{2-[6-(2-氯苯氧基)-5-氟嘧啶-4-基氧]苯基}(5,6-二氢-1,4,2-二噁嗪-3-基)甲酮O-甲基肟 | 887973-21-9

• 分子结构分类: 有机化合物 - 有机氧化合物
• 中文名称: {2-[6-(2-氯苯氧基)-5-氟嘧啶-4-基氧]苯基}(5,6-二氢-1,4,2-二噁嗪-3-基)甲酮O-甲基肟
• 中文别名: 氟嘧菌酯
• 英文名称: (Z)-(2-((6-(2-chlorophenoxy)-5-fluoropyrimidin-4-yl)oxy)phenyl)(5,6-dihydro-1,4,2-dioxazin-3-yl)methanone O-methyl oxime
• 英文别名: fluoxastrobin；(Z)-fluoxastrobin；Fluoxastrobin, (Z)-；(Z)-1-[2-[6-(2-chlorophenoxy)-5-fluoropyrimidin-4-yl]oxyphenyl]-1-(5,6-dihydro-1,4,2-dioxazin-3-yl)-N-methoxymethanimine
• CAS: 887973-21-9；193740-76-0；361377-29-9
• 化学式: C₂₁H₁₆ClFN₄O₅
• 分子量: 458.833
• InChiKey: UFEODZBUAFNAEU-ITYLOYPMSA-N

物化性质

• 沸点：
  497.3±55.0 °C(Predicted)
• 密度：
  1.43
• 颜色/状态：
  White crystalline solid
• 气味：
  Weak
• 熔点：
  103-108 °C
• 溶解度：
  Solubilities (20 °C, g/L): dichloromethane >250; xylene 38.1; isopropanol 6.7; n-heptane 0.04
• 蒸汽压力：
  6X10-7 mPa at 20 °C (extrapolated) /4.5X10-12 mm Hg at 20 °C/

计算性质

• 辛醇/水分配系数(LogP)：
  5.1
• 重原子数：
  32
• 可旋转键数：
  7
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.14
• 拓扑面积：
  96.6
• 氢给体数：
  0
• 氢受体数：
  10

ADMET

代谢

研究了(氯苯基-UL-(14)C)氟嘧菌胺或(甲氧基肟基甲苯基-UL-(14)C)氟嘧菌胺在蛋鸡体内的代谢。测试物质通过口服方式给予六只蛋鸡，每日一次，连续三天，剂量水平分别为187 ppm和198 ppm，分别代表实际使用率的75,000倍和79,000倍。在鸡蛋、脂肪和肌肉中发现了氟嘧菌胺及其Z-异构体作为主要残留物（11-48%的测试物质残留比），而在鸡肝中的含量较少（0.31-6.8%的测试物质残留比）。在鸡的商品组织中，代谢物在>10%的测试物质残留比下被鉴定为HEC5725-苯氧基-羟基嘧啶（鸡蛋中25%的测试物质残留比，鸡肝中21%的测试物质残留比，鸡肌肉中35%的测试物质残留比，鸡脂肪中21%的测试物质残留比），HEC5725-2-氯苯酚（在鸡蛋中最高达23%的测试物质残留比，在肝脏中最高达12%的测试物质残留比），以及HEC5725-水杨酸（鸡蛋中12%的测试物质残留比）。根据研究结果，申请人提出氟嘧菌胺在鸡体内的代谢途径包括：(i) 氯苯环的羟基化形成单羟基和二羟基异构体；(ii) 二噁唑环的羟基化随后发生氧化开环和二噁唑环的进一步降解；(iii) 氧化脱甲基化氧肟醚基团并裂解该基团形成酮和醇代谢物；(iv) 嘧啶部分的醚键裂解形成HEC5725-2-氯苯酚或HEC5725-苯氧基-羟基嘧啶，以及甲氧基肟基二噁唑环和甲氧基肟基环的代谢物；以及(v) 羟基团的葡萄糖醛酸化和硫酸化结合。代谢最终导致形成HEC5725-2-氯苯酚，其硫酸结合物，水杨酸，2-羟基扁桃酸，以及HEC5725-酮羧酸。

The metabolism of (chlorophenyl-UL-(14)C)fluoxastrobin or (methoxyiminotolyl-UL-(14)C)fluoxastrobin /was studied/ in laying hens. The test substance was administered orally to six hens at 187 ppm or 198 ppm in the diet once per day for three consecutive days; the dose levels represent exaggeration rates of 75,000x and 79,000x, respectively. Fluoxastrobin and its Z-isomer were found to be major residues in hen eggs, fat, and muscle (11- 48% TRR) but were found in smaller quantities in hen liver (0.31-6.8% TRR). Metabolites identified at >10% TRR in hen commodities were HEC5725-phenoxy-hydroxypyrimidine (eggs at 25% TRR, hen liver at 21% TRR, hen muscle at 35% TRR, and hen fat at 21% TRR), HEC5725-2-chlorophenol (up to 23% TRR in eggs and up to 12% TRR in liver), and HEC5725- salicylic acid (eggs at 12% TRR). Based on the results of the studies, the petitioner proposed that fluoxastrobin is metabolized in hens via: (i) hydroxylation of the chlorophenyl ring to mono- and dihydroxy isomers; (ii) hydroxylation of the dioxazine ring followed by oxidative ring opening and further degradation of the dioxazine ring; (iii) oxidative demethylation of the oximether group and cleavage of this group to the ketone and alcohol metabolites; (iv) cleavage of the ether group in the pyrimidine moiety to HEC5725-2-chlorophenol or HEC5725-phenoxyhydroxy-pyrimidine and methoxyiminotolyl-dioxazine ring and methoxyiminotolyl ring metabolites; and (v) conjugation of the hydroxyl groups to glucuronic acid and sulfate conjugates. The metabolism leads finally to the formation of HEC5725-2-chlorophenol, its sulfate conjugate, salicylic acid, 2-OHmandelic acid, and HEC5725-ketocarboxylic acid.

来源:Hazardous Substances Data Bank (HSDB)

代谢

研究了泌乳期山羊体内(methoxyiminotolyl-ring-UL-(14)C)氟嘧磺隆和(chlorophenyl-UL-(14)C)氟嘧磺隆的代谢。试验物质通过口服方式给予一只山羊，剂量为每天一次，连续三天，分别在饲料中为180 ppm（甲氧基亚氨基酚环标记）或265 ppm（氯苯标记）；这些剂量水平分别代表了15倍和22倍的夸张率。在山羊脂肪中发现了氟嘧磺隆及其Z-异构体作为主要残留物（12-46%的总放射性回收率），但在牛奶、山羊肌肉、肝脏和肾脏中的含量较少（0.31-6.8%的TRR）。在山羊产品中，超过10% TRR的代谢物被鉴定为HEC5725-苯氧基羟基嘧啶（牛奶中为11% TRR，鸡蛋中为25% TRR，山羊肌肉中为53% TRR，山羊肾脏中为25% TRR，山羊脂肪中为29% TRR），HEC5725-2-氰基酚-SA（牛奶中为23% TRR和山羊肾脏中为15%），HEC5725-二氧杂环己烷醇衍生物（山羊肝脏中为16% TRR），HEC5725-二羟基二烯嘧啶-OH（牛奶中为21% TRR）和HEC5725-羟基苯基（山羊肝脏中为11% TRR和山羊脂肪中为13% TRR）。根据山羊代谢研究结果，申请人提出氟嘧磺隆在山羊体内的代谢途径包括：（i）氯苯环的羟基化形成单羟基和二羟基异构体；（ii）氯苯环的双羟基化和还原形成二羟基二烯E-异构体；（iii）二氧杂环己烷环的羟基化，随后是氧化开环和二氧杂环己烷环的进一步降解；（iv）氧醚基团的氧化脱甲基化和裂解形成酮和醇代谢物；（v）嘧啶部分中醚键的裂解形成HEC5725-2-氯苯酚和HEC5725-去氯苯或形成HEC5725-苯氧基羟基嘧啶和HEC5725-去嘧啶；（vi）HEC5725-苯氧基羟基嘧啶的氯苯环的双羟基化和还原形成二羟基二烯E-异构体；（vii）羟基与葡萄糖醛酸和硫酸化合物的结合。

