Fatty acids, C12-18 (even-numbered), 3-methylbutyl esters

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Quality of whole database:

The available information comprises adequate, reliable (Klimisch score 2) studies from reference substances with similar structure and intrinsic properties. Read-across is justified based on common precursors and breakdown products of hydrolysis and consistent trends in environmental fate, ecotoxicological and toxicological profile (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, 8.7, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006.

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

Justification for read-across

There are no data on the reproduction toxicity of Fatty acids, C12-18, even numbered, 3-methylbutyl esters (CAS 1314963-50-2). The assessment was therefore based on studies conducted with analogue substances as part of a read-across approach, which is in accordance with Regulation (EC) No. 1907/2006, Annex XI, 1.5. For each specific endpoint the source substance(s) structurally closest to the target substance is/are chosen for read-across, with due regard to the requirements of adequacy and reliability of the available data. Structural similarities and similarities in properties and/or activities of the source and target substance are the basis of read-across. A detailed justification for the analogue read-across approach is provided in the technical dossier (see IUCLID Section 13).

Toxicity to reproduction

CAS 111-62-6

A subchronic 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 with additional assessment of oestrus cycle and sperm parameters. The purpose of the study was to determine the safety of Ethyl oleate in a 91-day feeding study in 20/rats/sex group. Ethyl oleate was mixed into the diet at levels of approx. 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. 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, haematology, clinical chemistry, urinalysis, organ weights, histopathology, and male and female reproductive assessments). Based on the absence of abnormalities concerning oestrus cyclus, sperm characterization and histopathologic evaluation of oestrus cycle in females, sperm characterization in males and histologic examinations (incl. epididymides, mammary gland, ovaries, prostate, seminal vesicles, testes, thyroid with parathyroid, uterus with uterine horns and vagina) the subchronic 90-day oral NOAEL for fertility in rats for Ethyl oleate was found to be approx. 5500 mg/kg bw/day.

CAS 123-95-5 

A reproduction/developmental toxicity screening test was performed with Butyl stearate (CAS 123-95-5) similar to OECD guideline 421 (Smith, 1953). 20 male and female Sprague-Dawley rats received butyl stearate at a concentration of 6.25% in the diet, corresponding to approx. 6000 mg/kg bw/day, for a period of 10 weeks. Negative control animals (12 males and females) were fed with the concurrent basal diet. After 10 weeks animals were mated. The date of parturition and the number and sex of pups in each litter were recorded. Litters were weaned 21 days postpartum and the weights of the weanlings determined. From each of the three groups of weanlings (those receiving the test material and the controls), 24 males and 24 females were chosen at random and for the next 21 days, the young were fed the same 6.25% diet as P animals. Diet intake and body weights were recorded daily; 21 days after weaning, the rats were sacrificed and necropsies were performed.

No adverse effects were observed with respect to litter size and survival of offspring. Only the growth during the pre-weaning and post-weaning periods was slightly retarded. However, this is was not determined to be toxicologically relevant.  No gross lesions were observed among these animals at sacrifice at the end of the 21-day post-weaning period. Therefore, the NOAEL for parental fertility as well as for offspring development was found to be 6000 mg/kg bw/day.

Conclusion for reproduction toxicity

A read-across approach was applied to assess the reproductive toxicity potential of the target substance Fatty acids, C12-18, even numbered, 3-methylbutyl esters (CAS 1314963-50-2). The studies on the structural analogous substances Ethyl oleate (CAS 111-62-6) and Butyl stearate (CAS 123-95-5) did not show treatment-related adverse effects up to the highest tested dose level. Therefore, as the available data did not identify any adverse hazard for reproduction toxicity, Fatty acids, C12-18, even numbered, 3-methylbutyl esters (CAS 1314963-50-2) is considered to have no toxic effects to reproduction.

Short description of key information:
Oral: OECD 408, rat, NOAEL fertility: 5500 mg/kg bw/day
Oral: OECD 421, rat, NOAEL fertility: 6000 mg/kg bw/day

Justification for selection of Effect on fertility via oral route:
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 the source and target substances and overall quality assessment (refer to the endpoint discussion for further details).

Effects on developmental toxicity

Description of key information

Oral: OECD 414, rat:
NOAEL maternal toxicity = 1000 mg/kg bw/day
NOAEL embryo-/fetotoxicity and teratogenicity = 1000 mg/kg bw/day

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Quality of whole database:

The available information comprises adequate, reliable (Klimisch score 2) studies from reference substances with similar structure and intrinsic properties. Read-across is justified based on common precursors and breakdown products of hydrolysis and consistent trends in environmental fate, ecotoxicological and toxicological profile (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, 8.7, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006.

