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Isoxaflutole ISOXAFLUTOLE First draft prepared by P.V. Shah 1 and Roland Alfred Solecki 2 1 Office of Pesticide Programs, Environmental Protection Agency, Washington, DC, United States of America (USA) 2 Federal Institute for Risk Assessment, Berlin, Germany Explanation ........................................................................................................................................... 393 Evaluation for acceptable daily intake .................................................................................................. 394 1. Biochemical aspects ............................................................................................................... 394 1.1 Absorption, distribution and excretion ............................................................................ 394 1.2 Biotransformation ........................................................................................................... 397 1.3 Dermal absorption ........................................................................................................... 399 2. Toxicological studies ............................................................................................................. 400 2.1 Acute toxicity .................................................................................................................. 400 (a) Oral administration .................................................................................................. 401 (b) Dermal application ................................................................................................... 401 (c) Exposure by inhalation ............................................................................................ 402 (d) Dermal irritation ...................................................................................................... 402 (e) Eye irritation ............................................................................................................ 402 (f) Dermal sensitization................................................................................................. 403 2.2 Short-term studies of toxicity .......................................................................................... 404 (a) Oral administration .................................................................................................. 404 (b) Dermal application ................................................................................................... 413 (c) Exposure by inhalation ............................................................................................ 414 2.3 Long-term studies of toxicity and carcinogenicity .......................................................... 414 2.4 Genotoxicity .................................................................................................................... 423 2.5 Reproductive and developmental toxicity ....................................................................... 424 (a) Multigeneration studies ............................................................................................ 424 (b) Developmental toxicity ............................................................................................ 425 2.6 Special studies ................................................................................................................. 429 (a) Acute neurotoxicity .................................................................................................. 429 (b) Subchronic neurotoxicity ......................................................................................... 430 (c) Developmental neurotoxicity ................................................................................... 431 (d) Microsomal enzymes ............................................................................................... 433 (e) Tyrosine levels ......................................................................................................... 434 (f) Thyroid mechanism ................................................................................................. 434 2.7 Studies on metabolites .................................................................................................... 444 (a) Metabolite RPA 202248: 2-Cyano-3-cyclopropyl-4-(2-methylsulfonyl-4- trifluoromethylphenyl)propan-1,3-dione ................................................................. 444 (b) Metabolite RPA 203328: IFT-BA (2-mesyl-4-trifluoromethylbenzoic acid) .......... 445 3. Observations in humans ......................................................................................................... 448 Comments ............................................................................................................................................. 448 Toxicological evaluation ...................................................................................................................... 451 References ............................................................................................................................................ 454 Explanation Isoxaflutole is the International Organization for Standardization–approved name for 5- cyclopropyl-4-(2-methylsulfonyl-4-trifluoromethylbenzoyl)-isoxazole (International Union of Pure and Applied Chemistry), with Chemical Abstracts Service No. 141112-29-0. The company code for isoxaflutole is RPA 201772. Isoxaflutole is an isoxazole herbicide that is used as a pre-emergent or early post-emergence broadcast treatment for the control of broadleaf and grass weeds. Its primary target in plants is the enzyme 4-hydroxyphenylpyruvate dioxygenase (HPPD); inhibition of the enzyme results in the bleaching of weeds due to the blockage of phenylquinone biosynthesis. ISOXAFLUTOLE 393–458 JMPR 2013 394 Isoxaflutole has not previously been evaluated by the Joint FAO/WHO Meeting on Pesticide Residues (JMPR) and was reviewed by the present Meeting at the request of the Codex Committee on Pesticide Residues. All critical studies contained statements of compliance with good laboratory practice (GLP). Evaluation for acceptable daily intake 1. Biochemical aspects Absorption, distribution, metabolism and excretion of isoxaflutole following a single gavage low dose, high dose and repeated dosing (14 days) have been studied in rats. Fig. 1 shows the radiolabelling position of isoxaflutole used in the absorption, distribution, metabolism and excretion studies in rats. Fig. 1. [14 C]Isoxaflutole (RPA 201772) * denotes the position of the uniformly labelled phenyl ring 1.1 Absorption, distribution and excretion In an absorption, distribution, excretion and metabolism study, [14 C]isoxaflutole (purity 98.7%) was administered to groups of male and female Sprague-Dawley (CD) rats (five of each sex per dose) by gavage at a single low oral dose (1 mg/kg body weight [bw]), repeated low oral dose (1 mg/kg bw in a 14-day repeated-dose series) and a single high dose (100 mg/kg bw). In addition, pharmacokinetics in blood was investigated using two groups of rats (five of each sex per dose) that received a single oral dose of [14 C]isoxaflutole at 1 or 100 mg/kg bw. Urine and faeces were collected at intervals of 0–24, 0–48, 0–96, 0–120, 0–144 and 0–168 hours, and tissues were collected at 168 hours post-dosing. Metabolite analysis was performed on the urine and faeces from animals of all dose groups and on the liver samples of male and female rats in the two low-dose groups (Filaquier, 1994). A separate time course tissue distribution study was conducted in Sprague-Dawley rats. In this study, [14 C]isoxaflutole (purity 98.7%) was administered to groups (16 of each sex per dose) of male and female Sprague-Dawley (CD) rats by gavage at a single low oral dose (1 mg/kg bw) and a single high oral dose (100 mg/kg bw). Four rats of each sex per dose were killed at 1, 24, 96 and 168 hours post-dosing, and isoxaflutole-derived radioactivity was measured in various tissues (Valles, 1999). The total recovery of radioactivity in male and female rats ranged from 97.3% to 100.4% of the administered dose (Table 1). The mean total recovery of radioactivity from the males and females was 98.09%. As there were no data available for isoxaflutole from intravenous administration or bile duct–cannulated rats, the extent of absorption is interpolated from available urinary excretion data. Based on urinary elimination, it appears that about 60%, 67% and 36% of the administered dose were absorbed in the low-dose, repeated low-dose and high-dose groups, respectively (Table 1) in 168 hours. The mean maximum estimated proportion of the dose absorbed was calculated from the radioactivity detected in the urine, cage washes and tissues, which yielded about 73%, 75% and 39% for the low-dose, repeated low-dose and high-dose groups, respectively. The urine was the major route of elimination for the low-dose groups (about 69–74% of the dose), whereas faeces was the major route of elimination for the high-dose group (about 55–63% of the dose). These results suggest ISOXAFLUTOLE 393–458 JMPR 2013 395 that significant absorption of the test material occurred at the low dose; as the dose increased, there was saturation of absorption, resulting in a major portion of the parent compound being excreted unchanged. The blood pharmacokinetic parameters for isoxaflutole are shown in Table 2. The maximal concentrations in blood ( Cmax ) were achieved between 0.5 and 1 hour post-dosing. The results indicate a direct dose–response relationship with the maximal
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