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HASPOC concluded that a DNT study is required for bifenazate: (i) observed treatment-related 

neurological effects in adult animal studies (i.e., clinical signs of neurotoxicity, neuropathology, 

functional or behavioral effects); (ii) observed treatment-related neurological effects in 

developing animals, following pre- and postnatal exposure (i.e., nervous system malformations 

or neuropathy, brain weight changes in offspring, functional or behavioral changes in the 

offspring); and (iii) the pesticide evokes a mechanism that is associated with adverse effects on 

the development of the nervous system (e.g., SAR relationship to known neurotoxicants, altered 

neuroreceptor, or neurotransmitter responses).

With the exception of a requirement for a DNT study, the toxicity database for bifenazate is 

adequate for risk assessment. A 10x database uncertainty factor (UFDB) will be retained for the 

lack of this study.

The qualitative nature of the residue in plants is adequately understood based on acceptable 

studies with apple, orange, cotton, and radish. The residues of concern in crops are bifenazate 

and its metabolite D3598 (calculated as the stoichiometric equivalent of bifenazate). The nature 

of the residue in livestock is adequately understood based on studies with lactating goats and 

laying hens. The residues of concern in livestock tissue (excluding fat), eggs, and milk are 

bifenazate and the metabolites D3598, A1530, and A1530-sulfate (calculated as the 

stoichiometric equivalent of bifenazate). The residues of concern for tolerance expression and 

risk assessment purposes in fat are bifenazate and D3598 (calculated as the stoichiometric 

equivalent of bifenazate). 

The HED Chemistry Science Advisory Council (ChemSAC) convened on July 16, 2008 to 

discuss residue data requirements for proposed uses of bifenazate on grasses, dry beans, and 

corn. ChemSAC concluded that new ruminant metabolism and feeding studies for bifenazate 

should be submitted if the dietary burden significantly increased above 10 ppm. If uses on corn 

and grasses were granted, then the dietary burden to ruminants would be significantly higher 

than 10 ppm. Therefore, new ruminant metabolism and feeding studies with higher dosing levels 

would be required. The registrant withdrew the use/tolerances request for bifenazate in/on corn 

and grasses.

The residue chemistry database for bifenazate is sufficient to support Registration Review and 

additional residue chemistry data are not required at this time. 

The dietary exposure database is adequate to support Registration Review. Revised assessments 

may be required under Registration Review in order to incorporate the most recent dietary 

exposure model, updated toxicological endpoints, updated estimated drinking water 

concentrations (EDWCs) provided by the Environmental Fate and Effects Division (EFED), and 

updated percent crop-treated data (PCT) from the Biological Economic Analysis Division 

(BEAD). 

The occupational exposure database is adequate to support the Registration Review process for 

bifenazate. Updated occupational handler exposure assessments may be required under 

Registration Review based upon revisions to the Agency’s scenario-specific handler exposure 

data. New exposure monitoring data may be incorporated, as necessary, during Registration 

Review. Updated occupational post-application exposure assessments may be required under 

Registration Review based upon revisions to the Agency’s post-application exposure data. In 

addition, revised occupational handler and post-application assessments may be needed if 
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toxicological endpoints change or other new data are received by the Agency that impact 

exposure estimates.

The residential exposure database is adequate to support the Registration Review process for 

bifenazate. Updated residential handler and post-application exposure assessments may be 

required under Registration Review based upon revisions to HED’s Residential Standard 

Operating Procedures (SOPs) and body-weight assumptions. In addition, revised residential 

handler and post-application assessments may be needed if toxicological endpoints change or 

other new data are received by the Agency that impact exposure estimates. Furthermore, 

because of the potential for residential bystander exposures due to bifenazate aerial and airblast 

applications, volatilization, and/or transport from treated areas, HED will evaluate the need for a 

bystander assessment during Registration Review. 

Introduction

Hazard Identification/Toxicology

Bifenazate is a selective miticide/insecticide that controls the motile stage of mites either by 

direct contact or through contact with foliar residues. Bifenazate binds to the GABA-activated 

chloride channels of susceptible pests resulting in paralysis of the peripheral nervous system. 

Even though its pesticidal mode of action involves neurotoxicity in insects, its effects in 

mammalian systems are indicative of hepatotoxicity and hematotoxicity. 

Low-dose male and female rats absorbed ~85% of the administered dose from the 

gastrointestinal tract as indicated by the amount of radiolabel recovered in the urine, cage wash, 

tissues/carcass, and bile. The Tmax (time to maximum concentration in blood or plasma) was 5 

and 6 hours (males and females) for the low-dose group. Absorption was saturated at the highdose in male and female rats, as 57-64% of the administered dose was recovered in the feces in 

the biliary study. The Tmax was 18 and 24 hours (males and females, respectively) for the highdose group. There was no significant tissue accumulation of the test material. The highest tissue 

levels were found in the liver and whole blood, although the concentration of the test material 

represented <3% of the administered dose 6 hours after treatment. 

The feces were the primary elimination route for low-dose rats with ~66% of the administered 

dose recovered in this media. Cmax (maximum concentration achieved in the blood or plasma) 

was reached earlier following a 10 mg/kg dose (5-6 hours) than the 1000 mg/kg dose (18-24 

hours). In addition, the plasma half-life (t1/2) was slightly longer at the 1000 mg/kg dose (12-16 

hours) than at the 10 mg/kg dose (12-13 hours). No apparent sex-related differences in the 

pharmacokinetics of bifenazate were observed. 

Bifenazate was classified as having low acute toxicity for the oral, dermal, and inhalation routes 

(all Toxicity Category IV). The dog is the most sensitive species. Subchronic and chronic 

studies in rats and dogs indicate that the liver and erythropoeitic system are the primary target 

systems in these species. The hematology profile revealed a mild anemia in multiple studies in 

mice, rats, and dogs. These effects were indicative of a regenerative anemia with increased redcell production by the bone marrow. Additional toxicity was seen in the kidney (dogs following 

chronic exposure) and adrenal cortex (male rats following subchronic exposure). Decreases in 

body weight, body-weight gain, and food consumption were also associated with liver and 

hematopoietic system toxicity in several studies. 
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In the rat developmental toxicity study, there was a treatment related increase in early resorptions 

at all doses tested, indicating an increased quantitative developmental susceptibility. The 

maternal effects consisted of clinical signs of toxicity, decreased body weight and body-weight 

gains, and reduced food consumption at the mid-dose. In the rabbit developmental toxicity 

study, there were no maternal or developmental effects up to the highest dose tested. In the 2-

generation rat reproduction study, the parental effects occurred at the mid-dose and consisted of 

decreased body weight and body-weight gains. The severity of these decreased body-weight 

gains did not decrease with dose. There were no reproductive or offspring effects up to the 

highest dose tested.

In the acute neurotoxicity study, effects were seen at all doses tested. At the low dose, there was 

a decrease in motor activity in females at 200 mg/kg/day. Effects at higher doses tested 

consisted of decreased motor activity (↓rearing in females; ↓center time in both sexes) and a 

slight increased absolute brain weights in males (↑7%). In the subchronic neurotoxicity study, 

effects were also only seen at the highest dose tested (34.5 mg/kg/day) and consisted of 

decreased landing foot splay (males), decreased fore- and hind-limb grip strength (males), and 

decreased motor-activity measurements consisting of center times (females) and rearing activity 

(both sexes). 

There were no effects in the immunotoxicity study up to the highest dose tested. There were no 

treatment-related effects on spleen or thymus weights, or the functional immune system tests 

such as the sheep red blood cell assay, or the natural killer cell assay.

In the 21-day dermal toxicity study in rats, adverse effects occurred at the mid-dose and 

manifested as kidney effects (↑urinary ketones, ↑urinary protein, ↑urinary specific gravity, and 

↓urinary volume in both sexes), and hematotoxic effects (↑incidences of extramedullary 

hematopoiesis in the spleen in both sexes). Similar to oral exposure studies, decreased body 

weights in females and decreased food consumption in both sexes were associated with the 

effects on the target organ systems. 

In the 28-day inhalation study, there were statistically significant decreased thymus weights 

(↓21-32%) in females at all of the concentrations tested. Without any changes in clinical 

chemistry or histopathology, these thymus weight changes were not considered adverse. Starting 

at the mid-concentration, there were clinical signs in females (dried red material around the 

nose), and decreased heart weights. There was a concentration-dependent increased incidence of 

slight to mild olfactory (nasal) epithelial degeneration (30% of males and 40-50% of females), 

and there was also an increased incidence of brown pigment in the spleen in females (80% at the 

mid-concentration and 90% at the high-concentration). At the highest concentration tested, there 

were decreased lung weights in both sexes (↓14%). Most of the effects described above 

increased in severity at the highest concentration tested. 

No evidence of carcinogenicity was seen in the rat and mouse studies, and bifenazate was 

classified as “Not Likely to be Carcinogenic to Humans.”

On July 12, 2012, HED’s HASPOC met to discuss the need for a DNT study to support the 

registered and proposed uses of bifenazate. Based on the following weight of evidence 

considerations, the HASPOC concluded that a DNT study is required for bifenazate: (i) 

observed treatment-related neurological effects in adult animal studies (i.e., clinical signs of 

neurotoxicity, neuropathology, functional or behavioral effects); (ii) observed treatment-related 

neurological effects in developing animals, following pre- and postnatal exposure (i.e., nervous 
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system malformations or neuropathy, brain weight changes in offspring, functional or behavioral 

changes in the offspring); and (iii) the pesticide evokes a mechanism that is associated with 

adverse effects on the development of the nervous system (e.g., SAR relationship to known 

neurotoxicants, altered neuroreceptor, or neurotransmitter responses).

Conclusions

The toxicity database for bifenazate is complete with the exception of a DNT study. 

The endpoints presented in Attachment 2 are from the most recent risk assessment for bifenazate 

(Memo, 7/14/2010, W. Wassell, et al., D371783). When the required study is submitted, the 

current toxicity endpoint/dose selection will need to be re-evaluated along with the Food Quality 

Protection Act Safety Factor (FQPA SF) for registration review.

Residue Chemistry

Bifenazate is registered for food/feed and non-food uses. The food/feed uses include the 

following crops: tropical fruits (including, but not limited to acerola, cherimoya, passion fruit 

and starfruit), tree nuts (group 14), pistachio, hops, okra, strawberry, cotton, dry bean seed, lowgrowing berry (subgroup 13-07G), pome fruit (group 11), small vine-climbing fruit (Subgroup

13-07F, except fuzzy kiwifruit), stone fruit (group 12), grape, succulent shelled pea and bean 

(subgroup 6B), mint, succulent shelled soybean, cucurbit vegetables (group 9), fruiting 

vegetables (group 8), edible-podded legume vegetables (subgroup 6A), and tuberous and corm 

vegetables (subgroup 1C). Tolerances for residues in conjunction with these uses are established 

(40 CFR §180.572). Additionally, tolerances are established for secondary residues of 

bifenazate in livestock commodities. The registered non-food uses include applications to nonbearing fruit crops, ornamental plants, landscapes, residences, 

public/commercial/industrial/intuitional areas, recreational sites (such as campgrounds, golf 

courses, parks, and athletic fields crops), and rights-of-ways. 

The qualitative nature of the residue in plants is adequately understood based on acceptable 

studies with apple, orange, cotton, and radish. A briefing document, summarizing the salient 

features of these studies (except the radish study), was presented to the HED Metabolism 

Assessment Review Committee (MARC). The MARC concluded that for tolerance expression 

and risk assessment purposes, the residues of concern in crops are bifenazate and its metabolite 

D3598 (calculated as the stoichiometric equivalent of bifenazate). 

