The plant and soil oxalamide (M23) and sulfonate (M27) metabolites of racemic dimethenamid, which also occur as products of metabolism in rats, were tested in studies of acute oral toxicity, assays for mutagenicity in bacteria and for micronucleus formation in bone-marrow cells of mice. Both compounds had low acute oral toxicity with LD50 values of > 5000 mg/kg bw. Neither compound was mutagenic in bacteria or induced micronucleus formation in bone-marrow cells of mice.
Racemic dimethenamid is rapidly and extensively metabolized. Only 1-2% of unchanged racemic dimethenamid was detected in excreta. About 40 metabolites were found in organic extracts that were analyzed by TLC. About 20 metabolites were identified. Metabolism occurred primarily via the glutathione conjugation pathways. Racemic dimethenamid was rapidly conjugated with glutathione and then passed through several steps to form cysteine conjugate (M25) and mercapturate (M17). M25 was further oxidized to form additional metabolites (M1, M2, M10, M13, M14, M16, M18, M19, M21, M22, M26, M27, M30, and M31). Although the glutathione adduct was not found in the study in rats, it was identified in the study in vitro. Other metabolites qualitatively identified in the study in vitro included the cysteine conjugate (M25), the mercapturate (M17), the sulfonate (M27), the sulfoxide of thiolactic acid (M30), the sulfoxide of thioglycolic acid (M31), and the thioglycolic acid (M30). Racemic dimethenamid was also metabolized by reductive dechlorination (M3), oxidation (M4, M23), hydroxylation (M5, M11, M15), O-demethylation (M7, M12) and cyclization (M6, M8, M9, M15, M20). In another supplementary study, metabolites found on maize, the sulfonate (M27) (0.025-0.030%) and sulfoxide of thioglycolic acid (M31) (0.002-0.007%), were identified in rat urine. These metabolites have also been identified in mouse urine.
Metabolism /in rats/ was primarily via the glutathione conjugation pathway, but racemic dimethenamid was also metabolized by cytochrome P450 enzymes via reductive dechlorination, oxidation, hydroxylation, O-demethylation, and cyclization pathways, as well as conjugation with glucuronic acid. Unchanged dimethenamid in excreta accounted for only 1-2% of the administered dose, more than 40 metabolites having been detected. At least 20 of these metabolites were structurally identified by mass spectrometry and nuclear magnetic resonance, and confirmed by reference to synthesized standards. There was no significant difference in metabolism between the sexes.
IDENTIFICATION AND USE: Dimethenamid is a herbicide and a racemic mixture of the M (or R) and P (or S) stereoisomers. When this compound was originally registered in various countries, all studies of toxicity were conducted with the racemic mixture. Later, it was discovered that only the P (or S) enantiomer has useful herbicidal activity. HUMAN STUDIES: In 50 people handling racemic dimethenamid and its formulated products over 7 years there were no reported cases of skin irritation or other adverse health effects. Dimethenamid did not increase sister chromatid exchange frequency in cultured human lymphocytes. ANIMAL STUDIES: In short-term studies with racemic dimethenamid, the signs of toxicity observed in mice, rats and dogs were similar, with reduced body-weight gain and liver enlargement being common features. Histopathology confirmed the liver as a target organ with observation of hypertrophy of hepatocytes. In addition, however, vacuolization of hepatocytes and dilatation of liver sinusoids occurred in dogs. Long-term feeding studies with racemic dimethenamid in rats and mice demonstrated that the primary target organ was the liver. There was no evidence for a carcinogenic potential in these studies. Apart from an equivocal result in one of three assays for unscheduled DNA synthesis in vitro with racemic dimethenamid, none of the other genotoxicity assays gave any indication that racemic dimethenamid might be genotoxic. The reproductive toxicity of racemic dimethenamid was investigated in a two-generation study in rats and in a study of developmental toxicity in rabbits. Reproductive function was not affected in rats in the two-generation study of racemic dimethenamid. In a study of developmental toxicity, rats were given racemic dimethenamid at doses of up to 425 mg/kg bw per day. Signs of maternal toxicity that were recorded included excess salivation at 215 mg/kg bw per day and 425 mg/kg bw per day, and urine-stained abdominal fur at 425 mg/kg bw per day. Fetal body weights were reduced and the frequency of early deaths was increased at doses of 215 mg/kg bw per day and 425 mg/kg bw. In a study of developmental toxicity in rabbits given racemic dimethenamid at doses of up to 150 mg/kg bw per day, significant maternal toxicity (body-weight loss preceded by reduced food consumption and associated with dry feces) was observed at the highest dose and less severe effects were noted at 75 mg/kg bw per day. Abortions in two rabbits at 150 mg/kg bw per day were considered to be treatment-related, but secondary to the clear maternal toxicity. ECOTOXICITY STUDIES: In minnow larvae, exposure to river water containing a mixture of pesticides including dimethenamid, upregulated androgen receptor gene expression whereas exposure to the sediment downregulated estrogen receptor a expression. Adult males previously exposed to both water and sediment were feminized through the induction of an ovipositor structure whereas no impacts were observed in other reproductive or sex characteristic endpoints for either sex based on exposure history. Dimethenamid induced significant modifications of the phytoplankton populations,
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).
