As part of a 3-month feeding study in rats, ... concentrations of chlorantraniliprole and the two major metabolites, IN-GAZ70 and IN-H2H20 (for structures, see Figure 1) were measured in the plasma. Groups of 10 male and 10 female Crl:CD(SD) IGS BR rats were given diets containing chlorantraniliprole (purity, 95.9%) at a concentration of 0, 600, 2000, 6000, or 20 000 ppm, equal to 0, 36.9, 120, 359, or 1188 mg/kg bw per day for males and 0, 47.0, 157, 460, or 1526 mg/kg bw per day for females. Concentrations of chlorantraniliprole, INGAZ70 and IN-H2H20 were determined by liquid chromatography (LC)/MS in plasma obtained on day 59. Statements of adherence to QA and GLP were provided. Chlorantraniliprole, IN-GAZ70 and IN-H2H20 were present in the plasma at greater concentrations in female rats (up to 0.83, 112 and 0.54 ug/mL, respectively) than in male rats (up to 0.18, 3.7 and 0.08 ug/mL, respectively) with concentrations of IN-GAZ70 being highest. The plasma concentrations of all three analytes were similar at the three higher dietary concentrations in both sexes
The metabolism of chlorantraniliprole was investigated in two studies in Sprague-Dawley Crl:CD(SD)IGS BR rats. ... The experiments were performed with a 1 : 1 (uCi : uCi) mixture of (benzamide carbonyl (14)C)chlorantraniliprole (radiochemical purity, 97%) and [pyrazole-carbonyl 14C]chlorantraniliprole (radiochemical purity, 99%), diluted with chlorantraniliprole technical (purity, 96.45%). The rats were given a single dose at 10 or 200 mg/kg bw or daily doses of 10 mg/kg bw by gavage for 14 days. Metabolites were identified and quantified by high-performance liquid chromatography (HPLC) and mass spectrometry (MS) or tandem mass spectrometry (MS/MS). Statements of adherence to QA and GLP were provided. The metabolism of chlorantraniliprole was extensive and characterized by tolyl methyl and N-methyl carbon hydroxylation, followed by N-demethylation, nitrogen-to-carbon cyclization with loss of a water molecule resulting in the formation of the pyrimidone ring, oxidation of alcohols to carboxylic acids, amide-bridge cleavage, amine hydrolysis, and O-glucuronidation. At both doses, a significant difference between the sexes was apparent in the profile of metabolites in the urine and faeces, which indicated greater potential for hydroxylation of the tolyl methyl and N-methyl carbon groups in male rats than in female rats. For example, in rats at 10 mg/kg bw, the percentage of the administered dose represented by the di-hydroxylated metabolite IN-K9T00 was greater in males (urine, 7.4%; feces, 10.4%) than in females (urine, 2.2%; feces, 4.8%). Concentrations of the methylphenyl mono-hydroxylated metabolite IN-HXH44 were higher in the urine (4.6%) and feces (7.4%) of males than urine (2.4%) and feces (3.5%) of females. IN-KAA24, a carboxylic-acid metabolite of IN-HXH44, was a significant metabolite observed in the urine and faeces of males (10.6% combined), but not in females. Percentages of the N-methyl carbon hydroxylated metabolite IN-H2H20 were higher in females (urine, 3.4%; feces, 15.0%) than in males (urine, 0.3%; feces, 1.4%). At the higher dose, excretion of the parent compound in the urine and feces (78.9-85.5%) was 12-16-fold that at the lower dose (4.9-7.3%). The profile of metabolites in rats at 200 mg/kg bw was similar to that in rats at 10 mg/kg bw. The profile of metabolites in the urine and faeces of rats given repeated doses was similar to that observed for rats given single doses. Some minor differences included an apparent increase in the percentages of hydroxylated and polar metabolites such as IN-H2H20, IN-K7H29, and INKAA24 after repeated doses. IN-GAZ70 was observed in the faeces of female rats after 7 and 14 days of repeated doses, but not after a single dose.
/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/
/GENOTOXICITY/ In a cytogenetic assay, primary human lymphocyte cultures were exposed to DPX-E2Y45 Technical (chlorantraniliprole) at concentrations up to precipitating levels (> or = 750 ug/mL) and there were no statistically significant increases in the percentages of cells with structural aberrations or in polyploidy.