The metabolism of (methoxyiminotolyl-ring-UL-(14)C)fluoxastrobin and (chlorophenyl-UL-(14)C)fluoxastrobin in lactating goats /was investigated/. The test substance was administered orally to a single goat at 180 ppm (methoxyiminotolyl label) or 265 ppm (chlorophenyl label) in the diet once per day for three consecutive days; the dose levels represent exaggeration rates of 15x and 22x, respectively. Fluoxastrobin and its Z-isomer were found to be major residues in goat fat (12-46% TRR) but were found in smaller quantities in milk, goat muscle, liver, and kidney (0.31-6.8% TRR). Metabolites identified at >10% TRR in goat commodities were HEC5725-phenoxyhydroxypyrimidine (milk at 11% TRR, eggs at 25% TRR, goat muscle at 53% TRR, goat kidney at 25% TRR, goat fat at 29% TRR), HEC5725-2-cyanophenol-SA (milk at 23% TRR and goat kidney at 15%), HEC5725-dioxazinyl-alcohol-derivative (goat liver at 16% TRR), HEC5725-di- OH-diene-pyrimidine-OH (milk at 21% TRR), and HEC5725-hydroxyphenyl (goat liver at 11% TRR and goat fat at 13% TRR). Based on the results of the goat metabolism studies, the petitioner proposed that fluoxastrobin is metabolized in goats via: (i) hydroxylation of the chlorophenyl ring to mono- and dihydroxy isomers; (ii) bis hydroxylation and reduction of the chlorophenyl ring to dihydroxy dien E-isomers; (iii) hydroxylation of the dioxazine ring followed by oxidative ring opening and further degradation of the dioxazine ring; (iv) oxidative demethylation of the oximether group and cleavage of this group to the ketone and alcohol metabolites; (v) cleavage of the ether group in the pyrimidine moiety to HEC5725-2-chlorophenol and HEC5725-des-chlorophenyl or to HEC5725-phenoxy-hydroxy-pyrimidine and HEC5725-des-pyrimidine; (vi) bis hydroxylation and reduction of the chlorophenyl ring of HEC5725-phenoxy-hydroxypyrimidine to dihydroxy dien E-isomers; and (vii) conjugation of the hydroxyl groups to glucuronic acid and sulfate compounds.

来源:Hazardous Substances Data Bank (HSDB)

代谢

在一项针对雄性大鼠的研究中，评估了在单次口服剂量1毫克/千克后48小时内，(嘧啶-2-(14)C)HEC 5725(福拉星卓宾；>98%的放射化学纯度，批号KML2621-A)和非放射性HEC 5725(/福拉星卓宾/ 98.8%的化学纯度，批号M00358)的代谢和分布情况。在一项为期168小时的全身自动放射性造影研究中，给予雄性和雌性大鼠单次口服3毫克/千克剂量的(pyrimidine-2-(14)C)HEC 5725(放射化学纯度>99%，批号12216/1)。... (嘧啶-2-(14)C)HEC 5725的代谢物特征研究表明，测试物品被广泛代谢。尿液和粪便中的代谢物占给药剂量的57-61%。在48小时尿液样本中鉴定出约7%的1毫克/千克剂量的8个组分。这些代谢物主要是羟基化/结合产物。尿液中未检测到母化合物。在大便中检测到12种代谢物和母化合物。粪便代谢物主要是羟基化产物，最常见的是HEC 5725-二-OH，异构体2(剂量的11.6%)，HEC5725-二-OH-二氧杂环-OH，异构体2(剂量的9.3%)和HEC5725-E-脱-氯苯基(剂量的7.2%)。所有粪便放射性均可由已鉴定的代谢物和母化合物解释，分别约占给药剂量的54%和1%。其他关于(methoxyiminotolyl-ring-UL-(14)C)HEC 5725的代谢/分布研究...表明，胆汁的贡献构成了大部分粪便放射性，并且测试物品的代谢不是细菌菌群的函数。这些研究结果与提出的代谢途径一致。

A study was conducted in male rats to assess the metabolism and disposition of (pyrimidine-2-(14)C)HEC 5725 (Fluoxastrobin; >98% radiochemical purity, batch no. KML2621-A) and non-radiolabeled HEC 5725 (/Fluoxastrobin/ 98.8% chemical purity, batch no. M00358) over 48 hours following a single oral dose of 1 mg/kg. A whole-body autoradiography study over a 168-hour period was also conducted in male and female rats given a single 3 mg/kg oral dose of (pyrimidine-2-(14)C)HEC 5725 (radiochemical purity >99%, lot no.12216/1). ... Metabolite characterization studies of (pyrimidine-2-(14)C)HEC 5725 indicated that the test article is extensively metabolized. The urinary and fecal metabolites accounted for 57-61% of the administered dose. Eight components, representing about 7% of the 1 mg/kg dose, were identified in the 48-hour urine samples. These metabolites were primarily hydroxylation/ conjugation products. No parent compound was detected in the urine. Twelve metabolites and parent compound were detected in the feces. Fecal metabolites were also primarily hydroxylation products, the most prevalent being HEC 5725-di-OH, isomer 2 (11.6% of the dose), HEC5725-di-OH-dioxazine-OH, isomer 2 (9.3% of the dose), and HEC5725-E-des- chlorophenyl (7.2% of the dose). All fecal radioactivity was accounted for by identified metabolites and parent compound being approximately 54% and 1%, respectively, of the administered dose. Other metabolism/disposition studies on (methoxyiminotolyl-ring-UL-(14)C) HEC 5725 ... have shown that biliary contributions account for most fecal radioactivity and that the metabolism of the test article is not a function of bacterial flora. The results of these studies are consistent with the proposed metabolism pathway.

来源:Hazardous Substances Data Bank (HSDB)

代谢

进行了一项代谢和动力学研究，其中年轻的雄性和雌性Wistar大鼠（每组性别各4只）被给予单次剂量（1毫克/千克或100毫克/千克）的（甲氧基亚胺基甲苯基环-UL-(14)C）HEC5725（Fluoxastrobin；批号11675/1、12250/1和12250/17；>99%的放射化学纯度）。对于多次剂量实验，大鼠连续14天每天通过灌胃给予非标记的HEC5725-E-异构体（批号M00358，98.8%纯度）剂量（1毫克/千克），然后给予单次剂量的放射性标记试验物质。使用另外一组带有胆管插管的12只雄性大鼠评估胆汁排泄。代谢和分布，包括血浆动力学，在给药后72小时内确定。... HEC5725被广泛代谢，这从尿液、粪便和胆汁中的广泛代谢物轮廓以及母体化合物相对缺失（除了给予100毫克/千克剂量的大鼠的粪便中）可以看出。测试组之间或男女之间在代谢物轮廓上没有显著的质量或数量差异。尿液中的代谢物主要是母体化合物第二和第三环之间断裂的结果。胆汁中的代谢物主要是环2、3和4断裂以及随后羟基化、甲氧基化和与葡萄糖醛酸结合的产物。HEC5725-E-去氯苯基和HEC5725-去氯苯基-二噁唑-OH是所有排泄基质中的主要代谢物。一些大鼠的代谢物似乎与哺乳山羊研究中的代谢物相同（例如，HEC5725-二-OH及其二噁唑-OH，HEC5725-E-去氯苯基及其衍生的酮，二噁唑-OH和乙二醇，以及几个二噁唑苯基两环代谢物）和产蛋鸡（例如，HEC5725-的几种葡萄糖苷酸结合物，包括单-OHGA和二-OHGA以及肟-GA，以及包括二噁唑肟、2-氰酚和水杨酸在内的单环和双环片段）。

