### UNITED ST A TES E NVIRONMENTAL PROT E CTION AGENCY WASHINGTON, D.C. 20460
OFF IC E O F CHEMICAL SAFETY AND POLLUTION PREVENTION



### MEMORANDUM

Date: 25-June

- 20 14



### SUBJECT: Bifenazate. Human-Health Risk Assessment. Section 3 Regi stratio n Request to Add New Uses on Timothy Forage and Hay; Herb, Subgroup 19A ; and to Expand Exi s ting Uses on Pome Fruit, Group 11

, and Fruiting Vegetables

, Group 8.

PC Code: 000586 DP Barcode: D388228 Decision No.: 446177 Registration Nos.: 400-503

, 400-514
Petition No.: 1E7847 Ree:u l atory Actions: Section 3 Regi st rati on Risk Assessment Sin g le Case No.: 7609 Type: Chemical/ Aggregate
TXR No.: NA CAS No. : 149877-41-8
MRID No.: None 40 CFR: ..§ 180.572



### - 

# ;W;Jt{!fJ

. Wilham D. Wassell, Chemist 

# IJ1J.j**~ ~** **~** FROM

. Anwar Y. Dunbar, Ph.D.

, Pharmacologist

## ~ 7 · //' t. ,- 1-- Lata Venkateshwara, Envi ronmental Scientist 

### L 

## J'h**v~** 

## ' · Risk Assessment Bran c h l (RAB 1 ) Health E ffect s Division ( HED; 7509P)



### THROUGH: Charles W. Smit h III

, Branch Chi ef<:.:::> George F. Kramer, Ph.D., Senior C hemist

### _A**;::A ~~;::;;;:._..~__,...,.**  __ RABl!HED (7509P)



### TO: Barb ara Madden

, RM 05 Re gistrat ion Division (RD, 7505P)

The HED ofthe Office of Pe st icide Pro grams (OPP) is charged wit h estimat in g the risk to human health from exposure to pe s t ic ides. T h e RD of OPP has requested that HED evaluate haz ard and
exposure data and conduct dietary, occupational, re s idential

, and aggregate expo s ure assessments, as needed

, to estimate the risk to human health that will result from the regi ste red and proposed uses of the miticide / insecticide bifenazate [ 1-methylethyl 2

- ( 4-methoxy[ 1

, I '

- biphenyl]-3-yl)hydrazinecarboxylate)].

A summary of the findings and an assessment of human-health risk resulting from the propo se d and registered uses of bifenazate are provided in this document. The ri sk assessment, dietary
exposure assessment, and residue chemistry asse ss men t were provided by Willi a m Wassell (RAB 1 ); the hazard characterization and endpoint selection by Anwar Dunbar (RA B 1 ); the occupational and r esi dential expos ure assessment by Lata Venkateshwara (RAB 1 ); and the

Pag e I of52Bifenazate Human-Health Risk Assessment DP#388228

dr inki n g water exposure assessment by J. Hetrick of the Environmental Fa te and Effects Division ( EFED).

The mo s t-recen t human-heal th risk assessment for bifenazate was for a Section 3 registration and tolerances to support a proposed use on tropical fruits and berries (Memo, 07114/2010, W

. Wassell, 

### et al., D371783).

Page 2 of 52Bifenazate Human

- Health Risk Assessment DP # 388228

Page 3 of 52 

### Table of Contents 1.0 Executive Summary

................................ ................................ ................................ ........... 5 2.0 HED Recommendations

................................ ................................ ................................ .. 10 2.1 Data Deficiencies

................................ ................................ ................................ .......... 10 2.2 Tolerance Considerations

................................ ................................ ............................ 12 2.2.1 Enforcement Analytical Method

................................ ................................ ............. 12 2.2.2 Recommended Tolerances

................................ ................................ ....................... 12 2.2.3 Revisions to Petitioned

- For Tolerances

................................ ................................ .. 12 2.2.4 International Harmonization

................................ ................................ ................... 13 2.3 Label Recommendations

................................ ................................ .............................. 13 3.0 Introduction

................................ ................................ ................................ ...................... 13 3.1 Chemical Identity

................................ ................................ ................................ ......... 13 3.2 Physical/Chemical Characteristics

................................ ................................ ............. 15 3.3 Pesticide Use Pattern

................................ ................................ ................................ .... 15 3.4 Anticipated Exposure Pathways

................................ ................................ ................. 16 3.5 Consideration of Environmental Justice

................................ ................................ .... 16 4.0 Hazard Characterization and Dose

- Response Assessment

................................ .......... 17 4.1 Toxicology Studies Available for Analysis

................................ ................................ . 17 4.2 Absorption, Distribution, Metabolism, and Excretion (ADME)

............................. 17 4.2.1 Dermal Absorption

................................ ................................ ................................ ... 17 4.3 Toxicological Effects

................................ ................................ ................................ .... 18 4.3.1 Summary of Toxicological Effects

................................ ................................ ........... 18 4.4 Safety Factor for Infants and Children (FQPA Safety Factor)

............................... 18 4.4.1 Completeness of the Toxicology Database

................................ .............................. 20 4.4.2 Evidence of Neurotoxicity

................................ ................................ ........................ 20 4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

........ 20 4.4.4 Residual Uncertainty in the Exposure D atabase

................................ ................... 20 4.5 Toxicity Endpoint and Point of Departure Selections

................................ .............. 20 4.5.1 Dose

- Response Assessment

................................ ................................ ...................... 20 4.5.2 Recommendation for Combining Routes of Exposures for Risk Asse ssment

..... 22 4.5.3 Cancer Classification and Risk Assessment Recommendation

............................ 2 2 4.5.4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk Assessment

................................ ................................ ................................ ............................... 22 5.0 Dietary Exposure and Risk Assessment

................................ ................................ ......... 2 4 5.1 Residues of Concern Summary and Rationale

................................ .......................... 24 5.2 Food Residue Profile

................................ ................................ ................................ .... 25 5.3 Water Residue Profile

................................ ................................ ................................ .. 26 5.4 Dietary Risk Assessment

................................ ................................ .............................. 27 5.4.1 Description of Residue Data Used in Dietary Assessment

................................ .... 27 5.4.2 Percent Crop Treated Used in Dietary Assessment

................................ .............. 27 5.4.3 Acute Dietary Risk Assessment

................................ ................................ ............... 28 5.4.4 Chronic Dietary Risk Assessment

................................ ................................ ........... 28 5.4.5 Cancer Dietary Risk Assessment

................................ ................................ ............. 28 5.4.6 Summary Table

................................ ................................ ................................ ......... 28 6.0 Resi dential (Non

- Occupational) Exposure/Risk Characterization

............................. 28 6.1 Residential (Non

- Occupational) Exposure/Risk Characterization

............................. 29 6.2 Residential Post

- Application Exposure/Risk Characterization

................................ .. 2 9 6. 3 Spray Drift

................................ ................................ ................................ ........................ 30 6 .4 Residential Bystander Post

- Application Inhalation Exposure

................................ .... 30 6

. 5 Residential Risk Estimates for Use in Aggregate Assessments

................................ .... 31Bifenazate Human

- Health Risk Assessment DP # 388228

Page 4 of 52 

### 7.0 Aggregate Exposure/Ris k Characterization

................................ ................................ .. 31 7.1 Acute Aggregate Risk

................................ ................................ ................................ ... 31 7.2 Short

- Term 

### Aggregate Risk

................................ ................................ .......................... 33 7. 3 Chronic Aggregate Risk

................................ ................................ .............................. 33 8.0 Cumulative Exposure/Risk Characterization

................................ ............................... 33 8. 1 Occupational Exposure/Risk Characterization

................................ ..................... 33 9.0 Occupational Handler Exposure/Risk Characterization

................................ ............. 33 9.1 Post

- application Exposure/Risk

................................ ................................ ............... 33 9. 2 Post

- application Exposure/Risk

................................ ................................ ............... 33 10.0 References

................................ ................................ ................................ ......................... 37 Appendices

................................ ................................ ................................ ................................ ... 39Bifenazate Human

- Health Risk Assessment DP # 388228

Page 5 of 52 

### 1.0 Executive Summary

Background: Bifenazate is a selective miticide/ insecticide that controls the motile stage of mites either by direct contact or through contact with foliar residues. There is conflicting evidence in the literature for bifenazate being a mitochondrial inhibitor or a G ABA (gamma

- aminobutyric acid) channel modulator.

Bifenazate is currently registered for application to ornamental plants, pome fruit, fruiting vegetables, cucurbit vegetables, tree nuts, tuberous and corm vegetables, legume vegetables, berries, tropical fruits, stone fruits , grape, strawberry, cotton, ho ps, okra, peppermint, and spearmint with tolerances ranging from 0.1 to 35 ppm (40 CFR § 

### 180.572(a)(1)). A Section 18 registration ha s also been established for application of bifenazate to timothy with tolerances ranging from 5 0 to 150 ppm (40 CFR § 

### 180.57 2(b)). Tolerances, as a result of secondary residues, are established for residues in milk, ruminant meat, ruminant fat, and ruminant meat byproducts at 0.02 to 0.10 ppm (40 CFR § 

### 180.572(a)(1) and (a)(2)).

The Interregional Research Project No. 4 (IR

- 4 ) has submitted a petition proposing the establishment of permanent tolerances for residues of the acaricide bifenazate and its metabolite D3598 [diazinecarboxylic acid, 2

- (4

- methoxy

- [1,1’biphenyl]

- 3

- yl, 1

- methylethyl ester], (expressed as bifenazate) in/o n the following raw agricultural commodities (RACs):

Commodity Proposed Tolerance Herb

, Subgroup 19A, fresh leaves 30 ppm Herb

, Subgroup 19A, dried leaves

, except chervil, dried

, and chive, dried 140 ppm
Fruit, Pome, Group 11

- 10 0.75 ppm Vegetable, Fruiting, Group 8

- 10 2.0 ppm

Note: Bifenazate tolerances are established for residues in/on pome fruit ( group 11) and fruiting vegetables ( group 8) at the requested levels. IR

- 4 has proposed expanding the existing tolerances to cover additional commodi ties that are included in the revised crop group s 11

- 10 and 8

- 10.

Additionally, IR

- 4 proposes the establishment of tolerances with regional registrations for residues of bifenazate and its metabolite D3598 in/on the following RACs:

Commodity Proposed Tolerance Timothy, forage 140 ppm Timothy, hay 120 ppm

The end

- use products (EPs) relevant to th ese registration request s are Acramite ® 

### 50WS (EPA Reg. No. 400

- 503), a 50% by weight wettable

- powder (WP) in water

- soluble bags (WSP), and Acramite ® 

### 4SC (EPA Reg. No. 400

- 514), a 4 lb/gal suspension

- concentrate (SC) formulation [equivalent to a flowable

- concentrate (FlC) f ormulation].

IR

- 4 has proposed one foliar spray application to herbs and timothy by ground or aerial (timothy only) equipment at a rate of 0.38 to 0.50 lb ai/A to herbs and 0.43 to 0. 75 lb ai/A for timothy. The proposed pre

- harvest intervals (PHIs) are 0 days for timothy forage, 7 days for timothy hay, and 3 days for herbs. The established use pattern for pome fruit and fruiting vegetables is oneBifenazate Human

- Health Risk Assessment DP # 388228

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### application using ground equipment at a maximum rate of 0.38 to 0.50 lb ai/A with PHIs of 3 and 7 days for f

ruiting vegetables and pome fruit, respectively. Application by aerial equipment is permitted for fruiting vegetables.

Hazard Assessment: The toxicological database for bifenazate is complete and adequate for Food Quality Protection Act Safety Factor ( FQPA SF) evaluation, selection of points of departure (PODs) for the various routes of exposure, and for dose

- response evaluation. Bifenazate was categorized as having low acute toxicity ( Toxicity Category IV) for the oral, dermal

, and inhalation routes of exposu re for this duration. For subchronic oral exposures

, the dog is the most sensitive species. For chronic oral exposures, the dog and the rat are equally sensitive. Subchronic and chronic studies in rats and dogs indicate that the liver and hemat opoietic system (spleen and bone marrow with associated hematological findings) are the primary target organs in these species. Additional toxicity was seen in the kidney (dogs following chronic exposure) and adrenal cortex (male rats following subchronic exposure ). Decreases in body weight , body

- weight gain, and food consumption were also associated with liver and hematopoietic system toxicity in several studies. In the rat developmental toxicity study, increases in early fetal resorptions occurred at t he same d oses that caused maternal toxicity. In the rabbit developmental toxicity study, there were no maternal or developmental effects up to the highest

- dose tested (HDT). In the two

- generation rat reproduction study, there were no reproductive or offs pring effects up to the HDT. In both of the neurotoxicity screening batteries, effects were seen only at the HDT and consisted of decreased landing foot splay

, decreased fore

- and hindl imb grip strength, and decreased motor activity measurements (center
t imes and rearing activity ) . There were no effects in the immunotoxicity study. In the 21

- day dermal toxicity study in rats, adverse effects occurred at the mid

- dose manifested as decreased body weight in females, decreased food consumption in both sexes, altered kidney parameters

, a nd effects on the hematopoietic system. In the 28

- day inhalation study, effects included dried

red material around the nose in females and minimal to mild degeneration of the olfactory epithelium within nasal levels III, IV, a nd V in both sexes, lower body weights and body

- weight gains, decreased food consumption, decreased heart and thymus weights in females, and increased incidences of mild brown pigmentation of the spleen . Bifenazate is classified as “ n ot likely ” to be carc inogenic to humans

.
Consistent with previous risk assessments for bifenazate (Memo, 07/14/2010, W. Wassell, et al.

, D371783 ), the bifenazate risk assessment team recommends that the 10x FQPA SF be reduced to 1 x for all exposure scenarios, as discussed in Section 4.4.

For purposes of the current risk assessment, PODs were selected for acute and chronic dietary, short

- and intermediate

- term incidental oral, and both residential and occupational short

- and interme diate

- term dermal and inhalation exposures. For the acute dietary exposure for the general population, the acute neurotoxicity study in rats established a no

- observed adverse

- effect level (NOAEL) of 600 mg/kg/day and a lowest

- observed adverse

- effect level (LOAEL) of 2000 mg/kg based on decreased motor activity measurements. For the acute dietary exposure for females 13

- 49 years of age, the prenatal developmental toxicity study in rats was chosen which established a NOAEL of 10 mg/kg/day and a LOAEL of 100 mg/kg/day based on maternal effects including clinical signs, decreased absolute body weight s and food consumption during the dosing period. At the same dose, there was an increased incidence of early fetal resorptions. For the ch ronic dietary exposure, co

- critical studies with similar NOAELs (1 and 1.5 mg/kg/day) were selected (chronic dog and mouse carcinogenicity , respectively ). Specifically, the chronic dog study established a LOAEL at 8.9 mg/kg/day based upon changes in hematological and clinical c hemistry parameters and histopathological changes in the bone marrow, liver, andBifenazate Human

- Health Risk Assessment DP # 388228

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### kidney. A similar LOAEL of 15.4 mg/kg/day was also established in the mouse carcinogenicity study based on changes in hematological parameters and kidney weights

.

For shor t

- and intermediate

- term incidental oral exposures, endpoints were derived from the 90

- day dog study where the NOAEL was 0.9 mg/kg/day. The LOAEL was 10.4 mg/kg/day based on changes in hematologic parameters. For short

- and interme diate

- term dermal expos ures, endpoints were derived from the 21

- day dermal rat study where the NOAEL was 80 mg/kg/day. The LOAEL was 400 mg/kg/day based upon decreased body weight in females, decreased food consumption in both sexes, as well as altered kidney parameters

, and effects on the hematopoietic system . For short

- and intermediate

- term inhalation exposures, the route

- specific 28

- day inhalation study was chosen which generated a NOAEL of 0.03 mg/L and a LOAEL of 0.075 mg/L for both sexes based upon portal

- of

- entry effe cts ( dried red material around the nose in females and minimal to mild degeneration of the olfactory epithelium within nasal levels III, IV, and V in both sexes). Using the reference concentration ( RfC ) methodology, human

equivalent concentrations (HECs), and human

- equivalent doses (HEDs) were generated for residential and occupational inhalation risk assessments.

The risk assessment team has concluded that the FQPA SF should be reduced to 1x. The following acceptable studies are available for FQPA con sideration: (1) d evelopmental toxicity stud ies in rats and rabbits; (2) t wo

- generation reproducti ve study in rats; and (3) a cute and subchronic neurotoxicity studies.

Food Residue Profile: The qualitative nature of the residue in plants and livestock are adequately understood based on acceptable studies with apple, orange, cotton, radish

, lactating goats , and laying hens . A briefing document, summarizing the salient features of the studies was presented to the Metabolism Assessment Review Committee (M ARC) (Memo, 07/31/2001, T. Bloem et al ., D276623) . 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 bife nazate).

