Bifenazate HED Human-Health Risk Assessment DP#: D371783 

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460 

OFFICE OF 

CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

MEMORANDUM

Date: 14-July-2010 

Subject: Bifenazate (000586); Petition to Add New Uses on: Avocado, Tropical Fruits (Sugar 

Apple, Cherimoya, Atemoya, Custard Apple, Ilama, Soursop, and Biriba), Small Vine 

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

Human-Health Risk Assessment. 

PC Code: 000586 DP Barcode: D371783 

Decision No.: 423556 Registration No.: 400-514 

Petition No.: 9E7642 Regulatory Action: Amended Section 3 

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 

Mary Clock-Rust, Biologist 

Risk Assessment Branch 1 (RAB1) 

Health Effects Division (HED, 7509P) 

Through: Dana Vogel, Branch Chief 

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

RAB1/HED (7509P) 

To: Barbara Madden, RM 05 

Registration Division (RD, 7505P) 

RD of the Office of Pesticide Programs (OPP) 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 all 

registered and proposed uses of bifenazate. A summary of the findings is provided in this 

document. The risk assessment, residue chemistry review, and dietary exposure assessment 

were provided by William Wassell of RAB1; the hazard characterization was provided by 

Anwar Dunbar of RAB1; the occupational/residential exposure and risk assessment was 

provided by Mary Clock-Rust of RAB1; and the drinking water assessment was provided by 

A. Al-Mudallal and M. Corbin of the Environmental Fate and Effects Division (EFED). 

NOTE: In 2003, HED completed a Section 3 risk assessment for the application of 

bifenazate to fruiting vegetables, cucurbit vegetables, tree nuts pistachio, okra, and 

mint (D286170, T. Bloem et al., 05/30/2003). The current document contains only those 

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Bifenazate HED Human-Health Risk Assessment DP#: D371783 

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aspects of the risk assessment which are affected by the addition of the proposed 

bifenazate uses. 
Bifenazate HED Human-Health Risk Assessment DP#: D371783 

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Table of Contents 

1.0 EXECUTIVE SUMMARY .....................................................................................................4 

2.0 PHYSICAL/CHEMICAL PROPERTIES.............................................................................9 

3.0 HAZARD CHARACTERIZATION ....................................................................................10 

3.1 Endocrine Disruption ......................................................................................................13 

3.2 Residues of Concern for Dietary Risk Assessment.......................................................13 

4.0 EXPOSURE ASSESSMENT AND CHARACTERIZATION...........................................14 

4.1 Summary of Registered Uses..........................................................................................14 

4.2 Summary of Proposed Uses ............................................................................................14 

4.3 Dietary Exposure/Risk Pathway.....................................................................................15 

4.4 Water Exposure/Risk Pathway.......................................................................................18 

4.5 Dietary Exposure Analysis..............................................................................................18 

4.6 Residential Exposure and Risk Assessment ..................................................................19 

4.7 Non-occupational Off-Target Exposure ........................................................................20 

5.0 AGGREGATE RISK ASSESSMENTS AND RISK CHARACTERIZATION................20 

6.0 CUMULATIVE RISK...........................................................................................................21 

7.0 OCCUPATIONAL EXPOSURE AND RISK ASSESSMENT..........................................21 

7.1 Handler Exposure and Risk Assessment .......................................................................21 

7.2 Postapplication Inhalation Exposure .............................................................................24 

7.3 REI ....................................................................................................................................24 

8.0 DEFICIENCIES.....................................................................................................................24 

8.1 Toxicology.........................................................................................................................24 

8.2 Residue Chemistry...........................................................................................................24 

8.3 Occupational/Residential ................................................................................................24 

Attachment 1: Chemical Structures...........................................................................................26 

Attachment 2: Toxicity Profile of Bifenazate Technical. .........................................................27 

Attachment 3: Percent Crop-Treated Data used for Bifenazate.............................................29 
Bifenazate HED Human-Health Risk Assessment DP#: D371783 

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1.0 EXECUTIVE SUMMARY

Bifenazate (1-methylethyl 2-(4-methoxy[1,1’-biphenyl]-3-yl) hydrazinecarboxylate) is a 

selective miticide/insecticide which controls the motile stage of mites either by direct contact or 

through contact with foliar residues. Bifenazate blocks or closes the GABA (gammaaminobutyric acid)-activated chloride channels of susceptible pests resulting in over-excitation 

of the peripheral nervous system. 