A metabolism and kinetics study was conducted in which young male and female Wistar rats (4/sex/group) were given a single (1 mg/kg or 100 mg/kg) dose of (methoxyiminotolyl-ring-UL-(14)C)HEC5725 (Fluoxastrobin; lot nos. 11675/1, 12250/1, and 12250/17; >99% radiochemical purity). For multiple-dose experiments, rats received 14 consecutive daily gavage doses (1 mg/kg) of non-labeled HEC5725-E-isomer (lot no. M00358, 98.8% purity) followed by a single dose (1 mg/kg) of radiolabeled test article. Biliary excretion was assessed using an additional group of 12 male rats with bile cannulae. Metabolism and disposition, including plasma kinetics, were determined up to 72 hours post dose. ... HEC5725 was extensively metabolized as shown by the extensive metabolite profiles from urine, feces and bile and the relative absence of parent compound (except in the feces of rats given the 100 mg/kg dose). There were no significant qualitative or quantitative differences in metabolite profiles among the test groups or between males and females. The urinary metabolites were primarily the result of cleavage between the second and third rings of the parent compound. Biliary metabolites were primarily products resulting from cleavage of rings 2, 3 and 4, and subsequent hydroxylation, methoxylation, and conjugation with glucuronic acid. HEC5725-E-des-chlorophenyl and HEC5725-des-chlorophenyl-dioxazine-OH were the major metabolites in all excretion matrices. Some of the rat metabolites seem to be in common with metabolites in studies from lactating goat (e.g., HEC5725-di-OH and its dioxazine-OH, HEC5725-E-des-chlorophenyl and its derived ketone, dioxazine-OH, and glycol, in addition to several dioxazine phenyl two ring metabolites) and laying hen (e.g., several glucuronide conjugates of HEC5725- including mono- and di-OHGA, and oxime-GA in addition to mono- and bi-ring fragments including dioxazine-oxime, 2- cyanophenol, and salicylic acid).

来源:Hazardous Substances Data Bank (HSDB)

代谢

在一项针对雄性大鼠的研究中，评估了单次口服剂量为1 mg/kg的（氯苯基-UL-(14)C）HEC 5725（Fluoxastrobin；>99%的放射化学纯度，批号12712/1，12712/5用于放射性同位素，98.9%的化学纯度，批号M0358或未标记）的代谢和处置情况。还针对雄性和雌性大鼠进行了单次口服剂量为3 mg/kg的全身体层放射自显影研究。此外，还检查了雄性大鼠单次口服剂量为5 mg/kg的代谢物，（苯基-UL-(14)C）2-氯酚（>98%的放射化学纯度，批号12071/1）的代谢和处置情况。在审查的研究中，放射性活性的回收率为91-102%，是可以接受的。第一级研究的结果清楚地表明，雄性大鼠在单次口服1 mg/kg剂量后，（氯苯基-UL-(14)C）HEC 5725（Fluoxastrobin）被迅速吸收和代谢。排泄和组织/器官负担数据显示，吸收率接近100%。血浆浓度在30分钟内达到峰值，血浆清除速度很快。大约77%的放射性活性的排泄在粪便中，大约14%在尿液中。通过呼出气体排泄的放射性活性小于或等于0.2%。总的放射性活性的排泄超过90%，并在24小时内完成。胆管插管实验表明，几乎100%的粪便放射性活性是由胆汁以羟基化、甲基化和结合产物形式贡献的。代谢物表征工作表明，HEC5725被广泛代谢，主要是通过羟基化和随后的甲基化，然后是葡萄糖醛酸或硫酸结合。在大鼠服用（氯苯基-UL-(14)C）HEC5725的24小时胆汁样本中，大约识别出19个组分。这些代谢物总共代表了大约44%的1 mg/kg给药剂量，HPLC表征的代谢物和未识别的极性化合物额外占给药剂量的33%。最常见的胆汁代谢物是甲氧基-OH-GA-二噁嗪-OH和甲氧基-OH-GA，每种都约占给药剂量的6%。在分析的物质中，母体化合物从未超过剂量的3%。提出的（氯苯基-UL-(14)C）HEC5725的代谢途径与研究报告的发现一致。在最初的实验中，组织/尸体负担在给药后48小时仅略超过1%的放射性活性。大部分这种放射性活性与肝脏（大约0.42%）和胃肠道（0.44%）有关。在终止时间为给药后1、4、8、24、48、72、120和168小时的自显影实验中，发现放射性活性广泛分布，但大部分与胃肠道、血液、参与消除的器官/组织以及脂肪有关。没有迹象表明测试物品或其代谢物被隔离。关于2-氯酚代谢物在雄性大鼠中的代谢和处置的研究报告显示，这种HEC5725的代谢物在口服给药后也被迅速且彻底地吸收，并且被广泛代谢。单次口服（14）C-2-氯酚的放射性活性的超过99%在尿液中排泄。尿液中大部分放射性活性与2-氯酚的葡萄糖醛酸结合物（大约占给药剂量的64%）和硫酸结合物（大约占给药剂量的28%）有关。代谢物和母体化合物（2-氯酚）几乎代表了HEC5725（Fluoxastrobin）的2-氯酚代谢物的全部（>98%）给药剂量。

A study was conducted in male rats to assess the metabolism and disposition of (chlorophenyl-UL-(14)C)HEC 5725 (Fluoxastrobin; >99% radiochemical purity, batch no. 12712/1, 12712/5 for radioisotopes, 98.9% chemical purity, batch no. M0358 or non-labeled) following a single oral dose of 1 mg/kg. A whole-body autoradiography study was also conducted in male and female rats given a single 3 mg/kg oral dose. Additionally, the metabolism and disposition of the metabolite, (phenyl-UL-(14)C)2-chlorophenol (>98% radiochemical purity, lot no. 12071/1), was examined in male rats give a single 5 mg/kg oral dose. Recovery of administered radioactivity was an acceptable 91-102% among the reviewed studies. Results of the Tier 1 study clearly indicated that (chlorophenyl-UL-(14)C)HEC 5725 (Fluoxastrobin) was rapidly absorbed and metabolized by male rats following a single 1 mg/kg oral dose. Excretion and tissue/organ burden data showed that absorption was nearly 100%. Peak plasma concentrations were achieved within 30 minutes and plasma clearance was rapid. Approximately 77% of administered radioactivity was excreted in the feces and about 14% was excreted in the urine. Excretion via expired air was < or = 0.2%. Overall excretion of administered radioactivity was >90% and complete within 24 hours. Bile duct cannulation experiments revealed that nearly 100% of the fecal radioactivity was contributed by the bile in the form of hydroxylation, methylation, and conjugation products. Metabolite characterization efforts indicated that HEC5725 was extensively metabolized primarily via hydroxylation and subsequent methylation, followed by glucuronide or sulfate conjugation. Approximately 19 fractions were identified in the 24-hour bile samples from rats dosed with the (chlorophenyl-UL-(14)C)HEC5725. These metabolites collectively represented approximately 44% of the administered 1 mg/kg dose with HPLC characterized metabolites and unidentified polar compounds accounting for a an additional 33% of the administered dose. The most prevalent of the biliary metabolites was methoxy-OH-GA-dioxazine-OH and methoxy-OH-GA each representing about 6% of the administered dose. In the matrices analyzed, parent compound never accounted for more than 3% of the dose. The proposed metabolism pathway for (chlorophenyl-UL-(14)C)HEC5725 appears to be consistent with the findings of the study reports. In the initial experiments, tissue/carcass burdens were only slightly in excess of 1% of the administered radioactivity at 48 hours post dose. Most of this radioactivity was associated with the liver (approximately 0.42%) and gastrointestinal tract (0.44%). Autoradiography experiments in which rats were terminated at 1, 4, 8, 24, 48, 72, 120, and 168 hours post dose, revealed that radioactivity was widely distributed but that most was associated with the gastrointestinal tract, blood, organs/tissues involved with elimination, and fat. There was no indication of sequestration of the test article or its metabolites. The study report on the metabolism and disposition of 2-chlorophenol metabolite in male rats showed that this metabolite of HEC5725 was also rapidly and thoroughly absorbed following oral administration, and was extensively metabolized. More than 99% of the radioactivity from a single oral dose of (14)C)-2-chlorophenol was excreted in the urine. The majority of urinary radioactivity was associated with a glucuronide conjugate (approximately 64% of the administered dose) and sulfate conjugate (approximately 28% of the administered dose) of 2-chlorophenol. The metabolites and parent compound (2-chlorophenol) represented essentially all (>98%) of the administered dose of the 2-chlorophenol metabolite of HEC5725 (Fluoxastrobin).