L ivestock feedstuffs are not derived from the proposed crops of the subject petition with the exception of timothy. The proposed use on timothy is for a regional use in two counties of Nevada (Eureka and Humboldt Counties). Applications can only be made t o timothy that is intended for use as horse feed. The use on timothy was discussed and approved by the Chemistry Science Advisory Council (ChemSAC, meeting of 0 1/12/2011). Thus, secondary residues of bifenazate in livestock tissues are not of concern for this petition.

The existing poultry metabolism study is adequate to conclude that tolerances for poultry tissues and eggs are not needed for the purpose of this petition (Category 3 of 40 CFR §180.6). There is no reasonable expectation of finite residue s in poultry matrices. This decision will be revisited in the future if additional crops with poultry feed stuffs are proposed for registration.

The qualitative nature of the residue in rotational crops is adequately understood based on an acceptable con fined rotational crop metabolism study. The MARC concluded that a 30

- day plantback interval (PBI) is appropriate based on the available data. Appropriate PBI s appear on the product labels for Acramite ® 

### 4SC and Acramite ® 

### 50WS.

IR

- 4 has submitted adequate field trial data for bifenazate on basil. Four field trials were conducted in the 2008 growing season. At each trial, basil was treated with a single foliar application of Acramite ® 

### 50 WS, at the approximate rate of 0.75 lb ai/A (1.5x the proposedBifenazate Human

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Page 8 of 52 

### appli cation rate). The maximum residues of bifenazate and its metabolite D3598 on fresh basil following a single foliar application at the approximate rate of 0.75 lb ai/A and a 3

- day PHI ranged from 3.4 to 15 ppm. For the trial that included dried basil, the maximum combined residues of bifenazate and D3598 were 9.5 ppm in fresh basil and 91 ppm in dried basil which represents a concentration factor of 9.6 x for residues in dried basil. The residue data for basil from the submitted crop field trials were analyzed using the Organization for Economic Co

operation and Development (OECD) tolerance

- calculation procedures. Based on the data set, the recommended tolerance for residues of bifenazate and D3598 (calculated as the stoichiometric equivalent of bifena zate) is 30 ppm in/on fresh herbs. The tolerance level for dried herbs is determined as the fresh herb tolerance multiplied by the concentration factor (30 x 9.6 = 288) and rounded up to 300 ppm. A tolerance for residues in/on herbs covers both fresh and dried commodities. Thus, the recommended tolerance level for residues of bifenazate and its metabolite (calculated as the stoichiometric equivalent of bifenazate) in or on herbs, subgroup 19A, except chervil and chive is 300 ppm.

IR

- 4 has submitted ad equate field trial data for bifenazate on grasses. These data are intended to satisfy requirements for residue data for timothy forage and hay. Thirteen field trials were conducted in the United States during the 2004 growing season. At each trial, gras ses received one foliar application of Acramite ® 

### 4SC at a rate of approximately 0.75 lb ai/A. Grass forage samples were collected 4 hours after application and grass hay samples at 6 to 7 days after application. The maximum combined residues of bifenazat e and D3598 in/on grass forage and hay were 83.5 and 76.3 ppm, respectively . The residue data for grass forage and hay from the submitted crop field trials were analyzed using the OECD tolerance

- calculation procedures. Based on the data set, the recommen ded tolerances for residues of bifenazate and D3598 (calculated as the stoichiometric equivalent of bifenazate) are 200 ppm in/on timothy forage and 150 ppm in timothy hay.

Exposure/Risk Assessment Characterization: Acute and chronic dietary (food plus d rinking water) exposure and risk assessments were conducted using the Dietary Exposure Evaluation Model

- Food Consumption Intake Database (DEEM

- FCID), Version 3.16. The assessments were conducted for dietary exposure based on the existing and proposed us es. D rinking water estimates were directly incorporated into the analysis

.
The acute analysis for the general population, including infants and children, was unrefined and used tolerance

- level residues and 100% crop

- treated (PCT). The acute analysis f or females 13 to 49 years old was highly refined and incorporated data from the U.S. Department of Agriculture ( USDA’s ) Pesticide Data Program (PDP), crop field trial data, and PCT estimates. DEEM, ver. 7.81

, default processing factors were assumed for al l commodities excluding apple juice, grape juice, and wine/sherry. The processing factors for these commodities were reduced to 1.0, based on data from processing studies. The analys i s also included the acute surface water point estimate generated using the FQPA Index Reservoir Screening Tool (FIRST) and the dry bean application scenario (highest registered/proposed use rate).

The chronic dietary exposure analysis for all population subgroups was partially refined and used tolerance

- level residues and PCT estimates. DEEM (ver. 7.81) default processing factors were assumed for all commodities excluding apple juice, grape juice, and wine/sherry. The processing factors for these commodities were reduced to 1.0 based on data from processing studies. The analyses also included the chronic surface water point estimate generated using the FIRST model and the dry bean application scenario (highest registered/proposed rate).Bifenazate Human

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### The acute and chronic exposure and risk estimates were not of concern. A cancer dietary assessment was not conducted because bifenazate is classified as “ n ot l ikely ” to b e c arcinogenic
to h umans

.
Residential Exposure/Risk: The proposed uses will not result in residential exposure; however, the currently registered garden and ornamental use has been reassessed in this document to reflect updates to HED’s 2012 Residential Standard Operating Procedures (SOPs). A total aggregat ed risk index (ARI) approach was used since the level s of concern (LOC s ) for dermal exposure (100) and inhalation exposure (30) are different. The dermal and inhalation exposure risk estimates for residential handlers are not of concern at baseline for al l scenarios. All the ARIs are above 1 and do not exceed HED’s LOC for all scenarios. All adult and children (6 ≤ 11 years) dermal post

- application risk estimates for exposure to treated trees and gardens are not of concern (margins of exposure or MOEs) ≥ 100).

Occupational Handler Exposure: Occupational handler short

- and intermediate

- term exposure is anticipated from the proposed uses. Chronic exposure is not expected for the proposed uses

. Bifenazate is classified as “not likely ” to be carcinogeni c to humans; therefore, a cancer assessment was not conducted. The label for Acramite ® 

### 50WS only requires protective eyewear, long

- sleeved shirt

, long pants , and shoes plus socks. The label does not require gloves. The label for Acramite ® 

### 4SC requires long

- sleeved shirt

, long pants, and shoes plus socks. It includes a statement that “ w hen not using a closed system, wear apron and chemically resistant gloves made of any waterproof material for mixing/loading activities.”

Inhalation risk estimates were not of concern for all scenarios

. MOEs ranged from 100 to 12,000 (MOEs ≥ 30). Dermal risk estimates were not of concern for all scenarios

. MOEs ranged from 110 to 33,000 (MOEs ≥ 100). All ARIs are greater than 1 except for the following scenarios that require single layer of gloves:

 Mixing/loading liquids for aerial and chemigation applications and

 Mixing/loading/application of liquids via mechanically pressurized handgun (foliar).

Occupational Post

- application Exposure: Post

- application dermal exposure will occur since bifenazate is applied post

- emergence as a foliar spray. Chemical

- specific dislodgeable

- foliar residue (DFR t 

### ) data are available and used for bifenazate. The short

- and intermediate

- term risk estimates are not of concern (i.e., MOEs ≥ 100) on the day of treatment (d ay 0 ) for the post

application exposure activities. Based on the Agency's current practices, a quantitativ e occupational post

- application inhalation exposure assessment was not performed for bifenazate at this time. If new policies or procedures are put in to place, the Agency may revisit the need for a quantitative occupational post

- application inhalation exp osure assessment for bifenazate.

The 12

- hour restricted

- entry interval (REI) listed on the label is adequate to protect agricultural workers from post

- application exposures to bifenazate.

Review of Human Research: This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. These data, which include Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1); the Agricultural Handler Exposure Task Force (AHETF) datab ase; the Outdoor Residential Exposure Task Force (ORETF) database; the Agricultural Reentry Task Force (ARTF), and the Residential SOPs (Gardens/Tr ees), are (1) subject to ethics review pursuant to 40 CFR § 26, (2) have received that review, and (3) are com pliant with applicable ethics requirements. For certain studies, the ethicsBifenazate Human

- Health Risk Assessment DP # 388228

Page 10 of 52 

### review may have included review by the Human Studies Review Board. De scriptions of data sources, as well as guidance on their use, can be found at the Agency website 1



### .

2.0 HED Recommendations

2.1 Data Deficiencies

Provided the petitioner submits revised Sections F (see below) and that the petitioner resolves the deficiency pertaining to the availability of analytical

- grade standards at the EPA National Pesticide Standards Repository (see below), there are no residue chemistry or toxicological data deficiencies that would preclude the establishment of permanent tol erances for residues of bifenazate and its metabolites as outlined in Table 2.2.2.

860.1550 Proposed Toleran ces

In the subject petition, the proposed tolerance expression is in terms of the combined residues of bifenazate (1

- methylethyl 2

- (4

- methoxy[1,1’

- biphenyl]

- 3

- yl)hydrazinecarboxylate) and diazinecarboxylic acid, 2

- (4

- methoxy

- [1,1’

- biphenyl]

- 3

- yl, 1

- methylethyl ester (expressed as bifenazate). The established tolerance expression for livestock commodities is in terms of the combined residues of bifenazate and diazinecarboxylic acid, 2

- (4

- methoxy

- [1,1’biphenyl]

- 3

- yl, 1

- methylethyl ester (D3598, expressed as bif

enazate), A1530 (1,1’

- biphenyl, 4

- ol) and A1530

- sulfate (expressed as A1530; 1,1’biphenyl, 4

- oxysulfonic acid). The proposed tolerance expressions need to be modified to comply with the interim guidance on tolerance expressions (Memo, 5/27/2008, S. Knizne r).

The current tolerance expressions for bifenazate tolerances in 40 CFR § 180.572(a)(1) and 40 CFR § 180.572(b) are as follows:

Tolerances are established for residues of bifenazate (1

- methylethyl 2

- (4

- methoxy[1,1'

- biphenyl]

- 3

- yl)hydrazinecarboxylate ) including its metabolites and degradates, in or on the commodities listed in the following table. Compliance with the tolerance levels specified are to be determined by measuring only the sum of bifenazate and its metabolite

, diazinecarboxylic acid, 2

- (4

- methoxy

- [1,1'

- biphenyl]

- 3

- yl), 1

- methylethyl

ester
, (expressed as bifenazate) in or on the following food commodities:

The tolerance expression should be changed to conform to current HED policy. Specifically, the tolerance expression for 40 CFR §180.57 2(a)(1) should be as follows:

Tolerances are established for residues of the insecticide 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 meas uring only the sum of bifenazate and its metabolite

, diazinecarboxylic acid, 2

- (4

- methoxy

- [1,1'

- biphenyl]

- 3

- yl), 1

- methylethyl ester

, (calculated as the stoichiometric equivalent of bifenazate) in or on the following food commodities:

1 http://www.epa.gov/pesticides/science/handler

- exposure

- data.html and http://www.epa.gov/pesticides/science/post

- app

- exposure

- data.htmlBifenazate Human

- Health Risk Assessment DP # 388228

Page 11 of 52 

### The current toleranc e expressions for bifenazate tolerances in 40 CFR § 180.572(a)(2) is 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

este r (expressed as bifenazate) ; 1,1′

- biphenyl, 4

- ol; and 1,1′

- biphenyl, 4

- oxysulfonic acid (expressed as 1,1′

- biphenyl, 4

- ol) in or on the following food commodities:

The tolerance expression for 40 CFR §180.572(a)(2) should be modified as follows:

Toleranc es are established for residues of the insecticide 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 tole rance 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:

860.1650 Submittal of Analytical Reference Standards

Analytical reference standards for bifenazate and its metabolites D23

- 06 (D3598), D23

- 15, D23

- 16 (A1530) and D23

- 19 (A1530) are currently available at the EPA National Pesticide Standards Repository (personal communication with Theresa Cole, Analytical Chemistry Branch (ACB), 01/25/2012). However, the standard for metabolites D23

- 15 and D23

- 16 expire d on 6/30/2012 and 05/31/2012, respective ly. Additionally, the Repository does not have standards for bifenazate metabolite D23

- 22. The registrant must either recertify the lots in the repository and send in an updated certificate of analysis (COA ), or submit new standards (different lot #) if the previous lots will not be recertified.

If new standards are being submitted, they should be sent to the Analytical Chemistry Lab, which is located at Fort Meade, to the attention of either Theresa Cole at the following address:

USEPA National Pesticide Standards Repository/Analytical Chemistry Branch/OPP 701 Mapes Road Fort George G. Meade, MD 20755

- 5350

(Note that the mail will be returned if the extended zip code is not used.)Bifenazate Human

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Page 12 of 52 

### 2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

Plant Commodities: There are adequate residue analytical methods for tolerance enforcement. For plants, 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 the Pesticides Analytical Manual

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

- D2341 are 0.01 and 0.005 ppm, respectively. In addition, a liquid chromatographic system with tandem mass spectrometers (LC

- MS/MS) method (NCL ME 245) was recently submitted as a confirmatory method and has been forwarded to FDA.

Livestock Commodities: For livestock, HPLC methods with fluorescence detection or ELCD are available as primary methods for the enforcement of tolerances for residues of bifenaz ate and its regulated metabolites in livestock matrices. The methods have undergone a successful validation by the Agency and have been forwarded to FDA for inclusion in PAM II. In addition, the LC

MS/MS Method NCL ME 259 was recently submitted as a conf irmatory method, and this method was also forwarded to FDA. The validated LOQ was 0.01 ppm for each analyte. The LOD was reported as 0.005 ppm.

2.2.2 Recommended Tolerances

In accordance with the most recent guidance concerning tolerance expressions, HED recommends that the tolerance expression for 40 CFR §180. 572 be changed as indicated above (see 860.1550 Proposed Tolerances) . A revised Section F specifying the new tolerance expression

, HED

- recommended tolerances

, and correct commodities should be submitted.

Table 2.2.2. Tolerance Summary for Bifenazate

.
Commodity Proposed Tolerance (ppm) Recommended

Tolerance (ppm) Correct Commodity

Definition/Comments

To be established under 40 CFR §180. 572 (a) General. ( 1 ) Herb, s ubgroup 19A, fresh leaves 30 30 0 Herb, subgroup 19A, except chervil and chive Herb, s ubgroup 19A, dried leaves

, except chervil, dried and chive, dried 140 Not Applicable Herb subgroup 19A, dried leaves

does not exist.

Timothy, forage 140 200 Tolerance with regional registrations Timothy, hay 120 150 Tolerance with regional registrations Fruit, pome, g roup 11

- 10 0. 75 0. 7 Tolerance level for harmonization with Codex. Vegetable, fruiting, g roup 8

- 10 2.0 4.0 Tolerance level for harmonization with PMRA

.



### 2.2.3 Revisions to Petitioned

- For Tolerances

The residue data for bifenazate and D3598 in/on basil, grass forage, and grass hay were analyzed using the OECD tolerance

- calculation procedures. The recommended tolerance for residues of bifenazate and its metabolite are 30 0 ppm in/on herbs, subgroup 19A (based on data for basil the representative crop for h erb

, s ubgroup 19A ), 200 ppm in/on grass forage (translated to timothy

,Bifenazate Human

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Page 13 of 52 

### forage), and 150 ppm in/on grass hay (translated to timothy , hay)

. Based on the data set, the

recom mended tolerance for residues of bifenazate and D3598 (calculated as the stoichiometric equivalent of bifenazate) is 30 ppm in/on fresh herbs. The tolerance level for dried herbs is determined as the fresh herb tolerance multiplied by the concentration factor (30 x 9.6 = 288) and rounded up to 300 ppm. A tolerance for residues in/on herbs , subgroup 19A, covers both fresh and dried commodities. Thus, the recommended tolerance level for residues of bifenazate and its metabolite (calculated as the stoichi ometric equivalent of bifenazate) in or on herbs, subgroup 19A, except chervil and chive is 300 ppm.

The recommended

- tolerance level for fruiting vegetables is based on comments from t he Pest Management Regulatory Agency (PMRA) of Health Canada ( c orresp ondence from M. Thomas, PMRA to D. Vogel, EPA, dated: 02/24/2014). PMRA has proposed a maximum residue limit (MRL) for bifenazate on fruiting vegetables at 4.0 ppm. Additionally, HED is proposing to harmonize the U.S. tolerance for residue s in or on pom e fruit with the established Codex MRL of 0.7 ppm. A revised Section F is required to adjust the tolerance level s , correct proposed commodities, and to change the tolerance expression (see Recommended Tolerances section).

2.2.4 International Harmonizatio n

There are currently no established Codex, Canadian, or Mexican maximum residue limits (MRLs) for bifenazate in/on herbs, and timothy forage and hay. The tolerance expression for plant commodities are harmonized between the U.S.

