Tetrachloroethylene

Endpoint summary

Description of key information

Short description of key information on bioaccumulation potential result: tetrachloroethylene is rapidly and extensively absorbed by the inhalation and oral routes of exposure. Hence, an inhalation and oral absorption of 100% are assumed. Skin absorption of liquid tetrachloroethylene has been detected in studies in humans, animals and in vitro. For tetrachloroethylene a worst-case absorption value of 50% is appropriate for risk assessment purposes. Human and animal evidence indicates that relatively little of the absorbed tetrachloroethylene is metabolised; the fraction of the absorbed dose which is metabolised decreases with increasing dose in a manner consistent with saturable metabolism. Maximum rates of metabolism have been measured in mice in which 25% of a low dose (20 mg/kg/day) was metabolised, compared with only 5% of a high dose (2000 mg/kg/day). In humans, less than 2% of the retained amount of tetrachloroethylene was metabolised and excreted in the urine within 67 hours following a 3-hour exposure to 87 ppm (600 mg/m3). A mean half-life of about 144 hours for the elimination of urinary metabolites following inhalation exposure has been calculated in humans. The metabolites of tetrachloroethylene are excreted in the urine (approx. 8% of an inhaled dose), with very low percentages of the absorbed amount exhaled as carbon dioxide (1%) or eliminated in the faeces (2%). The half-life of elimination of tetrachloroethylene in humans is estimated to be 6-10 days.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

Extensive investigations of the toxicokinetics of tetrachloroethylene have been conducted in animals and also in humans. In both humans and animals, tetrachloroethylene is rapidly and extensively absorbed by the inhalation and oral routes of exposure. Hence, an inhalation and oral of 100% are assumed. Skin absorption of liquid tetrachloroethylene has been detected in studies in humans, animals and in vitro. The rate of skin penetration appears to be markedly lower than for other solvents, with both the experimental data and the physico-chemical properties of tetrachloroethylene indicating that a worst-case absorption value of 50% is appropriate for risk assessment purposes. Although a study in animals suggested substantial dermal absorption of tetrachloroethylene vapour, human evidence indicates that dermal absorption of vapour would only contribute a minimal (~0.3-1%) amount of that which would be absorbed by inhalation under normal conditions. Following absorption tetrachloroethylene is subject to widespread systemic distribution to all organs and tissues with selective partitioning into fat. Tetrachloroethylene crosses the placenta and enters the foetus, and also enters breast milk.

 

Human and animal evidence indicates that relatively little of the absorbed tetrachloroethylene is metabolised; the fraction of the absorbed dose which is metabolised decreases with increasing dose in a manner consistent with saturable metabolism. Maximum rates of metabolism have been measured in mice in which 25% of a low dose (20 mg/kg/day) was metabolised, compared with only 5% of a high dose (2000 mg/kg/day). In humans, less than 2% of the retained amount of tetrachloroethylene was metabolised and excreted in the urine within 67 hours following a 3-hour exposure to 87 ppm (600 mg/m³). Since a mean half-life of about 144 hours for the elimination of urinary metabolites following inhalation exposure has been calculated in humans, it can be deduced that in total about 8% of an inhaled dose is eliminated as urinary metabolites. The metabolites of tetrachloroethylene are excreted in the urine (approx. 8% of an inhaled dose), with very low percentages of the absorbed amount exhaled as carbon dioxide (1%) or eliminated in the faeces (2%). Precise values for the half-life of elimination of tetrachloroethylene in humans cannot be identified from the available data, but rough estimates indicate values of 6-10 days. Furthermore, there is some evidence that with repeated exposures tetrachloroethylene accumulates in fat stores.

