Forty two groups of Sprague Dawley rats (up to 5/sex/group) were dosed by oral gavage with either (14)C-t-butyl-, (14)C-A-Ring-, or (14)C-B-Ring-Methoxyfenozide at doses of 10 or 1000 mg/kg. ... (14)C- Methoxyfenozide was extensively metabolized into 32 metabolites (26 identified) isolated from urine and feces, and 24 metabolites were found and characterized from the bile. Seven metabolites comprised of 59-69% and 42-56% of the dose at 10 and 1000 mg/kg dose levels, respectively. Parent comprised of 14-26% and 30-39% of the administered (14)C at 10 and 1000 mg/kg dose levels, respectively.
Parent compound was found only in the feces (not in the urine or bile) and comprised 14-26% and 30-39% of the administered dose for animals at the lower and higher doses, respectively, indicating that animals at the lower dose metabolized a greater fraction of the administered dose compared with animals at the higher dose. Seven metabolites (M10, M14, M16, M22, M24, M28, M30) were found to be present in feces plus urine each at >2% of the administered dose. The predominant metabolites were M14 (desmethylated parent) and M24 (hydroxy methyl derivative). Parent compound plus these seven metabolites accounted for 74-90% of the administered dose (in feces plus urine) in all groups. For each of these groups, the total of parent plus identified metabolites accounted for >/= 83% of the administered dose, i.e. the metabolic profile of methoxyfenozide in feces and urine was well defined. Less than 5% of the administered dose was present as metabolites formed from the cleavage of the amide bridge.
Two metabolites, M16 (A-ring glucuronide of M14) and M26 (A-ring glucuronide of M24), were the main metabolites in bile. M16 was present at 13% and 18% in males and females respectively, M26 was present at 5% in males and 11% in females, all other metabolites represented <3% of the administered dose. The presence of M16 and M26 at higher concentrations in bile than in feces indicates that these two metabolites were subject to subsequent hydrolysis.
The primary /metabolic/ pathway probably involves demethylation of the A-ring methoxy moiety to form the corresponding phenol (M14), which is conjugated with glucuronic acid to form M16. Hydroxylation on the B-ring methyl moieties is also a significant metabolic pathway. Cleavage of methoxyfenozide to release either of the rings or the t-butyl group is only a minor pathway; none of the cleaved metabolites (M06, M07, M13, M32-36) were present at >2% of the dose. In males, however, cleaved metabolites represented up to about 50% of the metabolites found in urine. There was an indication that males cleaved more of the absorbed dose than did females, on the basis of urinary metabolite patterns.
Results for the animals receiving diets containing methoxyfenozide for 14 days plus a single dose of (14C) methoxyfenozide at 10 mg/kg bw by gavage showed evidence of induction of metabolism. Concentrations of M22, M28 and M30 increased, while concentrations of M14 and M24 were reduced relative to concentrations in animals that received only a single dose of (14C) methoxyfenozide at 10 mg/kg bw.
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).
/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/
/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: Acute Exposure/ Methoxyfenozide was not irritating to rabbit skin and produced only minimal, transient irritation to rabbit eyes. Negative results were obtained in a Magnusson and Kligman maximization test for skin sensitization in guinea-pigs.
Forty two groups of Sprague Dawley rats (up to 5/sex/group) were dosed by oral gavage with either (14)C-t-butyl-, (14)C-A-Ring-, or (14)C-B-Ring-Methoxyfenozide at doses of 10 or 1000 mg/kg. Some treatments were performed by combining appropriate amount of non-labeled or (13)C-labeled Methoxyfenozide to the (14)C-Methoxyfenozide. Three types of experiments were performed: (1) determination of excretion, distribution, and mass balance 120 hours post dose; (2) pharmacokinetics in blood (Cmax and 1/2 Cmax); and (3) tissue distribution of (14)C at Cmax and 1/2 Cmax. The (14)C was mostly excreted during the first 24 hours with 58-77% of the administered dose recovered in the feces and 4-9% of the dose found in urine from day 0-1. The position of the carbon label did not alter the excretion profile significantly. Approximately, 0.07-0.23% of (14)C remained in the tissues, and 0.03-0.11% were recovered as (14)C-CO2 and volatile organics from day 0-5 post dose. The maximum concentrations of (14)C-Methoxyfenozide in the blood were observed at 15-30 minutes post dose for all three (14)C-labels. The highest tissue concentration of (14)C was in the liver. The (14)C residues were rapidly cleared from all organs in the rat. Based on the recovery of (14)C from the bile, urine, tissues and carcasses, 62-70% of the administered dose was systemically absorbed.