, Canada, and Codex. Can adian MRLs are established for residues in/on apples, bell peppers

, and tomatoes, but not for other crops in the pome fruit and fruiting vegetables crop groups. Codex MRLs are established for pome fruits, chili peppers, sweet peppers and tomato, but not f or other members of fruiting vegetables crop group. HED is proposing to harmonize the U.S. tolerance for residues on fruiting vegetables with the proposed Canadian MRL. Additionally, HED is not proposing to harmonize the U.S. tolerance for residues in po me fruit with the Canadian MRL f or residues in apples as the U.S. tolerance covers more commodities than the Canadian MRL. HED is proposing to harmonize the U.S. tolerance for residue s in or on pome fruit with the established Codex MRL of 0.7 ppm.

2.3 Label Recommendations

The proposed use directions for Acramite ® 

### 50WS (EPA Reg. No. 400

- 503) and Acramite ® 

### 4SC (EPA Reg. No. 400

- 514) on herbs and timothy grass are sufficient to allow for evaluation of the submitted residue data. Bifenazate is currently registered for use on pome fruits and fruiting vegetables. The available field trial data support the proposed use directions for bifenazate on herbs, subgroup 19A, t imothy , pome fruits, and fruiting vegetables

.

3.0 Introduction

3.1 Chemical IdentityBifenazate Human

- Health Risk Assessment DP # 388228

Page 14 of 52 Table 3.1. 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 ® 50WS (EPA Reg. No. 400

- 503) Acramite ® 4SC (EPA Reg. No. 400

- 514)

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 Human

- Health Risk Assessment DP # 388228

Page 15 of 52 

### 3.2 Physical/Chemical Characteristics

Bifenazate is a selective miticide/ insecticide that controls the motile stage of mites either by direct contact or through contact with foliar residues. Bifenazate is expected to be slightly mobile, but not persistent in the environment. Bifenazate is expected to rapidly dissipate in soil and aquatic env ironments as a result of aqueous hydrolysis

, direct aqueous photolysis , and aerobic degradation in soil (Memo, 10/17/2011, J

. Hetrick, et al ., D388230 )

.
A table of the physicochemical properties of bifenazate can be found in Appendix E

.

3.3 Pesticide Use Pattern

The proposed use directions are presented in Table 3 .3

, below. The information presented in Table 3 .3 was obtained from undated draft labels for Acramite ® 

### 50WS (EPA Reg. No. 400

- 503) and Acramite ® 

### 4SC (EPA Reg. No. 400

- 514).

Table 3 .3 . Su mmary of Proposed and Registered Directions for Use of Bifenazate. Applic. Timing, Type, and Equip. Formulation

[Reg. No.] Applic.

Rate (lb ai/A) Max. No.

Applic. per Season Max.

Seasonal Applic. Rate (lb ai/A) PHI

(days) Use Directions and

Limitations

Herb, Subgroup 19A (Except Chervil and Chive, Proposed Use)

Ground Application Acramite ®

50WS [400

- 503] 0.38 to

0.50 1 0.50 (implied) 3 Application is to be made in a minimum of 50 gal/A using ground equipment. For maximum control, applications must be made as soon as mites
appear. Pome Fruit, Group 8

- 10 (Registered Use)

Ground Application Acramite ® 4SC

[400

- 514] Acramite ® 50WS [400

- 503] 0.38 to

0.50 1 0.50 (implied) 7 Application is to be made in a minimum of 50 gal/A using ground equipment. For maximum control, applications must be made as soon as mites
appear. Fruiting Vegetables, Group 8

- 10 (Registered Use)

Ground Application Acramite ® 4SC

[400

- 514] Acramite ® 50WS [400

- 503] 0.38 to

0.50 1 0.50 (implied) 3 Application is to be made in a minimum of 50 gal/A using ground equipment or 10 gal/A using aerial equipment. For maximum control, applications must be made as so on as mites
appear.Bifenazate Human

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Page 16 of 52 Timothy (Proposed Use)

Ground or Aerial Application Acramite ® 4SC

[400

- 514] 0.43 to

0. 7 5 1 0. 7 5 (implied) 0 (forage) 7 (hay) Application is to be

made in a minimum of 20 gal/A using ground equipment or 10 gal/A by air. For maximum control, applications must be made as soon as mites appear.



### The following rotational crop restriction is specified: “This product has a plantback restriction of 30 days. Do not plant another crop within 30 days after last Acramite ® 

### application due to chances of bifenazate residues showing up in rotational crops.”

Conclusions: The proposed use directions are adequate to allow evaluation of the residue data relative to the proposed use.

3.4 Anticipated Exposure Pathways

RD has requested an assessment of human

- health risk to support the IR

- 4 proposed tolerances for residues of bifenazate and its metabolite D3598 in/on herbs, subgroup 19A, t imothy hay and forage, fruiting vegetables, g roup 8

- 10 and pome fruit, g roup 11

- 10. Humans may be exposed to bifenazate in food and drinking water, since bifenazate may be applied directly to growing crops and application s may result in bifenazate reaching surface and ground water sources of drinking water. In an occupational setting, a pplicators may be exposed while handling the pesticide prior to application, as well as during application. In addition, adults and children may be exposed to bifenazate in residential settings due to the currently registered uses. This risk assessment

c onsiders all of the exposure pathways based on the proposed new uses of bifenazate, but also considers the existing registered uses as well, particularly for the dietary and residential exposure
assessment.

3.5 Consideration of Environmental Justice

Pote ntial areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, “Federal Actions to Address Environmental Justice in Minority Populations and Low

- In come Populations,” (http:// epa.gov/compliance/ej/resources/policy/exec_order_12898.pdf ). As a part of every pesticide risk assessment, OPP considers a large variety of consumer subgroups according to well

- established procedures. In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water consumption, and ac tivities in and around the home that involve pesticide use in a residential setting. Extensive data on foo d consumption patterns are compiled by the USDA under the National Health and Nutrition Examination Survey, What We Eat in America, (NHANES/WWEIA; 20 03

- 2008) and are used in pesticide risk assessments for all registered food uses of a pesticide. These dat a are analyzed and categorized by subgroups based on age, season of the year, ethnic group, and region of the country. Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when condi tions or circumstances warrant. Whenever appropriate, non

- dietary exposures based on home use of pesticide products and associated risks for adult a pplicators and for toddlers, youths, and adults entering or playing on treated areas postapplication are ev aluated. FurtherBifenazate Human

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Page 17 of 52 

### considerations are currently in development as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to bystanders and farm workers as well as lifestyle and traditional diet ary patterns among specific subgroups.

4.0 Hazard Characterization and Dose

- Response Assessment

Bifenazate is a selective miticide/ insecticide that controls the motile stage of mites either by direct contact or through contact with foliar residues. Ther e is conflicting evidence in the literature for bifenazate being a mitochondrial inhibitor or a GABA channel modulator. Either mechanism has potential toxicological relevance for mammalian systems

.

4.1 Toxicology Studies Available for Analysis

The toxicological database for bifenazate is complete and adequate for FQPA evaluation, selection of PODs for the various routes of exposure, and for dose

- response evaluation. A ppendix A is a summary of the bifenazate toxicological database. In the previous human health risk assessment for bifenazate ( Memo, 07/14/2010, W. Wassell

, et al.

, D371783 ), the toxicity database deficiencies consisted of an immunotoxicity study as well as the neurot oxicity screening battery tests as specified in the revised 40 CFR § 15 8 requirements. A 90

- day inhalation toxicity study was also requested. Since that last risk assessment, all four studies have been submitted and reviewed, and are included in this hazard characterization.

The Hazard and Science Policy Council (HASPOC) c oncluded that a developmental neurotoxicity (DNT) study is not required for bifenazate (TXR # 0056728). The HASPOC’s original decision to require a DNT was based upon what was thought to be the presence of the three triggers necessary for the study includi ng; 1) an increased fetal sensitivity in the developmental rat study (treatment related early resorptions at all doses tested); 2) specific effects on the nervous system in both neurotoxicity screening battery tests; and 3) a neurotoxic pesticidal mechanis m of action. Syngenta provided comments regarding the Agency’s conclusions ( MRID 48997401) and subsequently submitted the raw historical control data (MRID 49271101) for the developmental rat study

, which ultimately removed the Agency’s concern for an inc reased fetal sensitivity ( Memo, 02/ 20/2014 , A. Dunbar et al ., D416994). The Agency further conducted i ts own statistical analyses in the neurotoxicity screening batteries, and determined that the effects observed were not neurotoxic in nature but instead those indicative of overt systemic toxicity. Finally, a rigorous literature search by the Agency and S yngenta revealed conflicting evidence concerning the pesticidal mechanism of action (EPA

HQ

- OPP

- 2012

- 0633; Weiland and Rao, Feb 11, 2013: Response to “An ticipated Data Needs” for bifenazate and DNT Guideline 870.6300 requirement).

4.2 Absorption, Di stribution, Metabolism, and Excretion (ADME)

Recovery of bifenazate was >93% of the administered dose and was recovered within 72 hours of treatment for both the low

- and high

- dose groups. Low

- dose male and female rats absorbed ~85% of the administered dose as indicated by the amount of radiolabel recovered in the urine, cage wash, tissues/carcass

, a nd bile. However, absorption was saturated at the high dose in male and female rats , as 57

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

There was no significant tissue accumulation of the test material observed. The hi ghest tissue levels were found in the liver and whole blood, although the concentration of the test materialBifenazate Human

- Health Risk Assessment DP # 388228

Page 18 of 52 

### represented <3% of the administered dose 6 hours after treatment. Comparison of the whole blood and red blood cell concentrations suggests that mo st of the test material was carried in the plasma.

The feces was 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 due to saturated absorption that resulted in subsequently greater unabsorbed test material. Urinary excretion was a relatively minor route with ~25% of the administered dose recovered in this media for both male and female low

- dose rats. For the high

- dose male and female rats urinary excretion 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, the half

- life was slightly longer a t 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 highly metabolized with eight primary metabolites identified in the fec es of both sexes for both low

- and high

- doses. These metabolites, as well as those identified in the urine and bile, were due to metabolic reactions including hydrazine oxidation, demethylation, ring hydroxylation, and molecular scission with loss of the hydrazine carboxylic acid portion with subsequent glucuronide or sulfate conjugation with glucuronic acid or sulfate. The parent compound represented <7.2% of the administered dose of low

- dose male and female rats, and >48% of the dose in high

- dose rats, consistent with the saturation of absorption observed for the high

- dose rats. Six metabolites were identified in the bile of both sexes ; however variations in their concentrations between bile and feces may represent further metabolic attack by intestinal bacteria.

4.2.1 Dermal Absorption

No studies are available to directly provide a dermal

- absorption factor. However, when the results of a 21

- day dermal rat study LOAEL = 400 mg/kg/day) were considered along with the results of the oral developmental to xicity rat study (LOAEL = 100 mg/kg/day), the ratio provided an estimated 25% dermal

- absorption factor (100 mg/kg/day  400 mg/kg/day) ( Memo, 05/20/2001, J. Rowland, TXR #0014576)

.

4.3 Toxicological Effects

4.3.1 Summary of Toxicological Effects

Bifenaz ate was categorized as having low acute toxicity ( Toxicity Category IV) for the oral, dermal and inhalation routes of exposure for this duration. For subchroni c oral exposures

, the dog is the most sensitive species. For chronic oral exposures, the dog and the rat are equally sensitive.

Subchronic and chronic studies in rats and dogs indicate that the liver and hematopoietic system (spleen and bone marrow with associated hematological findings) are the primary target organs in these species . Additional toxicity was seen in the kidney (dogs following chronic exposure) and adrenal cortex (male rats following subchronic exposure). Decreases in body weight

, body

weight gain, and food consumption were also associated with liver and hematopoietic system toxicity in several studies.Bifenazate Human

- Health Risk Assessment DP # 388228

Page 19 of 52 

### In the rat developmental toxicity study, the maternal effects consisted of clinical signs of toxicity, decreased body weight and body

- weight gai ns, and reduced food consumption at the mid

- dose. Increases in early fetal resorptions occurred at the same doses that caused maternal toxicity. In the rabbit developmental toxicity study, there were no maternal or developmental effects up to the HDT . I n the two

- generation rat reproduction study, the parental effects occurred at the mid

- dose and consisted of decreased body weight and body

- weight gains. There were no reproductive or offspring effects up to the HDT

.
In the acute neurotoxicity study, trea tment related effects were seen only at the HDT , and consisted of decreased motor activity (rearing in females; center time in both sexes). In the subchronic neurotoxicity study, effects were also only seen at the HDT (34.5 mg/kg/day) and consisted of dec reased landing foot splay (males) , decreased fore

- and hindlimb grip strength (males), 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 HDT

.

In the 21

- day dermal toxicity study in rats, adverse effects occurred at the mid

- dose of 400 mg/kg/day 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, decreas ed body weight s in females, and decreased food consumption in both sexes were associated with the target organ effects.

In the 28

- day inhalation study, there were statistically significant decreased thymus weights (↓21

- 32%) in females at all of the conc entrations tested. Starting at the mid

- concentration (0.075 mg/L), t here were clinical signs in females (dried

- red material around the nose), and decreased heart weights in females. There was a concentration

- dependent increased incidence of slight to mil d olfactory epithelial degeneration in nasal levels III, IV, and V (3 0% of males and 40

- 50% of females). There was also an increased incidence of brown pigment in the spleen in females (80% at the mid

- concentration and 90% at the high

- concentration). At the highest concentration tested, there were also decreased lung weights in both sexes (↓14%).

In the mouse carcinogenicity study, males and females were tested up to 225 ppm and 175 ppm, respectively. Dosing was considered adequate based on decreased body weight and body

- weight gains in females. In male mice, there was an increase in the incidence of liver adenomas only, which, while being slightly above historical control levels, was not statistically significant by pair

- wise comparison. There also was no progression of the adenomas to carcinomas in males in this study.

In addition, benign hepatocellular adenomas and hepatocellular carcinomas had low occurrences in high

- dose females and were within historical control ranges. In rats, the HDT was 200 ppm in males and 160 ppm in females (9.7 mg/kg/day, each). Toxicity at the high

- dose level was mild, and consisted mainly of small decreases in body weight

, body

- weight gain, and food consumption during weeks 52

- 77 of the study. A full battery of mut agenicity studies were negative for mutagenic or clastogenic activity.Bifenazate Human

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Page 20 of 52 

### 4.4 Safety Factor for Infants and Children (FQPA SF)

4.4.1 Completeness of the Toxicology Database

The risk assessment team has concluded that the FQPA SF should be reduced to 1x. The following acceptable studies are available for FQPA consideration: (1) d evelopmental toxicity studies in rats and rabbits; (2) t wo

- generation reproductive study in rats; and (3) a cute and subchronic neurotoxicity studies.

4.4.2 Evidence of Neurotoxicity

There is evidence of neurotoxicity in the bifenazate database. The LOC is low however because; 1) the observed effects are well characterized; 2) they occur only at the highest doses tested; and 3) they are protected for b y the studies used in the endpoint selection.

4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

There is no evidence of increased susceptibility of offspring following pre

- or postnatal exposure to bifenazate in rats or rabb its.

4.4.4 Residual Uncertainty in the Exposure Database

The exposure databases are sufficient to determine the nature/magnitude of the residue in food and water. For acute exposure for the general population and chronic exposure, t he dietary
exposure a nalyses are unlikely to underestimate exposure as they incorporated tolerance

- level residues, 100% CT (acute)

, PCT (chronic), and modeled drinking water estimates. For acute analysis for females 13 to 49 years, the dietary analysis is unlikely to underest imate exposure as PDP data, crop field trial data, PCT estimates and modeled drinking water estimates were utilized. The residential handler and post

- application exposure assessments are based upon the residential SOPs. The residential SOPs are based upo n rea sonable worst

- case assumptions and are not expected to underestimate risk.

4.5 Toxicity Endpoint and Point of Departure Selections

4.5.1 Dose

- Response Assessment

Acute Dietary Endpoint for All Populations: The endpoint used for establishing the acute population

- adjusted dose ( aPAD ) for the general population was selected from the acute neurotoxicity study in rats. An aPAD of 6 mg/kg/day was derived from a NOAEL of 600 mg/kg/day and a 100

- fold uncertainty factor (UF) that included a 10x UF for in ter

- species extrapolations, 10x UF for intra

- species variations, and a 1x FQPA SF

. Effects at the LOAEL of 2000 mg/kg included decreased motor activity (rearing in females; center time in both sexes)

. This study is appropriate for the duration of exposur e and it is protective for the general population.

