The rate of disappearance of azinphos-methyl effected by a hepatic oxidative desulfurating system and a demethylating system was investigated in liver homogenates from four different species (rat, guinea pig, chicken and monkey). Azinphos-methyl was metabolized by both systems and homogenates from all species were uniformly active.
The metabolism of azinphos-methyl was investigated by administration of ring-UL-(14)C-azinphos-methyl to male and female Sprague-Dawley rats. The metabolic pathway of azinphos-methyl in rats is proposed. Upon absorption, azinphos-methyl is rapidly metabolized by mixed function oxidases and GSH-transferases in the liver and other tissues, which results in the formation of azinphos-methyl oxygen analog, mercaptomethylbenzazimide, glutathionyl methylbenzazimide and desmethyl isoazinphos-methyl. Further hydrolysis, methylation and oxidation of mercaptomethyl-benzazimide forms benzazimide, methylthiomethylbenzazimide and its corresponding oxidized metabolites. Hydrolysis of glutathionyl methyl-benzazimide may result in the formation of cysteinylmethyl-benzazimide. Subsequent oxidation of cysteinyl-methylbenzazimide forms its corresponding sulfoxide and sulfone.
Azinphos-methyl is readily absorbed and metabolized in mammals. Dimethylphosphorothioic and Dimethylphosphoric acids, desmethyl azinphosmethyl and azinphos-methyloxon are principal metabolites as demonstrated in in-vitro mouse tissue studies. The benzotrianzine moiety is rapidly excreted without degradation, less than 0.1% of the radioactivity of peroral or intraperitoneal doses (0.1-0.2 mg/kg bw) of (14)C-labelled azinphos-methyl is eliminated as CO2. Approximately 65% of the radioactivity of these doses was eliminated in urine, about 25% in feces. In studies with dairy cows no residues of azinphos-methyl or gutoxon appeared in milk, four unidentified non-phosphorus containing metabolites were present in low concentration.
The bioactivation of azinphos-methyl (AZIN), chlorpyrifos (CPF), diazinon (DIA), and parathion (PAR), four widely used organophosphorothioate (OPT) pesticides has been investigated in human liver microsomes (HLM). In addition, the role of human cytochrome P450 (CYPs) in OPT desulfuration at pesticide levels representative of human exposure have been defined by means of correlation and immunoinhibition studies. CYP-mediated oxon formation from the four OPTs is efficiently catalyzed by HLM, although showing a high variability (>40-fold) among samples. Two distinct phases were involved in the desulfuration of AZIN, DIA, and PAR, characterized by different affinity constants (K(mapp1) = 0.13-9 uM and K(mapp2) = 5- 269 uM). Within the range of CPF concentrations tested, only the high-affinity component was evidenced (K(mapp1) = 0.27-0.94 uM). Oxon formation in phenotyped individual HLM showed a significant correlation with CYP1A2-, 3A4-, and 2B6-related activities, at different levels depending on the OPT concentration. Anti-human CYP1A2, 2B6, and 3A4 antibodies significantly inhibited oxon formation, showing the same OPT concentration dependence. Our data indicated that CYP1A2 is mainly involved in OPT desulfuration at low pesticide concentrations, while the role of CYP3A4 is more significant to the low-affinity component of OPT bioactivation. The contribution of CYP2B6 to total hepatic oxon formation was relevant in a wide range of pesticide concentrations, being a very efficient catalyst of both the high- and low-affinity phase.
Metabolism of organophosphates occurs principally by oxidation, by hydrolysis via esterases and by reaction with glutathione. Demethylation and glucuronidation may also occur. Oxidation of organophosphorus pesticides may result in moderately toxic products. In general, phosphorothioates are not directly toxic but require oxidative metabolism to the proximal toxin. The glutathione transferase reactions produce products that are, in most cases, of low toxicity. Paraoxonase (PON1) is a key enzyme in the metabolism of organophosphates. PON1 can inactivate some organophosphates through hydrolysis. PON1 hydrolyzes the active metabolites in several organophosphates insecticides as well as, nerve agents such as soman, sarin, and VX. The presence of PON1 polymorphisms causes there to be different enzyme levels and catalytic efficiency of this esterase, which in turn suggests that different individuals may be more susceptible to the toxic effect of organophosphate exposure.
Guthion is a cholinesterase or acetylcholinesterase (AChE) inhibitor. A cholinesterase inhibitor (or 'anticholinesterase') suppresses the action of acetylcholinesterase. Because of its essential function, chemicals that interfere with the action of acetylcholinesterase are potent neurotoxins, causing excessive salivation and eye-watering in low doses, followed by muscle spasms and ultimately death. Nerve gases and many substances used in insecticides have been shown to act by binding a serine in the active site of acetylcholine esterase, inhibiting the enzyme completely. Acetylcholine esterase breaks down the neurotransmitter acetylcholine, which is released at nerve and muscle junctions, in order to allow the muscle or organ to relax. The result of acetylcholine esterase inhibition is that acetylcholine builds up and continues to act so that any nerve impulses are continually transmitted and muscle contractions do not stop. Among the most common acetylcholinesterase inhibitors are phosphorus-based compounds, which are designed to bind to the active site of the enzyme. The structural requirements are a phosphorus atom bearing two lipophilic groups, a leaving group (such as a halide or thiocyanate), and a terminal oxygen.