Bifenazate is the active ingredient (ai) in Acramite® 50WS (formulated as a wettable-powder 

(WP) in water-soluble bags (WSB)). Bifenazate is currently registered for application to 

numerous commodities including ornamental plants, pome fruit, fruiting vegetables, cucurbit 

vegetables, tree nuts, tuberous and corm vegetables, legume vegetables, tropical fruits, nectarine, 

peach, plum, grape, and strawberry. Tolerances are established for residues of bifenazate and its 

metabolite D3598 diazinecarboxylic acid, 2-(4-methoxy-[1,1’-biphenyl]-3-yl, 1-methylethyl 

ester (expressed as bifenazate) ranging from 0.1 to 35 ppm (40 CFR 180.572(a)(1)). Section 18 

registrations have also been established for application of bifenazate to cherry, soybean, tomato, 

potato, and timothy with tolerances ranging from 0.05 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), on behalf of the IR-4 Project and Agricultural 

Experiment Stations of FL, PR, and MA has submitted a petition, PP#9E7642, proposing the 

establishment of permanent tolerances for residues of the insecticide bifenazate and its 

metabolite D3598 in/on the following raw agricultural commodities: 

Sugar Apple ..................................................................1.5 ppm 

Cherimoya.....................................................................1.5 ppm 

Atemoya........................................................................1.5 ppm 

Custard Apple ...............................................................1.5 ppm 

Ilama .............................................................................1.5 ppm 

Soursop .........................................................................1.5 ppm 

Biriba ............................................................................1.5 ppm 

Avocado ........................................................................7.0 ppm 

Fruit, Small, Vine Climbing, Subgroup 13-07F, 

Except Fuzzy Kiwifruit...............................................0.75 ppm 

Berry, Low-Growing, Subgroup 13-07G......................1.5 ppm 

Concurrently, IR-4 requests the amendment of the end-use product label for Acramite® 50 WS 

(EPA Reg. No. 400-503), a 50% WP formulation, to include new uses on avocado, tropical fruits 

(sugar apple, cherimoya, atemoya, custard apple, ilama, soursop, and biriba), subgroup 13-07F 

(small vine climbing fruit: grape, amur river grape, gooseberry, hardy kiwifruit, maypop, 

schisandra berry; and cultivars, varieties and/or hybrids of these, except fuzzy kiwifruit), and 

subgroup 13-07G (low-growing berry: strawberry, bearberry, bilberry, low-bush blueberry, 

cloudberry, cranberry, ligonberry, muntries, partridgeberry, cultivars, varieties and/or hybrids of 

these). The product is proposed for two foliar spray applications on the crops listed above with 

the exception of subgroup 13-07F for which one application is proposed using ground equipment 
Bifenazate HED Human-Health Risk Assessment DP#: D371783 

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at a maximum seasonal rate of 2.0 pounds active ingredient per acre (lb ai/A). The proposed preharvest intervals (PHIs) range from 1 to 14 days. 

Hazard Assessment: The acute toxicity data for bifenazate show that this chemical has low 

acute toxicity by the oral, inhalation, or dermal routes of exposure (Acute Toxicity Categories 

IV). It is minimally irritating to the eye (Acute Toxicity Category IV) and slightly irritating to 

the skin (Acute Toxicity Category IV). Bifenazate is a dermal sensitizer by the 

Magnusson/Kligman method, but not the Buehler method. 

Subchronic and chronic studies in rats and dogs indicate that the liver and hematopoietic system 

(spleen and/or bone marrow with associated hematological findings) are the primary target 

organs in these species, with additional toxicity in the kidney (chronic dog) and adrenal gland 

(male rats) also identified. Similarly, the hematopoietic system (spleen) was the primary target 

organ in the repeat-dose dermal toxicity study. Also associated with this toxicity in several 

studies were decreased body weight, body-weight gain, and food consumption. No evidence of 

carcinogenicity was seen in the rat and mouse studies and the HED Hazard Identification 

Assessment Review Committee (HIARC) classified bifenazate as "not likely" to be a human 

carcinogen by any relevant route of exposure. A full battery of mutagenicity studies were 

negative for mutagenic or clastogenic activity. The developmental studies in rats and rabbits did 

not demonstrate increased sensitivity of fetuses to bifenazate. Similarly, increased qualitative or 

quantitative susceptibility to offspring were not observed with bifenazate during pre- or postnatal 

development in the reproduction study. There was no evidence of neurotoxicity (clinical signs 

or neuropathology) in any of the toxicology studies conducted with bifenazate. A bifenazate 

developmental neurotoxicity (DNT) study was not required by the HIARC. It should be noted 

that bifenazate contains a hydrazine moiety as part of its chemical structure. This side chain is 

structurally similar to unsymmetrical dimethyl hydrazine (UDMH or 1,1-dimethylhydrazine), a 

B2 animal carcinogen (possible human carcinogen). Carcinogenicity studies performed with 

bifenazate in rats and mice did not result in any carcinogenic effects at a maximum dose of 10 

mg/kg/day and 35 mg/kg/day, respectively. The rat, livestock, and plant metabolism studies 

indicate that metabolism of bifenazate proceeds via oxidation of the hydrazine moiety of 

bifenazate to form D3598. The chemical structure of D3598 shows that the hydrazine structure 

is converted to a diazene moiety. D3598 is then metabolized to D1989 (methoxy biphenyl) and 

to bound residues by reaction with natural products. The petitioner proposed that the 

degradation route for D3598 to D1989 involved the formation of N2 and CO2 and not biphenyl 

hydrazine. The HED Metabolism Assessment Review Committee (MARC) reviewed the 

petitioner’s proposed degradation route and agreed that formation of free biphenyl hydrazine or 

other hydrazines is unlikely due to oxidation of the parent to the diazene metabolite. The MARC 

did suggest that if a future metabolism study is submitted, the petitioner should monitor for 

biphenyl hydrazine. Subsequently, Crompton Corporation submitted a radish metabolism study 

which did not result in the identification of biphenyl hydrazine. Based on the radish metabolism 

study, the lack of carcinogenic effects in the bifenazate carcinogenicity studies, and since 

biphenyl hydrazine was not identified in the excreta in the rat metabolism study, HED concluded 

that issues concerning the formation of hydrazine(s) in plants and livestock have been addressed. 

