... (14)C-Cyanophenyl-labelled azoxystrobin was given to bile duct cannulated and non-cannulated rats at a dose of 100 mg/kg bw. Samples of urine, feces and bile were collected for up to 72 hr. The purpose of this study was to reevaluate certain plant and goat metabolites that were previously not identified in rats and further elucidate the metabolic pathway of azoxystrobin in rats. Three further metabolites, previously detected in either plants or goats, were identified. Compound 13 (2-hydroxybenzonitrile), resulting from cleavage of the diphenyl ether link, was detected in the bile and urine as the glucoronide conjugate at a concentration of up to 1.8% of the administered dose. Compound 20 ((2-(6-(2-cyanophenoxy) pyrimidin-4-yloxy) phenyl)acetic acid) was also detected in the bile and urine at a concentration of up to 1.3%. Compound 35 (2-(2-(6-(2-cyanophenoxy) pyrimidin-4-yloxy) phenyl)glycolic acid) was detected in the urine, feces and bile at a concentration of up to 0.6%. Compounds 24 (Methyl 2-(2(6-(2-cyanophenoxy)pyrimidin-4-yloxy) phenyl)-glycolate) and 30 (2-(6-(2-cyanophenoxy) pyrimidin-4-yloxy) benzoic acid) were not detected.
Bile-duct cannulated rats were given azoxystrobin radiolabelled in either the pyrimidinyl, cyanophenyl or phenylacrylate rings at 100 mg/kg bw by gavage. Comparison of the rates and routes of excretion and the profile of the metabolites showed (as previously) that there were no significant differences in the metabolism of the three differently labelled forms, thus indicating that there was minimal cleavage of the ether linkages between the aromatic rings. Experiments designed to identify metabolites were therefore conducted in bile-duct cannulated rats given (14)C-pyrimidinyl labelled azoxystrobin by gavage. In the bile-duct cannulated rats, excreta, bile, and cage wash were collected at 6, 12, 24, 36, and 48 hr and stored at -20 °C. Samples of bile, feces and urine were collected between 0 hr and 48 hr and pooled. Samples for males and females were separated. Urine and feces were collected at up to 168 hr after dosing from rats given the single dose (higher or lower) and from rats receiving repeated doses for 14 days, and were used for quantification of metabolites. Some bile samples were enzymatically digested using cholylglycine hydrolase at 30 units/mL, pH 5.6 at 37 °C overnight. Metabolites were identified using various analytical techniques, such as thin-layer chromatography (TLC), high-performance liquid chromatography (HPLC), proton nuclear magnetic resonance spectroscopy (NMR) and mass spectrophotometry (MS). On the basis of biliary excretion data for rats given a single dose of either (14)C-pyrimidinyl-, (14)C-phenylacrylate-, or (14)C-cyanophenyl-labelled azoxystrobin at 100 mg/kg bw, 74.4% (males) and 80.7% (females) of the pyrimidinyl-derived radioactivity was excreted in the bile after 48 hr. For the cyanophenyl-derived radioactivity, 56.6% and 62.5% was excreted in the bile of males and females, respectively. For the phenylacrylate-derived radioactivity, 64.4% (males) and 63.6% (females) was excreted in the bile. Quantitatively, there were no significant differences in biliary excretion between males and females. Azoxystrobin was found to undergo extensive metabolism in rats. A total of 15 metabolites were detected in the excreta and subsequently identified. Seven additional metabolites were detected but not identified. None of the unidentified metabolites represented more than 4.9% of the administered dose. The quantitative data for the various metabolites in the faeces, urine and bile of rats receiving a single dose of azoxystrobin at 100 mg/kg bw ... . The mass balance for the study of metabolite identification indicated that a substantial percentage of the administered radiolabel (45.6-73.6%) was unaccounted for, although the studies of excretion showed total recovery of 91.75-103.99%, with 72.6-89.3% being in the feces. The percentage of unaccounted-for radiolabel was especially notable in the groups receiving a single lower dose and a repeated lower dose. The study authors indicated that the variable efficiency in recovery could be explained by the fact that, for metabolite identification, feces were extracted with acetonitrile which allowed partitioning of the parent compound when it was present in the faeces (i.e. rats receiving the higher dose). For the groups receiving a single lower dose or repeated lower dose (where quantities of the parent compound were minimal), most of the faecal radiolabel was associated with polar metabolites that would not be present in the acetonitrile extract. The resulting concentration of