Two goats were given radiolabelled fludioxonil orally at a level equivalent to 100 ppm in the feed for 4 consecutive days....The main component identified in muscle was fludioxonil, representing 24% and 43% of the TRR in the two goats. Likewise, fludioxonil was the main component of the residue in omental fat, representing 83% TRR. The main identified metabolite in muscle was the sulfate conjugate of the 2-hydroxy or 5-hydroxy derivative of fludioxonil (22% or 2% TRR). Minor metabolites identified in muscle (< 10% TRR) included the 2-O-glucuronide derivative of fludioxonil and the 5-O-glucuronide derivative of fludioxonil. (The position numbers refer to the pyrrole ring.) About 50% of the residue in muscle and 83% of the residue in fat were identified. Multiple components were found in kidney and liver. The following were identified in kidney: 2-Oglucuronide derivative of fludioxonil (23% TRR); 7prime-O-glucuronide derivative (8% TRR); 5-O-glucuronide derivative (15% TRR); fludioxonil (2% TRR); and 2- or 5-O-sulfate ester (0.7% TRR), for a total identification of 48%. In liver, only fludioxonil was identified (14% TRR). Two labile compounds (24% TRR) were also encountered. No compounds without the pyrrole-phenyl linkage were identified.
Five laying hens were given gelatin capsules containing [(14)C-pyrrole]fludioxonil for 8 consecutive days at a rate equivalent to about 89 ppm in the feed... The main metabolites identified in eggs were the sulfate conjugate of the 1-hydroxy derivative of fludioxonil (40% TRR) , the succinamic acid derivative (10% TRR) and the sulfate conjugate of the 2-hydroxy or 5-hydroxy derivative (13% TRR). Fludioxonil was a minor component (2.1% TRR) in eggs. The succinamic acid derivative was the only significant metabolite identified in liver, at about 6% TRR. The metabolites identified in kidney were the glucuronide conjugate of the 2-hydroxy or 5-hydroxy derivative (4.7% TRR), fludioxonil (2.6% TRR) and the 7prime-hydroxy derivative (2.8% TRR). The main components identified in breast muscle were fludioxonil (29% TRR) and the sulfate conjugate of the 1-hydroxy derivative. A similar situation existed for skin with attached fat, which contained fludioxonil (9.8%) and the sulfate conjugate of the 1-hydroxy derivative (14%). On the basis of the characterizations and identifications made in the study of metabolism in hens, .../it was/concluded that metabolism in poultry involves oxidation at the C-2, C-5 and N-1 positions in the pyrrole ring and at the C-7prime of the benzodioxol ring. This is followed by the formation of sulfate or glucuronide conjugates. The C-2 hydroxypyrrole further oxidizes to the 2,5-dioxo-2,5-dihydro pyrrole and succinamic acid derivatives. The last two compounds are unique to poultry. The remaining metabolites found in the hen and all the metabolites in ruminants were also found in rats.
fludioxonil and metabolites, determined as 2,2-difluoro-1,3- benzodioxole-4-carboxylic acid, are stable for at least 12 months in frozen muscle and for at least 18 months in frozen liver, milk and eggs.
After oral administration of radiolabelled fludioxonil, the radiolabel is rapidly and extensively (approximately 80% of the administered dose) absorbed, widely distributed, extensively metabolized and rapidly excreted, primarily in the feces (approximately 80%) via the bile (approximately 70%), with a small amount being excreted in the urine (approximately 20%). The maximum blood concentration is reached within 1 hr after administration. Elimination is biphasic, with half-lives of between 2 and 5 hr for the first phase and between 30 and 60 h for the second phase. Fludioxonil is rapidly cleared from the blood and tissues, and there is consequently negligible potential for accumulation. The metabolism of fludioxonil proceeds primarily through oxidation of the pyrrole ring, leading to one major (57% of the administered dose) and one minor (4% of the administered dose) oxo-pyrrole metabolite. Hydroxylation of the phenyl ring yields the corresponding phenol metabolite, which represents 2% of the administered dose. These phase I metabolites are subsequently excreted as glucuronyl and sulfate conjugates and, together with unabsorbed and unchanged fludioxonil excreted in feces, account for approximately 75% of the administered dose. The dimerization of the hydroxy pyrole metabolite produces a metabolite of an intense blue color.
A feeding study was conducted in which three groups of three dairy cows received 0.55 ppm, 1.6 ppm or 5.5 ppm fludioxonil in the diet for 28-30 days. Residues of fludioxonil and metabolites, determined as CGA-192155 (2,2-difluorobenzo[1,1]dioxole-4-carboxylic acid), were quantifiable only at the highest feeding level (5.5 ppm)... Only tissue samples from cows fed the 5.5 ppm diet were analyzed. No residues of fludioxonil or metabolites were found. The LOQ was 0.01 mg/kg in muscle and 0.05 mg/kg in liver, kidney and fat (perirenal and omental).
