Oral toxicity of carbon tetrachloride: acute, subacute, and subchronic studies in rats

This investigation was conducted to characterize the acute, subacute, and subchronic toxic potency of ingested carbon tetrachloride (CCl4). In the first acute and subacute toxicity study, male Sprague-Dawley rats of 300-350 g were gavaged with 0, 20, 40, or 80 mg CCl4/kg once daily for 5 consecutive days, rested for 2 days, and dosed once daily for 4 additional days. Rats of 200-250 g were gavaged with 0, 20, 80, or 160 mg CCl4/kg according to the same dosage regimen in the second acute and subacute study. In the first and second studies one group of rats at each dosage level was sacrificed for clinical chemistry and histopathological evaluation at 24 hr, 4 days, and 11 days after initiation of dosing. Single 20- and 40-mg/kg doses had no apparent toxic effect at 24 hr, although 80 mg/kg caused mild hepatic centrilobular vacuolization and significant increases in some serum enzyme levels. In general, there was progressively severe hepatic injury at each dosage level over the 11-day period. CCl4 was more hepatotoxic to the 200-250-g rats than to the 300-350-g rats. In the subchronic study, rats initially 200-250 g were gavaged 5 times weekly for 12 weeks with 0, 1, 10, or 33 mg CCl4/kg. Body weight and clinical chemistry indices were monitored during the 12 weeks of dosing and 2 weeks after cessation of dosing. A dose of 1 mg/kg had no apparent adverse effect; 10 mg/kg produced slight, but statistically significant increases in sorbitol dehydrogenase activity and mild hepatic centrilobular vacuolization; 33 mg/kg caused marked hepatotoxicity. Serum enzyme levels remained elevated during the 12-week dosing period, but returned toward normal within 13 days of cessation of CCl4 exposure. Microscopic examination of livers of the 33-mg/kg rats revealed cirrhosis, characterized by bile duct proliferation, fibrosis, lobular distortion, parenchymal regeneration, hyperplastic nodules, and single-cell necrosis. The fibrosis was not reversed within the 13-day recovery period.