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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

OFFICE OF

CHEMICAL SAFETY AND

POLLUTION PREVENTION

MEMORANDUM

Date: 15-May-2014

SUBJECT: Bifenazate. Human-Health Risk Assessment. Section 3 Registration Request to 

Add New Uses on Timothy Forage and Hay; Herb, Subgroup 19A; and to Expand 

Existing 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 Regulatory Actions: Section 3 Registration

Risk Assessment 

Type: 

Single 

Chemical/Aggregate

Case No.: 7609

TXR No.: NA CAS No.: 149877-41-8

MRID No.: None 40 CFR: §180.572

FROM: William D. Wassell, Chemist

Anwar Y. Dunbar, Ph.D., Pharmacologist

Lata Venkateshwara, Environmental Scientist 

Risk Assessment Branch 1 (RAB1)

Health Effects Division (HED; 7509P)

THROUGH: Charles W. Smith III, Branch Chief

George F. Kramer, Ph.D., Senior Chemist 

RAB1/HED (7509P)

TO: Barbara Madden, RM 05

Registration Division (RD, 7505P) 

The HED of the Office of Pesticide Programs (OPP) is charged with estimating the risk to human 

health from exposure to pesticides. The RD of OPP has requested that HED evaluate hazard and 

exposure data and conduct dietary, occupational, residential, and aggregate exposure 

assessments, as needed, to estimate the risk to human health that will result from the registered 

and proposed uses of the miticide/insecticide bifenazate [1-methylethyl 2-(4-methoxy[1,1’-

biphenyl]-3-yl)hydrazinecarboxylate)]. 

A summary of the findings and an assessment of human-health risk resulting from the proposed 

and registered uses of bifenazate are provided in this document. The risk assessment, dietary

exposure assessment, and residue chemistry assessment were provided by William Wassell 

(RAB1); the hazard characterization and endpoint selection by Anwar Dunbar (RAB1); the 

occupational and residential exposure assessment by Lata Venkateshwara (RAB1); and the 
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drinking water exposure assessment by J. Hetrick of the Environmental Fate and Effects Division 

(EFED). 

The most-recent human-health risk assessment for bifenazate was for a Section 3 registration and 

tolerances to support a proposed use on tropical fruits and berries (Memo, 07/14/2010, W. 

Wassell, et al., D371783). 
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Table of Contents

1.0 Executive Summary........................................................................................................... 5

2.0 HED Recommendations.................................................................................................. 10

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

2.2 Tolerance Considerations............................................................................................ 11

2.2.1 Enforcement Analytical Method ............................................................................. 11

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 ............................................................................. 14

3.3 Pesticide Use Pattern.................................................................................................... 14

3.4 Anticipated Exposure Pathways................................................................................. 16

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

4.0 Hazard Characterization and Dose-Response Assessment.......................................... 16

4.1 Toxicology Studies Available for Analysis................................................................. 16

4.2 Absorption, Distribution, Metabolism, and Excretion (ADME) ........................... 167

4.2.1 Dermal Absorption................................................................................................. 178

4.3 Toxicological Effects .................................................................................................... 18

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

4.4 Safety Factor for Infants and Children (FQPA Safety Factor) ............................. 189

4.4.1 Completeness of the Toxicology Database.............................................................. 19

4.4.2 Evidence of Neurotoxicity........................................................................................ 19

4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal........ 19

4.4.4 Residual Uncertainty in the Exposure Database ................................................... 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 Assessment..... 22

4.5.3 Cancer Classification and Risk Assessment Recommendation.......................... 222

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

Assessment............................................................................................................................... 22

5.0 Dietary Exposure and Risk Assessment....................................................................... 224

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.............................................................................................. 26

5.4.1 Description of Residue Data Used in Dietary Assessment.................................... 26

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

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

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

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

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

6.0 Residential (Non-Occupational) Exposure/Risk Characterization ............................. 28

6.1 Residential (Non-Occupational) Exposure/Risk Characterization ............................. 28

6.2 Residential Post-Application Exposure/Risk Characterization .................................. 29

6.3 Spray Drift........................................................................................................................ 30

6.4 Residential Bystander Post-Application Inhalation Exposure .................................... 30

6.5 Residential Risk Estimates for Use in Aggregate Assessments.................................... 31
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7.0 Aggregate Exposure/Risk Characterization.................................................................. 30

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

7.2 Short-Term Aggregate Risk........................................................................................ 321

7.3 Chronic Aggregate Risk .............................................................................................. 32

8.0 Cumulative Exposure/Risk Characterization ............................................................... 32

8.1 Occupational Exposure/Risk Characterization ..................................................... 32

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

Appendix A. Toxicology Profile and Executive Summaries 40

Appendix B. Methodologies for Human-Equivalent Concentration Calculations 45

Appendix C. Residential Handler and Post-application Algorithms 48

Appendix D. Summary of Occupational and Residential Non-cancer Algorithms 51

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

Assessment 51

Appendix F. Physical/Chemical Properties 53
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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 GABA (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, hops, okra, peppermint, and 

spearmint with tolerances ranging from 0.1 to 35 ppm (40 CFR §180.572(a)(1)). A Section 18 

registration has also been established for application of bifenazate to timothy with tolerances 

ranging from 50 to 150 ppm (40 CFR §180.572(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/on 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 commodities that are included in the revised crop groups 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 these registration requests 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) formulation]. 

