Bifenazate Registration Review Human

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Page 3 of 34 

### HASPOC concluded that a DNT study is required for bifenazat e: (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, t he toxicity database for bifenazate is adequate for risk asses sment. A 10x d atabase u ncertainty f actor (UF DB 

### ) 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

. T he 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 c oncern 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 bu rden to ruminants would be significantly higher than 10 ppm. Therefore, new ruminant metabolism and feeding stud ies with higher dosing levels would be required

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

Th e 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. R evis ed a ssessment s may be required under Registration Review in order to incorporate t he 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

- appl ication 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 ifBifenazate Registration Review Human

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Page 4 of 34 

### 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 assess ments 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 toxicolo gical 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 transp ort from treated areas, HED will evaluate the need for a bystander assessment during R egistration R eview.

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 p esticidal 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 ind icated by the amount of radiolabel recovered in the urine, cage wash, tissues/carcass

, and bile. The T max 

### (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 hig h

dose in male and female rats, as 57

- 64% of the administered dose was recovered in the feces in the biliary study. The T max 

### was 18 and 24 hours (males and females , respectively ) for the high

dose group. There was no significant tissue accumulation of th e 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

- d ose rats with ~66% of the administered dose recovered in this media. C max 

### (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 (t 1/2 

### ) 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 to xicity 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 thes e 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 red

cell production by the bone marrow. Additional toxicity was seen in the kidne y (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.Bifenazate Registration Review Human

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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, decrea sed 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, th e 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; ↓cent er 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) , decr eased 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 t he 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 wei ghts (↓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 inc idence 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 fo r 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 ad ult 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. , nervousBifenazate Registration Review Human

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Page 6 of 34 

### system malformati ons 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 ) fo r registration review

.
Residue Chemistry

Bifenazate is registered for food/feed and non

- food uses. The food/feed uses include the fo llowing crops: tropical fruits (including, but not limited to acerola, cherimoya, passion fruit and starfruit), tree nut s ( g roup 14), pistachio

, hops, okra, strawberry, cotton, dry bean seed, low

growing berry ( s ubgroup 13

- 07G), pome fruit ( g roup 11), small vine

- climbing fruit ( Subgroup 13

- 07F, except fuzzy kiwifruit), stone fruit ( g roup 12 ) , grape, succulent shelled pea an d bean ( s ubgroup 6B), mint, succulent shelled soybean, cucurbit vegetable s ( g roup 9), fruiting vegetables ( g roup 8), edible

- podded legume vegetables ( s ubgroup 6A), and tuberous and corm vegetables ( s ubgroup 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 non

bearing 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 hydrazine s 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 majorBifenazate Registration Review Human

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Page 7 of 34 

### residues. Hydroxylated D3598 and D2303 were also identified; biphenyl hydrazine was included as a reference standard but was not id entified as a residue in the study. The corn metabolism study was deemed unacceptable. The Residue Chemistry Test Guidelines (OPPTS 860.1300) specify that p rovided the results of metabolism studies on three dissimilar crops indicate a similar metabolic r oute in the crops, then additional plant metabolism data are not required. The metabolic route s in all crops studied were similar. Thus, a dditional plant metabolism data are not required for Registration Review.

The qualitative nature of the residue i n 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 th e 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 concer n in livestock tissue (excluding fat), eggs, and milk are bifen azate 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 purp oses 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 metabolis m 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

. D ifferences 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 an d 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 . M onitoring 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 hydraz ine 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
p roposed 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 w ou l d increase significantly . Therefore, new ruminant metabolism and feeding stud ies 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.Bifenazate Registration Review Human

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Page 8 of 34 

### The existing poultry metabolism study is adequate to allow HED to conclude that tolerances for secondary residue s 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 propos ed for registration. Additional poultry metabolism data are not required for Registration Review.