radiolabel in the extract would, therefore, be very low. For the group receiving the higher dose, greater amounts of parent compound were left unabsorbed, thereby resulting in greater amounts of parent compound available for partitioning into the acetonitrile extract. The glucuronide conjugate (metabolite V) was the most prevalent biliary metabolite in both males (29.3%) and females (27.4%). Metabolite I (parent compound) was not detected in the bile. Each of the other biliary metabolites accounted for between 0.9% and 9.0% of the administered dose. In the bile-duct cannulated rats, about 15.1% and 13.6% of the faecal radioactivity was metabolite I (parent compound) in male and female rats, respectively. No parent compound was detected in the urine of bile-duct cannulated male and female rats. The predominant metabolite in the urine of the bile-duct cannulated rats was unidentified metabolite 2, which accounted for about 1.8% and 2.0% of the administered dose in male and female rats, respectively. There was no evidence for a dose-influencing metabolism, but a sex-specific difference in biotransformation was observed, with females producing more metabolites than did males. Biotransformation was unaffected by dose. The study authors suggested that absorption was dose-dependent. The oral absorption at 1 mg/kg bw was nearly complete (100%) since no parent compound was detected. The oral absorption at the higher dose (100 mg/kg bw) was estimated to be approximately 74-81% since about 19-26% of the parent compound was detected. However, it is difficult to estimate the true oral absorption value owing to poor recoveries after extraction, especially at the lower dose. ... There were two principal metabolic pathway: hydrolysis to the methoxyacid, followed by glucuronide conjugation to give metabolite V; and glutathione conjugation of the cyanophenyl ring followed by further metabolism via a number of intermediates (VI, VII, and VIII) to the mercapturic acid metabolite IX. Azoxystrobin was also hydroxylated at the 8 and 10 positions on the cyanophenyl ring followed by glucuronide conjugation (metabolites II, III, IVa and IVb). There were several minor pathways involving the acrylate moiety, resulting in formation of the metabolite XIII and XIV. Three metabolites (X, XII, and XV) arising via the cleavage of the ether linkages were identified.
The metabolic fate of [(14)C]-methyl-(E)-2-[2-[6-(2-cyanophenoxy)pyrimidin-4-yloxy]phenyl]-3-methoxyacrylate (azoxystrobin) was determined in the male and female rat following a single oral dose of 1 and 100 mg x kg(-1) and in surgically prepared, bile duct-cannulated rats following a single oral dose of 100 mg x kg(-1). 2. Azoxystrobin was extensively metabolized with at least 15 metabolites. There was a sex difference, with females producing more metabolites than males. 3. The two principal metabolic pathways were hydrolysis of the methoxyacid followed by glucuronic acid conjugation and glutathione conjugation of the cyanophenyl ring followed by further metabolism leading to the mercapturic acid. There were also several other minor pathways.
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)
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
来源:Hazardous Substances Data Bank (HSDB)
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
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
毒理性
毒性数据
LC50 (大鼠) > 4670 mg/m³
LC50 (rat) > 4670 mg/m3
来源:Haz-Map, Information on Hazardous Chemicals and Occupational Diseases
Eight male and female rats were given 14 consecutive daily oral doses of unlabelled azoxystrobin at 1 mg/kg bw followed by a single oral dose of (14)C-pyrimidinyl-labelled azoxystrobin at 1 mg/kg bw. For the repeated doses, about 89.1% and 86.5% of the administered dose was excreted in the feces of the males and females rats within 7 days, respectively, and about 12.5% and 17.0% of the administered dose was excreted in the urine of the males and females rats within 7 days, respectively. In males and females, excretion of radioactivity was rapid, with > 96% being excreted during the first 48 hr. Approximately 0.62% and 0.39% of the administered dose was found in the carcass and tissues within 7 days after dosing in male and female rats, respectively. For the repeated dose, the highest concentrations of azoxystrobin-derived radioactivity were found in the kidneys (males and females, < 0.04 ug equivalents/g). The concentrations found in the liver were 0.02 and 0.01 ug equivalents/g for males and females, respectively. At termination, the total concentration of radioactivity in blood was 0.01 ug equivalents/g for males and females.
