Docket ID#: EPA HQ-OPP-2009-0890

COMPANY NOTICE OF FILING EPA Registration Division contact: Sidney Jackson, 703 -305-76 10 Interregional Research Project Number 4 (IR-4) PP# 9E7642 EPA has received a pesticide petition 9E7642 from the Interregional Research Project Number 4 (IR-4), IR-4 Project Headquarters, 500 College Road East, Suite 201 W, Princeton, NJ 08540, in cooperation with Chemtura Corp., 199 Benson Rd (2 -5), Middlebury, CT 06749 proposing, pursuant to section 408(d) of the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR part 180. 572 by establishing a tolerance for residues of the insecticide bifenazate (1 -methylethyl 2 -(4- methoxy [1,1' -biphenyl] -3 -yl)hydrazinecarboxylate) and diazinecarboxylic acid, 2 -(4 - methoxy- [1,1 ’ -biphenyl] -3 -yl), 1 -methylethyl ester (expressed as bifenazate) in or on the following food commodities : sugar apple, cherimoya, atemoya, custard apple, ilama, soursop, and biriba at 1.5 parts per million (ppm) ; avocado at 7.0 ppm ; fruit, s mall, vine climbing subgroup 13 -07F, except fuzzy kiwifruit at 0.75 ppm ; and berry, low growing, subgroup 13 -07G at 1.5 ppm. EPA has determined that the petition contains data or information regarding the elements set forth in section 408 (d)(2) of FDDCA; however, EPA has not fully evaluated the sufficiency o f the submitted data at this time or whether the data supports granting of the petition. Additional data may b e needed before EPA rules on the petition. A. Residue Chemistry 1. Plant metabolism. The nature of the residues of bifenazate in plants is adequately understood. T he major residue in all plant metabolism studies is bifenazate. Aminor, but significant metabolite is the diazene D3 598, which was found to interconvert readily to/from bifenazate in the plant matrix during the analytical procedure. 2. Analytical method. Chemtura Corporation has developed practical analytical methodology for detecting and measuring residues of bifenazate in or on raw agricultural commodities. As D3598, a significant metabolite, was found to interconvert readily to/from bifenazate, the analytical method was designed to convert all residues of D3598 to the parent compound (bifenazate) for analysis. T he method, “Determination of Combined Bifenazate and D3598 Residues in Sugar Apple”, utilizes reversed phase HPLC to separate the bifenazate from matrix2

derived interferences, and oxidative coulometric electrochemical detection for the identification and quantification of this analyte. The lowest level of method validation (LLMV) in this study was 0.05 ppm for each analyte. Based on recoveries of samples fortified at the LLMV, the limit of detection (LOD) and limit of quantitation (LOQ) were calculated as 0.0308 ppm and 0.0923 ppm, respectively, for bifenazate and as 0.0332 ppm and 0.0997 ppm, respectively, for D3598. 3. Magnitude of residues. A complete crop residue program has been completed for bifenazate in the major growing areas of the US for: Sugar Apple: A crop residue program has been completed for bifenazate using Acramite®- 50WS on sugar apple. T hree trials were conducted for this study in accordance with U.S. EPA OPPTS 860 series guidelines in South Florida (EPA Region 13) during the 2006 growing season. S ugar apple is a tropical fruit and can only be grown in Region 13. Each trial site included one untreated (control) plot and one treated plot. At each trial, two foliar applications of Acramite 50WS at a rate of approximately 0.5 lb ai/A each were made for a total of approximately 1.0 lb ai/A to the treated plot. All applications were made 21 days apart and timed so that commercially mature sugar apples could be collected 1 day after the final application. Combined residues of bifenazate and D3598 in sugar apple harvested at a 1 -day PHI showed residue levels between 0.04071 ppm to 1.313 ppm. A summary table is provided below:

