Fatty acids, C8-12, isopentyl 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) and consistent studies, from source substances with similar structure and intrinsic properties. Read-across is justified based on a common functional group, common precursors/breakdown products and similarities in PC/ECO/TOX properties (refer to endpoint discussion for further details).
The selected studies are thus 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

Toxicity to reproduction

Justification for read-across

There are no data regarding reproduction toxicity available for Fatty acids, C8-12, isopentyl ester. In order to fulfil the standard data requirements defined in Regulation (EC) No 1907/2006, Annex VIII, 8.7, read-across from 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, C8-12, isopentyl ester is a multi-constituent substance specified by C8, C10 and C12 linear saturated fatty acids esterified with isopentanol 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 (Lehninger, 1970; Mattson and Volpenhein, 1972). Considering the common metabolism, the read-across approach is based on the presence of common functional groups, common precursors and the likelihood of common breakdown products via biological processes, which result in structurally similar chemicals, common functional groups, structural similarities and 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 reproduction toxicity are available for Fatty acids, C8-12, isopentyl ester, read-across to reliable data on the analogue substances Ethyl Oleate (CAS 111-62-6) and Butyl Stearate (CAS 123-95-5), which allow a weight-of-evidence approach covering short and long chain fatty acids and saturated/unsaturated fatty acids, was conducted.

CAS 111-62-6

A 90-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 (Repeated Dose 90-Day Oral Toxicity in Rodents) with additional assessment of oestrus cycle and sperm parameters. Ethyl Oleate (EO) was mixed into AIN-93G purified diet at levels of 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. EO 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, or 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 20 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. Successfully mated pregnant females were housed individually in breeding cages. 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, these young were fed the same 6.25% diet as had been ingested by their parents. Diet intake and body weights were recorded daily; 21 days after weaning, the rats were sacrificed and necropsies were performed.

Based on reproduction, fertility index, litter size, survival index/viability index of offspring and necropsy at day 21 after weaning the NOAEL for parental fertility as well as for offspring development was found to be 6000 mg/kg bw/day.

Conclusion for reproduction toxicity

The available data show that the analogue substances do not possess intrinsic hazardous properties in regard to reproduction toxicity. Therefore, based on common functional groups and structural similarities, Fatty acids, C8-12, Isopentyl ester is considered to be non-hazardous regarding reproduction toxicity.

A waiver for the requirement to perform an extended one-generation reproductive toxicity study (OECD guideline 443, standard configuration or with additional modules) was included. In accordance with Regulation (EC) No 1907/2006, section 8.7.3, Column 1 the study is not scientifically necessary and, considering concerns regarding the use of vertebrate animals for experimental purposes, considered to be unjustified.

References

A detailed reference list is provided in the technical dossier (see IUCLID, section 13) and within the CSR.

Effects on developmental toxicity

Description of key information

The NOAEL for maternal and developmental toxicity for 2-ethylhexylstearate (CAS 91031-48-0) and for 2-ethyl hexyl stearate (CAS 22047-49-0) was found to be 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 and reliable studies (Klimisch score 2) from reference substances with similar structures and intrinsic properties. Read-across is justified based on a common functional group, common precursors/breakdown products and similarities in PC/ECO/TOX properties (refer to endpoint discussion for further details). The selected studies are thus 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

Developmental toxicity

Justification for read-across

There are no data regarding developmental toxicity available for Fatty acids, C8-12, isopentyl ester. In order to fulfil the standard data requirements defined in Regulation (EC) No 1907/2006, Annex VIII, 8.7, read-across from 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, C8-12, isopentyl ester is a multi-constituent substance specified by C8, C10 and C12 linear saturated fatty acids esterified with isopentanol 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 (Lehninger, 1970; Mattson and Volpenhein, 1972). Considering the common metabolism, the read-across approach is based on the presence of common functional groups, common precursors and the likelihood of common breakdown products via biological processes, which result in structurally similar chemicals, common functional groups, structural similarities and 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 developmental toxicity are available for Fatty acids, C8-12, isopentyl ester, read-across to reliable data on the analogue substances Fatty acids, C16-18, 2-Ethylhexyl esters (CAS 91031-48-0) and 2-Ethylhexyl Stearate (CAS 22047-49-0) was conducted. The substances were chosen based on their structural similarities regarding the branched alcohol component (2-ethylhexanol) and the linear fatty acid component (C8-12 and C16-18, respectively).

CAS 91031-48-0

A prenatal developmental toxicity study was performed with Fatty acids, C16-18, 2-Ethylhexyl esters (CAS 91031-48-0) 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 0, 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 systemic toxicity and the NOAEL for fertility 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 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 GLP conditions (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 0, 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 systemic toxicity and the NOAEL for fertility 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-/fetotoxicity and teratogenicity in rats for 2-Ethylhexyl Stearate was found to be 1000 mg/kg bw/day.

Conclusion on developmental toxicity

The available data for the source substances did not provide evidence to indicate that they negatively affect organogenesis or foetal development in utero. Thus, Fatty acids, C8-12, isopentyl ester is not expected to exhibit developmental toxicity/teratogenicity.

 

References

A detailed reference list is provided in the technical dossier (see IUCLID, section 13) and within the CSR.

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, C8-12, isopentyl ester, data will be generated from information on 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.

Therefore, based on the target substance information and analogue read-across approach, the available data on reproduction and developmental toxicity does not meet the classification criteria according to Regulation (EC) 1272/2008, and is therefore conclusive but not sufficient for classification.