Metabolism in rats and ruminants involves cleavage of the ester, followed by hydroxylation of the cyclohexane ring. In rats, metabolism continues with cleavage of the enol ring, leading to formation of the cyclohexyl ester of 2,4-dichloromandelic acid, which is further metabolised. The residue definition comprises spirodiclofen enol.
The primary initial product of ester cleavage (removing a 2,2-dimethylbutyric acid moiety) is designated BAJ 2510 (or BAJ 2740 enol). Two major products of this enol are the 4-OH and 3-OH addition products to the cyclohexyl ring, i.e. "4-OH BAJ 2510" and "3-OH BAJ 2510."
Groups of Wistar Hsd/Cpb: Wu rats (about 200 g at treatment) were dosed with labeled spirodiclofen (radiopurity > 98%) in 10 mL/kg of 0.5% CMC suspension as follows (showing group designations in brackets): single high dose (100 mg/kg, 4 M); single low dose (including CO2 measurement) (2 mg/kg, 4 M); single low dose (EPA basic test) (2 mg/kg, 4 M); single low dose (2 mg/kg, 4 F); 14 daily doses with 2 mg/kg/day non-radioactive a.i., then 1 labeled low dose (2 mg/kg, 4 M); and single low dose, bile cannulation study (2 mg/kg, 6 M). ... There was a sex difference in urinary metabolites: low dose females excreted 53% of administered dose as the enol, whereas low dose males excreted low amounts of the enol (< 5%), but instead favored subsequent hydroxylation of the cyclohexyl moiety of the enol at carbon 3 or 4. Positions of the ring hydroxyls in the plain of the ring (designated "e" for equitorial) were most abundant: low dose males had 26% to 30% of administered label as the 3-hydroxy-enol (e) metabolite, and 13% to 15% of administered label as the 4-hydroxy-enol (e) metabolite. The associated axial "a" isomers with the hydroxyls perpendicular to the ring were comparatively minor metabolites. The combined 3- and 4-hydroxy-enol metabolites in females constituted only 17% of administered dose. There were no other common urinary metabolites. Pre-treatment with unlabeled low doses of spirodiclofen for 2 weeks had no obvious effect on metabolism. Fecal metabolism yielded 1 to 4% of parent spirodiclofen after low dose exposure, compared to 16% in high dose males (consistent with reduced absorption). The enol constituted 4 to 7% of administered dose in feces of low-dose non-cannulated rats (16% in high dose M), with 3- and 4-hydroxy-enol (e) metabolites as modest contributors (1% to 7% of administered dose for each of these isomers). Fecal metabolites included a few percent of mandelic acid-cyclohexyl-methyl esters (created by oxidatively opening the 5-membered ring at the location of the enol hydroxyl group), and subsequent metabolic products. Glucuronides were not observed in feces. The two most common bile residues were the OH-enol glucuronide and 3-hydroxy-enol (e) (3% and 4% of administered dose, respectively).
At week 20, blood samples were taken from 4 dogs per sex at the high dose (600 ppm) at 0, 2, 4, 7, and 24 hours after feeding. Plasma concentrations of BAJ 2740 and the metabolite BAJ 2510 were evaluated by high performance liquid chromatography (HPLC). BAJ 2740 was below the limit of quantification since it was rapidly cleaved by esterases in plasma and liver to the metabolite BAJ 2510. No other metabolites were identified. Week 20 high dose group mean concentrations of metabolite BAJ 2510 in plasma were 24.8, 17.6, 19.1, 26.7, and 32.4 nmol/mL for males and 26.8, 15.9, 15.8, 25.0, and 28.1 nmol/mL in females at 0, 2, 4, 7, and 24 hours after feeding respectively. BAJ 2510 was also quantified in urine samples taken from 3 female and 1 male high dose (600 ppm) dogs at week 28. One hour after receiving treated diet, dogs were placed in metabolism cages for 5 hours. Urine volumes were 74, 281, and 305 mL in females and 18.6 mL in the male. BAJ 2510 concentrations in urine were 0.46, 0.16, and 0.12 umol/mL in females and 0.05 umol/mL in the male respectively.