Based on the results of the field trials on sugar apple, Chemtura Corporation is proposing a crop specific tolerance of 1.5 ppm on sugar apple (grouping also includes cherimoya, atemoya, custard apple, ilama, soursap, birida). Avocado: A ChemSAC decision stated that avocado can be assigned the highest tropical fruit tolerance determined for either lychee (5.0 ppm), guava (0.90 ppm), papaya (7.0 ppm) or sugar apple (1.5 ppm). Thus Chemtura is also p roposing a crop specific tolerance of 7.0 ppm on avocado. Low growing berry subgroup 13 -07G: In accordance with Federal Register Volume 72, December 7, 2007 (pp 69150- Commodity Application

Rate (lb ai/A) PHI

(days) Residue Levels (ppm)

n Min. Max. HAFT Mean Std. Dev. Sugar Apple 0.98- 1.04 1 12 0.04071 1.313 0.6658 0.3338 0.35393

69158) Final Rule/Pesticide Tolerance Crop Grouping, it is requested that strawberries be expanded to Low Growing Berry Subgroup 13 -07G. This subgroup contains strawberry, bearberry; bilberry; blueberry, lowbush; cloudberry; cranberry; lingonberry; muntries; partridgeberry; cultivars, varieties and/or hybrids of these. Small fruit vine climbing subgroup 13 -07F, except fuzzy kiwifruit: In accordance with Federal Register Volume 72, December 7, 2007 (pp 69150- 69158) Final Rule/Pesticide Tolerance Crop Grouping, it is requested that grapes be expanded to ‘Small Fruit Vine Climbing Subgroup 13 -07F, Except Fuzzy Kiwifruit’. This subgroup contains grape; Amur River grape; gooseberry; kiwifruit, hardy; maypop; schisandra berry; cultivars, varieties, and/or hybrids of these. B. Toxicological Profile 1. Acute toxicity. Bifenazate Technical, Acramite-50WS have low acute oral, dermal, and inhalation toxicity in laboratory animals. T he oral LD50 in rats and mice is greater than 5 g/kg for Acramite-50WS and the technical material. The dermal LD50 in rats of Bifenazate Technical and both formulations is greater than 5 g/kg. T he inhalation LC50 in the rats of Bifenazate Technical and Acramite 50WS was found to be greater than 4.4, 5.2 and 1.8 mg/l, respectively. In eye irritation studies, Acramite-50WS was a slight irritant, and Bifenazate Technical was nonirritating. Acramite-50WS was found to be non-irritating to the skin of rabbits and non-sensitizing on the skin of guinea pigs. Under the test conditions for the M&K maximization test, bifenazate technical was considered to be a sensitizer. 2. Genotoxicty. Bifenazate was evaluated and found to be negative in the Ames Reverse Mutation, Mouse Lymphoma, CHO Chromosome Aberration and Mouse Micronucleus assays. 3. Reproductive and developmental toxicity Rabbit Teratology Study: Arange-finding study conducted in pregnant New Zealand White rabbits at dosage levels of 125, 250, 500, 750 and 1,000 mg/kg/day demonstrated severe maternal toxicity at dosage levels of ≥500 mg/kg/day and abortions at dosage levels of ≥250 mg/kg/day. Bifenazate was then administered by oral gavage to pregnant New Zealand White rabbits at dosage levels of 10, 50 and 200 mg/kg/day. No test article related effects were seen at any dose level. The NOAEL for maternal and developmental toxicity was greater than 200 mg/kg/day, but less than 250 mg/kg/day. Rat Teratology Study: Bifenazate did not produce developmental toxicity when administered by oral gavage to pregnant Sprague-Dawley CD rats at dosage levels of 10, 100 and 500 mg/kg/day. Areduction in maternal body weight gain was seen at dosage levels of 100 and 500 mg/kg/day. Clinical observations at 500 mg/kg/day included red material/staining on body surfaces, pale extremities and brown discharge. No developmental or teratogenic effects were observed at any4

