3-methoxybutyl acetate

Endpoint summary

Additional information

Non-human information

The key study is a bacterial mutation assay (Hoechst, 1992a).  This is a recognised core assay type for investigating mutation in vitro. 3 -Methoxybutyl acetate was tested in the standard Ames test protocol in both the absence and presence of auxiliary metabolic activation (S9) using Salmonella typhimurium strains TA1535, TA1537, TA1538, TA98 and TA100.  A range of doses was used up to 5000 µg/plate.  3 -Methoxybutyl was negative in this assay.

No further mutagenicity data are available for 3-methoxybutyl acetate.  However, following a consideration of the structure of 3-methoxybutyl acetate, together with data from structurally related materials, a conclusion on the likely genotoxic activity of 3-methoxybutyl acetate can be made.

3-Methoxybutyl acetate is a simple alkyl structure containing no structural features or chemical groups that alert to likely genotoxic activity when examined with established structure-activity (SAR) considerations (Ashby & Tennant, 1988).  On the basis of this SAR evaluation, 3-methoxybutyl acetate would not be expected to show any significant genotoxic activity. The available data from the Ames test on 3 -methoxybutyl acetate support this assessment.

3-Methoxybutyl acetate is a simple aliphatic ester. In animals, a first step will be the cleavage of the ester to produce 3-methoxybutan-1-ol and acetate. The genetic toxicology of 3 -methoxybutyl acetate can be considered to be primarily that of these two component chemicals.

Genotoxicity data are available for chemicals that are similar to 3 -methoxybutyl acetate or its primary metabolites following cleavage of the ester bond, and contain the same combination of groupings, namely a short-chain alkyl backbone, an ester moiety (or component alcohol and acetate) and/or a methoxy moiety. Data considered relevant to an assessment of 3-methoxybutyl acetate are summarised below.

-         Data relevant to the intact ester structure

n-Butyl acetate

n-Butyl acetate has been examined in the Ames test in a range of Salmonella strains (Zeiger et al 1992) and in E coli (Shimizu et al 1985). It has also been examined for the ability to cause cytogenetic effects in vitro (Ishidate et al 1984). n-Butyl acetate was negative in both Ames tests and also in the in vitro cytogenetic assay. n-Butyl acetate has also been examined in other assays and a summary is provided in the Table.

These data support the conclusion that the simple ester moiety in 3-methyoxybutyl acetate is not genotoxic.

-         Data relevant to the component alcohol (3-methoxybutan-1-ol)

3-Methoxybutan-1-ol

3-Methoxybutan-1-ol has been examined in the Ames test in a range of Salmonella strains (Hoechst, 1992b).  It was negative in this assay.

3-Methoxybutan-1-ol has also been evaluated in an in vitro mammalian cell gene mutation test with L5178Y mouse lymphoma cells (Notox, 2010). It was also negative in this assay. These data indicate that the alcohol moiety in 3-methoxybutyl acetate, a potential primary metabolite, is not genotoxic.

n-Butanol

n-Butanol has been examined in the Ames test in a range of Salmonella strains, including TA102 (McCann et al., 1975; Jung et al., 1992). It has also been examined for the ability to cause cytogenetic effects both in vitro (Lasne et al., 1984) and in vivo (in the mouse bone marrow, as cited in ECETOC, 2003) using the micronucleus endpoint. This endpoint can assess for both chromosomal damage and also numerical changes in chromosomes, i.e. aneuploidy. N-Butanol was negative in the Ames test and also negative in both cytogenetic assays. n-Butanol has also been examined in other assays and these confirm that n-butanol is negative in established assays for evaluating genotoxic activity. The one reported positive result is in an non-standard assay using Aspergillus, and the finding is not considered to indicate any significant genotoxic activity for n-butanol, especially in view of the negative findings in mammalian cells in assays that can assess for possible numerical chromosomal changes (in vitro and in vivo micronucleus assays).

These data support the conclusion that the linear C-4 alcohol moiety in 3-methoxybutan-1-ol is not genotoxic.

3-Methoxy-3-methyl-1-butanol

3-Methoxy-3-methyl-1-butanol has been examined in the Ames test using both a range of Salmonella strains and an E coli strain (FDSC, Hatano Res. Inst., 2002a). It has also been examined for the ability to cause cytogenetic effects in vitro in CHL cells (FDSC, Hatano Res. Inst., 2002b). 3-Methoxy-3-methyl-1-butanol was negative in both assays. 

These data are from a close structural analogue of 3-methoxybutan-1-ol , which contains all the features of 3-methoxybutan-1-ol and only differs in having a single additional methyl group. The negative results support the conclusion that the linear C-4 alcohol moiety in 3-methoxybutan-1-ol, together with the 3-methoxy group, is not genotoxic.

Butane-1,3-diol

Butane-1,3-diol has been examined for genotoxic activity both in somatic cells in the bone marrow using an in vivo cytogenetic assay and in germ cells using a dominant lethal assay (Hess et al., 1981). It was reported negative in both assays.

These data support the conclusion that the linear C-4 alcohol moiety in 3-methoxybutan-1-ol is not genotoxic. In addition, they indicate that any conversion of 3-methoxybutan-1-ol to butane-1,3-diol would not result in genotoxic activity.

-         Data relevant to the acid component (acetate)

Acetate is the ionic form of acetic acid and is a ubiquitous and essential component of normal cellular function. It has been well examined and is not considered to have any significant genotoxic activity (EU DAR, 2008).

A consideration of these relevant structural analogues provides data that are relevant to an assessment of 3 -methoxybutyl acetate including data in the categories of in vitro gene mutation and cytogenetic activity (including both chromosomal damage) and also in vivo cytogenetic activity in both somatic and germ cells. The results for these structural analogues are negative across the range of endpoints and support the available data for 3 -methoxybutyl acetate itself that show a lack of genotoxic activity.

There is no human information.

Citations

Ashby J and Tennant RW (1988) Chemical structure, Salmonella mutagenicity and extent of carcinogenicity as indicators of genotoxic carcinogenesis among 222 chemicals tested in rodents by the U.S. NCI/NTP. Mutat Res 204: 17-115.

EU DAR (2008) European Union Draft Risk Assessment: Initial risk assessment provided by the rapporteur Member State Germany for the existing active substance Acetic acid of the fourth stage of the review programme referred to in Article 8(2)of Council Directive 91/414/EEC.

Short description of key information:
Considering the data from 3-methoxybutyl acetate together with the data from these relevant structural analogues, it is possible to draw a conclusion based on a weight of evidence that 3-methoxybutyl acetate does not have any significant genotoxic activity. This is based on data from in vitro gene mutation and cytogenetic assays (including both chromosomal damage) and also data from in vivo cytogenetic assays in both somatic and germ cells. An evaluation of the chemical structure of 3-methoxybutyl acetate using established SAR considerations supports this conclusion.
In view of the lack of an alert for likely genotoxicity for 3-methoxybutyl acetate, together with the consistency of negative findings across a range of endpoints for the primary metabolite and structural analogues, it is considered unnecessary to conduct further genotoxicity testing on 3-methoxybutyl acetate itself. The available data are sufficient to draw a conclusion, based on a weight of evidence, that 3-methoxybutyl acetate has no significant genotoxic activity.

Endpoint Conclusion: negative for genotoxicity activity

Justification for classification or non-classification

According to criteria in Regulation (EC) No.1272/2008, the substance is not classified for gentoxicity. The weight of evidence indicates that 3 -methoxybutyl acetate has no significant genotoxic activity