Fatty acids, C16-18, 1,2-ethanediylbis(oxy-2,1-ethanediyl) esters

Endpoint summary

Additional information

Justification for grouping of substances and read-across

Data is available on thebacterial gene mutation propertiesof Fatty acids, C16-18, 1,2-ethanediylbis(oxy-2,1-ethanediyl) esters (3EO) (CAS 91031-45-7). However, no data are available for thecytogenicity in mammalian cells and the in vitro mammalian cell gene mutation properties of the target substance. In order to fulfil the standard information requirements set out in Annex VIII, 8.4, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006, read-across from structurally related substances is conducted.

In accordance with 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).

Having regard to the general rules for grouping of substances and read-across approach laid down in Annex XI, Item 1.5, of Regulation (EC) No 1907/2006 whereby substances may be predicted as similar provided that their physicochemical, toxicological and ecotoxicological properties are likely to be similar or follow a regular pattern as a result of structural similarity.

Overview of Genetic toxicity

CAS #	91031-45-7	68583-51-7	91031-31-1	151661-88-0	853947-59-8
Chemical name	C16-18, 1,2-ethanediylbis(oxy-2,1-ethanediyl) esters (3EO)	Decanoic acid, mixed diesters with octanoic acid and propylene glycol	Fatty acids, C16-18, esters with ethylene glycol	Fatty acids, C18 and C18 unsatd. epoxidized, ester with ethylene glycol	Butylene glycol dicaprylate / dicaprate
Molecular weight	388.58 - 683.1	328.49-384.59	300.48-563.00	328.54-622.97	342.52-398.63
Genetic toxicity (mutagenicity) in bacteria in-vitro	Negative	Negative	Negative	Negative	Negative
Genetic toxicity (cytogenicity) in mammalian cells in-vitro	RA: CAS 853947-59-8	--	--	--	Negative
Genetic toxicity (mutagenicity) in mammalian cells in-vitro	RA: CAS 91031-31-1	--	Negative	--	--
Genetic toxicity cytogenicity) in mammalian cells in-vivo	RA: CAS 151661-88-0	--	--	Negative	--

The above mentioned substances are considered to be similar on the basis of the structural similar properties and/or activities. The available endpoint information is used to predict the same endpoints for Fatty acids, C16-18, 1,2-ethanediylbis(oxy-2,1-ethanediyl) esters (3EO) (CAS 91031-45-7).

A detailed analogue approach justification is provided in the technical dossier (see IUCLID Section 13).

 

Discussion

Genetic toxicity in vitro

One study investigating the potential induction of gene mutation in bacteria by Fatty acids, C16-18, 1,2-ethanediylbis(oxy-2,1-ethanediyl) ester (3EO) is available (Banduhn, 1991). The study was conducted according to OECD guideline 471 under GLP conditions. The tester strains, Salmonella typhimurium TA 98, TA 100, TA 1535, TA 1537 and TA 1538 were used. The experiments of the main study were performed according to the plate incorporation procedure at concentrations from 8 to 5000 µg/plate in the first and at 1.6 to 1000 µg/plate in the second experiment with and without a metabolic activation system (Aroclor 1254-induced rat liver S9-mix). The included positive and negative controls in the experiments showed the expected results and were therefore considered as valid. No increase in the number of revertant colonies was observed in any of the bacterial strains, with and without metabolic activation system. No cytotoxicity was observed up to the precipitating concentration of 1000 µg/plate. Under the conditions of this study, the test substance did not induce mutations in the bacterial mutation tests in the absence and presence of a metabolic activation system in any of the strains tested.

There are no data available investigating the cytogenicity in mammalian cells of Fatty acids, C16-18, 1,2-ethanediylbis(oxy-2,1-ethanediyl) esters (3EO) (CAS 91031-45-7). In order to fulfil the standard information requirements set out in Annex VIII, 8.4, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006, read-across from the structurally related analogue substance Butylene glycol dicaprylate / dicaprate (CAS 853947-59-8) is conducted.

The study was performed in accordance with OECD guideline 473 under GLP conditions (Dechert, 1997). The induction of structural chromosome aberrations was evaluated in vitro in Chinese hamster lung fibroblasts (V79) cells, incubated for 18 and 28 h with and without a metabolic activation system (S9-mix from rats treated with Aroclor 1245). Concentrations of 10-100 µg/mL (18 h incubation) and 80 and 100 µg/mL (28 h incubation) of the test substance in the vehicle ethanol were applied. The solubility limit of the test substance in the culture medium was determined to be 100 µg/mL. The negative as well as the positive controls showed the expected results and were within the range of historical control data. The frequency of polyploidy cells with and without metabolic activation was within the expected range (< 10%). In the experiments both with and without metabolic activation, a systematic influence of the test substance was observed, which led to a reduction in the mitotic index. No statistically or biologically significant increase in the incidence of chromosome aberrations was observed. Therefore, under the conditions of the study, the test substance did not show clastogenic activity in this chromosomal aberration test with and without metabolic activation performed in Chinese hamster lung fibroblasts in vitro.

