Chloroform is a volatile liquid at room temperature and pressure. It is well-absorbed by inhalation, orally and dermally. The principal route of elimination is via the lungs. Carbon dioxide is the main metabolite but metabolism to carbon dioxide is a saturable process. Phosgene is formed during the metabolism of chloroform; it largely undergoes spontaneous hydrolysis to carbon dioxide and (notionally) hydrochloric acid. Conjugation with glutatnione, or binding to cellular macromolecules, may also occur, but only to a limited extent. Chloroform is of low to moderate acute toxicity, as judged by lethality, following inhalation, oral administration, or dermal application. Deaths due to chloroform are either immediate, as a result of respiratory depression during a period of narcosis, or delayed due to hepatotoxicity. The acute toxicity of chloroform shows considerable species, strain and sexdependenca; this appears to be due to differences in tissue distribution and metabolism. Liquid chloroform is highly irritant to the eyes and skin, although the vapour has not been reported to have irritant effects. In repeated exposure studies, exposure to 25 ppm (and above) of chloroform for 7 hours/day, 5 days/week, for 6 months led to histopathological changes in the livers and kidneys of rats, rabbits and guinea pigs. These changes were not evident in rats allowed a 6-week recovery period. When chloroform was administered to rats orally, by gavage, in a toothpaste-base, increases in the relative liver and kidney weights occurred at 150 mg/kg/day, whereas no effects were seen at 30 mg/kg/day. In mice and dogs, indications of liver and kidney toxicity were seen following doses of 37 and 15 mg/kg/day respectively, when chloroform was administered orally in a toothpaste base. Clear no-effect levels were not identified for these two species. The genotoxic potential of chloroform has been investigated in a number of studies both in vitro and in vivo. The results of these studies have generally been negative. However, there is a single unconfirmed study which suggests that chloroform may possess some clastogenic activity in the rodent bone-marrow following in vivo administration. Studies conducted in rats and mice have indicated that chloroform is carcinogenic in these species. Sex and strain specificity occurs. Renal tumours have developed in male but not female rats administered chloroform orally by gavage, and in male rats given chloroform in the drinking water. The oral administration of chloroform induces cholangiofibromas and cholangiocarcinomas in the female rat, and induces a dose-dependent incidence of hyperplastic nodules in the livers of rats of both sexes. When administered orally by gavage in a toothpaste-base or in arachis oil, chloroform-induced renal tumours have developed in male mice of the Alderley Park strain, but not in three other strains. A high proportion of B6C3F1 mice of both sexes developed hepatocellular carcinoma where chloroform was administered orally by gavage but not when it was administered in the drinking water. Reproductive studies in animals have shown that fetal abnormalities have occurred in rats (acaudia, short tail, imperforate anus) and in mice (cleft palate) following inhalation exposure of the dam to 100 ppm of chloroform for 7 hours/day during gestation. These effects were not seen in embryos of pregnant rats similarly exposed to 300 ppm chloroform. The incidence of cleft palate was seen in association with a severe decrease in fetal body weight. Although teratogenic effects have not been observed in studies where chloroform has been orally administered to rats, mice or rabbits, at doses producing signs of maternal toxicity, fetoxicity occurred. A clear no-effect level for the fetotoxicity has not been identified in oral or inhalation reproductive studies. Deaths have occurred during chloroform anaesthesia either from respiratory depression or cardiovascular effects. Delayed deaths have also been reported following chloroform anaesthesia and have been attributed to the hepatotoxic effects of chloroform. Information from studies on occupational exposure has indicated that chloroform concentrations of 21-77 ppm lead to a variety of minor complaints including headache, lassitude, depression and digestive disturbances. Concentrations of 205 ppm and above have led to increased incidences of hepatomegaly. Toxic jaundice has resulted from occupational exposure to chloroform at a reported concentration of at least 400 ppm. In one worker exposed to chloroform vapour for 45-minute periods twice weekly at concentrations of 725-758 ppm acute hepatonephritis occurred, as indicated by clinical chemistry evaluation and examination of renal and hepatic biopsy specimens. Toxaemia of pregnancy and eclampsia occurred in two workers occupationally exposed to chloroform at concentrations of 300-1000 ppm. However, exposure to unknown concentrations of other solvents also occurred. No information on the carcinogenic or genotoxic potential of chloroform in man is available.