Investigators studied all major elements of a metabolism study in male and female Crl:CD BR rats ... Bile ducts were cannulated to assess degree of biliary excretion and associated metabolites. Investigators isolated 36 compounds including parent zoxamide in urine and/or feces. Bile contained 17 separable components. Major metabolites by each route were identified. ... Several metabolic routes were evident from analysis of fecal metabolites, including as initial steps: reductive dehalogenation, hydrolysis to provide an alpha-keto alcohol, or glutathione conjugation at the chloro group of the side chain. Often the final metabolites were products of subsequent oxidation to provide benzoic acid substituents or oxidation of the side chain to one of several carboxylic acid moieties, depending upon the amount of degradation of the side chain. There was no single dominant urinary metabolite. Most of these had been oxidized to expose several polar groups, and included several glutathione and glucuronide conjugation products. Rats treated with 10 mg/kg [(14)C]-/zoxamide/ following 2 weeks of administration of 200 ppm non-labeled zoxamide had excretion patterns similar to those of non-pre-treated rats. Biliary metabolites in cannulated rats constituted 46-48% of dose. Various glutathione derivatives predominated in the bile, and some residues underwent hydrolysis or reductive dehalogenation followed by glucuronide formation.
Four male Crl:CD BR rats were dosed by gavage in water once at 1000 mg/kg with 3,5-dichloro-4-hydroxymethyl benzoic acid, (RH-141,452), a metabolic product of zoxamide. Purity of unlabeled test article was 100%. Radiopurity of (14)C-ring-labeled test article was 98%. Investigators assessed recoveries in urine, feces, and exhaled air, and identified major metabolites in urine and feces. Urinary excretion was about 98% of dose, feces 1.7%, and expired air about 0.01%. Nearly all of urinary excretion was complete within 24 hr, and most fecal excretion occurred within 48 hr. About 94% of dose was excreted in urine as the test article. Collectively, three minor metabolites accounted for another 3% of urinary label (glucuronides of the hydroxyl or carboxylic acid groups, or glycine conjugate of the carboxylic acid group). Nearly all fecal label represented test article
Four male Crl:CD BR rats were dosed by gavage in water once at 1000 mg/kg with ring-labeled [(14)C]- RH-141,455 (this is the dicarboxylic acid metabolite of zoxamide). Purity of unlabeled RH-141,455 was 98.77%. Radiopurity of (14)C- RH-141,455 was > 96%. Investigators assayed residues in urine, feces, and exhaled air, and identified major metabolites in urine and feces. Tissues were not analyzed at 168 hr termination of rats, since nearly all label could be found in excreta. Recoveries of radiolabel averaged 75.5% in feces, 11.0% in urine, and 9.3% in cage rinse. Due to diarrhea, much of the cage rinse may have represented fecal output. About 0.01% of dose was found in expired air. Label recovery in feces, urine, or cage rinse dropped off quickly after the first 48 hr after dosing. Parent compound was the only significant peak detected after HPLC separation of extracts of fecal and urinary samples.
... Metabolism occurred by primary hydrolysis, glutathione mediated reactions and reductive dehalogenation; secondary oxidation of the aromatic methyl and the aliphatic side chain; and terminal glucuronic acid and amino acid conjugations. Induction of metabolism (glutathione transferase and/or glutathione cofactor) appeared to occur. ... Altogether, in urine and feces, 32 separate metabolites were identified; no single metabolite other than the parent accounted for more than 10% of the administered dose. ... There were no apparent sex related differences.
The in vitro mammalian metabolism of the fungicide zoxamide is related to its in vitro mammalian toxicity. After incubation of zoxamide with rat liver microsomes leading to practically 100% metabolism (mostly hydroxylated zoxamide), the cytotoxicity (methyl thiazole tetrazolium (MTT) test) and the mitosis-inhibiting potential (shown by cell count and by cell cycle analysis) for V79 were not distinguishable from those of zoxamide, demonstrating that the hydroxylation of zoxamide did not change the cytotoxicity or mitosis-inhibiting potential as determined by these assays. After incubation of zoxamide with rat liver S9 predominantly leading to conjugation with glutathione, and after incubation of zoxamide with rat liver slices predominantly leading to the glucuronide of the hydroxylated zoxamide, these activities were eliminated demonstrating that the glutathione conjugate and the glucuronide had lost the activities in these assays due either to no intrinsic potential of these conjugates or to their inability to penetrate the plasma membrane of mammalian cells. It is concluded that the metabolic hydroxylation of zoxamide did not change its activity in the assays used for investigating its influence on cell proliferation, cell cycle and cytotoxicity, while the formation of conjugates with glutathione or glucuronic acid led to the apparent loss of these activities. ...
IDENTIFICATION AND USE: Zoxamide is a fine, white powder. It is used as a fungicide. HUMAN EXPOSURE AND TOXICITY: Zoxamide is harmful if absorbed through the skin and causes moderate eye irritation. Prolonged or frequent repeated skin contact may cause allergic reactions in some individuals. It is a dermal sensitizer. ANIMAL STUDIES: Zoxamide was considered to be of low acute toxicity by the oral, dermal and inhalation routes in rats. It was moderately irritating when applied to the skin of rabbits, and was minimally irritating when instilled into the eyes of the same species. Results of skin sensitization testing in guinea pigs were positive. Acute and short-term (90-day) neurotoxicity studies conducted in the rat did not demonstrate any neurotoxic potential for zoxamide. It was not mutagenic in Salmonella typhimurium strains TA98, TA100, TA1535, TA1537, and TA102. ECOTOXICITY STUDIES: The NOEC of zoxamide for the early life-stages of the rainbow trout (Oncorhynchus mykiss) and the sheepshead minnow (Cyprinodon variegatus) were 3.48 ug a.i./L and 40 ug a.i./L, respectively, and for a full life cycle in the fathead minnow (Pimephales promelas) 60 ug a.i./L.
