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.
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.
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.
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).
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).
/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/
