Acute, short-term, and subchronic oral toxicity of 1,1,1-trichloroethane in rats

1,1,1-Trichloroethane (TRI) is a widely used solvent that has become a freq uent contaminant of drinking water supplies in the U.S. There is very littl e information available on the potential for oral TRI. to damage the liver or to alter its P450 metabolic capacity. Thus, a major objective of this in vestigation was to assess the acute, short-term, and subchronic hepatotoxic ity of oral TRI. In the acute study, male Sprague-Dawley (S-D) rats were ga vaged with 0, 0.5, 1, 2, or 4 g TRI/kg bw and killed 24 h later. No acute e ffects were apparent other than CNS depression. Other male S-D rats receive d 0, 0.5, 5, or 10 g TRI/kg po once daily for 5 consecutive days, rested fo r 2 days, and were dosed for 4 additional days. Groups of the animals were sacrificed for evaluation of hepatotoxicity 1, 5, and 12 days after initiat ion of the short-term experiment. This dosage regimen caused numerous fatal ities at 5 and 10 g/kg, but no increases in serum enzymes or histopathologi cal changes in the liver. For the subchronic study, male S-D rats were gava ged 5 times weekly with 0, 0.5, 2.5, or 5.0 g TRI/kg for 50 days. The 0 and 0.5 g/kg groups were dosed for 13 weeks. A substantial number of rats rece iving 2.5 and 5.0 g/kg died, apparently due to effects of repeated, protrac ted CNS depression. There was evidence of slight hepatocytotoxicity at 10 g /kg, but no progression of injury nor appearance of adverse effects were se en during acute or short-term exposure. Ingestion of 0.5 g/kg over 13 weeks did not cause apparent CNS depression, body or organ weight changes, clini cal chemistry abnormalities, histopathological changes in the liver, or fat alities. Additional experiments did reveal that 0.5 g/kg and higher doses i nduced hepatic microsomal cytochrome P450IIE1 (CYP2E1) in a dose- and time- dependent manner. Induction of CYP2E1 activity occurred sooner, but was of shorter duration than CYP2B1/2 induction. CYP1A1 activity was not enhanced. In summary, 0.5 g/kg po was the acute, short-term, and subchronic NOAEL fo r TRI, for effects other than transient CYP2E1 induction, under the conditi ons of this investigation. Oral TRI appears to have very limited capacity t o induce P450s or to cause liver injury in male S-D rats, even when adminis tered repeatedly by gavage in near-lethal or lethal dosages under condition s intended to maximize hepatic effects.