The major biotransformation reaction is cleavage of the oxadiazine ring to form the corresponding nitroguanidine compound (i.e., chlothianidin, the regulated metabolite in plants and livestock).
In the in vivo study compared rat and mouse plasma metabolite levels after 1-week or 10-week dietary exposures of 3000 ppm in rats and 2500 ppm in mice (N = 5). Plasma thiamethoxam levels were 12 and 4 ug/mL in 1-wk and 10- wk mice, and 7 and 19 ug/mL in respective rats. In mice, it appeared that metabolic induction was progressing over that interval, as CGA 265307 (downstream metabolite of both CGA 322704 and CGA 330050) increased from 2 to 5 ug/mL. CGA 322704 levels in mice stayed about the same and CGA 330050 levels were marginally reduced during this interval. In rats, CGA 322704 ranged from 1.0 to 0.6 ug/mL. Other metabolite levels were exceedingly low in rats: CGA 265307 at 0.05 to 0.09 ug/mL, and CGA 330050 at 0.10 to 0.14 ug/mL. Liver microsomal fractions were prepared from mice, rats, and humans for in vitro studies of metabolism of thiamethoxam to metabolites. In all cases, mice had the most rapid metabolic rates (i.e. for metabolism of thiamethoxam to CGA 322704, thiamethoxam to CGA 330050, CGA 322704 to CGA 265307, and CGA 330050 to CGA 265307). Rats had slightly higher metabolic rates than humans for these reactions.
Two male Tiflbm: RAI (SPF) rats/group were dosed once with 100 mg/kg [Oxadiazin-4-(14)C] CGA 293343 by gavage. Sacrifices were 0.5, 1, 2, 4, 6, 8, or 24 hrs after dosing. Blood was collected to assess total residues and to identify major metabolites. A TLC radiochromatogram of whole blood extracts taken 4 hrs post-dosing revealed 1 strong peak, one much lesser peak, and very little label outside those areas. The corresponding HPLC radiochromatogram revealed 2 perceptible peaks: thiamethoxam and CGA 322704. At peak levels of thiamethoxam (6 hrs after dosing), 99.8% of radiolabel was extractible. Extractible residues other than thiamethoxam and two metabolites were 1.74% of label. Maximum concentrations were at 6 hr for thiamethoxam and its metabolites. Estimated t1/2 were 2 hrs for thiamethoxam, 4 hrs for CGA 322704, and 8 hrs for CGA 265307. During the period from 0.5 to 8 hrs post-dosing, "other" residues graduated from 0.3% to 2.2% of extractible label. At 24 hours, total residues in blood were only 2% of the peak [6 hr] levels. Metabolic profile (as % of total radioactive residues of a given sampling time) for thiamethoxam, CGA 322704, and CGA 265307, respectively were 94.6%, 5.0%, and (below quantifiable levels) at 1 hr; 81.9%, 15.0%, and 1.2% at 6 hrs; and 15.5%, 30.6%, and 17.6% at 24 hrs. CGA 330050, a significant metabolite in mice, was not detectable.
Six male Tiflbm: MAG (SPF) mice/group were dosed once with 100 mg/kg [Oxadiazin-4-(14)C] Thiamethoxam by gavage. Sacrifices were 0.5, 1, 2, 4, 6, 8, or 24 hrs after dosing. Blood was collected to assess total residues and to identify major metabolites. A TLC radiochromatogram of whole blood extracts taken 1 hr post-dosing revealed 3 strong peaks, with very little label outside those areas. One of the peaks represented 2 constituents, so that the HPLC radiochromatogram revealed 4 perceptible peaks. These were thiamethoxam (dominant peak), and three metabolites: CGA 322704, CGA 265307, and CGA 330050. During the first hour, about 1.5% to 2.9% of label was non-extractible, whereas residues other than thiamethoxam and the above metabolites were below levels of detection. Kinetics parameters for TCmax (hr) 0.5 for thiamethoxam, and 2 for the three metabolites, and estimated t1/2 (hr) were 3 hr (for thiamethoxam and all metabolites). During the period from 4-8 hrs post-dosing, "other" residues constituted about 5% of extractible label. At 8 and 24 hours, respectively, total residues in blood were only 30% and 1% of the peak (0.5 hr) levels. Metabolic profile (as % of total radioactive residues of a given sampling time) for thiamethoxam, CGA 322704, CGA 265307, and CGA 330050, respectively were 77.5, 11.2, 3.2, and 6.6 at 0.5 hrs; 60.0, 15.7, 9.8, and 11.6 at 1 hr; and 39.5, 12.7, 30.4, and 9.0 at 8 hrs.