Acute Dietary Endpoint for F emales 13

- 49 Y ears of A ge: The endpoint for establishing the aPAD for females 13

- 49 years of age was selected from the prenatal developmental toxicity study in rats. An aPAD of 0.1 mg/kg/day was derived from a NOAEL of 10 mg/kg/day and 100

- fold UF that included a 10x UF for inter

- species extrapolations, 10x UF for intra

- speciesBifenazate Human

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Page 21 of 52 

### variations, and a 1x FQPA SF. At the LOAEL of 100 mg/kg/day, maternal effects included clinical signs, decreased absolute body weight s, and food consumption during the dosing period. At the same dose, the re was an increased incidence of early fetal resorptions. This study is appropriate for the duration of exposure as well as protective for pregnant females ages 13

- 49 years of age.

Chronic Dietary Endpoint for the General Population: The chronic dietary endpoint for the general population was selected from co

- critical studies with similar NOAELs ( 1 and 1.5 mg/kg/day). Specifically, the chronic dog study established a LOAEL at 8.9 mg/kg/day based upon changes in hematological and clinical chemistry param eters and histopathological changes in the bone marrow, liver, and kidney. A similar LOAEL of 15.4 mg/kg/day was also established in the mouse carcinogenicity study based on changes in hematological parameters and kidney weights

. Th e endpoint used for de riving the chronic PAD ( cPAD ) was selected from the chronic toxicity study in dogs. The cPAD of 0.01 mg/kg/day was derived from a NOAEL of 1 mg/kg/day and a 100

- fold UF that included a 10x UF for inter

- species extrapolations, 10x UF for intra

- species variations, and a 1x FQPA SF. The endpoint of concern was seen following repeated oral exposure in the most sensitive species and thus is appropr iate for assessing potential risk via chronic die tary exposure to bifenazate. This study is appropriate for t he duration of exposure and is protective of the general population.

Short

- and Intermediate

- Term Incidental Oral Endpoints: The short

- and intermediate

- term incidental oral endpoints were based upon the results from the subchronic 90

- day dog study where the NOAEL is 0.9 mg/kg/day. The LOAEL is 10.4 mg/kg/day based on changes in hematologic parameters. The LOC is 100 based upo n a 10x UF for inter

- species extrapolations, 10x UF for intra

- species variations, and a 1x FQPA SF. This study is appropriate for the durations of exposure and the population of concern, children in residential settings. It is noted that the effects and PODs seen in this study are consistent with the longer

- term dog and mouse studies used to set the chronic dietary endpoint.

Short

- (1

- 30 days) and Intermediate

- (1

- 6 months) Term Dermal Endpoints: The short

- and intermediate

- t erm dermal endpoints were de rived from the 21

- day dermal rat study where the NOAEL is 80 mg/kg/day. The LOAEL is 400 mg/kg/day based upon 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 incidences of extramedullary hematopoiesis in the sple en in both sexes. The LOC is 100 based upon a 10x UF for inter

- species extrapolations, and a 10x UF fo r intra

- species variations. This study protects for the early resorptions in the developmental rat study where the maternal and fetal effects occur at t he same dose. This study is appropriate for the route as well as the durations of exposure, in both residential and occupational settings.

Short

- (1

- 30 days) and Intermediate

- (1

- 6 months) Term Inhalation Endpoints: The short

- and intermediate

- term inha lation endpoints were derived from the route

- specific 28

- day inhalation study in r ats where the NOAEL is 0.030 mg/L. The LOAEL is 0.075 mg/L for both sexes based

on dried red material around the nose in females, lower body weight s and body

- weight gains, d ecreased food consumption, decreased heart and thymus weights in females, increased incidences of mild brown pigmentation of the spleen, and minimal to mild degeneration of the olfactory epithelium within nasal levels III, IV, and V in both sexes. HECs we re derived from this study based upon this degeneration of the olfactory epithelium which is considered a portal

of

- entry effect. For residential exposure, the HEC is 0.0009 mg/L, and for occupational
exposure , the HEC is 0.0039 mg/L. HEDs were subsequen tly calculated (0.14 mg/kg/day forBifenazate Human

- Health Risk Assessment DP # 388228

Page 22 of 52 

### residential exposure and 0.19 mg/kg/day for occupational exposure). For details regarding the calculation of the HECs and HEDs, see Appendix B . These HEDs are protective of the systemic effects observed thr ough the inhalation route. This study is thus appropriate for the route and duration of exposure, and is protective of adults in occupational and residential settings.

The methods and dosimetry equations described in EPA’s RfC guidance (1994) are suited for calcu lating HECs based on the inhalation toxicity N OAEL for use in MOE calculations. The regional deposited

- dose ratio (RDDR), which accounts for the particulate diameter (mass median aerodynamic diameter [MMAD] and geometric standard deviation [  g 

### ] of aerosol s), can be used to estimate the different dose fractions deposited along the respiratory tract. The RDDR is also based on interspecies differences in ventilation and respiratory

- tract surface areas. Thus, the RDDR can be used to adjust an observ ed inhala tion particulate exposure of an animal to the predicted inhalation exposure for a human. For the 4

- week inhalation study with bifenazate, an RDDR wa s estimated at 2. 8 based on the reported MMAD of 2.20 μm and standard deviation (  g 

### ) of 2.78 and the respir atory

- tract surface area of the rat relative to the human (see Appendix B for detailed calculations). Since the rat inhalation study was carried out for 6 hr/day for 5 days/week, the only exposure adjustment made was in the assumption of 8 hrs/day for hum an occupational exposures. The resulting HEC s are 0.0009 mg/L and 0.0 039 mg/L for residential and oc cupational exposures. The LOC is 30 which includes interspecies (3 x) , and intraspecies (10x ) uncertainty factors. The interspecies factor was reduced from 10x to 3x due to the HEC calculation accounting for pharmacokinetic (not pharmacodynam ic) interspecies differences.

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment

Based upon common effects (histopathology of the spleen and hematological parameters) between the two routes, dermal and inhalation exposures can be combined.

4.5.3 Cancer Classification and Risk Assessment Recommendation

The available data show no evi dence of carcinogenicity in rats at adequate dose levels, and no evidence of carcinogenicity in mice at adequate doses. In the mouse

, there was an increase in the incidence of adenomas only, which, while being slightly above historical control levels, was not statistically significant. There was also no progression of time for mouse adenomas to carcinomas. In accordance with the proposed Draft Guidelines for Carcinogen Risk Assessment (1996), the Hazard Identification Assessment Review Committee (HIARC) classified bifenazate

as “ n ot likely ” to be carcinogenic to humans ( Memo, 05/30/2001, J. Rowland, et al.

, TXR# 0014576 )

.

4.5.4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk AssessmentBifenazate Human

- Health Risk Assessment DP # 388228

Page 23 of 52 Table 4.5.4.1

. Summary of Toxicological Doses and Endpoints for Bifenazate for Use in Dietary and Non

Occupational Human

- Health Risk Assessments

.

Exposure/ Scenario P O D Uncertainty/FQPA SFs RfD, PAD,

Level of Concern for Risk Assessment Study and Toxicological Effects

Acute Dietary (General Population, including Infants and Children) NOAEL =

600 mg/kg/day UF A = 10x

UF H = 10x FQPA SF = 1x Acute RfD =

6 mg/kg/day aPAD = 6 mg/kg/day Acute Neurotoxicity Screening Battery

Rats LOAEL = 200 0 mg/kg/day based on decreased motor activity (rearing in females)

.
Acute Dietary (Females 13

- 49 years of age) NOAEL =

10 mg/kg/day UF A = 10x

UF H = 10x FQPA SF = 1x Acute RfD =

0.1 mg/kg/day aPAD = 0.1 mg/kg/day Prenatal Developmental Toxicity

- Rats

Developmental LOAEL = 100 mg/kg/day based upon clinical signs, decreased body weight and food consumption during the dosing period.

Chronic Dietary (All Populations) NOAEL =

1.0 mg/kg/day Co

- critical Study NOAEL = 1.5 mg/kg/day UF A = 10x

UF H = 10x FQPA SF = 1x Chronic RfD

= 0.01 mg/kg/day cPAD = 0.01 mg/kg/day Chronic Toxicity

- 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 in the one

- year dog feeding study. Carcinogenicity Study

- Mouse LOAEL = 15.4 (M) mg/kg/day based on hematology parameters and possibly kidney weights

.

Incidental Oral Short Term (1

- 30 days) and Intermediate Term NOAEL =

0.9 mg/kg/day UF A = 10x

UF H = 10x FQPA SF = 1x Residential

LOC for MOE = 100 90

- Day Subchronic

- Dogs

LOAEL = 10.4 mg/kg/day 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 histopat hologic al effects in both sexes.

Dermal Short

and Intermediate

Term (1

- 30 days and 1

- 6 months) LOAEL =

80 mg/kg/day UF A = 10x

UF H = 10x FQPA SF = 1x Residential

LOC for MOE = 100 21

- Day D ermal T oxicity

- Rat

LOAEL = 400 mg/kg/day based on decreased body weight in females, decreased food consumption in both sexes, increased urinary ketones, increased urinary protein, increased urinary specific gravity, and decreased urinary volume in both sexes, and increased incidence of extramedullary hematopoiesis in the spleen in both sexes.

Inhalation Short

- and Intermediate

Term (1

- 30 days, and 1

- 6 months) Rat

NOAEL = 0.03 mg/L
UF A = 3 x

UF H = 10x FQPA SF = 1x Residential

LOC for MOE = 30 28

- Day I nhalation T oxicity

- Rat

LOAEL = 0.075 mg/L [M/F] on dried red material around the nose in females, lower body weight s and body

- 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 degene ration of the olfactory epithelium within nasal levels III, IV, and V. HEC= 0.0009 mg/L HED = 0.14 mg/kg bw/day Cancer (oral, dermal, inhalation) Bifenazate is classified as "not likely to be a human carcinogen ”

.Bifenazate Human

- Health Risk Assessment DP # 388228

Page 24 of 52 a = 25% dermal

- absorption factor

. Point of d eparture (POD) = a data point or an estimated point that is derived from observed dose

- response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no

- ob served adverse

- effect level. LOAEL = lowest

observed adverse

- effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). UF L = use of a LOAEL to extrapolate a NOAEL. FQPA SF = FQPA Safety Factor. PAD = population

- adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern. N/A = not applicable.

Table 4.5.4.2 Summary of Toxicological Doses and Endpoints for Bifenazate for Use in Occupational Human Health Risk Assessments
Exposure/ Scenario POD Uncertainty Factors Level of Concern

for Risk Assessment Study and Toxicological Effects

Dermal Short

and Intermediate

Term (1

- 30 days and 1

- 6 months) LOAEL =

80 mg/kg/day UF A = 10x

UF H = 10x Occupational

LOC for MOE = 100 21

- Day D ermal T oxicity

- 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 incre ased incidence of extramedullary hematopoiesis in the spleen in both sexes.

Inhalation Short

- and Intermediate

Term (1

- 30 days, an d 1

- 6 months) Rat NOAEL

= 0.03 mg/L UF A = 3 x

UF H = 10x Occupational

LOC for MOE = 30 28

- Day I nhalation T oxicity

- Rat

LOAEL = 0.075 mg/L [M/F] based on dried red material around the nose, lower body weight s and body

- weight gains, decreased food consumption, mild brown pigmentation of the spleen, and minimal to mild degeneration of the olfactory epithelium within nasal levels III, IV, and V in both sexes. HEC = 0.0039 mg/L HED = 0.19 mg/kg bw/day Cancer (oral, dermal, inhalation) Bifenazate is classified as "not likely ” to be a human carcinogen

.

a = 25% dermal

- absorption factor

. Point of departure (POD) = a data point or an estimated point that is derived from observed dose

- response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no

- observed adverse

- effect level. LOAEL = lowest

observed adverse

- effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). MOE = margin of exposure. LOC = level of concern.



### 5.0 Dietary Exposure and Risk Assessment

An overview of the metabolism of bifenazate can be found in the most recent residue chemistry assessment (Memo, pending, W. Wassell, D 388800 ).

5.1 Residues of Concern Summary and Rationale

Plant Commodities: The qualitative nature of the residue in plants is adequately understood based on acceptable studies with ap ple, orange, cotton, and radish. Based upon these studies, the HED 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 equiva lent of bifenazate).Bifenazate Human

- Health Risk Assessment DP # 388228

Page 25 of 52 

### Livestock Commodities: The nature of the residue in livestock is adequately understood based on studies with lactating goats and laying hens. Based upon these studies, the HED MARC concluded that for tolerance expression and risk assessment purposes, the residues of concern in livestock tissues except fat are bifenazate, D3598, A1530, A1530

- sulfate (calculated as the stoichiometric equivalent of bifenazate). The residues of concern in fat are bifenazate and D3598 (calculated as th e stoichiometric equivalent of bifenazate).

Rotational Crops: The qualitative nature of the residue in rotational crops is adequately understood based on an acceptable confined rotational metabolism study. The MARC reviewed the confined rotational crop study and concluded that the residues of concern in/on rotationa l crops could not be determined from the available data. The MARC concluded that a 30

- day PBI is appropriate based on the available data.

D rinking Water: The HED MARC determined that the residue of concern in water is D1989

.

Table 5.1. Summary of Metabolites and Degradates to be I ncluded in Risk Assessment and Tolerance Expression.
Matrix Residues Included in Risk Assessment Residues Included in Tolerance Expression Plants bifenazate, D3598 (expressed as parent) bifenazate, D3598 (expressed as parent)
Livestock (excluding fat) bifenazate, D3598 A1530, A1530

- sulfate (expressed as parent), bifenazate, D3598, A1530, A1530

- sulfate (expressed as parent ) Livestock

– fat bifenazate, D3598 (expressed as parent) bifenazate, D3598 (expressed as parent) Rotational Crops could not be determined 1 could not be determined 1

Drinking Water D1989 Not applicable 1

. Based on the results of the confined rotational crop study conducted at 0.5 lb ai/acre (the application rate for the registered crops which are likely to be rotated), HED concluded that residues in rotated crops were unlikely and that tolerances were
unnecessary.



### 5.2 Food Residue Profile

The submitted magnitude of the residue data for basil will support the proposed use pattern for h erbs

, s ubgroup 19A

. IR

- 4 has submitted data for bifenazate and its metabolite D3598 on basil from a total of four crop field trials conducted during the 2008 growing season. The field trials were conducted in C A , SC, and G A (2 trials)

. The residue data were analyzed using the OECD tolerance

- calculation procedures. Based on the data set, the recommended tolerance for residues of bifenazate and D3598 (calculated as the stoichiometric equivalent of bifenazate) is 30 ppm in/on fresh herbs. The tolerance level for dried herbs is determined as the fresh herb tolerance multiplied by the concentration factor (30 x 9.6 = 288) and rounded up to 300 ppm. A tolerance for residues in/on herbs covers both fresh and dried c ommodities. Thus, the recommended tolerance level for residues of bifenazate and its metabolite (calculated as the stoichiometric equivalent of bifenazate) in or on herbs, subgroup 19A, except chervil and chive is 300 ppm.

The submitted magnitude of th e residue data for grass forage and hay will support the proposed use patterns for t imothy

. IR

- 4 has submitted data for bifenazate and its metabolite D3598 on grass forage and hay from thirteen crop field trials conducted during the 2004 growing season

. The field trials were conducted in MD (2 trials), NC (1 trial), NJ (1 trial), TN (1 trial), FL (2 trials), TX (1 trial), CO (1 trial), CA (1 trial), ID (1 trial), WA (1 trial), and OR (1 trial)

. The residue data were analyzed using the OECD tolerance

- c alculation procedures. The tolerance worksheet recommended a tolerance for residues of bifenazate and D3598 at 200 ppm in/on grass forage (translated to timothy , forage) and 150 ppm in/on grass, hay (translated to timothy

, hay).Bifenazate Human

- Health Risk Assessment DP # 388228

Page 26 of 52 

### Livestock feed items are not derived from herbs

. T imothy is used as horse feed

. The proposed use on timothy is for a regional use in two counties of Nevada (Eureka and Humboldt Counties). Applications can only be made to timothy that is intended for use as horse feed. The use on timothy was discussed and approved by the ChemSAC (meeting of 1/12/11). Tolerances are established for residues of bifenazate and its metabolites in/on horse fat, meat

, and meat byproduct.

Bifenazate is currently registered for use on pome fruit ( group 11). IR

- 4 has proposed expanding the existing tolerances to cover additional commodities that are included in the revised crop
group 11

- 10. The petitioner further states that the established tolerances for residues in/on pome fruit, group 11 may be deleted upon establishment of the uses and tolerances for residues in/on pome fruit, group 11

- 10. Residue data for the use on pome fruit w ere submitted and reviewed in conjunction with PP#0F6108 (Memo, 8/16/2001, T. Bloem, D277089). HED is proposing to harmonize the U.S. tolerance for residues in or on pome fruit with the established Codex MRL of 0.7 ppm (see discussion below).

