1.1.1. Nomenclature

• Chem. Abstr. Serv. Reg. No.: 116-14-3
• Chem. Abstr. Name: Tetrafluoroethene
• IUPAC Systematic Name: Tetrafluoroethylene
• Synonyms: Perfluoroethene; perfluoroethylene; 1,1,2,2-tetrafluoroethylene

1.1.2. Structural and molecular formulae and relative molecular mass

1.1.3. Chemical and physical properties of the pure substance

• (a) Description: Colourless gas (Lewis, 1993)
• (b) Boiling-point: −75.9°C (Lide, 1997)
• (c) Melting-point: −142.5°C (Lide, 1997)
• (d) Solubility: Insoluble in water (Lide, 1997)
• (e) Reactivity: May polymerize in the absence of an inhibitor, especially when heated or in the presence of oxygen (United States National Library of Medicine, 1998)
• (f) Explosive limits: Upper, 60%; lower, 11% by volume in air (United States National Library of Medicine, 1998)
• (g) Conversion factor: mg/m³ = 4.1 × ppm

3.1.1. Mouse

Groups of 58 male and 58 female B6C3F₁ mice, seven weeks of age, were administered tetrafluoroethylene (purity, > 98%) by whole-body inhalation at concentrations of 0, 312, 625 or 1250 ppm [0, 1280, 2560 or 5125 mg/m³] for 6 h per day on five days per week for 95–96 weeks. Ten male and 10 female mice from each exposure group were evaluated at 15 months. Survival in all of the dose groups of mice was significantly reduced, so that, at 90 weeks, the survivors in the control, low-, mid- and high-dose groups, respectively, were: males—41/48, 17/48, 9/48, 7/48; females—38/48, 20/48, 18/48, 10/48. All mice, except one in each of the middle and high-dose groups of females, were necropsied and tissues were examined histologically. At the 15-month evaluation, haemangiosarcomas in the liver were found in three males of the high-dose group and one female of the low-dose group. At termination, the incidences of haemangiosarcomas in the liver in the control, low-, mid- and high-dose groups, respectively, were: males—0/48, 21/48, 27/48, 37/48 (p ≤ 0.01 for all dose groups, Fisher's exact test); and females—0/48, 27/48, 27/47, 34/47 (p ≤ 0.01 for all dose groups). The incidences of hepatocellular adenomas were: males—17/48, 17/48, 12/48, 20/48; and females—15/48, 17/48, 20/47 (p ≤ 0.05), 15/47. The incidences of hepatocellular carcinomas were, for males, 11/48, 20/48, 33/48, 26/48 (p ≤ 0.01 for all dose groups) and, for females, 4/48, 28/48, 22/47, 20/47 (p ≤ 0.01 for all dose groups). The incidences of histiocytic sarcomas (all organs combined) also were increased as follows: males—0/48, 12/48, 7/48, 7/48 (p < 0.001 for all dose groups, life table test); and females—1/48, 21/48, 19/47, 18/47 (p < 0.001 for all dose groups, life table test) (United States National Toxicology Program, 1997).

3.1.2. Rat

Groups of 60 male Fischer 344 rats, seven weeks of age, were administered tetrafluoroethylene (purity, > 98%) by whole-body inhalation at concentrations of 0, 156, 312 or 625 ppm [0, 640, 1280 or 2560 mg/m³] and groups of 60 female Fischer 344 rats were administered concentrations of 0, 312, 625 or 1250 ppm [0, 1280, 2560 or 5125 mg/m³] for 6 h per day on five days per week for 104 weeks. Ten male and 10 female rats from each exposure group were evaluated at 15 months. Survival in the high-dose male rats was significantly reduced, so that, at two years, the survivors in the control, low-, mid- and high-dose groups, respectively, were: males—17/50, 12/50, 17/50 and 1/50; females—28/50, 16/50, 15/50 and 18/50. Mean body weights in high-dose males were reduced from week 81 until the end of the study, while there was a marginal reduction in body weight in females of the high-dose group at the end of the study. All rats were necropsied and tissues examined histologically. The incidences of renal tubule neoplasms in the control, low-, mid- and high-dose groups, respectively, were: males—adenomas, 2/50, 4/50, 9/50 (p ≤ 0.05, Fisher's exact test), 13/50 (p ≤ 0.01); carcinomas, 1/50, 1/50, 2/50, 0/50; and, females—adenomas, 0/50, 3/50, 3/50, 8/50 (p ≤ 0.01); carcinomas, 0/50, 0/50, 0/50, 3/50. Liver neoplasms were also increased in both males and females. The incidences were: males—hepatocellular carcinomas only, 1/50, 1/50, 10/50 (p ≤ 0.01), 3/50; hepatocellular adenomas and carcinomas combined, 4/50, 7/50, 15/50, 8/50; and females—hepatocellular carcinomas only, 0/50, 4/50 (p ≤ 0.05), 9/50 (p ≤ 0.01), 2/50; hepatocellular adenomas and carcinomas combined, 0/50, 7/50, 12/50, 8/50 (United States National Toxicology Program, 1997).

4.1.1. Humans

No data were available to the Working Group.

4.1.2. Experimental systems

Male rats exposed to 14 000 mg/m³ tetrafluoroethylene in air for 30 min excreted small amounts of fluoride ion in the urine over a 14-day period, indicating that metabolism can occur (IARC, 1979).

