Carbon tetrachloride exists as a colourless, volatile liquid at room temperature. It is well-absorbed by the oral, inhalation and dermal routes of exposure. One human volunteer study suggested that 60% of carbon tetrachloride inhaled was taken up by the lungs. Once absorbed, carbon tetrachloride and/or its metabolites are widely distributed in animals, the highest levels occurring in body fat. Carbon tetrachloride is metabolised via cytochrome P450-dependent dechlorination and subsequent free radical reactions, the free radical species generated probably being responsible for the toxic effects of carbon tetrachloride. Carbon dioxide and chloroform are exhaled metabolites of carbon tetrachloride in animals. In one study in rats, the proportions of unchanged carbon tetrachloride and of chloroform (the product of reductive metabolism) in expired air increased, relative to carbon dioxide (the product of oxidative metabolism) with increasing dose level, indicating saturation of carbon tetrachloride metabolism. Following inhalation or oral exposure in animals, a substantial proportion (approximately 30-50%) of the dose was exhaled as unchanged carbon tetrachloride or as carbon dioxide. Significant excretion also occurs in the faeces and, to a lesser extent, in the urine, although the nature of the metabolites present has not been identified. Carbon tetrachloride is of low acute lethality to animals. Inhalation LC50 values of 7228 ppm (for a 6-hour exposure) and 9528 ppm (for an 8-hour exposure) have been reported for the rat and mouse. Deaths resulted from CNS depression. Centrilobular hepatocyte degeneration (with a no-effect level of 50 ppm for a 7hour exposure in the rat) or central liver cell necrosis have been observed in several species. Oral LD50 values of 3000 mg/kg and above have been reported in a number of species but deaths occurred at 400 mg/kg in cats. Dermal LD50 values of greater than 10 g/kg have been reported in rabbit and guinea pig, although deaths occurred at 2000 mg/kg in another study in the guinea pig. Again, liver damage was the prominent effect following oral or dermal exposure, indications of liver damage have been observed following oral doses as low as 10 mg/kg (rat) and 32 mg/kg (mouse) Ethanol potentiates the acute hepatotoxic effects of carbon tetrachloride. In animal studies, carbon tetrachloride is a mild skin and eye irritant. No skin or respiratory sensitisation data were available. In inhalation studies involving repeated exposure for 7 hours/day for 3 months or more, no signs of toxicity or histopathological effects were observed in rats and guinea pigs at 5 ppm, rabbits at 10 ppm and, in one study, monkeys at 50 ppm. (In an early study, fatty degeneration of the liver was seen in monkeys repeatedly exposed to 50 ppm for 8 hours/day). At exposures two-fold or more higher than the above noobserved-effect levels, concentration-dependent fatty degeneration and cirrhosis of the liver was the principal effect observed. Such effects were also seen in dogs at 82 ppm. Kidney and testis degeneration was also noted in rodents at 200 ppm and above. A briefly-reported study claimed significant increases in serum aminotransferase activity, indicative of liver damage, in rats repeatedly exposed to 2.5 ppm (the lowest concentration tested) for 4 hours/day for 5 days. In inhalation studies involving continuous exposure for 90 days, fatty change and fibrosis in the liver were observed at 10 ppm in rats, guinea pigs, rabbits, dogs and monkeys. Liver damage at the histopathological level in rat, mouse and monkey occurred in one 90-day continuous exposure study at 25 ppm. In one study, body weight loss (monkey) or significantly decreased body weight gain (rabbit, guinea pig, dog) were observed but no treatment-related histopathological effects were noted at 1 ppm.Repeated oral administration of 1 mg/kg/day to rats and mice for 12 weeks resulted in no toxic effects being observed. Liver was the target organ at higher dose levels in rat and mouse. Carbon tetrachloride is not genotoxic in vitro in validated and well-conducted tests for reverse mutation in bacteria and chromosome damage and UDS in mammalian cells. When carbon tetrachloride was tested in fungal assays, genotoxic potential was observed but the significance of this finding is unclear. Carbon tetrachloride was not genotoxic in vivo when tested in a rat liver UDS assay. It was reported that an increase in chromatid damage occurred in a rat bone-marrow chromosome aberration test in vivo. There were several deficiencies in this study, however, and no firm conclusions could be drawn. Binding to DNA or alkylation of purines, but no DNA damage on performing alkaline elution, occurred following administration of carbon tetrachloride to rodents. Overall, the genotoxicity of carbon tetrachloride in vivo has been inadequately investigated; from the data available there is no good evidence for genotoxic activity. Several studies have shown that carbon tetrachloride is carcinogenic in the rat and mouse following repeated oral or parenteral administration, producing benign and/or malignant liver tumours. Where observations on the occurrence of non-neoplastic liver lesions were given, in most cases liver damage was seen at dose levels producing liver tumours. It is therefore likely that the liver tumours are a result of a non-genotoxic mechanism following chronic liver damage. There is also evidence that carbon tetrachloride is a liver carcinogen in rat by the inhalation route and in hamster by the oral route. Again, it would appear that the tumours arose as a consequence of chronic liver damage. Effects on fertility in animals have not been adequately investigated. Carbon tetrachloride was not teratogenic in a well-designed and conducted inhalation study in the rat which included a dose level resulting in significant maternal toxicity. There were also no indications of teratogenicity in other less adequate studies. Fetal death or retarded development have been observed in studies in rats and mice at maternally toxic exposure levels following inhalation, oral or parenteral administration. It appears that the potential for carbon tetrachloride to produce developmental effects at dose levels which are below the threshold for significant maternal toxicity has not been adequately tested. In limited studies using human volunteers, few or no adverse symptoms were reported following single inhalation exposures to 49-76 ppm for up to 21/2 hours c 158-254 ppm for 20-30 minutes. At higher exposure levels, CNS disturbances, nausea, vomiting and headache were noted. There are case reports outlining similar susceptibility in workers accidentally exposed. Ir contrast, one person died after exposure to 250 ppm for 15 minutes but the deceased had a history of heavy alcohol consumption. Liver, kidney or brain damage ha been observed following inhalation or ingestion incident in man. Alcohol consumption appears to be a contributory factor in many of these incidents. Reversible erythema, together with sensations of "cooling" or "burning", occurred on areas of skin in contact with carbon tetrachloride during a human volunteer study. With repeated exposure in humans, alcohol formed a likely contribution to toxic effects observed, especially i the more severe cases. Cirrhosis of the liver and othe cases of damage to liver and kidney, some fatal, occurred following repeated inhalation of unknown concentrations. Where exposure levels have been given, nausea, vomiting and other symptoms were reported in workers exposed to 45 ppm or above in twl studies and albuminuria was measured in some expos workers. No symptoms were noted following exposure to 0-9 ppm. No information is available on the genotoxicity or reproductive effects of carbon tetrachloride in humans. Although several case reports have implicated carbon tetrachloride as a cause of the liver cancers observed, the evidence has not been convincing. No firm conclusions can be drawn on the carcinogenic potential of carbon tetrachloride in humans from these case reports or from the one proportional mortality study available.