The first elongation step to form very-long-chain fatty acids (VLCFAs) is catalyzed by the VLCFA-synthase. CoA-activated fatty acids react with malonyl-CoA to condense a C2-unit. As shown with recombinant enzyme this reaction is specifically inhibited by chloroacetamide herbicides. The inhibition is alleviated when the inhibitor (e.g. metazachlor) is incubated together with adequate concentrations of the substrate (e.g. oleoyl-CoA). Malonyl-CoA has no influence. However, once a chloroacetamide has been tightly bound to the synthase after an appropriate time it cannot be displaced anymore by the substrate. In contrast, oleoyl-CoA, is easily removed from the synthase by metazachlor. The irreversible binding of the chloroacetamides and their competition with the substrate explains the very low half-inhibition values of 10(-8) M and below. Chiral chloroacetamides like metolachlor or dimethenamid give identical results. However, only the (S)-enantiomers are active.
/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 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/
Racemic dimethenamid was well absorbed after oral administration in rats, as demonstrated by addition of the amount of radioactivity excreted in the urine, via the bile duct and that remaining in the organs and carcass. Biliary excretion accounted for 75-82% of the radiolabelled carbon, with an additional 2-4% being found in the feces and 8-12% in the urine. The total excretion by bile and urine for males was 89.8% and for females was 87.5%. After adding the amount of radioactivity found in the carcass, the total absorption after oral administration was 94.5% in males and 92.8% in females; therefore, essentially 100%. Excretion was very rapid primarily in the bile. Within 7 hr, 45-64% of the orally administered dose was excreted in bile of the cannulated rats. By 168 hr after treatment, an average of 90% of the administered dose was eliminated by all routes. There were some dose-dependent differences in the pattern of excretion. At the lower dose (10 mg/kg bw), urinary radiocarbon accounted for 35-47% of the administered dose compared with 62-63% at the higher dose (1000 mg/kg bw). Radioactivity in feces was 48-58% for groups at the lower dose compared with 26-30% at the higher dose. These data indicated that biliary excretion might be saturated for the group at the higher dose, resulting in more radioactivity being eliminated via the kidney.
The concentration of radioactivity in the blood decreased slowly over the experimental period of 168 hr. Half-lives of elimination from blood were 255 +/-79 hr and 334 +/-192 hr for male and female rats, respectively. The radioactivity was mainly associated with erythrocytes (the concentration of radioactivity in the plasma being much lower). A similar binding phenomenon was not observed in human blood; this can be explained by differences between rat and human hemoglobins. After a single oral lower dose (10 mg/kg bw) the maximum concentration of blood radioactivity was reached at about 72 hr after administration (0.05 ug of test material/g blood in males and 0.1 ug of test material/g blood in females). Afterwards, radioactivity decreased slowly. For the oral high dose, the maximum blood radioactivity was also reached at 72 hr, but did not significantly decrease between 72 and 168 hr. In general, tissue concentrations of radioactivity were similar in both sexes, and the pattern of absorption, distribution and elimination after oral administration was similar. Radioactivity concentrations were higher at 1-4 hr in adrenals, pancreas, kidney, spleen, liver and blood. Residue concentrations decreased steadily over time, with the exception of blood. Overall, tissue concentrations were low by 168 hr after treatment. For the rats treated at the lower dose, the concentration was < 0.5 ppm in all organs and tissues. After oral administration, it appeared that there was no significant difference in the absorption, distribution, and elimination of racemic dimethenamid in males and females. There was only a slight difference in the rate of elimination of radiocarbon between single and multiple doses. Residue concentrations in tissues were similar for groups given single or multiple doses, indicating that racemic dimethenamid and its metabolites had no tendency to accumulate in rat tissues.
