VOL.: 73 (1999) (p. 277)
Chem. Abstr. No.:
Chem. Abstr. Name: 1,1,2,3,4,4-Hexachloro-1,3-butadiene
Exposure to hexachlorobutadiene has occurred principally as a result of its production and release as a by-product from the manufacture of chlorinated solvents and related products. It has been widely detected in ambient air, water, foods and human tissues.
5.2 Human carcinogenicity data
No data were available to the Working Group.
5.3 Animal carcinogenicity data
Hexachlorobutadiene was tested by oral administration in one study in rats, by skin application in mice and inadequately in one experiment in mice by intraperitoneal injection. After oral administration in rats, it produced benign and malignant tumours in the kidneys of animals of each sex. It did not produce skin tumours after repeated application or show initiating activity in a two-stage initiation–promotion study in mice. It enhanced the incidence of renal tubular tumours induced by N-nitrosoethylhydroxyethylamine in a two-stage model of renal carcinogenesis.
5.4 Other relevant data
Hexachlorobutadiene is metabolized exclusively by glutathione conjugation and g -glutamyl transpeptidase to its corresponding cysteine S-conjugate, S-(1,2,3,4,4-pentachloro-1,3-butadienyl)-L-cysteine, which is concentrated in the renal proximal tubules. This conjugate is partly acetylated to the corresponding mercapturic acid and excreted in urine. It is also a substrate for b -lyases, which have high activity in this part of the nephron and cleave the S-conjugate to produce a reactive thioketene, which can acylate proteins and DNA. This toxification pathway is responsible for the kidney-specific toxicity and carcinogenicity of hexachlorobutadiene in rodents. The metabolism of hexachlorobutadiene has not been investigated in humans; however, the demonstrated formation of mercapturic acids from the structurally related haloalkenes tri- and tetrachloroethylene in humans indicates that hexachlorobutadiene would be metabolized in humans in a manner similar to that in rodents.
In rats exposed during development, fetal growth retardation has been observed, usually at maternally toxic doses. Malformations have not been reported. Negative results were obtained in a short-term assay to screen for teratogenicity in mice exposed by gavage.
No data were available on the genetic and related effects of hexachlorobutadiene in humans or in rodents in vivo. There is weak evidence for its genotoxicity in mammalian cells in vitro. The findings for mutagenicity in bacteria are equivocal.
5.5 Evaluation
There is inadequate evidence in humans for the carcinogenicity of hexachlorobutadiene.
There is limited evidence in experimental animals for the carcinogenicity of hexachlorobutadiene.
Overall evaluation
Hexachlorobutadiene is not classifiable as to its carcinogenicity to humans (Group 3).
For definition of the italicized terms, see Preamble Evaluation.Previous evaluations: Vol. 20 (1979); Suppl. 7 (1987) (p. 64)
Synonyms
See Also:
Toxicological Abbreviations
Hexachlorobutadiene (EHC 156, 1994)
Hexachlorobutadiene (HSG 84, 1993)
Hexachlorobutadiene (ICSC)
Hexachlorobutadiene (IARC Summary & Evaluation, Volume 20, 1979)