The metabolic profile of flonicamid in rats was determined from the 0-48 hour interval rat urine after single dose administration of (14)C- pyridyl-flonicamid by oral gavage in male and female Sprague-Dawley rats at levels of 2 or 400 mg/kg body weight. Flonicamid was the major component in male and female rats with 52-72% of administered dose and the major metabolite is 4-trifluoromethylnicotinamide, with 18-25% of administered dose. Minor metabolites identified were: 4-trifluoromethylnicotinamide N-oxide (3% of administered dose), Flonicamid N-oxide (2% of administered dose), 4-trifluoromethylnicotinamide (1% of administered dose), 4-trifluoromethylnicotinamide conjugate (0.52% of administered dose), OH-4-trifluoromethylnicotinamide (0.44% of administered dose), TFNA (0.36% of administered dose), and 4-trifluoromethylnicotinamide N-Oxide conjugates (0.30% of administered dose). TFNG was not detected in the urine. Analysis of flonicamid rat metabolism for repeated dosing gave the following results: Flonicamid (46-54% of administered dose) and 4-trifluoromethylnicotinamide (21-27% administered dose) were the major components found in rat urine following multiple low doses of (14)C- pyridyl-flonicamid.
In liver samples, the major components in male rat liver following 0.5 and 6 hours were flonicamid (51% and 27% total radioactive residues, respectively) and N-(4-trifluoromethylnicotinoyl)glycine (24% and 8% of total radioactive residues, respectively). 4-Trifluoromethylnicotinamide was 10% of total radioactive residues after 0.5 hours and 45% after 6 hours. In the rat biliary study, flonicamid was rapidly absorbed and excreted in the urine within 24 hours. ... The metabolic pathway of flonicamid in rats involves hydrolysis of the cyano (-CN) and amide (-CONH2) functional groups in the flonicamid molecule, although in rats, flonicamid was further metabolized by several routes, including N-oxidation and hydroxylation of the pyridine ring, leading to multiple metabolites.
(14)C Flonicamid (radiolabelled = 98.5% pure; unlabelled = 99.7%) was used in 3 experiments in order to characterize metabolism in CRL:CD (SD)IGS BR rats: Study #1(Biliary): 4 rats/sex/dose were administered a single oral gavage dose of (14)C Flonicamid at 2 or 400 mg/kg, then terminated at 48 hours. Study #2 (Single-Dose Excretion): 3 or 5/sex/dose/time point were treated with a single oral gavage dose of (14)C Flonicamid at 2 or 400 mg/kg and terminated at 0.5, 6, 24 and 168 hours (2 mg/kg) or 3 (M), 1 (F), 14.5 (M), 8 (F), 24 and 168 hours. Study #3 (Multi-Dose Excretion): 2/sex/dose/time point were treated with 14 consecutive oral gavage doses of (12)C Flonicamid at 2 mg/kg, then one dose of (14)C Flonicamid on the 15th day before termination at 0.5, 6, 24 and 168 hours following (14)C Flonicamid administration. The negative control and vehicle was 0.75% methylcellulose/HPLC Grade H2O. Livers were collected and analyzed for metabolites in study #2 and #3. Excretion of Flonicamid and metabolites occurred primarily in the urine and to a lesser extent in the feces. It was metabolized by several routes, including nitrile hydrolysis, amide hydrolysis, N-oxidation and hydroxylation of the pyridine ring. Combinations of pathways occurred, leading to the formation of multiple metabolites.