dosage level. The NOAEL for maternal toxicity was 10 mg/kg/day and the NOAEL for developmental toxicity was greater than 500 mg/kg/day. Rat Reproduction Study: Bifenazate showed no effects on reproduction upon dietary administration to two generations of male and female Sprague-Dawley CD rats at dietary concentrations of 20, 80 and 200 ppm. At a dosage level of 200 ppm there was a reduction in body weight gain in F0males and females. Food consumption was unaffected. There was a reduction in body weight gain in F1 females at all dosage levels and in F1 males at 80 and 200 ppm in the absence of effects on food consumption. Since the 20 ppm F1 males did not have a significant reduction in body weight gain, this dosage level can be considered a NOEL for systemic adult toxicity. The reduction in body weight gain in the F1 females at 20 ppmwould not be considered biologically significant because no effects were observed on reproductive parameters or in the F2 litter. The reproductive and developmental NOAEL was greater than 2 00 ppm (10 mg/kg/day). 4. Subchronic toxicity. Thirteen Week Rat Feeding Study: Bifenazate was fed to male and female Sprague Dawley CD rats for thirteen weeks at dietary concentrations of 40, 200 and 400 ppm. At dosage levels of 200 and 400 ppm there was a reduction in red blood cell count and hemoglobin. Food intake was reduced for 200 ppm females and 200 and 400 ppm males. Histopathological effects were seen in the liver, spleen and adrenal cortex in males and females at 200 and/or 400 pm. T he maximu m tolerated dose (MTD) was exceeded in females at 200 ppm and in males and females at 400 ppm. The NOAEL for subchronic toxicity in rats was 40 ppm (2 mg/kg/day). Neurotoxicity Assessment: No treatment related effects were seen on neurobehavior in a standard Functional Observation Battery conducted at weeks 8 and 13 of the thirteen-week rat feeding study. No overt signs of anticholinergic activity, and no statistically significant effects on cholinesterase activity were seen in rats in a two week feeding study at dose levels up to 400 ppm. Plasma, erythrocyte and brain cholinesterase activity were evaluated in male and female rats fed bifenazate-treated diet at 0, 20, 200, or 400 ppm for two weeks. All animals survived until study termination and effects were only seen on body weight gain and food consumption. The NOAEL for cholinergic inhibition was greater than 400 ppm (20 mg/kg/day). Thirteen Week Dog Feeding Study: Bifenazate was fed to male and female Beagle dogs for thirteen weeks at dietary concentrations of 40, 400 and 1,000 ppm. At dosage levels of 400 and 1,000 ppm there was a reduction in red blood cell count, hemoglobin and hematocrit. Liver weights were increased at 400 and 1,000 ppm and centrilobular hepatocellular hypertrophy was seen in f emales at 400 ppm and males and females at 1,000 ppm. The NOAEL for subchronic toxicity in dogs was 40 ppm (1 mg/kg/day). 5. Chronic toxicity. Dog Chronic Feeding Study: Bifenazate was fed to5

