In mice treated orally every other day for 28 days with technical chlordane, cis- and trans-chlordane reached peak levels in the whole body on the first day and declined to lower levels in spite of repeated dosing; cis- and trans-nonachlor and oxychlordane increased during the entire study period. The ratio of cis- to trans-chlordane and cis- to trans-nonachlor in the test sample (6:7 and 1:4, respectively) and in the mouse body at termination of the experiment (5:3 and 1:7, respectively) suggests that trans-chlordane is metabolized more readily than cis-chlordane and that cis-nonachlor is metabolized more readily than trans-nonachlor. The decreasing content of the chlordane isomers and the increasing content of oxychlordane with repeated dosing suggests that chlordane induces its own metabolism.
来源:Hazardous Substances Data Bank (HSDB)
代谢
研究了雄性Sprague-Dawley大鼠肝脏微粒体体外代谢反式氯丹（氯丹）和氧氯丹的情况。将制备的肝脏微粒体与12.3纳米摩尔氯丹一起培养，在有或无还原型NADPH生成系统的存在下，于空气或氮气或一氧化碳气氛中，在37摄氏度下培养15分钟。将肝脏微粒体与11.8纳米摩尔氧氯丹在空气和NADPH的存在下培养，并在有或无0.2 mM 1,1,1-三氯丙烯-2,3-氧化物的情况下，在37摄氏度下培养15分钟。在NADPH存在和空气条件下，大约有11%的氯丹被代谢。当反应混合物中不存在NADPH时，不会发生代谢。当用氮气代替空气时，氯丹的降解减少了67%。在一氧化碳气氛下，氯丹的代谢不会发生。当孵化混合物中不存在1,1,1-三氯丙烯-2,3-氧化物时，氧氯丹会被显著代谢。当1,1,1-三氯丙烯-2,3-氧化物存在时，它会显著减少被代谢的氧氯丹的量。作者得出结论，氯丹的氧化降解是由肝微粒体细胞色素P-450催化的。氧氯丹是氯丹的氧化代谢产物，会进一步被肝环氧酶水解。
The metabolism of trans-chlordane (chlordane) and oxychlordane by rat liver microsomes was studied in vitro. Liver microsomes prepared from male Sprague-Dawley rats were incubated with 12.3 nmol chlordane in the presence or absence of a reduced NADPH generating system under air or atmospheres of nitrogen or carbon monoxide for 15 min at 37 degrees C. Rat liver microsomes were incubated with 11.8 nmol oxychlordane in air with NADPH and in the presence or absence of 0.2 mM 1,1,1-trichloropropene-2,3-oxide for 15 min at 37 degrees C. Approximately 11% of the chlordane was metabolized in the presence of NADPH and under air. No metabolism occurred when NADPH was absent from the reaction mixture. Degradation of chlordane was decreased by 67% when nitrogen was substituted for air. No chlordane metabolism occurred under the carbon-monoxide atmosphere. Oxychlordane was metabolized to an appreciable extent when 1,1,1-trichloropropene-2,3-oxide was absent from the incubation mixture. When present, 1,1,1-trichloropropene-2,3-oxide caused a sharp decrease in the amount of oxychlordane that was metabolized. The authors conclude that oxidative degradation of chlordane is catalyzed by hepatic microsomal cytochrome P-450. Oxychlordane, an oxidized metabolite of chlordane, is metabolized further by hepatic epoxide-hydrolase.
Metabolism appears to be largely oxidative, involving hepatic microsomal cytochrome P-450. Epoxide hydrolase is probably the predominant enzyme involved in further degradation of oxychlordane, but the process appears to be slow in animals and humans. In addition, reductive dehalogenation, probably resulting in the formation of reactive free radical intermediates, may be important in the toxicity of chlordane.
