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Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Studies based on which the toxicokinetic behaviour of the substance can be derived, considered acceptable for assessment. Also peer-reviewed under Regulation 793/93.
Cross-referenceopen allclose all
Reason / purpose:
reference to same study
Reason / purpose:
reference to other study

Data source

Reference
Reference Type:
other: European Union Risk Assessment Report (EU-RAR 2008)
Title:
European Union Risk Assessment Report: Tetrachloroethylene, CAS No 127-18-4, EINECS No 204-825-9. Final draft human health report for publication
Author:
Rapporteur: United Kingdom, on behalf of the European Union
Year:
2008

Materials and methods

Test guideline
Qualifier:
no guideline available
Principles of method if other than guideline:
no information available
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
no information available
Radiolabelling:
not specified

Test animals

Species:
other: rats and mice, dogs
Strain:
other: SD rats, F344 rats, Wistar rats, B6C3F1 mice, Osborne-Mendel rats, NMR1 mice, Beagle dogs
Sex:
not specified
Details on test animals and environmental conditions:
no information available

Administration / exposure

Route of administration:
other: oral, inhalation
Vehicle:
not specified
Details on exposure:
no information available
Duration and frequency of treatment / exposure:
no information available
Doses / concentrations
Remarks:
Doses / Concentrations:no information available
No. of animals per sex per dose:
no information available
Control animals:
not specified
Positive control:
no information available
Details on study design:
no information available
Details on dosing and sampling:
no information available
Statistics:
no information available

Results and discussion

Preliminary studies:
no information available
Main ADME resultsopen allclose all
Type:
absorption
Results:
Tetrachloroethylene is rapidly and extensively absorbed by the inhalation and oral routes of exposure. Hence, an inhalation and oral absorption of 100% are assumed.
Type:
distribution
Results:
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.
Type:
metabolism
Results:
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.
Type:
excretion
Results:
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).

Toxicokinetic / pharmacokinetic studies

Details on absorption:
Refer to node below
Details on distribution in tissues:
Refer to node below
Details on excretion:
Refer to node below

Metabolite characterisation studies

Details on metabolites:
Refer to node below

Bioaccessibility

Bioaccessibility testing results:
no information available

Any other information on results incl. tables

Toxicokinetics: Studies in animals

Inhalation

Absorption and distribution

Two recent reports have provided a considerable amount of good-quality information on the uptake and tissue disposition of tetrachloroethylene inhaled by Sprague-Dawley rats. In the first, groups of 6 male rats (each with an indwelling arterial cannula) breathed tetrachloroethylene through a face mask fitted with a one-way valve that allowed separate sampling of the inhaled and exhaled breath streams (Dallas et al, 1994a). The animals were given 2-hour exposures to tetrachloroethylene at 50 or 500 ppm (345 or 3450 mg/m3), and during this time and for up to 8 hours afterwards serial samples of blood and inhaled and exhaled breath were taken. Substantial respiratory elimination of unchanged tetrachloroethylene was evident, with near steady-state tetrachloroethylene levels reached in exhaled breath within 20 minutes and maintained for the duration of the exposure. The near steady-state exhaled breath concentrations of tetrachloroethylene were directly proportional to the inhaled concentrations (about 30 ppm at 50 ppm, about 300 ppm at 500 ppm).

 

Tetrachloroethylene was rapidly absorbed from the lungs, since relatively high arterial blood concentrations were measured at the first sampling time of 2 minutes. The blood tetrachloroethylene concentration then progressively increased over the 2-hour exposure.  After the initial rapid uptake phase during the first 30-60 minutes of exposure, blood levels at 500 ppm were 12-17 times higher than those at 50 ppm. Total cumulative uptakes of tetrachloroethylene during the 2-hour exposures were calculated to be 80 mg/kg body weight at 500 ppm, and 11 mg/kg at 50 ppm, and so were not proportional to the inhaled concentration. The percentage systemic uptake was relatively constant after the first 20 minutes of inhalation, being about 40% at 500 ppm and about 50% at 50 ppm. At the end of the inhalation period, tetrachloroethylene was eliminated very rapidly during the first minutes, particularly via the exhaled breath. After this initial phase, tetrachloroethylene levels in blood and breath decreased slowly.

 

In the second study, groups of 5 male Sprague-Dawley rats were exposed in chambers to 500 ppm (3450 mg/m3) tetrachloroethylene for 2 hours and samples of blood and various tissues obtained at 16 time-points ranging from 15 minutes into the exposure until 72 hours after the end (Dallas et al, 1994b). The maximum tetrachloroethylene concentration in perirenal adipose tissue was much higher than in non-fat tissues; mean values were 152 µg/g for liver, 108 µg/g for kidney, 107 µg/g for heart, 95 µg/g for lung, 87 µg/g for skeletal muscle, 174 µg/g for brain and 45 µg/g for blood, compared with 1536 µg/g for fat. Areas under the tetrachloroethylene concentration versus time curves were determined from the start of exposure to infinity; the value for fat was 175 times that of blood and 45-80 times those of the other tissues assayed.  The half-lives of tetrachloroethylene in the tissues ranged from 322 minutes in blood to 578 minutes in fat. The peak tissue concentration of tetrachloroethylene was reached by about 1 - 1.5 hours into the exposure in all cases except for fat, for which the peak occurred just after the end of the exposure.

 

In another study, when 10 male Sprague-Dawley rats were exposed to 200 ppm (1380 mg/m3) tetrachloroethylene for 6 hours/day for 4 days, then exposed on the fifth day for a further 0, 2, 3, 4 or 6 hours, the tissue tetrachloroethylene concentrations were consistently much higher in perirenal fat than in the other tissues measured (Savolainen et al, 1977). The results of these two studies indicate selective partitioning of tetrachloroethylene into fat tissue, as would be expected for a lipophilic solvent.

 

Finally, a specialised investigation of the distribution of inhaled tetrachloroethylene in pregnant mice has been carried out (Ghantous et al, 1986). Twenty-four pregnant mice (8 in each of early, mid and late gestation, days 11, 14 and 17 respectively) were exposed to14C‑labelled tetrachloroethylene of unspecified concentration for 10 minutes, and 2 mice from each gestation group were killed 0, 1, 4 or 24 hours later. One mouse from each of these pairs was subjected to conventional whole-body autoradiography, which registered only non‑volatile (metabolite) radioactivity, while a low-temperature method, designed to avoid loss of volatile radioactivity, was used for the other.

