Fatty acids, C18 unsaturated, ethyl & methyl esters

Endpoint summary

Description of key information

All available repeated dose toxicity studies (OECD 422 / 408) resulted in NOAELs ≥ 1000 mg/kg bw/day. 

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Quality of whole database:

The available information comprises adequate, reliable studies (Klimisch score 2) from reference substances with similar structure and intrinsic properties. Read-across is justified based on common functional group, common precursors/breakdown products and similarities in PC/ECO/TOX properties. Please refer to the endpoint discussion for further details.
Taken together, the information from these independent sources is consistent and provides sufficient weight of evidence for hazard assessment leading to an endpoint conclusion in accordance with Annex XI, 1.2, of Regulation (EC) No 1907/2006. Therefore, the available information as a whole is sufficient to fulfil the standard information requirements set out in Annex VIII-IX, 8.6, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006.

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Repeated dose toxicity

Justification for read-across

There are no data regarding repeated dose toxicity available for Fatty acids, C18 unsaturated, ethyl & methyl esters. In order to fulfil the standard data requirements defined in Regulation (EC) No 1907/2006, Annex IX, 8.6, read-across to appropriate substances is conducted in accordance with Regulation (EC) No 1907/2006, Annex XI, 1.5.

According to Article 13 (1) of Regulation (EC) No 1907/2006, "information on intrinsic properties of substances may be generated by means other than tests, provided that the conditions set out in Annex XI are met”. In particular for human toxicity, information shall be generated whenever possible by means other than vertebrate animal tests, which includes the use of information from structurally related substances (grouping or read-across) “to avoid the need to test every substance for every endpoint”.

Fatty acids, C18 unsaturated, ethyl & methyl esters is a multi-constituent substance specified by esters of ethanol and methanol with fatty acids C18 unsaturated (source canola oil) resulting in monoesters which meets the definition of an UVCB substance. Thus, the test substance represents fatty acid esters which undergo to a high extent hydrolysis by ubiquitous expressed gastrointestinal enzymes into the free fatty acid components and the respective alcohol moieties (Lehninger, 1970; Mattson and Volpenhein, 1972). Considering the common metabolism, the read-across approach is based on the presence of a common functional group, common precursors and the likelihood of common breakdown products via biological processes, which result in structurally similar chemicals with similar physico-chemical, toxicological and toxicokinetic behaviour. For further details on the read-across approach, please refer to the analogue justification in section 13 of the technical dossier.

As no data on repeated dose toxicity are available for Fatty acids, C18 unsaturated, ethyl & methyl esters, read-across to reliable data on the analogue substances Ethyl oleate (CAS 111-62-6) and Methyl laurate (CAS 111-82-0) was conducted for repeated dose toxicity. Ethyl oleate (CAS 111-62-6) is the main component of Fatty acids, C18 unsaturated, ethyl & methyl esters and Methyl laurate (CAS 111-82-0) is also a fatty acid ester which is composed of methanol (alcohol moiety) and lauric acid (C12 fatty acid moiety). Therefore, the two substances are regarded as structurally similar to Fatty acids, C18 unsaturated, ethyl & methyl esters and hence, are considered as suitable analogue substances.

CAS 111-62-6

A 91-day oral feeding study (Bookstaff, 2004) was performed with Ethyl oleate (CAS 111-62-6) according to the 1993 FDA draft "Redbook II" guidelines (Toxicological Principles for the Safety Assessment of Direct Food Additives and Color Additives Used in Food). The study was performed equivalently to OECD Guideline 408 and under GLP. The purpose of the study was to determine the safety of Ethyl oleate in a 91-day feeding study in Sprague-Dawley rats. Ethyl oleate was mixed into AIN-93G purified diet at levels of 0, 3.3, 6.7, and 10% by weight (approx. 0, 1900, 3800 and 6000 mg/kg bw/day). All diets were calorie- and fat-matched using high oleic safflower oil (HOSO) as the control fat. There were 20 male and 20 female rats per group.

Ethyl oleate in the diet was well tolerated and there were no toxicologically significant findings in any of the measured parameters (clinical observations, body weight gains, appearance of the faeces, ophthalmic examinations, hematology, clinical chemistry, urinalysis, organ weights, histopathology, or male and female reproductive assessments). The 91-day oral NOAEL was determined to be 10% Ethyl oleate, which corresponds to approximately 5500 mg/kg bw/day when administered by daily feeding to rats for 91-days.

CAS 111-82-0

Methyl laurate (CAS 111-82-0) was tested for oral toxicity in rats in an OECD Guideline 422 combined repeated dose and reproductive toxicity screening test under GLP conditions (Tanaka, 2000). 12 male and female Crj:CD (SD) rats per dose were administered doses of 0, 250, 500 and 1000 mg/kg/day by gavage. The animals were mated. The test material was administered to females from 14 days before mating until day 3 of lactation and to males for 45 days. Terminal sacrifice was on day 45 for males and on day 4 of lactation for females. The test substance showed no general toxicological effects in either sex. There were no clinical observations attributable to the administration of test substance and there was no mortality in any of the groups. No effects were observed in terms of body weights, food consumption, haematology, blood chemistry, organ weight, necropsy or histopathological findings. Therefore, under the experimental conditions of the study the NO(A)EL for Methyl laurate for repeated dose toxicity after oral administration is 1000 mg/kg bw/day in both sexes.

Conclusion on repeated dose toxicity

The available data show that the analogue substances do not possess intrinsic hazardous properties in regard to repeated dose toxicity. Therefore, based on common functional groups and structural similarities, Fatty acids, C18 unsaturated, ethyl & methyl esters is considered to be non-hazardous after repeated exposure.

A detailed reference list can be found in the CSR and in section 13 of the dossier.

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
No study was selected as hazard assessment is conducted by means of read-across from structural analogues. All available studies are adequate and reliable based on the identified similarities in structure and intrinsic properties between source and target substances and overall quality assessment (refer to the endpoint discussion for further details).

Justification for classification or non-classification

The available data on repeated dose toxicity do not meet the classification criteria according to Regulation (EC) 1272/2008 and are therefore conclusive but not sufficient for classification.