The tissue distribution of radioactivity was investigated after a single dose of A-ring-labelled or t-butyl-labelled methoxyfenozide administered by gavage (at Cmax, 1/2 Cmax and at 5 days after dosing at 10 or 1000 mg/kg bw), and after a single dose of B-ring-labelled methoxyfenozide (5 days after dosing at 10 mg/kg bw). Tissue distribution was also investigated after dosing with A-ring-labelled methoxyfenozide at 10 mg/kg bw as a pulse dose (5 days after dosing) and as a repeated dose (at 0.25 hr after the last dose, at about Cmax). Similar results were seen in all experiments. The absorbed radioactivity was widely distributed, with the highest concentration of absorbed radioactivity found in the liver at 0.5-2 hr after dosing (the higher concentrations found in the stomach and intestinal tract were attributed to largely unabsorbed material). ... Clearance from the body was extensive; 5 days after a single dose of 10 mg/kg bw, the highest percentage of radioactivity, representing <0.1% of the administered dose, was found in the liver.
The biliary excretion of radiolabel after a single oral dose of ((14)C-A-ring) methoxyfenozide at 10 mg/kg was investigated in bile-duct cannulated rats. Biliary excretion was rapid, with 22% (females) and 50% (males) of the administered dose being excreted within 12 hr. Overall, 38% (females) and 64% (males) of the radiolabel was excreted in bile within 72 hr. Considerable variability between individual animals was seen in cannulated female rats (bile, 13-55%; and urine, 5-43% within 72 hr), but the overall amount absorbed (in bile, urine, carcass and tissues) was similar for all four females (56-67%). Taking the biliary component into account, the overall extent of oral absorption of methoxyfenozide at a dose of 10 mg/kg bw was 60-70% in both sexes.
The dermal absorption in vivo of methoxyfenozide formulated as an aqueous flow-able liquid (RH-112,485 2F) or as a wettable powder (RH-112,485 280WP) was tested in rats in a study that was designed to comply with US EPA guidelines and GLP. The methoxyfenozide administered was uniformly labelled with (14)C on the methoxyphenyl ring; this is acceptable given the limited cleavage seen in studies of oral metabolism. To provide data on exposure to the concentrated product and in-use-dilutions, groups of four male Crl : CD BR rats received radiolabelled methoxyfenozide at three aqueous dilutions (0.025, 0.25, or 2.5% w/v), applied in a volume of 100 uL to a shaved area of about 10 sq cm for 1, 10, or 24 hr. Systemically absorbed methoxyfenozide was defined as the radiolabel found in the carcass, urine (plus urine funnel and cage washes), feces, and whole blood. For RH-112,485 2F, the total mean recovery of radiolabel in all groups ranged from 98% to 114%. After an exposure of 1, 10, or 24 hr to (14)C-labelled RH-112,485 2F formulation diluted in water to a concentration of 2.5, 0.25, or 0.025% w/v, a small amount of radiolabel (<1-4%) was systemically absorbed. For RH-112,485 280 WP, three animals with poor recoveries were excluded from further analysis. The total mean recovery of radiolabel in all groups ranged from 85% to 110%. After an exposure of 1, 10, or 24 hr to (14)C-labelled RH-112,485 280 WP at a concentration of 2.5, 0.25, or 0.025% w/v, <1-2% of radiolabel was systemically absorbed. Findings were similar for both formulations. The amount of radiolabel that was systemically absorbed did not increase linearly between the 10-hr and 24-hr exposure periods, indicating that most of the radiolabel that remained in or on the skin after washing was tightly bound and was not available for systemic absorption. This study shows that methoxyfenozide is poorly absorbed (<4%) after dermal exposure to either of the formulated products or in-use dilutions. The low rate of dermal absorption may be attributed to very low solubility in water (3.3 mg/L at 20 °C).
[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.
