The biotransformation of 1,1,2,2-tetrachloroethane is complex; dichloroacetic acid has been identified as the major urinary metabolite, along with trichloroethanol and trichloroacetic acid. The formation of the latter two metabolites was suggested to be due to reductive biotransformation of 1,1,2,2-tetrachloroethane to give trichloroethene, which may be further oxidized to chloral hydrate by cytochrome p450. Trichloroethanol and trichloroacetic acid are formed from chloral hydrate by reduction and respiratory oxidation and are major urinary metabolites of trichloroethene. Hydroxylation of 1,1,2,2-tetrachloroethane, yielding dichloroacetyl chloride, is the predominant pathway to dichloroacetic acid
Tetrachloroethane when admin for 8 hr as vapor at 200 ppm to rats & mice, produced fujiwara reaction-positive urinary metabolites, trichloroacetic acid, trichloroethanol & total trichloro cmpd in yields consistent with their vapor pressure & ease of metabolic conversion.
Incubation of 1,2-(14)C-labeled 1,1,2,2-tetrachloroethane with a reconstituted monooxygenase system or with intact rat liver microsomes led to the formation of a metabolite capable of binding covalently to proteins and other nucleophiles. The enzyme system responsible for metabolizing tetrachloroethane to both soluble and covalently bound metabolites was induced by phenobarbital or xylene but not by beta-naphthoflavone treatment. The results are consistent with a scheme whereby 1,1,2,2-tetrachloroethane is metabolized by cytochrome P450 to dichloroacetyl chloride, which can bind covalently to various nucleophiles or hydrolyze to dichloroacetic acid.
... 1,1,2,2-Tetrachloroethane appears to be metabolized by hepatic nuclear cytochrome P450, and ... converted to chlorinated metabolites after incubation with hepatic nuclei and an NADPH-generating system plus EDTA, with the omission of any component eliminating metabolite production.
1,1,2,2-tetrachloroethane appears to be distributed throughout the body, but may selectively accumulate to a degree in certain cells and tissues. Because it is a volatile, lipophilic molecule of small molecular size that appears to be readily absorbed from the respiratory and gastrointestinal tracts, passive diffusion is the most likely mechanism of absorption. The metabolism of 1,1,2,2-tetrachloroethane proceeds via multiple pathways. The predominant pathway appears to involve production of dichloroacetic acid, formed as an initial metabolite via stagewise hydrolytic cleavage of 1,1,2,2-tetrachloroethane, or by cytochrome P450-based oxidation of 1,1,2,2-tetrachloroethane. Dichloroacetic acid has been identified as the major urinary metabolite. Dichloroacetic acid can be further metabolized to glyoxylic acid, formic acid, and carbon dioxide, with carbon dioxide a potential major component of the end products. Other pathways involve the formation of trichloroethylene or tetrachloroethylene as initial metabolites, with subsequent reactions yielding trichloroethanol, trichloroacetic acid, and oxalic acid as important end products. Metabolism of 1,1,2,2-tetrachloroethane is generally extensive, with 68% or more of a total administered dose found as metabolites. Following absorption into the body, 1,1,2,2-tetrachloroethane is eliminated mainly as metabolites in the urine and as carbon dioxide and unchanged compound in expired air. (L336)
IDENTIFICATION AND USE: 1,1,2,2-Tetrachloroethane is a volatile synthetic chemical that is used as intermediate in the synthesis of other chlorinated hydrocarbons. HUMAN EXPOSURE AND TOXICITY: Intoxications have been fatal. Central nervous system and the liver are the target tissues in acute exposures. Liver, gastro-intestinal tract and nervous system (central peripheral) are the targets in chronic exposure. Toxic effects are also reported in the hematopoietic system. Acute and chronic exposures produce jaundice, liver enlargement, fatty degeneration, hepatic necrosis, and cirrhosis. Respiratory irritation and pulmonary edema may follow inhalation exposures. Skin contact may result in dryness, scaling, and inflammation. Severe lesions may occur. Eye contact may result in burning and serious eye damage. Inhalation may cause a burning sensation, wheezing, coughing, laryngitis, and shortness of breath. Ingestion may cause diarrhea and severe mucosal injury. Numerous deaths due to its ingestion, inhalation and cutaneous absorption have been recorded. The solvent effects primarily the central nervous system and the liver and caused polyneuritis and paralysis. Of 380 workers exposed to the solvent 133 (35%) exhibited tremor and other nervous symptoms. Accidental and occupational exposure produced liver damage, ranging from severe fatty degeneration to necrosis and acute atrophy, which was frequently fatal, and gastrointestinal disorders; toxic effects were also observed in the hematopoietic system. In case of emergency, it is important