Pharmacokinetics and metabolism of inhaled methyl chloride in the rat and dog.

Methyl chloride (MeCl) metabolism and pharmacokinetics were studied in male Fischer 344 rats and male beagle dogs. Apparent steady-state blood MeCl concentrations were proportionate to exposure concentration in rats and dogs exposed to 50 and 1000 ppm. Furthermore, blood MeCl concentrations were similar in both species when they were exposed to the same concentration. A linear two-compartment open model described the blood MeCl data: alpha and beta phase elimination half-times corresponded to approximately 4 and 15 min, respectively, in rats, and 8 and 40 min in dogs. Rats exposed for 6 hr to 0, 50, 225, 600, or 1000 [14C]MeCl were evaluated for tissue nonprotein sulfhydryl (NPSH), total 14C activity, nonextractable tissue 14C activity, and urinary metabolites. MeCl-induced NPSH depletion was dose-related and was greatest in liver. Total 14C in liver and kidney was approximately proportionate to exposure concentrations. Relative concentrations of nonextractable 14C decreased at 600 to 1000 ppm MeCl suggesting a dose-dependent metabolic pathway for MeCl in the rat. Metabolites in urine included N-acetyl-S-methylcysteine, methylthioacetic acid sulfoxide, and N-(methylthioacetyl)glycine. These metabolites are likely to be products of a reaction between MeCl and glutathione. A nonradiometric analysis of a putative MeCl metabolite (S-methylcysteine) was performed in dogs exposed to MeCl; this method was not a sensitive indicator of MeCl exposure.