Potential occupational carcinogen. NIOSH REL: TWA 20 ppb (240 mg/m3);
ACGIH TLV: TWA 0.02 ppm (adopted).
介电常数：
2.6（Ambient）
物理描述：
Hexachlorobutadiene appears as a colorless liquid with a mild odor. Insoluble in water and denser than water. Nonflammable. May be toxic by ingestion or inhalation. Used as a solvent and heat transfer fluid.
颜色/状态：
Clear, colorless liquid
气味：
Mild, turpentine-like odor.
蒸汽密度：
8.99 (NTP, 1992) (Relative to Air)
蒸汽压力：
0.22 mm Hg @ 25 °C
亨利常数：
0.01 atm-m3/mole
自燃温度：
1130 °F (610 °C)
分解：
When heated to decomposition it emits very toxic fumes of /chlorine/ Cl-.
粘度：
2.447 centipoise at 37.7 °C, 1.479 centistokes; 1.131 centipoise at 98.8 °C, 0.724 centistokes.
(14)C-hexachlorobutadiene (HCBD), a mutagenic and nephrocarcinogenic pollutant, was administered by oral gavage /at a dose/ of 100 mg/kg to female rats, and the radioactivity in 24 hr urine pooled. The average amount of radioactivity recovered in urine was 5.4% of the total (14)C-activity ingested. Solvent extraction, high performance liquid chromatography (HPLC), radio gas chromatography and gas chromatography/mass spectrometry were used for separation and identification of metabolites. After solvent extraction and high performance liquid chromatography, four fractions were separated containing 1%, 5%, 15% and 80% of radioactivity. In the 80% fraction one metabolite was identified after derivatization and comparison with the authentic compound as the mercapturic acid of HCBD (N-acetyl-S-1,1,2,3,4-pentachlorobutadienyl-L-cysteine). The mercapturic acid accounts for 10% of the urinary (14)C-activity. ... The results identify the formation of the intermediary step in the metabolism of hexachlorobutadiene.
The genotoxic properties of hexachloro-1,3-butadiene (HCBD) and its monooxidation product pentachloro-3-butenoic acid (PCBA) were investigated by comparative induction of unscheduled DNA synthesis (UDS) and morphological transformation in the same cell system (Syrian hamster embryo fibroblasts). Hexachloro-1,3-butadiene and pentachloro-3-butenoic acid induce unscheduled DNA synthesis both in the presence and absence of an exogenous metabolizing system. The lowest ED (ED) for unscheduled DNA synthesis induction is smaller for pentachloro-3-butenoic acid (1 ug/ml) than for hexachloro-1,3-butadiene (2 ug/ ml). The intensity of unscheduled DNA synthesis induction is increased approx 3-fold for both cmpd after metabolic activation. Hexachloro-1,3-butadiene and pentachloro-3-butenoic acid induce morphologic transformation. The lowest ED for transformation differs considerably between pentachloro-3-butenoic acid (0.8 ug/ml) and HCBD (10 ug/ml).
The major metabolite was S-(pentachlorobutadienyl)glutathione, and the major urinary metabolites included S-(pentachlorobutadienyl)-L-cyteine, N-acetyl-S-(pentachlorobutadienyl)- L-cysteine, and 1,1,2,3-tetrachlorobutenoic acid. The /data suggests/ that relevant metabolic pathway for hexachloro-1,3-butadiene renal toxicity in mice is conjugation of hexachloro-1,3-butadiene with glutathione, renal procesing of the glutathione-S-conjugate and formation of reactive intermediates by beta-lyase.
An early event in the nephrotoxicity of haloalkene cysteine conjugates is their metab by cysteine conjugate beta-lyase to generate a reactive thiol moiety which binds to protein. This reactive metabolite(s) has been reported to cause mitochondrial dysfunction. ... The effect of 3 haloalkene cysteine conjugate on the activity of rat renal cortical cytosolic glutathione reductase & mitochondrial lipoyl dehydrogenase, 2 enzyme which have been reported to be inhibited by S-(1,2-dichlorovinyl)-L-cyteine in the liver /have been examined/. N-acetyl-(1,2,3,4,4-pentachloro-1,3-butadienyl)-L-cysteine produced a time- & concn-dependent inhibition of glutathione reductase & kinetic studies showed that the inhibition was noncompetitive with a Ki of 215 microM. The enzyme activity from male rat kidney was more sensitive to N-acetyl-S-(1,2,3,4, 4-pentachloro-1,3-butadienyl)-L-cysteine than that from female rat kidney. Amino-oxyacetic acid, an inhibitor of cysteine conjugate beta-lyase, & bis-p-nitrophenyl phosphate, an amidase inhibitor, blocked the effect of N-acetyl-S-(1,2,3,4,4-pentachloro-1,3-butadienyl)-L-cysteine on glutathion reductase, indicating that metab by the cytosol is required to produce enzyme inhibition. S-(1,1,2,2-tetrafluoroethyl)-L-cysteine & -(1,2-dichlorovinyl)-L-cysteine are also noncompetitive inhibitors of glutathione reductase but are less active than N-acetyl-S-(1,2,3,4,4-pentachloro-1,3-butadienyl)-L-cysteine with Ki's of 2.6 & 6.2 mM for S-(1,2-dichlorovinyl)-L-cysteine & S-(1,1,2,2-tetrafluoroethyl)-L-cysteine, respectively, S-(1,2-dichlorovinyl)-L-cysteine produced a time- & concn-dependent inhibition of lipoyl dehydrogense & kinetic studies showed that the inhibition was noncompetitive with Ki of 762 umol. S-(1,1,2,2-tetrafluoroethyl)-L-cysteine & S-(1,2,3,4,4-pentachloro-1,3- butadienyl)-L-cysteine also inhibit lipoyl dehydrogenase. Aminooxyacetic acid blocked the effect of S-(1,2-dichlorovinyl)-L-cysteine, S-(1,1,2,2-tetrafluoroethyl)-L-cysteine, & S-(1,2,3,4,4-pentachloro-1,3- butadienyl)-L-cysteine on lipoyl dehydrogenase, indicating that metab by the mitochondrial fraction is required to produce enzyme inhibition. Glutathione reductase activity in the renal cortex of male rats treated with 200 mg/kg hexachloro-1,3-butadiene was inhibited as early as 1 hr after dosing, before signs of marked morphological damage. The activity of lipoyl dehydrogenase was also reduced but was only statistically significant 8 hr after dosing when there was marked renal dysfunction. These findings indicate that reactive thiol moiety formed by cysteine conjugate beta-lyase cleavage of S-(1,2,3,4,4-pentachloro-1,3-butadienyl)-L-cysteine can inhibit both glutathione reductase & lipoyl dehydrogenase activities in vivo following hexachloro-1,3- butadiene admin. We suggest that such inhibition is a general phenomenon, occurring with diverse & as yet unidentified renal proteins.