IDENTIFICATION AND USE: Fludioxonil comes in the form of odorless, yellowish or colorless crystals. It is a phenylpyrrole fungicide that interferes with glucose transport across fungal membranes. It is also used as an insecticide, and seed treatment/protectant. It is registered for pesticide use in the USA but approved pesticide uses may change periodically and so federal, state and local authorities must be consulted for currently approved uses. HUMAN EXPOSURE AND TOXICITY: Fludioxonil showed endocrine disruptor activity as antiandrogen in an androgen receptor reporter assay in engineered human breast cancer cells. Fludioxonil was also genotoxic in human HepG2 cells at concentrations of 4 uM. Treatment of human U251 (glial) and SH-SY5Y (neuronal) cells with fludioxinil significantly reduced cellular ATP at concentrations that were more than tenfold lower than those which significantly impaired cellular viability. The effects on energy metabolism were reflected in marked toxic effects on mitochondrial membrane potential. In addition, evidence of oxidative stress was seen. ANIMAL STUDIES: Fludioxonil has low acute toxicity in rats when administered by oral, dermal or inhalation routes, producing no deaths at 5000 and 2000 mg/kg bw and 2.6 mg/L of air, respectively, the highest doses tested. There were also no deaths in mice given fludioxonil at 5000 mg/kg bw by gavage. In other studies with repeated doses in mice and rats, the liver (necrosis, centrilobular hypertrophy, increased serum cholesterol and 5 'nucleotidase), the kidneys (nephropathy, inflammation, cysts) and hematopoietic system (mild anemia) were the principal targets. In mice, these effects were observed after 90 days of treatment at 450 mg/kg bw per day and at 590 mg/kg bw per day in one 18-month study, but not at 360 mg/kg bw per day in another such study. In rats, effects were seen at doses of > or = 400 mg/kg bw per day in short-term studies and at 110 mg/kg bw per day in a 2-year study; lower body-weight gains were also observed at these doses. Liver toxicity was generally manifested by increased concentrations of serum cholesterol and bilirubin and centrilobular hypertrophy and/or necrosis. Anemia was seen in mice (at > 590 mg/kg bw per day for 18 months) and rats (at 1300 mg/kg bw per day for 3 months). No hematological effects were observed in shorter studies in mice (at < or = 1050 mg/kg bw per day for 90 days) or rats (at < or = 2500 mg/kg bw per day for 20 days and at < or = 1000 mg/kg bw per day for 28 days). Blue discoloration of the urine, perineal fur, kidneys and gastrointestinal tract were common observations in all species. These effects were secondary to the formation of the blue metabolite in quantities that were sufficient, at high doses, to stain the various tissues. Fludioxonil is was not genotoxic, causing a negative result in assays for reverse mutation in S. typhimurium and E. coli, gene mutation in Chinese hamster V79 cells, unscheduled DNA synthesis in rat hepatocytes, micronucleus formation in bone marrow of rats and mice in vivo and chromosome aberration in Chinese hamsters in vivo. There was also no evidence of carcinogenic potential with fludioxonil in studies using rats. In a two-generation study of reproductive toxicity in rats, at a dose of 210 mg/kg bw per day, adult males had reduced body-weight gains and food consumption and pups had lower body-weight gains. ECOTOXICITY STUDIES: Data from concentrations of fludioxinil found in ponds collecting vineyard runoff water, suggest that the pesticide should not impair the establishment of vineyard pioneer plants.
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
对人类不具有致癌性（未被国际癌症研究机构IARC列名）。
No indication of carcinogenicity to humans (not listed by IARC).
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.
Nephrotoxin - The chemical is potentially toxic to the kidneys in the occupational setting.
ACGIH Carcinogen - Confirmed Animal.
来源:Haz-Map, Information on Hazardous Chemicals and Occupational Diseases
Consumers may be simultaneously exposed to several pesticide residues in their diet. A previous study identified the seven most common pesticide mixtures to which the French population was exposed through food consumption in 2006. The aim of this study was to investigate if the seven mixtures are potentially cytotoxic and genotoxic and if so, whether compounds in a same mixture have a combined effect. The cytotoxicity and genotoxicity of the seven mixtures were investigated with a new assay (gamma-H2AX) using four human cell lines (ACHN, SH-SY5Y, LS-174T, and HepG2). Mixtures were tested at equimolar concentrations and also at concentrations reflecting their actual proportion in the diet. Irrespective of the cell line tested, parallel cytotoxicity of the seven mixtures was observed. /Only mixture 4 contained fludioxonil (cyprodinil, fludioxonil, k-cyhalothrin, procymidone, iprodione)./ /This was the/ only mixture /that/ was genotoxic for the HepG2 cells at concentrations = 3 uM in equimolar proportion and at 30 uM in actual proportion. Caspase 3/7 activity, the comet assay, and reactive oxygen species production were also investigated using the same mixture and HepG2 cells. /The genotoxicity and the cytotoxicity of mixture 4 containing each pesticide at the actual concentration observed in the French diet (procymidone 42%, iprodione 