 The toxicological profile for bifenazate is included as Appendix 2. 

Dose-Response Assessment: The HIARC met on four occasions to examine the toxicology 

database for bifenazate and to determine the appropriate toxicological endpoints for dietary and 

occupational/residential exposure assessment (meeting dates: 08/21/01 (TXR No. 0014658), 
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04/24/01 (TXR No. 0014576), 04/13/99 (TXR No. 0013335), and 02/04/99 (TXR No. 0013277)). 

The HIARC found the toxicological database to be complete with the exception of a 28-day 

inhalation study. Based on toxicological considerations and the conservative assumptions used 

when generating the dietary, water, and residential exposure estimates, HED concludes that the 

Food Quality Protection Act Safety Factor (FQPA SF) may be reduced to 1x. 

Bifenazate has been classified as “not likely” to be a human carcinogen by any relevant route of 

exposure and an acute dietary endpoint was not identified for the general population including 

infants and children; therefore, acute dietary and cancer exposure assessments were not 

conducted. The RAB1 risk assessment team concluded that based on toxicological 

considerations and the residue assumptions used in the dietary and residential exposure analyses, 

the FQPA SF may be reduced to 1x. Since the FQPA SF has been reduced to 1x, the total 

uncertainty factor for all exposure assessments is 100x (10x for interspecies extrapolation and 

10x for intraspecies variation). Oral studies were selected for all durations of inhalation 

exposure assessment and the HIARC determined that a 100% inhalation-absorption factor is 

appropriate for route-to-route extrapolation. Since a dermal study was selected for all durations 

of dermal-exposure assessment, a dermal-absorption factor is not necessary. Oral, dermal, and 

inhalation exposures can be aggregated based on common endpoints (changes in body weights 

and body-weight gains, and hematological effects). Exposure assessments were conducted for 

the specific scenarios listed below. 

Table 1.0. Summary of Toxicological Endpoints used in the Current Risk Assessment1. 

Chronic dietary NOAEL = 1.0 mg/kg/day chronic RfD and cPAD = 0.01 mg/kg/day 

Short-term incidental oral NOAEL = 10 mg/kg/day LOC for MOEs ≤100 

Dermal (all durations) dermal NOAEL = 80 mg/kg/day LOC for MOEs ≤100 (occupational/residential)1

Short-term inhalation oral NOAEL = 10 mg/kg/day2 LOC for MOEs ≤100 (occupational/residential)1

Intermediate-term inhalation oral NOAEL = 0.9 mg/kg/day2 LOC for MOEs ≤100 (occupational/residential)1

1 NOAEL = no-observable-adverse-effect-level; RfD = reference dose = NOAEL ÷ 100; PAD = population-adjusted dose 

= RfD ÷ FQPA SF; LOC = level of concern; MOE = margin of exposure = NOAEL ÷ exposure. 2 100% inhalation absorption factor. 

Exposure Assessment

Residential Exposure: HED previously reviewed and approved homeowner application of 

Floramite SC (EPA Reg. No. 400-508) to ornamentals and non-bearing fruit trees. Based on the 

proposed use patterns, only short-term dermal and inhalation exposure are expected for 

homeowner applicators (exposures calculated using the 12/18/99 HED Draft Residential 

Standard Operational Procedures (SOPs)). The individual and aggregate margins of exposure 

(MOEs, 4,200) are not of concern. Post-application exposure is anticipated to be negligible and 

was not assessed (Memo, M. Dow and D. Vogel, 08/15/02, D284802). 

Dietary Food Exposure: Chronic dietary risk assessments were conducted using the Dietary 

Exposure Evaluation Model - Food Consumption Intake Database (DEEM-FCIDTM, ver. 2.03). 

DEEM-FCIDTM incorporates the food consumption data from the United States Department of 

Agriculture’s (USDA’s) Continuing Surveys of Food Intakes by Individuals (CSFII; 1994-1996 

and 1998). The chronic analyses incorporated tolerance-level residues for all commodities 

excluding squash, peach, and tomato (average field-trial residues were assumed) and milk (the 

tolerance level was adjusted upward to account for all of the residues of concern for risk 

assessment). The chronic analyses incorporated average percent crop-treated (%CT) information 
Bifenazate HED Human-Health Risk Assessment DP#: D371783 

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provided by the Biological Economic Analysis Division (BEAD; 09/18/2008). DEEMTM (ver. 