Low-temperature autoradiography showed high uptake of radioactivity in maternal body fat, brain, nasal mucosa, blood and well-perfused organs such as liver, kidney and lung. At 4 hours and later, low-temperature and conventional autoradiograms were similar, indicating that volatile radioactivity had left the tissues, except for retention of the label in body fat. Non-volatile radioactivity was present in maternal liver, kidney, lung, nasal mucosa and blood immediately after the inhalation, increasing to 4 hours when radioactivity was also apparent in the eye and intestinal contents. At 24 hours, levels had greatly decreased.

Both volatile and metabolite radioactivity reached embryonic and foetal tissues at all 3 stages of gestation studied. At early (day 11) gestation, radiolabel was distributed evenly, while at later stages the liver and blood accumulated more radiolabel than other tissues. A specific localisation of radioactivity in the ventricular cerebrospinal fluid, immediately and at 1 hour after the inhalation, was also apparent. Volatile radioactivity in the foetus was always lower than in the corresponding maternal tissues, and was gone by 4 hours. Non-volatile radioactivity in foetal tissues peaked at 4 hours. In early gestation, it was high in the neuroepithelium of the developing brain, while late in gestation it was lower in the foetal brain than in other organs. At later sacrifice times, the highest levels of non-volatile radioactivity were in the skeleton and urinary tract in the mice treated at late gestation.

Large amounts of non-volatile radioactivity were found in amniotic fluid at 1‑24 hours, following exposure to tetrachloroethylene at all 3 stages of gestation. Measurements of tetrachloroethylene in amniotic fluid revealed levels only 6‑14% of those of the corresponding maternal blood samples. Peak concentrations of trichloroacetic acid were reached in maternal plasma, amniotic fluid and the foetus at 4 hours. The highest values were present in amniotic fluid, where levels were still high at 24 hours. Trichloroethanol was not detected in plasma or amniotic fluid.

 

References

 

Dallas CE, Muralidhara S, Chen XMet al(1994a): Use of a physiologically based model to predict systemic uptake and respiratory elimination of perchloroethylene,Toxicol Appl Pharmacol.128; 60-68.

 

Dallas CE, Chen XM, O’Barr Ket al(1994b): Development of a physiologically based pharmacokinetic model for perchloroethylene using tissue concentration-time data,Toxicol Appl Pharmacol.128; 50-59.

 

Ghantous H, Danielson BRG, Derncker Let al(1986): Trichloroacetic acid accumulates in murine amniotic fluid after tri- and tetrachloroethylene inhalation,Acta Pharmacol Toxicol.58; 105-114.

 

Savolainen H, Pfaffli P, Tengen M and Vainio H (1977): Biochemical and behavioural effects of inhalation exposure to tetrachloroethylene and dichloromethane,Neuropath Exp Neurol.36; 941-949.

 

 

Metabolism and elimination

In a recent study the concentrations of a number of different tetrachloroethylene urinary metabolites (representing the product of metabolism via the cytochrome P450 or glutathione conjugation pathways) were measured in groups of 3 male and 3 female Wistar rats exposed to tetrachloroethylene at 10, 20 or 40 ppm (69, 138 or 276 mg/m3) for 6 hours (Volkel et al,1998). Dose-dependent increases in the excretion of trichloroacetic acid, dichloroacetic acid and N‑acetyl‑S‑(trichlorovinyl)-L-cysteine were observed, with cumulative levels of 6.55 mmol/kg bw, 0.72 mmol/kg bw and 23 nmol/kg bw respectively, being recorded at 40 ppm.

 

The excreted levels of trichloroacetic acid have also been investigated in male and female F344 rats following exposure to 0, 200, 400 and 800 ppm (0, 1380, 2760 and 5520 mg/m3) tetrachloroethylene for 6 hours/day for up to 28 days (Green, 1997). The levels of this major metabolite of tetrachloroethylene, were similar at all dose levels. However, the minor metabolite, N‑acetyl‑S‑(1,1,2‑trichlorovinyl)‑L‑cysteine was excreted in a dose-dependent manner with levels being 2-3 fold greater in male rats compared with females. The mean levels of urinary formic acid were elevated on exposure days 7 and 14 but inter-animal variations were considerable.

 

An earlier study also examined the relative importance of the metabolism of inhaled tetrachloroethylene in male F344 rats by the cytochrome P450 pathway and glutathione conjugation, by comparing the urinary concentrations of the final products of these pathways, respectively trichloroacetic acid and N-acetyl-S-1,2,2-trichlorovinylcysteine (Green et al, 1990). Exposure of groups of 3 rats to 10, 100, 400 or 1000 ppm (69, 690, 2760 or 6900 mg/m3) tetrachloroethylene for 6 hours produced an exponential increase in the mean urinary trichloroacetic acid levels to about 45 µg/ml at 100 ppm and 85 µg/ml at 1000 ppm. In contrast, the urinary N-acetyl-S-1,2,2-trichlorovinylcysteine level was at or near zero at 10, 100 and 400 ppm, rising to about 20 µg/ml at 1000 ppm. It was thus evident that the glutathione pathway was of little importance at low tetrachloroethylene exposures but took on increasing significance as the pathway to trichloroacetic acid became saturated at higher levels (from approx 600 ppm but more significantly at 1000 ppm in rats) . It was also reported that exposure to 1000 ppm tetrachloroethylene for 10 consecutive days had no significant effect on the concentrations of these metabolites compared to the single exposure. In the same study, the concentrations of N-acetyl-S-1,2,2-trichlorovinylcysteine measured in pooled urine samples from groups of 5 male and 5 female F344 rats were in the range 0.6‑2.0 µg/ml following exposure at 400 ppm (3760 mg/m3) tetrachloroethylene, 6 hours/day for 1, 7 or 14 days. Values obtained for male and female B6C3F1 mice given the same exposures were lower, in the range 0‑0.2 µg/ml.

 

The metabolism of14C-labelled tetrachloroethylene, has also been investigated following exposure of male F344 rats and male B6C3F1mice to atmospheres of14C-labelled tetrachloroethylene (ranging from 11 - 1201 ppm; 76 – 8287 mg/m3) for a 6 hour period (Reitz et al,1996). Metabolism was dose-dependent, with the majority of metabolites being recovered in the urine; the exhalation of unmetabolised material was the main route of elimination in both species. Results also indicated that at the highest exposure levels mice have a higher capacity to convert tetrachloroethylene to urinary metabolites than do rats.