The metabolic routes in all crops were similar with major residues being comprised of bifenazate

and lesser amounts of D3598. The metabolic route in tested plants proceeded via oxidation of 

the hydrazine moiety of bifenazate to form D3598 which is further degraded and bound by 

reaction with natural products. The MARC discussed the possible formation of hydrazine in 

plants and concluded that formation of hydrazines is unlikely due to the oxidation of the parent 

to the conjugated diazene. The MARC suggested that if the petitioner submits additional 

metabolism studies, the presence of biphenyl hydrazine should be monitored as a confirmatory 

measure.

Subsequent to the MARC decision, radish and corn metabolism studies were submitted. Radish 

plants were treated with a single spray application of bifenazate at 0.375 or 0.75 lb ai/A, and 

mature root and top samples were harvested 7 days after application. No further analytical work 

was performed in/on the radish root samples since the total radioactive residues (TRRs) were 

<0.01 ppm. Analysis of the radish tops indicated that bifenazate and D3598 were the major 
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residues. Hydroxylated D3598 and D2303 were also identified; biphenyl hydrazine was 

included as a reference standard but was not identified as a residue in the study. The corn 

metabolism study was deemed unacceptable. The Residue Chemistry Test Guidelines (OPPTS 

860.1300) specify that provided the results of metabolism studies on three dissimilar crops 

indicate a similar metabolic route in the crops, then additional plant metabolism data are not 

required. The metabolic routes in all crops studied were similar. Thus, additional plant 

metabolism data are not required for Registration Review. 

The qualitative nature of the residue in rotational crops is adequately understood based on an 

acceptable confined rotational metabolism study. The MARC reviewed the confined rotational 

crop study and concluded that the residues of concern in/on rotational crops could not be 

determined from the available data. The MARC concluded that a 30-day rotational crop 

restriction is appropriate based on the available data. Additional rotational crop data are not 

required for Registration Review. 

The qualitative nature of the residue in livestock is adequately understood based on acceptable 

studies with lactating goats and laying hens. The results of these studies have been presented to 

the MARC, and the MARC concluded that for tolerance expression and risk assessment 

purposes, the residues of concern in livestock tissue (excluding fat), eggs, and milk are 

bifenazate and the metabolites D3598, A1530, and A1530-sulfate (calculated as the 

stoichiometric equivalent of bifenazate). The residues of concern for tolerance expression and 

risk assessment purposes in fat are bifenazate and D3598 (calculated as the stoichiometric 

equivalent of bifenazate). 

Subsequent to the MARC decision, the petitioner submitted a radiovalidation study for the 

livestock enforcement method. Contrary to the ruminant metabolism study that indicated that 

A1530-sulfate was the major residue in milk and D9569 was a minor residue, the radiovalidation 

study indicated that D9569 was the major residue while A1530-sulfate was a minor residue. 

Differences in the fat and liver metabolic profile were not indicated. The petitioner has 

submitted data confirming the identity of A1530-sulfate in the ruminant metabolism study and 

confirming the identity of D9569 in the radiovalidation study. Therefore, the milk samples from 

the metabolism and radiovalidation studies resulted in different major residues. The petitioner 

proposed that this difference arose from the difference in the dosing levels.

Based on the currently available information, the dairy cow feeding study should have monitored 

for bifenazate, D3598, A1530, A1530-sulfate, and D9569 in milk. Monitoring for bifenazate, 

D3598, A1530, and A1530-sulfate in livestock tissues is acceptable. 

The metabolic routes in goats and hens were similar and proceeded via oxidation of the 

hydrazine moiety of bifenazate to form D3598 which is further degraded to D1989, D9569, 

A1530, and/or A1530-sulfate and to bound residues by reaction with natural products.

The ChemSAC convened on July 16, 2008 to discuss residue data requirements for pending 

proposed uses of bifenazate on grasses, dry beans, and corn. ChemSAC concluded that new 

ruminant metabolism and feeding studies for bifenazate should be submitted if the dietary burden 

significantly increased above 10 ppm. If the proposed uses were granted, then the livestock 

dietary burden for ruminants would increase significantly. Therefore, new ruminant metabolism 

and feeding studies with higher dosing levels and supporting storage stability data would be 

required. The registrant withdrew the use/tolerances request for bifenazate in/on corn and 

grasses. Additional ruminant metabolism data are not required for Registration Review. 
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The existing poultry metabolism study is adequate to allow HED to conclude that tolerances for 

secondary residues in poultry tissues and eggs are not required (Category 3 of 40 CFR §180.6). 

There is no reasonable expectation of finite residues in poultry matrices. This decision will be 

revisited in the future if additional crops with poultry feed stuffs are proposed for registration. 

Additional poultry metabolism data are not required for Registration Review. 

There are adequate residue analytical methods for tolerance enforcement. For plants, a highperformance liquid chromatography with oxidative coulometric electrochemical detector 

(HPLC/ELCD) Method UCC-D2341 is available as a primary enforcement method for the 

combined residues of bifenazate and its metabolite D3598. The method has been forwarded to 

the Food and Drug Administration (FDA) for inclusion in the Pesticides Analytical Manual, 

Volume II (PAM II). The limit of quantification (LOQ) and limit of detection (LOD) of Method 

UCC-D2341 are 0.01 and 0.005 ppm, respectively. In addition, a liquid chromatographic system 

with tandem mass spectrometers (LC-MS/MS) method (NCL ME 245) was recently submitted as 

a confirmatory method and has been forwarded to FDA. 

For livestock, HPLC methods with fluorescence detection or ELCD are available as primary 

methods for the enforcement of tolerances for residues of bifenazate and its regulated 

metabolites in livestock matrices. The methods have been forwarded to FDA for inclusion in 

PAM II. In addition, the LC-MS/MS method (NCL ME 259) was recently submitted as a 

confirmatory method, and this method was also forwarded to FDA. The validated LOQ was 0.01 

ppm for each analyte. The LOD was reported as 0.005 ppm. Additional residue methods data 

are not required for Registration Review. 

The requirements for Multiresidue Methods (MRMs) testing data are fulfilled. Bifenazate and 

the metabolites D3598, A1530, and A1530-sulfate are not quantitatively recovered through the 

FDA MRMs.

Storage stability data are available for residues of bifenazate and its metabolite D3598 in/on a 

variety of plant commodities. Residues of bifenazate and D3598 in/on raw agricultural 

commodities are generally stable for short intervals. Table 1 is a summary of the currently 

available storage stability data. Some of the previous storage stability studies for plants were 

conducted for only bifenazate; however, bifenazate and D3598 are the residues of concern for 

risk assessment and tolerance enforcement. 
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Table 1. Available Storage Stability Data for Bifenazate.

Crop Residue Interval of 

Demonstrated Stability Reference

Plant Commodities

Cantaloupe Bifenazate 2 months

DP#s 297604 and 318105, T. 

Bloem, 7/12/06

Tomato Bifenazate 5 months

Tomato paste Bifenazate 1 month

Tomato puree Bifenazate 1 month

Mint foliage Bifenazate 2.5 months

Pepper Bifenazate 5 months

Apple Bifenazate and D3598 42 days

DP# 277089, T. Bloem, 8/16/01

Grape Bifenazate and D3598 7 days

Peach Bifenazate and D3598 56 days - bifenazate

14 days – D3598

Cottonseed Bifenazate and D3598 <21 days1

Cotton gin byproducts Bifenazate and D3598 <44 days1

Cottonseed hulls Bifenazate and D3598 52 days

Cottonseed oil Bifenazate and D3598 28 days

Cottonseed meal Bifenazate and D3598 43 days - bifenazate

<43 days – D35981

Potato Bifenazate <7 days DP# 324430, T. Bloem, 7/19/06

Lychee Bifenazate <2 months DP# 337530, W. Wassell, 

12/14/07

Corn grain Bifenazate 6 weeks2

47453713.der.doc (Includes 

MRIDs 47467703 and 47467705)

Corn K+CWHR Bifenazate Instability shown for the 

intervals tested3

Corn stover Bifenazate 8 weeks

Corn forage Bifenazate Instability shown for the 

intervals tested4

Corn meal and flour Bifenazate 30 days 47453704.der.doc

Livestock Commodities

Milk and cow fat Bifenazate, D3598, and 

A1530

202 days for milk;

95 days for fat

DP# 277089, T. Bloem, 8/16/01

Cow muscle, liver,

and kidney Bifenazate and D3598 Instability shown for the intervals tested5

Cow muscle, liver, 

and kidney A1530

28 days for muscle,

14 days for liver; 

2 days for kidney

1 Shortest interval tested.

2 For corn grain, residues of bifenazate declined at the 12- and 24-week storage intervals tested; mean storage 

recoveries of bifenazate (corrected for mean concurrent recovery of the analytical method) were 56.1 and 40.5% at 

the 12- and 24-week storage intervals, respectively.

3 For corn K + CWHR, mean storage recoveries of bifenazate were 54.7%, 27.1%, and 14.1% at the 11-day, 3- and 

4-week storage intervals, respectively.

4 For corn forage, mean storage recoveries of bifenazate were 86.7%, 57.0%, 26.4%, and 33.5% at the 0-, 2-, 4- and 

8-week storage intervals, respectively.

5 Residues of bifenazate and D3598 are not stable in frozen muscle, liver, and kidney as recoveries dropped below 

70% after 2 days of storage (D3598 was stable in muscle for 2 days, but not 14 days).

As a result of these data, the registrant has been instructed to analyze samples from any future 

crop field trials within a few days of harvest. Additional storage stability data are not required 

for Registration Review with the exception of data for residues in/on hop cones. Storage 

stability data for bifenazate in/on hop cones has been submitted (MRID 46024201) and review is 

pending. 

Adequate crop field trial data are available for residues of bifenazate in/on apple, pear, apricot, 

cotton, grapes, hops, nectarine, peach, plum, strawberry, summer squash, pecan, bell and non-
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bell peppers, tomato, cantaloupe, almond, mint, cucumber, cherry, potato, peas, lychee, lima 

bean, guava, papaya, dry shelled beans, corn, and sugar apple. Additional crop field trial data are 

not required for Registration Review. 

Adequate processing studies have been submitted for residues of bifenazate in/on plum/prunes, 

grapes/raisins, tomato, mint, corn, apple, grape, and cotton. Generally, residues of bifenazate do 

not concentrate in processed commodities with the following exceptions: apple (wet pomace),

cotton gin by-products, and raisins. Additional processing data are not required for Registration 

Review. 

Conclusions

The qualitative nature of bifenazate residues in plants is adequately understood based on 

acceptable metabolism studies with apple, orange, cotton, and radish. The residues of concern in 

crops (and fat) are bifenazate and its metabolite D3598 (calculated as the stoichiometric 

equivalent of bifenazate). The nature of the residue in livestock is adequately understood based 

on studies with lactating goats and laying hens. The residues of concern in livestock tissue 

(excluding fat), eggs, and milk are bifenazate and the metabolites D3598, A1530, and A1530-

sulfate (calculated as the stoichiometric equivalent of bifenazate). The residues of concern for 

tolerance expression and risk assessment purposes in fat are bifenazate and D3598 (calculated as 

the stoichiometric equivalent of bifenazate). Adequate analytical enforcement methods are 

available. Additionally, adequate crop field trials, processing studies, and storage stability data 

are available. HED notes that if other major crops with livestock feed commodities are 

registered in the future, additional livestock metabolism and feeding studies may be required. 

Additional residue chemistry data are not required to support Registration Review of bifenazate. 

