Bis(pentabromophenyl) ether

Carcinogenicity

Description of key information

Two year studies in rats and mice performed by the U.S. National Toxicology Program on the commercial DecaBDE product at doses of 0, 2.5 and 5% of the diet.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Endpoint conclusion

Dose descriptor:

LOAEL

6 625 mg/kg bw/day

Justification for classification or non-classification

Classification of DecaBDE as a carcinogen is not justified. The chronic studies with BDE-209 suggest that low-dose exposures (e.g., ≤1.0 mg/kg-day) do not induce non-neoplastic or neoplastic changes in cells; and excessively high-dose exposures (e.g., 6650 mg/kg-day) may induce proliferative lesions in select tissues (e.g., thyroid follicular hyperplasia) that may progress to neoplasia via MOAs that are not relevant to humans. Therefore, doses of BDE-209 that do not produce nonneoplastic changes will be adequately protective against the development of neoplasia. See EURA 20402 EN and Hardy et al. (CRT 2009 39(S3):1 -44) for full discussion.

Additional information

No evidence of a genotoxic effect was detected in the Ames Salmonella, chromosome aberration, mouse lymphoma, or sister-chromatid exchange tests (McGregor et al., 1988; NTP 1986; Wagner & Klug, 1998). No cytogenic changes were observed in the bone marrow of rats (parents and offspring) undergoing a one-generation reproduction test using FR-300 -BA (Norris et al. 1975). The absence of positive genotoxicity findings, along with the absence of tumors in the chronic study by Kociba et al. (1975), and only strain- and sex-specific tumors present in excessively dosed animals in the NTP (1986) study support the following: the commercial BDE-209/BDE-209 is not genotoxic; does not induce tumors via a mutagenic mechanism of action; and that a possible threshold exists for induction of tumors.

Using its evidence of carcinogenicity categories of “clear,” “some,” “equivocal,” and “no,” the NTP (1986) concluded there was some (rats, increased incidence of neoplastic nodules in low-dose males and high-dose animals of both sexes), equivocal (male mice, increased incidence of hepatocellular adenomas or carcinomas [combined] in the low-dose and increased incidence of thyroid follicular cell adenomas or carcinomas [combined] in both dose groups), and no (female mice) evidence of carcinogenicity. Based on the dose levels used, it is remarkable that the responses observed were consistent with rodent- or strain-specific tumors commonly seen in high-dose groups (EPA, 1998f; Goodman et al., 1994). In the NTP (1986) study, the authors considered the increased incidence of neoplastic nodules of the liver in male and female rats to be suggestive evidence of carcinogenicity; however, as noted previously, this terminology has been abandoned and there was no increase in hepatocellular carcinomas, as would be expected if the increased incidence of neoplastic nodules was truly representative of benign neoplasia (Huff et al., 1989). The US NTP does not include BDE-209 in its list of carcinogens (NTP, 2005). Further, BDE-209 is not listed as a carcinogen by the US Occupational Safety and Health Administration (OSHA), and the International Agency for Research on Cancer (IARC) determined it is “ . . . not classifiable as to its carcinogenicity to humans (Group 3)” based on “ . . . limited evidence” in experimental animals (IARC, 1990; OSHA, 2008). In conclusion, the chronic studies with BDE-209 suggest that low-dose exposures (e.g., ≤1.0 mg/kg-day) do not induce non-neoplastic or neoplastic changes in cells; and excessively high-dose exposures (e.g., 6650 mg/kg-day) may induce proliferative lesions in select tissues (e.g., thyroid follicular hyperplasia) that may progress to neoplasia via MOAs that are not relevant to humans. Therefore, doses of BDE-209 that do not produce nonneoplastic changes will be adequately protective against the development of neoplasia. See Hardy et al. (CRT 2009 39(S3):1-44) for full discussion.

Carcinogenicity: via oral route (target organ): glandular: thyroids