 

In experiments with male Sprague-Dawley rats, groups of 3 animals were exposed for 6 hours to14C-radiolabelled tetrachloroethylene at 10 or 600 ppm (69 or 4140 mg/m3), then maintained for 72 hours in metabolism cages for collection of expired air, urine and faeces (Pegg et al, 1979). The percentages of total recovered radioactivity (determined using liquid scintillation spectrometry) were 68% and 88% for unchanged tetrachloroethylene in exhaled air, 4% and 1% for carbon dioxide, 19% and 6% for urine, 5% and 3% for faeces and 4% and 2% for carcasses, for the 10 and 600 ppm exposures respectively. Pulmonary elimination of tetrachloroethylene was monophasic with a half-life of approximately 7 hours. These findings are consistent with the metabolism of tetrachloroethylene being a saturable process in the rat. At 72 hours after the end of the 600 ppm exposure, radioactivity was found, in order of decreasing level, in kidney, liver, fat, lung and heart, with brain and the adrenals being below the detection limit. In liver, 85 to 90% of the total radioactivity was cleared within 72 hours. Non-extractable radioactivity, either bound or incorporated into hepatic macromolecular material, was cleared at a slower rate. Radioactivity present in urine was separated by high pressure liquid chromatography. Oxalic acid was identified by gas chromatography-mass spectrometry as the major urinary metabolite, trichloroacetic acid not being detected, and, in this respect, the findings are not consistent with those from other studies.

 

In a study of similar design but conducted with male B6C3F1 mice at 10 ppm (69 mg/m3) tetrachloroethylene only, at 72 hours after the end of exposure the percentage radioactivity recovery values were 12% for unchanged tetrachloroethylene in exhaled air, 8% for carbon dioxide, 62% for urine, 7% for faeces, 3% for carcass and 8% for cage-wash (Schumann et al, 1980). Comparing these results with those of the previous study, it is apparent that mice have a much higher capacity to convert tetrachloroethylene to urinary metabolites than do rats. In supplementary studies, male mice and rats exposed to 10 and 600 ppm tetrachloroethylene showed irreversible binding of radioactivity to hepatic macromolecules.

In the mice, peak binding was obtained at the first time-point (immediately after the end of the exposure), compared to 24 hours after in rats, and at the times of peak binding in mice 7‑9 times more radioactivity was bound than in the rats.

 

In a study of urinary metabolites, groups of 6 rats or 10 mice were exposed to 200 ppm (1380 mg/m3) tetrachloroethylene for 8 hours, and urine collected for 48 hours from the start of the exposure (Ikeda and Ohtsuji, 1972). For the rats, the mean values of urinary excretion for eight separate experiments were 5.3 (± 1.6) mg/kg body weight for trichloroacetic acid and 3.2 (± 1.2) mg/kg for trichloroethanol. The values for groups of unexposed control rats were 0 and 0.3 (± 0.1) mg/kg respectively. The individual values for the 2 experiments carried out in mice were 18.9 and 22.4 mg/kg for trichloroacetic acid and 4.1 and 4.5 mg/kg for trichloroethanol, control levels again being very low ( 0.2 mg/kg). Again, these findings indicate a greater metabolic capacity in mice compared to rats.

 

The formation of protein adducts in rats and humans have been investigated recently (Volkelet al,1999, Pahler et al, 1997; 1999a, b). Only the results of the rat investigations are reported here in detail, as the human findings have been detailed under the “Studies in humans” heading of this toxicokinetic section and are only briefly summarised here for comparison purposes. The formation of protein adducts in subcellular fractions of rat liver and kidney and in rat and human serum has been investigated following acute inhalation exposure of rats and human volunteers to 10, 40 or 400 (rats only) ppm (69, 276 or 2760mg/m3) tetrachloroethylene for 6 hours (Pahler et al,1999a,b). In the rat, the levels of formation of proteins containing Ne-(dichloroacetyl)-L-lysine (the protein adduct deriving from interaction with dichlorodithioketene, the final reactive metabolite of the glutathione conjugation/b-lyase pathway) and Ne‑(trichloroacetyl)-L-lysine (the protein adduct deriving from interaction with trichloroactic acid, the final metabolite of the oxidative pathway) adducts, quantified by densitometric measurements of immunoblots and GC-MS, were dose-dependent and similar in kidney cytosolic and mitochrondrial fractions. However, the levels of formation of Ne-(dichloroacetyl)-L-lysine were 5-10 fold lower in serum compared to the kidney, and very low in the liver. Higher levels of this adduct were seen in the kidney of males compared to females. Following exposure of rats to 40 ppm, 0.35 – 0.48 pmol (mean = 0.4 pmol) Ne-(dichloroacetyl)-L-lysine/mg protein were measured in serum. In human serum, no formation of Ne-(dichloroacetyl)-L-lysine was detected, indicatingthat there was no b-lyaseactivity in these 6 volunteers or, if there was any, it was below the limit of detection (0.01 pmol/mg protein) of this very sensitive technique. Proteins containingNe‑(trichloroacetyl)-L-lysine adducts were detected in both rat and human serum following exposure to 40 ppm tetrachloroethylene for 6 hours, and, although quantification of this adduct could not be performed, the response in rat was much more intensive than in humans.

 

There are a few other relevant findings. Ethylene glycol, trichloroacetic acid and oxalic acid were detected in the urine of rats exposed to 740 ppm (5106 mg/m3) tetrachloroethylene for 4 hours, or for 5 hours/day for 3 days (Dmitrieva, 1967). However, oxalic acid was also found, at lower levels, in the urine of control rats. Trichloroacetic acid was also found in the urine of rats exposed for 4 hours to 600, 1100, 1750 or 2500 ppm (4140, 12075 or 17250 mg/m3) tetrachloroethylene (Friberg et al, 1953). In dogs inhaling 700, 1500 or 2000 ppm (4830, 10350 or 13800 mg/m3) tetrachloroethylene for 1 hour, trichloroacetic acid and trichloroethanol were detected in the urine produced during the 3-hour period following the start of the exposure (Hobara et al, 1983).