Metabolism for the chlordane molecule involves four routes ... The first proposed metabolic route starts with hydroxylation at position three of the molecule to form 3-hydroxychlordane. This reaction is thought to be mediated by the microsomal mixed-function oxidase (MFO) system. Dehydration of 3-hydroxychlordane leads to 1,2-dichlorochlordene and eventually to other metabolites such as oxychlordane and l-hydroxy-2-chlorochlordene. Alternatively, 3-hydroxychlordane may undergo replacement of chlorines by hydroxyl groups to form monochlorodihydroxylated and -trihydroxylated derivatives. The second pathway starts with dehydrochlorination to form heptachlor. The mechanism of this reaction is not completely understood but is thought to be mediated by the cytochrome P-450 system and/or by glutathione-S-transferase type enzymes. Further metabolism of heptachlor leads to 1-hydroxychlordene, heptachlor epoxide, or eventually to 1-chloro-2,3-dihydroxydihydrochlordene. The third pathway starts with dehalogenation of chlordane to form l-chlorodihydrochlordene, probably mediated by microsomal MFO systems. Further reactions probably involve hydrolysis and conjugation with glucuronic acid. The fourth metabolic pathway, and probably the least understood, involves hydrolytic removal of a chlorine atom and its replacement by a hydroxyl group to form l-chloro-2-hydroxychlordene chlorohydrin. This product may undergo further metabolism to form monochlorodihydroxy- and trihydroxy- derivatives of dihydrochlordene. Studies with rat hepatic microsomes suggest that cytochrome P-450 may be the most important enzyme to catalyze degradation of trans-chlordane. Epoxide hydrolase is probably the predominant enzyme to catalyze degradation of oxychlordane. Reductive dehalogenation, with the production of free radicals, may also be important in the toxicity of chlordane.
In vivo and in vitro studies in rats have revealed /several/ routes of biotransformation of chlordane and shown that the metabolites include: trans-chlordane, 1,2-dichlorochlordene, oxychlordane, 1-hydroxy-2-chlorochlordene, 1-hydroxy-2-chloro-2,3-epoxy chlordene, chlordene chlorohydrin, and 1,2-trans-dihydroxy dihydrochlordene, as well as metabolites of heptachlor. In vitro studies showed that the liver of rat and man have almost identical capacity to degrade chlordane except that human liver has little capacity to convert trans-nonachlor to trans-chlordane.
来源:Hazardous Substances Data Bank (HSDB)
毒理性
致癌性证据
癌症分类：B2组可能的人类致癌物
Cancer Classification: Group B2 Probable Human Carcinogen
WEIGHT OF EVIDENCE CHARACTERIZATION: Chlordane is classified as B2, probable human carcinogen, using the 1986 Guidelines for Carcinogen Risk Assessment. ...HUMAN CARCINOGENICITY DATA: Inadequate evidence. ANIMAL CARCINOGENICITY DATA: Sufficient.
Evaluation: There is inadequate evidence in humans for the carcinogenicity of chlordane and heptachlor. There is sufficient evidence in experimental animals for the carcinogenicity of chlordane and heptachlor. Overall evaluation: Chlordane and heptachlor are possibly carcinogenic to humans (Group 2B).
来源:Hazardous Substances Data Bank (HSDB)
毒理性
致癌性证据
A3；已确认对动物有致癌性，但对人类的相关性未知。
A3; Confirmed animal carcinogen with unknown relevance to humans.
来源:Hazardous Substances Data Bank (HSDB)
毒理性
致癌性证据
国际癌症研究机构2B类, 国立职业安全与健康研究所-致癌性, 阈限值-吸入危险, 环境保护局B2类
IARC-2B, NIOSH-Ca, TLV-A3, EPA-B2
来源:Occupational Safety and Health Administration (OSHA)
吸收、分配和排泄
通过皮肤吸收，更容易通过肺部，以及从胃肠道吸收。
...Absorbed through skin, more readily via the lungs, and from ... /gastrointestinal/ tract.
来源:Hazardous Substances Data Bank (HSDB)
吸收、分配和排泄
在儿童中，脂肪浓度在单次剂量后继续上升至摄入后第8天，并且3个月后脂肪-血清分配比是1470:1。
In a child, fat concentration ... after single dose continued to rise through 8th post-ingestion day, and after 3 months fat-serum partition was 1470:1.
The chief route of excretion is biliary, although nearly all organochlorines yield measurable urinary metabolites. ... Many of the unmetabolized pesticides are efficiently reabsorbed by the intestine (enterohepatic circulation) substantially retarding fecal excretion. /Solid organochlorine insecticides/
... Wistar rats that received iv ... (14)C-alpha-chlordane showed that 29% of total injected radioactivity was excreted within 60 hr in feces and only 1% was excreted in urine. /cis-isomer/