 

The metabolism of tetrachloroethylene shows inter-species variability, with some differences in dose-response trends. The major route of metabolism in humans and animals involves cytochrome P450 oxidation; this proceeds more rapidly in mice than in rats, and more rapidly in rats than in dogs. The pathway leads to the formation of an epoxide (1,1,2,2-tetrachlorooxirane) and ultimately to trichloroacetic acid, which in turn may be reduced to trichloroethanol. There is clear animal and human evidence that the oxidative metabolism of tetrachloroethylene is a saturable process. The presence in rat and mouse urine of small quantities of a mercapturate metabolite indicates the existence of a further metabolic pathway, involving hepatic conjugation of tetrachloroethylene with glutathione to give S-1,2,2-trichlorovinylglutathione. The conjugate is then converted by the enzymes of mercapturic acid formation to S-1,2,2-trichlorovinylcysteine and ultimately to N-acetyl-S-1,2,2-trichlorovinylcysteine which is excreted in the urine. S-1,2,2-trichlorovinylcysteine is also a substrate for renal β-lyase, producing the reactive intermediate dichlorodithioketene. This intermediate is subsequently hydrolysed to yield dichloroacetic acid. Although one study indicates that the glutathione conjugation step of this pathway may occur in rats following exposure to relatively high concentrations (approx. 1000 ppm, 6900 mg/m³) of tetrachloroethylene, at which the P450 oxidation pathway tends to become saturated, more recent evidence using a more sensitive technique, shows that this pathway occurs with linear kinetics. Dose dependent increases in the levels of N-(dichloroacetyl)-L-lysine (the protein adduct deriving from interaction with dichlorodithioketone) were found in the kidney, serum and liver of rats exposed from 10 ppm (69 mg/m³) up to 400 ppm (2760 mg/m³) tetrachloroethylene for 6-hours.

 

Evidence that the first step of this metabolic pathway also occurs in humans comes from the detection of N-acetyl-S-(1,2,2-trichlorovinyl)-L-cysteine in the urine of occupationally-exposed workers (8h-TWA of 50 ppm) and human volunteers (from 10 up to 40 ppm, 69 to 276 mg/m³for 6 hours). Dose-dependent increases in the urinary excretion of N-acetyl-S-(1,2,2-trichlorovinyl)-L-cysteine in human volunteers further indicate that in humans, like rats, the glutathione conjugation of tetrachloroethylene is not an high dose phenomenon, but occurs with linear kinetics. The data also suggest that there are very large quantitative differences in the activity of the glutathione conjugation step between sexes and species. Studies in vivo have shown that in rats the urinary excretion of N-acetyl-S-(1,2,2-trichlorovinyl)-L-cysteine is 2-3 fold greater in males compared to females and is 10-fold greater in rats compared to mice. Exposure of rats and human volunteers to 40 ppm (276 mg/m³) tetrachloroethylene for 6 hours has shown that glutathione conjugation is also 10-fold more active in rats compared to humans. Overall, these data indicate that the first step of this pathway with the production of N-acetyl-S-(1,2,2-trichlorovinyl)-L-cysteine is more active in male rats compared to females and is roughly an order of magnitude lower in mice and humans.

 

There are also in vitro studies, which have investigated the rates of glutathione conjugation of tetrachloroethylene in human, rat and mouse microsomal and cytosolic fractions of liver and kidney. The rate of the S-(1,2,2-trichlorovinyl)glutathione formation was seen to be 4-5 times greater in male rats than in female rats and in mice of either sex. The formation of S-(1,2,2-trichlorovinyl)glutathione in humans was below the limit of detection even though glutathione S-transferase activity had been confirmed, which indicates that human liver samples exhibit the potential to conjugate tetrachloroethylene, but at a much lower extent than male rats (at least 80-fold lower). It is important to note that these in vitro data reinforce the picture obtained in vivo as they confirm that the first step of this pathway is more active in male rats compared to female rats and mice, and that humans are likely to be even less active in this pathway than mice.

