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，没有发生代谢。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，没有氯丹的代谢发生。当孵化混合物中不存在1,1,1-三氯丙烯-2,3-氧化物时，氧氯丹被大量代谢。当1,1,1-三氯丙烯-2,3-氧化物存在时，它导致氧氯丹代谢量急剧减少。作者得出结论，氯丹的氧化降解是由肝脏微粒体细胞色素P-450催化的。氧氯丹是氯丹的氧化代谢产物，可被肝脏环氧酶进一步代谢。
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.
Chlordane is highly lipophilic and is thus easily absorbed by ingestion, inhalation, and dermal exposure, then stored mainly in the fat. Chlordane is metabolized mainly in the liver and kidney. Metabolism is slow, and is believed to occur by multiple pathways involving cytochrome P-450 enzymes, glutathione-S-transferase type enzymes, and microsomal mixed-function oxidase systems. The metabolites are generally less toxic and include chlordene chlorohydrin, monohydroxylated dihydrochlordene, and oxychlordane. They are excreted in the urine and faeces. (L91)
IDENTIFICATION: Chlordane is a chlorinated cyclodiene insecticide. Chlordane is a synthetic product, technical chlordane is a viscous amber colored liquid with a pungent chlorine like odor. It is insoluble in water but soluble in most organic solvents including acetone, cyclohexanone, ethanol, deodorized kerosene, isopropanol and trichloroethylene. Chlordane is a persistent, non-systemic contact and ingested insecticide with some fumigant action. It is used on land against formicidae, coleoptera, noctuidae larvae, saltatoria, subterranean termites and many other insect pests. It also controls household insects, pests of man and domestic animals and is a wood preservative. All U.S. registrations of chlordane have been cancelled. HUMAN EXPOSURE: Chlordane is a central nervous system stimulant. The liver and kidney are the other organs affected by chlordane. A sudden onset of convulsions preceded by vomiting. Seizures caused by cyclodiene pesticides may appear as long as 48 hr after exposure and then may reappear periodically over several days following the initial episode. Tonic-clonic convulsions usually are accompanied by confusion, incoordination, excitability and in some instances coma, hypotension and respiratory failure. Do not give fats, oils or milk since these will enhance absorption from the intestinal tract. Accidental poisoning can occur in children, formulating workers, suicide attempts, individuals who live in chlordane treated residences. Individuals with a history of convulsive disorders would be expected to be at increased risk from exposure. Routes of exposure include ingestion, inhalation, dermal and eye contact. Oxychlordane is a metabolite of chlordane was found in breast milk samples. Serum half life in one child was 88 days. Another study a half life of 34 days was determined from an individual who consumed a product containing chlordane. During an acute exposure to chlordane, a man experienced a brief episode of oliguria with proteinuria, hematuria and mild hypertension. In a 30 yr old female exposed to chlordane had myoclonic jerks after a month delay, and from previous exposure had circumoral numbness, anorexia, nausea and fatigue. Dysfunctional bleeding was attributed to hepatic enzyme induction and increased metabolism of contraceptive medicine. One man occupationally exposed to chlordane developed episodes of paresthesia and latter twitching of the right hand and arm. Additional episodes, beginning in the same way ended with grand mal seizures followed by unconsciousness. Case reports of leukemia and other blood dyscrasias have been associated with exposure to chlordane/heptachlor primarily in domestic situations/ Small excess risks for other cancers including leukemia, non-Hodgkins lymphoma and soft tissue sarcomas and cancers of the brain, skin, bladder and stomach were observed. No evidence of mutagenicity was noted in human cells exposed to chlordane. ANIMAL/CELL STUDIES: In studies on 4 male rabbits a combination of (14)C-alpha and gamma-chlordane were administered orally at 4 day intervals it was well absorbed. Rats that inhaled (14)-chlordane vapor for 30 minutes retained 77% of the total inhaled chlordane. In rat and rabbit studies using radiolabelled chlordane administered orally the radioactivity was well distributed among tissues. Rats whether being treated with a single oral dose of chlordane or fed diets containing this compound, retained the highest levels of residues in adipose