Page 9: Guidelines for Canadian Drinking Water Quality: Guideline Technical Document – Carbon Tetrachloride

Part II. Science and Technical Considerations - Continued

8.0 Kinetics and metabolism

8.1 Absorption

Carbon tetrachloride is readily absorbed from the gastrointestinal tract into the systemic circulation in animals. In rats, 80-86% of an orally administered dose of 14C-labelled carbon tetrachloride was excreted in the expired air within 10-18 h (Paul and Rubinstein, 1963; Marchand et al., 1970). The type of vehicle used and the mode of administration have been shown to influence the oral absorption rate in experimental studies. Although carbon tetrachloride was rapidly and extensively absorbed from the gastrointestinal tract of fasted rats when administered in water or as an Emulphor aqueous emulsion, corn oil markedly delayed its oral absorption (Kim et al., 1990a). Studies in rats comparing the pharmacokinetics of carbon tetrachloride after gastric infusion and bolus gavage show that peak blood carbon tetrachloride concentrations were higher after bolus dosing than after infusion over 2 h (Sanzgiri et al., 1995). Although no quantitative studies were found regarding absorption in humans after oral exposure to carbon tetrachloride, numerous case studies of accidental or intentional ingestion of carbon tetrachloride suggest that absorption of carbon tetrachloride from the gastrointestinal tract in humans is likely to be extensive (ATSDR, 2005).

Animal studies indicate that carbon tetrachloride is readily absorbed from the lung into the systemic circulation. In monkeys exposed to 46 ppm carbon tetrachloride for up to 5 h, an average of 30% of the total amount inhaled was absorbed (McCollister et al., 1951). Following inhalation exposure of mice to 5 µL 14C-labelled carbon tetrachloride for 10 min, uptake was determined to be 84% of the administered dose (Bergman, 1979). Rapid absorption of carbon tetrachloride from the lung was observed in rats exposed to 100 or 1000 ppm for 2 h (Sanzgiri et al., 1995). Immediately following exposure of rats, mice, and hamsters to 20 ppm carbon tetrachloride vapour for 4 h, the initial body burdens of 14C-labelled carbon tetrachloride equivalents were 12.1, 1.97, and 3.65 µmol, respectively (Benson et al., 2001). Although there is little quantitative information on the absorption of inhaled carbon tetrachloride in humans, it is likely readily absorbed as there are numerous cases of human toxicity following exposure to carbon tetrachloride vapour (ATSDR, 2005).

Dermal absorption of liquid carbon tetrachloride has been demonstrated in mice, guinea pigs, and rats (Tsuruta, 1975; Jakobson et al., 1982; Morgan et al., 1991); however, dermal absorption of carbon tetrachloride vapour is low. In monkeys, dermal exposure to 14C-labelled carbon tetrachloride vapour for 4 h resulted in negligible amounts of radioactivity in blood and expired air (McCollister et al., 1951). In humans, carbon tetrachloride can be absorbed through the skin, although not to the extent of absorption via the inhalation and oral routes of exposure (ATSDR, 2005). Dermal absorption was significant in volunteers who immersed their thumbs in liquid carbon tetrachloride for 30 min (Stewart and Dodd, 1964).

8.2 Distribution

Animal studies indicate that, once absorbed, carbon tetrachloride is distributed to all major organs as a function of blood flow and fat content of the tissues, with highest concentrations in the fat, liver, kidney, brain, lung, bone marrow, and adrenals (McCollister et al., 1951; Dambrauskas and Cornish, 1970; Marchand et al., 1970; Bergman, 1983; Paustenbach et al., 1986a; Sanzgiri et al., 1997; Benson et al., 2001). Sanzgiri et al. (1997) compared the uptake and distribution of carbon tetrachloride administered to rats by inhalation, gastric infusion, and oral bolus dosing. Carbon tetrachloride levels in all tissues were much lower in the gastric infusion group than in the oral bolus or inhalation group. For all three groups, carbon tetrachloride concentrations in fat increased slowly but progressively, reaching higher levels than in other tissues and remaining elevated for a much longer time. The liver had the highest carbon tetrachloride levels of all non-lipid tissues following oral bolus dosing; in contrast, carbon tetrachloride levels were lower in the liver than in any other organ in the gastric infusion group. These results suggest that the oral bolus dose likely exceeded the capacity of first-pass hepatic and pulmonary elimination (Sanzgiri et al., 1997). Quantitative studies on the distribution of carbon tetrachloride in humans are not available.