 

In an early and relatively crude study, 5 female mice were exposed in a sealed flask for 2 hours to radiolabelled tetrachloroethylene vapour at a dose of about 1.3 g/kg (Yllner, 1961). Of the 20% of the total absorbed radioactivity that appeared in the urine over 4 days, 52% was trichloroacetic acid, 11% was oxalic acid and a trace was dichloroacetic acid. The rest was presumably unidentified; it was stated that no monochloroacetic acid, formic acid or trichloroethanol was detected. The nature of the urinary metabolites that were obtained suggested the formation of an epoxide, further rearranged to trichloroacetyl chloride and then to trichloroacetic acid, as one metabolic pathway for tetrachloroethylene.

 

Finally, the excretion of tetrachloroethylene in breast milk has been investigated in Sprague‑Dawley rats (Byczkowski and Fisher, 1994; Byczkowski et al, 1994). On day 10 or 11 after delivery of their young, groups of 5 lactating dams were exposed to tetrachloroethylene (20, 100, 200, 600 or 1000 ppm; 138, 690, 1380, 4140 or 6900 mg/m3) for 2 hours, then tetrachloroethylene was measured in milk shortly after. A linear relationship was found between the tetrachloroethylene concentration in air and that in milk, with milk levels of about 800 mg/l being reported at 1000 ppm. Another group of 20 lactating dams was exposed to 600 ppm (4140 mg/m3) for 2 hours, then returned to their nursing pups. Tetrachloroethylene concentrations measured in the gastro-intestinal tract of the pups peaked at about 70 mg/kg tissue at around 4 hours after the end of the maternal exposure, while the peak pup venous blood level was about 0.8 mg/l at about 8 hours. For solid tissues, the peak of 6 mg/kg was reached at 10 hours. It was estimated that within 24 hours after exposure to 600 ppm for 2 hours, about 5% of the tetrachloroethylene inhaled by the dams was passed to the pups.

 

References

 

Byczkowski JZ and Fisher JW (1994): Lactational transfer of tetrachloroethylene in rats,Risk Analysis.14; 339-349.

 

Byczkowski JZ, Kinkead ER, Leahy HFet al(1994): Computer simulation of the lactational transfer of tetrachloroethylene in rats using a physiologically based model,Toxicol Appl Pharmacol.125; 228-236.

 

Dmitrieva(1967): On the metabolism of tetrachloroethylene,Gig Tr Prof Zabol.11; 54-56.

Friberg L, Kylin B and Nystrom A (1953): Toxicities of trichloroethylene and tetrachloroethylene and Fujiwara’s pyridine-alkali reaction,Acta Pharmacol Toxicol.9; 303-312.

 

Green T (1997): Tetrachloroethylene: 28 day inhalation study to investigate effects on rat liver and kidney. Zeneca Central Toxicology Laboratory. Report No: CTL/R/1325 (study funding: ECSA / JAHCS / HSIA)

 

Green T, Odum J, Nash JA and Foster JR (1990): Perchloroethylene - induced rat kidney tumors: an investigation of the mechanisms involved and their relevance to humans,Toxicol Appl Pharmacol.103; 77-89.

 

Hobara T, Kobayashi H, Higashihara Eet al(1983): Experimental studies of uptake, elimination and metabolism of tetrachloroethylene in dogs,Jap J Ind Health.25; 367-374.

Ikeda M and Ohtsuji H (1972): A comparative study of the excretion of Fujiwara reaction-positive substances in urine of humans and rodents given trichlor- or tetrachlor- derivatives of ethane and ethylene,Br J Med.29; 99-104.

Pahler A, Birner G, Parker J, Dekant W (1997): Generation of antibodies to di- and trichloroacetylated proteins and immunochemical detection of protein adducts in rats treated with perchloroethene.Chem Res Toxicol.11; 995-1004.

 

Pahler A, Parker J and Dekant W (1999a): Dose-dependent protein adduct formation in kidney, liver and blood of rats and in human blood after perchloroethene exposure.Toxicol Sci.48; 5-13.

 

Pahler A, Volkel W and Dekant W (1999b): Quantitation of Ne-(dichloroacetyl)-L-lysine in proteins after perchloroethene exposure by gas chromatography-mass spectrometry using chemical ionisation and negative ion detection following immunoaffinity chromatography.J Chromatog A.847; 25-34.

 

Pegg DG, Zempel JA, Braun WH and Watanabe PG (1979): Disposition of tetrachloro-(14C)-ethylene following oral and inhalation exposure in rats,Toxicol Appl Pharmacol.51; 465-474.

Reitz, RH, Gargas ML, Mendrala AL, AM (1996):In vivoandin vitrostudies of perchloroethylene metabolism for physiologically based pharmacokinetic modeling in rats, mice and humans.Toxicol Appl Pharmacol.136; 289-306.

Schumann AM, Quast JF and Watanabe PG (1980): The pharmacokinetics and macromolecular interactions of perchloroethylene in mice and rats as related to oncogenicity,Toxicol Appl Pharmacol.55; 207-219.

Volkel W, Friedewald M, Lederer E, Pahler A, Parker J, Dekant W (1998): Biotransformation of perchloroethene: dose-dependent excretion of trichloroacetic acid, dichloroacetic acid, and N-acetyl-S-(trichlorovinyl)-L-cysteine in rats and humans after inhalation.Toxicol Appl Pharmacol.153; 20-27.

 

Volkel W, Pahler A and Dekant W (1999): Gas chromatography-negative ion chemical ionisation mass spectrometry as a powerful tool for the detection of mercapturic acids and DNA and protein adducts as biomarkers of exposure to halogenated olefins.J Chromat A.847; 35-46.

 

Yllner S (1961): Urinary metabolites of 14C - tetrachloroethylene in mice,Nature191; 820

Zielhuis, Gijsen R and van der Gulden JWJ (1989): Menstrual disorders among dry-cleaning workers,Scand J Work Environ Health.15; 238.

 

 

Oral

Absorption and distribution

Two recent reports have provided a considerable amount of good-quality information on the absorption and tissue distribution of tetrachloroethylene administered by gavage to male Sprague-Dawley rats and beagle dogs. In the first study, groups of 4 rats and 3 dogs received single doses of tetrachloroethylene of 10 mg/kg and then were killed at intervals (16 time points for rats, 6 for dogs) for up to 72 hours after dosing (Dallas et al, 1994c). Samples of blood and various other tissues were rapidly obtained and assayed for tetrachloroethylene by gas chromatography.