 

As mentioned above, the conjugate S-1,2,2-trichlorovinylcysteine is also a substrate for renal β-lyase, producing the reactive intermediate, dichlorodithioketene. Its hydrolysis yields the urinary metabolite dichloroacetic acid. This urinary metabolite has been detected in vivo in rats (cumulative levels of 0.72 μmol/kg bw at an exposure of 40 ppm for 6 hours), but not in humans indicating that there was no β-lyase activity or it was below the limit of detection (< 50 ng dichloroacetic acid/ml urine) in 6 volunteers exposed up to 40 ppm (276 mg/m³) tetrachloroethylene for 6 hours. In relation to mice, it is unclear from the data whether or not dichloroacetic acid was investigated and not detected or whether it was not measured at all. The result of no apparent β-lyase activity in humansin vivo has also been confirmed in a second study where no N-(dichloroacetyl)-L-lysine (the protein adduct deriving from interaction with dichlorodithioketene, the final reactive metabolite of the glutathione conjugation/β-lyase pathway) formation was detected in the serum of 6 volunteersexposed up to 40 ppm (276 mg/m³) tetrachloroethylene for 6 hours, in spite of using a very sensitive technique (limit of detection of 0.01 pmol/mg protein). In this study exposure of rats to 40 ppm (276 mg/m³) tetrachloroethylene resulted in the formation of 0.4 pmol of serum N-(dichloroacetyl)-L-lysine/mg protein which indicates that the activity of this overall pathway is at least 40 fold (0.4 pmol/limit of detection) lower in humans compared to rats. The only evidence of some limited β-lyase activity in humans comes from in vitro data showing that in kidney cytosol fractions the activity of the β-lyase was lower in humans and mice compared to rats and 2-fold greater in male rats compared to female rats. Overall, it can be concluded that there is likely to be little, if any, β-lyase activity in humans and that the conjugation/ β-lyase pathway is likely to be at least 40-fold less active in humans (and probably mice) compared to rats.

Discussion on bioaccumulation potential result:

Extensive investigations of the toxicokinetics of tetrachloroethylene have been conducted in animals and also in humans. In both humans and animals, tetrachloroethylene is rapidly and extensively absorbed by the inhalation and oral routes of exposure. Hence, an inhalation and oral absorption of 100% are assumed. Skin absorption of liquid tetrachloroethylene has been detected in studies in humans, animals and in vitro. The rate of skin penetration appears to be markedly lower than for other solvents, with both the experimental data and the physico-chemical properties of tetrachloroethylene indicating that a worst-case absorption value of 50% is appropriate for risk assessment purposes. Although a study in animals suggested substantial dermal absorption of tetrachloroethylene vapour, human evidence indicates that dermal absorption of vapour would only contribute a minimal (~0.3-1%) amount of that which would be absorbed by inhalation under normal conditions. Following absorption tetrachloroethylene is subject to widespread systemic distribution to all organs and tissues with selective partitioning into fat. Tetrachloroethylene crosses the placenta and enters the foetus, and also enters breast milk.

 

Human and animal evidence indicates that relatively little of the absorbed tetrachloroethylene is metabolised; the fraction of the absorbed dose which is metabolised decreases with increasing dose in a manner consistent with saturable metabolism. Maximum rates of metabolism have been measured in mice in which 25% of a low dose (20 mg/kg/day) was metabolised, compared with only 5% of a high dose (2000 mg/kg/day). In humans, less than 2% of the retained amount of tetrachloroethylene was metabolised and excreted in the urine within 67 hours following a 3-hour exposure to 87 ppm (600 mg/m³). Since a mean half-life of about 144 hours for the elimination of urinary metabolites following inhalation exposure has been calculated in humans, it can be deduced that in total about 8% of an inhaled dose is eliminated as urinary metabolites. The metabolites of tetrachloroethylene are excreted in the urine (approx. 8% of an inhaled dose), with very low percentages of the absorbed amount exhaled as carbon dioxide (1%) or eliminated in the faeces (2%). Precise values for the half-life of elimination of tetrachloroethylene in humans cannot be identified from the available data, but rough estimates indicate values of 6-10 days. Furthermore, there is some evidence that with repeated exposures tetrachloroethylene accumulates in fat stores.