In ... studies with enzyme prepn from arthrobacter specie, 2,4-D was converted to 2,4-D phenol & glyoxylate. Condensation of the two glyoxylate molecules occurred with loss of CO2 from one carboxyl group. A cmpd chromatographically identical to alanine was observed. With ring-labeled 2,4-D, labeled succinate was produced.
2,4-D esters are hydrolyzed in animals. The phenoxy acids are excreted predominantly as such in the urine of rats after their oral admin, although minor portion is conjugated with amino acids glycine & taurine & with glucuronic acid.
Soybean root callus cultures metabolized 2,4-D. Metabolites identified included 2,4-D-glutamic acid & 2,4-D-aspartic acid conjugates; other not identified 2,4-D amino acid conjugates; 2,5-dichloro-4-hydroxyphenoxyacetic acid (4-OH-2,5-D); and 5-OH-2,4-D ... in a comparison of 2,4-D metabolism by soybean callus, soybean plant and corn plants, no qualitative differences were observed. Hydroxy cmpd, mainly as glucosides, were identified as 5-OH-2,4-D, 4-OH-2,3-D, and 4-OH-2,5-D. Amino acid conjugates were identified as 2,4-D conjugates of aspartic acid, glutamic acid, alanine, valine, phenylalanine, tryptophan and leucine. There were some data that suggested the presence of amino acid conjugates of ring hydroxylated 2,4-D. /SRP: unspecified salt or ester of 2,4-D/
Male volunteers ingested single dose of 5 mg/kg. Excretion occurred mainly as 2,4-D (82.3%) with smaller amt as 2,4-D conjugate (12.8%). /SRP: unspecified salt or ester of 2,4-D/
Metabolism of 2,4-D is minimal in humans, with nearly all of it excreted unchanged as the parent compound. In particular, 2,4-D is rapidly excreted from the body, primarily in the urine. Much of the compound appears to be eliminated unchanged, although some 2,4-D is eliminated from the body as a conjugate. 2,4-D is metabolized to 2,4-dichlorophenol (2,4-DCP) by cytochrome P450 3A4 (CYP 3A4), the major form of monooxygenase enzyme in the human liver.
IDENTIFICATION AND USE: 2,4-Dichlorophenoxyacetic acid (2,4-D) is an herbicide. It is a white powder with a slightly phenolic odor. It is soluble in water and the ester products of 2,4-D vary in solubility in water. It is used as a solid alkali salt concentrate or as a salt based water miscible solution or as an ester based emulsifiable concentrate; also used in mixtures with other herbicides. It is a component of Agent Orange, a military defoliant. It is used to control broad leaved weeds in cereals, grain crops, road sides and farm buildings and to increase latex output of old rubber trees. HUMAN EXPOSURE AND USE: 2,4-D may be absorbed from the gastrointestinal tract, by inhalation and to a lesser extent by the intact skin. Observations were made on 220 men exposed from 0.5 to 22 years of 2,4-D in a manufacturing plant. Medical evaluation revealed no difference when compared to a control group of 4600 men. In the exposed group, 10 men were karyotyped. There was no effect on the structural integrity or arrangement of the genetic material of the lymphocyte chromosomes. However, in an in vitro study, 2,4-D both in the presence and in the absence of the metabolic activator caused an increase in chromatid and chromosome breaks, number of micronuclei and number of nuclear buds. Presence of the S9 mix additionally elevated the number of chromatid breaks and micronuclei in treated lymphocytes. Signs and symptoms reported among workers at a plant manufacturing the amine salt and butyl ester included general weakness, rapid fatigue, frequent headache and vertigo. Cases of arterial hypotension were noted. There were possible indications of liver dysfunction which was noted in workers with long exposure to herbicides. In two groups of agricultural workers, 250 and 45 people respectively, excessive fatigue, epigastric pains, anorexia and occasional respiratory tract symptoms, and impaired taste sensitivity were reported. Reported cases of poisoning have been mainly the result of accidental or suicidal ingestion. Peripheral neuropathy has been reported along with contact dermatitis. ANIMAL STUDIES: It may be absorbed by the gastrointestinal tract, by inhalation or through intact skin. Studies in vivo on liver mitochondria have demonstrated that this herbicide uncouples oxidative phosphorylation at low concentrations. Young female rats were given various doses of 2,4-D orally by stomach tube five times a week for up to four weeks. At higher doses animals showed varying degrees of gastrointestinal irritation, slight cloudy swelling of the liver and depressed growth rate. High doses mortality was elevated due to severe gastrointestinal irritation. Accumulation of effect may occur in the form of liver or kidney damage but no clear cut biochemical lesion associated with prolonged exposure. Female rats were fed various levels of 2,4-D in their diet for up to two years. There was no significant difference in mortality between test and control groups. At autopsy of those animals who survived for the two year period there was no difference in body weight and hematological parameters were normal except in the final examination after 22 months revealed a possible tendency to macrocytosis, polychromasia and hypochromasia. Bile duct proliferation, slight hepatitis and nephritis occurred slightly more in test animals rather than controls. 