INHALATION TOXICOLOGY OF DIMETHYLACETAMIDE (DMAC) IN MICE AND RATS: AGE-RELATED EFFECTS ON LETHALITY AND TESTICULAR INJURY

Abstract

Two 10-day inhalation toxicity studies were conducted with dimethylacetamide (DMAC, CAS no. 127-19-5). In one study, pubescent Crl:CD-1 mice (35 days old) were exposed to DMAC at 30, 100, 310, 490, or 700 ppm for 6 h/day, 5 days/wk for 10 days. Although well tolerated up to 310 ppm, exposure to 490 ppm or greater caused severe clinical signs and mortality. Hematologic changes in these groups included reduced erythrocyte and platelet counts, reduced hemoglobin concentration, and reduced hematocrit. Relative testes weights were decreased and relative liver weights were increased. In addition, centrilobular hepatocellular necrosis and hypertrophy, lymphoid organ atrophy and necrosis, bone marrow hypoplasia, and cortical adrenal gland necrosis occurred; these pathologic changes were not seen in mice from these groups sacrificed after a 14-day recovery period. Testicular damage, consisting of degeneration of seminifierous tubules and oligospermia, occurred in a concentration-dependent manner in mice exposed to from 310 to 700 ppm DMAC. In the mice showing lesser testicular injury, some evidence of reversibility was seen after a 14-day recovery period. Since the toxicity of DMAC was thought to be attributable to the use of pubescent mice, a second study was conducted with older, young adult mice (62 days old) and with rats (47 days old) at concentrations of 0, 52, 150, 300, and 480 ppm DMAC. While no mice died in this study, similar but morphologically less severe testicular lesions were noted but only at 480 ppm; sperm counts and testes weights in all groups were similar to controls. No adverse effects on body weights, clinical signs, testicular weights, or pathology were found in rats at any exposure level. The no-observed-adverse-effect level in this study was 100 ppm DMAC for pubescent mice and 300 ppm for young adult mice. Pubescent mice appeared to be more sensitive to the testicular effects of DMAC than young adult rats or mice.