Tetraethylammonium heptadecafluorooctanesulphonate

Carcinogenicity

Description of key information

The carcinogenic potential of perfluorooctane sulfonate was investigated in a 104-week dietary chronic toxicity and carcinogenicity study with perfluorooctane sulfonic acid potassium salt (PFOS) in Rats.
In this study, groups of 40-70 male and female Crl:CD (SD)IGS BR rats were given PFOS in the diets at concentrations of 0.5, 2, 5, or 20 ppm for 104 weeks. A control group was given diets containing acetone, the vehicle. A recovery group was given the test material at 20 ppm for 52 weeks and was observed till death. Five animals/sex in the treatment groups were sacrificed during weeks 4, 14 and 53; liver samples were collected for mitochondrial activity, hepatocellular proliferation rate, and determination of palmitoyl-CoA oxidase activity. Serum and liver specimens were collected for analyses of the presence and concentration of PFOS in liver and serum during and at the end of the in-life phase of the study. After termination of the study pathological examinations were conducted.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Endpoint conclusion

Dose descriptor:

NOAEL

0.25 mg/kg bw/day

Justification for classification or non-classification

Perfluorooctane sulfonic acid potassium salt (PFOS) is hepatoxic and carcinogenic, inducing tumors of the liver, and of the thyroid an

mammary glands in rats. There was a significant increase in the incidence of hepatocellular adenomas in males and females at the highest dose of 20 ppm; the females at 20 ppm also had a significant increase in combined hepatocellular adenomas and carcinomas. In addition, there was a significant increase in thyroid follicular cell adenomas and combined thyroid follicular cell adenomas and carcinomas in the male recovery group at 20 ppm. Several epidemiological studies were conducted on employees in facilities where PFOS has been manufactured. In a retrospective cohort mortality study, 145 deaths were identified in the cohort: 65 of these deaths were in the high exposure group. When the entire cohort was analyzed, SMRs were not elevated for most of the cancer types and for non-malignant causes. SMRs that were above 1 (cancer of the esophagus, liver, breast, urinary organs, bladder, and skin) were also elevated when the cohort was limited to any employee ever employed in a high exposure job (except breast cancer). Only 2 or 3 deaths were reported for each of these cause-specific categories and were not statistically significant, except for bladder cancer. Workers who were employed in high exposure jobs were greater than 12 times more likely to die of bladder cancer than the general population of Alabama (SMR = 12.77, 95% CI = 2.63 - 37.35). This effect remained when the data were analyzed using county death rates. Three male employees in the cohort died of bladder cancer, and all of the deaths occurred in employees who had worked in high exposure jobs for at least 5 years (SMR = 24.49, 3 observed deaths, 0.12 expected). All of them had worked at the Decatur plant for more than 20 years. Two deaths were reported for liver cancer. One was in the low exposure group and one in the high exposure group. The SMR for workers who were employed in either high or low exposure jobs was 3.08 (95% CI = 0.37 – 11.10). Five cases of cirrhosis of the liver were reported in this cohort, 2 in the high exposure group, 1 in the low exposure group, and 2 in the non-exposed. The observed did not exceed the expected mortality experience in any of these groups.Given the limitations of this study, it is unclear whether fluorochemicals are responsible for the excess of bladder cancer deaths, or whether other carcinogens may be present in the plant. Therefore a higher incidence of cancer in employess exposed to PFOS cannot be excluded but a clear relationship is not evident. In a further study, the incidence of bladder cancer was ascertained by postal questionnaire to all living current and former employees of the facility (NZ1895) and death certificates for deceased workers (NZ188). Exposure to PFOS was estimated with work history records and weighted with biological monitoring data. Standardized incidence ratios (SIRs) were estimated using U.S. population–based rates as a reference. Bladder cancer risk within the cohort was evaluated using Poisson regression by cumulative PFOS exposure. The questionnaires were returned by 1,400 of the 1895 cohort members presumed alive. Eleven cases of primary bladder cancer were identified from the surveys (n = 6) and death certificates (n = 5). The SIRs were 1.28 (95% confidence interval [CI] = 0.64–2.29) for the entire cohort and 1.74 (95% CI = 0.64–3.79) for those ever working in a high exposed job. Compared with employees in the lowest cumulative exposure category, the relative risk of bladder cancer was 0.83 (95% CI = 0.15–4.65), 1.92 (95% CI = 0.30–12.06), and 1.52 (95% CI = 0.21–10.99). The results offer little support for an association between bladder cancer and PFOS exposure, but the limited size of the population prohibits a conclusive exposure response analysis. Due to the ambiguous result of the epidemiological studies and the results of the animal study a classification as Carc. Cat 3, R40 (GHS Carc. 2, H351) seems appropriate for perfluorooctane sulfonic acid tetreaethylammonium salt.