Dietary Exposure

The results of the most recent chronic dietary exposure assessment for bifenazate were issued in 

conjunction with PP# 9E7642 (Memo, 7/14/2010, W. Wassell, D380060). An acute dietary 

assessment has not been conducted for bifenazate because an endpoint of concern attributable to 

a single dose was not identified. A chronic dietary (food plus drinking water) exposure 

assessment was conducted using the Dietary Exposure Evaluation Model - Food Consumption 

Intake Database (DEEM-FCID , ver. 2.03). DEEM-FCID incorporates the food consumption 

data from the United States Department of Agriculture’s (USDA’s) Continuing Surveys of Food 

Intakes by Individuals (CSFII; 1994-1996 and 1998). The chronic analyses incorporated 

tolerance-level residues for all commodities excluding squash, peach, and tomato (average fieldtrial residues were assumed) and milk (the tolerance level was adjusted upward to account for all 

of the residues of concern for risk assessment) and percent crop-treated information provided by 

BEAD. The chronic exposure estimate utilized 30% chronic population-adjusted dose (cPAD) 

for the U.S. population. The most highly exposed population subgroup was children 1 to 2 years 

old which utilized 81% of the cPAD. 

Conclusions

The most recent chronic dietary exposure assessments were below HED’s level of concern 

(LOC) for the general U.S. population and all population subgroups examined. The most recent 

dietary exposure assessment did not indicate any risks of concern, however, an updated dietary 

exposure and risk assessment for bifenazate may be required as part of Registration Review. 

These assessments should be completed using the most up-to-date dietary exposure and risk 

assessment model, the most up-to-date toxicological end-points, updated EDWCs, and PCT data. 
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Residential Exposure

Bifenazate is labeled for use as a miticide on ornamental plants and non-bearing fruit crops. The 

non-bearing crops include citrus, berries, currants, dates, figs, and persimmons with a minimum 

application interval of 12 months prior to harvest of mature fruit. Residential exposure may 

result with these non-food uses. The ornamental use sites include landscapes, residences, 

public/commercial/industrial/institutional areas, recreational sites (e.g., campgrounds, golf 

courses, parks, and athletic fields), and rights of ways and other easements. 

The two products registered for use on residential ornamentals are Floramite®SC (EPA Reg. No. 

400-508) and Prevamite®4SC (EPA Reg. No. 400-582). HED anticipates residential handler 

and post-application exposures from the ornamental uses on the Floramite®label, but only postapplication exposures from the registered uses on the Prevamite®

label since this product is a 

restricted-use pesticide. 

HED previously assessed the residential ornamental uses for bifenazate (Memoranda, 

03/13/2003, M. Dow, D285897 and 12/24/2009, K. Lowe, D365544). For residential handlers, 

the resulting dermal and inhalation margins of exposure (MOEs) were 4,200 and 430,000, 

respectively, and yielded a combined MOE of 4,200; therefore, residential handler exposure to 

bifenazate was not of concern. With respect to post-application residential exposures, previous 

HED policy specified that no significant post-application exposure was anticipated from 

landscape ornamentals; therefore, no residential post-application assessment was conducted. 

Since these assessments, HED’s Residential SOPs have been revised, and there have been 

Agency policy changes for body-weight assumptions. Therefore, a revised residential exposure 

assessment may be needed to support Registration Review. For residential handlers, the 

following scenarios may need to be assessed: 

1) mixer/loader/applicator (M/L/A) of liquids with manually-pressurized handwand, 

2) M/L/A of liquids with hose-end sprayer, 

3) M/L/A of liquids with backpack sprayer, and 

4) M/L/A of liquids with sprinkler can. 

For residential post-application exposure, the following scenarios may need to be assessed: 

1) dermal post-application exposure for adults from contact with treated gardens, 

2) dermal post-application for children (6 to <11 years old) from contact with treated 

gardens,

3) dermal post-application exposure for adults from contact with treated trees, and

4) dermal post-application exposure for children (6 to <11 years old) from contact with 

treated trees.

A dislodgeable foliar residue (DFR) study, Floramite®50WP on Spathiphylllum: Dislodgeable 

Foliar Residue Study (MRID No. 448597-01), was submitted by Uniroyal Chemical Company in 

1999. HED will incorporate all available chemical-specific data, as appropriate, into the 

residential exposure assessment for Registration Review. 

Based on the Agency’s current practices, a quantitative post-application inhalation exposure 

assessment has not been performed for bifenazate to date, primarily because it has a very low 

vapor pressure (<1 x 10-7 torr at 25oC). However, volatilization of pesticides may be a potential 

source of post-application inhalation exposure to individuals nearby pesticide applications. The 

Agency sought expert advice and input on issues related to volatilization of pesticides from its 
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Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) Scientific Advisory Panel (SAP) in 

December 2009. The Agency received the SAP’s final report on March 2, 2010 

(http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). The Agency is in the 

process of evaluating the SAP report and may, as appropriate, develop policies and procedures to 

identify the need for and, subsequently, the way to incorporate post-application inhalation 

exposure into the Agency's risk assessments. If new policies or procedures are put into place, the 

Agency may revisit the need for a quantitative post-application inhalation exposure assessment 

for bifenazate.

Spray Drift

Residential bystander exposures might occur as a result of bifenazate aerial and airblast 

applications and/or transport from treated areas. Spray drift is always a potential source of 

exposure to residents nearby to spraying operations. This is particularly the case with aerial 

application, but, to a lesser extent, could also be a potential source of exposure from the ground 

application method employed for bifenazate. The Agency has been working with the Spray Drift 

Task Force, EPA Regional Offices, and State Lead Agencies for pesticide regulation and other 

parties to develop the best spray-drift-management practices (see the Agency’s Spray Drift 

website for more information at http://www.epa.gov/opp00001/factsheets/spraydrift.htm). The 

Agency has completed its evaluation of the new database submitted by the Spray Drift Task 

Force, a membership of U.S. pesticide registrants, and is developing a policy on how to 

appropriately apply the data and the AgDRIFT®computer model to its risk assessments for 

pesticides applied by air, orchard airblast and ground hydraulic methods. After the policy is in 

place, the Agency may impose further refinements in spray-drift-management practices to reduce 

off-target drift with specific products with significant risks associated with drift.

Conclusions

The residential exposure database is adequate to support Registration Review for bifenazate. 

Updated residential handler and post-application exposure assessments may be required under 

Registration Review based upon revisions to HED’s Residential SOPs and body weight 

assumptions. These assessments will incorporate all available chemical-specific data as 

appropriate. In addition, revised residential handler and post-application assessments may be 

needed if toxicological endpoints change or other new data are received by the Agency that 

impact exposure estimates.

Aggregate Risk Assessment

The most recent aggregate assessment was completed as part of the risk assessment associated 

with PP# 9E7642 (Memo, 7/14/2010, W. Wassell, et al., D371783). Based on the anticipated 

residential exposure scenarios and since acute and cancer risk assessments are not required, only 

short-term (residential, food, and drinking water) and chronic (food and drinking water) aggregate 

exposure assessments were conducted. The short-term aggregate MOEs were ≥1800 for all 

population subgroups. Thus, short-term aggregate exposure to bifenazate is not of concern. 

Additionally, aggregate chronic (food and water) exposures were ≤81% of the cPAD for all 

population subgroups as a result of all registered/proposed uses. Thus, chronic and short-term 

aggregate exposures to bifenazate were not of concern in the previous risk assessment. 

Conclusions

There is sufficient information available to evaluate aggregate exposure to bifenazate in support 

of Registration Review. New aggregate exposure risk assessments that incorporate new or 

revised toxicological end-points, updated policies, a revised residential assessment, revised 
Bifenazate Registration Review Human-Health Assessment Scoping Document

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EDWCs, updated PCT data, and a dietary exposure assessment with the current version of 

DEEM-FCID may be required for Registration Review. 

Occupational Exposure

A wide range of uses, and the associated occupational handler and post-application scenarios, 

have previously been assessed for bifenazate. Bifenazate is registered for food/feed and nonfood uses. The food/feed uses include the many crops that were previously listed. The 

registered nonagricultural uses include applications to non-bearing fruit crops, ornamental plants, 

landscapes, residences, public/commercial/industrial/intuitional areas, recreational sites, and 

athletic fields crops) and rights-of-ways. 

Registered formulations of bifenazate include SC, FlC, WDG, and WP in WSP. Bifenazate is 

applied via ground applications, aerial applications, airblast applications, chemigation, and 

handheld sprayers. Based on these uses, there is a potential for dermal and inhalation exposure 

to bifenazate in occupational scenarios from handling bifenazate products during the application 

process (i.e., mixer/loaders, applicators, and mixer/loader/applicators). In addition, there is a 

potential for post-application worker exposure from entering into areas previously treated with 

bifenazate. 

Occupational Handlers: 

Occupational dermal and inhalation exposures resulting from agricultural uses have been 

evaluated quantitatively for all registered bifenazate uses. No chemical-specific handler data 

were submitted in support of these registrations. Therefore, handler dermal and inhalation 

exposure assessments were performed based on surrogate data from the Pesticide Handler’s 

Exposure Database (PHED, August 1998) and the Occupational Residential Exposure Task 

Force (ORETF). Occupational handler exposure (dermal and inhalation) scenarios resulting in 

MOEs equal to or greater than 100 are not of concern. All handler exposure scenarios assessed 

to date resulted in MOEs greater than 100 either at baseline (single-layer clothing) or with the 

addition of personal-protective equipment (PPE) such as gloves and a dust mist respirator or 

engineering controls. 

Occupational Post-application: 

All post-application activities associated with the registered crops, as identified in Science 

Advisory Council for Exposure (ExpoSAC) Policy #3, were assessed previously using the 

maximum application rate proposed on the labels. No dermal risks of concern were identified 

(i.e., MOEs > the LOC of 100).

Based on the Agency's current practices, a quantitative post-application inhalation exposure 

assessment has not been performed for bifenazate to date. However, there are multiple potential 

sources of inhalation exposure to individuals performing post-application activities in previously 

treated fields. These potential sources include volatilization of pesticides and re-suspension of 

dusts and/or particulates that contain pesticides. The Agency sought expert advice and input on 

issues related to volatilization of pesticides from its FIFRA SAP in December 2009, and received 

the SAP’s final report on March 2, 2010 

(http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). The Agency is in the 

process of evaluating the SAP report as well as available post-application inhalation exposure 

data generated by the Agricultural Reentry Task Force and may, as appropriate, develop policies 

and procedures, to identify the need for and, subsequently, the way to incorporate occupational 
Bifenazate Registration Review Human-Health Assessment Scoping Document

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post-application inhalation exposure into the Agency's risk assessments. If new policies or 

procedures are put into place, the Agency may revisit the need for a quantitative occupational 

post-application inhalation exposure assessment for bifenazate.

Conclusions

The occupational exposure database is adequate to support Registration Review for bifenazate. 

Updated occupational handler exposure assessments may be required under Registration Review 

based upon revisions to the Agency’s scenario-specific surrogate handler exposure data 

(http://www.epa.gov/pesticides/science/handler-exposure-table.pdf). Reviewers should 

incorporate new exposure monitoring data, as necessary, during Registration Review. Updated 

occupational post-application exposure assessments are also required under Registration Review 

based upon revisions to the Agency’s post-application exposure data. In addition, as stated in the 

Residential Exposure section, a DFR study, Floramite®50WP on Spathiphylllum: Dislodgeable 

Foliar Residue Study (MRID No. 448597-01) was submitted by Uniroyal Chemical Company in 

1999. HED will incorporate all available chemical-specific data, as appropriate, into the 

occupational exposure assessment for Registration Review. Additionally, revised occupational 

handler and post-application assessments may also be needed if toxicological endpoints change 

or other new data are received by the Agency that impact exposure estimates.

