Both the urine and feces were major routes of excretion /in rats/ at the low dose /0.5 mg/kg/ with most of the urinary radioactivity being a metabolite named CCBA (4-(4-chloro-2-cyanoimidazol-5-yl)benzoic acid). ... Irrespective of the dosing regimen, most of the recovered fecal radioactivity was unchanged parent compound; the major fecal metabolites were CCBA and 4-chloro-5-p-tolylimidazole-2-carbonitrile (CCIM) each of which being less than 5% of the administered dose.
Major metabolites in urine and feces were identified. There were no significant products of cleavage between phenyl and imidazole substituents. Most of administered label was absorbed following low dose treatment, although 16 to 20% of administered label was found as unchanged a.i. in feces. Males given low dose treatment excreted more label in urine than in feces (about 2:1), whereas in females the ratio was about 1:1. This difference probably reflects a greater excretion of absorbed material in females via the bile compared to males. High dose level was very poorly absorbed, evidenced by 86-87% of administered label being found in feces as unchanged a.i. All identified metabolites displayed hydrolytic cleavage of the N,Ndimethylsulfonamide group away from the imidazole ring. Of remaining substituents, the methyl group on the phenyl ring was either oxidized to a carboxylic acid (the major urinary metabolite), or conjugated by GSH and further modified to form a series of metabolites. The major two of these metabolites were alpha-(methylsulfinyl)-p-tolyl and alpha-(methylsulfonyl)-p-tolyl derivatives, both of which were primarily limited to urine of low dose females. Label clearance from blood and other tissues was rapid. In low dose rats there were typically about 10-fold reductions from peak concentrations at 0.5 hr after dosing to the next sampling at 5.5 hr after dosing.
Three biliary-cannulated rats/sex/group were dosed once by gavage with either low or high dose level of cyazofamid (0.5 or 1000 mg/kg): either phenyl-labeled ((14)C-Bz)-IKF-916), or imidazole-labeled ((14)C-Im)-IKF-916). The only strong peak found in urine (50% of administered dose in M and 38% in F) was CCBA. Virtually all label in the feces of low-dose cannulated rats was the parent cyazofamid. Bile accounted for 12-22% of administered dose (M) or 29-39% of administered dose (F). Bile HPLC profiles were rather complex, displaying mostly rather polar components. Investigators justifiably concluded in the footnotes to these pages that structures were "predominantly catabolic products of the glutathione conjugate of CCIM" (CCIM is 4-chloro-5-ptolylimidazole- 2-carbonitrile). The benzoic acid metabolite, CCBA, was also a significant component of bile (about 4% of administered dose in M and F). Complex HPLC profiles of bile extracts were progressively simplified to a few major peaks upon treatment with glucuronidase and acidification. A low-dose male bile profile after such treatment yielded 19% of label in bile as CHCN, and a slight increase over the pre-processing levels of CCBA. CHCN is CCIM with the methyl group on the phenyl ring oxidized to a hydroxymethyl. Together CHCN and CCIM comprised 46% of the bile extracts thus treated, and nearly all of the balance of radiolabel was found in two peaks of relatively polar material ... Thus it appears that conjugation of bile products to glucuronides is a quantitatively important process, in addition to conjugation by glutathione. It was noted in the core metabolism study that CH3SO2-CCIM and CH3SO-CCIM (two products of glutathione addition and subsequent modification) were abundant in urine of non-cannulated females; however cannulated rats of either gender in this study yielded no common urinary metabolites other than CCBA. This suggests that these two metabolites were biliary glutathione derivatives.