7.81) default processing factors were assumed for all commodities excluding apple juice, grape 

juice, wine/sherry, tomato paste, and tomato puree. The processing factors for these 

commodities were reduced to 0.23, 0.17, 0.17, 1, and 1, respectively, based on data from 

processing studies. The analyses also included the chronic surface water point estimate 

generated using the FQPA Index Reservoir Screening Tool (FIRST) and the dry bean application 

scenario (2 x 0.75 lb ai/acre; 14-day retreatment interval (RTI); highest registered/proposed rate, 

09/30/08, A. Al-Mudallal, D349290). The chronic exposure estimates are 30% of the chronic 

population-adjusted dose (cPAD) for the U.S. Population. The most highly-exposed population 

subgroup was children 1 to 2 years old which utilized 81% of the cPAD. 

Occupational Exposure Estimates: All potential exposure scenarios associated with the new 

uses have already been assessed previously by HED. For all use sites, only one application is 

permitted per season, with the exception of strawberries, which are limited to one application per 

crop (minimum of 21 days between applications). Risk estimates are provided for the short-term 

duration (1-30 days), and all handler MOEs are above 100 and not of concern to HED. For postapplication, all MOEs are above 100 and not of concern with the exception of grapes, which 

result in an MOE for the high-exposure post-application activities (tying, turning and girdling). 

The interim Worker-Protection Standard (WPS) restricted-entry interval (REI) of 5 days is 

necessary for grapes and is already on Acramite® 50WS labels. 

Bifenazate is classified in Acute Toxicity Category IV for acute dermal toxicity, acute inhalation 

toxicity, primary eye irritation and primary skin irritation. It is not a dermal sensitizer. 

Therefore, the interim WPS REI of 12 hours is sufficient to protect agricultural workers from 

postapplication exposures to bifenazate. 

Aggregate Exposure Assessment: In general, aggregate exposures are calculated by summing 

dietary (food and drinking water) and residential exposures (residential or other non-occupational 

exposures). Based on the anticipated residential exposure scenarios and since acute and cancer 

risk assessments are not required, only short-term (residential, food, and drinking water) and 

chronic (food and drinking water) aggregate exposure assessments were conducted. Since the 

short-term aggregate MOEs are ≥1800 for all population subgroups, short-term aggregate 

exposure to bifenazate is not of concern. Additionally, aggregate chronic (food and water) 

exposures were ≤81% the cPAD for all population subgroups as a result of all registered/proposed 

uses. Thus, chronic aggregate exposure to bifenazate is not of concern. 

Environmental-Justice Considerations: 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://www.hss.energy.gov/nuclearsafety/env/guidance/justice/eo12898.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 CSFII and are used in pesticide risk assessments for all registered food uses 
Bifenazate HED Human-Health Risk Assessment DP#: D371783 

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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 post-application 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. 

Review of Human Research Data: This risk assessment relies in part on data from studies in 

which adult human subjects were intentionally exposed to a pesticide to determine their dermal 

and inhalation exposure. Many such studies, involving exposure to many different pesticides, 

comprise generic pesticide exposure databases such as Pesticide Handlers Exposure Database 

(PHED), Outdoor Residential Exposure Task Force (ORETF), and the Agricultural Reentry Task 

Force (ARTF) databases. EPA has reviewed all the studies in these multi-pesticide generic 

exposure databases, and on the basis of available evidence has found them to have been neither 

fundamentally unethical nor significantly deficient relative to standards of ethical research 

conduct prevailing when they were conducted. There is no regulatory barrier to continued 

reliance on these studies, and all applicable requirements of EPA’s Rule for the Protection of 

Human Subjects of Research (40 CFR Part 26) have been satisfied. 

Recommendation for Tolerances and Registration: Pending submission of a revised Section F, 

there are no residue chemistry, occupational/residential exposure, or toxicology issues that 

would preclude granting a conditional registration for use of this miticide/insecticide on the 

crops requested or the establishment of permanent tolerances for residues of the insecticide 

bifenazate, including its metabolites and degradates, in or on the commodities listed below. 

Compliance with the tolerance levels specified below is to be determined by measuring only the 

sum of bifenazate (1-methylethyl 2-(4-methoxy[1,1’-biphenyl]-3-yl) hydrazinecarboxylate) and 

its metabolite diazinecarboxylic acid, 2-(4-methoxy-[1,1’-biphenyl]-3-yl, 1-methylethyl ester, 

calculated as the stoichiometric equivalent of bifenazate. 

Sugar Apple ..................................................................1.6 ppm 

Cherimoya.....................................................................1.6 ppm 

Atemoya........................................................................1.6 ppm 

Custard Apple ...............................................................1.6 ppm 

Ilama .............................................................................1.6 ppm 

Soursop .........................................................................1.6 ppm 

Biriba ............................................................................1.6 ppm 

Avocado ........................................................................7.0 ppm 

Fruit, Small, Vine Climbing, Subgroup 13-07F, 

Except Fuzzy Kiwifruit.................................................1.0 ppm 

Berry, Low-Growing, Subgroup 13-07G......................1.5 ppm 

Additionally, tolerances for residues of bifenazate in grapes and strawberry should be deleted as 

these crops are covered by the subgroup tolerances. 
Bifenazate HED Human-Health Risk Assessment DP#: D371783 

An immunotoxicity study, a 28-day inhalation study, and acute and subchronic neurotoxicity 

studies are required as conditions of registration. 

