2-chloroethanol

Endpoint summary

Additional information

In NTP TR 275 a summary is given of avaialable literature on genotoxicity (page 17 -18 and 58 -59):

"The genetic toxicity of 2-chloroethanol has been investigated in a wide variety of short-term studies, and the results are summarized in Table 1. 2 -Chloroethanol is a weak base-pair substitution mutagen in bacteria but is essentially negative in a variety of other systems, including fungi, Drosophila, mammalian cell cultures, and rodents. Of 17 studies in Salmonella, 14 show that 2-chloroethanol is a direct-acting base-pair substitution mutagen in Salmonella typhimurium strains TA1530, TA1535, and TA100 (Rosenkranz et al., 1974; Rosenkranz and Wlodkowski, 1974; Bartsch et al., 1975; Malaveille et al., 1975; McCann et al., 1975; Rannug et al., 1976; Lofroth, 1978; Nakamura et al., 1979; Rannug and Beije, 1979; Bignami et al., 1980a,b; Pfeif'fer and Dunkelberg, 1980; Stolzenberg and Hine, 1980; NTP TR 275, Appendix F). Confirmatory results have been obtained in other bacteria, including Klebsiella pneumoniae (Voogd and van der Vet, 1969; Voogd et al., 1972; Voogd, 1973) and Escherichia coli (Norpoth

et al., 1980); however, this chemical was negative in the bacterium Streptomyces coelicolor (Bignami et al., 1980a,b). The addition of

rat liver S9 enhanced the mutagenicity of 2 - chloroethanol in Salmonella, suggesting that 2 - chloroethanol is metabolized to an additional mutagenic form.

2-Chloroethanol induced DNA damage in E. coli (Rosenkranz et al., 1974; Rosenkranz and Wlodkowski, 1974) but not in Bacillus subtilis (Elmore et al., 1976; Laumbach et al., 1977). 2 - Chloroethanol was not mutagenic in yeast (Loprieno et al., 1977; Barale et al., 1979) and did not induce mitotic gene conversion in yeast (Loprieno et al., 1977); however, it was mutagenic in the fungus Aspergillus nidulans (Bignami et al., 1980a,b). 2-Chloroethanol did not induce sex-linked recessive-lethal mutations in Drosophila (Knaap et al., 1982; NTP TR 275, Appendix F), and it did not cause somatic crossing over in soybeans Wig, 1975). However, it was reported to induce abnormal metaphase chromosomes in onion root tips (Barthelmess and Elkabarity, 1962).

In mammalian cells in vitro, 2-chloroethanol was not mutagenic (Huberman et al., 1975; Knaap et al., 1982) and did not inhibit DNA synthesis (Painter and Howard, 1982). However, it did induce DNA repair in human fibroblasts in vitro (Stich et al., 1976). Isakova et al. (1971) reported that 2-chloroethanol increased the frequency of chromosomal aberrations in rat bone marrow after the animals were exposed by inhalation; however, detailed data were not provided.

Neither chromosomal aberrations nor micronuclei were found in mouse bone marrow cells after exposure to 2-chloroethanol by either the oral or intraperitoneal injection routes (Conan et al., 1979). In addition, 2-chloroethanol did not induce dominant-lethal mutations (Epstein et al., 1972) or heritable translocations in the mouse (Sheu et al., 1983)."

"2-Chloroacetaldehyde alkylates DNA (Oesch and Doerjer, 1982), causes errors during in vitro DNA synthesis (Hall et al., 1981), and is mutagenic

in bacterial virus (Garro and Phillips, 1980) and bacterial DNA transformation systems (Phillips et al., 1980). 2-Chloroacetaldehyde is weakly mutagenic and recombinogenic in yeast (Loprieno et al., 19771, is mutagenic in the fungus Aspergillus nidukizns (Bignami et al., 1980a,b) as well as in mammalian cell cultures (Huberman et al., 1975), and inhibits interferon induction when mouse embryo fibroblasts are challenged with Newcastle disease virus (Sonnenfeld et al., 1980). 2 -Chlorsacetaldehyde is more mutagenic in Salmonella than is the parent compound, 2-chloroethanol.

The addition of liver S9 reduces the mutagenicity of 2-chloroacetaldehyde, possibly by oxidation to chloroacetic acid, which is not mutagenic in

Salmonella (McCann et al., 1975; Bartsch et al., 1980; Bignami et al., 1980b1, E. coli (Mamber et al., 1983), or mammalian cells (Huberman et al.,

1975). Amacher and Turner (1982) reported, however, that chloroacetic acid may be weakly mutagenic in the mouse lymphoma assay in the

presence of liver S9.

In vivo studies in rats (Green and Hathway, 1977; Rannug and Beije, 1979) showed that 2 - chloroacetaldehyde is conjugated with glutathione by a glutathione S-epoxide transferase to produce a series of S-containing metabolites that are not mutagenic in Salmonella.

Taken together, these results suggest that 2 -chloroethanol is a weak mutagen that is metabolized to 2-chloroacetaldehyde, a potent mutagen and

alkylating agent. This metabolite then can be converted to 2-chloroacetic acid, which is not mutagenic, or conjugated to glutathione to form a series of nonmutagenic S-conjugates. The detoxification of 2-chloroacetaldehyde could prevent the realization of any carcinogenic potential of 2chloroethanol. The short-term test results for 2-chloroethanol (i.e., positive in bacteria but negative in a variety of eukaryotes, including fungi, Drosophila, mammalian cells, and rodents) support this view."

Short description of key information:
See discussion section.

Endpoint Conclusion:

Justification for classification or non-classification

2-chloroethanol is not classified as a germ cell mutagen.

2 -Chloroethanol is a weak base-pair substitution mutagen in bacteria but is essentially negative in a variety of other systems. 2-chloroethanol did not induce dominant-lethal mutations or heritable translocations in the mouse.