COMPANY NOTICE OF FILING

EPA Registration Division cont act: Andrew Ertman, 703-308-9367

Chemtura Corporation

PP# 1E7847

EPA has received a pesticide petition (1 E7847) from IR-4 Project Headquarters, Rutgers, The State University of NJ, 500 Co llege Road East, Suite 201 W, Princeton, NJ 08540 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 by establishing a tolerance for residues of bifenazate: hydrazine carboxy lic acid, 2-(4-methoxy-[ 1,1'-biphenyl]-3-yl) 1-methylethyl ester] in or on the raw agri cultural commodity herb subgroup 19A, fresh leaves at 30 parts per million (ppm), herb subgroup 19A, dried leaves, except chervil, dried and chive, dried at 140 ppm, Fruit, pome, group 11-10 at 0.75 ppm, Vegetable, fruiting, group 8-10 at 2.0 ppm, Timothy, fora ge at 140 ppm and Timothy, hay at 120 ppm. Upon approval of the proposed toleran ce listed about the petition also requests the deletion of tolerances for Vegetable, fr uiting, group 8 and Fruit, pome, group 11. 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 of the submitted data at this tim e or whether the data supports granting of the petition. Additional data may be 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. The major residue in al l plant metabolism studies is bifenazate. A minor, but significant metabolite is the diazene D3598, which was found to interconvert readily to/from bifenazate in the plant matrix during the analytical procedure.]

2. Analytical method. [Chemtura Corporation has de veloped practical analytical methodology for detecting and measuring residues of bifenazate in or on raw agricultural commodities. As D3598, a significant meta bolite, was found to interconvert readily to/from bifenazate, the analytical method wa s designed to convert all residues of D3598 to the parent compound (bifenazate) for an alysis. The method “NLC (North Coast Laboratories LTD) 20.082/Uniroya l RP-01015” for mint tops and oil was slightly modified for the analysis of basil. The final basil sample extract is analyzed using a liquid chromatograph with a tandem mass sp ectrometer. The lowest level of method validation (LLMV) in this study was 0.05 ppm fo r each analyte. Based on recoveries of samples fortified at the LLMV, the limit of detection (LOD) and limit if quantitation (LOQ) were calculated as 0.00948 ppm and 0.0285 ppm, respectively, for bifenazate on2

fresh basil; 0.00822 ppm and 0.0246 ppm, respec tively, for D3598 on fresh basil; 0.0115 ppm and 0.0345 ppm, respectively, for bifen azate on dried basi l; 0.0185 ppm and 0.0557 ppm, respectively, for D3598 on dried basil.

3. Magnitude of residues. A complete crop residue program has been completed for bifenazate in the major growing areas of the US for:

Basil: A crop residue program has been completed for bifenazate using Acramite®- 50WS on

basil. Four trials were conducted for this study in accordance with U.S. EPA OPPTS 860 series guidelines. One trial was conducted in California (EPA Regi on 10), one trial in South Carolina (EPA Region 2), and two tr ials in Georgia (EPA Region 2 during the 2008 growing season. The number of field trials exceeds OPPTS Guideline 860.1500.

Each trial site included one untre ated (control) plot and one tr eated plot. At each trial, a single foliar application of Ac ramite 50WS was made, at a rate of approximately 0.75 lb ai/A. A commercially available adjuvant ( non-ionic surfactant) was added to the spray mixture. The application was timed so that commercially mature samples of fresh basil could be harvested three days la ter. At the California trial, additional samples of fresh basil were harvested at the same time for drying.

Combined residues of bifenazate and D3598 in fresh basil harvested at a 3-day PHI ranged from 3.4 ppm to 15 ppm. Combined residues of bifenazate and D3598 in dried basil harvested at a 3-day PHI were 91 ppm.

A summary table is provided below:

1 These values represent the combin ed residues of bifenazate and D3598.

2 One foliar application of Acramite 50WS at approximately 0.75 lb ai/A was made.

3 HAFT = Highest average field trial.

4 NA = Not applicable

Based on the results of the fiel d trials on basil, Chemtura Co rporation is proposing a crop

Commodity Application

Rate (lb ai/A) 2 PHI (days) Residue Levels (ppm) 1

n Min. Max. HAFT 3 Mean Std. Dev.

Basil (fresh) 0.745-0.784 3 8 3.4 15 14.5 8.9 4.2

Basil (dried) 0.745 3 1 91 91 NA 4 NA NA3

specific tolerance of 30 ppm on Herb S ubgroup 19A, fresh leaves and 140 ppm on Herb subgroup 19A, dried leaves, except ch ervil, dried and chive, dried.