2.0 PHYSICAL/CHEMICAL PROPERTIES 

Bifenazate is a selective miticide which controls the motile stage of mites either by direct 

contact or through contact with foliar residues. The petitioner indicated that bifenazate 

blocks or closes the GABA-activated chloride channels of susceptible pests resulting in 

over-excitation of the peripheral nervous system. 

Table 2.1. Nomenclature of Bifenazate and its Metabolite D3598.

Compound 

O

N

H

N

H

O CH3

O CH3

CH3

Common name Bifenazate 

Company experimental name D2341 

IUPAC name 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 50® WS (50% WP; EPA Reg. No. 400-503) 

Compound 

O

N

N O CH3

O CH3

CH3

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 

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Table 2.2. Physicochemical Properties of the Technical Grade of Bifenazate.

Melting range 124-125 oC 

pH 6.78 

Density 1.19 g/cm3 

Water solubility 2.1 mg/L (20 °C) 

Solvent solubility 102 mg/mL ethyl acetate (20 °C) 

Vapor pressure <1 x 10-7 mm HG (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 

MRID 46064101 

3.0 HAZARD CHARACTERIZATION 

A detailed hazard characterization for bifenazate was presented in a previous HED risk 

assessment (D286170, T. Bloem et al., 05/30/03) and a summary of the bifenazate toxicological 

profile is provided in the executive summary. The HIARC met on four occasions to examine the 

toxicology database for bifenazate and to determine the appropriate toxicological endpoints for 

dietary and occupational/residential exposure assessment (meeting dates: 08/21/01 (TXR No. 

0014658), 04/24/01 (TXR No. 0014576), 04/13/99 (TXR No. 0013335), and 02/04/99 (TXR No. 

0013277)). As expressed in a waiver request response (Memo, 04/28/10, A. Dunbar et al., 

D376122) HED is requiring the 28-day inhalation toxicity study for the following reasons: 

• The low vapor pressure of this active ingredient (<1 x 10-7 mm Hg @ 25°) is irrelevant 

because of how the product is used. 

• Bifenazate is a wettable powder that is mixed with a liquid vehicle and then sprayed 

(aerosolized) in greenhouses, shadehouses, and nurseries; and on field-, landscape-, and 

interiorscape-grown ornamentals. 

• Extensive indoor spraying is a particular inhalation concern. 

• Because there is the potential for extensive human exposure to the aerosol particles, an 

inhalation risk assessment will be needed. This will require an appropriate inhalation 

toxicity study. 

Food Quality Protection Act Safety Factor Considerations: 

The RAB1 risk assessment team concluded that based on toxicological considerations and the 

residue assumptions used in the dietary and residential exposure analyses, the FQPA SF may be 

reduced to 1x. This recommendation is based on the following considerations: 

• There are no residual uncertainties in the toxicity database. The bifenazate toxicological 

database is complete with the exception of an inhalation study, acute and subchronic 

neurotoxicity studies, and an immunotoxicity study. The toxicology database for 

bifenazate does not indicate that the immune system is the primary target organ. The 

observed effects on the immune system have been well characterized and were seen at 

dose(s) that produce evidence of overt systemic toxicity. These effects included increased 
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spleen weight in females and histopathological changes in the spleen in males in a 90-day 

oral rat toxicity study, extramedullary hematopoiesis in the both sexes in a 21-day dermal 

toxicity study in rats, and changes in hematological parameters, clinical chemistry 

parameters in both sexes and histopathological effects in bone marrow (compensatory 

hyperplasia), liver, and kidney in both sexes in a 1-year chronic toxicity study. The overall 

weight of evidence suggests that bifenazate does not directly target the immune system, 

and these findings may be due to hematotoxicity (toxicity to red blood cells). Further, 

there is no evidence of neurotoxicity or neuropathology in the bifenazate database. 

Therefore, although immunotoxicity and acute and subchronic neurotoxicity studies are 

now required as a part of new data requirements in the 40CFR §158 for conventional 

pesticide registration, the Agency does not believe that conducting these studies will result 

in a lower point of departure (POD) than that currently used for overall risk assessment, 

and therefore, a database uncertainty factor (UFDB) is not needed to account for lack of 

these studies. 

• A 28-day inhalation study is not available; however, the EPA has determined that the 

additional FQPA safety factor is not needed. Residential inhalation risk was estimated by 

calculating exposure using the Agency's Residential SOPs. For chemicals with low vapor 

pressure (7.5 x 10-5 mmHg or below for outdoor uses at 20-300

C) these standard 

assumptions are expected to overestimate the exposure via the inhalation route. Bifenazate 

is such a compound (<1 x 10-7 mmHg at 250C) and exposure through the inhalation route is 

expected to be minimal. Therefore, the risk estimate is conservative and is considered 

protective and the additional FQPA SF is not needed. 

• Since all calculated inhalation MOEs for residential handlers are significantly greater 

than the level of concern (MOE >100), the lack of an inhalation study will not impact the 

FQPA SF. 