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 one 
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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 fruiting 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 exposure 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 

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. In the rat developmental toxicity

study, 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 highest-dose tested (HDT). In the two-generation rat reproduction study, there 

were no reproductive or offspring 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 hindlimb grip strength, and decreased motor activity measurements (center 

times 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,

and effects on the hematopoietic system. In the 28-day inhalation study, effects included driedred 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, 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 “not 

likely” to be carcinogenic 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 

1x 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 

intermediate-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 weights and food consumption during 

the dosing period. At the same dose, there was an increased incidence of early fetal resorptions. 

For the chronic 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 chemistry parameters and histopathological changes in the bone marrow, liver, and 
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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 short- 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 intermediate-term dermal exposures, 

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 effects (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, humanequivalent 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 consideration: (1) developmental toxicity

studies in rats and rabbits; (2) two-generation reproductive study in rats; and (3) acute 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 (MARC) (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 bifenazate).

Livestock 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 to 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 01/12/2011). 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 residues 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 confined rotational crop metabolism study. The MARC concluded that a 30-day

plantback interval (PBI) is appropriate based on the available data. Appropriate PBIs 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 proposed 
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application 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 preharvest interval 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 9.6x 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 bifenazate) is 30 ppm in/on fresh herbs (subgroup 19A) and 300 

ppm in/on dried herbs (subgroup 19A).

IR-4 has submitted adequate 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, grasses 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 bifenazate 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 recommended 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 drinking 

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 uses. Drinking 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 for 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 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 analysis 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). 

The acute and chronic exposure and risk estimates were not of concern. A cancer dietary

assessment was not conducted because bifenazate is classified as “not likely” to be carcinogenic 

to humans.
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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 

aggregated risk index (ARI) approach was used since the levels of concern (LOCs) 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 all 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 carcinogenic 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 “when 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 (DFRt) 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 (day 0) for the postapplication exposure activities. Based on the Agency's current practices, a quantitative 

occupational post-application inhalation exposure assessment was not performed for bifenazate 

at this time. If new policies or procedures are put into place, the Agency may revisit the need for 

a quantitative occupational post-application inhalation exposure assessment for bifenazate.

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) database; the Outdoor Residential Exposure Task Force 

(ORETF) database; the Agricultural Reentry Task Force (ARTF), and the Residential SOPs 

(Gardens/Trees), are (1) subject to ethics review pursuant to 40 CFR §26, (2) have received that 

review, and (3) are compliant with applicable ethics requirements. For certain studies, the ethics 

review may have included review by the Human Studies Review Board. Descriptions of data 

sources, as well as guidance on their use, can be found at the Agency website1. 

 

1

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

http://www.epa.gov/pesticides/science/post-app-exposure-data.html
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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 tolerances for residues of 

bifenazate and its metabolites as outlined in Table 2.2.2. 

860.1550 Proposed Tolerances

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 bifenazate), 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. Knizner). 

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 §180.572(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 measuring only the sum of bifenazate 

and its metabolite, diazinecarboxylic acid, 2-(4-methoxy-[1,1'-biphenyl]-3-yl), 1-

methylethyl ester, (calculated as the stoichiometric equivalent of bifenazate) in or on the 

following food commodities:

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

as follows: 

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

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

the commodities listed in the following table. Compliance with the tolerance levels 

specified are to be determined by measuring only the sum of bifenazate and its 

metabolites diazinecarboxylic acid, 2-(4-methoxy-[1,1′-biphenyl]-3-yl), 1-methylethyl 

ester (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:

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 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 expired on 6/30/2012 and 05/31/2012, respectively. 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.)

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, 
Bifenazate Human-Health Risk Assessment DP# 388228

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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 bifenazate 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 LCMS/MS Method NCL ME 259 was recently submitted as a confirmatory method, and this 

method was also forwarded to FDA. The validated LOQ was 0.01 ppm for each analyte. The 

LOD was reported as 0.005 ppm. 

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, subgroup 19A, fresh leaves 30 30 Herb, subgroup 19A, fresh leaves, 

except chervil and chive

Herb, subgroup 19A, dried leaves, 

except chervil, dried and chive, 

dried

140 300

Timothy, forage 140 200 Tolerance with regional registrations

Timothy, hay 120 150 Tolerance with regional registrations

Fruit, pome, group 11-10 0.75 0.75

Vegetable, fruiting, group 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 ppm in/on basil (translated to herb, subgroup 19A, fresh 

leaves, except chervil and chive), 200 ppm in/on grass forage (translated to timothy, forage), and 

150 ppm in/on grass hay (translated to timothy, hay). The recommended tolerance level of 300 

ppm for herb, subgroup 19A, dried leaves, except chervil, dried, and chive, dried is based on 

residue data that examined residue levels in fresh and dried basil. The tolerance level for pome 

fruit is based on the currently established tolerance. The recommended-tolerance level for 

fruiting vegetables is based on comments from the Pest Management Regulatory Agency

(PMRA) of Health Canada (correspondence 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. A revised Section F is required to adjust the tolerance levels, correct 

proposed commodities, and to change the tolerance expression (see Recommended Tolerances 

section).
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2.2.4 International Harmonization

There are currently no established Codex, Canadian, or Mexican MRLs for bifenazate in/on 

herbs, and timothy forage and hay. The tolerance expressions for plant commodities are 

harmonized between the U.S. and Canada, but not with Codex. Canadian MRLs are established 

for residues in/on apples, but not for other crops in the pome fruit crop group. The tolerance 

level for residues in/on fruiting vegetables is harmonized with Canada (see above). The 

Canadian MRL for residues in apples is not harmonized with the U.S. tolerance levels for 

residues in pome fruits. Codex MRLs are established for pome fruits, and for peppers and 

tomato (but not for the other members of the fruiting vegetables crop group). Additionally the 

Codex MRLs for residues in pome fruits, peppers, and tomato are not harmonized with the U.S. 

tolerance levels.