This classification complies with the Regulation (EC) No 1272/2008 Annex VI for perfluorooctane sulfonic acid, potassium perfluorooctanesulfonate, dieethanolamine perfluorooctane sulfonate, ammonium perfluorooctane sulfonate, and lithium perfluorooctane sulfonate.

Additional information

The chronic toxicity and carcinogenicity of perfluorooctane sulfonic acid potassium salt (PFOS) have been studied in rats. The results of the study show that PFOS is hepatotoxic and carcinogenic, inducing tumors of the liver, and of the thyroid and mammary glands. Based on the liver toxicity, the no-observed-adverse-effect level (NOAEL) for PFOS is considered to be 0.5 ppm (0.5  ppm corresponds with 0.017-0.057 mg/kg body weight/day ) in male rats and 2 ppm (2.0 ppm corresponds with 0.095-0.213 mg/kg bw/day) in female rats; the low observed-adverse-effect level (LOAEL) is 2 ppm in male rats and 5 ppm in female rats.

Treatment-related histomorphologic changes were seen in the liver in the males given 5 or 20 ppm and in the females given 20 ppm. The changes consisted of hypertrophy of hepatocytes in centrilobular areas in males and females, and midzonal to centrilobular hepatocytic

vacuolation. The incidence and severity of the changes tended to be greater in the males. Dietary administration of PFOS for approximately 53 weeks was associated with mildly to moderately lower cholesterol for males and females fed 20 ppm; and mildly higher alanine aminotransferase for males fed 20 ppm. In the unscheduled sacrifices between Weeks 54 and 105, animals given 20 ppm had increased hepatocellular centrilobular hypertrophy, eosinophilic hepatocytic granules, and centrilobular hepatocytic

pigment were noted. Increased hepatocellular centrilobular hypertrophy was seen in animals given 5 ppm.

At the terminal sacrifice, the livers of animals given 5 or 20 ppm exhibited a slight increase in macroscopic findings, including enlarged, mottled, diffuse darkened, or focally lightened. Hepatotoxicity, characterized by significant increases (P<0.05) in centrilobular hypertrophy, centrilobular eosinophilic hepatocytic granules, centrilobular hepatocytic pigment, or centrilobular hepatocytic vacuolation was noted in male and/or female rats given 5 or 20 ppm.

Read-across justification

- Group: The perfluorooctane sulfonate anion (PFOS) does not have a specific CAS number. The acid and salts have the following CAS numbers: acid (1763-23-1), ammonium (NH4 +) salt (29081-56-9), potassium (K+) salt (2795-39-3), tetraethylammonium (C2H5)4N+) salt (56773-42-3).

For the registration of tetraethylammonium perfluorooctanesulfonate (CAS 56773-42-3) the data on perfluorooctane sulfonate anion (PFOS) as well as the respective salts were taken into consideration and a read across approach was used due to the following reasons:

- Justification: REACH regulation EC 1907/2006 and ECHA guidance document R.6 state that substances whose physico-chemical, toxicological and ecotoxicological properties are likely to be similar, or follow a regular pattern as a result of structural similarity, may be considered as a group / category of substances. Properties of PFOS are mainly determined by the length of the fluorinated tail and not by the nature of the functional group. PFOS and its salts are dissociated in aqueous media, substituted amines and the corresponding sulfonyl fluorid are hydrolysed in aqueous media to PFOS. Therefore these compounds are members of a large family of perfluoroalkyl sulfonate substances. According to OECD, 2002, (ENV/JM/RD(2002)17/FINAL) “perfluorinated compounds represent a very unique chemistry”, at least substances with equal numbers of perfluorinated carbon atoms and functional groups.

Thus, in accordance with OECD, 2002, grouping and read-across based on the length of the perfluorinated carbon structure with a sulfonate moiety is in principle possible. The criterion of structural similarity is fulfilled and all substances may be regarded as group with respect to chemical behaviour. This judgement is in line with and confirmed by the existing classification of perfluoroalkyl sulfonates in Europe: according Annex VI to Regulation (EC) No 1272/2008 for classification and labeling several perfluoroalkyl sulfonates are considered as a group/category and therefore identical hazard class/category codes, and hazard statement codes applies. The following substances/CAS number are mentioned explicitly in the regulation: perfluorooctane sulfonic acid/1763-23-1, potassium perfluorooctanesulfonate/ 2795-39-3, diethanolamine perfluorooctane sulfonate/70225-14-8, ammonium perfluorooctane sulfonate/29081-56-9, lithium perfluoroocane sulfonate/29457-72-5.

This approach also apply to tetraethylammonium perfluorooctanesulfonate, as the evaluation of the toxicological data of tetraethylammonium perfluorooctanesulfonate substantiate the membership of the substance to the group and the same hazard class and statement codes are valid.

Therefore based on the available data as well as on earlier judgements by e.g. OECD and within the EU classification a read across approach is justified.

Carcinogenicity: via oral route (target organ): digestive: liver; glandular: mammary gland; glandular: thyroids