to wash skin with soap and water after removing contaminated clothing. Like others of this class, 1,1,2,2-tetrachloroethane could generate some hyperexcitability of the heart. The prognosis following intoxication with this chemical is that rapid progression of jaundice indicates a poor outcome. In some instances, mild symptoms will persist up to 3 months and then progress to acute yellow atrophy and death. Anuria may persist for as long as 2 weeks and still be followed by complete recovery. ANIMAL STUDIES: The acute toxicity of 1,1,2,2-tetrachloroethane in experimental animals is slight to moderate. The liver appears to be the most sensitive target organ. Minimal effects on the liver (reversible increase in lipid content) and other endpoints (an increase in levels of adrenocorticotropic hormone and reversible alteration in hematological parameters) have been observed in rats exposed to 13.3 mg/cu m for up to nine months. Reproductive and developmental effects have been observed in experimental animals only at doses that caused reductions in body weight. Long term ingestion of this chemical resulted in increased incidences of liver tumors in both male and female mice. However, similar exposure was not associated with a significant increase in tumors at any site in rats, although both species were exposed only for up to 78 wk. Based on the results of available in vivo and in vitro assays, 1,1,2,2-tetrachloroethane has, at most, weak genotoxic potential. 1,1,2,2-Tetrachloroethane was a potent promoter, but not an initiator, of gamma-glutamyltranspeptidase positive foci in the liver of rats. The profile for tumor induction by 1,1,2,2-tetrachloroethane is similar to that of dichloroacetic acid, its primary metabolite. ECOTOXICITY STUDIES: Exposure to 1,1,2,2-tetrachloroethane has been demonstrated to inhibit the activities of environmental bacteria (lowest reported IC50 was 1.4 mg/L) and cause immobilization of Daphnia magna (48 hr EC50 values of 23 mg/L and above). In fresh water fish species, the lowest LC50 (96 hr) was 18.5 mg/L in flagfish (Jordanella floridae), where the lowest observed effect concentration (LOEC) for longer term exposure was 7.2 mg/L, which resulted in reduced larval survival in the same species.I
The presence of the functional group consisting of a terminal dichloromethyl moiety in a molecule is known to confer toxicity. Moreover, the metabolism of 1,1,2,2-tetrachloroethane to reactive products is also likely to play a key role in its toxicity. Both nuclear and microsomal cytochrome P450 enzymes (of the CYPIIA, CYPIIB, CYPIIE, and CYPIIIA subfamilies) have been implicated in the metabolism of the compound, possibly releasing a number of biologically active compounds, including aldehydes, alkenes, acids, and free radicals that may react with biological tissues. In general, the highly lipophilic nature of chlorinated hydrocarbons, such as 1,1,2,2-tetrachloroethane, allows them to cross the blood-brain barrier readily and partition into lipids in neuronal membranes. This property allows them to interfere with neural membrane function, bringing about central nervous system depression, behavioral changes, and anesthesia. 1,1,2,2-Tetrachloroethane has been shown to bind to DNA in the liver and several other organs, indicating that this mechanism may contribute to the carcinogenic process. Several studies of 1,1,2,2-tetrachloroethane toxicity have reported increases in the number of hepatocytes in mitosis, but the possible role these effects may have on the carcinogenicity of 1,1,2,2-tetrachloroethane has not been evaluated. (L336)
Evaluation: There is inadequate evidence in humans for the carcinogenicity of 1,1,2,2-tetrachloroethane. There is limited evidence in experimental animals for the carcinogenicity of 1,1,2,2-tetrachloroethane. Overall evaluation: 1,1,2,2-Tetrachloroethane is not classifiable as to its carcinogenicity to humans (Group 3).
来源:Hazardous Substances Data Bank (HSDB)
毒理性
致癌性证据
癌症分类：C组可能的人类致癌物
Cancer Classification: Group C Possible Human Carcinogen
来源:Hazardous Substances Data Bank (HSDB)
毒理性
致癌性证据
分类：C；可能的人类致癌物。分类依据：小鼠肝细胞癌发生率增加。人类致癌性数据：无。
CLASSIFICATION: C; possible human carcinogen. BASIS FOR CLASSIFICATION: Increased incidence of hepatocellular carcinomas in mice. HUMAN CARCINOGENICITY DATA: None.
1,1,2,2-Tetrachloroethane is readily absorbed following inhalation, ingestion, and dermal exposure and rapidly distributed in tissue compartments by passive processes. Respiration is the route of excretion for non-transformed 1,1,2,2-tetrachlororethane, volatile metabolites and terminal metabolite CO(2). Most of the metabolites are excreted by the urinary route but also by the feces and skin. In mice, urinary metabolites represent about 1/3 of the absorbed dose.
Half of a dose of (14)C-labeled 1,1,2,2-tetrachloroethane (0.21-0.32 g/kg, ip) was expired from mouse as labeled CO2 within 3 days & 28% excreted in urine.