B. Toxicological Profile

1. Acute toxicity. [Bifenazate Technical, Acramite -50WS have low acute oral, dermal, and inhalation toxicity in laboratory animals. The oral LD50 in rats and mice is greater than 5 g/kg for Acra mite-50WS and the technical material. The dermal LD50 in

rats of Bifenazate Technical and both formulati ons is greater than 5 g/kg. The 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 ey e irritation studies, Acramite-50WS was a slight irritant, and Bifenazate Technical wa s non-irritating. Acramite-50WS was found to be non-irritating to the skin of rabbits and non-sensitizin g on the skin of guinea pigs.

Under the test conditions for the M&K ma ximization test, bifena zate 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: A range-findi ng 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 admini stered 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 th an 200 mg/kg/day, but less than 250 mg/kg/day.]

[Rat Teratology Study: Bifenazate did no t produce developmental toxicity when administered by oral gavage to pregnant Spra gue-Dawley CD rats at dosage levels of 10, 100 and 500 mg/kg/day. A reduction in ma ternal body weight gain was seen at dosage levels of 100 and 500 mg/kg/day. Cl inical observations at 500 mg/kg/day included red material/staining on body surfaces, pale extremities and brown discharge. No developmental or teratoge nic effects were observed at any dosage

level. The NOAEL for maternal toxici ty was 10 mg/kg/day and the NOAEL for developmental toxicity was greater than 500 mg/kg/day.]

[Rat Reproduction Study: Bifenazate show ed 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 F0 males and females. Food consumption was unaffected. There was a reduction in body wei ght 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 ppm would not be4

considered biologically significant because no effects were observed on reproductive parameters or in the F2 lit ter. The reproductive and de velopmental NOEL was greater than 200 ppm (10 mg/kg/day).]

4. Immunotoxicity: [Immunotoxicity evaluation of Bifenazate was conducted in CD-1 female mice using Anti-Sheep Red Bl ood Cell (SRBC) and Natural Killer (NK) Cell Activity treated for 28 days with 0, 20, 80 and 200 ppm Bife nazate (Bifenazate average dose levels ~5, 20, and 50 mg/kg/ day, respectively). Anti-SRBC IgM production was evaluated 5 days post- SRBC immunization, and NK cel l activity was evaluated concurrently in an unimmunized cohort. There were no significant effects of Bifenazate, at any dose, on food consumption, spleen we ight, thymus weight, or anti-SRBC IgM. NK cytolytic activity, as a meas ure of innate immunity, was also unchanged compared to vehicle control treated animals. Slight d ecreases in weekly water consumption and body weights at 200 ppm Bifenazate are consistent with previous findings for this test substance and, as such, are considered rela ted to test substan ce administration. In conclusion, the Bifenazate NOEL for this study is 80 ppm (ave rage dose level ~20 mg/kg/day) and the NOAEL is 200 ppm (average dose level ~50 mg/kg/day). With no effect on anti-SRBC IgM production or NK cell activity, Bifenazate was not immunotoxic in this study at diet ad mixture concentrations up to 200 ppm.]

5. 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 ma les and females at 200 and/or 400 pm. The maximum tolerated dose (MTD) was exceeded in females at 200 ppm and in males and females at 400 ppm. The NOAEL for subc hronic toxicity in rats was 40 ppm (2 mg/kg/day).

Neurotoxicity Assessment: No treatment rela ted effects were seen on neurobehavior

in a standard Functional Observation Ba ttery conducted at weeks 8 and 13 of the

thirteen-week rat feed ing study. No overt signs of an ti-cholinergic activity, and no statistically significant effects on cholinestera se 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 w eeks. All animals su rvived 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: Bifenaza te was fed to male and female Beagle dogs for thirteen weeks at dietary concen trations 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 weight s were increased at 400 and 1,000 ppm and centrilobular hepatocellular hypertrophy was seen in females 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

6. Chronic toxicity. [Dog Chronic Feeding Study: Bifenazate was fed to 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, hemogl obin and hematocrit and an increase in bilirubin at 400 and 1,000 ppm. Histopath ological effects 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 ppm in males. Body weight gain was reduced in males and fe males at the high dosage levels. A reduction

in red blood cell count and an increase in splenic pigment we re seen in females at 160 ppm, while high dose males exhibited a reduc tion 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 toxici ty 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 concentrati ons of 10, 100 and 175 ppm in females and 10, 100 and 225 ppm in ma les. Body weight ga in was reduced in males and females at the high dose leve l. 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.]

7. Animal metabolism. [In rat, [14C]-bifenazat e, [14C-Phenyl] Hydrazine carboxylic acid, 2-(4-methoxy-[1,1?-bipheny l]-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 dos ed radioactivity was excreted in the feces, bifenazate depicted a good degree of ab sorption as indicated from the level of radioactivity in the bile. In the bile radioactivity study, abou t 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 porti on of the molecule to yield 4-methoxybiphenyl (D1989) follo wed by demethylation to form 4- hydroxybiphenyl (A1530). Metabo lites resulted from ar omatic hydroxylation, and conjugation with glucuronic acid or sulfate were also identified.