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, timothy, pome fruits, and fruiting vegetables. 

3.0 Introduction

3.1 Chemical Identity

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)

O

N

H

N

H

O CH3

O CH3

CH3
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Table 3.1. Test Compound Nomenclature.

Compound

Common name None

Company experimental name D3598

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

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

CAS registry number 149878-40-8

Compound

OH

Common name None

Company experimental name A1530

IUPAC name 1,1’-biphenyl, 4-ol

CAS name p-hydroxybiphenyl

CAS registry number 92-69-3

Compound

OSO3H

Common name None

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

IUPAC name Unknown

CAS name Unknown

CAS registry number Unknown

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 environments 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).

O

N

N O CH3

O CH3

CH3
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Table 3.3. Summary 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 soon as mites 

appear. 

Timothy (Proposed Use)

Ground or 

Aerial 

Application

Acramite®4SC

[400-514] 0.43 to 

0.75

1 0.75 (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.
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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, dried and fresh, 

timothy hay and forage, fruiting vegetables, group 8-10 and pome fruit, group 8-10. Humans 

may be exposed to bifenazate in food and drinking water, since bifenazate may be applied 

directly to growing crops and applications may result in bifenazate reaching surface and ground 

water sources of drinking water. In an occupational setting, applicators 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 considers 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

Potential 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-Income 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 activities in and around the home that involve pesticide use in a residential 

setting. Extensive data on food consumption patterns are compiled by the USDA under the 

National Health and Nutrition Examination Survey, What We Eat in America, 

(NHANES/WWEIA; 2003-2008) and are used in pesticide risk assessments for all registered 

food uses of a pesticide. These data 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 conditions or circumstances warrant. Whenever appropriate, non-dietary exposures based 

on home use of pesticide products and associated risks for adult applicators and for toddlers, 

youths, and adults entering or playing on treated areas postapplication are evaluated. Further 

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 dietary 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. There 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. Appendix 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 
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consisted of an immunotoxicity study as well as the neurotoxicity screening battery tests as specified 

in the revised 40 CFR §158 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) concluded 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 including; 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 mechanism 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 increased fetal sensitivity (Memo, 02/20/2014, A. Dunbar et al., D416994). The 

Agency further conducted its 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 

Syngenta revealed conflicting evidence concerning the pesticidal mechanism of action (EPAHQ-OPP-2012-0633; Weiland and Rao, Feb 11, 2013: Response to “Anticipated Data Needs” for 

bifenazate and DNT Guideline 870.6300 requirement). 

4.2 Absorption, Distribution, 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, and 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 highest tissue 

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

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

blood and red blood cell concentrations suggests that most of the test material was carried in the 

plasma. 

The feces 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. Cmax

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 at the 1000 mg/kg dose (12-16 hours) than at 

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

bifenazate were observed. 

Bifenazate was highly metabolized with eight primary metabolites identified in the feces of both 

sexes for both low- and high-doses. These metabolites, as well as those identified in the urine 
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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 toxicity 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

Bifenazate was categorized as having low acute toxicity (Toxicity Category IV) for the oral, 

dermal and inhalation routes of exposure 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 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, bodyweight gain, and food consumption were also associated with liver and hematopoietic system 

toxicity in several studies. 

In the rat developmental toxicity study, the maternal effects consisted of clinical signs of 

toxicity, decreased body weight and body-weight gains, 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. In 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, treatment 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 decreased 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.
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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, 

decreased body weights 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 concentrations tested. Starting at the mid-concentration (0.075 

mg/L), there 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 

mild olfactory epithelial degeneration in nasal levels III, IV, and V (30% 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 mutagenicity studies were 

negative for mutagenic or clastogenic activity. 

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) developmental toxicity

studies in rats and rabbits; (2) two-generation reproductive study in rats; and (3) acute 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 by 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 rabbits.
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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, the dietary

exposure analyses 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 underestimate 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 upon reasonable 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 inter-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 exposure and it is protective for the general 

population.

Acute Dietary Endpoint for Females 13-49 Years of Age: 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-species 

variations, and a 1x FQPA SF. At the LOAEL of 100 mg/kg/day, maternal effects included 

clinical signs, decreased absolute body weights, and food consumption during the dosing period. 

