, Saurat JH, Sipes IG,
Tagami H (2007) A toxicologic and dermatologic assessment of salicylates when used as fragrance
ingredients. Food and Chemical Toxicology 45 (suppl.1): S318S361. The RIFM Expert Panel.

Council of Europe, 2006. Plants in cosmetics - Potentially harmful components. Volume III. Council of
Europe Publishing. ISBN-10: 92-871-5912-2; ISBN-13: 978-92-871-5912-0. F-67075 Strasbourg
Cedex.

Council of Europe, 2008. Active ingredients used in cosmetics: safety survey (2008). ISBN 978-92-
871-6298-4

Hansen PL, Tnnig K, Pommer K, Malmgren B, Hansen OC & Poulsen M. Survey and health risk
assessment of products for treatment of sports injuries and pains. Survey of chemical substances in
consumer products no. 79, 2006. Danish Technological Institute. Danish Environmental Protection
Agency (EPA).

IUCLID, 2000. European Communities. Joint Research Centre. Institute for Health and Consumer
Protection, European Chemicals Bureau. Available at: [Link]
[Link]

Lapczynski A, Jones L, McGinty D, Bhatia SP, Letizia CS, Api AM (2007) Fragrance material review
on phenyl salicylate. Food Chem Toxicol. 45 (Suppl. 1): S472-6. Epub 2007 Sep 14. Review. PubMed
PMID: 18031889.

SLV. 2000. Letter from the Norwegian Medicines Agency (Statens Legemiddelverk) to distributor of a
cosmetic product containing 9% methyl salicylate. 14.08. 2000.

Online:
[Link]. Beta-sitosterol. Available at:
[Link] (accessed Aug 27,
2012).

EWGs Skin Deep Cosmetic Safety Database. Environmental Working Group. Available at:
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Tobacco inforation. Methyl salicylate. Purpose: Flavour compound. Available at: [Link]
[Link]/toxicfolder/011.%E5%B8%9D%E5%9C%8B%E8%8F%B8%E8%8D%89/1
[Link]

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10. Annexes

Annex 1: Examples of uses for methyl salicylate in cosmetic products

Product Distributor Markets retail Cosmetic References /internet

Name /Manufacturer trade category links
(intended use)

(Tabell i Annex 1: fyll inn)

Annex 2: Ingredient usage as a function of product type (taken from CIR, 2003)

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