Reproductive effects of inhaled methyl chloride in the male Fischer 344 rat. I. Mating performance and dominant lethal assay

Abstract

Methyl chloride (MeCl) is a direct-acting mutagen in bacteria, induces renal adenocarcinomas in male mice, and is a potent reproductive toxicant in the male Fischer 344 (F-344) rat. A dominant lethal assay was performed to examine the possibility that MeCl may be a germ cell mutagen in the F-344 male rat. Groups of 40 rats each were exposed to 0, 1000, or 3000 ppm MeCl 6 hr/day for 5 consecutive days, or received a single ip injection of 0.2 mg triethylenemelamine (TEM)/kg as a positive control. Each male was bred to a single female weekly for 8 weeks, and the standard criteria of dominant lethal tests were recorded. Exposure to 1000 ppm MeCl caused no consistent change in any parameter relative to control values. TEM caused increases in pre- and postimplantation loss indices in Weeks 1 to 5 postexposure, corresponding to sperm exposed in the epididymis and as early to late stage spermatids in the testis. Exposure to 3000 ppm MeCl caused a slight increase in postimplantation loss at Week 1 postexposure only, i.e., in sperm exposed in the epididymis or vas deferens, and increases in preimplantation loss throughout the 8 weeks postexposure. Fertility of the 3000 ppm MeCl-exposed males was significantly decreased by Week 2 after exposure, and never recovered to control values during the period of observation. It is suggested that the increased preimplantation losses are due, at least in part, to cytotoxic rather than genotoxic effects. High concentrations of inhaled MeCl, however, do induce dominant lethal mutations (reflected as an increased level of postimplantation fetal deaths) in sperm located within the vas deferens and epididymis at the time of exposure.