8.3 Metabolism

Carbon tetrachloride metabolism occurs primarily in the liver, although it may also occur in other tissues. In rats and mice, cytochrome P450 (CYP) 2E1 is primarily responsible for the bioactivation of carbon tetrachloride (Raucy et al., 1993; Wong et al., 1998). Studies in human liver microsomes have shown that CYP2E1 is the major human enzyme responsible for carbon tetrachloride activation at lower, environmentally relevant levels (Zangar et al., 2000). This isoenzyme catalyses the reductive dechlorination of carbon tetrachloride, forming the reactive trichloromethyl radical (CCl3·). Under anaerobic conditions, this radical can bind to lipids and proteins, react with hydrogen to produce chloroform (CHCl3), dimerize to form hexachloroethane, or undergo further reduction, producing carbon monoxide (Uehleke et al., 1973; Wolf et al., 1977). Aerobically, the trichloromethyl radical can react with oxygen, forming the trichloromethylperoxyl radical (CCl3OO·). This highly reactive radical may initiate lipid peroxidation or may react further, producing phosgene (COCl2) (Mico and Pohl, 1983; Pohl et al., 1984). Carbon dioxide is formed by the hydrolytic dechlorination of phosgene (Shah et al., 1979).

8.4 Excretion

Carbon tetrachloride is excreted primarily in exhaled air, in the faeces, and, to a lesser extent, in the urine. In animal studies, excretion of carbon tetrachloride and its metabolites has been shown to vary by species, dose, and route of exposure. Reynolds et al. (1984) orally administered a range of doses of 14C-labelled carbon tetrachloride to rats and then monitored the recovery of carbon tetrachloride and its metabolites in exhaled breath, liver, urine, and faeces for 24 h. At the lowest dose (0.1 mmol/kg), less than half of the dose was recovered in the breath: 28% as carbon dioxide, 19% as carbon tetrachloride, and <1% as chloroform. In contrast, at doses of 0.3 mmol/kg or higher, the majority of the dose (71-89%) was recovered in exhaled breath as carbon tetrachloride. Efficient first-pass removal of the lowest dose of carbon tetrachloride by the liver likely diminished the amount of carbon tetrachloride available for pulmonary clearance. As the dose of carbon tetrachloride increased, the fraction of the dose recovered as metabolites decreased, indicating that the metabolic capacity for carbon tetrachloride was saturated or impaired. Of total metabolites recovered in 24 h, the largest proportion were recovered as exhaled carbon dioxide (50-86%). A significant proportion of total metabolites was also recovered in the faeces (7-30%) and as chloroform in exhaled breath (0.3-19%); smaller fractions were recovered in the urine (2.7-9.7%) and liver (1.9-4.3%) (Reynolds et al., 1984).

Benson et al. (2001) exposed rats, mice, and hamsters to 20 ppm 14C-labelled carbon tetrachloride vapour by inhalation for 4 h. In the 48 h following exposure, 65-83% of the initial body burden of 14C activity was eliminated in exhaled breath as carbon dioxide and VOCs. Rats exhaled approximately 3 times as much radioactivity as VOCs (61%) than as carbon dioxide (22%), whereas mice and hamsters exhaled approximately equal amounts of radioactivity as VOCs and carbon dioxide (30-39%). Rats eliminated less than 10% of the initial body burden of carbon tetrachloride equivalents in urine and faeces combined, whereas mice and hamsters eliminated >20% in urine and faeces (Benson et al., 2001). In an earlier study by Paustenbach et al. (1986b), rats were repeatedly exposed to 100 ppm 14C-labelled carbon tetrachloride vapour for 1-2 weeks. Of the total radioactivity excreted in the 64-108 h following exposure, 32-59% was excreted in expired air as carbon tetrachloride, less than 2% was excreted in expired air as carbon dioxide, 32-62% was excreted in the faeces, and 4-8% was excreted in the urine (Paustenbach et al., 1986b). Based on a PBPK model developed to describe these results, a small amount of the initially metabolized carbon tetrachloride was directly converted to carbon dioxide and rapidly eliminated; however, the vast majority of metabolized carbon tetrachloride became bound in compartments and was slowly eliminated in the faeces and urine (Paustenbach et al., 1988).

There is little quantitative information available on the elimination of carbon tetrachloride in humans; however, unchanged carbon tetrachloride has been detected in the expired air following oral, inhalation, and dermal exposures (Stewart et al., 1961, 1963; Stewart and Dodd, 1964).

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