Bifenaza te is currently registered for use on fruiting vegetables ( group 8). IR

- 4 has proposed expanding the existing tolerances to cover additional commodities that are included in the revised crop group 8

- 10. Residue data for the use on fruiting vegetables w er e submitted and reviewed in conjunction with PP# 3E6517 (Memo, 5 / 29 /200 3 , T. Bloem, D 290053 ). The recommended

- tolerance level for fruiting vegetables is based on comments from the Pest Management Regulatory Agency (PMRA) of Health Canada (correspondence fr om M. Thomas, PMRA to D. Vogel, EPA, dated: 02/24/2014). PMRA has proposed a MRL for bifenazate on fruiting vegetables at 4.0 ppm. HED proposes to harmonize the fruiting vegetables bifenazate tolerance/MRL.

Canadian MRLs are established for residues in/on apples, bell peppers

, and tomatoes, but not for other crops in the pome fruit and fruiting vegetables crop groups. Codex MRLs are established for pome fruits, chili peppers, sweet peppers

, and tomato, but not for other members of fruiting vegetables crop group. HED is not proposing to harmonize the U.S. tolerance for residues on fruiting vegetables with Codex MRLs as the U.S. tolerance covers more commodities that the Codex MRLs. Additionally, HED is not proposing to harmonize the U.S. tolerance fo r residues in pome fruit with the Canadian MRL f or residues in apples as the U.S. tolerance covers more commodities than the Canadian MRL. HED is proposing to harmonize the U.S. tolerance for residues in or on pome fruit with the established Codex MRL of 0.7 ppm.

Poultry feed items are not derived from herbs, timothy, pome fruit

, and fruiting vegetables. A poultry metabolism study was previously submitted. Based on this study and the dietary burden

, HED concludes that there is no reasonable expectation of finite residues of bifenazate in poultry commodities [Category 3 of 40 CFR §180.6(a)] ; therefore, tolerances for secondary residues in poultry tissues and eggs are not required.

5.3 Water Residu e Profile

The information concerning the environmental fate and drinking water assessment of bifenazate were provided by EFED (Memo

, 10/17/2011 , J. Hetrick

, et al

., D 388230 ; and Memo, 7/25/2012

, J. Hetrick

, et al

., D 402952 ). Surface and ground water

- moni toring data are not available for bifenazate

. Since water

- monitoring data are not available , estimates of bifenazate levels in surface and ground water were provided by EFED using computer models. Bifenazate isBifenazate Human

- Health Risk Assessment DP # 388228

Page 27 of 52 

### expected to be slightly mobile, but not persistent in the environment. Bifenazate is expected to rapidly dissipate in soil and aquatic environments as a result of aqueous hydrolysis, direct aqueous photolysis, and aerobic degradation in soil. EFED provided estimates of drinking water
concentra tions (EDWC s ) for bifenazate using the FQPA FIRST model and the dry bean application scenario (highest registered/proposed use rate). The resulting chronic EDWCs in ground and surface water were 0.000014 ppm (30

- year

- annual average) and 0.0112 ppm (annual average), respectively. The resulting acute EDWC (daily peak) was 0.0373 ppm.

Table 5.3. Bifenazate EDWCs

.

Exposure Scenario EDWC (ppm) 30

- year Annual Average (not used) 0.000014 Annual Average (used in chronic analysis) 0.0112 Daily Peak (used in acute analysis) 0.0373



### 5.4 Dietary Risk Assessment

5.4.1 Description of Residue Data Used in Dietary Assessment

A cute and chronic dietary (food plus drinking water) risk assessment s were conducted using the DEEM

- FCID, Version 3.16, which uses food consumption data from the USD A’s NHANES/WWEIA. This dietary survey was conducted from 2003 to 2008. The analyses were conducted in support of a human

- health risk assessment for the proposed to lerances for bifenazate and D3598 on timothy and h erb, s ubgroup 19A; and to expand existing uses on p ome f ruit, group 11, and f

ruiting v egetables, group 8.

The acute analysis for the general population, including infants and children, was unrefined and used tolerance

- level residues and 100% PCT. The acute analysis for females 13 to 49 years old was highly refined and incorporated data from the USDA’s PDP data , crop field trial data, and PCT estimates. DEEM (ver. 7.81 ) default processing factors were as sumed for all commodities excluding apple juice, grape juice, and wine/sherry. The processing factors for these commodities were reduced to 1.0, based on data from processing studies. The analyses also included the acute surface water point estimate (0.0 373 ppm) generated using the FIRST model.

The chronic dietary exposure analysis for all population subgroups was partially refined and used tolerance

- level residues and PCT estimates. DEEM (ver. 7.81 ) default processing factors were assumed for all com modities excluding apple juice, grape juice, and wine/sherry. The processing factors for these commodities were reduced to 1.0 based on data from processing studies. The analyses also included the chronic surface water point estimate (0.0112 ppm) generat ed using the FIRST model.

5.4.2 Percent Crop Treated Used in Dietary Assessment

The acute analysis for general population, including infants and children, used 100% PCT estimates. The acute analysis for females 13 to 49 years old and the chronic analy sis use d PCT estimates provided by BEAD.

The following maximum PCT estimates (Memo, 5/16/12, C. Doucoure, D401788) were used in the acute dietary risk assessment: almonds: 10%; apples: 5%; apricots: 10%; beans, green: 2.5%; caneberries: 30%; cantaloupes: 2.5%; cherries: 5%; cucumbers: 5% ; grapefruit: 5%; grapes: 20%; nectarines: 10%; oranges: 2.5%; peaches: 20%; pears: 30%; pecans: 2.5%;Bifenazate Human

- Health Risk Assessment DP # 388228

Page 2 8 of 52 

### peppers: 10%; pistachios: 2.5%; plums/prunes: 20%; potatoes: 5%; pumpkins: 5%; squash: 2.5%; strawberries: 65%; tomatoes: 10%; walnuts: 5 %; and watermelon: 2.5%.

The following average PCT estimates were used in the chronic dietary risk assessment: almonds: 5%; apples: 5%; apricots: 5%; beans, green: 1%; caneberries: 25%; cantaloupes: 1%; cherries: 2.5%; cucumbers: 2.5%; grapefr uit: 5%; grapes: 10%; nectarines: 5%; oranges: 1%; peaches: 10%; pears: 15%; pecans: 1%; peppers: 5%; pistachios: 2.5%; plums/prunes: 5%; potatoes: 5%; pumpkins: 2.5%; squash: 1%; strawberries: 45%; tomatoes: 5%; walnuts: 2.5%; and watermel on: 1%.

5.4.3 Acute Dietary Risk Assessment

The acute risk estimate utilizes <1% (0.04 0155 mg/kg/day) of the aPAD for the U.S. population at the 95 th 

### percentile of exposure. The most highly exposed population subgroup was children 1 to 2 years old which utilized 1.9% (0.11 2309 mg/kg/day) of the aPAD at the 95 th 

### percentile of exposure. The acute risk estimate utilizes 15 % (0.0 15485 mg/kg/day) of the aPAD for females 13 to 49 years old at the 99.9 th 

### percentile of exposure. Thus, acute dietary exposure to bifenazate for all population subgroups is not of concern.

5.4.4 Chronic Dietary Risk Assessment

The chronic risk estimate utilizes 24% (0.0023 56 mg/kg/day) of the cPAD for the U.S. population. The most highly exposed population subgroup was children 1 to 2 years old that utilized 74% (0.0074 08 mg/kg/day) of the cPAD. Thus, chronic dietary exposure to bifenazate for all population subgroups is not of concern.

5.4.5 Cancer Dietary Risk Assessment

Bifenazate is classified as "not likely ” to be a human carcinogen. Therefore, a cancer dietary exposure assessment is not required.

5.4.6 Summary Table

Table 5.4.6. Summary of Dietary (Food and Drinking Water) Exposure Risk for Bifenazate 1

.
Population Subgroup Acute Dietary (95 th Percentile) Chronic Dietary Dietary Exposure (mg/kg/day) % aPAD Dietary Exposure (mg/kg/day) % cPAD
General U.S. Population 0.040 155 <1 0.002 356 2 4 All Infants (<1 year old) 0.07 7748 1.3 0.00 3691 37 Children 1

- 2 years old 0.11 2309 1.9 0.007 408 7 4 Children 3

- 5 years old 0.0980 48 1.6 0.00 5619 56 Children 6

- 12 years old 0.0 55322 <1 0.00 3046 31 Youth 13

- 19 years old 0.031 128 <1 0.00 1856 19 Adults 20

- 49 years old 0.03120 3 <1 0.00 2104 21 Adults 50

- 99 years old 0.02 7976 <1 0.00 1680 17 Females 13

- 49 years old 0.0 15485 2 15 0.00 1948 20 1

. The values for the highest exposed population for each type of risk assessment are bolded. 2

. The acute exposure data for females 13 to 49 years is from 99.9 th percentile.



### 6.0 Residential (Non

- Occupational) Exposure/Risk CharacterizationBifenazate Human

- Health Risk Assessment DP # 388228

Page 29 of 52 

### The proposed uses do not involve applications by homeowners or commercial applicators in residential settings. Therefore, no new residential exposure is expected. However, there are existing residential uses that have been reassessed in this document to reflect updates to HED’s 2012 Residential SOPs ( http://www.epa.gov/pesticides/science/residential

- exposure

- so p.html ) along with policy changes for body we ight assumptions.

6.1 Residential (Non

- Occupational) Exposure/Risk Characterization

The residential handler exposure assessment estimates dermal and inhalation exposures for individuals using bifenazate on residential ornamentals. The quantitative exposure/risk assessment developed for residential handlers is based on the following scenarios:

(1) mixing/loading/applying liquids with manually

- pressurized handwand, (2) mixing/loading/applying liquids with hose

- end sprayer, (3) mixing/loading/ applying liquids with backpack, and (4) mixing/loading/applying liquids with sprinkler can.

Unit exposure values and estimates for area treated were taken from HED’s 2012 Residential SOPs: Gardens and Trees. An ARI was used since the LOCs for dermal exposure (100) and inhalation exposure (30) are different. The target ARI is 1; therefore, ARIs of less than 1 result in risk estimates of concern. The ARI was calculated as follows.

Aggregate Risk Index (ARI) = 1÷ [(Dermal LOC ÷ Dermal MOE) + (Inhalati on LOC ÷ Inhalation MOE)]



### Short

- term risk estimates for residential handlers are presented in Table 6.1. Intermediate

- term exposures are not likely because of the intermittent nature of applications by homeowners. Short

- term dermal and inhalation risk e stimates to residential handlers do not exceed HED’s LOC for all scenarios. All the ARIs are above 1 and do not exceed HED’s LOC for all scenarios.

Table 6.1. Residential Handler Exposure and Risk Estimates for Bifenazate Applications to Ornamentals.

E xposure Scenario Application

Rate 1 Area

Treated Daily 2 Baseline Unit

Exposures (mg/lb ai) Baseline Dose 4 (mg/kg/day) Baseline MOE 5 ARI 6 Dermal 3 Inhalation 3 Dermal Inhalation Dermal (LOC = 100) Inhalation

(LOC = 30) Mixer/Loader/Applicator for Soluble Concentrates( Liquids) Manually

pressurized handwand 0.00125 lb

ai/gal 5 gal 63 0.018 0.00 49 0.0000014 1 6,000 100,000 150

Hose

- end
sprayer 0.00125 lb

ai/gal 11 gal 58 0.0014 0.0 10 0.00000024 8 ,000 580,000 80

Backpack 0.00125 lb

ai/gal 5 gal 130 0.14 0.0 10 0.000011 7,9 00 13,000 66
Sprinkler

can 0.00125 lb

ai/gal 5 gal 58 0.0014 0.00 45 0.00000011 18,000 1,300,000 180

1. Application rates based on communication between the registrant and EPA regarding the maximum rates allowed on the labels for the residential use sites. From label 400

- 508: 2.0 lb ai/gal/128 fl oz gal * 8 fl oz/100 gal = 0.00125 lb ai/gal

. 2. Based on H ED’s SOPs: Gardens and Trees (HED’s 2012 Residential SOPs)

. 3. Baseline Dermal: long

- sleeve shirt, long pants, shoes, socks, and no gloves

. Baseline Inhalation: no respirator. 4. Dose (mg/kg/day) = daily unit exposure (mg/lb ai) x application rate (lb ai/gal) x gal treated x % Absorption (100% dermal and 100% inhalation assumed) / Body weight ( 80 kg). 5. MOE = NOAEL (Dermal = 80 mg/kg/day; Inhalation = 0.14 mg/kg/day) / daily dose (mg/kg/day).
6. ARI = Aggregate Risk Index = 1÷ [(Dermal LOC ÷ Dermal MOE) + (Inhalation LOC÷ Inhalation MOE)].



### 6.2 Residential Post

- Application Exposure/Risk CharacterizationBifenazate Human

- Health Risk Assessment DP # 388228

Page 30 of 52 

### Non

- cancer Exposure/Risk Estimates: Short

- term dermal exposure and risk estimates have been assessed for bifenazate. The scenarios, routes of exposure and lifestages assessed include:

 Gardens and Trees: adults (dermal) and children 6 ≤ 11 years old (dermal).

The lifestages (i.e., adults and children 6 ≤ 11 years old) selected for each post

- application scenario are based on an analysis provided as an Appendix in the 2012 Residential SOPs. These lifestages are not the only lifestages that could be potentially exposed for these post

- application scenarios; how ever, the assessment of these lifestages is health protective for the exposures and risks for any other potentially exposed lifestages.

Residential Post

- application Exposure Data and Assumptions: A series of assumptions and exposure factors served as t he basis for completing the residential post

- application risk assessment. Each assumption and factor is detailed in the 2012 Residential SOPs ( http://www.epa.gov/pesticide s/science/residential

- exposure

- sop.html ).

Residential Post

- application Non

- Cancer Exposure and Risk Equations: The algorithms used to estimate residential post

- application exposure and dose can be found in the 2012 Residential SOPs ( http://www.epa.gov/pesticides/science/residential

- exposure

- sop.html ). For this assessment a chemical

- specific dislodgeable foliar residue (DFR t 

### ) value of 0.161 μg/cm 2 

### was

us ed ( MRID 44859701 )



### .
Table 6.2 lists the updated assessments of currently registered residential post

- application exposures and risk estimates . All adult and children dermal post

- application risk estimates for exposure to treated trees and to treated gardens are not of concern (MOEs ≥ 10 0).

Table 6.2. Short

- and Intermediate

- Term Residential Post

- application Exposure and Risk Estimates for Bifenazate. Liquid Formulations
Lifestage Post

- application Exposure Scenario Dose a MOEs b (LOC = 100) Adult Garden

- sprays 0.0 37 2,2 00
Child 6 < 11 years old 0.0 25 3,1 00

Adult Tree

– sprays 0.00 34 23, 000 Child 6 < 11 years old 0.00 23 34, 000

a

. Dermal Dose (mg/kg/day) = DFRt (0.161 μg/cm 2 ) x 0.001 (mg/μg) x short

- term TC (cm 2 /hr) x ET (hr/day) x Dermal Absorption (100%) BW (kg)

. b. Dermal MOE = NOAEL ( 80 mg/kg/day) / Dermal Dose (mg/kg/day)

.



### 6.3 Spray Drift

Spray drift is a potential source of exposure to those nearby pesticide applications. This is particularly the case with aerial application, but, to a lesser extent, spray drift can also be a potential source of exposure from the ground application methods (e.g., groundboom and airblast) employed for bifenazate . The Agency has been working with the Spray Drift Task Force (a task force composed of various registrants which was developed as a result of a Data Call

- In issued by EPA), EPA Regional Offic es and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices (see the Agency’s Spray D rift website for more information) 2



### . The Agency is also taking means to qualitatively and

2 Available: http://www.epa.gov/opp00001/factsheets/spraydrift.htmBifenazate Human

- Health Risk Assessment DP # 388228

Page 31 of 52 

### quantitati vely a ddress spray drift as a potential source of exposure in risk assessments for pesticides through existing programs such as AgDrift ® 

### and chemical spe cific properties of pesticides. The potential for spray drift will be quantitatively evaluated for each pest icide during the Registration Review process that ensures that all uses for that pesticide will be considered concurrently.

6.4 Residential Bystander Post

- Application Inhalation Exposure

Based on the Agency's current practices, a quantitative post

- appli cation inhalation exposure assessment was not performed for bifenazate at this time primarily because of the low acute inhalation toxicity (To xicity C ategory IV), low vapor pressure , and the low proposed use rate. However, volatilization of pesticides may be a source of post

- application inhalation exposure to individuals nearby pesticide applications. The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 ( http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html ). The A gency is in the process of evaluating the SAP report and may, as appropriate, develop policies and procedures to identify the need for and, subsequently, the way to incorporate post

application inhalation exposure into the Agency's risk assessments. If ne w policies or
p rocedures are developed, the Agency may revisit the need for a quantitative post

- application inhalation exposure assessment for bifenazate.

6.5 Residential Risk Estimates for Use in Aggregate Assessments

Table 6.5 reflects the residential risk estimates that are recommended for use in the aggregate assessment for bifenazate.

