COMPANY NOTICE OF FILING 

EPA Registration Division contact: Andrew Ertman, 703-308-9367 

Chemtura Corporation

PP# 1E7847 

 EPA has received a pesticide petition (1E7847) from IR-4 Project Headquarters, 

Rutgers, The State University of NJ, 500 College 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 carboxylic acid, 2-(4-methoxy-[1,1'-biphenyl]-3-yl) 

1-methylethyl ester] in or on the raw agricultural 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, forage at 140 ppm and Timothy, hay at 120 

ppm. Upon approval of the proposed tolerance listed about the petition also requests the 

deletion of tolerances for Vegetable, fruiting, 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 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 “NLC (North Coast 

Laboratories LTD) 20.082/Uniroyal 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 spectrometer. 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 if quantitation 

(LOQ) were calculated as 0.00948 ppm and 0.0285 ppm, respectively, for bifenazate on 
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fresh basil; 0.00822 ppm and 0.0246 ppm, respectively, for D3598 on fresh basil; 0.0115 

ppm and 0.0345 ppm, respectively, for bifenazate on dried basil; 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 Region 10), one trial in 

South Carolina (EPA Region 2), and two trials 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 untreated (control) plot and one treated plot. At each trial, a 

single foliar application of Acramite 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 later. 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 combined 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 field trials on basil, Chemtura Corporation is proposing a crop 

Commodity 

Application 

Rate 

(lb ai/A)2 

PHI 

(days) 

Residue Levels 

(ppm)1 

n Min. Max. HAFT3 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 NA4 NA NA 
3

specific tolerance of 30 ppm on Herb Subgroup 19A, fresh leaves and 140 ppm on Herb 

subgroup 19A, dried leaves, except chervil, 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 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 non-irritating. 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 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 
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considered biologically significant because no effects were observed on reproductive 

parameters or in the F2 litter. The reproductive and developmental 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 Blood Cell (SRBC) and Natural Killer (NK) 

Cell Activity treated for 28 days with 0, 20, 80 and 200 ppm Bifenazate (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 cell activity was evaluated 

concurrently in an unimmunized cohort. There were no significant effects of Bifenazate, 

at any dose, on food consumption, spleen weight, thymus weight, or anti-SRBC IgM. NK 

cytolytic activity, as a measure of innate immunity, was also unchanged compared to 

vehicle control treated animals. Slight decreases 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 related to test substance administration. In 

conclusion, the Bifenazate NOEL for this study is 80 ppm (average 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 admixture 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 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 anti-cholinergic 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).]
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 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, 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.] 

 7. 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, calculated 

as ppm D2341 equivalents) was reached much earlier following the low dose (5-6 h) 
6

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.]

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 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.] 

 9. 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 

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, 
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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 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 SCIGROW 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 
8

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 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 
9

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.]