Toxicological Review of Methyl Chloride [and IRIS Summary] (External Peer Review Draft)
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Methyl chloride (CAS No. 74-87-3) is a gaseous chlorohydrocarbon under ambient conditions. It is principally used in the manufacture of silicones, agrichemicals, methyl cellulose and quaternary amines. Numerous case reports involving overexposure over the last 60 years indicate that it is a central nervous system depressant exhibiting effects such as ataxia, confusion, slurred speech, hallucinations, dizziness, coma, and death. Only one rodent chronic inhalation toxicology study has been conducted. Cerebellar degeneration was observed in both the rat and mouse at the highest concentration (1,000 ppm) tested. Shorter-term studies in other mouse and rat strains at lower concentrations and extended exposure times have also noted cerebellar degeneration. However, histopathological evidence of axonal swelling and degeneration in spinal nerves at the lowest concentration (50 ppm) in the chronic study was selected for the development of the RfC. These effects, as well as brain lesions, were also observed in dogs exposed continuously to 500 ppm for 3 days. An RfC of 0.02 mg/m3 was derived. An overall uncertainty factor of 1,000 was used in the derivation. The few human studies that examined MCs potential carcinogenicity have failed to demonstrate an association between exposure and cancer. In the two-year bioassay, renal adenomas were observed in the only male mouse kidney in the highest concentration group. Neoplasia was not found at any other site. This limited evidence, coupled with evidence of in vitro genotoxicity only at high concentrations in S. typhimurium and evidence that the probable mode of action for the induction of mouse renal tumors may not be relevant to humans under normal exposure conditions, suggest that MC would best be characterized as not likely to cause cancer in humans. Metabolic studies in rodents indicate that MC depletes glutathione and, in this process, generates reactive metabolites. The cytochrome P450 system also is important in the metabolic conversion of methyl chloride, but to a lesser extent than the glutathione pathway. Metabolic studies in humans have shown that there is a subset of individuals that metabolize MC more slowly than expected and demonstrate genetic polymorphisms. It is not known how these observations relate to possible human toxicity.