There are adequate residue analytical methods for tolerance enforcement

. For plants, a high

performance 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 t he 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) m ethod ( 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 m ethod ( NCL ME 259 ) was recently submitted as a confirmatory method, and this method was also forwar ded 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.

St orage 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.Bifenazate Registration Review Human

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Page 9 of 34 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 days 1 Cotton gin byproducts Bifenazate and D3598 <44 days 1
Cottonseed hulls Bifenazate and D3598 52 days Cottonseed oil Bifenazate and D3598 28 days

Cottonseed meal Bifenazate and D3598 43 days

- bifenazate <43 days

– D3598 1
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 weeks 2

47453713.der.doc (Includes MRIDs 47467703 and 47467705) Corn K+CWHR Bifenazate Instability shown for the intervals tested 3
Corn stover Bifenazate 8 weeks
Corn forage Bifenazate Instability shown for the intervals tested 4
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 tested 5

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, mea n 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 storag e 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 Regist ration 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, nectari ne, peach, plum, strawberry, summer squash, pecan, bell and non

-Bifenazate Registration Review Human

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Page 10 of 34 

### 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 ar e not required for Registration Review.

A dequate processing studies have been submitted for residues of bifenazate in/on plum/ prunes, grapes /raisins , tomato, mint, corn, apple, grape, and cotton. Generally, re s idues 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 a dequately 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 bifen azate and the metabolites D3598 , A1530, and A1530

- sulfate ( ca lculated 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 enfor cement methods are available. Additionally, adequate crop field trial s , processing studies , and storage stability data are available. HED notes that if other major crops with livestock feed commodities are registered in the futu re, 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 i ssued in conjunction with PP# 9E7642 (Memo, 7/14/2010, W. Wassell, D380060). An acute dietary assessment has not been conducted for b ifenazate because an endpoint of concern attributable to a single dose was not identified. A chronic dietary (food plus d rinking 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 field

trial 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. T he chronic exposure estimate utilized 30% chronic population

- adjusted dose (cPAD) for the U .S. population. The most highly exposed population s ubgroup 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 b ifenazate may be required as part of R egistration 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.Bifenazate Registration Review Human

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Page 11 of 34 

### 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 . R esidential 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 post

application exposures from the registered u ses on the Prevamite ® 

### label since this product is a restricted

- use pesticide

.
HED previously assessed the residential ornamental uses for bifenazate (Memo randa

, 03/13/2003, M. Dow

, D285897 and 12/24/2009, K. Lowe, D 365544 ). 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

- applicatio n 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 assu mptions. 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) de rmal 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 Uniroy al 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 expo sure to individuals nearby pesticide applications. The Agency sought expert advice and input on issues related to volatilization of pesticides from itsBifenazate Registration Review Human

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Page 12 of 34 

### 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 id entify 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 in halation 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 r esidents 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 w ith 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/o pp00001/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

- ap plication 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 c hronic (food and drinking water) aggregate exposure assessments were conducted . T he 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 w ere not of concern in the previous risk assessment.

Conclusions Th ere is sufficient information available to evaluate aggregate exposure to bifenazate in support of Registration Review. N ew aggregate exposure risk assessment s that incorporate new or revised toxicological end

- points, updated policies, a revised residential assessment, revisedBifenazate Registration Review Human

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Page 13 of 34 

### 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 non

food uses. The food/feed uses include the many crops that were prev iously 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

- way s.

