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Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics in vitro / ex vivo
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2001
Report Date:
2001

Materials and methods

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Tetrafluoroethylene (TFE) 99%; CTL reference number Y00462/001/004 was supplied by Imperial Chemical Industries PLC.
S-(1,1,2,2-tetrafluoroethyl)glutathione (TFE-GSH), S-(1,1,2,2-tetrafluoroethyl)-L-cysteine (TFE-CYS) and N-acetyl-S-(1,1,2,2-tetrafluoroethyl)-L-cysteine (TFE-NAC) were synthesised as described previoiusly (Odum and Green, 1984).
[Acetyl-1-14C]-coenzyme A (40-60mCi per mmol) was obtained from Amersham-Pharmacia Cardiff

Test animals

Details on test animals and environmental conditions:
Female F344 rats (150 - 180g) and femal B6C3F1 mice (18 -20g) were obtained from Harlan Olac UK. The clinical condition of all animals was monitored prior to the start of the experiments and any animal showing adverse clinical signs was removed.
The animals received Rat and Mouse Number 1 (RM1) pelleted diet from special Diet

Results and discussion

Metabolite characterisation studies

Metabolites identified:
yes
Details on metabolites:
S-(1,1,2,2-tetrafluoroethyl)-glutathione
S-(1,1,2,2-tetrafluoroethyl)-cysteine
N-acetyl-S-(1,1,2,2-tetrafluoro)-L-cysteine

Any other information on results incl. tables

Table A: Metabolism of TFE and its cysteine conjugates in liver and kidney fractions from rats, mice and humans

   GSTa  C-S lyaseb       N-acetyl transferaseb  Acylasec  
 Organ/  Vi  Km  Vmax  Km  Vmax  Km  Vmax
 Species  (nmol/min/  (mM)  (nmol/min/  (mM)  (nmol/min/  (mM)  (nmol/min/
    mg protein)    mg protein)    mg protein)    mg protein)
 Liver              
 Rat  94  2.0  5.9  2.0  3.9  0.3  37
 Mouse  79  3.0  40  7.0  69  0.2  18
 Human  87  5.4  1.7  4.9  3.5  0.3  48
 Kidney              
 Rat  ND  2.6  21.9  2.9  91  0.4  216
 Mouse  ND  5.9  4.0  9.0 48   1.0  248
 Human  ND  5.0  3.4  4.2  56  0.4  91

aGlutathione S-transferase (GST) activity was measured with TFE

bC-S lyase and N-acetyl transferase activities were measured with S-(1,1,2,2 -tetrafluoroethyl)-L-cysteine

cAcylase activity was measured with N-acetyl-S-(1,1,2,2 -tetrafluoroethyl)-L-cysteine

ND: not determined

Applicant's summary and conclusion

Conclusions:
The results suggest that the human kidney is at significantly less risk from the potentially adverse effects of TFE than the rat kidney. Comparisons of the same metabolic rates in mouse and human liver also leads to the conclusion that the risks to human liver are significantly lower than those to mouse liver following exposure to TFE.
Executive summary:

Tetrafluoroethylene (TFE) is metabolised by glutathione conjugation and the ß-lyase and mercapturic acid pathways. The major metabolic steps in these pathways, the conjugation of TFE with glutathione, the metabolism of S-(1,1,2,2 -tetrafluoroethyl)-L-cysteine (TFE-Cys), by ß-Lyase, the N-acetylation of TFE-Cys by N-acyl transferases, and the de-acylation of N-acetyl-S-(1,1,2,2 -tetrafluoroethyl)-L-cysteine (TFE-NAC) by acylases, have been compared in vitro in rat, mouse and human liver and kidney fractions.

Glutathione conjugation of TFE in the liver was comparable in all three species. The highest ß-lyase activities were found in mouse liver and rat kidney, the target organs in the NTP cancer bioassay. Human ß-lyase activities were significantly lower, the rate in human liver being 23 -fold lower than that in mouse liver and in human kidney, 6 -fold lower than that in rat kidney. N-acetyl transferase activity was heavily localised in the kidney in rats and humans but in the mouse the liver had the highest activity. Acylase activity was also concentrated in the kidney with the activity in rodents approximately double that in the human kidney. Overall, these results suggest that the human kidney is at significantly less risk from the potentially adverse effects of TFE than the rat kidney. Comparisons of the same metabolic rates in mouse and human liver also leads to the conclusion that the risks to human liver are significantly lower than those to mouse liver following exposure to TFE.