/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/
/ENDOCRINE MODULATION/ This study evaluated the effects of spirodiclofen, BAJ 2510, and one of the hydroxy BAJ 2510 metabolites, primarily on hormone response elements in human cell lines (MCF 7 breast cancer cell line or prostate PC-3 cell line for estrogen and androgen receptor, respectively). Hormone response was quantified via luciferase reporter genes using a chemiluminescence reader. In some cases, binding studies for alpha and beta estrogen receptors followed, using a fluorescence polarization technique which could be performed in microtiter wells. At pH's of 6 to 6.5, BAJ 2510 displayed estrogenic and anti-estrogenic activities. BAJ 2510 bound to alpha and beta estrogen receptors in this pH range. BAJ 2510 had no effects in the reporter or receptor binding assays at physiological pH (7 or higher). Spirodiclofen and hydroxy BAJ 2510 were uniformly negative in all assays.
/LABORATORY ANIMALS: Acute Exposure/ Non-irritating to skin and eyes (rabbits). Maximization tests on active ingredient and SC formulation showed potential for skin sensitization; but Buehler test on SC formulation was negative.
来源:Hazardous Substances Data Bank (HSDB)
吸收、分配和排泄
迅速吸收，广泛分布，大部分在48小时内排出。
Rapidly absorbed, widely distributed and mostly excreted within 48 hr.
Groups of Wistar Hsd/Cpb: Wu rats (about 200 g at treatment) were dosed with labeled spirodiclofen (radiopurity > 98%) in 10 mL/kg of 0.5% CMC suspension as follows (showing group designations in brackets): [6] single high dose (100 mg/kg, 4 M); [7] single low dose (including CO2 measurement) (2 mg/kg, 4 M); [8] single low dose (EPA basic test) (2 mg/kg, 4 M); [9] single low dose (2 mg/kg, 4 F); [10] 14 daily doses with 2 mg/kg/day non-radioactive a.i., then 1 labeled low dose (2 mg/kg, 4 M); and [13] single low dose, bile cannulation study (2 mg/kg, 6 M). In low dose groups, about 70% of administered dose was absorbed, with most of the label found in the urine, and about 12% of administered dose found in the bile. In the high dose (100 mg/kg) group, 61% of label was found in feces, vs. 35% in urine, suggesting saturable absorption at high dose levels. Very little label (0.05% of administered dose) was found in exhaled CO2. Peak plasma concentrations were observed between 2.5 hr to 3.9 hr in low dose groups, vs. 5.6 hr in high dose rats.
This study employed 2 male monkeys, each dosed with about 0.2 mg/kg spirodiclofen in a single treatment. The iv treatment was prepared as a PEG 200 solution in water, and the dermal treatment was a suspension of fine spirodiclofen crystals in water. The patch for the dermal treatment was removed after 8 hr, after which the application area was washed with 1% Ivory detergent solution followed by tape stripping and alcohol swab wiping. Monkeys were maintained in metabolism cages after dosing (except that the first 8 hr after the iv treatment was spent in a primate chair). Following iv dosing, urinary excretion was rapid: 64% of administered dose was obtained in urine within the first 8 hr, with an additional 18% in the next 16 hr. A total of 87% of dose was obtained in urine, and an additional 15% in cage debris/rinse (attributed primarily to urine). About 5% of administered dose was found in feces in the iv test. Measured recovery was slightly more than theoretical. Following dermal treatment, 1.1% of administered dose was found in urine, 0.3% in cage wash, and 0.2% in feces. Most of the dermally administered dose was found in the detergent swab process. An additional 9% was found in the patch or containment dome, and 10% was obtained with the alcohol swab step. Thus the dermal response from this one subject suggested only about 1.6% total absorption.
This study employed 5 male monkeys, each dosed dermally with an average of 0.04 mg/kg spirodiclofen as the SC 240 formulation in a single treatment, considered to represent a plausible field exposure level. About 2.0% of administered dose was recovered in urine plus cage rinse and other collected label attributed to urine. About 0.1% of administered dose was found in feces. Most of the material balance was found in skin wash soap swabs or ethanol extracts of the swabs (>74% of administered dose), plus small additional amounts in the patch, patch securing materials, tape strips, and alcohol swabs. Thus absorption was determined to be about 2.1% of administered dose.