The metabolism of tetrafluoroethylene has been studied in rat liver fractions; both microsomal and cytosolic glutathione S-transferases catalyse the formation of S-(1,1,2,2-tetrafluoroethyl)glutathione. The rate with microsomes was four times greater than with cytosol. Fluoride ion release was equivalent to approximately 20% of the glutathione used. The quantities of glutathione used and of fluoride ion released in incubations were identical whether cytochrome P450 was active or had been inactivated with carbon monoxide. Thus, cytochrome P450 oxidation, a pathway common to many haloalkenes, does not appear to be involved in the metabolism of tetrafluoroethylene. Evidence for the glutathione conjugation pathway in vivo comes from the identification of the cysteinylglycine and cysteine conjugates of tetrafluoroethylene in rat bile, following oral administration of l-[³⁵S]cysteine and then inhalation exposure to 6000 ppm [24 600 mg/m³] tetrafluoroethylene for 6 h. S-(1,1,2,2-Tetrafluoroethyl)-l-cysteine is metabolized in vitro in rat renal cortex slices to give pyruvate and ammonia, a reaction that is catalysed by β-lyase and which also generates a reactive thiol (Figure 1) that is probably important in renal cytotoxicity (Odum & Green, 1984; Green & Odum, 1985).

Figure 1

Proposed mechanism for the metabolic activation of tetrafluoroethylene.

4.2.1. Humans

No data were available to the Working Group.

4.2.2. Experimental systems

No gross lesions were noted in any of the organs of male rats exposed to 14 000 mg/m³ tetrafluoroethylene in air for 30 min (IARC, 1979).

In male Alderley Park rats exposed to a tetrafluoroethylene atmosphere of 6000 ppm [24 600 mg/m³] for 6 h, there was marked renal necrosis involving the pars recta of the proximal tubules (Odum & Green, 1984). In addition, a review of largely unpublished data on the toxicity of tetrafluoroethylene (Kennedy, 1990) indicates that, in rats exposed to 2500 ppm [10 250 mg/m³] for 6 h per day on five days per week for two weeks, or to 2000 ppm [8200 mg/m³] for 6 h per day on five days per week for 18 weeks, there was decreased body weight gain and renal proximal tubule damage, which was more severe after the longer-duration exposure. Renal toxicity was also observed in Fischer 344/N rats in the 16-day and 13-week studies preliminary to the carcinogenicity test described above (Section 3.1.2) at 625 ppm [2560 mg/m³] and higher concentrations; the damage was located predominantly at the corticomedullary junction. In the 13-week study, liver weights were increased in both male and female rats exposed to 5000 ppm [20 500 mg/m³]. In the two-year carcinogenicity study, increases in renal degeneration were observed in male rats at 156 ppm [640 mg/m³] and in female rats at 625 ppm and increases in renal hyperplasia were observed in both male and female rats at 625 ppm (United States National Toxicology Program, 1997).

According to the review by Kennedy (1990), Syrian hamsters exposed to 2500 ppm [10 250 mg/m³] for 6 h per day on five days per week for two weeks or to 2000 ppm [8200 mg/m³] for 6 h per day on five days per week for 18 weeks showed no sign of renal toxicity, but there was testicular atrophy. No sign of toxicity was observed in dogs exposed to 1000 ppm [4100 mg/m³] for 6 h per day on five days per week for six weeks (reviewed by Kennedy, 1990).

In the 16-day toxicity study with B6C3F₁ mice preliminary to the carcinogenicity study described above (Section 3.1.1), there were increases in liver weight of female mice exposed to 2500 ppm [10 250 mg/m³] or more and in kidney weight of females exposed to 5000 ppm [20 500 mg/m³]. Renal tubule karyomegaly was observed, mainly in the inner cortex, of males and females exposed to 1250 ppm [5125 mg/m³] or more. Karyomegaly was observed in the same region in the subsequent 13-week study at the same concentrations. In the two-year carcinogenicity test, renal tubule karyomegaly was increased at 625 ppm in male mice and at 1250 ppm in female mice. In the same study, liver angiectasis was increased at or above 312 ppm in both male and female mice, while there was increased liver and spleen haematopoietic cell proliferation in female mice at these dose levels (United States National Toxicology Program, 1997).

Identical clinical evidence of nephrotoxicity comes from inhalation of tetrafluoroethylene at atmospheric concentrations greater than 2000 ppm [8200 m/gm³] and from oral administration of tetrafluoroethylcysteine to male rats, suggesting that the latter is an important metabolite in the cytotoxic response. The cytotoxicity of the cysteine conjugate has also been demonstrated in vitro in rat kidney slices by reduced uptake of both organic anion, para-aminohippuric acid and the cation, tetraethylammonium bromide (Odum & Green, 1984; Green & Odum, 1985).

4.4.1. Humans

No data were available to the Working Group.

4.4.2. Experimental systems (see Table 1 for references)

Table

No increases were observed in the frequency of micronucleated erythrocytes from the peripheral blood of mice exposed by inhalation for 13 weeks. This appears to be the only study with tetrafluoroethylene itself. However, S-(1,1,2,2-tetrafluoroethyl)-l-cysteine was not mutagenic to Salmonella typhimurium in either the presence or absence of an exogenous metabolic system based upon rat kidney S9.