Organic nitriles are converted into cyanide ions through the action of cytochrome P450 enzymes in the liver. Cyanide is rapidly absorbed and distributed throughout the body. Cyanide is mainly metabolized into thiocyanate by either rhodanese or 3-mercaptopyruvate sulfur transferase. Cyanide metabolites are excreted in the urine. (L96)
TOXICOLOGICAL SUMMARY. Acute Toxicity: Technical grade cyazofamid has minimal to moderate acute toxicity in acute oral, dermal and inhalation tests, it is minimally irritating to the eyes and skin, and is a weak dermal sensitizer. Subchronic Toxicity: Following repeated administration in more than one species, cyazofamid seems to have mild or low toxicity. The kidney seemed to be a target organ following 13 weeks of dietary feeding in male rats .... which had increased microscopic kidney lesions characterized as increased number of basophilic tubules, graded as slight in addition to mild increases in urinary output, protein, and pH. Female rats of the same study were less sensitive; with the only change being a marginal increase in urine volume and pH ... Chronic Toxicity: Skin lesions, which may be due to systemic allergy, were observed in the males of the 18 month carcinogenicity study. At the high dose, approaching 1,000 mg/kg/day, male mice suffered hair loss due to scratching which was confirmed at necropsy by increased incidence of body sores (head, neck, trunk, limb, and/or tail), and was correlated histologically with increased incidence of acanthosis (hyperplasia), chronic active dermatitis, ulceration, and premature death. ... Cyazofamid's overall toxicity ... in dogs seems to be limited. In both the 13 week and one year dog studies, there were no major toxicity findings up to a dose of 1,000 mg/kg/day. The only possible effect was increased cysts in parathyroids of both sexes and pituitary in females observed in the high dose groups of the one year study. ... Carcinogenicity: There is no evidence that cyazofamid may be carcinogenic, as indicated in both the rat and the mouse carcinogenicity studies. It is classified as not likely to be carcinogenic to humans based on the lack of evidence of carcinogenicity in both the rat and the mouse. Developmental and Reproductive Toxicity: The pre- and post-natal toxicology database for cyazofamid includes rat and rabbit developmental toxicity studies and two-generation reproduction toxicity study in rats. There was some evidence of increased susceptibility following in utero exposure to rats in the prenatal developmental toxicity study; the increased incidence of bent ribs in the high dose fetuses was considered adverse ... . In the prenatal developmental toxicity study in rabbits, there were no maternal or developmental effects at any dose up to the limit dose of 1,000 mg/kg/day. In the two-generation reproduction study, the highest dose tested (>1,000 mg/kg/day) did not cause maternal systemic toxicity nor did it elicit reproductive or offspring toxicity. Neurotoxicity: In the acute neurotoxicity study, there were no indications of treatment-related adverse neurotoxicity findings including clinical signs, qualitative or quantitative neurobehavioral effects, brain weight, or gross/microscopic pathology. The Agency concluded that the slight increase in motor activity at day 14 among the mid- and high-dose males is marginal and should not be considered an adverse finding. Mutagenicity: Cyazofamid does not appear to have mutagenicity potential, based on several negative in vivo and in vitro studies.
Organic nitriles decompose into cyanide ions both in vivo and in vitro. Consequently the primary mechanism of toxicity for organic nitriles is their production of toxic cyanide ions or hydrogen cyanide. Cyanide is an inhibitor of cytochrome c oxidase in the fourth complex of the electron transport chain (found in the membrane of the mitochondria of eukaryotic cells). It complexes with the ferric iron atom in this enzyme. The binding of cyanide to this cytochrome prevents transport of electrons from cytochrome c oxidase to oxygen. As a result, the electron transport chain is disrupted and the cell can no longer aerobically produce ATP for energy. Tissues that mainly depend on aerobic respiration, such as the central nervous system and the heart, are particularly affected. Cyanide is also known produce some of its toxic effects by binding to catalase, glutathione peroxidase, methemoglobin, hydroxocobalamin, phosphatase, tyrosinase, ascorbic acid oxidase, xanthine oxidase, succinic dehydrogenase, and Cu/Zn superoxide dismutase. Cyanide binds to the ferric ion of methemoglobin to form inactive cyanmethemoglobin. (L97)
来源:Toxin and Toxin Target Database (T3DB)
毒理性
致癌物分类
对人类无致癌性（未列入国际癌症研究机构IARC清单）。
No indication of carcinogenicity to humans (not listed by IARC).
来源:Toxin and Toxin Target Database (T3DB)
毒理性
副作用
皮肤致敏剂 - 一种可以诱导皮肤产生过敏反应的制剂。
Skin Sensitizer - An agent that can induce an allergic reaction in the skin.
来源:Haz-Map, Information on Hazardous Chemicals and Occupational Diseases
毒理性
毒性数据
LC50 (大鼠) >5,500 mg/m³
LC50 (rat) >5,500 mg/m3
来源:Haz-Map, Information on Hazardous Chemicals and Occupational Diseases
Pharmacokinetics and metabolism studies in rats following administration of a single low (0.5 mg/kg) or high (1,000 mg/kg) dose, showed relatively rapid absorption (irrespective of dose tcmax = 0.25-0.5 hrs) and elimination (t1/2 4.4-5.8 hrs) at the low dose and saturated absorption with prolonged elimination (t1/2 of 7.6-11.6 hrs) at the high-dose. The extent of absorption (expressed as percent of administered dose) was highly dose-dependent, being nearly 75% at the low dose and only about 5% at the high dose. Both the urine and feces were major routes of excretion at the low dose with most of the urinary radioactivity being a metabolite named CCBA (4-(4-chloro-2-cyanoimidazol-5-yl)benzoic acid). Results of biliary excretion experiments showed biliary elimination of radiolabel to be highly variable at the low dose (about 12-39% of the administered low dose) and negligible (<2%) in the high-dose groups. Urinary or biliary excretion in rats of the high-dose groups was low (each about 2%) with most of the radioactivity being CCBA. Irrespective of the dosing regimen, most of the recovered fecal radioactivity was unchanged parent compound; the major fecal metabolites were CCBA and 4-chloro-5-p-tolylimidazole-2-carbonitrile (CCIM) each of which being less than 5% of the administered dose. Tissue burdens at t1/2, tmax, and at 168 hours post dose were indicative of rapid clearance and low tissue burdens suggesting little or no bioaccumulation or sequestration.
[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.
