The major metabolic pathway for fenamiphos is oxidation and formation of the sulfoxide and sulfone analogs. Loss of the isopropyl and probably the isopropyl amine moieties are also likely. Subsequent hydrolysis, conjugation, and excretion in urine gives nonorganosoluble compounds whose molecular weights are 400-800.
In pigs given fenamiphos sulfoxide orally, excreted metabolites were primarily conjugated phenols of the sulfoxide and sulfone. The metabolic pathway was hydrolysis and/or oxidation followed by conjugation. /Fenamiphos sulfoxide/
Rats treated iv or orally with fenamiphos excreted fenamiphos phenols in different stages of oxidation at the sulfur atom and their respective sulfuric acid conjugates.
The metabolic fate of labelled fenamiphos was studied in rats in vivo and in rat liver microsomes in vitro. The compounds were labelled with (14)C in the ethyl or isopropyl position or with (3)H in the thiomethyl position. Fenamiphos was excreted within 12-15 hr after a single oral dose of 2 mg/kg bw. In vitro a small quantity of an unknown metabolite, possibly resulting from the N-dealkylation of fenamiphos, was observed. Apart from this minor component, metabolism in animals and plants followed the same pattern: oxidation of the thioether to the sulfoxide and sulfone, dearylation to yield the methyl thioether phenol (or its sulfoxide and sulfide), and potential dealkylation of the ethyl, isopropyl, or isopropylamino moiety of the phosphate ester. Treatment of rats with fenamiphos sulfoxide or sulfone produced the same excretion pattern and almost identical urinary metabolites.
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.
Fenamiphos 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：人类非致癌性证据E组
Cancer Classification: Group E Evidence of Non-carcinogenicity for Humans
来源:Hazardous Substances Data Bank (HSDB)
毒理性
致癌性证据
A4；不可归类为人类致癌物。
A4; Not classifiable as a human carcinogen.
来源:Hazardous Substances Data Bank (HSDB)
毒理性
致癌物分类
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).
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 pharmacokinetics of phenamiphos in male white rats ... following a single oral administration of 6 mg/kg in corn-oil were investigated. Rats were sacrificed at 0.5, 1.0, 1.5, 3, 6, 12, 24, 48, or 72 hours following exposure, and blood /and brain samples ... collected for analysis. The total recovered phenamiphos from brain and plasma tissues peaked at the first time interval and disappeared bi-exponentially to the end of the study. The rapid distribution resulted from the quick absorption of the compound in the intestine of the rat. Phenamiphos was more highly concentrated in the brain than in the plasma tissue. The half life in these tissues was 100 and 212 hours, respectively...
About 93-95% of an oral dose of fenamiphos was absorbed by rats and excreted by 12-15 hr after treatment. 48 hr later, residues in tissues were greatest in liver and kidney; less in fat, GI tract, and heart; and minimal in brain and muscle. Similar results were obtained in a whole body autoradiographic study of rats treated orally with fenamiphos which showed that oral absorption was virtually complete, distribution volumes were low, and excretion was rapid and nearly complete by 8 hr after dosing. Pretreatment of rats for 14 days before treatment with fenamiphos did not alter absorption, distribution, or elimination patterns. Distribution following oral doses was rapid in brain, and plasma and concentrations in brain exceeded concentrations in plasma by about 1.3-fold to twofold. Concentrations in brain and plasma were highest 0.5 hr after dosing and declined... .
Oral absorption of fenamiphos sulfoxide was equally rapid in pigs and reached max blood concentrations 2 hours after a 0.9 mg/kg dose. 57% of the administered dose was excreted within 5 hours and 90% was recovered after 48 hours. Tissue residues were minimal; only liver and kidney contained residues >0.1ppm. /Fenamiphos sulfoxide/
In vitro dermal absorption of fenamiphos by human and rat skin accounted for 0.42-9.95% of the applied dose and was 2.07 + or - 0.33 ug/sq cm/hr (human) and 3.15 + or - 0.40 ug/sq cm/hr (rat. Dermal absorption of a granular formulation was considerably less (0.01-0.03 ug/sq cm/hr) and dermal absorption of a liquid formulation was considerably more (13.0 + or - 1.87 ug/sq cm/hr (human) and 49.0 + or - 2.69 ug/sq cm/hr (rat)) during 24 hours.
[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.