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

Justification for read-across

There are no data on the developmental toxicity of Fatty acids, C12-18, even numbered, 3-methylbutyl esters (CAS 1314963-50-2). The assessment was therefore based on studies conducted with analogue substances as part of a read-across approach, which is in accordance with Regulation (EC) No. 1907/2006, Annex XI, 1.5. For each specific endpoint the source substance(s) structurally closest to the target substance is/are chosen for read-across, with due regard to the requirements of adequacy and reliability of the available data. Structural similarities and similarities in properties and/or activities of the source and target substance are the basis of read-across. A detailed justification for the analogue read-across approach is provided in the technical dossier (see IUCLID Section 13) and within Chapter 5.1 of the CSR.

CAS 91031-48-0

The developmental toxicity of Fatty acids, C16-18, 2-ethylhexyl esters (CAS 91031-48-0) was investigated according to OECD guideline 414 (Pittermann, 1994). Groups of 24 female Sprague-Dawley rats received daily oral gavage doses of the test substance in arachidis oil at dose levels of 100, 300 and 1000 mg/kg bw/day during gestational days 6 to 15. On day 20 of gestation the animals were euthanized and examined for maternal and fetal parameters. Based on the number of implantations, number of total litter losses by resorption, mortality, clinical signs, body weight, gross pathology and organ weights of maternal animals the NOAEL for maternal toxicity was found to be 1000 mg/kg bw/day. Examination of fetus litter size and weights, offspring viability (number alive and number dead), sex ratio, grossly visible abnormalities, external, head, soft tissue and skeletal abnormalities showed no differences to control and no indication for teratogenic effects. Therefore, the NOAEL for embryo-/foetotoxicity and teratogenicity in rats for Fatty acids C16-18, 2-ethylhexyl esters was found to be 1000 mg/kg bw/day.

CAS 22047-49-0

The developmental toxicity of 2-Ethylhexyl stearate (CAS 22047-49-0) was investigated according to OECD guideline 414 and in compliance with GLP (Aulmann, 2000). Groups of 24 female Sprague-Dawley rats received daily oral gavage doses of the test substance in arachidis oil at dose levels of 100, 300 and 1000 mg/kg bw/day during gestational days 6 to 15. On Day 20 of gestation the animals were euthanized and examined for maternal and fetal parameters. Based on the number of implantations, number of total litter losses by resorption, mortality, clinical signs, body weight, gross pathology and organ weights of maternal animals the NOAEL for maternal toxicity was found to be 1000 mg/kg bw/day. Examination of fetus litter size and weights, offspring viability (number alive and number dead), sex ratio, grossly visible abnormalities, external head, soft tissue and skeletal abnormalities showed no differences to control and no indication of teratogenic or developmental effects. Therefore, the NOAEL for embryo-/fetotoxicity and teratogenicity in rats for 2-Ethylhexyl stearate was considered to be 1000 mg/kg bw/day.

Conclusion for developmental toxicity

A read-across approach was applied to assess the developmental toxicity potential of the target substance Fatty acids, C12-18, even numbered, 3-methylbutyl esters (CAS 1314963-50-2). The developmental studies on the structural analogous substances 2-Ethylhexyl stearate (CAS 22047-49-0) and Fatty acids, C16-18, 2-ethylhexyl esters (CAS 91031-48-0)

did not show any treatment-related effects up to and including the highest tested dose level of 1000 mg/kg bw/day. Therefore, as the available data did not identify any hazard for developmental toxicity, Fatty acids, C12-18, even numbered, 3-methylbutyl esters (CAS 1314963-50-2) is considered to have no toxic effects to fetal development. 

Justification for selection of Effect on developmental toxicity: via oral route:
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 the source and target substances and overall quality assessment (refer to the endpoint discussion for further details).

Justification for classification or non-classification

According to Article 13 of Regulation (EC) No. 1907/2006 "General Requirements for Generation of Information on Intrinsic Properties of substances", information on intrinsic properties of substances may be generated by means other than tests e.g. from information from structurally related substances (grouping or read-across), provided that conditions set out in Annex XI are met. Annex XI, "General rules for adaptation of this standard testing regime set out in Annexes VII to X” states that “substances whose physicochemical, toxicological and ecotoxicological properties are likely to be similar or follow a regular pattern as a result of structural similarity may be considered as a group, or ‘category’ of substances. This avoids the need to test every substance for every endpoint". Since the analogue concept is applied to Fatty acids, C12-18, even numbered, 3-methylbutyl esters (CAS 1314963-50-2), data will be generated from data for reference source substance(s) to avoid unnecessary animal testing. Additionally, once the analogue read-across concept is applied, substances will be classified and labelled on this basis. Based on the analogue read-across approach, the available data on toxicity to reproduction and developmental toxicity does not meet the classification criteria according to Regulation (EC) 1272/2008 or Directive 67/548/EEC, and is therefore conclusive but not sufficient for classification.