At the same dose, there 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 parameters 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. The endpoint used for deriving 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 appropriate for assessing 

potential risk via chronic dietary exposure to bifenazate. This study is appropriate for the 

duration of exposure and is protective of the general population.
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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 upon 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-term dermal endpoints were derived 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 spleen in both sexes. The LOC is 

100 based upon a 10x UF for inter-species extrapolations, and a 10x UF for intra-species 

variations. This study protects for the early resorptions in the developmental rat study where the 

maternal and fetal effects occur at the 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 inhalation endpoints were derived from the route-specific 28-day inhalation 

study in rats 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 weights 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 degeneration of the 

olfactory epithelium within nasal levels III, IV, and V in both sexes. HECs were derived from 

this study based upon this degeneration of the olfactory epithelium which is considered a portalof-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 subsequently calculated (0.14 mg/kg/day for 

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 through 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 

calculating HECs based on the inhalation toxicity NOAEL 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 aerosols), 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 observed inhalation particulate exposure of an animal to the 

predicted inhalation exposure for a human. For the 4-week inhalation study with bifenazate, an 

RDDR was estimated at 2.8 based on the reported MMAD of 2.20 μm and standard deviation 

(g) of 2.78 and the respiratory-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 human 

occupational exposures. The resulting HECs are 0.0009 mg/L and 0.0039 mg/L for residential 

and occupational exposures. The LOC is 30 which includes interspecies (3x), and intraspecies 
Bifenazate Human-Health Risk Assessment DP# 388228

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(10x) uncertainty factors. The interspecies factor was reduced from 10x to 3x due to the HEC 

calculation accounting for pharmacokinetic (not pharmacodynamic) 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 evidence 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 “not 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 

Assessment

Table 4.5.4.1. Summary of Toxicological Doses and Endpoints for Bifenazate for Use in Dietary and NonOccupational Human-Health Risk Assessments.

Exposure/ 

Scenario POD

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

UFA = 10x

UFH = 10x

FQPA SF = 1x

Acute RfD = 

6 mg/kg/day

aPAD = 6

mg/kg/day

Acute Neurotoxicity Screening BatteryRats

LOAEL = 2000 mg/kg/day based on 

decreased motor activity (rearing in 

females).

Acute Dietary 

(Females 13-

49 years of 

age)

NOAEL = 

10 

mg/kg/day

UFA = 10x

UFH = 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

UFA = 10x

UFH = 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.
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Table 4.5.4.1. Summary of Toxicological Doses and Endpoints for Bifenazate for Use in Dietary and NonOccupational Human-Health Risk Assessments.

Exposure/ 

Scenario POD

Uncertainty/FQPA 

SFs

RfD, PAD, 

Level of 

Concern for 

Risk 

Assessment

Study and Toxicological Effects

Incidental Oral 

Short Term (1 

-30 days) and 

Intermediate 

Term

NOAEL = 

0.9 

mg/kg/day

UFA = 10x

UFH = 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 

histopathological effects in both sexes.

Dermal Shortand 

IntermediateTerm (1-30 

days and 1-6 

months)

LOAEL = 

80 

mg/kg/day

UFA = 10x

UFH = 10x

FQPA SF = 1x

Residential 

LOC for 

MOE = 100

21-Day Dermal Toxicity-Rat

LOAEL = 400 mg/kg/day based on 

decreased body weight in females, 

decreased food consumption in both 

sexes, increased urinary ketones, increased 

urinary protein, increased urinary specific 

gravity, and decreased urinary volume in 

both sexes, and increased incidence of 

extramedullary hematopoiesis in the 

spleen in both sexes.

Inhalation 

Short- and 

IntermediateTerm (1-30 

days, and 1-6 

months)

Rat 

NOAEL = 

0.03 mg/L 

UFA = 3x

UFH = 10x

FQPA SF = 1x

Residential

LOC for 

MOE = 30

28-Day Inhalation Toxicity-Rat

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

material around the nose in females, lower 

body weights 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 degeneration 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”.

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 = lowestobserved adverse-effect level. UF = uncertainty factor. UFA = extrapolation from animal to human (interspecies). 

UFH = potential variation in sensitivity among members of the human population (intraspecies). UFL = 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.
Bifenazate Human-Health Risk Assessment DP# 388228

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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 Shortand 

IntermediateTerm (1-30 

days and 1-6 

months)

LOAEL = 

80 

mg/kg/day

UFA = 10x

UFH = 10x

Occupational 

LOC for MOE = 

100

21-Day Dermal Toxicity- Rat

LOAEL = 400 mg/kg/day based on 

decreased body weight in females, 

decreased food consumption in both sexes, 

increased urinary ketones, increased 

urinary protein, increased urinary specific 

gravity, and decreased urinary volume in 

both sexes, and increased incidence of 

extramedullary hematopoiesis in the spleen 

in both sexes.

Inhalation 

Short- and 

IntermediateTerm (1-30 

days, and 1-6 

months)

Rat NOAEL

= 0.03 mg/L 

UFA = 3x

UFH = 10x

Occupational

LOC for MOE = 

30

28-Day Inhalation Toxicity-Rat

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

dried red material around the nose, lower 

body weights 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 = lowestobserved adverse-effect level. UF = uncertainty factor. UFA = extrapolation from animal to human (interspecies). 

UFH = 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, D388800).

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 apple, 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 

equivalent of bifenazate). 

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 the stoichiometric equivalent of bifenazate). 
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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 rotational 

crops could not be determined from the available data. The MARC concluded that a 30-day PBI

is appropriate based on the available data. 

Drinking Water: The HED MARC determined that the residue of concern in water is D1989. 