/LABORATORY ANIMALS: Acute Exposure/ In a study of dermal sensitization using the Magnusson and Kligman maximization test, 20 Dunkin Hartley guinea-pigs were exposed to chlorantraniliprole technical (purity, 96.45%; solid powder). During the preliminary testing phase, the concentrations of the test substance used for the intradermal induction, topical induction and topical challenge, respectively, were 5% (w/w), 80% (w/w) and 20% (w/w), the highest non-irritating concentration. The vehicle was mineral oil. The control group consisted of 10 guinea-pigs. The first induction phase involved three paired intradermal injections of 0.1 mL of test substance, 0.1 mL of 50% (v/v) mixture of complete Freund adjuvant in distilled water and 0.1 mL of complete Freund adjuvant with test substance. The guinea-pigs in the control group were treated similarly with vehicle only. The topical induction phase was carried out 1 week later: the guinea-pigs were pre-treated with sodium lauryl sulfate 24 hr before topical applications of 0.5 g of chloroantraniliprole on a gauze pad for 48 hr under occlusion. In the challenge phase, 21 days after study initiation, the guinea-pigs received topical applications of 0.5 mL of the challenge dose and 0.5 ml of a 33% dilution of the challenge dose for 24 hr. At 24 hr and 48 hr after patch removal, the degree of dermal irritation was scored according to the Magnusson and Kligman grading scale. Data from appropriate historical controls exposed to alpha-hexylcinnamaldehyde technical (HCA) were used as the positive control. Statements of adherence to QA and GLP were included. After the intradermal and topical induction phases, very faint to moderate erythema (scores, 0.5-2) was noted at the treatment site in most guinea-pigs receiving chlorantraniliprole and in the control group. At challenge, very faint erythema (score, 0.5) was noted in some guinea-pigs receiving chlorantraniliprole at the highest non-irritating concentration and in some guinea-pigs in the control group. At treatment sites to which the 33% dilution was applied, no dermal reactions were noted.
/A lactating goat/ was given a single daily oral dose of 1:1 mixture of BC-labeled and PC-labeled chlorantraniliprole at 10 ppm for 7 consecutive days. Feces and urine were collected once daily and milk collected twice daily. The goat was sacrificed 23 hours after the last dose. The major metabolites were formed by N-demethylation, hydroxylation at the benzylic position and further oxidation to carboxylic acid and cyclization with loss of water to yield various cyclic metabolites. The majority of the administered dose was eliminated through the feces and urine. Undegraded parent was the major terminal residue identified in kidney, muscle, and fat, and it was also a residue in liver and milk.
Groups of at least five male and five female Crl:CD (SD)IGS BR rats were given chlorantraniliprole (purity, approximately 100%) at a dose of 0, 25, 100 and 1000 mg/kg bw per day by gavage for 14 consecutive days. Blood was collected from three male rats in each of the groups at 25, 100, and 1000 mg/kg bw on test days 14 and 15 immediately before dosing, and then 30 and 60 min, 2, 4, 8, 12, and 24 hr after dosing for determination of plasma concentrations of chlorantraniliprole. On day 14, liver tissue of five male and five female rats per group was processed for hepatic biochemical evaluations (beta-oxidation activity, total and specific cytochrome P450 content). Blood was separated into plasma and erythrocytes. In additional male rats assigned to the groups at 25, 100, and 1000 mg/kg bw per day, fat samples were collected for the purpose of assessing potential bioaccumulation of the test substance. The area under the curve of concentration time (AUC) for chlorantraniliprole was not proportional to dose, indicating that absorption was decreased at higher doses. Calculated half-lives for chlorantraniliprole in rats in the groups at 25, 100, and 1000 mg/kg bw per day were 3.4, 3.4, and 4.0 hr, respectively). Peak plasma concentrations occurred at 0.25, 0.42 and 2.75 h in the groups at 25, 100, and 1000 mg/kg bw per day. The maximum plasma concentrations (up to 0.48 ug/ml at 25 mg/ kg bw) were similar at all doses. The concentrations of the test substance in fat were below the limit of quantitation at 24 hr after dosing, indicating no significant accumulation of the parent compound.