/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/
/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/
来源:Hazardous Substances Data Bank (HSDB)
毒理性
解毒与急救
/SRP:/ 高级治疗：对于无意识、严重肺水肿或严重呼吸困难的病人，考虑进行口咽或鼻咽气管插管以控制气道。使用气囊面罩装置的正压通气技术可能有益。考虑使用药物治疗肺水肿……。对于严重的支气管痉挛，考虑给予β激动剂，如沙丁胺醇……。监测心率和必要时治疗心律失常……。开始静脉输注D5W /SRP: "保持开放"，最低流量/。如果出现低血容量的迹象，使用0.9%生理盐水（NS）或乳酸林格氏液。对于伴有低血容量迹象的低血压，谨慎给予液体。注意液体过载的迹象……。使用地西泮或劳拉西泮治疗癫痫……。使用丙美卡因氢氯化物协助眼部冲洗……。 /Poisons A and B/
/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/
/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ Thiamethoxam (CGA-293343 Technical, purity 98.6%), suspended in 0.5% (w/v) carboxymethylcellulose in 0.1% (w/v) aqueous polysorbate 80, was applied to the clipped skin of 5 Tif: RAIf (SPF) hybrids of RII/1 x RII/2 (Sprague-Dawley derived) rats per sex per dose at dose levels of 0 (vehicle only), 20, 60, 250, or 1000 mg/kg/day for 6 hours per day 5 days per week for 4 weeks using an occlusive dressing. No animals died. No treatment-related clinical signs or signs of local irritation were observed. Dose-related increases in mean serum glucose and mean serum triglycerides in females at 250 and 1000 mg/kg/day were observed. Also, a treatment-related increase in mean serum alkaline phosphatase level was observed in females at 250 and 1000 mg/kg. Microscopic examination revealed treatment-related hyaline change in renal tubules of males at 1000 mg/kg/day and treatment-related minimal-moderate inflammatory cell infiltration in the liver of females at 60, 250, and 1000 mg/kg/day. Possible adverse effect: treatment-related hyaline change in the renal tubules of high dose males. NOEL (systemic, M)=250 mg/kg/day based on hyaline change in renal tubules, NOEL (systemic, F)=60 mg/kg/day based on elevated alkaline phosphatase and abnormal liver histology, NOEL (dermal, M/F)=1000 mg/kg/day based on no signs at HDT.
/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ Thiamethoxam (CGA-293343 Technical, purity 98.6%) was admixed to the pelleted food at dose levels of 0, 50, 250, 1000, and 2500/2000 ppm (0, 1.58, 8.23, 32.04, and 54.81 mg/kg/day, respectively, for males and 0, 1.80, 9.27, 33.87, and 50.45 mg/kg/day, respectively, for females) and fed to 4 beagle dogs per sex per dose level for a period of 13 weeks. No deaths occurred. No treatment-related clinical signs were observed. Treatment-related decreases in mean body weight and mean food consumption in females at 2500/2000 ppm were observed. Treatment-related decreases in mean cell hemoglobin and mean alanine aminotransferase levels in both sexes at 1000 and 2500/2000 ppm were observed. A statistically significant decrease in mean relative testes weight at 2500/2000 ppm was observed. Microscopic examination revealed moderate bilateral tubular atrophy of the testes in one animal at 2500/2000 ppm, and treatment-related reduced spermatogenesis (bilateral) in the testes, the presence of spermatic giant cells (bilateral) in spermatogenic epithelium of the testes, and immature ovaries (bilateral) and uteri at 2500/2000 ppm. Possible adverse effect: decrease in mean relative testes weight and bilateral tubular atrophy, presence of spermatic giant cells, and reduced spermatogenesis in the testes. NOEL (M)= 32.04 mg/kg/day (1000 ppm, reduced spermatogenesis and testicular atrophy) and (F)= 33.87 mg/kg/day (1000 ppm, immature ovaries and uteri).