The metabolism of flonicamid was investigated in livestock using lactating goats and laying hens. The test substance was [14C] flonicamid (labeled at the 3 position of the pyridine ring; specific activity 100,000 dpm/ug). In goats, the test substance was administered orally at 10 ppm (4.2x) in the diet for five consecutive days. Milk was collected twice daily throughout the study, and tissues (liver, kidney, muscle, and fat) were collected at sacrifice. In hens, the test substance was also administered orally at 10 ppm (25x) in the diet for five consecutive days. Eggs were collected twice daily throughout the study, and tissues (liver, muscle, skin, and fat) were collected at sacrifice. The available data indicate that the metabolism of flonicamid is similar in goats and hens. The majority of the dose was rapidly excreted. TFNA-AM (4-trifluoromethylnicotinamide) was the major metabolite (29-92% TRR) in goats (tissues and milk) and in laying hens (tissues and eggs). Flonicamid was found in minor quantities in goat and hen matrices, at <6% TRR. TFNAAM was also identified in goat muscle, liver, and kidney in significant quantities (23-31% TRR) in the acid hydrolysates of nonextractable residues. A metabolite determined to be an unstable conjugate of TFNA was identified in goat kidney at 12% TRR and the metabolite OH-TFNAAM was identified in liver acid hydrolysate at 11% /total residues recovered/ (TRR). The metabolism of flonicamid in livestock shows the main pathway of metabolism involves hydrolysis of the cyano and amide functional groups in the molecule ...
This report describes /a case/ of acute exposure to a mixture of spinosad and flonicamid that resulted in a substantial clinical toxicities. An 80-year-old depressed female attempted suicide by drinking a mixture of 80-mL Conserve (Dow AgroSciences, Taipei, Taiwan) and 2-3 gram powder of flonicamid (Ishihara Sangyo Kaisha, Taipei, Taiwan). Spinosad was the main compound ingested. The clinical manifestations were mostly neurological, i.e. consciousness disturbance, shock, respiratory failure, pneumonitis and urinary retention. Endoscopic examination found grade 2a corrosive esophageal injury. After resuscitation, detoxification procedures and intensive care, the patient recovered fully without leaving any chronic sequels. An emerging question arising from this report is, why are the clinical symptoms so severe, given that both compounds were claimed safe in laboratory animals? The answer is unclear. One possible explanation is, the amount of spinosad ingested was far beyond the physiological safety dose that can be handled by human body. Other potential contributors to the clinical toxicities in this patient are the solvent compositions that were found in the Conserve insecticide formulation.[Su TY et al; Hum Exp Toxicol Mar 7 2011
/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"，最小流量/。如果出现低血容量的迹象，使用0.9%的生理盐水（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/
来源:Hazardous Substances Data Bank (HSDB)
毒理性
人类毒性摘录
这份报告描述了一个因急性接触 spinosad 和 flonicamid 混合物而导致严重临床毒性的案例。一位80岁的抑郁女性试图自杀，她喝下了一种混合物，其中包含80毫升的Conserve（陶氏益农，台北，台湾）和2-3克粉状的flonicamid（石原产业，台北，台湾）。spinosad 是摄入的主要化合物。临床表现主要是神经系统的，即意识障碍、休克、呼吸衰竭、肺炎和尿潴留。内镜检查发现2a级腐蚀性食管损伤。在复苏、解毒程序和重症监护后，患者完全康复，没有留下任何慢性后遗症。这份报告引发的一个问题是，尽管这两种化合物在实验室动物中被认为安全，但为何临床症状会如此严重？答案尚不清楚。一个可能的解释是，摄入的spinosad量远远超过了人体能够处理的生理安全剂量。这位患者临床毒性的其他潜在因素可能是Conserve杀虫剂配方中发现的溶剂组成。[Su TY et al; Hum Exp Toxicol 2011年3月7日]
/CASE REPORTS/ This report describes /a case/ of acute exposure to a mixture of spinosad and flonicamid that resulted in a substantial clinical toxicities. An 80-year-old depressed female attempted suicide by drinking a mixture of 80-mL Conserve (Dow AgroSciences, Taipei, Taiwan) and 2-3 gram powder of flonicamid (Ishihara Sangyo Kaisha, Taipei, Taiwan). Spinosad was the main compound ingested. The clinical manifestations were mostly neurological, i.e. consciousness disturbance, shock, respiratory failure, pneumonitis and urinary retention. Endoscopic examination found grade 2a corrosive esophageal injury. After resuscitation, detoxification procedures and intensive care, the patient recovered fully without leaving any chronic sequels. An emerging question arising from this report is, why are the clinical symptoms so severe, given that both compounds were claimed safe in laboratory animals? The answer is unclear. One possible explanation is, the amount of spinosad ingested was far beyond the physiological safety dose that can be handled by human body. Other potential contributors to the clinical toxicities in this patient are the solvent compositions that were found in the Conserve insecticide formulation.[Su TY et al; Hum Exp Toxicol Mar 7 2011
Five CRL:CD (SD)IGS BR rats/sex/level were dosed by gavage in 0.75% methylcellulose suspension with single administrations of either low or high doses of flonicamid. Intended dose levels were 2 and 50 mg/kg for both the pilot excretion study and for the pilot pharmacokinetics study. By error, the actual mean administered doses for the pilot excretion study were 0.85 and 21 mg/kg, which was unlikely to have affected results. The pilot excretion study assessed exhaled CO2 as well as urine, cage washings, and feces at intervals of 24 hr or less for 7 days. No measurable CO2 was detected in exhaled air. Urine plus cage wash samples accounted for 89-92% of administered label. About 5-6% of administered label was found in feces. Only 2-3% of label resided in carcasses at day 7. ... Tmax was estimated to be 0.3 to 0.6 hr.