 

The maximum tetrachloroethylene concentrations reached in perirenal adipose tissue was much higher than in non-fat tissues. For the rats, the mean values for peak levels in liver (12.3 µg/g), kidney (5.5 µg/g), brain (5.1 µg/g), heart (2.9 µg/g), blood (1.0 µg/g), skeletal muscle (2.1 µg/g) and lung (1.6 µg/g) compared with 36.0 µg/g for fat. These peak concentrations were obtained at the 10, 10, 15, 15, 15, 60, 60 and 360 minute sampling times, respectively. Areas under the tetrachloroethylene concentration versus time curves were determined from the start of the experiment to infinity, and ranged from 320 (blood), 1060 (kidney), 1670 (liver) and 1380 (brain) up to 49960 µg.min/ml for adipose tissue. The half‑lives of tetrachloroethylene in the tissues ranged from 310 minutes in muscle to 695 minutes in adipose tissue.

 

In the dog study, the highest peak tetrachloroethylene concentrations were similarly found in fat (42.8 µg/ml) then liver (6.3 µg/ml), heart (5.7 µg/ml), kidney (4.9 µg/ml), muscle (3.1 µg/ml), lung (2.4 µg/ml) and blood (1.5 µg/ml). These maximum concentrations were reached at 60 minutes into the exposure (the first sampling time) in all cases except fat, for which the peak occurred at 720 minutes. Areas under the curve were generally larger than for the same tissue in rats, and half-lives other than that for fat were much longer, ranging from 494 (fat), 865 (blood) and 2448 (liver) to 4641 minutes for brain. It was calculated that mean whole-body clearance of tetrachloroethylene was 30.1 ml/min/kg for rats but only 12.8 ml/min/kg in the dogs.

 

In the second study, the animals (groups of 5 or 6 rats, 4 or 8 dogs) were each fitted with an indwelling jugular vein cannula to allow serial blood sampling, and a range of tetrachloroethylene doses (1, 3 or 10 mg/kg) was used (Dallaset al, 1995). Blood samples were collected at intervals up to 96 hours following gavage and tetrachloroethylene concentrations were measured by gas chromatography.

Tetrachloroethylene was rapidly and extensively absorbed from the gastro-intestinal tract in both rats and dogs. Maximum blood tetrachloroethylene concentrations were reached within 15 - 40 minutes for all 3 doses in rats and the top 2 doses in the dogs (at the low dose the concentrations rapidly fell below the detection limit). High bioavailability of the administered tetrachloroethylene (in rat about 95% at 1 and 3 mg/kg, 82% at 10 mg/kg; in dog, 100% at 3 mg/kg) was apparent. For rat, the areas under the curve were slightly more than proportional to the increases in dose, and mean clearance values for the 3 doses were in the range 30 - 37 ml/min/kg. The clearance half-lives from blood were about 8 hours at 3 mg/kg and 15.5 hours at 10 mg/kg, suggesting the onset of saturation of elimination of tetrachloroethylene. The data were not complete for dogs, but in general the areas under the curve and half-life values were greater and the clearance of tetrachloroethylene from the blood significantly slower than with the corresponding dose in rats.

 

In a drinking water study, groups of 15 NMRI mice were given tetrachloroethylene (0, 0.05 or 0.1 mg/kg/day) for 7 weeks, with or without an 8-week exposure-free recovery period (Marth, 1987). For the limited range of tissues assayed, tetrachloroethylene was found at by far the highest concentration (69 mg/kg) in the adipose tissue of the high dose group sampled after the recovery period (no adipose tissue sample could be obtained immediately after the exposure). Much lower levels (17 µg/kg for spleen, 4 µg/kg for kidney, brain and liver) were found in other tissues, even in high dose animals killed at the end of the exposure period. Tetrachloroethylene concentrations for these tissues were lower still after the recovery period, with the high dose spleen level being only about 3 µg/kg. Thus, this study provides further evidence for the selective partitioning of tetrachloroethylene into fat tissue, as would be expected for such a lipophilic substance.

 

References

 

Dallas CE, Chen XM, Muralidhara Set al(1994c): Use of tissue disposition data from rats and dogs to determine species differences in input parameters for a physiological model for perchloroethylene,Environ Res.67; 54-67.

 

Dallas CE, Chen XM, Muralidhara Set al(1995): Pharmacologically based pharmacokinetic model useful in prediction of the influence of species, dose and exposure route on perchloroethylene pharmacokinetics,J Toxicol Environ Health.44; 301-317.

 

Marth E (1987): Metabolic changes following oral exposure to tetrachloroethylene in subtoxic concentrations,Arch Toxicol.60; 293-299.

 

 

Metabolism and elimination

The metabolism of14C-labelled tetrachloroethylene in 2 female Wistar rats and 3 female NMRI mice was followed over a 72-hour period after single gavage doses of 800 mg/kg (Dekant et al, 1986a). Exhalation of unchanged tetrachloroethylene was the main route of elimination, accounting for 91% of the administered radioactivity in rats, and there were minor amounts of label detected in urine (2.3%), faeces (2.0%), carcass (3.2%) and in exhaled carbon dioxide (0.1%). The corresponding values for the mice were respectively 85, 7.1, 0.5, 3.1 and 0.1%. Analysis of the pooled 72-hour urine samples revealed the presence of trichloroacetic acid (54 and 58% of urinary radioactivity in respectively rats and mice), trichloroethanol (free and conjugated; 8.7, 9.0%), oxalic acid (8.0, 2.9%), N‑oxalylaminoethanol (6.2, 6.1%), N-trichloroacetylaminoethanol (5.4, 5.7%), dichloroacetic acid (5.1, 4.4%), conjugated trichloroacetic acid (1.8, 1.3%) and N‑acetyl‑S‑1,2,2‑trichlorovinylcysteine (1.6, 0.5%), as well as an unidentified metabolite (9.1, 10%). Urinary N-acetyl-S-1,2,2-trichlorovinylcysteine has subsequently been detected in a further study, with concentrations measured for male F344 rats given daily oral doses of 1500 mg tetrachloroethylene/kg being 23, 41 and 33 µg/ml for 1, 17 and 42 days respectively (Green et al, 1990).