• There is no quantitative or qualitative evidence of increased susceptibility of rats or 

rabbit fetuses to in utero exposure in developmental studies, nor following pre/post-natal 

exposure to rats in the two generation reproduction study. 

• A developmental neurotoxicity study (DNT) is not required because there is no evidence 

of neurotoxicity or neuropathology in the bifenazate database. 

• The dietary food and drinking water exposure assessments will not underestimate the 

potential exposures for infants and children; and the residential use (ornamentals) is not 

expected to result in post-application exposure to infants and children. 
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Table 3.0. Summary of Toxicological Dose and Endpoints for Bifenazate. 

Exposure 

Scenario 

Dose Used in Risk 

Assessment, UF 

FQPA SF and LOC 

for Risk Assessment Study and Toxicological Effects 

Acute Dietary; all 

populations 

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

endpoint attributed to a single dose. 

Chronic Dietary; 

all populations 

NOAEL = 1.0 mg/kg/day 

UF = 100 

cRfD = 0.01 mg/kg/day 

FQPA SF = 1x 

cPAD = 0.01 

mg/kg/day 

Chronic Toxicity in Dogs 

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

based on changes in hematological 

and clinical chemistry parameters, 

and histopathology in bone marrow, 

liver, and kidney in the one-year dog 

feeding study. 

Incidental Oral, Short 

Term (1-30 days) 

oral NOAEL = 

10 mg/kg/day 

LOC for MOE ≤100 

residential and 

occupational 

Prenatal Developmental in Rats 

Maternal LOAEL = 100 mg/kg/day 

based on clinical signs, decreased 

body weight and food consumption 

during the dosing period in the rat 

developmental study. 

Incidental Oral, 

Intermediate Term (30 

days-six months) 

oral NOAEL = 

0.9 mg/kg/day 

LOC for MOE ≤100 

residential and 

occupational 

90-Day Oral Toxicity non-RodentsDog 

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

based on changes in hematologic 

parameters in the 90-day subchronic 

dog study. 

Short-, Intermediateand Long-Term Dermal 

(1-30 days, 30 days-six 

months, and six months 

to lifetime) 

dermal NOAEL = 

80 mg/kg/day 

LOC for MOE ≤100 

residential and 

occupational 

21-Day Dermal Toxicity-Rat 

LOAEL = 400 mg/kg/day based on 

decreased body weight and food 

consumption, hematologic effects, 

increased spleen weight and 

extramedullary hemapoiesis in the 

spleen in the 21-day dermal toxicity 

study in rats. 

Short-Term 

Inhalation (1-30 days) 

oral NOAEL = 

10 mg/kg/day 

Inhalation absorption rate 

= 100% 

LOC for MOE ≤100 

residential and 

occupational 

Prenatal Developmental in Rats 

maternal LOAEL = 100 mg/kg/day 

based on clinical signs, decreased 

body weight and food consumption 

during the dosing period in the rat 

developmental study. 

Intermediate-Term 

Inhalation (30 days-six 

months) 

oral NOAEL = 

0.9 mg/kg/day 

inhalation absorption rate 

= 100% 

LOC for MOE ≤100 

residential and 

occupational 

90-Day Oral Toxicity non-RodentsDog 

LOAEL = 10.4/10.7 mg/kg/day based 

on changes in hematologic 

parameters in the 90-day dog feeding 

study. 

Long-Term Inhalation 

(six months-lifetime) 

oral study NOAEL = 

1.0 mg/kg/day 

inhalation absorption rate 

= 100% 

LOC for MOE ≤100 

residential and 

occupational 

Chronic Toxicity in Dogs 

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

based on changes in hematological 

and clinical chemistry parameters in 

both sexes and histopathological 

effects in bone marrow 

(compensatory hyperplasia), liver, 

and kidney in both sexes. 

Cancer (oral, dermal, 

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

1

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

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

of concern; MOE = margin of exposure. 
Bifenazate HED Human-Health Risk Assessment DP#: D371783 

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3.1 Endocrine Disruption

As required under FFDCA section 408(p), EPA has developed the Endocrine Disruptor 

Screening Program (EDSP) to determine whether certain substances (including pesticide active 

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

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

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

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

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

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

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

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

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

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

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

group of 67 chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. 

This list of chemicals was selected based on the potential for human exposure through pathways 

such as food and water, residential activity, and certain post-application agricultural scenarios. 

This list should not be construed as a list of known or likely endocrine disruptors. 

Bifenazate was not among the group of 58 pesticide active ingredients on the initial list to be 

screened under the EDSP. Under FFDCA sec. 408(p) the Agency must screen all pesticide 

chemicals. Accordingly, EPA anticipates issuing future EDSP test orders/data call-ins for all 

pesticide active ingredients. 

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

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

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

3.2 Residues of Concern for Dietary Risk Assessment 

A detailed discussion of the metabolism and residue chemistry of bifenazate was included in a 

previous HED risk assessment (D286170, T. Bloem et al., 05/30/03). Table 3.2 is a summary of 

the MARC decisions concerning the residues of concern in plants, livestock, rotational crops, 

and drinking water (D276801, T. Bloem, 08/16/01; D290053, T. Bloem, 05/29/03). 