Quickly and completely absorbed, rapidly distributed in the body and rapidly eliminated. The toxicokinetics and metabolism are not influenced by the route of administration, the dose level, pre-treatment, the site of label or the sex of animals.
In rats, thiamethoxam is absorbed rapidly and extensively, and is widely distributed, followed by very rapid elimination, mostly in the urine. The highest tissue concentrations are in skeletal muscle (10-15% of administered dose). Very low tissue residues were reported after 7 days. Within 24 hours, approximately 84-95% of the administered dose was excreted in urine, while 2.5-6% was excreted in the feces. Most was excreted as unchanged parent (70-80% of dose). ... Enterohepatic circulation is negligible.
Fifteen Tiflbm: MAG (SPF) mice/group were dosed with non-labeled thiamethoxam in diet for 29 days at 0, 100, 500, or 2500 ppm. Labeled thiamethoxam (10 mg/kg b.w.) was given by gavage to all groups on day 30, and again 72 hours later (non-labeled dietary treatments continued until termination). Mice were killed 6 hours after the second radio-labeled treatment. Investigators evaluated urine, feces, liver, plasma, and bile for radiolabel and metabolites. Regardless of dose, 58-76% of the first dose was found in urine and 24-36% of first dose in feces within 72 hours (accounting for 94-102% of administered dose). Six hours after the 2nd dose, liver contained about 0.9 to 1.5% of that dose, pooled bile from the gall bladders contained only 0.01 to 0.22% of that dose, and plasma contained 0.3 to 0.4% of that dose (no effect of pre-treatment for liver, bile, or plasma). Excreta and other samples showed no influence of dose on metabolite patterns. ...
Non-radiolabeled Thiamethoxam (purity >98%); Radiolabeled [Thiazol-2-(14)C] Thiamethoxam (Batch #Ko-73.1A and Ko-73.2A-1, specific activity 68.9 and 57.3 uCi/mg, respectively, purity of >97%) and [Oxadiazin-4-(14)C] Thiamethoxam (Batch Ko-75.2A-2 and Ko- 75.2A-3, specific activity of 87.0 and 84.6 uCi/mg, purity >96%) were administered to 4 or 5 Tif:RAI f (SPF) rats/sex/dose at 0.5 mg/kg, to 5 rats/sex at 0.5 mg/kg (after 14 days of unlabeled Thiamethoxam) and to 5 rats/sex at 0.5 or 100 mg/kg by oral gavage or iv. Three groups of 4 male Tiflbm:MAG (SPF) mice receiving [Thiazol-2-(14)C] Thiamethoxam for 14 days at 118 mg/kg to determine excretion and metabolic fate in mice. In rats, the dose was rapidly absorbed from the G.I. tract into the general circulation with maximum blood levels (tCmax (hr) achieved 1 to 4 hours independent of the radiolabel site, dose level or sex. Cmax ranged from 0.17 to 0.20 ppm (low dose) and 33 to 43 ppm (high dose) and levels declined rapidly (tCmax/2 about 8 hours). Bioavailability 0.6 to 0.8 (males) and 0.7 to 0.9 (females) indicated sizable oral absorption. Absorbed material was primarily excreted via the urine (approximately 90%) compared to about 4% in feces within 24 hours. The preponderance of fecal elimination originated from biliary excretion. Half-lives in all tissues ranged from 2 to 6 hours. Comparison of metabolite patterns in mice and rats indicated that the major metabolic pathways were similar.
In mice, approximately 72% of the administered dose was excreted in the urine and 19% was excreted in feces. Small but measurable amounts were detected in expired air (approximately 0.2% of dose). Parent (33-41% of administered dose) and 2 predominant metabolites: 8-12% and 9-18% of administered dose were found. These are the same structures that were most commonly observed in rat excreta; however, the proportions are quite different in mouse excreta. One additional significant metabolite (mouse R6) was isolated from feces samples. Between 30-60% of the administered dose was excreted as metabolites.
[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.