 

Consideration of the structures of these urinary metabolites indicated that in rats and mice orally administered tetrachloroethylene is metabolised by two pathways. The major pathway is evidently the cytochrome P450-mediated conversion in the liver to an epoxide (1,1,2,2‑tetrachlorooxirane), followed by rearrangement to trichloroacetyl chloride then hydrolysis to trichloroacetic acid. Addition of water to the epoxide followed by elimination of hydrogen chloride from the resulting unstable diol forms oxalyl chloride; oxalic acid is the final urinary product. The presence of N-trichloroacetylaminoethanol and N‑oxalylaminoethanol in the urine is likely to be the result of alkylation of the ethanolamine moiety of phospholipids in the membranes of the endoplasmic reticulum by the various short‑lived intermediates. The reduction of trichloroacetic acid (via chloral hydrate) would lead to trichloroethanol.

The presence in the urine of N-acetyl-S-1,2,2-trichlorovinylcysteine implies the existence of a second pathway. The current knowledge of this bioactivation pathway has been reviewed recently for haloalkenes, including tetrachloroethylene (Dekant and Henschler, 1999). This essentially involves the conjugation of tetrachloroethylene with glutathione (catalysed by glutathione transferases), then conversion of the conjugate by the enzymes of mercapturic acid formation. Indeed, the glutathione conjugate of tetrachloroethylene (S‑1,2,2‑trichlorovinylglutathione) was identified in the bile of male F344 rats following dosing with tetrachloroethylene by gavage (Greenet al, 1990). The precursor of the final urinary metabolite, S-1,2,2-trichlorovinylcysteine, is however also a substrate for renal ‑lyase, producing the reactive intermediate dichlorodithioketene. This intermediate is likely to be responsible for the mutagenicity associated with S-1,2,2-trichlorovinylcysteine (see section 4.1.2.7) and its hydrolysis would yield dichloroacetic acid, which was identified as a urinary metabolite.

 

The excretion and bioactivation of S-1,2,2-trichlorovinylcysteine have been investigated recently in male and female Wistar rats following intravenous administration at 40 mmol/kg (Birner et al, 1997). The only urinary metabolite was mercapturic acid. Urinary g‑glutamyltransferase, a marker of proximal tubular damage, was also present at significantly higher levels in exposed animals compared to those treated with vehicle. The levels excreted by male animals were approximately twice those of the females. Histopathological investigations revealed necroses of the renal proximal tubules exclusively in male S‑1,2,2‑trichlorovinylcysteine-exposed rats.

 

In experiments with male Sprague-Dawley rats, groups of 3 animals were given14C‑radiolabelled tetrachloroethylene (1 or 500 mg/kg in corn oil) by gavage, then maintained for 72 hours in metabolism cages for collection of expired air, urine and faeces (Pegg et al, 1979). The percentages of total recovered radioactivity were 72% and 90% for unchanged tetrachloroethylene in exhaled air, 3% and 1% for carbon dioxide, 16% and 5% for urine, 6% and 4% for faeces and 3% and 1% for carcass, for the 1 and 500 mg/kg doses respectively.  These findings are consistent with the metabolism of tetrachloroethylene being a saturable process in the rat. At 72 hours after the end of the 500 mg/kg dose, radioactivity was found, in order of decreasing level, in fat, kidney, liver, lung and heart, with brain and the adrenals being below the detection limit. Oxalic acid was identified as the major urinary metabolite, trichloroacetic acid not being detected, and, in this respect, the findings are not consistent with those from other studies.

 

In a study of similar design but conducted with male B6C3F1mice at only the 500 mg/kg dose of tetrachloroethylene, at 72 hours after the end of exposure the percentage radioactivity recovery values were 83% for unchanged tetrachloroethylene in exhaled air, 1% for carbon dioxide, 10% for urine, 1% for faeces, 1% for carcass and 4% for cage-wash (Schumann et al, 1980). In supplementary studies, male mice and rats exposed to 500 mg/kg tetrachloroethylene showed irreversible binding of radioactivity to hepatic macromolecules. In the mice, peak binding was obtained at 6 hours after dosing, compared to 24 hours after dosing in rats, and at the times of peak binding in mice 8 times more radioactivity was bound than in the rats.

 

Finally for single dose studies, groups of 5 or 10 male B6C3F1mice were given gavage doses of tetrachloroethylene (100, 536 or 1072 mg/kg in corn oil) and blood sampled at intervals up to 48 hours (Gearhart et al, 1993). Dose-related increases in the blood concentrations of tetrachloroethylene and of trichloroacetic acid were obtained, peaking at about 2‑5 and 8‑10 hours respectively.

The reports of two studies involving repeated administration of tetrachloroethylene by gavage are available. In one, male Swiss-Cox mice were given tetrachloroethylene (0, 20, 100, 500, 1000, 1500 or 2000 mg/kg/day, in corn oil) on 5 days/week for 6 weeks (Buben and O’Flaherty, 1985). Urine was collected for several 24-hour periods during the study, and gas chromatography identified trichloroacetic acid as the only metabolite of tetrachloroethylene present: oxalic acid was found at similar levels in control and test animals, and ethylene glycol was not detected. The fraction of each dose metabolised was found to decrease with increasing dose in a manner consistent with saturable metabolism. Thus about 25% of a very low dose (20 mg/kg/day) of tetrachloroethylene was metabolised to trichloroacetic acid, but only 5% of a very high dose (2000 mg/kg/day). Values for various indices of hepatotoxicity, such as serum alanine aminotransferase, correlated well with total urinary metabolite levels, suggesting that hepatotoxicity might be directly related to the extent of metabolism.

 

In the other study, groups of male Osborne-Mendel rats and B6C3F1mice were given tetrachloroethylene (1000 and 900 mg/kg/day, respectively) on 5 days/week for 4 weeks, followed by a single dose of radiolabelled substance (Mitoma et al, 1985). Elimination of the radioactivity was measured over the subsequent 48 hours. For rat, mean values of about 80, 2, 2 and 1% of the administered radioactive dose appeared in respectively expired air (as unchanged tetrachloroethylene), carbon dioxide, urine and faeces combined, and carcass. For the mice, the values were 57, 2, 14 and 5%. The major urinary metabolite was found to be trichloroacetic acid in both species. Thus, again, it was evident that mice have a greater capacity than rats to metabolise tetrachloroethylene by the oxidative pathway.