Registered formulations of bifenazate include SC, F l C, 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 handli ng 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 registratio ns. 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 additio n 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

- a pplication 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 potent ial 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 r eceived 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 Ag ricultural Reentry Task Force and may, as appropriate, develop policies and procedures, to identify the need for and, subsequently, the way to incorporate occupationalBifenazate Registration Review Human

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Page 14 of 34 

### post

- application inhalation exposure into the Agency's risk assessments. If new policie s 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 hand ler exposure data ( http://www.epa.gov/pesticides/science/handler

- exposure

- table.pdf ). Reviewers should incorporate new exposure monitoring data, as necessary, during Registrati on 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 asses sment for Registration Review. A ddition ally , 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 b ifenazate reported to the Office of Pesticide Programs (OPP) Incident Data System (IDS) has been provided for the docket (Memo, 0 7/10/2012, 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 (201 2 )

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 human

health incidents from various sources, including mandatory F IFRA 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 prod uct 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 m odule. 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 inform ation 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 Aggreg ate 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

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Page 15 of 34 

### Bifen azate 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 con cern 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 Ha rmonization

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 bifen azate 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 defini tions and MRLs for b ifenazate 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 C ODEX. 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 ) ; howe ver, 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 harmo nized. 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 toxic ity. These studies include endpoints that may be susceptible to endocrine influence, including effectsBifenazate Registration Review Human

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Page 16 of 34 

### on endocrine target organ histopathology, organ weights, estrus cyclicity, sexual maturation, fertility, pregnancy rates, reproductive loss, and sex rat ios 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 Endocr ine 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

c hemical 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 relatio nship 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 contain s 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 ord ers/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 batte ry, 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 accor dance 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 highe st 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
peop le 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 b ifenazate and other pesticides and substances with a common mode/mechanism of toxicity. Bifenazate is a classified as a carbazate acaricide; there are no o ther compounds within this classification that are registered as for use as pesticides. The Agency considered structuralBifenazate Registration Review Human

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Page 17 of 34 

### similarities, common effects that exist between b ifenazate 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 b ifenazate has a common mode/mechanism of toxicity with any other chemical; therefore, the risk assessment took into account only exposures resulting from b ifenazate uses. Should the Agency determine that new information on b ife nazate 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 b ifenazate 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 relat ive 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 continue d reliance on these studies.

Data Requirements Required Under Registration Review

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

Toxicology :

DNT Study (O CSPP 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

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Page 18 of 34 

### 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.

R eferences

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 AssessmentBifenazate Registration Review Human

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Page 19 of 34 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 D 286170 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. Re view 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 D 308696 10/28/2004 Crop Field Trial

– Cotton

T. Bloem D313261 07/12/2006 Storage Stability

- Apple J uice and P omace
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

- SBifenazate Registration Review Human

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Page 20 of 34 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

– P otato

T. Bloem D 330587 07/1 9 /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 Rev iews (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 Gro up 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 Re sponse 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

- PapayaBifenazate Registration Review Human

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Page 21 of 34 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, Succu lent

- 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. Su mmary of Analytical Chemistry and Residue Data.

W. Wassell D 347496 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 Pe a 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 Jam bu, Starfruit, Passionfruit, and Acerola.

W. Wassell

, et al. D 348242 0 1/1 1 /200 8 PP#6E7167; Bifenazate; (000586). Petition for Establishment of Tolerances for Uses on Caneberry (Crop Subgroup Group 13A); Wild Raspberry; Edible

- podded Legume Vegetable (C rop 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, Pulas an, Guava, Feijoa, Jaboticaba, Wax Jambu, Starfruit, Passionfruit, and Acerola. HED Human

- Health Risk Assessment.

W. Wassell D355496 0 2/ 03 /200 9 Bifenazate; 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, L ychee, 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, Ate moya, 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

- Healt h 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: B ifenazate and Its Metabolites Chemical Identity Tables

. Attachment 2: B ifenazate 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 (R AB1), L. Venkateshwara (RAB1) RDI: RAB1 ( 08 / 14 / 20 12 ), D. Vogel ( 0 8/ 17 / 20 12), J. Rowland ( 0 8/ 28 / 20 12) , G. Waleko (09/24/2012) W. Wassell : S

- 109 58 : Potomac Yard 1 (PY1): (703)305

- 6135) : 7509P: RAB1Bifenazate 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. No s . 400

- 5 03 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

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

Common name None Company experimental name A1530 sulfate, biphenyl

- 4

- ol

- sulfate
IUPAC name Unknown
CAS name Unknown CAS registry number UnknownBifenazate Registration Review Human

- Health Assessment Scoping Document

Page 25 of 34 

### 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) O ral 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) O ral NOAEL = 0.9 mg/kg/day LOC for MOE 100 residential and occupational 90

- Day Oral Toxicity non

- Rodents

Dog LOAEL = 10.4/10.7 mg/kg/day [M/F] based on changes in hematologic parameters.