(14)C Flonicamid (radiolabelled = 98.5% pure; unlabelled = 99.7%) was administered by oral gavage to CRL:CD (SD)IGS BR rats at 0 (0.75% methylcellulose/HPLC Grade H2O; 1/sex/dose at 6 and 168 hr termination), 2 mg/kg (3/sex/time point at 0.5, 6, 24 hours and 5/sex at 168 hour termination) and 400 mg/kg (3/sex/time point at 0.5, 6, 24 hours and 5/sex at 168 hour termination) to determine elimination and distribution. At 2 and 400 mg/kg, (14)C Flonicamid radioactivity was rapidly absorbed and excreted. A quantitative recovery was achieved during the 168 hour collection period. Urine contained 90% (including cage wash) of administered radioactivity, the majority of which was obtained within 24 hours of dosing at 2 mg/kg and by 48 hours at 400 mg/kg. Fecal elimination at 2 and 400 mg/kg was 5% of administered dose. In tissues, radioactivity levels increased rapidly with maximum concentrations mirroring those observed in the blood. While radioactivity was observed at all early time points in tissues, by 168 hours the levels had (where detectable) decreased by 50 - 100 fold. By 168 hours the carcasses contained 2% of radioactivity and liver had the highest tissue content (< 0.15%). At 2 mg/kg the greatest concentrations of radioactivity at 0.5 hours post dose for males and females respectively in liver (2.54-2.50 ug eq/g), kidney (2.35-2.67 ug eq/g), adrenals (5.07-6.52 ug eq/g), thyroid (4.02-4.26 ug eq/g) and ovaries (females - 3.77 ug eq/g). At 400 mg/kg males had the greatest concentration of radiolabel at 3 hours post dose in the liver (442 ug eq/g), kidney (311 ug eq/g), adrenals (672 ug eq/g) and thyroid (652 ug eq/g). Females had the greatest radiolabel concentrations at 1 hour post dose for liver (325 ug eq/g), kidney (359 ug eq/g), adrenals (689 ug eq/g) and thyroid (782 ug eq/g).
(14)C Flonicamid (radiolabelled = 98.5% pure; unlabelled = 99.7%) was administered by oral gavage to CRL:CD (SD)IGS BR rats at 0 (0.75% methylcellulose/HPLC Grade H2O; 1/sex/dose), 2 and 400 mg/kg (4/sex/dose), followed by a 48 hour termination time. At 2 and 400 mg/kg, (14)C Flonicamid radioactivity was rapidly absorbed and excreted. A quantitative recovery was achieved during the 48 hour collection period. Urine contained 85% (including cage wash) of administered radioactivity at 2 mg/kg and 80% at 400 mg/kg, the majority of which was excreted within 24 hours of dosing. Biliary excretion was low (4% at 2 mg/kg and 5% at 400 mg/kg) and the majority of radiolabel was excreted within the first 24 hours. Low levels of radioactivity were in feces (3.5-5.0%) and carcass (2.0-3.2%) at 2 mg/kg and in feces (3.8%) and carcass (1.5-2.1%). Therefore, biliary excretion was not a significant route of elimination of radioactivity. Increasing dose level had little effect on the disposition of radioactivity and there was no accumulation of radioactivity in the residual carcass. No sex-related differences were observed in any of the parameters measured.
[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.