 

When 4 male Sprague-Dawley rats were given radiolabelled tetrachloroethylene (mean dose about 8 mg/kg) in the drinking water over a 12-hour period, the recovery of radioactivity over the subsequent 72 hours was largely (88%) as unchanged tetrachloroethylene in expired air (Frantz and Watanabe, 1983). Radioactivity was also found in expired carbon dioxide (2%), urine (7%), faeces (2%) and in the carcasses (1%). Low levels of radiolabel were detected in samples of liver, kidneys, fat, lungs and adrenals taken at 72 hours after the end of the exposure. The half-life for the pulmonary elimination of tetrachloroethylene was 7.1 hours.

 

Finally, there is some limited information regarding non-laboratory animals. In cows, tetrachloroethylene was rapidly absorbed following ingestion in the feed, appearing in blood within 20 minutes and in the first milking at 8 hours (Wanner et al, 1982). It was estimated that about 1% of the tetrachloroethylene in the feed was eliminated in the milk. In pigs fattened from about 20 to 100 kg in weight with diets supplemented with tetrachloroethylene, the tetrachloroethylene in subcutaneous fat and “flare fat” reached levels similar to those present in the air-dried feed (Vemmer et al, 1984). Tetrachloroethylene levels in the other tissues analysed (spinal cord, liver, kidney and muscle) reached only about 1 - 2% of those found in the fat.

 

References

 

Buben JA and O’Flaherty EJ (1985): Delineation of the role of metabolism in the hepatotoxicity of trichloroethylene and perchloroethylene: A dose effect study.Toxicol Appl Pharmacol.78; 105-122.

Birner G, Bernauer U, Werner M and Dekant W (1997): Biotransformation, excretion and nephrotoxicity of haloalkane-derived cyteine S-conjugates.Arch Toxicol.72; 1-8.

Dekant W, Metzler M and Henschler D (1986a): Identification of S-1,2,2-trichlorovinyl-N-acetylcysteine as a urinary metabolite of tetrachloroethylene: bioactivation through glutathione conjugation as a possible explanation of its nephrocarcinogenicity,J Biochem Toxicol.1; 57-72.

 

Frantz SW and Watanabe PG (1983): Tetrachloroethylene: Balance and tissue distribution in male Sprague-Dawley rats by drinking water administration,Toxicol Appl Pharmacol.69; 66-72 (data owner: Dow Chemical Company)

 

Gearhart JM, Mahle DA, Greene RJet al(1993): Variability of physiologically based pharmacokinetics (PBPK) model parameters and their effects on PBPK model predictions in a risk assessment for perchloroethylene (PCE),Toxicol Lett.68; 131-144.

 

Green T, Odum J, Nash JA and Foster JR (1990): Perchloroethylene - induced rat kidney tumors: an investigation of the mechanisms involved and their relevance to humans,Toxicol Appl Pharmacol.103; 77-89.

 

Mitoma C, Steeger T, Jackson SEet al(1985): Metabolic disposition study of chlorinated hydrocarbons in rats and mice,Drug Chem Toxicol.8; 183-194.

 

Pegg DG, Zempel JA, Braun WH and Watanabe PG (1979): Disposition of tetrachloro-(14C)-ethylene following oral and inhalation exposure in rats,Toxicol Appl Pharmacol.51; 465-474.

 

Schumann AM, Quast JF and Watanabe PG (1980): The pharmacokinetics and macromolecular interactions of perchloroethylene in mice and rats as related to oncogenicity,Toxicol Appl Pharmacol.55; 207-219.

 

Vemmer H, Rohleder K, Wieczoreck H and Haeseler E (1984): Perchloroethylene in the tissues of fattening pigs,Landwirtsch Forsch.37; 36-43.

 

Wanner M, Lehmann E, Morel J and Christen R (1982): Transfer of tetrachloroethylene from feed into milk,Mitt Geb Lebensmittel Unters Hyg.73; 82 -87.

 

 

Studies in vitro

The existence of the 2 metabolic pathways indicated by the pattern of urinary metabolites found inin vivostudies has been substantiated by identification of many of the intermediates in in vitro systems involving rat hepatic microsomal and cytosolic fractions (Dekant et al., 1987 and reviewed by Lash and Parker, 2001).

 

A recent study has investigated the rates of glutathione conjugation of tetrachloroethylene in rat, mouse (undefined strains) and human microsomal and cytosolic fractions of kidney and liver (Dekant et al,1998). Human tissue from both sexes (n=11) was obtained from tissue banks or from unsuitable, non-tumourous transplantation material. The formation of S-(1,1,2-trichlorovinyl)glutathionefrom tetrachloroethylene was not observed (limit of detection 1 pmol/mg per min) in liver or kidney microsomal fractions from any species or in human liver and kidney cytosolic fractions in which glutathione S-transferease activity had been confirmed. However, conjugation of tetrachloroethylene was seen in rat and mouse liver cytosol, with the rate of formation being 4 times greater in male (84.5 pmol/mg per min) than in female rats (19.5 pmol/mg per min) and in mice of either sex (27.9 and 26.0 pmol/mg per min). Low rates of S-(1,1,2-trichlorovinyl)glutathione formation were also seen in kidney cytosol from mice, but not from rats. Human liver cytosolic fractions, however, exhibited glutathione S-transferase activity (as determined using 1-chloro-2,4-dinitrobenzene and hexachlorobutadiene as substrates). These in vitro results suggest that human liver samples exhibit the potential to conjugate tetrachloroethylene, but at a much lower extent than male rats (at least 80-fold lower).

 

The conjugation of tetrachloroethylene with glutathione has also been measured in freshly isolated renal cortical cells and hepatocytes from F344 male and female rats and in liver and kidney microsomes and cytosol obtained from rats and B6C3F1male and female mice (Lashet al,1998). The formation of S-(1,1,2-trichlorovinyl)glutathione was broadly similar in male and female rat liver and kidney cells. However, the relative levels in males were somewhat higher than those seen in female animals.

