Fatty acids, C8-12, isopentyl esters

Endpoint summary

Description of key information

Based on a weight of evidence approach, all available subacute and subchronic repeated dose toxicity studies resulted in NOAELs of 800 mg/kg bw/day or greater. 

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 from reference 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).
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, C8-12, isopentyl ester. In order to fulfil the standard data requirements defined in Regulation (EC) No 1907/2006, Annex VIII, 8.6, 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 repeated dose toxicity are available for Fatty acids, C8-12, isopentyl ester, read-across to reliable data on the analogue substances Isopropyl Myristate (CAS 110-27-0); Fatty acids, C8-16, 2-Ethylhexyl esters (CAS 135800-37-2); Hexyl Laurate (CAS 34316-64-8); Fatty acids, C16-18 and C18-unsatd., branched and linear, bButyl Esters (CAS 163961-32-8) and Ethyl Oleate (CAS 111-62-6) was conducted for repeated dose toxicity. The substances were chosen based on their structural similarities regarding the branched alcohol component (Isopropyl Myristate (CAS 110-27-0) and Fatty acids, C8-16, 2-Ethylhexyl esters (CAS 135800-37-2)) and / or the linear fatty acid component (Isopropyl Myristate (C14; CAS 110-27-0), Fatty acids, C8-16, 2-Ethylhexyl esters (CAS 135800-37-2) and Hexyl Laurate (CAS 34316-64-8)). Furthermore, data of the structural analogue substances Fatty acids, C16-18 and C18-unsatd., branched and linear, Bu esters (CAS No. 163961-32-8) and Ethyl Oleate (CAS 111-62-6) were considered to allow a weight-of-evidence approach covering short and long chain fatty acids and saturated/unsaturated fatty acids.

 

CAS 110-27-0

A repeated dose 28-day oral toxicity study was performed with Isopropyl Myristate (CAS 110-27-0) equivalent to OECD Guideline 407 (Gloxhuber, 1982). Groups of 10 male and 10 female Wistar rats received daily oral gavage doses of the test substance at dose levels of 0, 100, 500 and 1000 mg/kg/day in olive oil. Concurrent negative control animals received the vehicle alone.

Clinical observations, body weight changes, haematology, clinical chemistry, organ weight measurements as well as gross and histopathological examinations revealed no treatment-related abnormalities or adverse effects. Based on the study results, the 28-day oral NOAEL for male and female Wistar rats was found to be 1000 mg/kg bw/day.

CAS 135800-37-2

The oral toxicity after daily oral administration for 28 consecutive days of Fatty Acids, C8-16, 2-Ethylhexyl esters (CAS 135800-37-2) was tested according to OECD guideline 407 and GLP (Fitzgerald, 1991). Groups of 5 male and 5 female Sprague-Dawley rats received daily oral gavage doses of the test substance in corn oil at dose levels of 0, 100, 300 and 1000 mg/kg bw/d. Concurrent negative control animals received the vehicle alone. Based on clinical observations, neurological observations, examination of various blood parameters (haematology and clinical chemistry), necropsy observations, organ weights, body weights, food consumption and histopathological findings, the 28-day oral NOAEL for male and female rats was found to be 1000 mg/kg bw/day.

CAS 34316-64-8

A 90-day oral feeding toxicity study with Hexyl Laurate (CAS 34316-64-8) was performed according to OECD guideline 408 (Potokar, 1973). Groups of 10 male and 10 female Wistar rats were continuously exposed to the substance at 10000 ppm in the diet via an automatic feeding system (approximately 800 mg/kg bw/day) for 90 days. Control animals received liquefied margarine. Animals were observed for clinical signs, body weight, food consumption, food efficiency, water consumption, haematology, clinical chemistry, urinalysis, organ weights, gross necropsy and histopathological examinations.

Overall there were no adverse effects found after feeding of the animals with the test substance for 16 weeks. The histopathologic changes in the liver and lung observed frequently occur in untreated ageing animals of both sexes and therefore are not considered as adverse effects. Therefore a 90-day oral NOAEL of 800 mg/kg bw/day was found for Hexyl Laurate in male and female rats.

CAS 163961-32-8

A 90-day oral gavage toxicity study with Fatty acids, C16-18 and C18-unsatd., branched and linear, Butyl esters (CAS 163961-32-8) was performed according to OECD guideline 408 and GLP (McRae, 2004). Groups of 10 male and 10 female Sprague-Dawley rats received daily oral gavage doses of the test substance in arachis oil at concentrations of 0, 5, 50 and 1000 mg/kg/day. Animals were observed for clinical signs, body weight, food consumption, food efficiency, water consumption, ophthalmoscopic examination, haematology, clinical chemistry, neurobehavioral examination, organ weights, gross necropsy and histopathological examinations.

At 1000 mg/kg bw/day, slightly elevated plasma cholesterol and creatinine levels were detected for males and a marginal effect on hepatocyte size was observed during the histopathologic examination in females. Males and females treated with 1000 mg/kg bw/day showed increased liver weight accompanied in 1000 mg/kg bw/day males only by an increase in spleen weight and in females only by increases in adrenal and kidney weight. No such effects were detected among animals from the remaining treatment groups. These effects were considered to be adaptive responses and not adverse effects. Therefore a 90-day oral NOAEL of 1000 mg/kg bw/day was found for Fatty acids, C16-18 and C18-unsatd., branched and linear, Butyl Esters in male and female rats.

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. Ethyl Oleate (EO) 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. 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, and 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 (actual dose received) when administered by daily feeding to rats for 91-days.

Conclusion on repeated dose toxicity

The available data show that the analogue substances do not possess intrinsic hazardous properties in regard to subacute and subchronic repeated dose toxicity. Therefore, based on common functional groups and structural similarities, Fatty acids, C8-12, isopentyl ester is considered to be non-hazardous following repeated exposure.

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 the repeated dose toxicity via the oral route do not meet the classification criteria according to Regulation (EC) 1272/2008 or Directive 67/548/EEC, and are therefore conclusive but not sufficient for classification.

There is no data available on repeated dose toxicity by the inhalation and dermal routes.