 The recommended residential exposure for use in the adult aggregate assessment reflects dermal post

- application exposure to treated gardens.

 The recommended resid ential exposure for use in the children 6 to 11 years old aggregate assessment reflects dermal post

- application exposure to treated gardens.

Table 6.5. Short

- Term Residential Exposures for the Bifenazate Combined Residential Risk Calculations

.

Population Handler Exposure

(mg/kg/day) 1 Post

- application Exposure (mg/kg/day) 2 Recommended Post

application Exposure for Aggregate (mg/kg/day) 3 Dermal Inhalation Dermal Inhalation Oral

Adult 0.0045 0.000011 0.0 37 N/A N/A 0.037 Children 6 < 11 yrs old N/A N/A 0.0 25 N/A N/A 0.025
1

. Handler exposure represents high

- end handler exposure, where the appropriate duration is appropriate to assess. 2

. Postapplication exposure represents high

- end dermal, inhalation and/or incidental oral exposure for the relevant exposure duration. 3

. The highest estimated total residential exposure (for adults and child populations) should be used as the basis of the aggreg ate
assessments.



### 7.0 Aggregate Exposure/Risk Characterization

In accordance with the FQPA, HED must consider aggregate pesticide exposures and risks from three major sources: food, drinking water, and residential exposures. In an aggregate assessment, exposures from relevant sources are added together and compared t o quantitative estimates of hazard (e.g., a NOAEL or PAD) , or the risks themselves can be aggregated. WhenBifenazate Human

- Health Risk Assessment DP # 388228

Page 32 of 52 

### aggregating exposures and risks from various sources, HED considers both the route and duration of exposure.

For bifenazate, aggregate exposure ris k assessments were performed for acute, short

- and interm ediate

- term, and chronic exposure

. Bifenazate is classified as "not likely" to be a human carcinogen and thus no cancer aggregate risk assessment is required.

7.1 Acute Aggregate Risk

The acute aggregate risk assessment takes into account acute exposure estimates from dietary consumption of bifenazate (food and drinking water). The acute dietary exposure estimates are not of concern to HED (<100% aPAD) for the general U.S. population a nd all population subgroups (see Table 5.4.6).

7.2 Short

- Term Aggregate Risk

The short

- and intermediate

- term toxicological POD s for bifenazate are the same for each route of exposure. Therefore, for residential exposure scenarios, only short

- term exp osures were assessed, and are considered to be protective of intermediate

- term exposure and risk.

It was appropriate to aggregate postapplication dermal exposures with dietary (food and water) exposures for the short

- and intermediate

- term duration. The dermal postapplication exposure to gardens and ornamentals scenario is the residential exposure scenario with the greatest risk estimate for both adults and children 6< 11 years old; therefore, the exposure estimates for this scenario are protective of any other exposure scenarios.

For the adult and children 6 ≤ 11 years old short

- and intermediate

- term aggregate risk assessment, the MOE approach was used to estimate aggregate exposures as the t here are different PODs for oral and dermal routes of exposur e but the LOC are the same

. The chronic dietary exposure estimate for Adults 20

- 49 years old and Children 6

- 1 2 years old were used in the aggregate risk estimate for adults and children 6 ≤ 11 years old, respectively.

All of the adult and children 6 ≤ 11 years old chronic dietary + dermal aggregate risk estimates do not exceed HED’s LOC (MOEs ≥ 100)

. The results of the adult and children’s aggregate risk determinations are presented in Table 7.2.

Table 7.2 Short

- Term and/or Intermediate Term Aggregate Risk Calculations (Option 2: 1/MOE Approach

– All Levels of Concern are Identical)

.

Population Short

- or Intermediate

- Term Scenario

LOC for Aggregate Risk 1 Dietary

MOE 2 MOE Oral

Residential Exposure MOE

Dermal Residential Exposure 3 MOE

Inhalation Residential Exposure Aggregate

MOE (food, water, and residential) 4 Adult 20 < 49 100 430 N/A 2,200 N/A 360 Children 6 11 100 290 N/A 3,100 N/A 270 1. Indicate in this footnote the basis for the LOC (include the standard inter

- and intra

- species uncertainty factors totaling 100, as well as additional uncertainty factors/safety factors as appropriate.) 2

. MOE dietary = [(short

- and intermediate

- term or al NOAEL)/(chronic dietary exposure)] or [(0.9 mg/kg/day)/(0.00210 4 mg/kg/day)] for adults and [(0.9 mg/kg/day)/(0.0030 46 mg/kg/day)] for children 6 < 11 years old. 3

. MOE dermal = [(short

- or intermediate

- term dermal NOAEL)/( high

- end dermal residential exposure)] or [(80 mg/kg/day)/(0.037 mg/kg/day)] for adults and [(80 mg/kg/day)/(0.025 mg/kg/day)] for children 6 < 11 years old.Bifenazate Human

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Page 33 of 52 4

. MOE Aggregate = 1/[(1/MOE dietary) + (1/MOE dermal)]

.



### 7. 3 Chronic Aggregate Risk

The chronic ag gregate risk assessment takes into account average exposure estimates from dietary consumption of bifenazate (food and drinking water). The chronic dietary exposure estimates are not of concern to HED (<100% cPAD) for the general U.S. population and all
p opulation subgroups (see Table 5.4.6).

8.0 Cumulative Exposure/Risk Characterization

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as
to bifenazate and any other substances and bifenazate does not appear to produ ce a toxic metabolite produced by other substances. For the purposes of this tolerance action, therefore, EPA has not assumed that imazapic has a common mechanism of toxicity with other substances. For information regarding EPA’s efforts to determine whi ch chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA’s Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating eff ects from substances found to have a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/.

8.1 Occupational Exposure/Risk Characterization

The proposed uses are on agri cultural crops; therefore, there is potential for occupational handler and post

- application exposure.

9

. 0 Occupational Handler Exposure/Risk Estimates

The proposed uses are on agricultural crops; therefore, there is potential for occupational handler

an d post

- application exposure.

9

. 1 Post

- application Exposure/Risk

HED uses the term handlers to describe those individuals who are involved in the pesticide application process. HED believes that there are distinct job functions or tasks related to appli cations and exposures can vary depending on the specifics of each t ask. Job requirements (amount of chemical used in each application), the kinds of equipment used, the target being treated, and the level of protection used by a handler can cause exposure levels to differ in a manner specific to each application event.

Based on the anticipated use patterns, current labeling, and types of equipment that can potentially be used, occupational handler exposure is expected from the proposed uses. The quantitative exposure/risk assessment developed for occupational handlers is based on the following scenarios:

Mixer/Loader: 1. mixing/loading water

- soluble bags (engineering controls for the wettable

- powder scenario) for aerial application; 2. mixing/loading water

- soluble bags (engineering controls for the wettable

- powder scenario)Bifenazate Human

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Page 34 of 52 

### for groundboom application; 3. mixing/loading water

- soluble bags (engineering controls for the wettable

- powder scenario) for airblast application; 4. open mixing/loading liquids for aer ial application; 5. open mixing/loading liquids for groundboom application; and 6. open mixing/loading liquids for chemigation ;

Applicator: 7. application of sprays via aerial application; 8. application of sprays via groundboom equipment; 9. application of sprays via airblast application; and 10. application of sprays via chemigation;

Mixer/Loader/Applicator: 11. application of liquids via mechanically pressurized handgun (foliar); 12. application of wettable

- powder in water

- soluble bags via mechanically pressurized handgun (foliar);

Flagger: 13. flagging to support aerial spray applications.

Occupational Handler Exposure Data and Assumptions: A series of assumptions and exposure factors served as the basis for completing the occupational handler risk assessments. Each assumption and factor is detailed in pending memo L. Venkateshwara, D388802. The algorithms used to estimate non

- cancer exposure and dose for occupational handlers can be found in Appendix C

. A total ARI was used since the LOC values for dermal exposure (100) and inhalation exposure (30) are different. The target ARI is 1; therefore, ARIs of less than 1 result in risk estimates of concern. The ARI was calculated as follows.

Aggregate Risk Index (ARI) = 1÷ [(Dermal LOC ÷ Dermal MOE) + (Inhalation LOC ÷ Inhalation MOE)]



### Summary of Occupational Handler Non

- Cancer Exposure and Risk Estimates: Table 9.1 provides a summary of the estimated exposures and risks to occupational pesticide handlers. An MOE ≥ 100 is adequate to protect occupational pesticide handlers from dermal exposures and an MOE ≥ 30 from i nhalation exposures

. Inhalation and dermal risk estimates were not of concern for all scenarios

. All ARIs are greater than 1 and are not risks of concern , except for the following scenarios that requir e single layer of gloves:

 Mixing/loading liquids for aerial and chemigation applications and

 Mixing/loading/application of liquids via mechanically pressurized handgun (foliar).Bifenazate Human

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Page 35 of 52 Table 9.1. Short

- /Intermediate

- Term Occupational Exposure and Risk Estimates for Bifenazate.

Exposure Scenario Dermal Unit

Exposure (ug/lb ai) 1 Inhalation Unit

Exposure (ug/lb ai) 1 Application

Rate 2 Amount

Treated Daily 3 Dose (mg/kg/day) 4,5 MOE 6,7 Total

Dermal Inhalation Dermal (LOC = 100) Inhalation (LOC = 30) ARI 9

Mixer/Loader Wettable Powder in Water Soluble Bags
Aerial Application Eng Control 8 :

9.8 Eng Control 8 :

0.24 0.5 lb ai/A 350 A EC : 0.0 215 EC : 0.00053 EC : 3, 700 EC : 360 EC : 9.1

Airblast Applications 0.5 lb ai/A 40 A EC : 0.00 245 EC : 0.00006 EC : 33 ,000 EC : 3,200 EC : 81

Groundboom applications 0.5 lb ai/A 80 A EC : 0.00 49 EC : 0.00012 EC : 16 ,000 EC : 1,600 EC : 40

Mixer/Loader Liquids
Aerial Application

Base: 220 Base: 0.219 0.75 lb ai/A 350 A Base: 0. 723 SL/G: 0.123 Base: 0.00072 Base: 110 SL/G: 650 Base: 260 Base: 0.98 SL/G: 3.7 Chemigation Applications 0.75 lb ai/A 350 A Base: 0. 723 SL/G: 0.123 Base: 0.00072 Base: 110 SL/G: 650 Bas e: 260 Base: 0.98 SL/G: 3.7 Groundboom applications 0.75 lb ai/A 80 A Base: 0. 165 Base: 0.000 16 Base: 480 Base: 1,200 Base: 4.3

Applicator Applicator, Aerial EC: 2.08 EC: 0.0049 0.75 lb ai/A 350 A EC: 0.00 683 EC : 0 .0000161 EC: 12,000 EC : 12,000 EC : 92 Applicator, Open Cab Groundboom Base: 78.6 Base: 0.34 0.75 lb ai/A 80 A Base : 0 .0 0365 Base: 0.443 Base : 180 Base: 750 Base: 1.3
Applicator, Open Cab, Airblast Base: 1770 Base: 4.71 0.5 lb ai/A 40 A Base : 0

. 00383 Base: 0.059 Base: 1,400 Base: 160 Base: 9

Mixer/Loader/Applicator Mixing/Loading Applying Liquids with Mechanically Pressurized Handgun (foliar) Base: 1,300

SLw/G: 390 Base: 3.9 0.0375 lb ai/gallon 1,000

Gallons Base : 0.61 Base : 0.00183 Base : 130

SLw/G: 440 Base: 100 Base : 0 .94 SLw/G + Base: 1.9

Mixing/Loading Applying Water Soluble Packets with Mechanically Pressurized Handgun (foliar) Base: 1,300 Base: 3.9 0.01 lb ai/gallon 1,000

Gallons Base: 0.163 Base: 0.000488 Base : 490 Base : 390 Base : 3.6

Flagger

Flagger Base:

11 Base: 0.35 0.75 lb ai/A 350 A Base : 0.0361 Base: 0.0011 Base : 2,200 Base: 170 Base: 4.5

1. Based on “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (March 2013); includes data from PHED /AHETF (level of mitigation: Baseline, PPE, Eng. Controls): Base = single layer and no gloves; no respirator; SL w/G = single layer w/glove; EC = Engineering control; PF5 = dust/mist respirator. 2

. Based on proposed labels for bifenazate (see Table 3.3). 3

. Exposure Science Advisory Council Policy #9.1. 4

. Dermal Dose = Dermal Uni t Exposure (ug/lb ai) x CF (0.001 mg/ug) x Application Rate (lb ai/acre) x Area Treated (A/day)

x % Absorption (100% dermal) / Body weight (80 kg). 5

. Dermal MOE = Dermal NOAEL (80 mg/kg/day)/Dermal Dose (mg/kg/day). 6

. Inhalation Dose = Inhalation Unit Exposure (ug/lb ai) x CF (0.001 mg/ug) x Application Rate (lb ai/acre) x Area Treated (A/day) /BW (80 kg). 7

. Inhalation MOE = Inhalation NOAEL ( 0.19 mg /kg/day)/ Inhalation Dose (mg/kg/day). 8

. Engineering controls for the wettable

- powder scenario. 9

. ARI = Aggregate Risk Index = 1÷ [(Dermal LOC ÷ Dermal MOE ) + (Inhalation LOC ÷ Inhalation MOE)].



### 9.2 Post

- application Exposure/Risk

Dermal: HED expects that post

- application dermal exposure wi ll occur since bifenazate is applied post

- emergence as a foliar spray to upper and lower leaf surfaces. Post

- application exposure is expected to be short

- and intermediate

- term based on information provided onBifenazate Human

- Health Risk Assessment DP # 388228

Page 36 of 52 

### proposed labels (e.g., according to the label there is a maximum of 1 spray per season at a maximum rate of 0.75 lb ai/A). Only short

- term exposure was assessed, how ever the assessment is protective of intermediate

- term exposures since the dermal endpoints are the same.

Data and Assumptions for Post

- application Exposure Scenarios : It is the policy of HED to use the best available data to assess post

- application exposure. Sources of generic post

application data, used as surrogate data in the absence of chemical

- specific data, are derived from ARTF exposure

- monitoring studies, and, as proprietary data, are subject to the data protection provisions of FIFRA. The standard values recommended for use in predicting post

application exposure that are used in this assessment, known as “transfer coeffi cients

, ” are presented in the ExpoSAC, Policy 3 (http://www.epa.gov/pesticides/science/exposac_policy3.pdf), which, along with additional information about the ARTF data, can be found at http://www.epa.gov/pesticides/science/post

app

- exposure

- data.html

.

Chemical

- specific DFR da t a were available for bifenazate; however, the data were not for the currently proposed crops. Since DFR data are not available for the specific crops currently proposed for bif

enazate, the available data were used as surrogates. Based on a review of the available data, it was decided that the DFR data for Spathiphyllum (Peace Lily) in greenhouses would be used as a surrogate for the proposed field cro ps (fruiting vegetable

, Group 8

- 10, herb S ubgroup 19 A, pome fruit Group 11

- 10, and timothy forage and hay).

Even though the data are not for the specific crops, it is the only chemical

- specific data submitted to HED. There are several limitations that were considered such as (1) the study represents DFR data collected in a greenhouse which may potentially be a more conservative estimate of residue dissipation compared to field crops; (2) the formulation in the study is a wettable

- powder packaged in a water

- soluble bags whereas one of the proposed labels (EPA Reg.#400

- 514) is for a product that is a SC (liquid); (3) the application rate was lower in the study (0.29 lb ai/A) compared to the proposed labels (0.5 lb ai/A and 0.75 lb ai/A); and (4) the application was made with a calibrated hand

- held boom sprayer.

Tables 9.2.1 provide a summary of the data for use i n the post

- application exposure and risk calculations. See L. Venkateshwara, pending

, D388802 for summaries of the studies and references.

Table 9.2.1. Summary of DFR Values and Regression Analysis Results for Treated Spathiphyllum (Peace Lily) in Gre enhouses with Bifenazate (MRID# 448597

- 01).

Input/Parameter Site: Florida

Bifenazate Application Rate (lb ai/A) a Study Target Rate = 0.29 lb ai/A 0.29 lb ai/A

Spray Volume (GPA) 5 gallons/1000 ft 2 Measured Average Day 0 Residue (μg/cm 2 ) 0.151 Predicted Day 0 Residue (μg/cm 2 ) b 0.161 Slope

- 0.07 Half

- life (days) 9.9 R 2 0.8433 a. The application was conducted using hand

- held boom sprayer. b. Regressions are based on data collected after second application.



### HED has determined that short

- and intermediate

- term risk estimates are not of concern (i.e., MOEs <100) on the day of treatment (day 0) for all the post

- application exposure activities

.Bifenazate Human

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Page 37 of 52 

### Estimates were calculated for the highest transfer coefficients and are protective of all other activities. Table 9.2.2 presents the risk estimates for all crops for the highest transfer coefficient associated with that crop; this represents the activitie s with the highest estimated risk.

