Registration Dossier

Administrative data

Key value for chemical safety assessment

Additional information

Regarding the in vitro data, gene mutation tests with prokaryotes, a gene mutation study with mammalian cells and a chromosome aberration test with mammalian cells are available, all performed in accordance with (or to a method similar to) OECD guidelines and under GLP.

No mutagenic activity was seen in two well-conducted bacterial assays which were both considered key (Bayer AG, 1991 and Exxon Biomedical Sciences Inc, 1989a). A study incorporating the TA102 strain using the read across substance methyl t-butyl ether was also negative (RBM, 1996). A negative result was also observed in Chinese hamster ovary cell when the ability of TAME to cause point mutations was investigated (Microbiological Associates Inc., 1996a). However, TAME caused a clear increase of chromosome aberrations, which increased with dose, in Chinese hamster ovary cells in vitro when metabolic activation was present (Microbiological Associates Inc., 1996b). As the aberrations occurred only with S9 activation, it appears that one of the TAME metabolites causes the positive response in the chromosome aberration assay. At the first stage of the metabolic pathway tert-amyl alcohol and presumably formaldehyde are formed. For a structural analogue of TAME, MTBE, the role of formaldehyde in in vitro genotoxicity has been demonstrated by co-incubation with aldehyde dehydrogenase. MTBE was tested in an in vitro mouse lymphoma assay (which measures the frequency of forward mutations) and resulted in a positive result only in the presence of metabolic activation. This was hypothesised to have been caused by the formation of formaldehyde extracellularly. In the human body (in vivo) formaldehyde is not likely to play a significant role since it is cleared rapidly by formaldehyde dehydrogenase present in several tissues.

Furthermore, the available well-conducted in vivo micronucleus study (using a method similar to OECD guideline 474) in mice gave a negative response at all sampling times (Exxon Biomedical Sciences Inc, 1989b).

Moreover, the compound structure does not give rise to concern for mutagenic activity.


Short description of key information:
No mutagenic activity was observed in two bacterial assays or in a gene mutation test with Chinese hamster ovary cells (CHO/HGPRT). Although a clear positive result was obtained in the in vitro CHO clastogenicity assay in the presence of S9 activation, it is probable that the cause for this was formaldehyde, which is transiently formed during metabolism. However, formaldehyde is not likely to be a concern in vivo because it is efficiently cleared from the tissues by formaldehyde dehydrogenase. This is supported by the result from a valid mouse micronucleus study, which showed that TAME does not cause chromosome aberrations in vivo. TAME is therefore not mutagenic.

Endpoint Conclusion: No adverse effect observed (negative)

Justification for classification or non-classification

Based on the available data and in accordance with the EU Classification, Labeling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008, classification is not necessary for mutagenicity.