male and female Beagle dogs for one year at dietary concentrations of 40, 400 and 1,000 ppm. At dose levels of 400 and 1,000 ppm, there was a reduction in food consumption in males and reduced body weight gain in males and females. There was a reduction in red blood cell count, hemoglobin and hematocrit and an increase in bilirubin at 400 and 1,000 ppm. Histopathological ef fects on bone marrow, kidney and liver were also seen at these dose levels. The NOAEL for chronic toxicity in dogs was 40 ppm (1 mg/kg/day). Rat Chronic Feeding/Oncogenicity Study: Bifenazate was not oncogenic in rats when fed to male and female Sprague-Dawley CD rats for two years at dietary concentrations of 20, 80 and 160 in females or 20, 80 and 200 ppmin males. Body weight gain was reduced in males and females at the high dosage levels. A reduction in red blood cell count and an increase in splenic pigment were seen in females at 160 ppm, while high dose males exhibited a reduction in total cholesterol and an increase in splenic pigment. At a dose level of 80 ppm there was a reduction in body weight gain, a decrease in red blood cell count and an increase in splenic pigment in females. There was no increase in tumor incidence in males or females as a result of bifenazate administration. The NOAEL for chronic toxicity in rats was 20 ppm (1 mg/kg/day). Mouse Oncogenicity Study: Bifenazate was not oncogenic when fed to male and female CD - 1 mice for eighteen months at dietary concentrations of 10, 100 and 175 ppm in females and 10, 100 and 225 ppm in males. Body weight gain was reduced in males and females at the high dose level. A reduction in red blood cell, total leukocyte and lymphocyte counts was seen in males at 225 ppm. There was no increase in tumor incidence in males or females as a result of bifenazate administration. 6. Animal metabolism. In rat, [14C] -bifenazate, [14C -Phenyl] Hydrazine carboxylic acid, 2-(4-methoxy- [1,1? -biphenyl] -3 -yl)- 1 -methylethyl ester was extensively metabolized when it was given orally in two dose levels low (10 mg/kg), and high (1000 mg/kg). Although 2/3 of the dosed radioactivity was excreted in the feces, bifenazate depicted a good degree of absorption as indicated from the level of radioactivity in the bile. In the bile radioactivity study, about 70% of the C - 14 was collected from the cannulated bile ducts of low dosed rats indicating an active level of absorption and enterohepatic circulation. In general, the major metabolites present in feces, urine and bile resulted from several well known metabolic reactions, including hydrazine oxidation to diazene (D3598), molecular scission with loss of the hydrazine carboxylic acid portion of the molecule to yield 4 -methoxybiphenyl (D1989) followed by demethylation to form 4 -hydroxybiphenyl (A1530). Metabolites resulted from aromatic hydroxylation, and conjugation with glucuronic acid or sulfate were also identified. Pharmacokinetic parameters: The maximum plasma concentration (Cmax,6

calculated as ppmD2341 equivalents) was reached much earlier following the low dose (5-6 h) than the high dose (18-24 h). Elimination half -lives (t1/2) were marginally longer at the high dose (12- 16 h) than at the low dose (12- 13 h). There were no obvious and consistent sex differences in the pharmacokinetic parameters. 7. Metabolite toxicology

. In a single dose oral toxicity limit test in rats, the oral LD50 of the diazene product of bifenazate was estimated to be approximately 5,000 mg/kg. At two hours and at seven days post-dosing, no effects were seen on erythrocyte cholinesterase inhibition in male or female rats. In addition, no effect on plasma cholinesterase inhibition was seen in male rats at seven days only. Since this effect was seen only in plasma of females at one time point, it is most likely a pseudocholinesterase effect without biological significance. In a dermal toxicity screen, the LD50 of the diazene was estimated to be >2,000 mg/kg. Mutagenicity screens with the diazene showed it to be weakly positive in the Salmonella plate incorporation (Ames) assay in TA98 with activation and negative in the L5178Y mouse lymphoma and mouse micronucleus assays. 8. Endocrine disruption

. There are no known reported adverse reproductive or developmental effects in domestic animals or wildlife as a result of exposure to this chemical. A standard battery of required toxicity tests have been conducted on bifenazate. No effects were seen in the reproduction or teratology studies to indicate that bifenazate has an effect on the endocrine system. Bifenazate administration to rats for 90 days at dose levels of 200 and 400 ppm resulted in an increased incidence of vacuolation in the zona fasciculate of the adrenal cortex in male rats. No effect was seen at a dose level of 40 ppm (2 mg/kg/day). However, in the chronic rat feeding study, no effect was seen on the adrenal cortex in male rats fed 200 ppm for one year. Furthermore, fasting glucose levels were not reduced at any dose level in males or females in either study. The zona fasciculate is the site of cortisol production and cortisol is required for gluconogenesis during fasting. The finding that fasting glucose levels are not affected would suggest that adrenal cortex functionality is not impaired at any dose level by bifenazate. C. Aggregate Exposure 1. Dietary exposure. Based on dietary, drinking water, and non-occupational exposure assessments, there is reasonable certainty of no harm to the US population, any population subgroup, or infants and children from chronic exposure to bifenazate. Food. Chronic dietary exposures were estimated utilizing the Dietary Exposure Evaluation Model software with Food Commodity Intake Database (DEEM-FCID), version 2.16 . The most current and proposed crops are included in EPA’s 20077

