Tetrafluoroethylene

Basic toxicokinetics

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

Test material information

Constituent 1

Reference substance name:

Tetrafluoroethylene

EC Number:

204-126-9

EC Name:

Tetrafluoroethylene

Cas Number:

116-14-3

Molecular formula:

C2F4

IUPAC Name:

tetrafluoroethene

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 or test system 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

	GST^a	C-S lyase^b		N-acetyl transferase^b		Acylase^c
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.