Isopentyl acetate

Endpoint summary

Key value for chemical safety assessment

Genetic toxicity in vitro

Description of key information

The following information in vitro information is available:

7.6.1.001: Study performed according to OECD TG 471 (Bacterial Reverse Mutation Assay, Ames Test), test substance: isoamyl acetate.

Result: clearly negative. ZEIGER et al.; ENVIRON. MOL. MUTAGEN. 19, SUPPL. 21: 2-141, 1992; essential data on pages: 2, 3, 7, 88, 89

7.6.1.002: Study performed with methodology equivalent or similar to OECD TG 471 (Bacterial Reverse Mutation Assay, Ames Test), test substance:

CAS 123-92-2 (isopentyl acetate); result: negative, without metabolic activation. Toxnet (EMIC): ISHIDATE et al., FOOD CHEM TOXICOL 22(8): 623-636,1984.

7.6.1.003: in vitro mammalian chromosome aberration test; result: (-) negative, without metabolic activation. ISHIDATE et al., FOOD CHEM TOXICOL 22(8): 623-636, 1984.

7.6.1.004: The ability of the test substance to induce mitotic chromosomal malsegregation, mitotic recombination, and point mutation in a diploid yeast strain was investigated. Result: "negative". ZIMMERMANN FK et al., MUTAT RES 149, p. 339-351, 1985

7.6.1.005: bacteria reverse mutation assay (isoamyl acetate); result: "negative"

7.6.1.006: mammalian cell gene mutation study (isoamyl acetate); result: "negative"

7.6.1.007: in vitro mammalian chromosome aberration test (n-pentyl acetate, 2-methylbutyl acetate); result: "negative"

7.6.1.008: mammalian cell gene mutation assay (n-pentyl acetate, 2-methylbutyl acetate); result: "negative"

7.6.1.009: in vitro mammalian cell micronucleus test (3-methyl-1-butanol); result: "negative"

7.6.1.010: mammalian cell gene mutation assay (3-methyl-1-butanol); result: "negative"

7.6.1.011: mammalian cell gene mutation assay (3-methyl-1-butanol); result: "negative"

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (negative)

Genetic toxicity in vivo

Description of key information

The following information in vivo information is available:

7.6.2.001: in vivo mutagenicity (3-methylbutanol-1), OECD TG 474: Mammalian Erythrocyte Micronucleus Test; result: "negative"

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (negative)

Additional information

In bacteria gene mutation studies all results were "negative" (tested substance isopentyl acetate). In all mutagenicity and cytogenicity studies on isopentyl acetate or closely related substances which where considered as acceptable for the read across approach, the result was "negative".

For the judgement on in vitro cytogenicity and mutagenicity in mammalian cells plus in vivo mutagenicity (standard information requirement under "8.4 Mutagenicity", Annex VIII of REACH), a weight of evidence (WoE) approach was chosen. For this purpose adequate studies on isopentyl acetate itself, closely related structural isomers (n-pentyl acetate (CAS Nr. 628-63-7), 2-methylbutyl acetate (CAS Nr. 624-41-9) or 3-methyl-1-butanol (CAS Nr. 123-51-3) were used.

All data presented under "7.6.1 Genetic toxicity in vitro" of this IUCLID dossier where the purpose flag is set on Weight of Evidence are part of this WoE argument, and the conclusion is "no adverse effect observed (negative)". All data presented under "7.6.2 Genetic toxicity in vivo" of this IUCLID dossier where the purpose flag is set on Weight of Evidence are part of this WoE argument, and the conclusion is "no adverse effect observed (negative)".

The implementation of the weight of evidence approach was guided by information on WoE in "Guidance on information requirements and chemical safety assessment, Chapter R.4: Evaluation of available information" (ECHA, December 2011) and "Guidance on information requirements and chemical safety assessment, Chapter R.5: Adaptation of information requirements" (ECHA, December 2011).

Justification for read-across as part of WoE (1):

3-methyl-1-butanol is suspected to be the immediate metabolite of isopentyl acetate upon hydrolysis in the body (besides acetic acid which is assumed to exhibit low toxicity). Based on the information in the WHO Food Additives Series 40 (1998), “Esters of aliphatic acyclic primary alcohols with aliphatic linear saturated carboxylic acids” and supporting information in Dahl et al. (1987), the hydrolysis of isopentyl acetate in the body can be assumed:

Information in the WHO document:

“ 2.3.1 Absorption and metabolism

Generally, linear and branched-chain alkyl esters are hydrolysed to their component alcohols and carboxylic acids in the intestinal tract, blood and most tissues throughout the body…”

Reference Dahl et al. (1987):

Carboxylesterases in the respiratory tracts of rabbits, rats and Syrian hamsters; Dahl et al., Toxicology Letters, 36, 129-136 (1987).

From the introductory abstract of Dahl et al.: "... Because esters are often volatile and, therefore, readily inhaled, the capacity of respiratory tract tissues as well as liver S-9 homogenates from rats, rabbits, and Syrian hamsters to hydrolyze a variety of esters was investigated. A new technique to deterrnine hydrolysis rates by measuring carboxylic acid residues using ion chromatography was proven effective. The results indicated that esters, including potentially carcinogenic ß-Iactones, are readily hydrolyzed by respiratory tract enzymes. ..."

The read-across approach with 3-methyl-1-butanol is therefore regarded as appropriate.

Justification for read-across as part of WoE (2):

The constituents of the tested mixture of n-pentyl acetate/2-methylbutyl acetate (65%/35 %) are esters of acetic acid and a structural isomer of pentanol (branched as for 2-methyl-1-butanol and linear as for n-pentanol). The target compound isopentyl acetate or synonymously 3-methyl-1-butyl acetate is a closely related ester consisting of one molecular part acetic acid and 3-methyl-1-butanol (which is a branched structural isomer of pentanol). The esters themselves are in fact all structural isomers (“pentyl acetates”).

The read-across approach with a mixture of n-pentyl acetate/2-methylbutyl acetate (65%/35 %) is therefore regarded as appropriate. The delivered information is in particular relevant to point to a potential genotoxic effect of isopentyl acetate before it is hydrolysed.

Justification for classification or non-classification

No positive results were found in mutagenicity and cytogenicity studies on bacteria and mammalian cells or in an in-vivo mutagenicity study in which isopentyl acetate itself or acceptable read-across substances were used. Therefore the substance is regarded as not mutagenic and will accordingly not be classified.