Section 1. IDENTIFICATION OF THE SUBSTANCE/MIXTURE Product identifiers Product name : Spirodiclofen CAS-No. : 148477-71-8 Relevant identified uses of the substance or mixture and uses advised against Identified uses : Laboratory chemicals, Manufacture of substances Section 2. HAZARDS IDENTIFICATION Classification of the substance or mixture Classification according to Regulation (EC) No 1272/2008 [EU-GHS/CLP] Skin sensitization (Category 1) Classification according to EU Directives 67/548/EEC or 1999/45/EC May cause sensitization by skin contact. Label elements Labelling according Regulation (EC) No 1272/2008 [CLP] Pictogram Signal word Warning Hazard statement(s) H317 May cause an allergic skin reaction. Precautionary statement(s) P280 Wear protective gloves. Supplemental Hazard none Statements According to European Directive 67/548/EEC as amended. Hazard symbol(s) R-phrase(s) R43 May cause sensitization by skin contact. S-phrase(s) S36/37 Wear suitable protective clothing and gloves. Caution - substance not yet tested completely. Other hazards - none Section 3. COMPOSITION/INFORMATION ON INGREDIENTS Substances Formula : C21H24Cl2O4 Molecular Weight : 411,32 g/mol Component Concentration Butanoic acid, 2,2-dimethyl-, 3-(2,4-dichlorophenyl)-2-oxo-1-oxaspiro(4.5)dec-3-en-4-yl ester CAS-No. 148477-71-8 - Section 4. FIRST AID MEASURES Description of first aid measures General advice Consult a physician. Show this safety data sheet to the doctor in attendance. If inhaled If breathed in, move person into fresh air. If not breathing, give artificial respiration. Consult a physician. In case of skin contact Wash off with soap and plenty of water. Consult a physician. In case of eye contact Flush eyes with water as a precaution. If swallowed Never give anything by mouth to an unconscious person. Rinse mouth with water. Consult a physician. Most important symptoms and effects, both acute and delayed Indication of any immediate medical attention and special treatment needed no data available Section 5. FIREFIGHTING MEASURES Extinguishing media Suitable extinguishing media Use water spray, alcohol-resistant foam, dry chemical or carbon dioxide. Special hazards arising from the substance or mixture Carbon oxides, Hydrogen chloride gas Advice for firefighters Wear self contained breathing apparatus for fire fighting if necessary. Further information no data available Section 6. ACCIDENTAL RELEASE MEASURES Personal precautions, protective equipment and emergency procedures Use personal protective equipment. Avoid dust formation. Avoid breathing vapors, mist or gas. Ensure adequate ventilation. Avoid breathing dust. Environmental precautions Prevent further leakage or spillage if safe to do so. Do not let product enter drains. Discharge into the environment must be avoided. Methods and materials for containment and cleaning up Pick up and arrange disposal without creating dust. Sweep up and shovel. Keep in suitable, closed containers for disposal. Reference to other sections For disposal see section 13. Section 7. HANDLING AND STORAGE Precautions for safe handling Avoid contact with skin and eyes. Avoid formation of dust and aerosols. Provide appropriate exhaust ventilation at places where dust is formed.Normal measures for preventive fire protection. Conditions for safe storage, including any incompatibilities Store in cool place. Keep container tightly closed in a dry and well-ventilated place. Specific end uses no data available Section 8. EXPOSURE CONTROLS/PERSONAL PROTECTION Control parameters Components with workplace control parameters Exposure controls Appropriate engineering controls Handle in accordance with good industrial hygiene and safety practice. Wash hands before breaks and at the end of workday. Personal protective equipment Eye/face protection Face shield and safety glasses Use equipment for eye protection tested and approved under appropriate government standards such as NIOSH (US) or EN 166(EU). Skin protection Handle with gloves. Gloves must be inspected prior to use. Use proper glove removal technique (without touching glove's outer surface) to avoid skin contact with this product. Dispose of contaminated gloves after use in accordance with applicable laws and good laboratory practices. Wash and dry hands. The selected protective gloves have to satisfy the specifications of EU Directive 89/686/EEC and the standard EN 374 derived from it. Body Protection Complete suit protecting against chemicals, The type of protective equipment must be selected according to the concentration and amount of the dangerous substance at the specific workplace. Respiratory protection For nuisance exposures use type P95 (US) or type P1 (EU EN 143) particle respirator.For higher level protection use type OV/AG/P99 (US) or type ABEK-P2 (EU EN 143) respirator cartridges. Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU). Section 9. PHYSICAL AND CHEMICAL PROPERTIES Information on basic physical and chemical properties a) Appearance Form: powder b) Odour no data available c) Odour Threshold no data available d) pH 4 at 100 g/l e) Melting point/freezing no data available point f) Initial boiling point and no data available boiling range g) Flash point no data available h) Evaporation rate no data available i) Flammability (solid, gas) no data available j) Upper/lower no data available flammability or explosive limits k) Vapour pressure no data available l) Vapour density no data available m) Relative density no data available n) Water solubility insoluble o) Partition coefficient: n- log Pow: 5,8 at 20 °C octanol/water p) Autoignition no data available temperature q) Decomposition no data available temperature r) Viscosity no data available s) Explosive properties no data available t) Oxidizing properties no data available Other safety information no data available Section 10. STABILITY AND REACTIVITY Reactivity no data available Chemical stability no data available Possibility of hazardous reactions no data available Conditions to avoid no data available Incompatible materials no data available Hazardous decomposition products Other decomposition products - no data available Section 11. TOXICOLOGICAL INFORMATION Information on toxicological effects Acute toxicity LD50 Oral - rat - > 2.500 mg/kg LD50 Dermal - rat - > 2.000 mg/kg Skin corrosion/irritation Skin - rabbit - No skin irritation Serious eye damage/eye irritation Eyes - rabbit - No eye irritation Respiratory or skin sensitization May cause sensitization by skin contact. Germ cell mutagenicity Genotoxicity in vitro - Ames test - Not mutagenic in Ames Test. Carcinogenicity IARC: No component of this product present at levels greater than or equal to 0.1% is identified as probable, possible or confirmed human carcinogen by IARC. Reproductive toxicity no data available Specific target organ toxicity - single exposure no data available Specific target organ toxicity - repeated exposure no data available Aspiration hazard no data available Potential health effects Inhalation May be harmful if inhaled. May cause respiratory tract irritation. Ingestion May be harmful if swallowed. Skin May be harmful if absorbed through skin. May cause skin irritation. Eyes May cause eye irritation. Additional Information RTECS: Not available Section 12. ECOLOGICAL INFORMATION Toxicity Toxicity to fish LC0 - Lepomis macrochirus (Bluegill) - > 0,045 mg/l - 96 h Persistence and degradability no data available Bioaccumulative potential no data available Mobility in soil no data available Results of PBT and vPvB assessment no data available Other adverse effects no data available Section 13. DISPOSAL CONSIDERATIONS Waste treatment methods Product Offer surplus and non-recyclable solutions to a licensed disposal company. Contact a licensed professional waste disposal service to dispose of this material. Dissolve or mix the material with a combustible solvent and burn in a chemical incinerator equipped with an afterburner and scrubber. Contaminated packaging Dispose of as unused product. Section 14. TRANSPORT INFORMATION UN number ADR/RID: - IMDG: - IATA: - UN proper shipping name ADR/RID: Not dangerous goods IMDG: Not dangerous goods IATA: Not dangerous goods Transport hazard class(es) ADR/RID: - IMDG: - IATA: - Packaging group ADR/RID: - IMDG: - IATA: - Environmental hazards ADR/RID: no IMDG Marine pollutant: no IATA: no Special precautions for user no data available SECTION 15 - REGULATORY INFORMATION N/A
[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.