Table 5.1. Summary of Metabolites and Degradates to be Included 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 determined1could not be determined1

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 

Herbs, Subgroup 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 CA, SC, and GA. The residue data were analyzed using the OECD tolerancecalculation procedures. The tolerance worksheet recommended a tolerance for residues of 

bifenazate and D3598 at 30 ppm in/on basil (translated to herb, subgroup 19A, fresh leaves, 

except chervil and chive). The recommended tolerance level of 300 ppm for herb, subgroup

19A, dried leaves, except chervil, dried, and chive, dried, is based on residue data that examined 

residue levels in fresh basil and dried basil. 

The submitted magnitude of the residue data for grass forage and hay will support the proposed 

use patterns for timothy. 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-calculation 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). 

Livestock feed items are not derived from herbs. Timothy 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. 
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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 were submitted and reviewed in 

conjunction with PP#0F6108 (Memo, 8/16/2001, T. Bloem, D277089).

Bifenazate 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. The petitioner further states that the established tolerances for residues 

in/on fruiting vegetables, group 8 may be deleted upon establishment of the uses and tolerances 

for residues in/on fruiting vegetables, group 8-10. Residue data for the use on fruiting vegetables 

were submitted and reviewed in conjunction with PP#3E6517 (Memo, 5/29/2003, T. Bloem, 

D290053).

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 Residue 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., D388230; and Memo, 7/25/2012, 

J. Hetrick, et al., D402952). Surface and ground water-monitoring 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 is 

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 

concentrations (EDWCs) 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

Acute and chronic dietary (food plus drinking water) risk assessments were conducted using the 

DEEM-FCID, Version 3.16, which uses food consumption data from the USDA’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 tolerances for 
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bifenazate and D3598 on timothy and herb, subgroup 19A; and to expand existing uses on pome 

fruit, group 11, and fruiting vegetables, 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 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 acute surface water point estimate (0.0373 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 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 (0.0112 ppm) generated 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 analysis used 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%; 

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%; grapefruit: 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 watermelon: 1%. 

5.4.3 Acute Dietary Risk Assessment

The acute risk estimate utilizes <1% (0.040436 mg/kg/day) of the aPAD for the U.S. population 

at the 95th percentile of exposure. The most highly exposed population subgroup was children 1 

to 2 years old which utilized 1.9% (0.113582 mg/kg/day) of the aPAD at the 95th percentile of 

exposure. The acute risk estimate utilizes 9.9% (0.009941 mg/kg/day) of the aPAD for females 

13 to 49 years old at the 99.9th percentile of exposure. Thus, acute dietary exposure to bifenazate 

for all population subgroups is not of concern. 
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5.4.4 Chronic Dietary Risk Assessment

The chronic risk estimate utilizes 24% (0.002360 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% (0.007438 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 Bifenazate1.

Population Subgroup

Acute Dietary (95th Percentile) Chronic Dietary

Dietary Exposure 

(mg/kg/day) % aPAD Dietary Exposure(mg/kg/day) % cPAD

General U.S. Population 0.040436 <1 0.002360 24

All Infants (<1 year old) 0.079571 1.3 0.003713 37

Children 1-2 years old 0.113582 1.9 0.007438 74

Children 3-5 years old 0.098092 1.6 0.005635 56

Children 6-12 years old 0.055662 <1 0.003053 31

Youth 13-19 years old 0.031028 <1 0.001858 19

Adults 20-49 years old 0.031220 <1 0.002106 21

Adults 50-99 years old 0.028073 <1 0.001681 17

Females 13-49 years old 0.00994129.9 0.001950 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 99.9th percentile.

6.0 Residential (Non-Occupational) Exposure/Risk Characterization

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-sop.html)

along with policy changes for body weight 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 
Bifenazate Human-Health Risk Assessment DP# 388228

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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)]

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 estimates 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.

Exposure 

Scenario

Application 

Rate1

Area 

Treated 

Daily2

Baseline Unit 

Exposures (mg/lb ai)

Baseline Dose4

(mg/kg/day) Baseline MOE5

ARI6

Dermal3Inhalation3 Dermal Inhalation Dermal

(LOC = 100)

Inhalation 

(LOC = 30)

Mixer/Loader/Applicator for Soluble Concentrates( Liquids)

Manuallypressurized 

handwand

0.00125 lb 

ai/gal 5 gal 63 0.018 0.0049 0.0000014 16,000 100,000 150

Hose-end 

sprayer

0.00125 lb 

ai/gal 11 gal 58 0.0014 0.010 0.00000024 8,000 580,000 80

Backpack 0.00125 lb 

ai/gal 5 gal 130 0.14 0.010 0.000011 7,900 13,000 66

Sprinkler 

can

0.00125 lb 

ai/gal 5 gal 58 0.0014 0.0045 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 HED’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 Characterization

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; however, 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 the basis for completing the residential post-application risk 

assessment. Each assumption and factor is detailed in the 2012 Residential SOPs 

(http://www.epa.gov/pesticides/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 
Bifenazate Human-Health Risk Assessment DP# 388228

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SOPs (http://www.epa.gov/pesticides/science/residential-exposure-sop.html). For this 

assessment a chemical-specific dislodgeable foliar residue (DFRt) value of 0.161 μg/cm2 was 

used (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 ≥ 100).

Table 6.2. Short- and Intermediate-Term Residential Post-application Exposure and Risk 

Estimates for Bifenazate.