Table 9.2.2. Dermal Post

- application Exposure and Risk for Bifenazate Using Chemical

- Specific DFR Data.

Crop Application

Rate (lb ai/A) Highest Transfer

Coefficient for Crop (cm 2 /hr) and Associated Activity DFR 1

(ug/cm 2 ) Days After

Treatment Daily Dose 2

(mg/kg/ day) MOE 3

Fruiting vegetable Group 8

- 10 0.5 1,900 (irrigation; hand

set) 0.278 0 (12 hours) 0.0528 1,500

Herbs Subgroup 19A 0.5 1,900 (irrigation; hand

- set) 0.278 0 (12 hours) 0.01528 1,500

Pome fruit Group 11

- 10 0.5 3,600 (thinning fruit) 0.278 0 (12 hours) 0. 10 800
Timothy forage and hay 0.75 1,900 (irrigation; hand

set) 0.416 0 (12 hours) 0.079 1,000

1. Chemical

- specific DFR = predicted chrysanthemum DFR data for Spathiphyllum (Peace Lily) in greenhouses for a surrogate for the proposed field crops (fruiting vegetable group 8

- 10, herb subgroup 19 A, pome fruit group 11

- 10, and timothy forage and hay)

. Application rate in studies is less than the proposed application rate. 2. Dermal Dose = [DFR (ug/cm 2 ) x TC (cm 2 /hr) x 0.001 mg/ug x 8 hrs/day xDA (25%)]  body weight (69 kg). 3

. MOE = NOAEL (Short

- and Intermedi ate

- term NOAEL 80 mg/kg/day)/Daily Dose (LOC=100)).



### Inhalation: Based on the Agency's current practices, a quantitative occupational post

application inhalation exposure assessment was not performed for bifenazate at this time primarily because it has a low acute inhalation toxicity (Toxicity Category IV), has a low vapor pressure, and is applied at a low use r ate

. However, there are multiple potential sources of post

application inhalation exposure to individuals performing post

- application activities in previously treated areas. These potential sources include volatilization of pesticides and resuspension of dusts and/or particulates that contain pesticides. The Agency sought expert advice and input on issues related to volatilization of pesticides from its FIFRA SAP in December 2009, and received the SAP’s final report on March 2, 2010 ( http://www.epa.gov/s cipoly/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 ARTF and may, as appropriate, develop policies and procedures, to ident ify the need for and, subsequently, the way to incorporate occupational post

- application inhalation exposure into the Agency's risk assessments. If new policies or procedures are put into place, then the Agency may revisit the need for a quantitative occu pational post

- application inhalation exposure assessment for bifenazate.

REI: Bifenazate is classified in acute Toxicity Category IV for acute dermal, inhalation, and oral toxicity, primary eye irritation, and primary skin irritation

. Bifenazate is a de rmal sensitizer by the Magnusson/Kligman method, but not the Buehler method. T he 12

- hour REI listed on the label is adequate to protect agricultural workers from post

- application exposures to bifenazate.

10.0 References

Previous Risk Assessment:

 Memo, 07/14/2010 , W. Wassell

, et al. , D 371783.Bifenazate Human

- Health Risk Assessment DP # 388228

Page 38 of 52 

### Registration Review Scoping Document:

 Memo, 11/15/2012, W. Wassell, et al. , D402278.

HIARC :

 Memo, 05/30/2001, J. Rowland, et al ., TXR# 0014576.

Residue Chemistry:

 Memo, pending, W. Wassell, D38 8800

.

 Memo, 08/16/2001, T. Bloem, et al ., D276801.

 Memo, 0 8/16/2001, T. Bloem, D277089.

 Memo, 0 5/29/2003, T. Bloem, D290053.

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

HASPOC Memo:

 Memo, J. Van Alstine, 0 4/17/2012, TXR # 0052356.

Drinking Water Memo:

 Memo, 1 0/1 7 /20 1 1, J. Hetrick

, et al

., D 388230

 Memo, 0 7 / 25 /20 12 , J. Hetrick

, et al

., D 402952

Dietary Memo:

 Memo, pending, W. Wassell, D384709.

ORE Memo:

 Memo, pending, L. Venkateshwara, D388802

Attachments

Appendix A. Toxicology Profile and Executive Summaries Appendix B. Methodologies for Human

- Equivalent Concentration Calculations. Appendix C. Residential Handler and Post

- application Algorithms Appendix D. Summary of Occupational and Residential Non

- cancer Algorithms A ppendix E. Summaries of Dislodgeable Foliar Residue Studies and Proposed Use in Assessment Appendix F. Physical/Chemical Properties

RDI: RAB1 (04/09/2014) W. Wassell : S

- 10958: Potomac Yard 1 (PY1): (703)305

- 6135): 7509P: RAB1Bifenazate Human

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Page 39 of 52 

### Appendix A. Toxicology Profile and Executive Summaries

A.1 Toxicology Data Requirements The requirements (40 CFR 158.340) for food use for imazapic are in Table 1. Use of the new guideline numbers does not imply that the new (1998) guideli ne protocols were used.

Study Technical Required Satisfied 870.1100 Acute Oral Toxicity

................................ ....................... 870.1200 Acute Dermal Toxicity

................................ .................. 870.1300 Acute Inhalation Toxicity

................................ .............. 870.2400 Acute Eye Irritation

................................ ....................... 870.2500 Acute Dermal Irritation

................................ ................. 870.2600 Skin Sensitization

................................ .......................... yes yes yes yes yes yes yes

yes yes yes yes yes 870.3100 90

- Day Oral Toxicity in Rodents

................................ .. 870.3150 90

- Day Oral Toxicity in Non

- rodents

............................ 870.3200 21/28

- Day Dermal Toxicity

................................ ........... 870.3250 90

- Day Dermal Toxicity

................................ ................ 870.3465 28

- Day Inhalation Toxicity

................................ ........... yes yes yes yes yes yes

no yes

no yes 870.3700a Prenatal Developmental Toxicity (rodent)

..................... 870.3700b Prenatal Developmental Toxicity (non

- rodent)

............. 870.3800 Reproduction and Fertility Effects

................................ . yes yes yes yes

yes yes 870.4100a Chronic Toxicity (rodent)

................................ .............. 870.4100b Chronic Toxicity (non

- rodent)

................................ ....... 870.4200a Carcinogenicity (rat)

................................ ...................... 870.4200b Carcinogenicity (mouse)

................................ ................ 870.4300 Combined Chronic Toxicity/Carcinogenicity

................ no yes

no yes yes no

yes

no yes yes 870.5265 Mutagenicity

— Ames Assay

................................ .......... 870.5300 Mutagenicity

— Mammalian Cell Gene Mutation Test

.. 870.5375 Mammalian Cytogenetics Assay (CHO

- K1 Cells)

........ 870.5 385 Mouse Bone Marrow Micronucleus Assay

.................. yes yes yes yes yes

yes yes yes 870.6200a Acute Neurotoxicity Screening Battery (rat)

................. 870.6200b 90

- Day Neurotoxicity Screening Battery (rat)

............... 870.6300 Developmental Neurotoxicity

................................ ........ yes yes

no yes

yes yes 870.7485 Metabolism and Pharmacokinetics

................................ 870.7600 Dermal Penetration

................................ ........................ 870.7800 Immunotoxicity

................................ ............................. yes

no yes yes

no yesBifenazate Human

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### A.2 Toxicity Profiles

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 A.2.2

. 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 = 0.3 /1.9 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 histopathological effects in both sexes. 870.3200 21

- Day dermal

toxicity (rat) 44778401 (1998)

Acceptable/Guideline 0, 80, 400, 1,000 mg/kg/day NOAEL = 80 mg/kg/day in males and females mg/kg/day

. LOAEL = 400 mg/kg/day based on decreased body weight in females, decreased food consumption in both sexes, increased urinary ketones, increased urinary protein, increased urinary specific grav ity, and decreased urinary volume in both sexes, and increased incidence of extramedullary hematopoiesis in the spleen in both sexes. 870.3465 28

- Day

inhalation toxicity (rat) 48723301 (2012)

Acceptable/Guideline 0, 0.03, 0.075, 0.15 mg/L (0, 30, 75, 150 mg/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 i n females, increased incidences of mild brown pigmentation of the spleen, and minimal to mild degeneration of the olfactory epithelium within nasal levels III, IV, and V. 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 = not established LOAEL = 10 mg/kg/day based upon an increased incidence of early resorptions

.Bifenazate Human

- Health Risk Assessment DP # 388228

Page 41 of 52 Table A.2.2

. 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

. Maternal toxicity was seen as increased deaths and decreased body weight at 7 50 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 i n the range finding stu dy, 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 gain s in males and females

. Reproductive NOAEL  2 00 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

.

870.4200b 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 gain s

. No evidence of carcinogenicity

. 870.4300 Chronic/

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

.Bifenazate Human

- Health Risk Assessment DP # 388228

Page 42 of 52 Table A.2.2

. Bifenazate Subchronic, Chronic, and Other Toxicity Profile

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

Gene Mutation 870. 5265 Ames Assay 44464947 (1996) Acceptable/Guideline 0, 10, 33, 100, 333, 1000, 3333, 5000 μg/plate (±S9) Non

- mutagenic when tested up to 5000 ug/plate, in presence and absence of activation, in S. typhimurium strains TA98, TA100, TA1535 and TA1537 and E. coli strain WP2uvra. Gene Mutation 870.5300 Mammalian Cell

Gene Mutation Assay 44464949 (1996)

Acceptable/Guideline 0, 15, 20, 25, 30, 40, 50 μg/ml (

- S9) 0, 25, 50, 100, 150, 250, 350 μg/ml (+S9) 0,100, 150, 200, 250, 350, 500 μg/ml (+S9) Non

- mutagenic at the TK locus in L5178Y mouse lymphoma cells tested up to cytotoxic concentrations or limit of solubility, in presence and absence of S

- 9 activation.

Cytogenetics 870.5375 Mammalian

Cytogenetics Assay (CHO

- K1 Cells) 44464950 (1996)

Acceptable/Guideline 0, 12, 24, 47, 94, 188, 375 μg/ml (

- S9) 0, 20, 40,79,157, 313, 625, 1250 μg/ml (+S9) 0,12,24, 36, 47, 71, 94 μg/ml (

- S9) 0, 20, 40, 79, 119, 157, 236 μg/ml (+S9) Did not induce structural chromosome aberration in CHO

- K1 cell cultures in the presence and absence of activation up to cytotoxic concentrations.

Micronucleus 870.5385 Mouse Bone

Marrow Micronucleus Assay 44464948 (1996)

Acceptable/Guideline 0, 96/50, 192/100, 384/200 mg/kg [M/F] Non

- mutagenic in ICR mouse bone marrow micronucleus chromosomal aberrations assay up to cytotoxic concentrations.

870.6200a Acute

neurotoxicity screening battery 48395101 (2010)

Acceptable/Guideline 0, 200, 600, or 2000 mg/kg bw NOAEL = 600 mg/kg/day

. LOAEL = 2000 mg/kg/day based on decreased motor activity (rearing 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 Human

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Page 43 of 52 Table A.2.2

. 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 m g/kg acceptable/guideline Absorption, distribution, and metabolism of bifenazate was rapid, with > 93% of the administered dose being recovered within 72 hours of treatment for both the low

- and high

dose groups. As a result of this rapid turnaround, no signi ficant tissue accumulation of the test material was found. The highest tissue levels were foun d in the liver and whole blood, although the concentration of the test material represented <3% of the administered dose 6 hours after treatment. Comparison of the whole blood and red blood cell concentrations suggests that most of the test material was c arried 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 i n the feces was greater for the high

- dose rats (823%) due to saturated absorption that resulted in subsequently greater unabsorbed test material. Urinary excretion was a relatively minor route with ~25% of the administered dose recovered in this media for both male and female low

- dose rats. For the high

- dose male and female rats urinary excretion 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 bifenazate were observed. Eight primary metabolites were identified in the feces of male and female rats given oral doses of 10 mg/kg or 1000 mg/kg bifenazate

. 870.7800 Immunotoxicity

(rat) 48305501 (2010)

Acceptable/Guideline 0, 20, 80, or 200 ppm (0, 5, 20, or 50 mg/kg/day [F]) Systemic NOAEL = 50 mg/kg/day

. LOAEL = not established. Immunotoxic NOAEL = 50 mg/kg/day

. LOAEL = not established.



### Appendix B. Methodologies for Human

- Equivalent Concentration (HEC) Calculations.

The RfC methodology applies a dosimetric adjustment that takes into consideration not only the differences in ventilation rate (MV) but also the physicochemical properties o f the inhaled compound, the type of toxicity observed ( e.g. systemic vs. port of entry) and the pharmacokinetic (PK) but not pharmacodynamic (PD) differences between animals and humans. Based on the EPA’s RfC guidance (1994), the methodology for RfCs deri vation is an estimate of the quantitative dose

- response assessment of chronic non

- cancer toxicity for individual inhaled chemicals and includes dosimetric adjustment to account for the species

- specific relationships of exposure concentration to deposited/d elivered dose. This adjustment is influenced by theBifenazate Human

- Health Risk Assessment DP # 388228

Page 44 of 52 

### physicochemical properties of the inhaled compound as well as the type of toxicity observed ( e.g. systemic vs. port

- of

- entry), and takes into consideration the PK differences between animals and humans. Though the RfC methodology was developed to estimate toxicity of inhaled chemicals over a lifetime, it can be used for other inhalation exposures ( e.g

. acute and short

- term exposures) since the dosimetric adjustment incorporates mechanistic determinants o f disposition that can be applied to shorter duration of exposures provided the assumptions underlying the methodology are still valid. These assumptions, in turn, vary depending on the type of toxicity observed. Thus

, the derivation of a HEC for inhaled gases is described by the following equation:

Where: POD study 

### : Point of departure identified in the critical toxicology study

. D animal exposure 

### : Duration of animal exposure (hrs/day; days/wk)

. D anticipated exposure 

### : Anticipated human duration of exposure (hrs/day; days/wk)

. RGDR: Regional Gas Dose Ratio

.
Calculations used to estimate the inhalation risk to humans from aerosols are dependent not on the RGDR as for gases, but on the regional deposited dose ratio (RDDR). Inhalation studies using aerosols characterize particulate exposure by defining the particulate diameter (mass median aerodynamic diameter [MMAD]) and the geometric standard deviation (σ g 

### ), which is then used to determine the RDDR. The RDDR is a multiplicative factor used to adju st an observed inhalation particulate exposure concentration of an animal (A) to the predicted inhalation particulate exposure concentration for a human (H) that would be associated with the same dose delivered to the rth region or target tissue.

RDDR r 

### = (RDD r



### /Normalizing Factor) A 

### (RDD r 

### /Normalizing Factor) H



### As with calculations for gases, the r regions and potential target tissues are the three respiratory regions (ET, TB, PU). The RDDR is easily calculated by using a software program designed specifically for computing the RDDR from the MMAD and σ g 

### defined from an aerosol inhalation study. The values for the species

- specific parameters used to calculate the RDDR are provided in the EPA document “Methods for Derivation of Inhalation Reference C oncentrations and Application of Inhalation Dosimetry.”

Regional Deposited Dose Ratio (RDDR) for B ifenazate :

MMAD = 2.20 Sigma g = 2.78

Body Minute SPECIES Weight (g) Ventilation (VE, ml)

----------------------------------------------------------------------------- rat 204 171.5 human 70000 13800.0

-----------------------------------------------------------------------------

ExtrathoracicBifenazate Human

- Health Risk Assessment DP # 388228

Page 45 of 52 

### SA (m^2) deposited fraction

-------------------------------------------------------------------------------- rat 15 0.413 human 200 0.391

------- ------------------------------------------------------------------------- RATIO 0.075 0.740

RDDR = (VE/SA) animal 

### /(VE/SA) human 

### * deposited fraction animal 

### /deposited fraction human 

### = (171.5/15) animal 

### /(13800/200) human 

### * 0.413/0.391

= 0.175

The magnitude of the UFs applied is dependent on the methodology used to calculate risk. The RfC methodology takes into consideration the PK differences

, but not the PD differences

. Consequently, the UF for interspecies extrapolation may be reduced to 3X (to account for the PD differences) while the UF for intraspecies variation is retained at 10X . Thus, the UF when using the RfC methodology is customarily 30X.

B.1. HEC Calculations for Short

- and Intermediate

- term Res idential Exposure:

Assume residents will be exposed for 24 hrs/day and 7 days/week:

HEC = NOAEL study * (daily duration of exposure animal /daily duration of exposure human ) * (days/week of
exposure animal /days/week of exposure human ) * RDDR

HEC = 0.03 mg/L * (6/24) * (5/7) * 0.175 = 0.00094 mg/L.