assessment assuming tolerance-level residues and 100% crop treated. EPA used anticipated residues for some crops (i.e., average residues from field trials for squash, peach and tomato) and percent crop treated estimates for some foods (i.e., almonds, apples, apricots, cherries, cucumbers, grapes, nectarines, oranges, peaches, pears, pecans, peppers, pistachios, p runes & plums, strawberries, tomatoes, walnuts and watermelons). C hemical-specific processing factors are also included for apple juice (0.23), grape juice (0.17), wine/sherry (0.17), tomato paste (1.0) and tomato puree (1.0). The percent crop treated for soybeans is 0% because there was no use on soybeans in 2005 or 2006 or 2007, and there are no plans to pursue future use of bifenazate on soybeans. Market projections are 1 % for tropical fruit (except avocados) group 6B and 10% for caneberries. Total chronic exposures to registered and proposed crops range from 0.001171 mg/kg/day (11.7% of cPAD) for youth aged 13 - 19 years to 0.005506 (55.1% of cPAD) for children aged 1 -2 years old. Chronic dietary exposure for the U.S. population is estimated to be 0. 001943 mg/kg/d (19.4% of cPAD). Chronic dietary exposures less than 100% of the cPAD are not of concern. The dietary exposures presented here are only slightly greater than those estimated by EPA in the December 14, 2007, assessment supporting registration of caneberries (Subgroup 13A), wild raspberry, Subgroups 6A and 6B, succulent-shelled soybeans and assorted tropical fruit. It should be noted that assumption of 100% crop treated on most crops in this assessment is extremely conservative. Chemtura proj ects a market share for most crops of approximately 1% for minor crops in crop groups and the low susceptibility of the minor crops to mites. Unless mites are present, bifenazate will not be used. The chronic exposures estimated here are conservative because tolerance-level residues are also assumed for most crops and because the percent crop treated assumption for most crops is 100%. Existing crop treated data show only minimal treatment of registered crops with bifenazate. Use on most crops, especially those significant in children’s diets, is estimated to be 1% (apples, cherries), 5% (grapes, plums) or 10% (peaches, pears). ii. Drinking water

. Exposure to bifenazate and potential residues in drinking water is expected to be negligible. Bifenazate (half -life of 30 minutes) degrades rapidly under aerobic conditions to D3598 (half -life of 7 hours), which degrades rapidly to D1989 (half -life of 96 days). Photodegradation and other routes of dissipation of bifenazate do not appear to be significant. Based on these data, the residue of concern was considered to be D1989. Parent and D3598 were not included as residues of concern in drinking later due to the short half -lives of these compounds and the lack of an acute dietary endpoint. As reported in the Febru ary 4, 2004 Federal Register (69 CFR 5289-5297), the annual average estimated environmental concentrations (EECs) for bifenazate (6.38 ppb in surface water and < 0.001 ppb in ground water) are based on a single application of 0.75 lb ai/acre to strawberries, since the application to grass was assumed not to impact the EECs estimated by EPA. Chronic estimated environmental concentrations (EECs) of D1989 in surface and8

ground water were generated using FIRST and SCI-GROW (1 application at 0.75 lbs ai/acre). The FIRST model generated an EEC of 6.4 ppb and SCI-GROW model generated an EEC of <0.001 ppb. These EEC values are lower than the drinking water levels of concern (DWLOC) for adults (260 ppb) and infants 1 -2 years of age (8.8 ppb). Uses on proposed crops were assumed not to impact the EEC estimates. 2. Non