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

/SRP:/ 立即急救：确保已经进行了充分的中和。如果患者停止呼吸，请开始人工呼吸，最好使用需求阀复苏器、球囊阀面罩设备或口袋面罩，按训练操作。如有必要，执行心肺复苏。立即用缓慢流动的水冲洗受污染的眼睛。不要催吐。如果患者呕吐，让患者身体前倾或将其置于左侧（如果可能，头部向下）以保持呼吸道畅通，防止吸入。保持患者安静，维持正常体温。寻求医疗救助。 /毒物A和B/

/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/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

/SRP:/ 基本治疗：建立专利气道（如有需要，使用口咽或鼻咽气道）。如有必要，进行吸痰。观察呼吸不足的迹象，如有需要，协助通气。通过非循环呼吸面罩以10至15升/分钟的速度给予氧气。监测肺水肿，如有必要，进行治疗……。监测休克，如有必要，进行治疗……。预期癫痫发作，如有必要，进行治疗……。对于眼睛污染，立即用水冲洗眼睛。在运输过程中，用0.9%的生理盐水（NS）持续冲洗每只眼睛……。不要使用催吐剂。对于摄入，如果患者能够吞咽、有强烈的干呕反射且不流口水，则用温水冲洗口腔，并给予5毫升/千克，最多200毫升的水进行稀释……。在去污后，用干燥的无菌敷料覆盖皮肤烧伤……。/毒药A和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"，最低流量/。如果出现低血容量的迹象，使用0.9%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/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 非人类毒性摘录

实验室动物：急性暴露/进行了一项初步研究，给一只雄性猕猴单次静脉注射或皮肤涂抹（EC 100配方）20微居里（200微克）的(14)C HEC 5725（/fluoxastrobin/，批号12250/39，纯度>99%）。静脉注射剂量作为100%生物利用度的参考。在主要研究中，给五只雄性猕猴单次皮肤涂抹（EC 100配方）15微居里（150微克）的(14)C HEC 5725（批号12250/39，纯度>99%）。皮肤涂抹持续八小时。监测排泄物长达192小时（静脉注射剂量）或120小时（皮肤涂抹）。没有发现可以归因于试验物品的显著不良反应。一只猴子在涂抹后4小时呕吐，另一只（都在皮肤暴露组；主要研究）出现软便。实际剂量为195微克（静脉注射），172微克（初步皮肤涂抹），和148微克（主要皮肤涂抹）。这些剂量相当于60.9微克/千克，7.17微克/平方厘米，和6.12微克/平方厘米；仅分别为名义剂量的2.5%，14%和1%。...

/LABORATORY ANIMALS: Acute Exposure/ A preliminary study was conducted in which a single 20 uCi (200 ug) dose of (14)C HEC 5725 (/fluoxastrobin/ lot no. 12250/39, purity >99%) was administered intravenously or dermally (EC 100 formulation) to one male rhesus monkey. The intravenous dose served as a reference for 100% bioavailability. For the main study a single 15 uCi (150 ug) dose of (14)C HEC 5725 (lot no. 12250/39, purity >99%) was administered dermally (EC 100 formulation) to five male rhesus monkeys. The dermal application was for eight hours. Excreta were monitored for up to 192 hours (intravenous dose) or 120 hours (dermal application). There were no significant adverse effects that could be attributed to the test article. One monkey vomited and another (both in the dermal exposure group; main study) exhibited soft stools at 4 hours post-application. Actual doses were 195 ug (iv), 172 ug (preliminary dermal), and 148 ug (main dermal). These doses correspond to 60.9 ug/kg, 7.17 ug/ sq cm, and 6.12 ug/ sqcm; only 2.5, 14, and 1% from nominal, respectively. ...

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 非人类毒性摘录

实验室动物：亚慢性或亚前慢性暴露/ 在一项亚急性（28天）研究中，HEC 5725（/fluoxastrobin/ 95.1% a.i.（98.8 % E-异构体，1.2 % Z-异构体），批号 # 06261/0008）和HEC 5725 A [ /fluoxastrobin/ 97.7% a.i.（62.5% E-异构体，35.2% Z-异构体），批号 # NLL 6112-31] 分别以0、100、500、2500或10,000 ppm的浓度通过饮食给予5只/性别/剂量的Wistar大鼠（除了HEC 5725A没有0 ppm组）。在雄性中，这些剂量相当于0、8.3、41.5、209.7或1005.6 mg/kg bw/day的HEC 5725，在雌性中相当于0、10.0、52.7、261.2或1451.7 mg/kg bw/day。HEC 5725A在雄性中的剂量相当于8.5、42.1、226.6或1001.5 mg/kg bw/day，在雌性中相当于8.8、47.7、247.6或1419.5 mg/kg bw/day。由于饮食中测试化合物水平在每周喂食期结束时降至60%，HEC 5725A的实际平均测试摄入量可能比名义值低20%。在死亡率、临床体征、血液学或大体病理学方面没有与治疗相关的影响。高剂量雄性大鼠（接受HEC 5725和HEC 5725 A治疗）的体重和高剂量组（男性和女性）的体重增加略有下降。尿检参数没有出现毒理学上的显著影响，绝对或相对器官重量也没有出现毒理学上的显著影响。所有高剂量组（男性和女性）接受两种测试物质的肾上腺皮质细胞肥大，细胞质内有细小空泡。尽管HEC 5725 A的稳定性问题，HEC 5725和HEC 5725 A的效果非常相似。基于雄性大鼠体重下降和两性肾上腺细胞肥大伴细小细胞质空泡，HEC 5725和HEC 5725 A在雄性大鼠的LOAEL为10,000 ppm（分别为1005.6 mg/kg/day和1001.5 mg/kg bw/day），在雌性大鼠为2500 ppm（分别为261.2 mg/kg bw/day和247.6 mg/kg bw/day）。对于雄性大鼠，NOAEL为2500 ppm（分别为209.7 mg/kg/day和226.6 mg/kg bw/day），对于雌性大鼠，NOAEL为500 ppm（分别为52.7 mg/kg bw/day和47.7 mg/kg bw/day）。