Table 3.2. Residues for Tolerance Expression and Risk Assessment. 

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 (expressed as parent), 

A1530, A1530-sulfate (expressed as A1530) 

Bifenazate, D3598 (expressed as parent), 

A1530, A1530-sulfate (expressed as A1530) 

and D9569 (milk only) 

Livestock – fat Bifenazate, D3598 (expressed as parent) Bifenazate, D3598 (expressed as parent) 

Rotational Crops Could not be determined1 Could not be determined1

Drinking Water D1989 Not applicable 1

 Based on the results of the confined rotational crop study conducted 0.5 lb ai/acre and the application rate for the registered 

and proposed crops which are likely to be rotated, HED concluded that residues in rotated crops were unlikely and that 

tolerances were unnecessary.
Bifenazate HED Human-Health Risk Assessment DP#: D371783 

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4.0 EXPOSURE ASSESSMENT AND CHARACTERIZATION

Residue Chemistry Memo, pending, W.D. Wassell, D371943. 

Residue chemistry Memo, pending, W.D. Wassell, D380061 

Dietary Exposure Memo, pending, W.D. Wassell, D371941 

Dietary Exposure Memo, pending, W.D. Wassell, D380061 

Memo (drinking water), 09/30/08, A. Al-Mudallal, D349290 

Memo (drinking water), 01/28/10, M. Corbin, et al. D371784 

Memo (residential exposure assessment), 01/12/10, M. Clock-Rust, D371944 

4.1 Summary of Registered Uses

Bifenazate is currently registered for application to pome fruit, fruiting vegetables, cucurbit 

vegetables, tree nuts, tuberous and corm vegetables, legume vegetables, berries, tropical fruits, 

stone fruit, cucurbit vegetables, succulent shelled pea and bean, dry bean seed, grape, strawberry, 

cotton, hops, okra, peppermint, spearmint, succulent shelled soybean with tolerances ranging 

from 0.1 to 35 ppm (40 CFR 180.572(a)(1)). Section 18 registrations have also been established 

for application of bifenazate to cherry, soybean, tomato, potato, and timothy with tolerances 

ranging from 0.05 to 150 ppm (40 CFR 180.572(b)). Tolerances, as a result of secondary 

residues, are established in milk; and the meat, fat, and meat byproducts of cattle, goats, hogs, 

horse, and sheep at 0.02 to 0.10 ppm (40 CFR 180.572(a)(1) and (a)(2)). 

4.2 Summary of Proposed Uses

The petitioner has submitted an undated draft label/Section B for the 50% WP in WSB 

formulation (Acramite® 50 WS; EPA Reg. No. 400-503). A summary of the proposed use 

patterns is detailed in Table4.2. 

Table 4.2. Summary of Proposed Directions for Use of Bifenazate. 

Applic. Timing, 

Type, and Equip. 

Formulation 

[EPA Reg. No.] 

Max. Single 

Applic. Rate 

(lb ai/A) 

Max. No. Applic. 

Per Season 

Max. Seasonal 

Applic. Rate 

(lb ai/A) 

PHI 

(days) 

Avocado

50% WP 

[400-503] 0.38 to 0.5 2 1.0 (implied) 7 

Foliar spray 

Ground Use Directions and Restrictions: Application is to be made in a minimum of 50 gal/A using 

ground equipment. The minimum RTI is 21 days. Application through any type of irrigation 

system is prohibited. 

Small vine climbing fruit (subgroup 13-07F), except fuzzy kiwifruit: grape, Amur river grape, gooseberry, 

hardy kiwifruit, maypop, schisandra berry; and cultivars, varieties and/or hybrids of these. 

50% WP 

[400-503] 0.38 to 0.5 1 0.5 (implied) 14 Foliar spray 

Ground Use Directions and Restrictions: Application is to be made in a minimum of 50 gal/A using 

ground equipment. Application through any type of irrigation system is prohibited. 

Low-growing berry (subgroup 13-07G): strawberry, bearberry, bilberry, low-bush blueberry, cloudberry, 

cranberry, ligonberry, muntries, partridgeberry, cultivars, varieties and/or hybrids of these. 

50% WP 

[400-503] 0.38 to 0.5 2 1.0 (implied) 1 Foliar spray 

Ground and 

Chemigation 

(cranberry only) 

Use Directions and Restrictions: Application is to be made in a minimum of 20 gal/A using 

ground equipment. The minimum RTI is 21 days. With the exception of cranberry, application 

through any type of irrigation system is prohibited. For cranberry only, application in 0.1 to 0.2 

acre inches of water is specified for chemigation application. 
Bifenazate HED Human-Health Risk Assessment DP#: D371783 

Page 15 of 29

Table 4.2. Summary of Proposed Directions for Use of Bifenazate. 

Applic. Timing, 

Type, and Equip. 

Formulation 

[EPA Reg. No.] 

Max. Single 

Applic. Rate 

(lb ai/A) 

Max. No. Applic. 

