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Carcinogenicity

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Description of key information

No reliable carcinogenicity study is available for TAME. However TAME is not genotoxic, and the available repeated dose studies give no clear evidence that it can induce hyperplasia and/or pre-neoplastic lesions. An absence of structural alerts together with results from carcinogenicity testing for the related substance MTBE, indicate that carcinogenicity is not an endpoint of concern.

Key value for chemical safety assessment

Additional information

No reliable carcinogenicity study is available for TAME. Results are available from a single oral carcinogenicity study which is considered unreliable (Belpoggi et al, 2002). The dosing regime used to treat the animals was unusual and only two dose levels were used. Moreover, the animals were allowed to live out their natural life span and no adjustment for mortality was available. The neoplasia in this study were of lymphoid origin and derived from cells originating from the bone marrow, however, results from a mouse micronucleus study with TAME, which measure the substance’s ability to induce damage in chromosomes of the bone marrow cells, was negative. The publication’s reporting was inadequate in many aspects resulting in a low level of confidence of the results. Therefore, an analysis of effective group numbers and tumour incidence were difficult to analyse. As the study is deemed unreliable, a summary is not included in the CSR.

A reliable two-year drinking water guideline carcinogenicity study in Wistar rats is available with the structural analogue MTBE (methyl tertiary butyl ether) by the oral route. The reasons why MTBE is considered a suitable surrogate are included in a separate document attached to chapter 13 of the IUCLID dossier. These include the facts that comparable effects are observed in repeated dose toxicity studies of TAME and MTBE. The carcinogenicity study was conducted with exposure at 0, 0.5, 3, 7.5mg/ml in males and females, 0, 0.5, 3, and 15mg/ml (Dodd, 2010; 2013). The study showed body weights were unaffected and water consumption reduced in MTBE-exposed males and females. Wet weights of male kidneys were increased at the end of two years of exposure to 7.5mg/ml MTBE. Chronic progressive nephropathy was observed in males and females, was more severe in males, and was exacerbated in the high MTBE exposure groups. In this drinking water carcinogenicity study, a statistically significant finding of neoplasms was seen in the brain. One astrocytoma (1/50) was found in a female rat (15mg/ml). The incidence of brain astrocytomas in male rats was 1/50, 1/50, 1/50 and 4/50 for the 0, 0.5, 3 and 7.5mg/ml exposure groups, respectively. This was a marginally significant statistical trend, but not statistically significant when pairwise comparisons were made or when multiple comparisons were taken into account. The incidence of astrocytoma fell within historical control ranges for Wistar rats and the authors note that brain has not been identified as a target organ following chronic administration of MTBE or tertiary butyl alcohol (the prime metabolite) to mice and rats. The study report concludes that the astrocytomas observed were not associated with exposure to MTBE The conclusion that can be reached is that MTBE has no carcinogenic properties relevant to humans.

Negative results from mutagenicity studies on TAME suggest that mutagenicity is not a contributing mode of action in the formation of tumours. In addition, no evidence of pre-neoplastic lesions was observed in the available repeated dose studies with TAME. An absence of structural alerts together with results from carcinogenicity testing for the related substance MTBE, indicate that carcinogenicity is not an endpoint of concern for TAME.

Justification for classification or non-classification

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