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EC number: 201-201-8
CAS number: 79-38-9
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.
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.
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.
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.
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
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.
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