Short

- , Intermediate

and Long

- Term Dermal (1

- 30 days, 30 days

- 6 months, and six months to lifetime) D ermal 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 i n both sexes.Bifenazate Registration Review Human

- Health Assessment Scoping Document

Page 26 of 34 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) O ral 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) O ral NOAEL = 0.9 mg/kg/day inhalation absorption rate = 100% LOC for MOE 100 residential and occupational 90

- Day Oral Toxicity non

- Rodents

Dog LOAEL = 10.4/10.7 mg/kg/day based on changes in hematologic parameters

.

Long

- Term Inhalation ( 6 months

- lifetime) O ral 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

Page 27 of 34 

### 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 LD 50 >5,000 mg/kg IV 870.1200 Acute Dermal 44464936 LD 50 >5000 mg/kg IV 870.1300 Acute Inhalation 44464937 LC 50 >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 /1 3 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. 870.3 200 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
t oxicity (rat) 48723301 (2012)

Acceptable/Guideline 0, 0.03, 0.075, 0.15 mg/L (0, 30, 75, 150 mg/m 3 ) (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, a nd 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

.Bifenazate Registration Review Human

- Health Assessment Scoping Document

Page 28 of 34 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 Materna l 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. Mater nal 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. Developmenta l 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 F 1 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 o bserved. 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

.Bifenazate Registration Review Human

- Health Assessment Scoping Document

Page 29 of 34 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 s olubility, 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 = n ot 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

Page 30 of 34 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 administer

ed 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 f ound 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 wa s 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 resu lted 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 low

dose rats. For the high

- dose male and female rats urinary excret ion was notably lower (<10% of the administered dose) due to saturated absorption. C max was reached earlier following a 10 mg/kg dose (5

- 6 hours) than the 1000 mg/kg dose (18

- 24 hours). In addition, t 1⁄2 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 fema le 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 e stablished

. Immunotoxic NOAEL = 50 mg/kg/day LOAEL = not e stablished

. (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

Page 31 of 34 

### 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 MOE 1 Dietary

MOE 2 Dermal

MOE 3 Inhalation

MOE 4 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 de rmal 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 MOE dietary )+ (1 MOE dermal ) + (1 MOE inhalation )).Bifenazate Registration Review Human

- Health Assessment Scoping Document

Page 32 of 34 

### 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 Mexico 1 

### Codex 2

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: Bifenazat e 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 Bi fenazate and bifenazatediazene, diazinecarboxylic acid, 2

- (4

- methoxy

- [1,1'

- biphenyl]

- 3

- yl), 1

- methylethyl ester (expressed as bifenazate)

Bifenazate is a fat

soluble compound. 

### Commodity Tolerance (ppm) /Maximum Residue Limit (mg/kg) US Canada Mexico 1 

### Codex 2

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 1.6Bifenazate Registration Review Human

- Health Assessment Scoping Document

Page 33 of 34 

### Summary of US and International Tolerances and Maximum Residue Limits

. Residue Definition : US Canada Mexico 1 

### Codex 2 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, edible

podded, 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 Mexico 1 

### Codex 2 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 Mexico 1 

### Codex 2Bifenazate Registration Review Human

- Health Assessment Scoping Document

Page 34 of 34 

### Summary of US and International Tolerances and Maximum Residue Limits

. Residue Definition : US Canada Mexico 1 

### Codex 2 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.