来源:Hazardous Substances Data Bank (HSDB)
毒理性
致癌性证据
癌症分类：不太可能对人类致癌
Cancer Classification: Not Likely to be Carcinogenic to Humans
The toxicity of zoxamide includes the increase of the weights of liver and thyroid, liver histopathological change and increases in alkaline phosphatase. Zoxamide is classified as “not likely to be carcinogenic to humans”
来源:Toxin and Toxin Target Database (T3DB)
毒理性
副作用
职业性肝毒素 - 第二性肝毒素：在职业环境中的毒性效应潜力是基于人类摄入或动物实验的中毒案例。
Occupational hepatotoxin - Secondary hepatotoxins: the potential for toxic effect in the occupational setting is based on cases of poisoning by human ingestion or animal experimentation.
来源:Haz-Map, Information on Hazardous Chemicals and Occupational Diseases
Mean plasma radioactivity concentrations peaked at 8 hr following 10 mg/kg or 1000 mg/kg zoxamide, and time of one-half peak concentration was 22 hr. Tissue levels as percentage of administered dose were generally about twice as high in the 10 mg/kg groups compared to high dose rats, consistent with the above evidences of poor absorption at 1000 mg/kg. Only the alimentary tract and liver had remarkably high concentrations at 8 hr, with marked reduction in most tissues by 22 hr after dosing. Thus zoxamide and its metabolites tend not accumulate in the body. There were no remarkable sex differences in zoxamide disposition.
Investigators studied all major elements of a metabolism study in male and female Crl:CD BR rats, including excretion patterns following a single gavage dose (in corn oil) of 10 mg/kg or a single dose of 1000 mg/kg labeled zoxamide, or single dose of 10 mg/kg labeled zoxamide after 2 weeks of administration of 200 ppm non-labeled zoxamide in diet. Tissue distribution of residues was determined after 8, 22, and 120 hr ... and blood kinetics were assessed. Exhaled air was evaluated for (14)C content (this was found not to be a significant route). ... Administration of 10 mg/kg zoxamide led to appreciable recovery of unaltered zoxamide in feces (12-23%). Much higher unaltered zoxamide were found in feces (72-74%) following a 1000 mg/kg dose. At least 71% of administered dose was found in feces after 10 mg/kg treatment (with or without dietary pre-treatment).
Zoxamide was rapidly and extensively absorbed, metabolized and excreted. Approximately 61% of the administered dose was systemically absorbed. Absorption was less complete in high dose groups. Plasma concentrations peaked approximately 8 hr post dose. Residue concentrations were highest in organs associated with absorption (liver, stomach, intestines). ... Elimination from plasma was bi-phasic with an elimination half-life of 12-14 hr. No residues were detected in expired air. Altogether, in urine and feces, 32 separate metabolites were identified; no single metabolite other than the parent accounted for more than 10% of the administered dose. Over 85% of the administered dose in single dose studies was excreted within 24-48 hr; the predominant route of excretion was hepatobiliary. No evidence of accumulation of the parent compound or its metabolites was observed. There were no apparent sex related differences.
The two major potato metabolites (RH-141452 and RH-141455), which were minor rat metabolites, were studied in separate metabolism studies. More than 97% of the administered dose (RH-141452) was excreted within 24 hr. Greater than 94% was eliminated unchanged in urine. Two glucuronide conjugates and a glycine conjugate (about 3% of the administered dose) were found in urine. An additional 1.6% of the administered dose was excreted unchanged in the feces. Excretion of RH-141455 was slower: 47% of the administered dose was excreted within 24 hr, with an additional 32% of the administered dose excreted between 24 and 48 hr. Greater than 92% of the administered dose was recovered (about 73% in feces, 11% in urine and 9% in cage rinse) as unchanged RH-141455 (>96%). /Metabolites/
[EN] ACC INHIBITORS AND USES THEREOF<br/>[FR] INHIBITEURS DE L'ACC ET UTILISATIONS ASSOCIÉES
申请人：GILEAD APOLLO LLC
公开号：WO2017075056A1
公开（公告）日：2017-05-04
The present invention provides compounds I and II useful as inhibitors of Acetyl CoA Carboxylase (ACC), compositions thereof, and methods of using the same.
[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.
[EN] SUBSTITUTED QUINAZOLINES AS FUNGICIDES<br/>[FR] QUINAZOLINES SUBSTITUÉES, UTILISÉES EN TANT QUE FONGICIDES
申请人：SYNGENTA PARTICIPATIONS AG
公开号：WO2010136475A1
公开（公告）日：2010-12-02
The present invention relates to a compound of formula (I) wherein wherein the substituents have the definitions as defined in claim 1or a salt or a N-oxide thereof, their use and methods for the control and/or prevention of microbial infection, particularly fungal infection, in plants and to processes for the preparation of these compounds.