Public Health and Pesticide Epidemiology Data

A summary report listing incidents for bifenazate reported to the Office of Pesticide Programs 

(OPP) Incident Data System (IDS) has been provided for the docket (Memo, 07/10/2012, S. 

Recore). The report represents incidents occurring in the U.S. from January 1, 2007 to present 

(June 13, 2012).

Human Incident Data: OPP IDS (2012)

For this evaluation, the OPP IDS was utilized to retrieve pesticide incident data for bifenazate. 

The purpose of the database search is to identify potential patterns in the frequency and severity 

of health effects attributed to bifenazate exposure. The IDS includes reports of alleged humanhealth incidents from various sources, including mandatory FIFRA Section 6(a)(2) reports from 

registrants, other federal and state health and environmental agencies, and individual consumers. 

Since 1992, OPP has compiled these reports in IDS. IDS contains reports from across the U.S. 

and most incidents have all relevant product information recorded. Reports submitted to the IDS 

represent anecdotal reports or allegations only, unless otherwise stated in the report. 

IDS records incidents resulting in higher severity outcomes in more detail, in a module called the 

Main IDS module. This system stores incident data for death, major and moderate incidents, and 

includes more details about the location, date, and nature of the incident. Main IDS incidents 

involving only one pesticide are considered to provide more certain information about the 

potential effects of exposure from the pesticide. The less severe human incidents (minor, 

unknown, or no effects outcomes) are reported by registrants as counts called aggregate 

summaries and are recorded in a separate module called Aggregate IDS. 

In Aggregate IDS, from January 1, 2007 to June 13, 2012, there were four reported incidents 

involving bifenazate. For the Main IDS, from January 1, 2007 to June 13, 2012, there was one

incident reported for bifenazate in the database. 
Bifenazate Registration Review Human-Health Assessment Scoping Document

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Bifenazate is not included in the Agricultural Health Study (AHS); therefore, this study does not 

provide information for this incident report.

Based on the low frequency and severity of incident cases reported for bifenazate, there does not 

appear to be a concern at this time that would warrant further investigation. The Agency will 

continue to monitor the incident information and if a concern is triggered, additional analysis 

will be included in the risk assessment.

Tolerance Assessment and International Harmonization

The tolerance expression should be changed to conform to current HED policy. Specifically, the 

tolerance expression for 40 CFR §180.572(a)(1) should be as follows:

Tolerances are established for residues of bifenazate (1-methylethyl 2-(4-methoxy[1,1'-

biphenyl]-3-yl)hydrazinecarboxylate) including its metabolites and degradates, in or on the 

commodities listed in the following table. Compliance with the tolerance levels specified are to 

be determined by measuring only the sum of bifenazate and its metabolite diazinecarboxylic 

acid, 2-(4-methoxy-[1,1'-biphenyl]-3-yl), 1-methylethyl ester, calculated as the stoichiometric 

equivalent of bifenazate, in or on the following food commodities:

Additionally, the tolerance expression for 40 CFR §180.572(a)(2) should be as follows:

Tolerances are established for residues of bifenazate (1-methylethyl 2-(4-methoxy[1,1′-

biphenyl]-3-yl) hydrazinecarboxylate) including its metabolites and degradates, in or on the 

commodities listed in the following table. Compliance with the tolerance levels specified are to 

be determined by measuring only the sum of bifenazate and its metabolites diazinecarboxylic 

acid, 2-(4-methoxy-[1,1′-biphenyl]-3-yl), 1-methylethyl ester; 1,1′-biphenyl, 4-ol; and 1,1′-

biphenyl, 4-oxysulfonic acid, calculated as the stoichiometric equivalent of bifenazate, in or on 

the following food commodities:

U.S. permanent tolerances (listed in 40 CFR §180.572) and maximum residue limits (MRLs) are 

summarized in Attachment 5. Residue definitions and MRLs for bifenazate have been 

established by Codex and Canada. Mexico adopts U.S. tolerances and/or Codex MRLs for 

export purposes. The tolerance expression for plant commodities and fat is harmonized between 

the U.S. and Canada, but not with CODEX. For livestock commodities (except fat), the 

tolerance expression is not harmonized with Canada or CODEX. For plant commodities, some 

tolerance levels are harmonized between the U.S. and Canada (caneberries, raisins, tree nuts, and 

strawberry); however, most tolerance levels are not harmonized. Additionally, the tolerance 

levels for residues in plant commodities are generally not harmonized with CODEX. For 

livestock commodities, tolerance levels for residues in/on meat and meat byproducts are 

harmonized. The U.S. has established tolerances for residues on many plant commodities that 

are not registered by Canada or CODEX.

Endocrine Disruption

As required by FIFRA and the Federal Food, Drug, and Cosmetic Act (FFDCA), EPA reviews 

numerous studies to assess potential adverse outcomes from exposure to chemicals. 

Collectively, these studies include acute, subchronic, and chronic toxicity, including assessments 

of carcinogenicity, neurotoxicity, developmental, reproductive, and general or systemic toxicity. 

These studies include endpoints that may be susceptible to endocrine influence, including effects 
Bifenazate Registration Review Human-Health Assessment Scoping Document

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on endocrine target organ histopathology, organ weights, estrus cyclicity, sexual maturation, 

fertility, pregnancy rates, reproductive loss, and sex ratios in offspring. For ecological hazard 

assessments, EPA evaluates acute tests and chronic studies that assess growth, developmental,

and reproductive effects in different taxonomic groups. As part of the reregistration decision, 

EPA reviewed these data and selected the most sensitive endpoints for relevant risk assessment 

scenarios from the existing hazard database. However, as required by FFDCA section 408(p), 

bifenazate is subject to the endocrine screening part of the Endocrine Disruptor Screening 

Program (EDSP). 

EPA has developed the EDSP to determine whether certain substances (including pesticide 

active and other ingredients) may have an effect in humans or wildlife similar to an effect 

produced by a “naturally occurring estrogen, or other such endocrine effects as the Administrator 

may designate.” The EDSP employs a two-tiered approach to making the statutorily required 

determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a 

chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal 

systems. Chemicals that go through Tier 1 screening and are found to have the potential to 

interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA 

will determine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 

testing is designed to identify any adverse endocrine-related effects caused by the substance, and 

establish a dose-response relationship between the dose and the E, A, or T effect. 

Under FFDCA section 408(p), the Agency must screen all pesticide chemicals. Between 

October 2009 and February 2010, EPA issued test orders/data call-ins for the first group of 67 

chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. Bifenazate is 

not among the group of 58 pesticide active ingredients on the initial list to be screened under the 

EDSP. Accordingly, as part of Registration Review, EPA will issue future EDSP orders/data 

call-ins, requiring the submission of EDSP screening assays for bifenazate. For further 

information on the status of the EDSP, the policies and procedures, the list of 67 chemicals, 

future lists, the test guidelines and the Tier 1 screening battery, please visit our website: 

http://www.epa.gov/endo/.

Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in the 

human-health risk assessment, in accordance with U.S. Executive Order 12898, “Federal Actions 

to Address Environmental Justice in Minority Populations and Low-Income Populations,” 

(http://www.hss.energy.gov/nuclearsafety/env/guidance/justice/eo12898.pdf). The OPP 

typically considers the highest potential exposures from the legal use of a pesticide when 

conducting human-health risk assessments, including, but not limited to, people who obtain 

drinking water from sources near agricultural areas, the variability of diets within the U.S., and 

people who may be exposed when harvesting crops. Should these highest exposures indicate 

potential risks of concern, OPP further refines the risk assessments to ensure that the risk 

estimates are based on the best available information.

Cumulative 

As part of the risk assessment process, the Agency assessed the potential risk from cumulative 

effects of bifenazate and other pesticides and substances with a common mode/mechanism of 

toxicity. Bifenazate is a classified as a carbazate acaricide; there are no other compounds within 

this classification that are registered as for use as pesticides. The Agency considered structural 
Bifenazate Registration Review Human-Health Assessment Scoping Document

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similarities, common effects that exist between bifenazate and other compounds that could 

potentially result in effects similar to those of bifenazate including decreased motor activity 

(rearing in females) and changes in hematological and clinical chemistry parameters, and 

histopathology in bone marrow, liver, and kidney. The available data did not suggest that 

bifenazate has a common mode/mechanism of toxicity with any other chemical; therefore, the 

risk assessment took into account only exposures resulting from bifenazate uses. Should the 

Agency determine that new information on bifenazate is available that could potentially affect 

the cumulative risk assessment and result in a risk of concern, the Agency will revisit the 

cumulative risk assessment.

Human Studies

Past bifenazate risk assessments rely in part on data from studies in which adult human subjects 

were intentionally exposed to a pesticide to determine their dermal and inhalation exposure. 

Many such studies, involving exposure to many different pesticides, comprise generic pesticide 

exposure databases such as PHED and the ARTF Database. EPA has reviewed all the studies 

supporting these multi-pesticide generic exposure databases, and has found no clear and 

convincing evidence that the conduct of any of them was either fundamentally unethical or 

significantly deficient relative to the ethical standards prevailing at the time the research was 

conducted. All applicable requirements of EPA’s Rule for the Protection of Human Subjects of 

Research (40 CFR Part 26) have been satisfied, and there is no regulatory barrier to continued 

reliance on these studies.

Data Requirements Required Under Registration Review

Data needs required under Registration Review for bifenazate are as follows:

Toxicology:

DNT Study (OCSPP Guideline 830.6300). 

Residue Chemistry/Dietary Exposure:

None. 

Occupational Exposure:

None. 

Risk Assessment Updates Required Under Registration Review

Toxicology:

Reevaluation of toxicity endpoint/dose selection and the (FQPA SF) once the DNT study 

is submitted.
Bifenazate Registration Review Human-Health Assessment Scoping Document

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Residue Chemistry/Dietary Exposure:

Updated dietary exposure and risk assessments for bifenazate may be required for 

Registration Review. These assessments should be completed using the most up-to-date 

dietary exposure and risk assessment model, the most up-to-date toxicological end-points,

updated EDWCs, and updated PCT data, as available. 

The tolerance expression should be changed to conform to current HED policy (see the 

Tolerance Assessment and International Harmonization section of this document for 

details.

Occupational Exposure:

Updated occupational handler and residential exposure assessments may be required

under Registration Review based upon revisions to the Agency’s scenario-specific 

surrogate handler-exposure data, updated policies, and revised toxicological endpoints. 

References

Table 2. Memoranda Relevant to Registration Review.

Author DP 

Barcode Date Title

M. Christian, et al. D244865 05/26/1999 ID# 400-UIR. Bifenazate on Ornamentals. HED Risk Assessment.

T. Bloem D271330 12/21/2000

PP# 0F06108 - Application of Bifenazate to Cotton, Grapes, Hops, 

Pome Fruit, Stone Fruit, and Strawberries. Petition Method 

Validation. 

T. Bloem D2730 

67 03/06/2001

PP# 0F06108 - Bifenazate in/on Nectarine, Apple, Strawberry, 

Cotton, Hops, Peach, Apricot, and Grape. Multiresidue Method 

(MRM) Testing of Bifenazate. 

T. Bloem D274300 05/09/2001 ID# 01TX0007: Section 18 for Application of Bifenazate to 

Tomatoes in Texas. Chronic Dietary Exposure Analysis. 

T. Bloem, et al. D272458 05/23/2001 ID# 01TX0007: Section 18 for Application of Bifenazate to 

Greenhouse Tomatoes in Texas. HED Risk Assessment.

