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Key value for chemical safety assessment

Additional information

The genotoxicity of tetrachloroethylene has been extensively investigated in experimental in vitro and in vivo test systems.

 

Convincing negative results have been obtained in an extensive series of bacterial tests (Bartsch et al, 1979; Kringstad et al, 1981; Haworth et al, 1983; Connor et al, 1985; Milman et al, 1988; Warner et al, 1988; Vamvakas et al, 1989) and in a mouse lymphoma gene mutation assay (National Toxicology Programme, 1986). However, metabolites of tetrachloroethylene associated to both the cytochrom P450 oxidation pathway (tetrachloroethylene oxide) as well as to the gluthathion-S-transferase conjugation pathway (S-1,2,2-trichlorovinylglutathione, S-1,2,2-trichlorovinylcystein and N-acetyl-S-1,2,2-trichlorovinylcysteine) have been identified as genotoxic in bacterial test systems. A positive result for clastogenicity and aneugenicity was obtained in a novel in vitro micronuleus test (Doherty et al, 1996), but this is considered to be unreliable as the test method and the cell system employed appear to be oversensitive and unspecific. Other in vitro have also produced negative findings, but deficiencies in the conduct and/or reporting of these studies prevent conclusions being drawn with full confidence.

 

Generally, the pattern of the in vivo results is negative. Tetrachloroethylene of high purity gave a negative response in two bone marrow cytogenetics studies (Cerna and Kypenova, 1977; Beliles et al, 1980; Rampy et al, 1978), in an i.p. erythrocyte micronucleus assay (Murakami and Horikawa, 1995), and in a gavage kidney SSB study (Potter, 1996). In the majority of these studies, exposure was up to doses causing systemic toxicity or presumed to cause systemic toxicity. A positive result was observed in an i.p. liver micronucleus test (Murakami and Horikawa, 1995); however, this was likely to be an unspecific effect (due to cytotoxicity) from direct exposure to tetrachloroethylene under unphysiological conditions (hepatectomy) or related to the mode-of-action of tetrachloroethylene for liver tumour induction in mice, which is peroxisome proliferation (not considered relevant for humans). A positive result (only at 1 hour but not at 23 hours after dosing) was also seen in an i.p. liver and kidney SSB study (Walles, 1986); however, again, this was likely to be the consequence of direct exposure to tetrachloroethylene in the i.p. cavity.

 

In humans, three studies have looked for evidence of genotoxicity in relation to occupational exposure to tetrachloroethylene (Ikeda et al, 1980; Toraason et al., 2003; Seiji K, 1990). These studies proved negative, but limitations in the design of two of them (the older ones) mean that no firm conclusions can be drawn.

 

Overall, although positive results were obtained in vitro with metabolites of tetrachloroethylene associated to both the cytochrome P450 oxidation pathway as well as to the gluthathione-S-transferase conjugation pathway, these were not expressed in vivo by relevant routes of exposure.


Justification for selection of genetic toxicity endpoint
No studies selected as overall evidence from available in vitro and in vivo studies indicate that tetrachloroethylene is not mutagenic.

Short description of key information:
Overall evidence from available in vitro and in vivo studies suggests that tetrachloroethylene is not mutagenic.

Endpoint Conclusion: No adverse effect observed (negative)

Justification for classification or non-classification

Considering the negative pattern of results obtained in the available studies, it can be concluded that tetrachloroethylene does not possess mutagenic activity in vivo. Based on these results, tetrachloroethylene does not need to be classified as mutagenic according to EU Directive 67/548/EEC and EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008.