The mutagenicity of hexachloro-1,3-butadiene and its S-conjugates 1-(glutathione-S-yl)1,2,3,4,4- penttachloro-1,3-butadiene, 1,4-(bis-glutathione-S-yl-1,2,3,4-tetrachloro-1,3- butadiene and 1,4-(bis-cystein-S-yl)-1,2,3,4-tetrachloro-1,3-butadiene was investigated in Salmonella typhimurium TA100 using a modified preincubation assay. 1-(glutathione-S-yl)-1,2,3,4,4-pentachloro-1,3-butadiene was a direct-acting mutagen; the mutagenic potency of 1-(glutathione-S-yl)-1,2,3,4,4- pentachloro-1,3-butadiene was markedly enhanced by rat kidney microsomes or mitochondria and less so by cytosol. The bis-conjugates 1,4-(bis-glutathione-S- yl-1,2,3,4-tetrachloro-1,3-butadiene and 1,4-(bis-cystein-S-yl)-1,2,3,4- tetrachloro-1,3-butadiene were not mutagenic in the strains TA100, TA2638 and TA98. Purified hexachloro-1,3-butadiene was not mutagenic either with exogenous metabolic activation or with rat liver microsomes fortified with NADPH. Preincubation with rat liver microsomes and glutathione resulted in an unequivocal mutagenic activity of hexachloro-1,3-butadiene which was increased by additional inclusion of rat kidney microsomes. The cysteine conjugate beta- lyase inhibitor aminooxyacetic acid decreased the mutagenicity of hexachloro-1,3-butadiene and its S-conjugates. These results provide strong evidence that formation of the corresponding monoglutathione S-conjugate from hexachloro-1,3-butadiene and subsequent cleavage of this conjugate by gamma-glutamylltranspeptidase and beta-lyase may be responsible for the nephrocarcinogenicity of the parent compound in vivo, whereas formation of the bis-glutathione S-conjugate probably plays no role in the organ specific effects of hexachloro-1,3-butadiene.
It is believed that intermediates produced by modification of the S- 1,1,2,3,4-pentachlorodienyl cysteine derivative metabolite by gamma-glutamyltransferase are responsible for the observed effects on the proximal tubules of the nephrons. These metabolites uncouple oxidative phosphorylation, preventing the generation of ATP, and also inhibit cytochrome c-cytochrome oxidase activity and electron transport. The carcinogenic properties of hexachlorobutadiene are proposed to result from binding of the sulfenic acid degradation product or a thioketene intermediate to cellular DNA. The binding of hexachlorobutadiene to alpha 2u-globulin is believed to be an important factor in its nephrotoxicity. (L94, A54)
CLASSIFICATION: C; possible human carcinogen. BASIS FOR CLASSIFICATION: Observation of renal neoplasms in male and female rats in one study. HUMAN CARCINOGENICITY DATA: None.
来源:Hazardous Substances Data Bank (HSDB)
毒理性
致癌性证据
没有关于人类的数据。动物致癌性的证据有限。总体评估：第3组：该物质对人类致癌性无法分类。
No data are available in humans. Limited evidence of carcinogenicity in animals. OVERALL EVALUATION: Group 3: The agent is not classifiable as to its carcinogenicity to humans.
来源:Hazardous Substances Data Bank (HSDB)
毒理性
致癌性证据
A3：已确认的动物致癌物，对人类的相关性未知。
A3: Confirmed animal carcinogen with unknown relevance to humans.
IN RATS, HEXACHLOROBUTADIENE WAS FOUND IN LUNG, BLOOD, LIVER, BRAIN, KIDNEY, SPLEEN & MESENTERY AFTER A SINGLE INJECTION (UNSPECIFIED) & WAS EXCRETED WITH THE URINE FOR 7 DAYS. IN THE KIDNEY, THE HIGHEST CONCN WAS OBSERVED IN THE PROXIMAL SECTION OF THE NEPHRON.