33%, cyprodinil 16%, fludioxonil 9%, and k-cyhalothrin 1%, were also tested. Five final concentrations of the mixture were tested (1, 3, 10, 30, and 100 lM). Clear genotoxic and cytotoxic effects were observed but at higher concentrations (30 vs. 3 lM) than in mixture 4 at equimolar concentration. The lower genotoxic and cytotoxic effects of the mixture in the real proportion compared to the equimolar concentrations concentrations could be partially explained by the fact that the proportion of the fludioxonil in the real proportion mixture was lower than in the equimolar mixture (9 vs. 20%)./ Our results suggest that pesticide metabolites from the mixture generated by HepG2 cells were responsible for the observed damage to DNA. Among the five compounds in the genotoxic mixture, only fludioxonil and cyprodinil were genotoxic for HepG2 cells alone at concentrations = 4 and 20 uM, respectively. Our data suggest a combined genotoxic effect of the mixture at low concentrations with a significantly higher effect of the mixture of pesticides than would be expected from the response to the individual compounds. /Mixture/
The metabolism of (14)C-pyrrole-labelled fludioxonil was studied in goats... Two goats were given radiolabelled fludioxonil orally at a level equivalent to 100 ppm in the feed for 4 consecutive days. The levels of radioactive residue, calculated as fludioxonil, were: 0.07 mg/kg in tenderloin muscle, 0.19 mg/kg in fat, 5.8 mg/kg in liver, 2.9 mg/kg in kidney and 2.2 mg/kg in milk on day 4. Organic solvents released 35% of the TRR in liver, 76% in muscle, 50% in kidney, 35% in liver, 87% in fat and 90% in milk. Protease treatment of the solid residues from solvent extraction of liver, kidney and muscle released 75-91% of the remaining activity. Less than half of this released activity was characterized as proteins by derivatization with 2,4-dinitrofluorobenzene.
Five laying hens were given gelatin capsules containing [(14)C-pyrrole]fludioxonil for 8 consecutive days at a rate equivalent to about 89 ppm in the feed. The vast majority of the radiolabelled residue was eliminated in the excreta (88-102% of the total administered dose). The levels of radioactive residues, calculated as fludioxonil, in the tissues and eggs were as follows: liver, 8.9 mg/kg; muscle, 0.12 mg/kg; skin with fat, 0.25 mg/kg; peritoneal fat, 0.17 mg/kg; egg yolk, 1.8 mg/kg (day 7); egg white, 0.054 mg/kg (day 7). A series of organic solvent extractions released 61% TRR in liver, 33% in kidney, 62% in muscle, 42% in skin with fat, 74% in egg white and 83% in egg yolk. The solids remaining after solvent extraction of liver (33% TRR), kidney (54%) and muscle (34%) were solubilized with protease and characterized by treatment with 2,4-dinitrofluorobenzene. Protease solubilized 54% of the unextracted activity in liver, 63% of that in kidney and 67% of that in muscle. About 25% of the released radioactivity (< 10% TRR) was derivatized by 2,4-dinitrofluorobenzene at pH 2, indicating the terminal amino group of amino acids. Alkaline hydrolysis (15% KOH, 95 oC) released all the remaining radioactivity from the solvent-extracted liver (33% TRR), but it could be characterized only as acidic, polar compounds. About 69% of the TRR in eggs, 24% in liver, 14% in kidney, 44% in muscle and 29% in skin with fat were identified...
A feeding study was conducted in which three groups of three dairy cows received 0.55 ppm, 1.6 ppm or 5.5 ppm fludioxonil in the diet for 28-30 days. Residues of fludioxonil and metabolites, determined as CGA-192155 (2,2-difluorobenzo[1,1]dioxole-4-carboxylic acid), were quantifiable only at the highest feeding level (5.5 ppm)... No quantifiable residue was found in the tissues of ruminants at levels 60 times (cows) and 80 times (beef cattle) the calculated dietary burden. Fludioxonil and metabolites were detected in liver and kidney at concentrations of 0.014-0.017 mg/kg and 0.022-0.025 mg/kg, respectively, at the 5.5 ppm feeding level. None was detected in fat or muscle.
The dermal absorption of fludioxonil, excluding material bound to the skin, is low in rats in vivo (< 5%) and in human skin in vitro (< 0.5%). In a study of dermal penetration in rats in vitro, values for dermal absorption at low levels of application were comparable to those obtained in a study performed in vivo (< 2%), but at higher levels significantly overestimated absorption in vivo (38%).
Immunoreagents and Competitive Assays to Fludioxonil
摘要：
Fludioxonil is a new-generation fungicide widely used for postharvest fruit protection. The aim of this study was to produce hitherto unreported immunoreagents for Fludioxonil analysis by immunoassay. Derivatives of this agrochemical were synthesized with different linker tethering sites. Those functionalized haptens were activated, and the purified active esters were efficiently conjugated to different carrier proteins for immunogen and assay antigen preparation. Antibodies to Fludioxonil were raised in rabbits, and their selectivity and affinity were characterized, revealing the significance of the linker. Those antibodies were evaluated using homologous and heterologous conjugates by direct and indirect competitive ELISA formats. Finally, a pair of immunoreagents was identified showing an IC50 value for Fludioxonil of 5.7 mu g/L.
[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.
