Thirteen-week inhalation toxicity of carbon tetrachloride in rats and mice

Subchronic toxicity of carbon tetrachloride (CCl4) was examined by inhalation exposure of F344 rats and BDF1 mice of both sexes to 0, 10, 30, 90, 270 or 810 ppm (v/v) CCl4 vapor for 13 wk (6 h/d and 5 d/wk). In the high exposure levels at 270 and 810 ppm, altered cell foci in the livers of both rats and mice, and fibrosis and cirrhosis in the rat liver were observed. Hematoxylin and eosin-stained altered cell foci of rats were recognized as glutathione-S-transferase placental form (GST-P) positive foci, which are preneoplastic lesions of hepatocarcinogenesis. The most sensitive endpoint of CCl4-induced toxicity was fatty change with large droplets in rats of both sexes and male mice, and cytoplasmic globules in male mice, as well as increased relative liver weight in male rats. Those endpoints were manifested at 10 ppm and the LOAEL was determined as 10 ppm for the hepatic endpoints in rats and mice. Enhanced cytolytic release of liver transaminases into plasma in rats and mice and its close association with hepatic collapse in mice were observed at medium and high levels of inhalation exposure. Both CCl4-induced hematotoxicity and nephrotoxicity were observed in both rats and mice, but those toxicities were manifested at higher exposure concentrations than hepatotoxicity. The LOAEL for the hepatic endpoint and the GST-P-stained altered cell foci provide relevant animal data for reconsidering the occupational exposure limit val1ue of 5 ppm for CCl4 and strengthen the evidence of CCl4-induced hepatocarcinogenicity which is used in its carcinogenicity classification.