/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ In a subacute (28-day) study, HEC 5725 (/fluoxastrobin/ 95.1% a.i. (98.8 % E-isomer, 1.2 % Z-isomer), Batch # 06261/0008) and HEC 5725 A [ /fluoxastrobin/ 97.7% a.i. (62.5% E-isomer, 35.2% Z-isomer), Batch # NLL 6112-31] were each administered to 5 Wistar rats/sex/dose in the diet at concentrations of 0, 100, 500, 2500, or 10,000 ppm (except that HEC 5725A had no 0 ppm group). In males, these doses were equivalent to 0, 8.3, 41.5, 209.7, or 1005.6 mg/kg bw/day HEC 5725 and in females to 0, 10.0, 52.7, 261.2, or 1451.7 mg/kg bw/day. Doses were equivalent to 8.5, 42.1, 226.6, or 1001.5 mg/kg bw/day HEC 5725A in males, and to 8.8, 47.7, 247.6, or 1419.5 mg/kg bw/day in females. Actual mean test intake of HEC 5725A may have been up to 20% less than the nominal values due to limited stability in the diet resulting in test compound levels as low as 60% in dietary mixtures at the end of the weekly feeding periods. There were no treatment-related effects on mortality, clinical signs, hematology, or gross pathology. There was a marginal decrease in body weight of high-dose male rats treated with both HEC 5725 and HEC 5725 A and in body weight gain of all high-dose groups, male and female, treated with both test substances. There were no toxicologically significant effects on urinalysis parameters and no toxicologically significant effects were seen on absolute or relative organ weight. Adrenal cortical cytomegaly with fine vacuolization was seen in all high dose groups (male and female) treated with both test substances and in one female each at 2500 ppm in the HEC 5725 and HEC 5725 A groups. The effects of HEC 5725 and HEC 5725 A were very similar despite the stability problem with the latter. The LOAEL for HEC 5725 and HEC 5725 A in male rats is 10,000 ppm (1005.6 mg/kg/day and 1001.5 mg/kg bw/day, respectively) and for female rats is 2500 ppm (261.2 mg/kg bw/day and 247.6 mg/kg bw/day for HEC 5725 and HEC 5725 A, respectively), based on decreased body weight in males and adrenal cytomegaly with fine cytoplasmic vacuolation in both sexes. The NOAEL for male rats is 2500 ppm (209.7 mg/kg/day and 226.6 mg/kg bw/day for HEC 5725 and HEC 5725 A, respectively) and for female rats is 500 ppm (52.7 mg/kg bw/day and 47.7 mg/kg bw/day for HEC 5725 and HEC 5725 A, respectively).

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

进行了一项在雄性大鼠中的研究，以评估单次口服剂量1 mg/kg后48小时内(嘧啶-2-(14)C)HEC 5725（Fluoxastrobin；>98%放射性纯度，批号KML2621-A）和非放射性标记的HEC 5725（/Fluoxastrobin/ 98.8%化学纯度，批号M00358）的代谢和处置。还进行了一项为期168小时的全身自动放射性造影研究，研究对象为给予单次3 mg/kg口服剂量(嘧啶-2-(14)C)HEC 5725（放射性纯度>99%，批号12216/1）的雄性和雌性大鼠。在最初的研究中，给予放射性活性的回收率为84.9-86.7%的给药剂量... ... 在全身自动放射性造影实验中，给予放射性活性的回收率为104-112%。两项研究都证实了嘧啶标记的HEC 5725的快速吸收和完全排泄。在最初的代谢/处置研究中，给药后6-8小时达到血浆峰浓度。在48小时的研究中，通过粪便排泄是消除的主要途径（48小时内剂量的72-73%），在168小时的全身自动放射性造影研究中，通过粪便排泄的剂量为94-99%。肾排泄是次要途径（12-16%），通过呼出气体消除放射性活性的量微不足道（大约0.1%），但证实了标记的稳定性。在给药后48小时，组织和尸体负担约占给予放射性活性的1%。大部分这种放射性活性与肝脏、皮肤（各约0.2%）和胃肠道（约0.4%）相关。自动放射性造影实验证实，放射性活性在与吸收/排泄功能相关的器官和组织（例如，胃肠道、肝脏、肾脏）中最高。时间过程分析表明，测试材料及/或代谢物在给药后1小时内达到最高浓度，随后迅速减少。对于所有组织和器官，放射性残留物在给药后168小时接近或低于LOD或LOQ。全身自动放射性造影实验的结果显示，嘧啶-2-(14)C)HEC 5725在组织分布和处置方面没有显著的性别差异。...

A study was conducted in male rats to assess the metabolism and disposition of (pyrimidine-2-(14)C)HEC 5725 (Fluoxastrobin; >98% radiochemical purity, batch no. KML2621-A) and non-radiolabeled HEC 5725 (/Fluoxastrobin/ 98.8% chemical purity, batch no. M00358) over 48 hours following a single oral dose of 1 mg/kg. A whole-body autoradiography study over a 168-hour period was also conducted in male and female rats given a single 3 mg/kg oral dose of (pyrimidine-2-(14)C)HEC 5725 (radiochemical purity >99%, lot no.12216/1). Recovery of administered radioactivity in the initial study was 84.9-86.7% of the administered dose ... .. In the whole-body autoradiography experiment, recovery of administered radioactivity was 104-112%. Both studies affirmed the rapid absorption and complete excretion of pyrimidine-labeled HEC 5725. Peak plasma concentration was attained at 6-8 hours following dosing in the initial metabolism/ disposition study. Excretion via the feces was the major route of elimination (72-73% of the dose over 48 hours in the 48 hour study) and 94-99% of the dose over the 168-hour duration wholebody autoradiography study. Renal excretion was a secondary route (12- 16%), and elimination of radioactivity via expired air was inconsequential (approximately 0.1%) but confirmed stability of the label. Tissue/carcass burdens accounted for about 1% of the administered radioactivity at 48 hours post dose. Most of this radioactivity was associated with the liver, skin (each approximately 0.2%) and gastrointestinal tract (approximately 0.4%). Autoradiography experiments confirmed that radioactivity was greatest in organs and tissues associated with absorption/ excretory function (e.g., gastrointestinal tract, liver, kidneys). Time-course analysis indicated that test material and/or metabolites reached greatest concentrations within 1 hour of dosing and decreased rapidly thereafter. For all tissues/organs, radioactivity residue was approaching or below LOD or LOQ at 168 hours post dose. Results of the whole-body autoradiography experiments showed no significant gender-related differences in the tissue distribution and disposition of 9pyrimidine-2 -(14)C)HEC 5725. ...