Liquid Formulations

Lifestage Post-application Exposure 

Scenario Dosea MOEsb(LOC = 100)

Adult

Garden - sprays

0.037 2,200

Child 6 < 11 years old 0.025 3,100

Adult Tree – sprays0.0034 23,000

Child 6 < 11 years old 0.0023 34,000

a. Dermal Dose (mg/kg/day) = DFRt (0.161 μg/cm2) x 0.001 (mg/μg) x short-term TC (cm2/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 Offices and State Lead Agencies for pesticide regulation 

and other parties to develop the best spray drift management practices (see the Agency’s Spray

Drift website for more information) 2. The Agency is also taking means to qualitatively and 

quantitatively address spray drift as a potential source of exposure in risk assessments for 

pesticides through existing programs such as AgDrift®and chemical specific properties of 

pesticides. The potential for spray drift will be quantitatively evaluated for each pesticide 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-application inhalation exposure 

assessment was not performed for bifenazate at this time primarily because of the low acute 

inhalation toxicity (Toxicity Category 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 

Agency is in the process of evaluating the SAP report and may, as appropriate, develop policies 

and procedures to identify the need for and, subsequently, the way to incorporate postapplication inhalation exposure into the Agency's risk assessments. If new policies or 

 

2 Available: http://www.epa.gov/opp00001/factsheets/spraydrift.htm 
Bifenazate Human-Health Risk Assessment DP# 388228

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procedures 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 residential 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 Postapplication Exposure 

for Aggregate 

(mg/kg/day) Dermal Inhalation Dermal Inhalation Oral 3

Adult 0.0045 0.000011 0.037 N/A N/A 0.037

Children 6 < 11 yrs old N/A N/A 0.025 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 aggregate 

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 to quantitative 

estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can be aggregated. When 

aggregating exposures and risks from various sources, HED considers both the route and 

duration of exposure.

For bifenazate, aggregate exposure risk assessments were performed for acute, short- and 

intermediate-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 and all population 

subgroups (see Table 5.4.6). 

7.2 Short-Term Aggregate Risk

The short- and intermediate-term toxicological PODs for bifenazate are the same for each route 

of exposure. Therefore, for residential exposure scenarios, only short-term exposures were 

assessed, and are considered to be protective of intermediate-term exposure and risk.
Bifenazate Human-Health Risk Assessment DP# 388228

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There are two aggregate risk scenarios that are of interest to HED: 1) adult dermal 

postapplication exposure to gardens and ornamentals, and 2) children 6 ≤ 11 years old dermal 

postapplication exposure to gardens and ornamentals. Exposure from these two scenarios is 

aggregated with chronic dietary exposure that is considered to be background exposure.

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 there are 

different PODs for oral and dermal routes of exposure but the LOC are the same. The chronic 

dietary exposure estimate for Adults 20-49 years old and Children 6-12 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 

Risk1

Dietary

MOE2

MOE Oral 

Residential 

Exposure 

MOE 

Dermal 

Residential 

Exposure3

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 oral NOAEL)/(chronic dietary exposure)] or [(0.9 

mg/kg/day)/(0.002106 mg/kg/day)] for adults and [(0.9 mg/kg/day)/(0.003053 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. 

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

7.3 Chronic Aggregate Risk

The chronic aggregate 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 

population 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 produce 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 which 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 effects from substances found to have a common 

mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/.
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8.1 Occupational Exposure/Risk Characterization

The proposed uses are on agricultural 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 

and 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 

applications and exposures can vary depending on the specifics of each task. 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) 

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 aerial 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.
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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 inhalation 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 require 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-Health Risk Assessment DP# 388228

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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 

Rate2

Amount 

Treated 

Daily3

Dose (mg/kg/day)4,5 MOE6,7 Total

Dermal Inhalation

Dermal

(LOC = 

100)

Inhalation

(LOC = 30) ARI9

Mixer/Loader Wettable Powder in Water Soluble Bags

Aerial 

Application Eng Control8

: 

9.8

Eng Control8: 

0.24

0.5 lb ai/A 350 A EC: 0.0215 EC: 0.00053 EC: 3,700 EC: 360 EC: 9.1

Airblast 

Applications 0.5 lb ai/A 40 A EC: 0.00245 EC: 0.00006 EC: 33,000 EC: 3,200 EC: 81

Groundboom 

applications 0.5 lb ai/A 80 A EC: 0.0049 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: 110SL/G: 650 Base: 260 Base: 0.98SL/G: 3.7

Chemigation 

Applications 0.75 lb ai/A 350 A Base: 0.723SL/G: 0.123 Base: 0.00072 Base: 110SL/G: 650 Base: 260 Base: 0.98SL/G: 3.7

Groundboom 

applications 0.75 lb ai/A 80 A Base: 0.165 Base: 0.00016 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: 0.00683 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: 0.00365 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 Unit 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 will 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 on 
Bifenazate Human-Health Risk Assessment DP# 388228

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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, however 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 postapplication 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 postapplication exposure that are used in this assessment, known as “transfer coefficients,” 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/postapp-exposure-data.html.

Chemical-specific DFR data 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 bifenazate, 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 crops (fruiting vegetable, Group 8-10, herb 

Subgroup 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 in 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 Greenhouses with Bifenazate (MRID# 448597-01).

