O-acetylsalicylic acid

Additional toxicological data

Administrative data

Endpoint:

additional toxicological information

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Comprehensive peer-reviewed safety assessment of salicylate esters providing a detailed review of experimental data on all toxicological endpoints.

Data source

Reference

Reference Type:

review article or handbook

Title:

A toxicologic and dermatologic assessment of salicylates when used as fragrance ingredients

Author:

RIFM Expert Panel (Belsito D, Bickers D, Bruze M et al)

Year:

2007

Bibliographic source:

Food Chem Toxicol 45:S318-S361

Materials and methods

Test guideline

Qualifier:

no guideline required

Principles of method if other than guideline:

Peer-reviewed safety assessment

Test material

Test material information

Constituent 1

Reference substance name:

Methyl salicylate

EC Number:

204-317-7

EC Name:

Methyl salicylate

Cas Number:

119-36-8

IUPAC Name:

methyl salicylate

Applicant's summary and conclusion

Conclusions:

This comprehensive, peer-reviewed, safety assessment of salicylate esters summarises data covering all toxicological endpoints, from both published sources and unpublished reports not otherwise accessible. Data published in this report are considered acceptable for use as supporting information under a number of specific toxicological endpoints.

Executive summary:

The RIFM Expert Panel (2007) reviewed data on salicylates used as fragrance ingredients. The conclusions of the review and safety assessment were summarized.

* The salicylates are well absorbed by the oral route, and oral bioavailability is assumed to be 100%. Absorption by the dermal route in humans is more limited with bio- availability in the range of 11.8-30.7%.

* The salicylates are expected to undergo extensive hydrolysis, primarily in the liver, to salicylic acid. In the liver, salicylic acid is conjugated with either glycine or glucuronide and is excreted in the urine as salicyluric acid and acyl and phenolic glucuronides. The hydrolyzed side chains are metabolized by common and well-characterized metabolic pathways leading to the formation of innocuous end products. The expected metabolism of the salicylates does not present toxicological concerns.

* The acute dermal toxicity of the salicylates is very low, with LD50 values in rabbits reported to be greater than 5000 mg/kg body weight. The acute oral toxicity of the salicylates is moderate, with toxicity generally decreasing with increasing size of the ester R-group and with LD50's between 1000 and >5000 g/kg.

* In dermal subchronic toxicity studies, extreme doses of methyl salicylate (~5 g/kg body weight/day) possibly were nephrotoxic but the data were minimal. The subchronic oral NOAEL is concluded to be 50 mg/kg body weight/day. At higher doses, in excess of 300-450 mg/kg body weight/day, methyl salicylate is associated with increased density of the metaphyses of the long bones in rats. The oral NOAEL of 50 mg/kg body weight/day can be used in the risk assessment of the use of the salicylates as fragrance ingredients.

* Oral chronic toxicity data for methyl salicylate are consistent with the oral subchronic toxicity data in that the lowest NOAEL value identified was 50 mg/kg body weight/day in both rats and dogs.

*Genetic toxicity data, for methyl salicylate, a few other salicylates and for structurally related alkyl- and alkoxy-benzyl derivatives are negative for genotoxicity. Since the metabolites of the salicylates are simple alcohols and acids, the salicylates as a group are considered to be non-genotoxic.

* Limited long-term oral studies in rats and an i.p. injection study in mice using methyl salicylate provided no evidence of carcinogenicity. Given the metabolism of salicylate and the evidence that they are non-genotoxic, it can be concluded that the salicylates are without carcinogenic potential.

* The reproductive and developmental toxicity data on methyl salicylate demonstrate that high, maternally toxic doses result in a pattern ofembryotoxicity and teratogenesis similar to that characterized for salicylic acid. The no-adverse-effect levels for reproductive toxicity (e.g., fertility, neonatal growth and survival, etc.) are lower than doses reported to be teratogenic and are consistent with the NOAELs available from subchronic and chronic toxicity studies. The Cosmetic Ingredient Review Board has concluded that use of salicylates and salicylic acid in cosmetic products would not pose a risk for reproductive or developmental effects in humans.

* At concentrations likely to be encountered by humans through the use of the salicylates as fragrance ingredients, these chemicals are considered to be non-irritating to the skin.

* The salicylates in general have no or very limited skin sensitization potential. However, benzyl salicylate has been reported to cause skin sensitization in several human studies and in a number of animal studies and Nakayama (1998) has classified benzyl salicylate as a common cosmetic sensitizer and primary sensitizer. IFRA (2007) has established a Standard on the use of benzyl salicylate as a fragrance ingredient. Other salicylates with aromatic side chains have also shown sensitization in standard guinea pig tests.

* The salicylates are non-phototoxic and have no photoirritant or pholoallergenic activity.

* The use of the salicylates in fragrances produces low levels of exposure relative to doses that elicit adverse systemic effects in laboratory animals exposed by the dermal or oral route. The estimates for maximum systemic exposure to salicylates of humans using cosmetic products range from 0.0002 to 0.4023 mg/kg/day based on the assumption of 100% bioavailability. Considering that bioavailability of the salicylates is actually likely in the range of 11.8-30.7%), systemic exposures are likely lower, in the range of 0.00002-0.124 mg/kg body weight/day.

* Based on the above considerations, and using the NOAEL values of 50 mg/kg body weight/day identified in the subchronic (Webb and Hansen, 1963; Abbott and Harrisson, 1978; Drake et al., 1975) and the chronic toxicity studies (Packman et al., 1961; Webb and Hansen, 1962, 1963), a margin of safety for systemic exposure of humans to the individual salicylates in cosmetic products may be calculated to range from 125 to 2,500,000 (depending upon the assumption of either 12-30% or 100% bioavailability following dermal application) times the maximum daily exposure.