Table B.1. HEC Array for Residental Risk Assessment.

Relevant Study LOAEL (mg/L) NOAEL

(mg/L) Da Dh Wa Wh RDDR HEC (mg/L) inter intra UF

Short

- & Intermediate

- Term Exposure

Inhalation

– Rat (MRID 48723301 ) 28

- day ET 0.075 0.03 6 24 5 7 0.175 0.00094 3 10 NA

Long

- Term Exposure: n ot appropriate for bifenazate.

Key for Array Tables LOAEL : Lowest observed adverse effect level NOAEL : No observed adverse effect level Da : Daily animal exposure (hrs/day) Dh : Anticipated daily human exposure (hrs/day) Wa : Weekly animal exposure (days/week) Wh : Anticipated weekly human exposure (days/week) RRDR : Regional Deposited Dose Ratio HEC : Human Equivalent Concentration inter : interspecies extrapolation UF intra : intraspecies variation UF UF : Other UF(s) ET: Extra thoracic region



### Route

- to

- Route Extrapolation

More information and details see : Memo, “Route

- to

- Route Extrapolations” J. Whalen and H. Pettigrew, 10/10/98.

HED’s route

- to

- route extrapolation converts human and animal values from mg/L concentrations to mg/kg oral

- equivalent doses. The equation uses a single conversion factor to account forBifenazate Human

- Health Risk Assessment DP # 388228

Page 46 of 52 

### default body weight s and respiratory volumes. An activity factor is used to account for increased exposure resul ting from increased respiration.

Using the HEC calculated (based upon terminal airway inflammation in males), a conversion of the inhalation concentration to a dose (mg/L to mg/kg/day) was conducted as follows:

Human

- Equivalent Dose (HED, mg/kg/day) = Dose (systemic HEC value, mg/L) x A x CF (L/hr/kg) x D (hours) x AF = mg/kg

Where: A = absorption: ratio of deposition and absorption in respiratory tract compared to

absorption by the oral route. CF = conversion Factor; a L/hr/kg factor which accounts for respiratory volume and body

weight for a given species and strain (Table 1 of J. Whalen and H. Pettigrew, 10/10/98). D = duration; duration of daily animal or human exposure (hours). AF = activity Factor; animal default is 1.



### Therefore, the resident ial human equivalent dose for bifenazate is calculated as follows:

Residential HED: (0.0009 mg/L) x 1 x 6 x 8 x 1 = 0.135 mg/kg/day

B.2. HEC Calculations for Short

- and Intermediate

- term Occupational Exposure:

Assume workers will be in the field for 8 hrs/day and 5 days/week:

HEC = NOAEL study * (daily duration of exposure animal /daily duration of exposure human ) * (days/week of
exposure animal /days/week of exposure human ) * RDDR

HEC = 0.03 mg/L * (6/8) * (5/5) * 0.175 = 0.00394 mg/L.

Table B. 2 . HEC Array for Occupational Risk Assessment.

Relevant Study LOAEL (mg/L) NOAEL

(mg/L) Da Dh Wa Wh RDDR HEC (mg/L) inter intra UF

Short

- & Intermediate

- Term Exposure

Inhalation

– Rat (MRID 48723301 ) 28

- day ET 0.075 0.03 6 8 5 5 0.175 0.00394 3 10 NA

Long

- Term Exposure: Not appropriate for bifenazate.

Key for Array Tables LOAEL : Lowest observed adverse effect level NOAEL : No observed adverse effect level Da : Daily animal exposure (hrs/day) Dh : Anticipated daily human exposure (hrs/day) Wa : Weekly animal exposure (days/week) Wh : Anticipated weekly human exposure (days/week) RRDR : Regional Deposited Dose Ratio HEC : Human Equivalent Concentration inter : interspecies extrapolation UF intra : intraspecies variation UF UF : Other UF(s) ET: Extra thoracic region



### Route

- to

- Route Extrapolation

More information and details see : Memo, “Route

- to

- Route Extrapolations” J. Whalen and H. Pettigrew, 10/10/98.Bifenazate Human

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Page 47 of 52 

### HED’s route

- to

- route extrapolation converts human and animal values from mg/L concentrations to mg/kg oral

- equivalent doses. The equation uses a single conversion factor to account for default body weight s and respiratory volumes. An activity factor is u sed to account for increased exposure resulting from increased respiration.

Using the HEC calculated (based upon terminal airway inflammation in males), a conversion of the inhalation concentration to a dose (mg/L to mg/kg/day) was conducted as follows:

Human

- Equivalent Dose (HED, mg/kg/day) = Dose (systemic HEC value, mg/L) x A x CF (L/hr/kg) x D (hours) x AF = mg/kg Where: A = absorption: ratio of deposition and absorption in respiratory tract compared to

absorption by the oral route. CF = conversi on Factor; a L/hr/kg factor which accounts for respiratory volume and body

weight for a given species and strain (Table 1 of J. Whalen and H. Pettigrew, 10/10/98). D = duration; duration of daily animal or human exposure (hours). AF = activity Factor; ani mal default is 1.



### Therefore, the occupational human equivalent dose for bifenazate is calculated as follows:

Occupational HED: (0.0039 mg/L) x 1 x 6 x 8 x 1 = 0.187 mg/kg/day

Based on the current bifenazate label, HED believes exposures can be short

- (1

- 30 days) or intermediate

- (1 to 6 months) term in duration. Long

- term exposures are not anticipated for bifenazate based on proposed labeled uses. For the short

- and intermediate

- term scenarios, inhalation data from the 28

- day inhalation rodent study was most appropriate for determining HECs. In the RfC methodology, different HECs may be calculated for the same experimental NOAEL due to the following:

1. Different algorithms are used to derive HECs for systemic versus port

- of

- entry effects. Typically, HECs are calculated separately for systemic versus port

- of

- entry effect. For bifenazate, port

- of

- entry irritation was observed and, therefore, only port

- of

- entry HECs were derived. 2. Time adjustments are traditionally needed for non

- occupational (bystande r) versus occupational exposure scenarios. Traditionally, HECs for non

- occupational exposure are based on the number of hours an individual may be at home. Therefore, the most conservative estimate of hours spent at home would be 24 hours/day and 7 days/ week. In comparison, the average workweek for an occupational worker is 8 hours/day and 5 days/week. The HEC array table reflects the time adjustment in the calculations. 3. Appendix C. Residential Handler and Post

- application Algorithms

1.0 Residential Handlers

1.1 Residential Handler Exposure Calculations

1.1.1 Turf, Gardens and Trees, Indoor Environments

Dermal and Inhalation Handler Exposure Algorithm Daily dermal and inhalation exposure (mg/day) for residential pesticide handlers, for a given form ulation

- application method combination, is estimated by multiplying the formulation

-Bifenazate Human

- Health Risk Assessment DP # 388228

Page 48 of 52 

### application method

- specific unit exposure by an estimate of the amount of active ingredient handled in a day, using the equation below:

E = UE * AR * A

where:

E = exposu re (mg/day); UE = unit exposure (mg/lb ai); AR = application rate (e.g., lb ai/ft 2 

### , lb ai/gal); and A = area treated or amount handled (e.g., ft 2 

### /day, gal/day).

1.2 Residential Handler Dose Calculations

Dermal and/or inhalation absorbed doses normalized to body weight are calculated as:

D = E *AF / BW where:

D = dose (mg/kg

- day); E = exposure (mg/day); AF = absorption factor (dermal and/or inhalation); and BW = body weight (kg).

2.0 Residential Post

- application

3.1 Gardens and Trees 3.2 Post

- application Dermal Exposure Algorithm Exposure resulting from contacting previously treated gardens and trees while performing physical activities is calcula ted as shown below. Residential post

- application exposur e assessment must include calculation of exposure on the day of application. Therefore, though an assessment can present exposures for any day “t” following the application, it must include “day 0” exposure.

E = DFR t 

### * CF1 * TC * ET where :

E = exposure (mg/day); DFR t 

### = dislodgeable foliar residue on day "t" (μg/cm 2 

### ); CF1 = weight unit conversion factor (0.001 mg/μg); TC = transfer coefficient (cm 2 

### /hr); and ET = exposure time (hrs/day).

In the absence of chemical

- specific data, DFR t 

### can be cal culated as follows:

DFR t 

### = AR * F

AR 

### * (1

- F

D 

### ) t 

### * CF2 * CF3 where :

DFR t 

### = dislodgeable foliar residue on day "t" (μg/cm 2 

### );Bifenazate Human

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### AR = application rate (lbs ai/ft 2 

### or lb ai/acre); F AR 

### = fraction of ai as dislodgeable residue following application (unitless); F D 

### = fraction of residue that dissipates daily (unitless); t = post

- application day on which exposure is being assessed; CF2 = weight unit conversion factor (4.54 x 10 8 

### μg/lb); and CF3 = area unit conversion factor (1.08 x 10

- 3 

### ft 2 

### /cm 2 

### or 2.47 x 10

- 8 

### acre/c m 2 

### ).

Absorbed dermal dose, normalized to body weight , is calculated as:

where : D = dose (mg/kg

- day); E = exposure (mg/day); AF = absorption factor (dermal and/or inhalation); and BW = body weight (kg).

Table 3. 2. Gardens, Trees, and “Pick

- your - own” Farms

– Inputs for Residential Post

- application Dermal Exposure

. Algorithm Notation Exposure Factor (units) Point Estimate(s)

AR Application rate (mass ai per unit area) [input]

F AR DFR following application, if chemical

- specific is unavailable (fraction) 0.25

F D Daily residue dissipation, if chemical

- specific is unavailable (fraction) 0.10

TC Transfer

Coefficient (cm 2 /hr) Gardens a Adults 8

, 400 Children 6 ≤ 11 years old 4

, 600 Trees, Retail Plants (if applicable) a Adults 1

, 700

Children 6 ≤ 11 years old 930

Indoor Plants Adults 220 Children 6 ≤ 11 years old 120

ET Exposure

Time (hours per day) Home activities b Gardens Adults 2.2 Children 6 ≤ 11 years old 1.1
Trees, Retail Plants (if applicable) Adults 1.0

Children 6 ≤ 11 years old 0.50

Indoor Plants Adults 1.0

Children 6 ≤ 11 years old 0.50

“Pick

- your

- own” Farms (if applicable) Adults 5.0

Children 6 ≤ 11 years old 1.9

BW Body weight (kg) Adults 69

Children 6 ≤ 11 years old 32

a Transfer coefficient point estimates from a composite distribution assuming equal proportion of time spent conducting various activities. See “Transfer Coefficient” section below. Children 6 ≤ 11 years old TC derived using surface area adjustment (see Section 2.3 ).

b Activity time point estimates from a composite distribution assuming equal proportion of each respective activity. Time for children 6 < 11 years old derived using hrs/day ratio adju stment.Bifenazate Human

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### Appendix D. Summary of Occupational and Residential Non

- cancer Algorithms

Average Daily Dose Potential daily exposures for occupational handlers are calculated using the following formulas: E=UE * AR * A * 0.001 mg/ug where: E = exposure (mg ai/day), UE = unit exposure (μg ai/lb ai), AR = maximum application rate according to proposed label (lb ai A or lb ai/gal), and A = area treated or amount handled (e.g., A/day, gal/day).

The daily doses are calculated using the following formula:

ADD= E * AF
BW where: ADD = average daily dose absorbed in a gi ven scenario (mg ai/kg/day), E = e xposure ( mg ai/day), AF = absorption factor (dermal and/or inhalation), and BW = body weight (kg).

Margin of Exposure (MOE) Non

- cancer risk estimates for each application handler scenario are calculated using a n MOE that is a ratio of the toxicological endpoint to the daily dose of concern. The daily dermal and inhalation dose received by occupational handlers are compared to the appropriate POD (i.e., NOAEL) t o assess the risk to occupational handlers for each exposure route. All MOE values are calculated using the following formula:

MOE= POD
ADD where: MOE = margin of exposure: value used by HED to represent risk estimates (unitless), POD = point of departure (mg/kg/day), and ADD = average daily dose absorbed in a given scenario (mg ai/kg/day).

Appendix E. Summaries of Dislodgeable Foliar Residue Studies and Proposed Use in Assessment

.

Proposed Uses for Bifenazate

.

Commodity Foliage Type a Product Name Application

Equipment Applicatio

n Rate (lb ai/A) Maximum

Number Applications Per Season Herbs subgroup 19 A (except chives, chervil) Unknown

Florimite® 50WP Groundboom,

Aerial Airblast 0.5 1 Fruiting vegetable Group 8

- 10 smooth

Pome fruit Group 11

- 10 smooth Timothy forage hay varied Airblast 0.75 1 a. Based on information in the ARTF/ORETF DFR Guidance



### DFR Studies Available:

Florimite® 50WP on Spathiphyllum: Dislodgeable Foliar Residue Study (MRID 448597

- 01)

. (HED Review: Memo, L. Venkateshwara, pending , D 388802 

### )Bifenazate Human

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### This study was designed to collect data to evaluate dislodgeable foliar residue (DFR) dissipation for the compound bifenazate from Spathiphyllum (Peace Lily) foliage grown in a greenhouse at one site in Florida. One field trial was conducted in two greenh ouses, one containing treated Spathiphyllum (Peace Lily) plants and the other containing untreated plants. Primary review of the study was conducted by Versar Inc., 07/07/ 2000 (MRID 448597

- 01).

F lorimite® 50WP is a wettable

- powder packaged in water

- soluble bags that contains 50 % bifenazate as the active ingredient. Floramite ® 50WP was applied with a hand

- held boom sprayer at 0.29 lb ai/A. Three applications were made with a 30

- day application interval. DFR samples were collected were up to 28 da ys after the first two treatments and up to 35 days after the last treatment. Samples were analyzed for combined residues of bifenazate and a breakdown product UCC

- D3598.

Study results indicate that the range of DFR values quantified were quite similar after all three applications. The maximum DFR analyzed was 72 μ g/sample (after correction for 68 percent field recovery), found on DAT

- 1 after the first application. DFR va lues did not decline to <LOQ (i.e. 2 μ g/sample) within the 21

- day sampling period following the first two applications. DFR values did decline to <LOQ by DAT

- 35 after the third application.

Assuming first order kinetics, HED modeled dissipation rates and estimated half

- lives for bifenazate of 9.9 days in Florida (R 2 

### = 0.8433).

Summary of DFR Values and Regression Analysis Results for Treated Spathiphyllum (Peace Lily) in Greenhouses with Bifenazate (MRID# 448597

- 01).

Input/Parameter Site: Florida Bifenazate Application Rate (lb ai/A) a Study Target Rate = 0.29 lb ai/A 0.29 lb ai/A
Spray Volume (GPA) 5 gallons/1000 ft 2 Measured Average Day 0 Residue (μg/cm 2 ) 0.151 Predicted Day 0 Residue (μg/cm 2 ) b 0.161 Slope

- 0.07 Half

- life (days) 9.9 R 2 0.8433 a. The application was conducted using hand

- held boom sprayer. b. Regressions are based on data collected after second application.



### Proposed use of DFR data:

 Use the greenhouse 

### Spathiphyllum (Peace Lily) DFR data to estimate post

- application exposure for h erbs subgroup 19 A (except chives, chervil), fruiting vegetable group 8

- 10, pome fruit group 11

- 10, Timothy forage hay (use predicted values).Bifenazate Human

- Health Risk Assessment DP # 388228

Page 52 of 52 Crop DFR Data Sites Proposed use of DFR Data Characterization

Herbs subgroup 19 A (except chives, chervil), Fruiting vegetable group 8

- 10, Pome fruit group 11

- 10, Timothy forage hay Spathiphyllum (Peace Lily) (Greenhouse) FL Predicted DFR values  DFR data collected in greenhouse; is a

conservative estimate.

 The formulation in the study is a wettable

- powder packaged in a water

soluble bag whereas in one of the proposed labels (EPA Reg#400

- 514) the formulation is a SC (liquid). The second label (EPA Reg#400

- 503) the formulation is a wettable

- powder in a
water

- soluble bag.

 The application rate was lower in the study (0.29 lb ai/A) compared to the proposed label (0.5 lb ai/A and 0.75 lb ai/A).

 Application method is not application method for proposed crops.



### Appendix F . Physical/Chemical Properties

TABLE B. Physicochemical Properties of the Technical Grade of Bifenazate.
Parameter Value Reference Melting point/range 124

- 125oC MRID 46064101 pH 6.78 Density 1.19 g/cm 3 Water solubility (25 ± 1°C) 2.1 mg/L (20°C) Solvent solubility 102 mg/mL ethyl acetate (20°C) Vapor pressure at 25 ± 1°C <1 x 10

- 8 atm M 3 /mole (25°C) Dissociation constant (pK a ) 12.94 at 23 C Octanol/water partition coefficient Log(K OW ) 3.4 UV/visible absorption spectrum Max 264 nm in water NA = not available.