2,4,-D is not considered a carcinogen. In a two year feeding study in rats there was a slight increase in tumor incidence in female rats, however the raw data did not show enough evidence to determine if 2,4-D is carcinogenic. In a number of developmental experiments in which rats, guinea pigs, hamsters and mice received high doses of 2,4-D there appeared to be an increased incidence of minor skeletal abnormalities. 2,4-D was also maternally toxic and embryolethal in rats, and it induced urogenital malformations in rat fetuses. The agent was also teratogenic and embryotoxic in mice. ECOTOXICITY STUDIES: Crayfish was exposed to three sublethal levels of 2,4-D for 96 hr and placed into a Y-maze system with a fish gelatin food source placed randomly in the right or left arm were impaired in their ability to forage effectively. These inabilities to locate and consume adequate amounts of food could result in lower body weights and decreased fitness in populations of crayfish exposed to 2,4-D in natural habitats. A mixture of 2,4-D and monosodium methanearsonate may compromise gill function, increasing the sensitivity of the crawfish to herbicide toxicity.
2,4-Dichlorophenoxyacetic acid is a strong oxidant and is known to cause lipid peroxidation and the generation of free radicals that can modify lipids and proteins. It is also known to inhibit glutathione S transferase which leads to a depletion of ATP, NADPH and glutathione (A3122, A3123). These actions can cause cell toxicity and apopotosis among metabolically active cells. Some of the endocrine effects of 2,4-D may be mediated by the 2,4-D mediated displacement of sex hormones from the sex hormone binding globulin or the 2,4-D mediated blocking or OAT6 transport proteins that are needed for the transport of functional organic ions and dicarboxylates (including estrone sulfate).
来源:Toxin and Toxin Target Database (T3DB)
毒理性
致癌性证据
癌症分类：D组 不可归入人类致癌性类别
Cancer Classification: Group D Not Classifiable as to Human Carcinogenicity
Classification of carcinogenicity: 1) evidence in humans: limited; overall summary evaluation of carcinogenic risk to humans is Group 2B: The agent is possibly carcinogenic to humans. /SRP: The older literature indicated that these compounds were carcinogenic. It was discovered that this was due to contamination, including dioxin./ /Chlorophenoxy herbicides; From table/
Life-stage-dependent toxicity and dose-dependent toxicokinetics (TK) were evaluated in Sprague Dawley rats following dietary exposure to 2,4-dichlorophenoxyacetic acid (2,4-D). 2,4-D renal clearance is impacted by dose-dependent saturation of the renal organic anion transporter; thus, this study focused on identifying inflection points of onset of dietary nonlinear TK to inform dose selection decisions for toxicity studies. Male and female rats were fed 2,4-D-fortified diets at doses to 1600 ppm for 4-weeks premating, <2 weeks during mating, and to test day (TD) 71 to parental (P1) males and to P1 females through gestation/lactation to TD 96. F1 offspring were exposed via milk with continuing diet exposure until postnatal day (PND) 35. As assessed by plasma area under the curve for the time-course plasma concentration, nonlinear TK was observed > or = 1200 ppm (63 mg/kg/day) for P1 males and between 200 and 400 ppm (14-27 mg/kg/day) for P1 females. Dam milk and pup plasma levels were higher on lactation day (LD) 14 than LD 4. Relative to P1 adults, 2,4-D levels were higher in dams during late gestation/lactation and postweaning pups (PND 21-35) and coincided with elevated intake of diet/kg body weight. Using conventional maximum tolerated dose (MTD) criteria based on body weight changes for dose selection would have resulted in excessive top doses approximately 2-fold higher than those identified incorporating critical TK data. These data indicate that demonstration of nonlinear TK, if present at dose levels substantially above real-world human exposures, is a key dose selection consideration for improving the human relevance of toxicity studies compared with studies employing conventional MTD dose selection strategies.
