Metabolism of ¹⁴C-dichloroethyne in rats

Abstract

1. The metabolism of ¹⁴C-dichloroethyne was studied in rats by inhalation in a dynamic nose-only exposure system. ¹⁴C-Dichloroethyne was generated in 95–99% yield from ¹⁴C-trichloroethene by alkaline dehydrochlorination.

2. After inhalation of 20 ppm and 40 ppm dichloroethyne for 1 h, the retention rates were 17.6% and 15.6% of the radioactivity introduced into the exposure system, respectively. During the period of observation (96 h), almost quantitative elimination of the dose was observed. Elimination with urine accounted for 60.0% (40ppm) and 67.8% (20ppm) of absorbed radioactivity and elimination with faeces for 27% (40ppm) and 27.7% (20ppm), 3.4-3.5% remained in the carcasses.

3. Metabolites of dichloroethyne identified are: N-acetyl-S-(1,2-dichlorovinyl)-L-cysteine, dichloroethanol, dichloroacetic acid, oxalic acid and chloroacetic acid in urine; N-acetyl-S-(1,2-dichlorovinyl-L-cysteine in faeces.

4. In bile of rats exposed to 40ppm of dichloroethyne, S-(1,2-dichIoro-vinyl)glutathione was the only metabolite identified. Biliary cannulation did not influence the renal excretion of N-acetyl-S-(1,2-dichlorovinyl)-L-cysteine, indicating that glutathione conjugate formation occurs in the kidney.

5. The results suggest that two metabolic pathways are operative in dichloroethyne metabolism in vivo. Cytochrome P450-dependent oxidation represents a minor pathway accounting for the formation of 1,1-dichloro compounds after chlorine migration. The major pathway is the biosynthesis of toxic glutathione conjugates. Organ-specific toxicity and carcinogenicity of dichloroethyne is due most likely to the topographical distribution of γ-glutamyl transpeptidase which is concentrated mainly in the kidney in rats.