In toxicokinetic studies, groups of male and female Alpk:APfSD rats (five to eight per group, depending on experiment) were given azoxystrobin (purity, 99%) with or without pyrimidinyl label as a single dose at 1 or 100 mg/kg bw by gavage or as 14 repeated doses of 1 mg/kg bw per day. Biliary metabolites were assessed using rats with cannulated bile ducts given a single dose at 100 mg/kg bw by gavage. The vehicle was polyethylene glycol (PEG 600) at 4 mL/kg bw. Treated rats were housed in stainless steel metabolism cages for 7 days. Urine was collected at 6 hr, and urine and feces were collected separately at 12, 24, 36, 48 h and at 24 hr intervals until 7 days after dosing. At each collection, cages were rinsed with water and cage-washing collected together with the urine. At the end of the study, cages were thoroughly rinsed with ethanol/water (1:1 v/v) and retained for radiochemical analysis. Carbon dioxide and volatiles were trapped. After 7 days, various organs and tissues were removed and analyzed for radioactivity. ... For rats receiving a single lower dose (1 mg/kg bw), total excretion of radioactivity (urine, feces, and cage wash) was 93.75% and 91.44% for males and females, respectively over the 7 days. Most (> 85%) of the urinary and fecal excretion took place during the first 36 hr after dosing. In these rats, about 83.2% and 72.6% of the administered dose was excreted in the feces of males and females within 7 days, respectively, and about 10.2% and 17.9% of the administered dose was excreted in the urine of the males and females within 7 days, respectively. Approximately 0.34% and 0.31% of the administered dose was found in the carcass and tissues within 7 days after dosing in males and females, respectively. For rats at this dose (1 mg/kg bw), the highest concentrations of radiolabel were found in the liver (mean for males and females, 0.009 ug equivalents/g) and in the kidneys (males, 0.027 ug equivalents/g; and females, 0.023 ug equivalents/g). At termination, the total concentration of radioactivity in blood was 0.004 ug equivalents/g for males and females. Less than 0.6% of the administered dose was recovered in the expired. For rats receiving the single higher dose (100 mg/kg bw), total excretion of radioactivity (urine, feces, and cage wash) was 98.29% and 97.22% for males and females, respectively, over the 7 days. Most (> 82%) of the urinary and fecal excretion took place during the first 48 hr after dosing. At this dose, about 89.37% and 84.53% of the administered dose was excreted in the feces of the males and females within 7 days, respectively, and about 8.54% and 11.54% of the administered dose was excreted in the urine of the males and females within 7 days, respectively. Approximately 0.33% and 0.33% of the administered dose was found in the carcass and tissues within 7 days after dosing in males and females rats, respectively. At this higher dose, the highest concentrations of radiolabel were found in the kidneys (males, 1.373 ug equivalents/g; and females, 1.118 ug equivalents/g) and in the liver (males, 0.812 ug equivalents/g; and females, 0.714 ug equivalents/g). At termination, the total concentration of radioactivity in blood was 0.389 ug equivalents/g for males and 0.379 ug equivalents/g for females
The excretion and tissue distribution of radioactivity was investigated for 48 h in male and female rats given a single dose of azoxystrobin at 1 mg/kg bw by gavage. Treated rats were housed in metabolism cages to facilitate the collection of urine, feces, exhaled air and volatiles. One male and one female rat receiving azoxystrobin radiolabelled in each position were killed at 24 hr and 48 hr after dosing. Each carcass was frozen and sectioned in preparation for whole-body radiography. About 89% and 86% of the administered dose of (14)C-pyrimidinyl-labelled azoxystrobin was excreted within 48 hr in the urine and feces of male and female rats, respectively. Most of the radioactivity was excreted in the feces, with < 17% in the urine. The male and female rats treated with (14)C-phenylacrylate-labelled azoxystrobin excreted about 80% and 97% of the administered dose within 48 hr, respectively. Most of the radioactivity was excreted via the feces with < 21% in the urine. At 48 hr, males and females, excreted approximately 0.01% of the administered dose as carbon dioxide trap and approximately 0.01% as volatile metabolites. The male and female rats treated with (14)C-cyanophenyl- labelled azoxystrobin excreted about 95% and 98% of the administered dose within 48 hr, respectively. Most of the radioactivity was excreted via the feces, with < 16% in the urine. At 48 hr, males and females excreted small amounts of radioactivity as carbon dioxide (< 0.3%) and as volatile metabolites (0.01%). For all radiolabels, the distribution of radioactivity was similar in males and females, as shown by whole-body autoradiography. At 24 hr, most of the radiolabel was present in the alimentary canal, moderate amounts in the kidneys and small amounts in the liver. Forty-eight hours after dosing, the whole-body autoradiography results showed a marked reduction in radioactivity. The results of these studies indicated that there were no significant differences between the rates and routes of excretion or tissue distribution of azoxystrobin labelled in one of three positions. No sex-related difference in excretion profile was evident. Minor differences in excretion were primarily due to the small numbers of rats used in the study. No significant differences in the amount of radioactivity recovered in the exhaled air and as volatiles were observed between the three radiolabels or between sexes. On the basis of the results of this study, other studies of excretion and tissue retention were conducted using only pyrimidinyl-labelled azoxystrobin.
[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.
