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1,2,5,6,9,10-Hexabromocylodecan (HBCD)
(CAS-Nr.: 3194-55-6/25637-99-4)

Ausgabe: September 2001
Stand: Mai 2001

Proposal made by the "advisory group on toxicology" on the hazardous substances committee with regard to the classification of Hexabromocyclododecane (HBCD) (CAS Nos. 3194-55-6; 25637-99-4 (mixed stereo isomers))

Genotoxicity:

In vitro:

Hexabromocyclododecane (HBCD) has been tested in a Salmonella typhimurium assay in presence and absence of metabolic activation systems with the tester strains Ta 1535, Ta 1537, Ta 1538, Ta 98 and Ta 100 in doses ranging from 1 up to 5,000 µg/plate (TSCATS, 1990e). HBCD was not mutagenic nor toxic. The same results were obtained in several other respective bacterial tests (Oesch, 1978; Zeiger et al., 1987; Ogaswara and Hanafusa, 1993, EPA, 1990; TSCATS, 1990a; TSCATS, 1990d).

An in vitro gene mutation assay in Saccharomyces cerevisiae with doses from 0.5-50 µg/ plate with and without metabolic activation was also negative (TSCATS, 1990a).

An in vitro mammalian cytogenetic test using human peripheral blood lymphocytes with doses from 10 up to 600 µg/ml in activated and nonactivated systems showed no significant increase in structural chromosome aberrations nor in numerical aberrations; toxicity more than 50% was observed in the 2 upper doses (300 and 600 µg/ml) [Gudi and Schadly, 1996].

In an in vitro test with respect to recombination HBCD has been examined at an endogenous locus in mammalian test cells (V79). Treatment was 24 hours with 5 doses ranging from 2 up to 20 µg/ml. HBCD caused a low (2-fold) but statistically significant increase in recombination frequency in this system. This assay cannot be fully assessed since relevant information is missing in the publication, e.g.: purity of the test substance, details of culture conditions (e.g. pH or osmolality may influence the results), observed cytotoxicity. Furthermore, no information is given whether a twofold increase is convincing as compared to historical control data. Information on the reproducibility of the results, validation of the test system and dose effect response are also missing. The result shows that the recombination activity is rather low and its relevance is questionable (Helleday et at., 1999).

a UDS-assay (TSCATS, 1990b) in primary rat hepatocytes without metabolic activation (dose range 0.05-1,000 µg/well) performed in 1978 according to Williams' method (no further details given) with positive outcome cannot be assessed. The test substance "FM residue" was only described as "brittle, black solid" without any chemical characterization, whereas HBCD is a white crystalline solid. This result will not be regarded in the final assessment. Remark: With this test substance also a questionable positive result in an Ames test was found by the same laboratory.

In vivo:

HBCD (test substance: 85.1 % -, 8.8% - and 6.1 % -isomer) was tested according to OECD No. 474 and 92/69/EEC,B12 under GLP conditions for clastogenicity (small micronuclei) and for the ability to induce spindle poison effects (large micronuclei) in NMRI mice using the micronucleus test method. For this purpose, the test substance was administered twice intraperitoneally, with a 24- hour interval between administrations, to male animals at dose levels of 500 mg/kg, 1,000 mg/kg and 2,000 mg/kg body weight. The administration of the test substance led to evident signs of toxicity. According to the results of this study, the intraperitoneal administration of HBCD did not lead to any increase in the number of polychromatic erythrocytes containing either small or large micronuclei. The rate of micronuclei was always in the same range as that of the concurrent negative control in all dose groups and within the range of the historical control data. Thus, HBCD did not have any chromosomedamaging (clastogenic) effect, and there were no indications of any impairment of chromosome distribution in the course of mitosis [BASF, 2000].

Carcinogenicity:

There is one longterm study in mice:

In a 18 months study groups of 50 male and 50 female mice (B6C3F1) received diets containing 0, 100, 1,000 or 10,000 ppm of HBCD (equivalent to about 0, 13, 130 or 1,300 mg/kg bw-d; no information on test substance characterization given) (Kurokawam et al., 1996). Survival and growth rates for the treated groups were similar to controls. Remarkable liver changes were observed in the 1,000- and 10,000-ppm groups. The results of the histopathological examinations are given in the table:

table:summary of histopathological findings in mice fed HBCD for 18 months