The rates of dermal penetration of racemic [(14)C]dimethenamid through human and rat skin were compared in vitro. After correcting for the difference in skin thickness, the rate of penetration through human skin is three to seven times less than that through rat skin. However, saturation has occurred at the highest dose in the rat skin, as the penetration rate no longer continues to increase linearly with dose. The predicted exposure of workers involved in the mixing, loading and application of racemic dimethenamid is at most 0.4 mg/sq cm. Therefore, the comparative values for rat/human skin at the lower doses is considered to be more appropriate for use in predicting human exposure. Overall the rate of dermal penetration of racemic dimethenamid in humans is predicted to be approximately 4%.
The pharmacokinetic studies indicated that dimethenamid may bind to blood components in rats. This was based on 3% of the radiolabeled material administered remaining in the blood fraction. Therefore, the nature of the interaction between dimethenamid and rat blood was investigated. The results of the study showed that dimethenamid did not produce methemoglobin in rat blood following a four day treatment. Dimethenamid was shown to bind to rat hemoglobin, primarily to the globin portion, but no binding was demonstrated using human blood. The difference in hemoglobin binding between humans and rats is explained by the difference in three dimensional structure between the 2 species. It is known from the literature that the cysteine residue beta-125 in rat hemoglobin is accessible for chemical substitution, but in human hemoglobin, the sequence does not contain a cysteine residue in position 125. In summary, it can be concluded that the interaction between dimethenamid and hemoglobin is a species-specific reaction. This binding is irrelevant for humans.
[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] 3-[(HYDRAZONO)METHYL]-N-(TETRAZOL-5-YL)-BENZAMIDE AND 3-[(HYDRAZONO)METHYL]-N-(1,3,4-OXADIAZOL-2-YL)-BENZAMIDE DERIVATIVES AS HERBICIDES<br/>[FR] DÉRIVÉS DE 3-[(HYDRAZONO))MÉTHYL]-N-(TÉTRAZOL-5-YL)-BENZAMIDE ET DE 3-[(HYDRAZONO)MÉTHYL]-N-(1,3,4-OXADIAZOL-2-YL)-BENZAMIDE UTILISÉS EN TANT QU'HERBICIDES
申请人：SYNGENTA CROP PROTECTION AG
公开号：WO2021013969A1
公开（公告）日：2021-01-28
The present invention related to compounds of Formula (I): or an agronomically acceptable salt thereof, wherein Q, R2, R3, R4, R5 and R6 are as described herein. The invention further relates to compositions comprising said compounds, to methods of controlling weeds using said compositions, and to the use of compounds of Formula (I) as a herbicide.
[EN] INSECTICIDAL TRIAZINONE DERIVATIVES<br/>[FR] DÉRIVÉS DE TRIAZINONE INSECTICIDES
申请人：SYNGENTA PARTICIPATIONS AG
公开号：WO2013079350A1
公开（公告）日：2013-06-06
Compounds of the formula (I) or (I'), wherein the substituents are as defined in claim 1, are useful as pesticides.
式(I)或(I')的化合物，其中取代基如权利要求1所定义的那样，可用作杀虫剂。
[EN] HERBICIDALLY ACTIVE HETEROARYL-S?BSTIT?TED CYCLIC DIONES OR DERIVATIVES THEREOF<br/>[FR] DIONES CYCLIQUES SUBSTITUÉES PAR HÉTÉROARYLE À ACTIVITÉ HERBICIDE OU DÉRIVÉS DE CELLES-CI
申请人：SYNGENTA LTD
公开号：WO2011012862A1
公开（公告）日：2011-02-03
The invention relates to a compound of formula (I), which is suitable for use as a herbicide wherein G is hydrogen or an agriculturally acceptable metal, sulfonium, ammonium or latentiating group; Q is a unsubstituted or substituted C3-C8 saturated or mono-unsaturated heterocyclyl containing at least one heteroatom selected from O, N and S, or Q is heteroaryl or substituted heteroaryl; m is 1, 2 or 3; and Het is an optionally substituted monocyclic or bicyclic heteroaromatic ring; and wherein the compound is optionally an agronomically acceptable salt thereof.
The present invention provides triazole compounds useful as inhibitors of Acetyl CoA Carboxylase (ACC), compositions thereof, and methods of using the same.