 

An earlier study demonstrated the formation of sulfoxides derived from N‑acetyl‑S‑(1,1,2‑trichlorovinyl)-L-cysteine in male rat liver microsomes; formation was not however detected in microsomes from female rats or in kidney microsomes from either sex (Werner et al, 1996). The involvement of cytochrome P450 3A1/2 in sulfoxide formation was demonstrated and interestingly this P450 form is expressed constituitively in male but not in female rats. In addition, this study demonstrated that exposure of isolated rat kidney cortex cells to sulfoxides resulted in a significantly greater degree of cytotoxicity compared with exposure to the corresponding mercapturates.

Two investigations comparing the activities in key enzymes assayed in subcellular fractions from various species have also reported similar findings (Greenet al, 1990). In the first, conjugation of tetrachloroethylene with glutathione was measured in microsomes and cytosol of livers from F344 rats, B6C3F1mice and humans. The human liver samples were obtained from an unspecified number of renal transplant donors. Hepatic conjugation of tetrachloroethylene with glutathione occurred primarily in the cytosol, with the rate for the rats being about 5 times greater than that for the mice. In contrast to the findings of Dekant et al (1998 – see above), glutathione conjugation could not, however, be detected in cytosolic or microsomal fractions derived from the human livers. Based on the detection limit of the assays used, the rate must have been at least 10 times less than the already very low level measured in rats. The metabolic capability of the cytosolic fractions was checked using a standard substrate for glutathione-S-transferases (1‑chloro‑2,4‑dinitrobenzene), and much higher activities were found compared to tetrachloroethylene, with no significant difference between values for rats and humans.

 

In the second investigation, the activity of beta-lyase was determined in kidney cytosol fractions using the cysteine conjugate of tetrachloroethylene as substrate. The mean values for Kmwere lower and for Vmaxhigher for groups of 4 male and 4 female F344 rats, compared to those for groups of 4 B6C3F1mice, 3 men and 4 women. Values of Vmax/ Kmwere 5.9 for male and 2.9 for female rats, with those for humans being about 0.2 and similar to those for the mice. The human kidney samples were obtained from morphologically normal parts of kidneys immediately after their removal because of renal failure or cancer. Thesein vitrodata show that the activity of b-lyase measured in kidney cytosol fractions is  lower in humans and B6C3F1mice compared to F344 rats and 2-fold greater in male rats compared to female rats.

 

Conversion of14C-labelled tetrachloroethylene to water-soluble radioactivity by rat, mouse and human liver microsomes has been examined (Reitz et al, 1996). Mouse microsomal preparations appeared to be significantly more active than human or rat preparations. However, it should be noted that the overall levels of conversion were relatively low with somewhat limited reproducibility.

 

Rodent studies have previously demonstrated increases in the numbers of peroxisomes within the liver following exposure to certain so-called peroxisome proliferator chemicals, including tetrachloroethylene and trichloroethylene. Activation of the peroxisome proliferator-activated receptor, PPARa, has been shown to be involved ultimately in the hepatotoxic and hepatocarcinogenic effects observed following exposure to such chemicals. Thein vitroactivation of cloned human and mouse PPAR a and g by tetrachloroethylene and certain of its metabolites has now been reported (Maloney and Waxman, 1999). Tetrachloroethylene did not activate PPARa or PPARg; however trichloroacetic acid and dichloroacetic acid were both shown to activate the PPARa form in both species with similar sensitivity. Activation of the PPARg form from either species did not occur in the presence of any metabolite.

 

Finally the levels of mRNA for the cytochrome P450 forms, CYP2E1 and CYP2B, have been measured in the liver of male Wistar rats following intraperitoneal administration of 0.5 g/kg tetrachloroethylene (Mizunoet al, 2001). The mRNA levels of CYP2B increased transiently at 6 hours following dosing, whereas CYP2E1 mRNA levels were reduced by approximately 35% compared with controls.

 

References

 

Dekant W, Martens G, Vamvakas Set al(1987): Bioactivation of tetrachloroethylene. Role of glutathione S-transferase-catalysed conjugationversuscytochrome P-450-dependent phospholipid alkylation,Drug Metab Dispos.15; 702-709.

 

Dekant W, Birner G, Werner M, Parker J (1998): Glutathione conjugation of perchloroethene in subcellular fractions from rodent and human liver and kidney. Chemico-Biol Interact.116, 31-43.

Green T, Odum J, Nash JA and Foster JR (1990): Perchloroethylene - induced rat kidney tumors: an investigation of the mechanisms involved and their relevance to humans,Toxicol Appl Pharmacol.103; 77-89.

 

Lash L, Qian W, Putt D, Desai K, Elfarra A, Sicuri AR, Parker J (1998): Glutathione conjugation of perchloroethylene in rats and micein vitro: sex-, species- and tissue-dependent differences.Toxicol Appl Pharmacol.150, 49-57.

 

Lash LH and Parker JC (2001): Hepatic and renal toxicities associated with perchloroethylene.Pharmacol Rev.53; 177-208.

 

Maloney EK and Waxman DJ (1999): trans-activation of PPARa and PPARg by structurally diverse environmental chemicals.Toxicol Appl Pharmacol.161; 209-218.

 

Werner M, Birner G, Dekant W (1996): Sulfoxidation of mnercapturic acids derived from tir- and tetrachloroethene by cytochromes P450 3A: A cysteine conjugate b-lyase mediated cleavage.Chem Res Toxicol9; 41-49.

 

Reitz, RH, Gargas ML, Mendrala AL, Schumann AM (1996):In vivoandin vitrostudies of perchloroethylene metabolism for physiologically based pharmacokinetic modeling in rats, mice and humans.Toxicol Appl Pharmacol.136; 289-306.

 

Tsuruta H (1977): Percutaneous absorption of organic solvents. 2) A method for measuring the penetration rate of chlorinated solvents through excised rat skin,Ind Health.15; 131-139

 

Ikeda M and Ohtsuji H (1972): A comparative study of the excretion of Fujiwara reaction-positive substances in urine of humans and rodents given trichlor- or tetrachlor- derivatives of ethane and ethylene, Br J Med. 29; 99-104

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): no bioaccumulation potential based on study resultsBased on the findings of the various studies, there is no bioaccumulation potential for tetrachloroethylene.
Executive summary:

A number of studies were conducted in species ranging from mice, rats, dogs to humans to evaluate the bioaccumulation potential of tetrachloroethylene. The findings from these studies revealed that 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 t 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. Based on the findings of the various studies, there is no bioaccumulation potential for tetrachloroethylene.