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Genetic toxicity in vitro

A high number of in vitro studies on the genotoxic potential of 1,1-dichloroethene in vitro are available. An extensive review of these studies is provided in the CICAD report No 51 on 1,1-dichloroethylene (Benson, 2003) which concluded that overall, 1,1-dichloroethene appears to show genotoxic activity in in vitro testing systems, especially in the presence of metabolic activation.

1,1 -dichloroethene induced mutations in Salmonella typhimurium (TA100 and TA1530) in Ames test conducted in desiccator, in the presence of an exogenous metabolic activation system only (Bartsh et al., 1975). The Ara forward mutation test performed using Salmonella typhimurium BA13 and BAL13 elicited positive response in the presence of an external metabolizing system (Roldan-Arjona et al., 1991). In Saccharomyces cerevisiae, 1,1 -dichloroethene induced reverse mutation in D7 strain and aneuploidy in D61.M strain (Koch et al., 1988). In Aspergillus nidulans, 1,1 -dichloroethene was found to be positive for the induction of chromosome malsegregation (Crebelli et al., 1992). Chromosomal aberrations and Sister Chromatid Exchanges in vitro were found in Chinese Hamster lung fibroblast in the presence of metabolic activation (Sawada et al., 1987). In a mouse lymphoma assay conducted with L5178Y cells, 1,1 -dichloroethene showed positive response in the presence of metabolic activation and ambiguous results without metabolic activation (McGregor et al., 1991). However, in Chinese Hamster lung cells (V79), no mutagenic activity was found either in the absence or presence of metabolic activation (Bartsh et al., 1975). Result of Unscheduled DNA Synthesis (UDS) in vitro assay showed a positive response using hepatocytes from male Long-Evans rats.

Genetic toxicity in vivo

As indicated in 8.4.3. of Annex VIII, appropriate in vivo mutagenicity studies shall be considered in case of a positive result in any of the genotoxicity studies in Annex VII or VIII.

Several in vivo studies are available: Micronucleus studies (3 in mice, 1 in rats), Dominant Lethal assays (1 in rats, 1 in mice), and a Sex-Linked Recessive Lethal Mutation assay in Drosophila melanogaster addressing lethal mutations in germ cells. In addition 1 mechanistic study investigating DNA replication and DNA repair in both rats and mice and 1 gene profiling study in rats are provided. In 2016, an in vivo Comet assay has been added to the genotoxicity dataset.

- Chromosome aberrations

The 4 micronucleus studies provide information on the tendency of 1,1-dichloroethylene to lead to chromosome aberrations. As all 4 studies are negative, it can be concluded that 1,1-dichloroethylene does not exert such effects.

- Gene mutations

Information on the tendency of 1,1 -dichloroethylene to lead to gene mutations can be obtained from the 2 dominant lethal assays, although these studies are primarily aimed at detecting chromosomal aberrations. According to ECHA R7a guidance "The test identifies substances that induce dominant lethal effects causing embryonic or foetal death resulting from inherited dominant lethal mutations induced in germ cells of an exposed parent, usually the male." Indeed, OECD guideline 478 states that “dominant lethals are generally accepted to be the result of chromosomal aberrations (structural and numerical anomalies), but gene mutations and toxic effects cannot be excluded”. It can be concluded from this phrase that although chromosomal aberrations are the “main target” of the assay, a (strong) gene mutation activity might well have not gone undetected in the 2 dominant lethal assays performed with 1,1-dichloroethene. The 2 studies were however both negative.

- DNA damage

Information on the tendency of 1,1-dichloroethylene to incur DNA damage is available from the Comet assay. In the Comet assay, statistical significant and biologically relevant DNA damage without adverse histopathological findings was observed for some of the tested concentration in lung cells and kidney cells (lung: 1 mg/L (= 250 ppm; 1000 mg/m3); kidney: 1 mg/L (= 250 ppm; 1000 mg/m3) and 3 mg/L (= 750 ppm; 3000 mg/m3)) indicating that 1,1-dichloroethylene induced DNA damage in these cells. It has been concluded that the increased DNA damage observed, under the conditions of the test and in the absence of histopathological findings, is caused by a genotoxic effect. Furthermore, DNA damage was found to occur in combination with histopathological findings in lungs at and above 3 mg/L (750 ppm; 3000 mg/m3), in kidneys at 25 mg/L (6350 ppm; 25000 mg/m3) and in liver as of 1 mg/L (250 ppm; 1000 mg/m3).

- Germ cell mutagenicity

Information on the tendency of 1,1 -dichloroethylene to cause germ cell mutagenicity can be obtained from the two Dominant Lethal (DL) assays available, one in mice and another in rats. According to OECD guideline 478 (Rodent Dominant Lethal test), "DL mutations cause embryonic or fetal death. Induction of DL mutations after exposure to a test chemical indicates that the chemical has affected the germ cells of the test animal. A DL assay is useful for confirmation of positive results of tests using somatic in vivo endpoints, and is a relevant endpoint for the prediction of human hazard and risk of genetic diseases transmitted through the germline." As both DL assays available for 1,1 -dichloroethylene are negative, it can thus be concluded that 1,1 -dichloroethylene is not a germ cell mutagen.

As mentioned above, one Sex-Linked Recessive Lethal Mutation assay in Drosophilia melanogaster is also available. The test addresses lethal mutations in germ cells. The test showed no tendency of 1,1-dichloroethylene to cause germ cell mutations in insects, supporting the above conclusion.

Finally, one study by Reitz et al. (1980), is also included in the genotoxicity dataset. In this mechanistic study DNA replication and DNA repair in both rats and mice after inhalation exposure is examined. Reitz reported that exposure to tumorigenic doses of 1,1 -dichloroethylene resulted in massive tissue damage but induced minimal DNA alkylation or DNA repair synthesis.

Short description of key information:
- Chromosome aberration: based on 4 negative in vivo micronucleus tests it was concluded that 1,1 -dichloroethylene does not exert effects of chromosome aberration.

- Gene mutations: based on 2 negative dominant lethal assays does not exert a (strong) gene mutation activity.

- DNA damage: based on the in vivo Comet assay it was concluded that 1,1-dichloroethylene should be considered as genotoxic after a 3-day inhalation exposure of male Wistar rats.

- Germ cell mutagenicity: based on the 2 negative dominant lethal assays it was concluded that 1,1 -dichloroethylene is not a germ cell mutagen.

Endpoint Conclusion: Adverse effect observed (positive)

Justification for classification or non-classification

For the classification for germ cell mutagenicity, the possibility of the test substance to induce heritable mutations in the germ cells of humans has to be assessed.

Based on the positive in vivo Comet assay in male rats by inhalation, it is concluded that 1,1 -dichloroethylene incurs DNA damage in somatic cells. However, 1,1 -dichloroethylene did not induce dominant lethal mutations in mice and rat after inhalation exposure. Therefore, it can be concluded that 1,1 -dichloroethylene does not induce heritable genetic damage, and thus classification is not warranted in accordance with the EU regulation 1272/2008 on Classification, Labeling and Packaging of substances and mixtures (CLP).