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Only small amounts of CTFE can be absorbed frompulmonary alveoli. The kidney, bone, and lung had the highest distribution for CTFE. Absorbed CTFE can be further metabolised, conjugated and excreted via urine.
CTFE is not directly toxic but after a multi-step bioactivation process that occurs within the liver and kidney the metabolites (CTFG, CTFC and unstable thiolate metabolites) can react with cellular constituents of the kidney and result in concentration-dependent proximal tubular necrosis.

Key value for chemical safety assessment

Additional information

Absorption Distribution and Excretion

As the CTFE is a gas, only the inhalation route was considered as the likely exposure route for CTFE. The dermal and ingestion route for CTFE can be ignored.

There are few investigations on absorption rate and distribution profiles for CTFE. The only available research was published in an old Chinese journal. In the study, after exposure of rabbits to trifluorochloroethylene at a concentration of 0.1 % in air (1000 ppmV), the alveolar absorption rate was 5.80 %. After exposure trifluorochloroethylene was detected in blood and urine. The kidney, bone, and lung had the highest distribution among various organs examined.

A dose-related increase in urinary fluoride was seen in rats following single exposures to 100 to 540 ppm CTFE. This finding was repeated in rats inhaling approximately 100 or 250 ppm for 7 weeks. In rats inhaling 395 ppm CTFE for 5 consecutive days, daily levels of urinary fluoride were increased to 3 to 6 mmol/24 h per rat. This coincided with a brief elevation of serum fluoride at the end of each exposure. Elevations in urinary fluoride and fluorine levels were seen in rats exposed by inhalation to from 29 to 241 ppm CTFE.

The fluoride content in the urine decreased as the exposure time increased, with this observation being more marked in males. Serum fluoride levels in the high exposure group were generally less than 10 times greater than background, which suggests that the material is only moderately absorbed or rapidly eliminated.

Metabolism and Bioactivation

Investigations of the metabolism of CTFE indicated that it may be metabolized in the liver, in the presence of glutathione, to ultimately yield a CTFE analog of vinyl cystine. In the kidney, this vinyl cystine conjugate is further metabolized to a toxic, sulfur-containing metabolite and pyruvate. When this analog was administered to mice, it produced a toxic response in the kidney similar to that seen with CTFE. In the kidney, this vinyl cystine conjugate is further metabolized to a toxic sulfur-containing metabolite and pyruvate.

Both S-(2-chloro-1,1,2-trifluoroethyl) glutathione (CTFG) and S-(2-chloro-1,1,2,- -trifluoroethyl) cysteine, the cysteine S-conjugates, were shown to be potent nephrotoxins in male rats. Biosynthesis of CTFG and the activities of cytosolic and microsomal glutathione S-transferases were measured in rat and human hepatocytes and in human hepatoma derived Hep G2 cells. The results showed that cytosolic and microsomal glutathione S-transferase activities were lower in Hep G2 cells than in rat and human liver tissues. These results demonstrate that human hepatocytes and Hep G2 cells are competent to synthesize CTFG.

In a subsequent study with rat hepatic cytosolic and microsomal fractions, CTFE functioned as a substrate for glutathione S-transferase. The reaction product was isolated and identified as CTFG. In a study using isolated rabbit renal tubule suspensions, exposure of the tubules to CTFE also resulted in consumption of the CTFE and formation of the glutathione adduct CTFG. In this investigation, when S-(l,2-dichloroethyl) glutathione was used to study the toxicity and metabolism of this type of compound, it inhibited rabbit renal tubule transport and was converted to the cysteine S-conjugates. These studies provide good evidence that CTFE is first metabolized to the glutathione adduct and then to the cysteine S-conjugates. This cysteine S-conjugates appears to be a potent nephrotoxin. A further study demonstrated that uptake of cysteine S-conjugates by the kidneys, and renal cysteine conjugate can be β-lyase-catalyzed to a thiol. The haloalkyl and haloalkenyl thiols thus released are unstable and yield reactive intermediates whose interactions with cellular constituents are thought to contribute to the observed toxicity of S-conjugates.

On the other hand some CTFE may be further metabolized as indicated by increases in fluoride excretion following CTFE exposure of rats. In studies with the rat, it was shown that liver CYP-450 may be involved in a detoxification pathway of CTFE. Induction of CYP-450 with β-naphthoflavone or phenobarbital afforded some protection against the nephrotoxicity of inhaled CTFE.

In summary, CTFE is not directly toxic but instead requires a multi-step bioactivation process that occurs within the liver and kidney (figure 1). Bioactivation is initiated by an addition reaction with glutathione catalyzed by glutathione-S-transferase (GST) in the liver yielding S-(2-chloro-l,l,2-trifluoroethyl)glutathione (CTFG). Although no direct evidence has been reported in the literature, it is hypothesized that unchanged CTFG enters the enterohepatic circulation, eventually enters the blood and is transported to the kidney where it is acted on by γ-glutamyl transpeptidase (GGT) and renal cysteinyl-glycine dipeptidase (DP) to form the cysteine conjugate S-(2-chloro-l,l,2-trifluoroethyl)-L-cysteine (CTFC). CTFC is transported into the cells of the proximal tubule where it is further metabolized by cysteine β-lyase to form pyruvate, ammonia, and a reactive thiol.

This metabolic scheme has been characterized in many cell preparations and in vivo. It has been shown that CTFG is formed in both rat hepatocytes and human hepatocytes. Studies have also demonstrated the nephrotoxicity of CTFE and its conjugates . These investigators have clearly shown that the nephrotoxicity of CTFE is regiospecific in that it occurs almost exclusively in the S3 segment of the proximal tubule.