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
致癌性证据
A4；不能归类为人类致癌物。
A4; Not classifiable as a human carcinogen.
来源:Hazardous Substances Data Bank (HSDB)
毒理性
致癌物分类
喷洒和应用非砷杀虫剂涉及到的暴露可能对人类有致癌风险（2A组）。
Spraying and application of nonarsenical insecticides entail exposures that are probably carcinogenic to humans (Group 2A). (L135)
Acute exposure to cholinesterase inhibitors can cause a cholinergic crisis characterized by severe nausea/vomiting, salivation, sweating, bradycardia, hypotension, collapse, and convulsions. Increasing muscle weakness is a possibility and may result in death if respiratory muscles are involved. Accumulation of ACh at motor nerves causes overstimulation of nicotinic expression at the neuromuscular junction. When this occurs symptoms such as muscle weakness, fatigue, muscle cramps, fasciculation, and paralysis can be seen. When there is an accumulation of ACh at autonomic ganglia this causes overstimulation of nicotinic expression in the sympathetic system. Symptoms associated with this are hypertension, and hypoglycemia. Overstimulation of nicotinic acetylcholine receptors in the central nervous system, due to accumulation of ACh, results in anxiety, headache, convulsions, ataxia, depression of respiration and circulation, tremor, general weakness, and potentially coma. When there is expression of muscarinic overstimulation due to excess acetylcholine at muscarinic acetylcholine receptors symptoms of visual disturbances, tightness in chest, wheezing due to bronchoconstriction, increased bronchial secretions, increased salivation, lacrimation, sweating, peristalsis, and urination can occur. Certain reproductive effects in fertility, growth, and development for males and females have been linked specifically to organophosphate pesticide exposure. Most of the research on reproductive effects has been conducted on farmers working with pesticides and insecticdes in rural areas. In females menstrual cycle disturbances, longer pregnancies, spontaneous abortions, stillbirths, and some developmental effects in offspring have been linked to organophosphate pesticide exposure. Prenatal exposure has been linked to impaired fetal growth and development. Neurotoxic effects have also been linked to poisoning with OP pesticides causing four neurotoxic effects in humans: cholinergic syndrome, intermediate syndrome, organophosphate-induced delayed polyneuropathy (OPIDP), and chronic organophosphate-induced neuropsychiatric disorder (COPIND). These syndromes result after acute and chronic exposure to OP pesticides.
The pharmacokinetic behavior of benzazimide was investigated in rats using the ring-labeled (14)C-compound. After oral administration the (14)C-activity was almost completely absorbed from the gastrointestinal tract. Elimination of the activity took place quickly, 24 hours after administration only 1.3% of the amount administered was present in the animal not including the gastrointestinal tract. More than 99% of the amount administered was eliminated within 48 hours (54 to 66% in the urine and 33 to 45% via the feces). /benzazimide metabolite/
The pharmacokinetic behavior of carbonyl-(14C)-labelled azinphos-methyl was investigated in rats. The material was almost completely absorbed from the digestive tract, and irrespective of dose and route of administration, 60 to 70% was eliminated in the urine and 25 to 35% in the feces within 48 hours. Less than 0.1% of the administered activity was eliminated with the respiratory air within 24 hours of dosing, and in rats with biliary fistulas around 30% of the intravenously administered activity was eliminated in the bile within 24 hours of dosing. Two days after dosing the total activity content in the animal (excluding digestive tract) was less than 5% of the administered dose; by 4 days this had declined to 2% and by 16 days to 1%. Six hours after dosing, the highest concentrations of radioactivity were found in the organs of elimination (liver and kidney) with relatively high concentrations found in blood. The activity concentrations decayed rapidly in all organs up to 2 days post dosing, but thereafter the activity was more slowly eliminated. At 16 days after dosing the highest concentration was found in the erythrocytes. In vitro studies, in which whole blood was incubated with labeled parent compound, did not show any accumulation of radioactivity in the blood constituents.
来源:Hazardous Substances Data Bank (HSDB)
吸收、分配和排泄
甲基嘧啶磷可能通过胃肠道吸收，通过完好皮肤；以及通过吸入细喷雾或粉尘。
Azinphos-methyl may be absorbed from the gastrointestinal tract, through the intact skin; and by inhalation of fine spray mist or dusts.
When radioactive azinphos-methyl was administered IV to volunteers, radioactivity equivalent to about 1.5% of the administered dose per hr was recovered in the urine during the first 12 hr. Recovery decreased gradually but was still slightly over 0.1% 96-120 hr after injection. The total recovery during 120 hr was 69.5% of the dose following IV administration and 15.9% following dermal application.
[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.