J. Rowland et al. TXR# 

0014576 05/30/2001 Hazard Identification Assessment Review Committee (HIARC) Report.

T. Bloem, et al. D276623 07/31/2001

ID# 0F06108 - Bifenazate in/on Apple, Apricot, Cotton, Grapes, 

Hops, Nectarines, Peaches, Pear, Plumes (Prunes), and 

Strawberries. Metabolism Assessment Review Committee 

(MARC) Briefing Document. 

T. Bloem D277089 08/16/2001

ID# 0F06108 - Bifenazate in/on Apple, Apricot, Cotton, Grape, 

Hops, Nectarine, Peach, Pear, Plum (Prune), and Strawberry. 

Evaluation of Residue Data and Analytical Methods. 

T. Bloem D277489 08/30/2001

ID# 0F06108: Section 3 for Request for Application of Bifenazate 

to Apple, Apricot, Cotton, Grape, Hops, Nectarine, Peach, Pear, 

Plum (Prune), and Strawberry. Chronic Dietary Exposure 

Analysis. 

W. Dykstra, et al. D264893 09/27/2001

PP# 0F06108. Bifenazate In/On Apples, Apricots, Cotton, Grapes, 

Hops, Nectarines, Peaches, Pears, Plums (Prunes), and 

Strawberries For Control Of Mites. HED Risk Assessment. 

T. Bloem D281973 08/29/2002

ID# 0F06108 - Application of Bifenazate to Cotton, Grapes, Hops, 

Pome Fruit, Stone Fruit, and Strawberries. Results of Petition 

Method Validation.

M. Dow D285897 03/13/2003 Bifenazate (000586); Residential Exposure Assessment
Bifenazate Registration Review Human-Health Assessment Scoping Document

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Table 2. Memoranda Relevant to Registration Review.

Author DP 

Barcode Date Title

T. Bloem D288660 03/20/2003

Bifenazate (PC Code 000586). Section 3 Registration for 

Application of Bifenazate to Apple, Apricot, Cotton, Grape, Hops, 

Nectarine, Peach, Pear, Plum (Prune), and Strawberry (ID# 

0F06108). Petitioners Response (9-May-2002) to Deficiencies 

Identified in HED’s Residue Chemistry Review (D277089, T. 

Bloem, 16-Aug-2001). 

T. Bloem D290053 05/29/2003 Crop Field Trial – Pecan

T. Bloem D290054 05/29/2003 Bifenazate Chronic Dietary Exposure. 

T. Bloem D290053 05/29/2003 Crop Field Trial - Summer Squash

T. Bloem D290053 05/29/2003 Crop Field Trial - Bell and Non-bell Pepper

T. Bloem D290053 05/29/2003 Crop Field Trial - Greenhouse Tomato

T. Bloem D290053 05/29/2003 Crop Field Trial – Tomato

T. Bloem D290053 05/29/2003 Processed Food and Feed - Tomato

T. Bloem D290053 05/29/2003 Crop Field Trial – Cantaloupe

T. Bloem D290053 05/29/2003 Crop Field Trial – Almond

T. Bloem D290053 05/29/2003 Crop Field Trial – Mint

T. Bloem D290053 05/29/2003 Processed Food and Feed – Mint

T. Bloem D290053 05/29/2003 Crop Field Trial – Cucumber

T. Bloem D290053 05/29/2003 Nature of the Residue – Radish

T. Bloem D290053 05/29/2003

ID#: 3E06517. Bifenazate (PC Code 000586). Section 3 

Registration for Application of Bifenazate to Fruiting Vegetables 

(Crop Group 8), Cucurbit Vegetables (Crop Group 9), Tree Nuts 

(Crop Group 14), Okra, and Mint. Summary of Residue 

Chemistry Data. 

T. Bloem D293801 09/22/2003 ID#: 03WA35. Bifenazate (000586). Chronic Dietary Exposure 

Assessment. 

M. Clock-Rust D293440 10/06/2003 ID# 03WA35 and 03OR33. Section 18 Specific Exemption for the 

Use of Bifenazate on Potatoes in Washington and Oregon. 

T. Bloem D286170 04/20/2003

Bifenazate (PC Code 000586). Section 3 Registration for 

Application of Bifenazate to Fruiting Vegetables (Crop Group 8), 

Cucurbit Vegetables (Crop Group 9), Tree Nuts (Crop Group 14), 

Okra, and Mint. Review of Amendment Dated 7-November-2003 

Submitted in Response to Residue Chemistry Deficiencies 

Identified D290053 (T. Bloem, 29-May-2003).

M. Sahafeyan D308696 12/09/2004

Bifenazate (PC Code 000586). Registration of A New 

Formulation (AcramiteTM -4SC (43.2% bifenazate) for 

Application to Cotton. Summary of Residue Chemistry Data. 

J. Tyler D308822. 10/29/2004 ID#04DE13. Bifenazate. Chronic Dietary Exposure Assessment.

J. Tyler D305565 10/29/2004 ID# 04DE13. Section 18 Specific Emergency Exemption for the 

Use of Bifenazate on Soybeans in Delaware. 

M. Sahafeyan D308696 10/28/2004 Crop Field Trial – Cotton

T. Bloem D313261 07/12/2006 Storage Stability - Apple Juice and Pomace

T. Bloem D297604 07/12/2006 Storage Stability – Cantaloupe

T. Bloem D297604 07/12/2006 Storage Stability - Tomato Paste and Puree

T. Bloem D297604 07/12/2006 Storage Stability - Mint Foliage

T. Bloem D297604 07/12/2006 Storage Stability – Pepper

T. Bloem D297604 07/12/2006 Storage Stability – Tomato

T. Bloem D297604 07/12/2006 Multiresidue Analytical Methods - Bifenazate Metabolite A1530-S
Bifenazate Registration Review Human-Health Assessment Scoping Document

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Table 2. Memoranda Relevant to Registration Review.

Author DP 

Barcode Date Title

T. Bloem D297604 07/12/2006 Multiresidue Analytical Methods - Bifenazate Metabolite A1530

T. Bloem D297604 07/12/2006 Storage Stability – Strawberry

T. Bloem D297604 07/12/2006 Residue Analytical Method - Plant Commodities

T. Bloem D297604 07/12/2006 Crop Field Trial/Residue Decline - Stone Fruit

T. Bloem D297604 07/12/2006 Crop Field Trial – Cherry

T. Bloem D297604 07/12/2006 Residue Analytical Method - Ruminant Commodities

T. Bloem D297604 07/12/2006 Residue Analytical Method - Livestock

T. Bloem D297604 07/12/2006 Crop Field Trial – Potato

T. Bloem D297604 07/12/2006 Crop Field Trial - Pea (Succulent Shelled and Edible Podded)

T. Bloem D297604 07/12/2006 Storage Stability – Potato

T. Bloem D330587 07/19/2006

Bifenazate - Chronic Dietary Exposure and Risk Assessment. 

Application of Bifenazate to succulent Pea, Tuberous and Corm 

Vegetables (subgroup 1c), and Stone Fruit. 

T. Bloem D313261 07/19/2006

Bifenazate (PC Code 000586). Section 3 Registration for 

Application of Bifenazate to Apple, Apricot, Cotton, Grape, Hops, 

Nectarine, Peach, Pear, Plum (Prune), and Strawberry. Petitioners 

Response to Deficiencies Identified in HED’s Residue Chemistry 

Reviews (D277089, T. Bloem, 16-Aug-2001 and D288660, T. 

Bloem, 20-Mar-2003). 

T. Bloem D297604 07/12/2006

Bifenazate (PC Code 000586). Section 3 Registration for 

Application of Bifenazate to Fruiting Vegetables (Crop Group 8), 

Cucurbit Vegetables (Crop Group 9), Tree Nuts (Crop Group 14), 

Okra, and Mint. Review of Amendment Submitted in Response to 

Residue Chemistry Deficiencies Identified D286170 (T. Bloem, 

20-April-2004). 

T. Bloem D324430 07/19/2006

Bifenazate (PC Code 000586). Section 3 Registration for 

Application of Bifenazate to Tuberous and Corm Vegetable (crop 

subgroup 1c) and Succulent Pea. Summary of Residue Chemistry 

Data. 

T. Bloem, et al. D323893 07/26/2006

Subject: Bifenazate (PC Code 000586). Application of Bifenazate 

to Tuberous and Corm Vegetables, Succulent Peas and Stone Fruit. 

HED Human-Health Risk Assessment. 

T. Bloem D337517 08/01/2007 Crop Field Trial – Almond

T. Bloem D337517 08/22/2007

Bifenazate (PC Code 000586). Section 3 Registration for 

Application of Bifenazate to Fruiting Vegetables (Crop Group 8), 

Cucurbit Vegetables (Crop Group 9), Tree Nuts (Crop Group 14), 

Okra, and Mint. Review of Amendment (dated 1-Feb-2007) 

Submitted in Response to Residue Chemistry Deficiencies 

Identified D297604 (T. Bloem, 12-July-2006). 

W. Wassell D337530 12/14/2007 Crop Field Trial/Residue Decline - Lychee

W. Wassell D337530 12/14/2007 Storage Stability – Lychee

W. Wassell D337530 12/14/2007 Residue Analytical Method - Lychee

W. Wassell D337530 12/14/2007 Crop Field Trial/Residue Decline – Caneberry, Crop Subgroup 

13A

W. Wassell D337530 12/14/2007 Crop Field Trial/Residue Decline – Bean (Edible-Podded and 

Succulent-Shelled)

W. Wassell D337530 12/14/2007 Crop Field Trial/Residue Decline – Lima Bean (Succulent Shelled)

W. Wassell D337530 12/14/2007 Crop Field Trial/Residue Decline - Guava

W. Wassell D337530 12/14/2007 Crop Field Trial/Residue Decline - Papaya
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Table 2. Memoranda Relevant to Registration Review.

Author DP 

Barcode Date Title

W. Wassell D337530 12/14/2007

PP#6E7167; Bifenazate; (000586). Petition for Establishment of 

Tolerances for Uses on Caneberry (Crop Subgroup Group 13A); 

Wild Raspberry; Edible-podded Legume Vegetable (Crop 

Subgroup 6A); Succulent-shelled Pea and Bean (Crop Subgroup 

6B); Soybean, Succulent-shelled; and Various Tropical Fruits 

Including Papaya, Star Apple, Black Sapote, Mango, Sapodilla, 

Canistel, Mamey Sapote, Lychee, Longan, Spanish Lime, 

Rambutan, Pulasan, Guava, Feijoa, Jaboticaba, Wax Jambu, 

Starfruit, Passionfruit, and Acerola. Summary of Analytical 

Chemistry and Residue Data.

W. Wassell D347496 12/14/2007

PP#6E7167; Bifenazate (000586); Chronic Dietary Exposure and 

Risk Assessment. Petition for Establishment of Tolerances for 

Uses on Caneberry (Crop Subgroup Group 13A); Wild Raspberry; 

Edible-podded Legume Vegetable (Crop Subgroup 6A); 

Succulent-shelled Pea and Bean (Crop Subgroup 6B); Soybean, 

Succulent-shelled; and Various Tropical Fruits Including Papaya, 

Star Apple, Black Sapote, Mango, Sapodilla, Canistel, Mamey 

Sapote, Lychee, Longan, Spanish Lime, Rambutan, Pulasan, 

Guava, Feijoa, Jaboticaba, Wax Jambu, Starfruit, Passionfruit, and 

Acerola. 