tissue, liver, kidney, brain and muscle. More of the gamma isomer was retained compared to the alpha isomer. The tissue distribution of chlordane in rabbits was similar to rats. Chlordane is metabolized slowly. Most metabolites of chlordane are less toxic but oxychlordane is acutely more toxic. In vivo and in vitro studies in rats have revealed two routes of biotransformation of chlordane and shown that metabolites include trans-chlordane, 1,2-didichlorochlordene, oxychlordane, 1-hydroxy-2-chloro-2,3-epoxychlordene, chlordene, chlorohydrin and 1,2-trans-dihydroxydihydrochlordene as well as metabolites of heptachlor. Chlordane is excreted in the feces. Chlorinated hydrocarbon insecticides act by altering the electrophysiological and associated enzymatic properties of nerve cell membranes, causing a change in sodium and potassium ion flow through the membrane. Disturbances of calcium transport and Ca+2-ATPase activity may also be involved. The cyclodiene compounds antagonize the action of gamma-aminobutyric acid (GABA) which induces the uptake of chloride ions by neurons. The blockage of this activity by cyclodiene insecticides results in only partial repolarization of the neuron and a state of uncontrolled excitation. Chlordane and technical chlordane induced tumors in mice and rats after oral administration. The studies demonstrated increases of hepatocellular neoplasms in mice of both sexes. Increased incidences of thyroid follicular cell neoplasms were observed in rats treated with chlordane. An increased incidence of malignant fibrous histiocytomas was observed in one study in male rats treated wi th chlordane. A small increase in liver adenomas was seen in one study in male rats treated with technical grade chlordane. No evidence of teratogenicity was found in animal studies. Alpha-chlordane and gamma-chlordane tested in the Ames Salmonella microsome assay showed no mutagenicity. Chlordane did not cause dominant lethal effects in mice. Chlordane did inhibit gap junctional intercellular communication and induced gene mutations in rodent cells but did not induce unscheduled DNA synthesis. Chlordane did not damage bacterial or plasmid DNA. Protein deficiency has been shown to double the acute toxicity of chlordane in rats. Chlordane has shown to increase the hepatotoxic effects of carbon tetrachloride in rats.[
Chlordane is believed to bind irreversibly to DNA, leading to cell death or altered cellular function. It also affects transcription by antagonizing estrogen-related receptors. Chlordane induces hepatic cytochrome P-450, causing a large increase in the volume of the smooth endoplasmic reticulum, which results in hepatocellular enlargement and hypertrophy. Chlordane has also been shown to bind and activate retinoic acid receptor, causing various developmental defects, and inhibit alkaline phosphatases in hepatic and renal tissues. (L91, A52, A53, A68, A69)
来源:Toxin and Toxin Target Database (T3DB)
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)
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/ tract。
...Absorbed through skin, more readily via the lungs, and from ... /gastrointestinal/ tract.
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/
[EN] BICYCLYL-SUBSTITUTED ISOTHIAZOLINE COMPOUNDS<br/>[FR] COMPOSÉS ISOTHIAZOLINE SUBSTITUÉS PAR UN BICYCLYLE
申请人：BASF SE
公开号：WO2014206910A1
公开（公告）日：2014-12-31
The present invention relates to bicyclyl-substituted isothiazoline compounds of formula (I) wherein the variables are as defined in the claims and description. The compounds are useful for combating or controlling invertebrate pests, in particular arthropod pests and nematodes. The invention also relates to a method for controlling invertebrate pests by using these compounds and to plant propagation material and to an agricultural and a veterinary composition comprising said compounds.
The present invention relates to azoline compounds of formula (I) wherein A, B1, B2, B3, G1, G2, X1, R1, R3a, R3b, Rg1 and Rg2 are as defined in the claims and the description. The compounds are useful for combating or controlling invertebrate pests, in particular arthropod pests and nematodes. The invention also relates to a method for controlling invertebrate pests by using these compounds and to plant propagation material and to an agricultural and a veterinary composition comprising said compounds.