Pharmacokinetic parameters: The maximum pl asma concentration (Cmax, calculated as ppm D2341 equivalents) wa s reached much earlier foll owing the low dose (5-6 h)6

than the high dose (18-24 h). Elimination hal f-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.]

8. 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 inhi bition in male or female ra ts. In addition, no effect on plasma cholinesterase inhibiti on was seen in male rats at seven days only. Since this effect was seen only in plasma of female s at one time point, it is most likely a pseudocholinesterase effect without biologi cal significance. In a dermal toxicity screen, the LD50 of the diazene was estimated to be >2,000 mg/kg.

Mutagenicity screens with the diazene s howed 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.]

9. Endocrine disruption . [There are no known repor ted adverse reproductive or developmental effects in domestic animals or wildlife as a result of exposure to this

chemical.

A standard battery of required toxicity te sts have been conducted on bifenazate. No effects were seen in the reproduction or tera tology studies to indicate that bifenazate has an effect on the endocrine system. Bifen azate 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 feed ing study, no effect

was seen on the adrenal cortex in male ra ts 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 co rtisol is required for gluconogenesis during fas ting. The finding that fast ing 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, drinki ng 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 chr onic exposure to bifenazate.]

Food. [Chronic dietary exposures were esti mated utilizing the Dietary Exposure

Evaluation Model software with Food Co mmodity Intake Database (DEEM-FCID),

version 2.16. The most current and proposed cr ops are included in EPA’s 2007 assessment assuming tolerance-level resi dues and 100% crop treated. EPA used anticipated residues for some crops (i.e., aver age residues from field trials for squash, peach and tomato) and percent crop treated estimates for some foods (i.e., almonds,7

apples, apricots, cherries, cucumbers, grapes, nectarines, oranges, peaches, pears, pecans, peppers, pistachios, prunes & plums, strawber ries, tomatoes, walnuts and watermelons). Chemical-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 soybean s 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 di etary exposures presented here are only slightly greater than t hose estimated by EPA in the December 14, 2007, assessment supporting registration of caneberries (Subgr oup 13A), wild raspberry, Subgroups 6A and 6B, succulent-shelled soybeans a nd assorted tropical fruit. It should be noted that assumption of 100% crop treated on most cr ops in this assessment is extremely conservative. Chemtura projects a market sh are 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 c onservative because to lerance-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, espe cially 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 (hal f-life of 30 minutes) de grades 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 signi ficant. Based on these data, the residue of c oncern was considered

to be D1989. Parent and D3598 we re 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 February 4, 2004 Federa l Register (69 CFR 5289-5297), the annual average estimated environmental concentr ations (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 applica tion to grass was assumed not to impact the EECs estimated by EPA. Chronic estimated e nvironmental concentr ations (EECs) of D1989 in surface and ground water were generated using FIRST and SCI-GROW (1 application at 0.75 lbs ai/acr e). The FIRST model generate d an EEC of 6.4 ppb and SCIGROW model generated an EEC of <0.001 pp b. These EEC values are lower than the drinking water levels of concern (DWLOC) fo r adults (260 ppb) and infants 1-2 years of age (8.8 ppb). Uses on proposed crops were a ssumed not to impact the EEC estimates.]

2. Non-dietary exposure . [As reported in the Septem ber 26, 2003 Federal Register8

notice (68 FR 55494-55503), EPA estimated a combined MOE for 4200 for residents applying a product to home orname ntal 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 re sidential exposures. Calculations were performed for population subgroups that might apply bifenazat e 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 2300-2800. Estimated aggregate MOEs in excess of the target MOE (100) indicate reasonable ce rtainty of no harm resulting from aggregate bifenazate exposures from food, dri nking 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 sp ecies 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 mechanis m of toxicity finding as to bifenazate and any other substances and bi fenazate does not appear to produce a toxic metabolite produced by other substances.]

E. Safety Determination

1. U.S. population. [Based on the toxicology databa se and available information on anticipated residues, chroni c dietary exposure to the U.S. population (total) was 19.4%

of the cPAD. The FIRST m odel generated an EEC of 6.4 ppb and SCI-GROW model generated an EEC of <0.001 ppb. These EEC va lues are lower than the drinking water levels of concern (DWLOC) for adults (260 ppb). The combined MO E 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. population or any population subgroup from exposure to bifenazate.]

2. Infants and children . [Based on the toxicology database and available information on anticipated residues, chronic di etary exposure to infa nts (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 mo del generated an EEC of <0.001 ppb. These EEC values are lowe r 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 is 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 internati onal MRLs or toleran ces for the requested uses identified in this peti tion. In Argentina, the followi ng 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 Toleranc e/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 important9

tolerance is also published fo r 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 establis hed: 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, a nd 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.]