The major metabolites of malathion are the diacid and monoacid metabolites, namely, malathion dicarboxylic acid (DCA) and malathion monocarboxylic acid (MCA). Malaoxon, the active cholinesterase-inhibiting metabolite of malathion, is a minor metabolite. Both malathion and malaoxon are detoxified by carboxyesterases leading to polar, water-soluble compounds that are excreted.
Malathion is either oxidized in the liver to malaoxon by microsomal cytochrome P450 enzymes or to monoacids by a microsomal carboxyesterase. ... The other products of malathion and malaoxon metabolism are detoxification products. Malaoxon is also subject to hydrolysis and carboxyesterase. There is evidence that the linkage at P-S is enzymatically broken by another cytosolic esterase as well (A-esterase) and forms O,O-dimethyl phosphorothioate. There is some evidence that the monoacids can then be S-methylated, and that the C-S bond of either malaoxon or malathion can be further hydrolyzed.
Malathion is rapidly metabolized in vivo principally by hydrolysis of the carboxyl ester linkage to inactive metabolites by carboxylesterases. Because this detoxification reaction occurs much more rapidly in mammals than in susceptible insects, malathion exhibits a relative degree of selective toxicity in insects.
Malathion ... is oxidized by the hepatic microsomal monooxygenase system to malaoxon, an active, toxic metabolite. Metabolism of malaoxon typically occurs at a faster rate than its formation from malathion, and little accumulation of this highly toxic metabolite occurs in mammals.
Malathion is metabolically converted to its structurally similar metabolite, malaoxon (oxidation of the P=S moiety to P=O), in insects and mammals. Both malathion and malaoxon are detoxified by carboxyesterases leading to polar, water-soluble, compounds that are excreted. Mammalian systems show greater carboxyesterase activity, as compared with insects, so that the toxic agent malaoxon builds up more in insects than in mammals. This accounts for the increased toxicity of malathion in insects.
IDENTIFICATION AND USE: Malathion is a clear colorless liquid when pure. It has been employed for control of citrus orchard-destructive Mediterranean fruit flies and mosquitoes. Malathion is used for the topical treatment of head lice infestation. The drug also has been used for the topical treatment of pubic lice infestation, body lice infestation, and scabies (mite infestation). HUMAN EXPOSURE AND TOXICITY: Manifestations of acute intoxication may include a mix of muscarinic, nicotinic, and CNS effects. Following ingestion of malathion, symptoms may appear rapidly or may be delayed up to 12 hours. Initial signs and symptoms of malathion poisoning may be largely due to excessive muscarinic effects, which may predominate in milder cases; such effects may include nausea, vomiting, abdominal cramps, diarrhea, urinary and/or fecal incontinence, hyperhidrosis, sialorrhea, miosis (pinpoint pupils), bradycardia, lacrimation, and increased nasal, pharyngeal, and bronchial secretions. Nicotinic effects, including muscle fasciculation, muscle weakness, tachycardia, weakness or paralysis of respiratory muscles, and hypotonia, may occur in moderate and severe intoxications. CNS effects may include anxiety, restlessness, and headache. In more severe cases, tremors, confusion, dizziness, drowsiness, a reduction or loss of deep tendon reflexes, seizures, bradycardia, and coma also have been reported; death may occur. Respiratory failure may result from a combination of muscarinic, nicotinic, and CNS effects. In children, the signs and symptoms of poisoning may be predominantly related to the CNS (e.g., seizures, alterations in mental status including lethargy and coma). Hypotonia, muscle weakness, miosis, and excessive salivation also have occurred in children, while some of the typical cholinergic effects (e.g., bradycardia, muscular fasciculation, excessive lacrimation, sweating, bronchial secretion) may be observed less frequently than in adults. Concentrations of up to 400 ug/mL of 95% malathion failed to increase chromosomal aberrations in human hematopoietic cell cultures; however, others reported a positive result in human lymphocytes with 99% pure malathion. A significant increase in chromosomal aberrations was found in the lymphocytes of 14 people intoxicated with a commercial formulation of malathion, as compared with that in healthy controls. Aberrations observed included chromatid breaks, chromatid isobreaks, chromatid exchanges and unstable chromosomal and structural aberrations. There is limited evidence of malathion carcinogenicity in humans for non-Hodgkin lymphoma and prostate cancer. ANIMAL STUDIES: Undiluted malathion dropped on rabbit's eye caused slight immediate irritation. A daily dose of 46 mg/kg malathion ip for fifteen days affected the activity of the adrenal gland and liver glycogen in rats. Neurotoxicity, reflected by the occurrence of leg weakness in atropinized chickens given single, subcutaneous doses of 100 mg/kg malathion. A bioassay of malathion for possible carcinogenicity was conducted in rats. Groups of 49 or 50 rats of each sex were fed diets containing 2,000 or 4,000 ppm malathion for 103 weeks. All surviving rats were killed at 105 or 106 weeks. Malathion was not carcinogenic in male or female rats. Zebrafish larvae were used in order to determine the effects of malathion, on zebrafish behavior and AChE activity. Embryos and larvae were exposed to malathion during different time points in development and then tested at 5 days post-fertilization for behavioral, neurodevelopmental and AChE abnormalities. Malathion altered behaviors in the larvae such as swim speed and rest. Larvae treated with malathion also had significantly smaller forebrain and hindbrain regions compared to controls by 5 days post-fertilization. Malathion was ineffective in inducing sex linked recessive lethal mutations in Drosophila melanogaster. The clastogenic effect of malathion was studied in mice. At 230 mg/kg, increasing the frequencies of abnormal metaphases and chromosomal aberrations were noted in animals killed 6 or 24 hr after injection. Mice injected with 460 mg/kg, exhibited significant increments of abnormal metaphases, gaps, breaks, and chromatid exchanges in relation to controls. Malathion was tested by the plate incorporation assay with Salmonella typhimurium strains TA1535, TA1537, TA1538, TA98 and TA100 as well as with Escherichia coli strain WP2 uvrA-. No increases in revertants with any strain were reported. ECOTOXICITY STUDIES: Moribund mullet, Mugil cephalus, in an estuary sprayed with malathion (3 oz/acre) during a large scale mosquito control operation had about 98% inhibition of brain acetylcholinesterase. Inhibition of acetylcholinesterase and mortality were noted in pinfish 24, 48, and 72 hours at measured concentrations of 142, 92, and 58 ug/L, respectively. A concentration of 31 ug/L caused 34 percent acetylcholinesterase inhibition in pinfish but no deaths in 72 hours. Growth of oyster, Crassostrea virginica, was reduced 32% by 96 hr exposure to 1 mg/L. Bullfrogs (Rana catesbeiana) were exposed to malathion in water in a 28-day static renewal test. Survival was decreased at the level of 2,500 ug/L and higher. Development of tadpoles was significantly delayed by malathion exposure.