Input/Parameter Site: Florida

Bifenazate

Application Rate (lb ai/A) aStudy Target Rate = 0.29 lb 

ai/A

0.29 lb ai/A

Spray Volume (GPA) 5 gallons/1000 ft2

Measured Average Day 0 Residue (μg/cm2) 0.151

Predicted Day 0 Residue (μg/cm2) b0.161

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-Health Risk Assessment DP# 388228

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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 activities 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 (cm2/hr) 

and Associated 

Activity

DFR1

(ug/cm2)

Days After 

Treatment

Daily Dose2

(mg/kg/

day)

MOE3 

Fruiting 

vegetable 

Group 8-10

0.5

1,900

(irrigation; handset)

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; handset)

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/cm2) x TC (cm2/hr) x 0.001 mg/ug x 8 hrs/day xDA (25%)]  body weight (69 kg).

3. MOE = NOAEL (Short- and Intermediate-term NOAEL 80 mg/kg/day)/Daily Dose (LOC=100)). 

Inhalation: Based on the Agency's current practices, a quantitative occupational postapplication 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 rate. However, there are multiple potential sources of postapplication 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/scipoly/SAP/meetings/2009/120109meeting.html). The Agency is in the 

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

data generated by the ARTF and may, as appropriate, develop policies and procedures, to 

identify 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 occupational 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 dermal sensitizer 

by the Magnusson/Kligman method, but not the Buehler method. The 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., D371783.
Bifenazate Human-Health Risk Assessment DP# 388228

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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, D388800.

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

 Memo, 08/16/2001, T. Bloem, D277089.

 Memo, 05/29/2003, T. Bloem, D290053.

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

HASPOC Memo: 

 Memo, J. Van Alstine, 04/17/2012, TXR # 0052356. 

Drinking Water Memo: 

 Memo, 10/17/2011, J. Hetrick, et al., D388230

 Memo, 07/25/2012, J. Hetrick, et al., D402952

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

Appendix 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: RAB1
Bifenazate Human-Health Risk Assessment DP# 388228

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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) guideline 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)........

870.5385 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

yes
Bifenazate Human-Health Risk Assessment DP# 388228

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A.2 Toxicity Profiles

Guideline

No. Study Type MRID # Results Toxicity Category

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

870.1200 Acute Dermal 44464936 LD50 > 5000 mg/kg IV

870.1300 Acute Inhalation 44464937 LC50 > 4.4 mg/L IV

870.2400 Primary Eye Irritation 44464938 slight irritation IV

870.2500 Primary Skin Irritation 44464939 slight irritation IV

870.2600 Dermal Sensitization 45385101 dermal sensitizer Magnusson/Kligman

870.2600 Dermal Sensitization 44464940 not a dermal sensitizer Buehler

Table 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 gravity, and decreased urinary 

volume in both sexes, and increased incidence 

of extramedullary hematopoiesis in the spleen 

in both sexes.

870.3465 28-Day

inhalation 

toxicity (rat)

48723301 (2012)

Acceptable/Guideline

0, 0.03, 0.075, 0.15 mg/L 

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

(0, 7.83, 19.58, 39.15 

mg/kg/day [M/F])

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

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

red material around the nose in females, lower 

body weights and weight gains, decreased food 

consumption, decreased heart and thymus 

weights in females, increased incidences of 

mild brown pigmentation of the spleen, and 

minimal to mild degeneration of the olfactory 

epithelium within nasal levels III, IV, and V.

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

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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

Maternal NOAEL = 200 mg/kg/day.

LOAEL = not established; doses for the main 

study were selected based on a range-finding 

study in which groups of 5 rabbits each 

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

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

gavage. Maternal toxicity was seen as 

increased deaths and decreased body weight at 

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

increase in the number of does aborting was 

seen at 250 mg/kg/day and above.

Developmental NOAEL = 200 mg/kg/day.

LOAEL = not established; due to only one or 

two litters available in each of the treated 

groups in the range finding study, a clear 

assessment of developmental toxicity was not 

possible. Based on these results, doses of 10, 

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

main study.

870.3800 Reproduction 

and fertility 

effects

(rat)

45076503 (1999)

Acceptable/Guideline

0, 20, 80, or 200 ppm

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

15.3/17.2 mg/kg/day in 

the P animals [M/F], and 

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

17.4/19.4 mg/kg/day in F1

animals [M/F], 

respectively)

Parental/Systemic NOAEL = 20 ppm (1.6/1.8

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

LOAEL = 80 ppm (equivalent to 6.5/7.4 

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

weights and cumulative body-weight gains in 

males and females.

Reproductive NOAEL 2 00 ppm (16.4/18.3 

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

LOAEL = not observed.

Offspring NOAEL 200 ppm (16.4/18.3 

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

LOAEL = not observed.

870.4100b Chronic toxicity 

(dog)

45052221 (1999)

Acceptable/Guideline

0, 40, 400, or 1000 ppm 

(0/0, 1.014/1.051, 

8.949/10.422, 

23.942/29.192 mg/kg/day 

[M/F])

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

[M/F]).

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

[M/F]) based on hematological and clinical 

chemistry parameters and histopathological 

changes in the bone marrow, liver, and kidney.

870.4200b 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 gains.