-dietary exposure . As reported in the September 26, 2003 Federal Register notice (68 FR 55494-55503), EPA estimated a combined MOE for 4200 for residents applying a product to home ornamental plants and fruit trees. Therefore, for the current short-term aggregate assessment this MOE was included in estimating the short-term aggregate MOE resulting from dietary and residential exposures. Calculations were performed for population subgroups that might app ly bifenazate to ornamentals and fruit trees (i.e., youth 13 - 19 years old, adults 20-49 years old, females 13 -49 years old, adults 50+ years old and the general population). The short term oral endpoint for this scenario is 10 mg/kg/d. MOEs range from 23 00-2800. E stimated aggregate MOEs in excess of the target MOE (100) indicate reasonable certainty of no harm resulting from aggregate bifenazate exposures from food, drinking water and residential uses. D. Cumulative Effects

. The mechanism/mode of action of bifenazate on the mammalian red blood cell, which is target organ in the species tested, remains to be elucidated. The lack of information on bifenazate mode of action precludes an assessment of cumulative effects. EPA has not made a common mechanism of toxicity finding as to bifenazate and any other substances and bifenazate does not appear to produce a toxic metabolite produced by other substances. E. Safety Determination 1. U.S. population. Based on the toxicology database and available information on anticipated residues, chronic dietary exposure to the U.S. pop ulation (total) was 19.4 % of the cPAD. The FIRST model generated an EEC of 6.4 ppb and SCI-GROW model generated an EEC of <0.001 ppb. These EEC values are lower than the drinking water levels of concern (DWLOC) for adults (260 ppb). The combined MOE from the limited potential for short-term exposure from residential uses is >1000. Based on these assessments, it can be concluded that there is reasonable certainty of no harm to the U.S. p opulation or any population subgroup from exposure to bifenazate. 2. Infants and children

. Based on the toxicology database and available information on anticipated residues, chronic dietary exposure to infants (under 1 year of age) was 40.7 % of the cPAD and to children (1 -2 years of age) was 55.1 % of the cPAD. The FIRST model generated an EEC of 6.4 ppb and SCI-GROW model generated an EEC of <0.001 ppb. These EEC values are lower than the drinking water levels of concern (DWLOC) for infants 1 -2 years of age (8.8 ppb). The combined MOE from the limited potential for short-term exposure from residential uses is >1000. Based on these assessments, it can be concluded that there is9

reasonable certainty of no harm to the U.S. Population or any population subgroup from exposure to bifenazate. F. International Tolerances There are no CODEX or other international MRLs or tolerances for the requested uses identified in this petition. In Argentina, the following Tolerance/MRLs have been established: Apples 1 (mg/kg). In Australia, Tolerance/MRL’s have been established: Apricot 0.5, Apple 2.0, Nectarine 0.5, Peach 2.0, Pear 2.0, Plum including prune 0.5, and Pome Fruits 2 (mg/kg). In Canada Tolerance/MRLs have been established: Apple 0.6, Cucumber 0.25, Grape 1.0, Pepper 1.1, Raisins 1.2 and Tomato 0.35 (ppm). An important tolerance is also published for strawberry (1.5 ppm). In Chile, Tolerance/MRLs have been established: Apple 0.75, Nectarine 1.7, Peach 1.7, Pear 0.75, Plum 0.3 (mg/kg). In Japan Tolerance/MRLs have been established: Apple 2.0, Cherry 3.0, Citrus Fruit 1.0, Cucumber 0.75, Eggplant 2.0, Grape 3.0, Melon 0.2, Peach 2.0, Pear 2.0, Plum 3.0, Strawberry 5 .0, Tea 2.0, Tomato 1 .0, and Watermelon 0.3 (mg/kg). In Korea Tolerance/MRLs have been established: Apple 1.0, Citrus 0.1, Eggplant 0.5, Peach 0.3, Pear 0.2, Rose N/A, Watermelon 0.1 (mg/kg). The EU commission has set MRLs of 2 mg/kg for Strawberries and Peppers, 0.5 for Aubergines and Tomatoes and 0.3 for Cucurbits with edible peel.