Chlorantraniliprole was readily absorbed after oral administration /in Sprague Dawley Crl:CD(SD)IGS BR rats/, although absorption was incomplete and dose-related, with Tmax values of 5-9 hr after the lower dose and 11-12 hr after the higher dose. At a dose of 10 mg/kg bw, plasma concentrations peaked at 3.0 and 5.4 ug equivalents/g in males and females, respectively. After 24 hr, plasma concentrations in males and females were about 1.4 and 3.6 ug equivalents/g. At 200 mg/kg bw, plasma concentrations peaked at 5.1 and 7.1 ug equivalents/g in males and females, respectively. In the experiment with bile-duct cannulated rats, total absorption was 73-85% after a dose of 10 mg/kg bw and 12-13% after a dose of 200 mg/kg bw. At the lower dose, 48 hr after dosing 18-30% and 49-53% of the absorbed radiolabel was excreted in urine and bile respectively, while 2-6% and 10-20% was found in tissue and feces respectively. At the higher dose, 48 hr after dosing 4% and 5-7% of the absorbed radiolabel was excreted in the urine and bile, respectively, while 3% and 55-71% was found in tissue and feces, respectively. (14)C residues showed extensive distribution in the tissues. In the rats at the lower dose, 0.8% and 3.3% of the administered dose was recovered from the tissues of males and females, respectively, at 168 hr after dosing. At this time-point, tissues of males and females at the higher dose contained 0.2% and 0.5%, respectively, of the administered dose. No significant radioactivity was exhaled as (14)C-labelled volatiles or (14)CO2. Concentrations of (140C residues were lower in erythrocytes and tissues than in plasma. The mean plasma elimination half-lives were shorter in males (38-43 hr) than in females (78-82 hr) rats.
In a kinetic study that complied with OECD guideline 417, male and female Sprague-Dawley Crl:CD(SD)IGS BR rats were given up to 14 daily doses of [14C]chlorantraniliprole at 10 mg/kg bw per day by gavage. The experiments were performed with a 1 : 1 uCi/uCi mixture of (benzamide carbonyl (14)C)-chlorantraniliprole (radiochemical purity, 97%) and (pyrazole-carbonyl (14)C)chlorantraniliprole (radiochemical purity, 99%), diluted with chlorantraniliprole technical (purity, 96.45%). Rats were checked daily for clinical signs of toxicity. In three females per group, (14)C residues were quantified in whole blood, plasma, erythrocytes, fat, kidney, liver and muscle on days 5, 9, 12, 17, and 27. An evaluation of the distribution of (14)C residues in 21 tissues of three males and three females per group was performed on days 15 and 21. Material balance and rate and extent of urine and faecal excretion by male and female rats was quantified until day 21 (seven days after the last dose). Metabolites in urine and feces (% of accumulating dose), collected for intervals of 24 hr after the first, seventh, and last (fourteenth) day of dosing were profiled. ... More than 98.4% of the administered dose was recovered. Plasma and tissue concentrations indicated that steady-state kinetic behaviour was reached in male rats after 14 days of dosing. In female rats, concentrations of radiolabel in the plasma and tissue were near steady-state at the end of the 14-day dosing period. At day 15, plasma concentrations peaked at 4.6 and 32 ug equivalents/g in males and females, respectively, these concentrations being about two- and seven-fold higher than 24 hr after a single dose at 10 mg/kg bw. The concentrations of (14)C residues in tissues were higher in females than in males (2.35% vs 0.35% of the administered dose) at 168 hr after the last dose. After dosing, the concentration of 14C residues in the selected tissues of female rats declined, with half-lives ranging from 3.9 to 7.7 days. The half-life in plasma (T1/2 = 7.2 days) was approximately twofold that determined from plasma collected for up to 5 days after administration of a single dose (T1/2 = 3.4 days). A more extensive evaluation of tissue residues in 21 different tissues produced profiles of concentration and percent of dose that were similar to those observed in the single-dose study. Ratios of concentrations in tissue and plasma were less than 1. Most of the administered dose was excreted in the faeces (males, 72.9%; females, 81.6%). In the urine, 16.7% and 12.1% of the administered dose was excreted by males and females, respectively. The overall pattern of distribution and excretion for multiple dosing (10 mg/kg bw per day X 14 days) generally resided between the pattern observed for administration of a single low dose (10 mg/ kg bw) and a single high dose (200 mg/kg bw).
[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.