Malathion 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：有致癌性的提示性证据，但不足以评估对人类致癌的可能性
Cancer Classification: Suggestive Evidence of Carcinogenicity, but Not Sufficient to Assess Human Carcinogenic Potential
There is limited evidence in humans for the carcinogenicity of malathion. Positive associations have been observed with non-Hodgkin lymphoma and cancer of the prostate. There is sufficient evidence in experimental animals for the carcinogenicity of malathion. Malathion is probably carcinogenic to humans (Group 2A).
Malathion in an acetone vehicle has been reported to be absorbed through normal human skin only to the extent of 8% of the applied dose. Absorption may be increased when malathion is applied to damaged skin. Malathion is rapidly and effectively absorbed by practically all routes including the gastrointestinal tract, skin, mucous membranes, and lungs. However, it is readily excreted in the urine, and does not accumulate in organs or tissues.
Concentrations of pesticides and selected metabolites in rat urine and amniotic fluid were determined as biomarker upon oral administration of Wistar rats to two pesticide mixtures consisting of three to five pesticides (bitertanol, propiconazole, cypermethrin, malathion, and terbuthylazine). The pesticides and their metabolites were found in rat amniotic fluid and urine, generally in dose-response concentrations in relation to dosage. The measurement of the substances in the amniotic fluid indicated that the fetus was exposed to the pesticides as well as their metabolites. Moreover, the pesticides detected in urine demonstrated the exposure as well as the ability of the rat to excrete these compounds.
O,O,S-Trimethyl phosphorothioate (OOS-TMP) is an impurity present in widely used organophosphorus insecticides such as malathion. Oral treatment of rats with the compound produces prominent bronchiolar epithelial necrosis. Following the administration of [(3)H]OOS-TMP to rats, substantial amounts of radiolabeled material were covalently bound to lung with a concomitant depletion of glutathione (GSH). Other organs showing significant covalently bound radioactivity were liver, kidneys, and ileum. The maximal accumulation occurred in the tissues within 6 hr, and reached a plateau between 6 and 12 hr. Pretreatment of rats with either phenobarbital or piperonyl butoxide decreased the level of radiolabeled material bound in lung, GSH depletion, and the toxicity of OOS-TMP. These results suggest that the covalent binding is due to a metabolite(s) of OOS-TMP and that the metabolite(s) is involved in the mechanism of toxicity of OOS-TMP. ... /(3)H-O,O,S-trimethyl phosphorothioate/
... /The/ objective was to determine the percutaneous absorption of chronically applied malathion in man and to compare chronic absorption to single-dose absorption. The experimental design was to first topically apply [(14)C]malathion to human male volunteers. This procedure was followed by repeated administration of nonradioactive malathion to the same site of application (ventral forearm). [(14)C]Malathion was reapplied (Day 8) when urinary excretion of radioactivity from the first application reached minimum detectable levels. The first [(14)C]malathion absorption was compared to the second [(14)C]malathion application. The percutaneous absorption from the first [(14)C]malathion application was 4.48 +/- 1.3% (SD) of the applied dose. The absorption from the second [(14)C]malathion administration was 3.53 +/- 1.0%, a value not significantly (p greater than 0.05) different from the first application. Therefore, for malathion the single-dose application data are relevant for predicting the toxic potential for longer-term exposure.
Eight autopsy samples from an individual who had ingested a large amount of malathion were analyzed. ... The highest concentrations were found in gastric contents (8621 ppm) and adipose tissue (76.4 ppm). Malaoxon was identified in some tissues at very low levels; a significant amount was found only in fat (8.2 ppm). Malathion monocarboxylic acid & malathion dicarboxylic acid were found in greater abundance: 221 ppm in bile, 106 ppm in kidney, and 103 ppm in the gastric contents.
[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.