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

进行了一项关于年轻雄性和雌性Wistar大鼠（每性别/组4只）的代谢和动力学研究，给予它们单一剂量（1毫克/公斤或100毫克/公斤）的（甲氧基亚氨基酚基环-UL-(14)C）HEC5725（Fluoxastrobin；批号11675/1，12250/1和12250/17；>99%的放射化学纯度）。对于多次剂量实验，大鼠连续14天每天通过灌胃接受非标记的HEC5725-E-异构体（批号M00358，98.8%纯度）的剂量（1毫克/公斤），然后给予单一剂量的放射性标记试验物质。使用另外12只带有胆管的大鼠评估胆汁排泄。代谢和分布，包括血浆动力学，在给药后72小时内确定。一项放射性自显影研究...评估了在给予单一3毫克/公斤灌胃剂量后48小时内，雄性和雌性大鼠中（甲氧基亚氨基酚基环-UL-(14)C）HEC5725（Fluoxastrobin；批号12250/1和12250/37；>99%的放射化学纯度）的分布情况。所有实验中给药放射活性的质量平衡是可以接受的91-107%。排泄轮廓和血浆浓度数据显示，在给予单一或多次低剂量（1毫克/公斤）后，HEC5725被迅速且彻底吸收（tmax为0.4-1.4小时），但在100毫克/公斤剂量时吸收似乎达到饱和（tmax为5.4-8.0小时）。有限的吸收反映在AUC值上（高剂量组为54.10 - 61.30微克/毫升/小时，低剂量和多次剂量组为1.18 - 1.52微克/毫升/小时），以及比低剂量组高14-33倍的Cmax值。血浆消除是双相的，低剂量单一或多次剂量组的初始相在0.7-3.5小时，高剂量组在2.3-4.1小时，次级相在大约10小时和7小时，分别对应低剂量和高剂量组。血浆浓度-时间曲线暗示了肠肝循环，但这很小，仍然允许相对快速和彻底地排出给药的放射活性。分布和动力学数据没有表明在测试的剂量方案中有潜在的隔离，并且没有显示出性别相关的变异性。主要的排泄途径是通过胆汁，随后通过粪便。尿液排泄是次要但重要的途径。通过呼出空气的消除是微不足道的（0.02%）。尿液排泄在给药后24小时内基本完成（>90%），并占给药低剂量的16.9-20.2%，高剂量的11.0-14.9%。大部分放射性在24小时内通过粪便排出。在没有胆管的大鼠中，粪便排泄在48小时内占给药低剂量的70.4-84.7%。在高剂量组中，粪便排泄略高（86.4-91.1%），大部分粪便放射性（43-54%的给药剂量）归因于由于饱和吸收而未变化的母化合物。在有胆管的大鼠中，胆汁排泄占剂量的87.4%，相应的粪便排泄较低（10.6%）。重复给药没有影响排泄轮廓，并且没有生物学上相关的性别相关变异性。组织/器官/尸体负担是最小的（<1%的给药放射活性），这些发现通过放射性自显影实验得到证实。大部分放射性与胃肠道、血液以及与代谢和排泄直接相关的器官/组织相关。组织水平在8小时后迅速降低，到48小时时降至不可检测水平。

A metabolism and kinetics study was conducted in which young male and female Wistar rats (4/sex/group) were given a single (1 mg/kg or 100 mg/kg) dose of (methoxyiminotolyl-ring-UL-(14)C)HEC5725 (Fluoxastrobin; lot nos. 11675/1, 12250/1, and 12250/17; >99% radiochemical purity). For multiple-dose experiments, rats received 14 consecutive daily gavage doses (1 mg/kg) of non-labeled HEC5725-E-isomer (lot no. M00358, 98.8% purity) followed by a single dose (1 mg/kg) of radiolabeled test article. Biliary excretion was assessed using an additional group of 12 male rats with bile cannulae. Metabolism and disposition, including plasma kinetics, were determined up to 72 hours post dose. An autoradiography study ... assessed disposition of (methoxyiminotolyl-ring-UL-(14)C)HEC5725 (Fluoxastrobin; lot nos. 12250/1, and 12250/37; >99% radiochemical purity) in male and female rats over 48 hours following a single 3 mg/kg gavage dose. Mass balance for administered radioactivity in all experiments was an acceptable 91-107%. Excretion profiles and plasma concentration data showed that HEC5725 was rapidly and thoroughly absorbed following single or multiple low (1 mg/kg) doses (tmax of 0.4-1.4 hrs) but absorption appeared to be saturated at the 100 mg/kg dose (tmax of 5.4-8.0 hrs). Limited absorption was reflected by the AUC values (54.10 - 61.30 ug/mL/hr for the high dose groups vs. 1.18 - 1.52 ug/mL/hr for the low and multiple-dose groups), and by Cmax values that were 14-33 fold greater than the low-dose groups. Plasma elimination was biphasic with an initial phase at 0.7-3.5 hrs for the low single or multiple dose groups and 2.3-4.1 hrs for the high-dose groups and a secondary phase at approximately 10 hours and 7 hours for the low and high-dose groups, respectively. Plasma concentration-time plots were suggestive of enterohepatic circulation but this was minimal and still allowed for relatively rapid and complete excretion of administered radioactivity. Distribution and kinetic data did not indicate potential for sequestration at the dose regimens tested and revealed no gender-related variability. The major route of excretion was via the bile and subsequently the feces. Urinary excretion was a secondary but significant route. Elimination via expired air was inconsequential (0.02%). Urinary excretion was essentially complete (>90%) at 24 hours postdose and accounted for 16.9-20.2% of the administered low dose and 11.0-14.9% of the high dose. The majority of fecal excretion of radioactivity occurred within 24 hours. In rats without bile cannulae, fecal excretion accounted for 70.4-84.7% of the administered low dose over 48 hours. In high-dose groups, fecal excretion was slightly higher (86.4-91.1%) with much of the fecal radioactivity (43-54% of administered dose) attributed to parent compound due to saturated absorption. In rats with bile cannulae, biliary excretion represented 87.4% of the dose and fecal excretion was correspondingly lower (10.6%). Repeated dosing did not affect excretion profiles and there was no biologically relevant gender-related variability. Tissue/organ/carcass burdens were minimal (<1% of administered radioactivity), findings which were confirmed by the autoradiography experiments. Most radioactivity was associated with the gastrointestinal tract, blood, and organs/tissues directly associated with metabolism and excretion. Tissues levels rapidly diminished after 8 hours to non-detect levels at 48 hours.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

进行了一项在雄性大鼠中的研究，以评估单次口服剂量1 mg/kg下（氯苯基-UL-(14)C）HEC 5725（氟氧菌素；>99%的放射性纯度，批号12712/1, 12712/5用于放射性同位素，98.9%的化学纯度，批号M0358或无标记）的代谢和分布。还进行了在给予单次3 mg/kg口服剂量的雄性和雌性大鼠中的全身自动放射性造影研究。此外，还检查了雄性大鼠在单次5 mg/kg口服剂量下的代谢物（苯基-UL-(14)C）2-氯苯酚（>98%的放射性纯度，批号12071/1）的代谢和分布。在审查的研究中，施用放射性活性的回收率为91-102%，是可以接受的。第一级研究的结果清楚地表明，雄性大鼠在单次1 mg/kg口服剂量后，（氯苯基-UL-(14)C）HEC 5725（氟氧菌素）被迅速吸收和代谢。排泄和组织/器官负担数据显示，吸收率接近100%。血浆浓度在30分钟内达到峰值，血浆清除迅速。大约77%的施用放射性活性通过粪便排出，大约14%通过尿液排出。通过呼出空气的排泄小于或等于0.2%。施用放射性活性的总排泄量超过90%，并在24小时内完成。胆管插管实验显示，几乎100%的粪便放射性活性是由胆汁以羟基化、甲基化和结合产物的形式贡献的。...

A study was conducted in male rats to assess the metabolism and disposition of (chlorophenyl-UL-(14)C)HEC 5725 (Fluoxastrobin; >99% radiochemical purity, batch no. 12712/1, 12712/5 for radioisotopes, 98.9% chemical purity, batch no. M0358 or non-labeled) following a single oral dose of 1 mg/kg. A whole-body autoradiography study was also conducted in male and female rats given a single 3 mg/kg oral dose. Additionally, the metabolism and disposition of the metabolite, (phenyl-UL-(14)C)2-chlorophenol (>98% radiochemical purity, lot no. 12071/1), was examined in male rats give a single 5 mg/kg oral dose. Recovery of administered radioactivity was an acceptable 91-102% among the reviewed studies. Results of the Tier 1 study clearly indicated that (chlorophenyl-UL-(14)C)HEC 5725 (Fluoxastrobin) was rapidly absorbed and metabolized by male rats following a single 1 mg/kg oral dose. Excretion and tissue/organ burden data showed that absorption was nearly 100%. Peak plasma concentrations were achieved within 30 minutes and plasma clearance was rapid. Approximately 77% of administered radioactivity was excreted in the feces and about 14% was excreted in the urine. Excretion via expired air was < or = 0.2%. Overall excretion of administered radioactivity was >90% and complete within 24 hours. Bile duct cannulation experiments revealed that nearly 100% of the fecal radioactivity was contributed by the bile in the form of hydroxylation, methylation, and conjugation products. ...

