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

COMPANY NOTICE OF FILING 

EPA Registration Division contact: Sidney Jackson, 703-305-7610

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, 

small, 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 of the submitted data at 

this time 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 all 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 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. The 

method, “Determination of Combined Bifenazate and D3598 Residues in Sugar 

Apple”, utilizes reversed phase HPLC to separate the bifenazate from matrix 
2

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. Three 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. Sugar 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 proposing 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 0.3539
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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. The 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. 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 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: A range-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. A reduction 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 any 
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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 F0 males 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 ppm would 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 200 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. The maximum 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 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. Chronic toxicity. Dog Chronic Feeding Study: Bifenazate was fed to 
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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 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 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 ppm D2341 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 2007 
7

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, prunes & plums, strawberries, 

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 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 projects 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 February 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 and 
8

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 apply 

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 

2300-2800. Estimated 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. population 

(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. 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 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 is 
9

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.