Distribution of 2,4-D occurs throughout the body, but there is no evidence that it is accumulated. Transformation in mammals appears to occur only to a slight extent & mainly involves the production of 2,4-D conjugates with sugars or amino acids. A single dose is excreted within a few days, mainly with the urine, & to a much lesser extent in the bile & feces.
Pretreatment of rats with 2,4-D (250 mg/kg, sc) so occupied binding sites on plasma proteins that the distribution of (14)C-2,4-D admin iv 3.5 to 4.5 hr later was changed relative to controls, the concn being less in the plasma & kidney & greater in the liver, brain, spinal fluid, testis, lung, heart, & muscle.
... Human beings excrete 2,4-D mainly in the urine, & the blood plasma clearance times depend on the dose, individual characteristics, & the presence or absence of cmpds that may competitively inhibit 2,4-D excretion. For single oral doses of 2,4-D, the biological half-life in blood plasma is about one day, depending on the circumstances. However, forced alkaline diuresis may reduce this to as little as 3.7 hr.
1.周国泰，化学危险品安全技术全书，化学工业出版社，1997 2.国家环保局有毒化学品管理办公室、北京化工研究院合编，化学品毒性法规环境数据手册，中国环境科学出版社.1992 3.Canadian Centre for Occupational Health and Safety,CHEMINFO Database.1998 4.Canadian Centre for Occupational Health and Safety, RTECS Database, 1989
设计并合成了一系列芳氧基乙酸衍生物，作为4-羟基苯基丙酮酸双加氧酶（HPPD）抑制剂。初步的生物测定结果表明，这些衍生物是有前途的拟南芥HPPD（At HPPD）抑制剂，特别是化合物I12（K i = 0.011 µM）和I23（K i = 0.012 µM），其活性与市售甲基磺草酮相似。 HPPD除草剂（K i = 0.013 µM）。此外，新合成的化合物在150 g ai / ha的剂量下对被测杂草显示出显着的温室除草活性。特别是II4在芽前处理中表现出较高的除草活性，略高于甲基磺草酮。此外，化合物II4对于玉米田中150 g ai / ha的杂草防治是安全的，并且被确定为新型HPPD抑制剂除草剂的最有效候选者。本文所述的化合物可为设计新的抑制HPPD的除草剂及其修饰提供有用的指导。
[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.
The present invention provides triazole compounds useful as inhibitors of Acetyl CoA Carboxylase (ACC), compositions thereof, and methods of using the same.
Photodecarboxylative Amination of Redox-Active Esters with Diazirines
作者：Vishala Maharaj、Preeti P. Chandrachud、Wen Che、Lukasz Wojtas、Justin M. Lopchuk
DOI：10.1021/acs.orglett.1c03344
日期：2021.11.19
Diazirines have been recently demonstrated to serve as electrophilic amination reagents that afford diaziridines, versatile heterocycles that are readily transformed into amines, hydrazines, and nitrogen-containing heterocycles. Here, we report the photodecarboxylative amination of redox-active esters with diazirines using inexpensive photoactivators under mild conditions with an enhanced scope for
Derivatives of phenyl tribromomethyl sulfone as novel compounds with potential pesticidal activity
作者：Krzysztof M Borys、Maciej D Korzyński、Zbigniew Ochal
DOI：10.3762/bjoc.8.27
日期：——
and fungicides. The synthesis of tribromomethyl phenyl sulfone derivatives as novel potential pesticides is reported. The title sulfone was obtained by following three different synthetic routes, starting from 4-chlorothiophenol or 4-halogenphenyl methyl sulfone. Products of its subsequent nitration were subjected to the S(N)Ar reactions with ammonia, amines, hydrazines and phenolates to give 2-nitroaniline
Studies on Fused β-Lactams: Synthesis of 1-Aza Analogs of Cephem
作者：S. D. Sharma、Verinder Kaur、Punita Bhutani、J. P. S. Khurana
DOI：10.1246/bcsj.65.2246
日期：1992.8
Annelation of 2-methylthio-3,4-dihydropyrimidine (3) with two moles of phenoxyacetyl chloride in presence of triethylamine did not yield the expected β-lactam (6) and instead the N-acylated compound 5a was obtained. Various N-acylated pyrimidines 5a–d also failed to yield any β-lactam. However, β-lactam ring has been conveniently grafted on to 2-methylthio-3,6-dihydropyrimidines 9a–d, 12 by annelating them with in situ prepared aryloxyketenes to furnish novel 1-aza analogs of cephem 10a–e and 13.