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

进行了一项初步研究，给一只雄性猕猴静脉注射或通过皮肤（EC 100配方）给予单次20 uCi（200 ug）剂量的(14)C HEC 5725（/fluoxastrobin/，批号12250/39，纯度>99%）。静脉注射剂量作为100%生物利用度的参考。在主要研究中，给五只雄性猕猴通过皮肤（EC 100配方）给予单次15 uCi（150 ug）剂量的(14)C HEC 5725（批号12250/39，纯度>99%）。皮肤应用持续8小时。监测排泄物长达192小时（静脉注射剂量）或120小时（皮肤应用）。... 实际剂量为195 ug（静脉注射）、172 ug（初步皮肤）和148 ug（主要皮肤）。这些剂量相当于60.9 ug/kg、7.17 ug/平方厘米和6.12 ug/平方厘米；仅占标称剂量的2.5%、14%和1%。相应测试组的放射性质量平衡可接受，分别为94.0%、102.0%和93.4%。静脉给药后，52.99%的给药放射性通过尿液排出，19.91%通过粪便排出，在192小时的实验期间，从笼子碎片/冲洗中回收了额外的21.1%。大约93%的尿液排泄发生在48小时内。静脉给药后粪便中放射性标记的排泄虽然显著（19.91%），但约为尿液的37.6%。在8小时皮肤应用后，大部分放射性与皮肤拭子和那些拭子的提取物相关（约占总应用放射性的84.3-88.4%）。仅2.7-12.9%的放射性与覆盖材料相关，证实了研究者们的观点，即大部分应用剂量可用于吸收，并未与器具材料结合。初步研究的结果清楚地表明，在静脉给药允许100%生物利用度的情况下，HEC 5725在48小时内迅速且几乎完全通过尿液和粪便排出。在雄性猕猴进行8小时皮肤应用后，吸收可以忽略不计（初步为1.16%，主要研究为2.16%）。由于主要皮肤组动物没有给予静脉注射剂量，因此无法计算主要研究的标准化吸收值。

A preliminary study was conducted in which a single 20 uCi (200 ug) dose of (14)C HEC 5725 (/fluoxastrobin/ lot no. 12250/39, purity >99%) was administered intravenously or dermally (EC 100 formulation) to one male rhesus monkey. The intravenous dose served as a reference for 100% bioavailability. For the main study a single 15 uCi (150 ug) dose of (14)C HEC 5725 (lot no. 12250/39, purity >99%) was administered dermally (EC 100 formulation) to five male rhesus monkeys. The dermal application was for eight hours. Excreta were monitored for up to 192 hours (intravenous dose) or 120 hours (dermal application). ... Actual doses were 195 ug (iv), 172 ug (preliminary dermal), and 148 ug (main dermal). These doses correspond to 60.9 ug/kg, 7.17 ug/ sq cm, and 6.12 ug/ sqcm; only 2.5, 14, and 1% from nominal, respectively. Radioactivity mass balances for the respective test groups were acceptable at 94.0, 102.0, and 93.4%. Following intravenous administration, 52.99% of the administered radioactivity was excreted via the urine, 19.91 via feces, and an additional 21.1% was recovered from cage debris/rinses over the 192-hour experimental period. Approximately 93% of excretion in the urine occurred by 48 hours. Fecal excretion of radiolabel following intravenous administration, although significant (19.91%), was approximately 37.6% of that for urine. Following the 8-hour dermal application, the majority of radioactivity was associated with the dermal swabs and the extracts of those swabs (approximately 84.3-88.4% of applied radioactivity). Only 2.7-12.9% of the radioactivity was associated with the cover material affirming the investigators' contention that most of the applied dose was available for absorption and not bound to the appliance materials. The results of the preliminary study clearly showed that following intravenous administration allowing for 100% bioavailability, HEC 5725 is rapidly and nearly totally excreted in the urine and feces within 48 hours. Following an 8-hour dermal application in a male monkey, absorption was negligible (1.16% preliminary, 2.16% main). As the intravenous dose was not given to the animals of the main dermal group, a normalized absorption value for the main study could not be calculated.

来源:Hazardous Substances Data Bank (HSDB)

制备方法与用途

毒性
大鼠急性经口LD₅₀>2500mg/kg，大鼠急性经皮LD₅₀>2000mg/kg。对兔眼睛有刺激作用，但对兔皮肤和豚鼠皮肤无刺激及致敏作用。未发现对大鼠或兔的胚胎毒性、繁殖毒性和致畸作用，也无致癌和神经毒性。鹌鹑经口LD₅₀>2000mg/kg；鳟鱼LC₅₀>0.44mg/L (96h)；水蚤EC₅₀0.48mg/L (48h)；蚯蚓LC₅₀>1000mg/kg土；蜜蜂LD₅₀>843 μg/只。

化学性质
纯品为白色结晶固体，熔点75℃。在20℃时的蒸气压为6×10^-10Pa，分配系数为2.86，在pH值为7的水中溶解度为2.29 mg/L。土壤中降解半衰期为16～119天。

用途
氟嘧菌酯是一种新颖、广谱二氢噁嗪类内吸性茎叶处理用杀菌剂，作为线粒体呼吸抑制剂，通过在细胞色素b和c₁间电子转移抑制线粒体的呼吸。它具有快速击杀和持效期长的双重特征，并且对作物有良好的相容性，适当的加工剂型可以进一步提高其透过角质层进入叶部的能力。此药剂能有效防治禾本科作物、马铃薯、蔬菜、咖啡等作物的所有真菌纲（子囊菌纲、担子菌纲、卵菌纲和半知菌类）病害，如锈病、颖枯病、网斑病、白粉病和霜霉病。使用剂量通常为50～300g有效成分/hm²。虽然它的种子和根部吸收能力较弱，但在作为种子处理剂时对幼苗的种传和土传病害有很好的杀灭作用及持效性。但对于大麦白粉病或网斑病等气传病害无效。防治咖啡锈病可使用75～100g有效成分/hm²药液进行茎叶喷雾；防治马铃薯早疫病、晚疫病、蔬菜叶斑病和霜霉病，可用100～200g有效成分/hm²药液进行茎叶喷雾。对禾谷类作物的叶斑病、颖枯病、褐锈病、条锈病、云纹病、网斑病、褐斑病等使用200g有效成分/hm²药液进行喷雾，也可兼治白粉病和全蚀病。用于禾谷类作物的种子处理时，每100kg种子需加入5～10g有效成分，以防治雪霉病、腥黑穗病及坚黑穗病等种传或土传病害，同时还可以防治散黑穗病和叶条纹病。

生产方法
中间体制备：使用2-氟并二酸二乙酯和邻羟基苯乙酸作为原料，通过一系列反应步骤得到3-{1-[2-(4,5-二氟嘧啶-6-基氧基)苯基]-1-（甲氧氨基）-甲基}-5，6-二氢-1，4，2-二噁嗪。然后利用此中间体与邻氯苯酚、碳酸钾和氯化亚铜在DMF溶剂中反应得到氟嘧菌酯。