W. Wassell, et al. D348242 01/11/2008

PP#6E7167; Bifenazate; (000586). Petition for Establishment of 

Tolerances for Uses on Caneberry (Crop Subgroup Group 13A); 

Wild Raspberry; Edible-podded Legume Vegetable (Crop 

Subgroup 6A); Succulent-shelled Pea and Bean (Crop Subgroup 

6B); Soybean, Succulent-shelled; and Various Tropical Fruits 

Including Papaya, Star Apple, Black Sapote, Mango, Sapodilla, 

Canistel, Mamey Sapote, Lychee, Longan, Spanish Lime, 

Rambutan, Pulasan, Guava, Feijoa, Jaboticaba, Wax Jambu, 

Starfruit, Passionfruit, and Acerola. HED Human-Health Risk 

Assessment. 

W. Wassell D355496 02/03/2009

Bifenazate; Petition for Establishment of Tolerances for Uses on 

Caneberry (Crop Subgroup Group 13A); Wild Raspberry; Ediblepodded Legume Vegetable (Crop Subgroup 6A); Succulent 

Shelled Pea and Bean (Crop Subgroup 6B); Soybean, Succulentshelled; and Various Tropical Fruits Including Papaya, Star Apple, 

Black Sapote, Mango, Sapodilla, Canistel, Mamey Sapote, Lychee, 

Longan, Spanish Lime, Rambutan, Pulasan, Guava, Feijoa, 

Jaboticaba, Wax Jambu, Starfruit, Passionfruit, and Acerola. 

Waiver Request for Decline Data (Amendment dated: 5/27/2008).

W. Wassell D349556 03/09/2009

Bifenazate. Petition for the Establishment of Permanent 

Tolerances on Corn (Field and Sweet), Dry Beans and Grass. 

Summary of Analytical Chemistry and Residue Data.

W. Wassell D349556 03/09/2009 Nature of the Residues in Plants – Corn

W. Wassell D349556 03/09/2009 Crop Field Trial – Dry Bean (Shelled)

W. Wassell D349556 03/09/2009 Crop Field Trial/Residue Decline – Corn

W. Wassell D349556 03/09/2009 Processed Food and Feed – Corn

W. Wassell D349556 03/09/2009 Storage Stability – Corn, Forage, Stover, Grain, and K+CWHR

W. Wassell D349556 03/09/2009 Livestock Feeding Study – Dairy Cattle

W. Wassell D349556 03/09/2009 Residue Analytical Method – Corn

W. Wassell D349289 03/25/2009

Bifenazate. Petition for the Establishment of Permanent 

Tolerances on Dry Beans and Grass. Justification For Removing 

Grass From PP#8E7318.

W. Wassell D364305 09/30/2009

Bifenazate. Petition for the Establishment of Permanent 

Tolerances for Bifenazate In/on Dry Beans. Response to 

Deficiencies (dated: 04/02/2009).
Bifenazate Registration Review Human-Health Assessment Scoping Document

Page 22 of 34

Table 2. Memoranda Relevant to Registration Review.

Author DP 

Barcode Date Title

W. Wassell D366479 09/30/2009

Registration Nos: 400-503, 400-514; Bifenazate; (000586). Label 

Amendment For The Use Of Bifenazate On Caneberry (Crop 

Subgroup Group 13A).

W. Wassell, et al. D369852 09/30/2009

PP#8E7318; Bifenazate (000586); Petition for Establishment of 

Tolerances for the Use of Bifenazate on Dry Bean Seed. HED 

Human-Health Risk Assessment. 

W. Wassell D364305 09/30/2009 Storage Stability – Succulent and Dried Beans

W. Wassell D369851 09/30/2009

Bifenazate (000586); Chronic Dietary Exposure and Risk 

Assessment. Petition for Establishment of Tolerances for the use 

of Bifenazate on Dry Bean Seed.

W. Wassell, et al. D371229 11/10/2009

PP#8E7318; Bifenazate (000586); Petition for Establishment of 

Tolerances for the Use of Bifenazate on Dry Bean Seed. Revised 

HED Human-Health Risk Assessment. 

M. Clock-Rust D365544 12/24/2009 Bifenazate (000586); Residential exposure Assessment 

W. Wassell D365345 03/02/2010 Bifenazate. Request for Registration of New Formulation for Use 

on Grapes. Submission of Bridging Data.

W. Wassell D365345 03/02/2010 Crop Field Trial/Residue Decline – Grapes

W. Wassell D371943 05/25/2010 Field Trial – Sugar Apple

W. Wassell D371943 05/25/2010

Bifenazate. Section 3 Registration Request to Add New Uses on: 

Avocado, Tropical Fruits (Sugar Apple, Cherimoya, Atemoya, 

Custard Apple, Ilama, Soursop, and Biriba), Small Vine Climbing 

Fruit (Subgroup 13-07F) and Low-Growing Berry (Subgroup 13-

07G). Residue Chemistry Summary Document.

W. Wassell D371941 05/25/2010

Bifenazate (000586); Chronic Dietary Exposure and Risk 

Assessment. Petition to Add New Uses on: Avocado, Tropical 

Fruits (Sugar Apple, Cherimoya, Atemoya, Custard Apple, Ilama, 

Soursop, and Biriba), Small Vine Climbing Fruit (Subgroup 13-

07F) and Low-Growing Berry (Subgroup 13-07G). 

W. Wassell D380060 07/14/2010

Bifenazate (000586); Chronic Dietary Exposure and Risk 

Assessment. Harmonization of Tolerances for Residues in/on 

Grapes and Small Vine Climbing Fruit (Subgroup 13-07F) with 

Canadian Maximum Residue Limits (MRLs).

W. Wassell, et al. D371783 07/14/2010

Bifenazate (000586); Petition to Add New Uses on: Avocado, 

Tropical Fruits (Sugar Apple, Cherimoya, Atemoya, Custard 

Apple, Ilama, Soursop, and Biriba), Small Vine Climbing Fruit 

(Subgroup 13-07F), and Low-Growing Berry (Subgroup 13-07G). 

HED Human-Health Risk Assessment. 

W. Wassell D380061 07/20/2010

Bifenazate. Section 3 Registration Request from RD to Harmonize 

Tolerances/MRLs for Residues in/on Grapes. Residue Chemistry 

Summary Document.

S. Recore D404198 07/10/2012 Bifenazate: Review of Human Incidents.

J. Van Alstine N/A 07/18/2012

Bifenazate: Summary of Hazard and Science Council (HASPOC) 

Meeting of July 12, 2012: Recommendations on the requirement of 

the developmental neurotoxicity screening study for bifenazate.

Attachments:

Attachment 1: Bifenazate and Its Metabolites Chemical Identity Tables.

Attachment 2: Bifenazate Endpoint Selection Table.

Attachment 3: Toxicity Profile of Bifenazate Technical.

Attachment 4: Exposure Potential for Adult and Child Aggregate Risk Estimates.

Attachment 5: Bifenazate International Residue Limit Status.
Bifenazate Registration Review Human-Health Assessment Scoping Document

Page 23 of 34

cc: A. Dunbar (RAB1), L. Venkateshwara (RAB1)

RDI: RAB1 (08/14/2012), D. Vogel (08/17/2012), J. Rowland (08/28/2012), G. Waleko (09/24/2012)

W. Wassell: S-10958: Potomac Yard 1 (PY1): (703)305-6135): 7509P: RAB1
Bifenazate Registration Review Human-Health Assessment Scoping Document

Page 24 of 34

Attachment 1: Bifenazate and Its Metabolites Chemical Identity Table.

Table 3. Test Compound Nomenclature.

Compound

Common name Bifenazate

Company experimental name D2341

IUPAC name isopropyl 3-(4-methoxybiphenyl-3-yl)carbazate or

isopropyl 2-(4-methoxybiphenyl-3-yl)hydrazinoformate

CAS name 1-methylethyl 2-(4-methoxy[1,1′-biphenyl]-3-yl)hydrazinecarboxylate

CAS registry number 149877-41-8

End-use products (EPs) Acramite (EPA Reg. Nos. 400-503

Floramite (EPA Reg. No. 400-481)

Prevamite (EPA Reg. No. 400-572) 

Compound

Common name None

Company experimental name D3598

IUPAC name isopropyl-(4-methoxy-[1,1’-biphenyl]-3-yl)diazenecarboxylate

CAS name diazenecarboxylic acid, 2-(4-methoxy-[1,1’-biphenyl]-3-yl), 1-methylethyl ester

CAS registry number 149878-40-8

Compound

OH

Common name None

Company experimental name A1530

IUPAC name 1,1’-biphenyl, 4-ol

CAS name p-hydroxybiphenyl

CAS registry number 92-69-3

Compound

OSO3H

Common name None

Company experimental name A1530 sulfate, biphenyl-4-ol-sulfate

IUPAC name Unknown

CAS name Unknown

CAS registry number Unknown

O

N

H

N

H

O CH3

O CH3

CH3

O

N

N O CH3

O CH3

CH3
Bifenazate Registration Review Human-Health Assessment Scoping Document

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Attachment 2: Bifenazate Endpoint Selection Table.

Table 4. Summary of Toxicological Dose and Endpoints for Bifenazate

(Memo, 7/14/2010, W. Wassell, et al., D371783).

Exposure

Scenario

Dose Used in Risk 

Assessment, UF

FQPA SF and LOC 

for Risk Assessment Study and Toxicological Effects

Acute Dietary; all 

populations

An acute dietary endpoint was not selected based on the absence of an appropriate 

endpoint attributed to a single dose.

Chronic Dietary;

all populations

NOAEL = 1.0 mg/kg/day

UF = 100

cRfD = 0.01 mg/kg/day

FQPA SF = 1x 

cPAD = 0.01 

mg/kg/day

Chronic Toxicity in Dogs

LOAEL = 8.9/10.4 mg/kg/day [M/F] 

based on changes in hematological 

and clinical chemistry parameters, and 

histopathology in bone marrow, liver, 

and kidney.

Incidental Oral, Short 

Term (1-30 days)

Oral NOAEL = 

10 mg/kg/day

LOC for MOE 100

residential and 

occupational

Prenatal Developmental in Rats

Maternal LOAEL = 100 mg/kg/day 

based on clinical signs, decreased 

body weight, decreased body weight 

gain and food consumption during the 

dosing period.

Incidental Oral, 

Intermediate Term (30 

days-6 months)

Oral NOAEL = 

0.9 mg/kg/day

LOC for MOE 100

residential and 

occupational

90-Day Oral Toxicity non-RodentsDog

LOAEL = 10.4/10.7 mg/kg/day [M/F] 

based on changes in hematologic 

parameters.

Short-, Intermediateand Long-Term Dermal 

(1-30 days, 30 days-6 

months, and six months 

to lifetime)

Dermal NOAEL = 

80 mg/kg/day

LOC for MOE 100

residential and 

occupational

21-Day Dermal Toxicity-Rat

LOAEL = 400 mg/kg/day based on 

decreased body weight in females, 

decreased food consumption in both 

sexes, increased urinary ketones, 

increased urinary protein, increased 

urinary specific gravity, and 

decreased urinary volume in both 

sexes, and increased incidence of 

extramedullary hematopoiesis in the 

spleen in both sexes.
Bifenazate Registration Review Human-Health Assessment Scoping Document

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Table 4. Summary of Toxicological Dose and Endpoints for Bifenazate

(Memo, 7/14/2010, W. Wassell, et al., D371783).