There are no data available investigating the mutagenicity in mammalian cells of Fatty acids, C16-18, 1,2-ethanediylbis(oxy-2,1-ethanediyl) esters (3EO) (CAS 91031-45-7). In order to fulfil the standard information requirements set out in Annex VIII, 8.4, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006, read-across from the structurally related analogue substance Fatty acids, C16-18, esters with ethylene glycol (CAS 91031-31-1) is conducted.

The in vitro mammalian cell gene mutation study of Fatty acids, C16-18, esters with ethylene glycol was carried out according to OECD guideline 476 under GLP conditions (Verspeek-Rip, 2010). Gene mutations in the thymidine kinase locus were investigated in L5178Y mouse lymphoma cells in the presence and absence of a metabolic activation system (Phenobarbital/β-naphtoflavone-induced rat liver S9-mix). In the first experiment, cells were exposed for 3 h to test substance at concentrations of 0.1-333 µg/mL (in DMSO) with and without metabolic activation. Concentrations of the second experiment without metabolic activation for an exposure time of 24 h ranged from 3 to 175 µg/mL and with metabolic activation (3 h; 12% S9-mix) from 0.1 to 333 µg/mL. The vehicle and positive controls in the study showed the expected results and were within the range of historical control data. No cytotoxicity was observed up to the precipitating concentration of 100 µg/mL and up to 333 µg/mL, respectively. There was no significant increase in the number of forward mutations at the thymidine kinase locus of L5178Y mouse lymphoma cells treated with the test material, neither in the presence nor in the absence of a metabolic activation system. Under the conditions of the study, Fatty acids, C16-18, esters with ethylene glycol did not show gene mutation activity in this test performed in L5178Y mouse lymphoma cells in vitro.

Genetic toxicity in vivo

Since no study is available investigating the cytogenetic properties in vivo of Fatty acids, C16-18, 1,2-ethanediylbis(oxy-2,1-ethanediyl) esters (3EO) (CAS 91031-45-7), a study with the structural related analogue substance Fatty acids, C18 and C18 unsatd., epoxidized, ester with ethylene glycol (CAS 151661-88-0) was considered.

The in vivo micronucleus assay with Fatty acids, C18 and C18 unsatd., epoxidized, ester with ethylene glycol was carried out according to OECD guideline 474 under GLP conditions (Banduhn, 1990). Based on the results of a preliminary dose range finding study, the test substance diluted in arachis oil was administered at 3000, 4000 and 5000 mg/kg bw as single oral doses to groups of 6 male and female CFW1 mice, observed for 24, 48 and 72 h post-dose. A concurrent negative control with the vehicle alone and a positive control group given cyclophosphamide were included in the study, showing the expected results. No mortality and no signs at clinical examinations were reported. The test substance did not induce a statistically significant increase in the number of micronucleated polychromatic erythrocytes in the bone marrow of the animals. Therefore, under the conditions of the study, Fatty acids, C18 and C18 unsatd., epoxidized, ester with ethylene glycol did not induce chromosomal mutations in the bone marrow of mice.

Conclusion for genetic toxicity

In summary, the study withFatty acids, C16-18, 1,2-ethanediylbis(oxy-2,1-ethanediyl) ester (3EO) investigatinggenetic mutations in bacteria in-vitro provided negative results. Furthermore, no cytogenicity in mammalian cells in-vitro (CAS 853947-59-8), no mutagenicity in mammalian cells in-vitro (CAS 151661-88-0) and no Genetic toxicity in-vivo (CAS 91031-31-1) was observed with structurally similar analogue substances.

Therefore, the available data do not provide any indications for a potential genetic toxicity of1,2-ethanediylbis(oxy-2,1-ethanediyl) ester (3EO).

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

Justification for selection of genetic toxicity endpoint
Hazard assessment is in part conducted by means of read-across based on an analogue approach. No study was selected since all available in vitro and in vivo genetic toxicity studies were negative. All available studies are adequate and reliable based on the identified similarities in structure and intrinsic properties between source and target substance and overall quality assessment (refer to the endpoint discussion for further details).

Short description of key information:
Negative results in Salmonella typhimurium TA 98, TA 100, TA 1535 and TA 1537, with and without metabolic activation (OECD 471, GLP).
Negative results in mammalian chromosomal aberration test with Chinese hamster lung cells (OECD 473, GLP).
Negative results in mammalian cell gene mutation tests using Chinese hamster ovary cells, with and without metabolic activation (OECD 476, GLP).
Negative results in mammalian erythrocyte micronucleus test in vivo (OECD 474, GLP).

Endpoint Conclusion: No adverse effect observed (negative)

Justification for classification or non-classification

Based on the available data of Fatty acids, C16-18, 1,2-ethanediylbis(oxy-2,1-ethanediyl) esters (3EO) (CAS 91031-45-7) and read-across from analogue substances following an analogue and weight of evidence approach, all available data on genetic toxicity do not meet the criteria for classification according to Regulation (EC) 1272/2008 or Directive 67/548/EEC, and the data are therefore conclusive but not sufficient for classification.