最终合成：将124.1g (0.333mol) 3-{1-[2-(4,5-二氟嘧啶-6-基氧基)-苯基]-1-（甲氧氨基）-甲基}-5，6-二氢-1，4，2-二噁嗪、42.8g (0.333mol) 邻氯苯酚、46g （0.333mol）碳酸钾和3.3g 氯化亚铜加入到1L DMF中加热至100℃。减压脱溶后冷却，分层并干燥滤液得到148.2g (97%) 的氟嘧菌酯成品。

反应信息

• 作为反应物：
  描述：

  {2-[6-(2-氯苯氧基)-5-氟嘧啶-4-基氧]苯基}(5,6-二氢-1,4,2-二噁嗪-3-基)甲酮O-甲基肟 在 甲烷磺酸 作用下， 以95.92%的产率得到氟嘧菌酯
  参考文献：
  名称：

  [EN] PROCESS FOR PREPARING FLUOXASTROBIN
  [FR] PROCÉDÉ DE PRÉPARATION DE FLUOXASTROBINE

  摘要：

  制备氟吡唑的过程包括：(i) 在酸的存在下，将苯并呋喃-3(2H)-酮O-甲基肟(10)与烷基亚硝酸酯反应，形成(3E)-2,3-苯并呋喃二酮O3-甲基二肟(11A)作为主要异构体；(ii) 将(3E)-2,3-苯并呋喃二酮O3-甲基二肟(11A)与2-卤乙醇反应，形成(3E)-苯并呋喃-2,3-二酮O2-(2-羟乙基)O3-甲基二肟(12A)；(iii) 将(3E)-苯并呋喃-2,3-二酮O2-(2-羟乙基)O3-甲基二肟(12A)与碱反应，形成(E)-(5,6-二氢-1,4,2-二噁嗪-3-基)(2-羟基苯基)甲酮O-甲基肟(13)；(iv) 在溶剂的存在下，可选地在碱的存在下，将4,6-二卤-5-氟嘧啶(5)，其中X1是卤素，与(E)-(5,6-二氢-1,4,2-二噁嗪-3-基)(2-羟基苯基)甲酮O-甲基肟(13)反应，形成(E)-(2-((6-卤-5-氟嘧啶-4-基)氧基)苯基)(5,6-二氢-1,4,2-二噁嗪-3-基)甲酮O-甲基肟(14)；(v) 在溶剂的存在下，可选地在碱的存在下，将(E)-(2-((6-卤-5-氟嘧啶-4-基)氧基)苯基)(5,6-二氢-1,4,2-二噁嗪-3-基)甲酮O-甲基肟(14)与2-氯苯酚反应，形成氟吡唑。

  公开号：

  WO2015006203A1

文献信息

• NOVEL COMPOUNDS
  申请人：Berthon Guillaume

  公开号：US20140045890A1

  公开（公告）日：2014-02-13

  Compounds of the general formula (I) wherein the substituents are as defined in claim 1 , are useful as fungicides.

  通式（I）中的化合物，其中取代基如权利要求1中定义的那样，可用作杀真菌剂。
• [EN] QUINOLINE DERIVATIVES AS FUNGICIDES<br/>[FR] DÉRIVÉS DE QUINOLÉINE UTILISÉS EN TANT QUE FONGICIDES
  申请人：SYNGENTA PARTICIPATIONS AG

  公开号：WO2011154240A1

  公开（公告）日：2011-12-15

  Compounds of the general formula (I) wherein the substituents are as defined in claim 1, are useful as fungicides.

  通式（I）中取代基如权利要求1所定义的化合物，可用作杀真菌剂。
• Quinoline derivatives as fungicides
  申请人：Syngenta Participations AG

  公开号：EP2397467A1

  公开（公告）日：2011-12-21

  Compounds of the general formula wherein the substituents are as defined in claim 1, are useful as fungicides.

  通式为的化合物，其中取代基如权利要求书中定义的那样，可用作杀真菌剂。
• [EN] N-CYCLOPROPYLMETHYL-2-(QUINOLIN-6-YLOXY)-ACETAMIDE DERIVATIVES AND THEIR USE AS FUNGICIDES<br/>[FR] DÉRIVÉS DE N-CYCLOPROPYLMÉTHYL-2-(QUINOLIN-6-YLOXY)-ACÉTAMIDE ET LEUR UTILISATION COMME FONGICIDES
  申请人：SYNGENTA PARTICIPATIONS AG

  公开号：WO2014044642A1

  公开（公告）日：2014-03-27

  Compounds of the general formula (I) wherein the substituents are as defined in claim 1, are useful as fungicides.

  通式（I）中取代基如权利要求1所定义的化合物，可用作杀真菌剂。
• 5-phenypyrimidines their preparation compositions comprising them and their use
  申请人：Gypser Andreas

  公开号：US20060148764A1

  公开（公告）日：2006-07-06

  5-Phenylpyrimidines of the formula I in which the substituents and the index are as defined below: R 1 ,R 2 are hydrogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkenyl, haloalkenyl, alkynyl or haloalkynyl, and R 1 and R 2 together with the nitrogen atom to which they are attached may also form a saturated or unsaturated ring which may be interrupted by an ether, thio, sulfoxyl or sulfonyl group and may be substituted by one to four groups R a and/or R b ; R 3 is hydrogen, halogen, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy or alkenyloxy; R 4 is hydrogen, halogen, cyano, hydroxyl, mercapto, azido, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkenyloxy, alkynyloxy, haloalkoxy, alkylthio, alkenylthio, alkynylthio, haloalkylthio, —ON═CR a R b , —CR c ═NOR a , —NR c N═CR a R b , —NR a R b , —NR c NR a R b , —NOR a , —NR c C(═NR c′ )NR a R b , —NR c C(═O)NR a R b , —NR a C(═O)R c , —NR a C(═NOR c )R c′ , —OC(═O)R c , —C(═NOR c )NR a R b , —CR c (═NNR a R b ), —C(═O)NR a R b or —C(═O)R c ; in which R a , R b and R c are as defined in the description; X is halogen, alkyl, alkoxy or haloalkyl; and m is an integer from 1 to 5; processes for preparing these compounds, compositions comprising them and their use for controlling harmful fungi are described.

  式I中的5-苯基嘧啶，其中取代基和指数定义如下：R1，R2为氢，烷基，卤代烷基，环烷基，卤代环烷基，烯基，卤代烯基，炔基或卤代炔基，而且R1和R2连同它们所连接的氮原子也可以形成一个饱和或不饱和的环，该环可以被醚，硫，亚硫氧基或磺酰基所中断，并且可以被一个到四个Ra和/或Rb基团取代；R3为氢，卤素，氰基，烷基，卤代烷基，烷氧基，卤代烷氧基或烯氧基；R4为氢，卤素，氰基，羟基，巯基，偶氮基，烷基，烯基，炔基，卤代烷基，烷氧基，烯氧基，炔氧基，卤代烷氧基，烷硫基，烯硫基，炔硫基，卤代烷硫基，-ON═CRaRb，-CRc═NORa，-NRcN═CRaRb，-NRaRb，-NRcNRaRb，-NORa，-NRcC(═NRc′)NRaRb，-NRcC(═O)NRaRb，-NRaC(═O)Rc，-NRaC(═NORc)Rc′，-OC(═O)Rc，-C(═NORc)NRaRb，-CRc(═NNRaRb)，-C(═O)NRaRb或-C(═O)Rc；其中Ra，Rb和Rc如描述中所定义；X为卤素，烷基，烷氧基或卤代烷基；m为1至5之间的整数；描述了制备这些化合物的方法，包括它们的组成物和用于控制有害真菌的用途。