Exposure

Scenario

Dose Used in Risk 

Assessment, UF

FQPA SF and LOC 

for Risk Assessment Study and Toxicological Effects

Short-Term

Inhalation (1-30 days)

Oral NOAEL = 

10 mg/kg/day 

Inhalation absorption rate 

= 100%

LOC for MOE 100

residential and 

occupational

Prenatal Developmental in Rats

maternal LOAEL = 100 mg/kg/day 

based on clinical signs, decreased 

body weight, decreased body weight 

gain and food consumption during the 

dosing period..

Intermediate-Term 

Inhalation (30 days-6 

months)

Oral NOAEL = 

0.9 mg/kg/day

inhalation absorption rate 

= 100%

LOC for MOE 100

residential and 

occupational

90-Day Oral Toxicity non-RodentsDog

LOAEL = 10.4/10.7 mg/kg/day based 

on changes in hematologic 

parameters.

Long-Term Inhalation 

(6 months-lifetime)

Oral study NOAEL = 

1.0 mg/kg/day

inhalation absorption rate 

= 100%

LOC for MOE 100

residential and 

occupational

Chronic Toxicity in Dogs

LOAEL = 8.9/10.4 mg/kg/day [M/F] 

based on changes in hematological 

and clinical chemistry parameters in 

both sexes and histopathological 

effects in bone marrow 

(compensatory hyperplasia), liver, and 

kidney in both sexes.

Cancer (oral, dermal, 

inhalation) Bifenazate is classified as "not likely" to be a human carcinogen.

1 UF = uncertainty factor; NOAEL = no-observed-adverse-effect-level; LOAEL = lowest-observed-adverse-effect 

level; RfD = reference dose (NOAEL 100); PAD = population-adjusted dose (NOAEL FQPA SF); LOC = level 

of concern; MOE = margin of exposure.
Bifenazate Registration Review Human-Health Assessment Scoping Document

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Attachment 3: Toxicity Profile of Bifenazate Technical.

Table 5. Bifenazate Acute Toxicity Profile.

Guideline No. Study Type MRID # Results Toxicity Category

870.1100 Acute Oral 44464934 LD50 >5,000 mg/kg IV

870.1200 Acute Dermal 44464936 LD50 >5000 mg/kg IV

870.1300 Acute Inhalation 44464937 LC50 >4.4 mg/L IV

870.2400 Primary Eye Irritation 44464938 slight irritation IV

870.2500 Primary Skin Irritation 44464939 slight irritation IV

870.2600 Dermal Sensitization 45385101 dermal sensitizer Magnusson/Kligman

870.2600 Dermal Sensitization 44464940 not a dermal sensitizer Buehler

Table 6. Bifenazate Subchronic, Chronic and Other Toxicity Profile.

Guideline 

No. Study Type MRID No. (year)/ Classification /Doses Results

870.3100 90-Day oral 

toxicity (rat)

43214321 (1997)

Acceptable/Guideline

0, 40, 200, 400 ppm

(0, 2.7/ 3.2, 13.8/ 16.3, 

27.7/ 32.6 mg/kg/day 

[M/F])

NOAEL = 13.8/3.2 mg/kg/day [M/F].

LOAEL = 27.7/16.3 mg/kg/day based on 

decreased body weight gain in both sexes, 

decreased liver weight in males, increased 

spleen weight in females, and histopathology in 

liver in both sexes, and histopathological 

changes in the spleen and adrenal cortex in 

males.

870.3100 90-Day oral 

toxicity (dog)

43214321 (1997)

Acceptable/Guideline

0, 200, 800, 400 ppm

(0, 0.9/ 1.3, 10.4/ 10.7, 25/ 

28.2 mg/kg/day [M/F]

NOAEL = 0.9/13 mg/kg/day [M/F].

LOAEL = 10.4/10.7 mg/kg/day based [M/F] 

based upon changes in hematological 

parameters in both sexes, increased bilirubin in 

the urine in males, increased absolute and 

relative liver weight in females and liver 

histopathologic effects in both sexes.

870.3200 21-Day dermal 

toxicity (rat)

44778401 (1998)

Acceptable/Guideline

0, 80, 400, 1,000 

mg/kg/day

NOAEL = 80 mg/kg/day in males and females

mg/kg/day.

LOAEL = 400 mg/kg/day based on decreased 

body weight in females, decreased food 

consumption in both sexes, increased urinary 

ketones, increased urinary protein, increased 

urinary specific gravity, and decreased urinary 

volume in both sexes, and increased incidence 

of extramedullary hematopoiesis in the spleen 

in both sexes.

870.3465 28-Day 

inhalation 

toxicity (rat)

48723301 (2012)

Acceptable/Guideline

0, 0.03, 0.075, 0.15 mg/L 

(0, 30, 75, 150 mg/m3)

(0, 7.83, 19.58, 39.15 

mg/kg/day [M/F])

NOAEL = 0.03 mg/L [M/F].

LOAEL = 0.075 mg/L [M/F] based on dried 

red material around the nose in females, lower 

body weights and weight gains, decreased food 

consumption, decreased heart and thymus 

weights in females, increased incidences of 

mild brown pigmentation of the spleen, and 

minimal to mild degeneration of the olfactory 

epithelium within nasal levels III, IV, and V in 

both sexes.

870.3700a Prenatal 

developmental in 

(rat)

44464945 (1999)

Acceptable/Guideline

0, 10, 100, 500 mg/kg/day

Maternal NOAEL = 10 mg/kg/day.

LOAEL = 100 mg/kg/day based on increased 

clinical signs, and decreased body weight, body 

weight gain, and food consumption.

Developmental NOAEL was not established.

LOAEL = 10 mg/kg/day based upon on 

increased early resorptions.
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Table 6. Bifenazate Subchronic, Chronic and Other Toxicity Profile.

Guideline 

No. Study Type MRID No. (year)/ Classification /Doses Results

870.3700b Prenatal 

developmental in 

(rabbit)

44464943, 44464944 

(1997)

Acceptable/Guideline

0, 10, 50, 200 mg/kg/day

Maternal NOAEL = 200 mg/kg/day.

LOAEL = not established; doses for the main 

study were selected based on a range-finding 

study in which groups of 5 rabbits each 

received 0, 125, 250, 500, 750, or 1,000 

mg/kg/day during gestation days 6-19 by 

gavage. Maternal toxicity was seen as 

increased deaths and decreased body weight at 

750 mg/kg/day and above. A treatment-related 

increase in the number of does aborting was 

seen at 250 mg/kg/day and above.

Developmental NOAEL = 200 mg/kg/day.

LOAEL = not established due to only one or 

two litters available in each of the treated 

groups in the range finding study, a clear 

assessment of developmental toxicity was not 

possible. Based on these results, doses of 10, 

50, and 200 mg/kg/day were selected for the 

main study.

870.3800 Reproduction 

and fertility 

effects

(rat)

45076503 (1999)

Acceptable/Guideline

0, 20, 80, or 200 ppm

(0/0, 1.5/1.7, 6.1/6.9, and 

15.3/17.2 mg/kg/day in 

the P animals [M/F], and 

0/0, 1.7/1.9, 6.9/7.8, and 

17.4/19.4 mg/kg/day in F1

animals [M/F], 

respectively)

Parental/Systemic NOAEL = 20 ppm (1.6/1.8

mg/kg/day [M/F]).

LOAEL = 80 ppm (equivalent to 6.5/7.4 

mg/kg/day [M/F]) based on decreased body 

weights and cumulative body weight gains in 

males and females.

Reproductive NOAEL 200 ppm (16.4/18.3 

mg/kg/day [M/F]).

LOAEL = not observed.

Offspring NOAEL 200 ppm (16.4/18.3 

mg/kg/day [M/F]).

LOAEL = not observed.

870.4100b Chronic toxicity 

(dog)

45052221 (1999)

Acceptable/Guideline

0, 40, 400, or 1000 ppm 

(0/0, 1.014/1.051, 

8.949/10.422, 

23.942/29.192 mg/kg/day 

[M/F])

NOAEL = 40 ppm (1.014/1.051 mg/kg/day 

[M/F]).

LOAEL = 400 ppm (8.949/10.422 mg/kg/day

[M/F]) based on hematological and clinical 

chemistry parameters and histopathological 

changes in the bone marrow, liver, and kidney.

870.4300 Carcinogenicity

(rat)

45076504 (1999)

Acceptable/Guideline

0, 20, 80, or 200 ppm (M) 

and 160 ppm (F) 

(0/0, 1.0/1.2, 3.9/4.8, and 

9.7/9.7 mg/kg/day [M/F], 

respectively)

NOAEL = 80 ppm (3.9/4.8 [M/F]) mg/kg/day. 

LOAEL = 200 ppm (9.7 mg/kg/day ([M/F]) 

based on decreased body weight, body weight 

gain, and food consumption in both sexes.

No evidence of carcinogenicity.

870.4300 Carcinogenicity

(mouse)

45052222 (1999)

Acceptable/Guideline

0, 10, 100, or 225 ppm 

(M) and 175 ppm (F) 

(0/0, 1.5/1.9, 15.4/19.7, 

and 35.1/35.7 mg/kg/day 

[M/F], respectively)

NOAEL = 1.5 (M)/ 19.7 (F) mg/kg/day.

LOAEL = 15.4 (M) mg/kg/day based on 

hematology parameters and possibly kidney 

weights.

LOAEL = 35.7 (F) mg/kg/day based on

decreased body weights and body weight gains.

No evidence of carcinogenicity.
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Table 6. Bifenazate Subchronic, Chronic and Other Toxicity Profile.

Guideline 

No. Study Type MRID No. (year)/ Classification /Doses Results

Gene 

Mutation

870. 5265

Ames Assay 44464947 (1996)

Acceptable/Guideline

0, 10, 33, 100, 333, 1000, 

3333, 5000 μg/plate (±S9)

Non-mutagenic when tested up to 5000 

ug/plate, in presence and absence of activation, 

in S. typhimurium strains TA98, TA100, 

TA1535 and TA1537 and E. coli strain 

WP2uvra.

Gene 

Mutation 

870.5300

Mammalian Cell 

Gene Mutation 

Assay

44464949 (1996)

Acceptable/Guideline

0, 15, 20, 25, 30, 40, 50 

μg/ml (-S9)

0, 25, 50, 100, 150, 250, 

350 μg/ml (+S9)

0,100, 150, 200, 250, 350, 

500 μg/ml (+S9)

Non-mutagenic at the TK locus in L5178Y 

mouse lymphoma cells tested up to cytotoxic 

concentrations or limit of solubility, in presence 

and absence of S-9 activation.

Cytogenetics 

870.5375

Mammalian 

Cytogenetics 

Assay (CHO-K1 

Cells)

44464950 (1996)

Acceptable/Guideline

0, 12, 24, 47, 94, 188, 375 

μg/ml (-S9)

0, 20, 40,79,157, 313, 

625, 1250 μg/ml (+S9)

0,12,24, 36, 47, 71, 94 

μg/ml (-S9)

0, 20, 40, 79, 119, 157, 

236 μg/ml (+S9)

Did not induce structural chromosome 

aberration in CHO-K1 cell cultures in the 

presence and absence of activation up to 

cytotoxic concentrations.

Micronucleus

870.5385

Mouse Bone 

Marrow 

Micronucleus 

Assay

44464948 (1996)

Acceptable/Guideline

0, 96/50, 192/100, 

384/200 mg/kg [M/F]

Non-mutagenic in ICR mouse bone marrow 

micronucleus chromosomal aberrations assay 

up to cytotoxic concentrations.

870.6200a Acute 

neurotoxicity 

screening battery

48395101 (2010)

Acceptable/Guideline

0, 200, 600, or 2000 

mg/kg bw

NOAEL = not observed.

LOAEL = 200 mg/kg/day based on decreased 

motor activity in females.