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.
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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-Health Risk Assessment DP# 388228

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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 mg/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 highdose groups. As a result of this rapid 

turnaround, no significant tissue accumulation 

of the test material was found. The highest 

tissue levels were found in the liver and whole 

blood, although the concentration of the test 

material represented <3% of the administered 

dose 6 hours after treatment. Comparison of 

the whole blood and red blood cell 

concentrations suggests that most of the test 

material was carried in the plasma.

The feces were the primary elimination route 

for low-dose rats with ~66% of the 

administered dose recovered in this media. 

Radioactivity in the feces was greater for the 

high-dose rats (823%) due to saturated 

absorption that resulted in subsequently greater 

unabsorbed test material. Urinary excretion 

was a relatively minor route with ~25% of the 

administered dose recovered in this media for 

both male and female 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. 

Cmax was reached earlier following a 10 mg/kg 

dose (5-6 hours) than the 1000 mg/kg dose (18-

24 hours). In addition, t1⁄2 was slightly longer at 

the 1000 mg/kg dose (12-16 hours) than at the 

10 mg/kg dose (12-13 hours). No apparent sexrelated 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 of 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 derivation 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/delivered dose. This adjustment is influenced by the 
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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 of 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:

PODstudy: Point of departure identified in the critical toxicology study.

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

Danticipated 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 (σg), which is 

then used to determine the RDDR. The RDDR is a multiplicative factor used to adjust 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.

RDDRr = (RDDr/Normalizing Factor)A

 (RDDr/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 σg 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 Concentrations 

and Application of Inhalation Dosimetry.” 

Regional Deposited Dose Ratio (RDDR) for Bifenazate:

MMAD = 2.20

Sigma g = 2.78

 Body Minute 

SPECIES Weight (g) Ventilation (VE, ml) 

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

 rat 204 171.5 

 human 70000 13800.0 

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

 Extrathoracic 

HEC = POD *

D 

D 

*

W

W

study * RGDR animal exposure (hrs/ day)

human exposure (hrs/ day)

animal exposure (days / wk)

human exposure (days/ wk)
Bifenazate Human-Health Risk Assessment DP# 388228

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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 fractionanimal/deposited fractionhuman

= (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 Residential Exposure:

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

HEC = NOAELstudy * (daily duration of exposureanimal/daily duration of exposurehuman) * (days/week of 

exposureanimal/days/week of exposurehuman) * 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: 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.

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 
Bifenazate Human-Health Risk Assessment DP# 388228

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default body weights and respiratory volumes. An activity factor is used 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 = 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 residential 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 = NOAELstudy * (daily duration of exposureanimal/daily duration of exposurehuman) * (days/week of 

exposureanimal/days/week of exposurehuman) * 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-Health Risk Assessment DP# 388228

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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 weights and respiratory volumes. An activity factor is used 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 = 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 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 (bystander) 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 

formulation-application method combination, is estimated by multiplying the formulation-
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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 = exposure (mg/day);

UE = unit exposure (mg/lb ai);

AR = application rate (e.g., lb ai/ft2, lb ai/gal); and

A = area treated or amount handled (e.g., ft2/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 calculated as shown below. Residential post-application exposure 

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 = DFRt * CF1 * TC * ET

where:

E = exposure (mg/day);

DFRt = dislodgeable foliar residue on day "t" (μg/cm2);

CF1 = weight unit conversion factor (0.001 mg/μg);

TC = transfer coefficient (cm2/hr); and

ET = exposure time (hrs/day).

In the absence of chemical-specific data, DFRt can be calculated as follows:

DFRt = AR * FAR * (1-FD)

t

* CF2 * CF3

where:

DFRt = dislodgeable foliar residue on day "t" (μg/cm2);
Bifenazate Human-Health Risk Assessment DP# 388228

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AR = application rate (lbs ai/ft2or lb ai/acre);

FAR = fraction of ai as dislodgeable residue following application (unitless);

FD = 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 108μg/lb); and

CF3 = area unit conversion factor (1.08 x 10-3ft2/cm2or 2.47 x 10-8acre/cm

2

).

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

BW

E AF D*



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]

FAR

DFR following application, if chemical-specific is unavailable

(fraction) 0.25

FD

Daily residue dissipation, if chemical-specific is unavailable

(fraction) 0.10

TC

Transfer 

Coefficient

(cm2/hr)

Gardensa 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 activitiesb

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 adjustment. 
Bifenazate Human-Health Risk Assessment DP# 388228

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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 given scenario (mg ai/kg/day),

E = exposure (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 an 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) to 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 Typea 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

Fruiting vegetable 0.5 1

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, D388802)
Bifenazate Human-Health Risk Assessment DP# 388228

Page 52 of 53

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 greenhouses, 

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). 

Florimite® 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 days 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 μg/sample (after correction for 

68 percent field recovery), found on DAT-1 after the first application. DFR values did 

not decline to <LOQ (i.e. 2 μg/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 (R2= 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 ft2

Measured Average Day 0 Residue (μg/cm2) 0.151

Predicted Day 0 Residue (μg/cm2) b0.161

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 herbs 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 53 of 53

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 watersoluble 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/cm3

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 10-8atm M3/mole (25°C)

Dissociation constant (pKa) 12.94 at 23 C

Octanol/water partition coefficient Log(KOW) 3.4

UV/visible absorption spectrum Max 264 nm in water

NA = not available.