870.6200b Subchronic 

neurotoxicity 

screening battery

48526101 (2010)

Acceptable/Guideline

0, 80, 200, or 600 ppm (0, 

5.2/5.8, 13.4/14.9, or 34.5/

40.3 mg/kg bw/day

[M/F])

NOAEL = 13.4/14.9 mg/kg/day.

LOAEL = 34.5/ 40.3 mg/kg/day based on 

decreased landing foot splay (males), decreased 

fore- and hindlimb grip strength (males), 

decreased motor activity [center time (females) 

and rearing activity (both sexes).
Bifenazate Registration Review Human-Health Assessment Scoping Document

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Table 6. Bifenazate Subchronic, Chronic and Other Toxicity Profile.

Guideline 

No. Study Type MRID No. (year)/ Classification /Doses Results

870.7485 Metabolism and 

pharmacokinetics

(Rat)

45052223 (1998)

10 mg/kg or 1000 mg/kg

acceptable/guideline

Absorption, distribution, and metabolism of 

D2341 was rapid, with >93% of the administered dose being recovered within 72 hours of 

treatment for both the low- and high-dose 

groups. Because of this rapid turnaround, no 

significant tissue accumulation of the test 

material was found. The highest tissue levels 

were found in the liver and whole blood, 

although the concentration of the test material 

represented <3% of the administered dose 6 

hours after treatment. Comparison of the whole 

blood and red blood cell concentrations 

suggests that most of the test material was 

carried in the plasma. The feces were the 

primary elimination route for low-dose rats 

with ~66% of the administered dose recovered 

in this media. Radioactivity in the feces was 

greater for the high-dose rats (823%) due to 

saturated absorption that resulted in 

subsequently greater unabsorbed test material. 

Urinary excretion was a relatively minor route 

with ~25% of the administered dose recovered 

in this media for both male and female lowdose rats. For the high-dose male and female 

rats urinary excretion was notably lower (<10% 

of the administered dose) due to saturated 

absorption. Cmax was reached earlier following 

a 10 mg/kg dose (5-6 hours) than the 1000 

mg/kg dose (18-24 hours). In addition, t1⁄2 was 

slightly longer at the 1000 mg/kg dose (12-16 

hours) than at the 10 mg/kg dose (12-13 hours). 

No apparent sex-related differences in the 

pharmacokinetics of D2341 were observed. 

Eight primary metabolites were identified in the 

feces of male and female rats given oral doses 

of 10 mg/kg or 1000 mg/kg D2341.

870.7800 Immunotoxicity

(mouse)

48305501 (2010)

Acceptable/Guideline

0, 20, 80, or 200 ppm 

(0, 5, 20, or 50 mg/kg/day 

[F])

Systemic NOAEL = 50 mg/kg/day

LOAEL = not established.

Immunotoxic NOAEL = 50 mg/kg/day

LOAEL = not established.

(There were no treatment-related effects on 

spleen or thymus weights, the sheep red blood 

cell assay, or the natural killer cell assay).
Bifenazate Registration Review Human-Health Assessment Scoping Document

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Attachment 4: Exposure Potential for Adult and Child Aggregate Risk Estimates.

(From Memo, 07/14/2010, W. Wassell, et al., D371783)

Table 7. Summary of Chronic Dietary Exposure and Risk for Bifenazate (Drinking Water Exposure 

Included).

Population Subgroup cPAD (mg/kg/day) Chronic

Exposure (mg/kg/day) %cPAD

General U.S. Population 0.01 0.003036 30

All Infants (<1 year old) 0.006661 67

Children 1-2 years old 0.008094 81

Children 3-5 years old 0.006120 61

Children 6-12 years old 0.003749 37

Youth 13-19 years old 0.002164 22

Adults 20-49 years old 0.002523 25

Adults 50+ years old 0.002591 26

Females 13-49 years old 0.002382 24

Table 8. Short-Term Aggregate Exposure.

Population Target Aggregate

MOE1

Dietary 

MOE2

Dermal 

MOE3

Inhalation 

MOE4

Aggregate MOE

(dietary and residential)5

General U.S. pop.

100

3,300 4,200 430,000 1,800

Youth 13-19 years old 4,600 4,200 430,000 2,200

Adults 20-49 years old 4,000 4,200 430,000 2,000

Adults 50+ years old 3,900 4,200 430,000 2,000

Females 13-49 years old 4,200 4,200 430,000 2,100

1 Total uncertainty factor for all routes of exposure is 100x; therefore, the target MOE is 100.

2 Dietary MOE = short-term incidental oral NOAEL chronic dietary exposure; where short-term incidental oral NOAEL = 

10 mg/kg/day.

3 Adult dermal MOE = short-term dermal NOAEL dermal residential handler exposure.

4 Adult inhalation MOE = short-term inhalation NOAEL inhalation residential handler exposure.

5 Adult aggregate MOE (dietary and residential) = 1 ((1 MOEdietary)+ (1 MOEdermal) + (1 MOEinhalation)).
Bifenazate Registration Review Human-Health Assessment Scoping Document

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Attachment 5: Bifenazate International Residue Limit Status.

Bifenazate (000586; 07/25/2012)

Summary of US and International Tolerances and Maximum Residue Limits.

Residue Definition:

US Canada Mexico1 Codex2

40 CFR 180.572:

Plant: Sum of Bifenazate (1-

methylethyl 2-(4-methoxy[1,1'-

biphenyl]-3-yl)hydrazinecarboxylate) 

and its metabolite diazinecarboxylic 

acid, 2-(4-methoxy-[1,1'-biphenyl]-3-

yl), 1-methylethyl ester (D3598) 

(expressed as bifenazate) 

Livestock Fat: Bifenazate and D3598 

(expressed as bifenazate)

Plant/Livestock including 

fat: 1-methylethyl 2-(4-

methoxy[1,1'-biphenyl]-3-

yl)

hydrazinecarboxylate, 

including the metabolite

diazenecarboxylic acid, 2-

(4-methoxy-[1,1'-biphenyl]-

3-yl),1-methylethyl ester

Sum of Bifenazate 

and 

bifenazatediazene, 

diazinecarboxylic 

acid, 2-(4-methoxy-

[1,1'-biphenyl]-3-

yl), 1-methylethyl 

ester (expressed as 

bifenazate) 

Bifenazate is a fatsoluble compound.

Commodity Tolerance (ppm) /Maximum Residue Limit (mg/kg)

US Canada Mexico1 Codex2

Acerola 0.90

Almond, hulls 15 10

Apple, wet pomace 1.2

Atemoya 1.6

Avocado 7.0

Bean, dry seed 0.60 0.3 beans (dry)

Berry, low-growing subgroup 

13–07G

1.5

Biriba 1.6

Black sapote 7.0

Caneberry subgroup 13-07A 5.0 5.0 blackberries, 

loganberries, raspberries, 

wild raspberries

7 blackberries, 

raspberries, red, black, 

dewberries (including 

boysenberry and 

loganberry)

Canistel 7.0

Cattle, goat, hogs, horses and 

sheep fat

0.10 0.01

Cherimoya 1.6

Cotton, gin byproducts 35

Cotton, undelinted seed 0.75 0.3 cotton seed

Custard apple 1.6

Feijoa 0.90

Fruit, pome, group 11 0.75 0.6 apples 0.7 pome fruits

Fruit, small, vine climbing 

subgroup 13–07F, except 

fuzzy kiwifruit

1.0 0.7 grape

Fruit, stone, group 12, except 

plum

2.5 2 stone fruits

Grape 0.75 1.0 0.7

Grape, raisin 1.2 1.2 raisins 2 dried grapes 

(=currants, raisins, 

and sultanas)

Guava 0.9

Hop, dried cones 15 20 hops, dry

Jaboticaba 0.90

Ilama 1.6
Bifenazate Registration Review Human-Health Assessment Scoping Document

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Summary of US and International Tolerances and Maximum Residue Limits.

Residue Definition:

US Canada Mexico1 Codex2

Longan 5.0

Lychee 5.0

Mango 7.0

Nut, tree, group 14 0.20 0.2 tree nuts

Okra 2.0

Papaya 7.0

Passionfruit 0.90

Pea and bean, succulent 

shelled, subgroup 6B

0.70 7 legume vegetables

Peppermint, tops 25

Pistachio 0.20 0.2 tree nuts

Plum 0.20 2 stone fruits

Pulasan 5.0

Rambutan 5.0

Sapodilla 7.0

Sapote, mamey 7.0

Soursop 1.6

Soybean, succulent shelled 0.70 7 legume vegetables

Spanish lime 5.0

Spearmint, tops 25

Star apple 7.0

Starfruit 0.90

Strawberry 1.5 1.5 2 

Sugar apple 1.6

Vegetable, cucurbit, group 9

0.75

0.25 cucumbers 0.5 fruiting 

vegetables, 

cucurbits

Vegetable, fruiting, group 8

2.0

1.1 bell peppers

0.35 tomatoes

3 peppers chili

2 peppers, sweet 

(including pimento 

or pimiento)

0.5 tomato

Vegetable, legume, ediblepodded, subgroup 6A 6.0 7 legume vegetables

Vegetable, tuberous and 

corm, subgroup 1C 0.10

Wax jambu 0.90

US [40 CFR §180.572(a)(2)] Canada Mexico1 Codex2

Livestock (except fat): sum of 

bifenazate and its metabolites 

diazinecarboxylic acid, 2-(4-methoxy-

[1,1′-biphenyl]-3-yl), 1-methylethyl 

ester (expressed as bifenazate); 1,1′-

biphenyl, 4-ol; and 1,1′-biphenyl, 4-

oxysulfonic acid (expressed as 1,1′-

biphenyl, 4-ol) 

Livestock/dairy 

commodities except fat: 1-

methylethyl 2-(4-

methoxy[1,1'-biphenyl]-3-

yl)hydrazinecarboxylate, 

including the metabolites 

diazenecarboxylic acid, 2-

(4-methoxy-[1,1'-biphenyl]-

3-yl), 1-methylethyl ester 

and [1,1'-biphenyl]-4-ol and 

[1,1'-biphenyl]-4-ol sulfate

Sum of Bifenazate 

and 

bifenazatediazene, 

diazinecarboxylic 

acid, 2-(4-methoxy-

[1,1'-biphenyl]-3-

yl), 1-methylethyl 

ester (expressed as 

bifenazate) 

Commodity Tolerance (ppm) /Maximum Residue Limit (mg/kg)

US Canada Mexico1 Codex2
Bifenazate Registration Review Human-Health Assessment Scoping Document

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Summary of US and International Tolerances and Maximum Residue Limits.

Residue Definition:

US Canada Mexico1 Codex2

Cattle, goat, hogs, horses and 

sheep meat

0.02 0.02 0.05 (fat) meat 

(from mammals 

other than marine 

mammals)

Cattle, goat, hogs, horses and 

sheep meat byproducts

0.02 0.02 0.01 (*) edible offal 

(mammalian)

Milk 0.02 0.02 0.01 (*)

MRLs With No US Equivalent

Eggs 0.01 (*)

Milk fats 0.05

Mints 40

Poultry meat 0.01 (*) (fat)

Poultry, edible offal of 0.01 (*)

Completed: M. Negussie; 08/01/2012

1 Mexico adopts US tolerances and/or Codex MRLs for its export purposes.

2 * = absent at the limit of quantification; Po = postharvest treatment, such as treatment of stored grains. PoP = 

processed postharvest treated commodity, such as processing of treated stored wheat. (fat) = to be measured on the 

fat portion of the sample. MRLs indicated as proposed have not been finalized by the CCPR and the CAC.