Per Season 

Max. Seasonal 

Applic. Rate 

(lb ai/A) 

PHI 

(days) 

Tropical fruit: sugar apple, cherimoya, atemoya, custard apple, ilama, soursop, and biriba. 

50% WP 

[400-503] 0.38 to 0.5 2 1.0 (implied) 1 

Foliar spray 

Ground Use Directions and Restrictions: Application is to be made in a minimum of 20 gal/A using 

ground equipment. The minimum RTI is 21 days. Application through any type of irrigation 

system is prohibited. 

The following rotational crop restriction is specified for the 50% WP formulation: Do not plant 

another crop within 30 days after last Acramite® 50WS application due to chances of bifenazate 

residues showing up in rotational crops. 

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

proposed use. 

4.3 Dietary Exposure/Risk Pathway

Enforcement Analytical Method - Plants: 

HPLC Method UCC-D2341 is available as a primary enforcement method for the combined 

residues of bifenazate and its metabolite D3598 in/or plant matrices. The method has undergone 

a successful petition method validation (PMV) and has been forwarded to FDA for inclusion in 

PAM Volume II as a Roman Numeral method. The LOQ and LOD of Method UCC-D2341 are 

0.01 and 0.005 ppm, respectively. In addition, LC/MS/MS Method NCL ME 245 was recently 

submitted as a confirmatory method and has been forwarded to FDA. The LC/MS/MS method 

includes instructions for monitoring two transitional ions (primary transition for quantitation and 

a secondary transition ion for confirmation). 

Enforcement Analytical Method - Livestock: 

Tolerances for secondary residues of bifenazate in or on milk and ruminant meat, fat, and meat 

byproduct are currently established and a method is available for enforcement of these tolerances 

(D281973, T. Bloem, 29-Aug-2002; D281979, T. Bloem, 29-Aug-2002). 

Magnitude of the Residue - Plants: 

IR-4 has submitted field trial data for bifenazate on sugar apple (MRID 47915501). Three field 

trials were conducted in the North American Free Trade Agreement (NAFTA) Growing Zone 13 

(South Florida) during the 2006 growing season. In each trial, the test formulation used was 

Acramite® 50WS (EPA Reg. No. 400-503). At all trials, the treated plots received two foliar 

applications of Acramite® 50WS at a rate of approximately 0.5 lb ai/A. No adjuvants were 

added to the spray mixture. The RTI was 21 days and commercially mature sugar apples were 

collected 1 day after the final application. The results from the trials show that residues of 

bifenazate and D3598 following application of approximately 1.0 lb ai/A and a PHI of 1 day 

ranged from 0.086 ppm to 0.99 ppm. 
Bifenazate HED Human-Health Risk Assessment DP#: D371783 

Page 16 of 29

A summary of residue data from the sugar apple field trials is presented in Table 4.3.1. 

Table 4.3.1. Summary of Residue Data from Crop Field Trials with Bifenazate.

Residue Levels (ppm)1 

Commodity 

Total Applic. 

Rate 

 (lb ai/A) 

PHI 

(days) N Min. Max. HAFT2 Mean Std. Dev3

. 

Sugar apple 0.98 to 1.04 1 6 0.08628 0.9890 0.6087 0.3156 0.3345 1 Residue levels are reported as bifenazate equivalents. 

2 HAFT = highest-average field trial. 

3

 Std. Dev. = standard deviation. 

Avocado:

No residue data were submitted to support the proposed use on avocado; however, the request is 

consistent with guidance provided by the ChemSAC (Minutes of the August 2, 2006 Meeting). 

IR-4 requests data for bifenazate in/on lychee, guava, papaya, and sugar apple be translated to 

avocado. 

Residue data for bifenazate in/on lychee, guava, and papaya were submitted and reviewed in 

conjunction with a previous petition, PP# 6E7167 (Memo, 12/14/07, W.D. Wassell, D337530). 

Residue data for sugar apple were submitted in conjunction with the subject petition. Based 

upon these data, HED has recommended for the establishment of tolerances for bifenazate and its 

metabolite (expressed as bifenazate) in/on lychee at 5.0 ppm, guava at 0.90 ppm, papaya at 7.0 

ppm, and sugar apple at 1.6 ppm. IR-4 has proposed the establishment of a tolerance for 

residues of bifenazate and its metabolite (expressed as bifenazate) in/on avocado at 7.0 ppm. 

Small Vine Climbing Fruit (Subgroup 13-07F), Except Fuzzy Kiwifruit:

No residue data were submitted to support the proposed use on subgroup 13-07F; however, 

grapes are the representative commodity for this subgroup. Residue data for bifenazate and its 

metabolite in/on grapes were submitted and reviewed in conjunction with a previous petition, 

PP# 0F6108 (Memo, 08/16/01, T. Bloem, D277089). Based upon these data, HED 

recommended for the establishment of a tolerance for bifenazate and its metabolite (expressed as 

bifenazate) in/on grape at 0.75 ppm. However, HED has revaluated the data and determined that 

the tolerance for residues on grapes should be harmonized with the Canadian MRL of 1.0 ppm. 

IR-4 has proposed the establishment of a tolerance for residues of bifenazate and its metabolite 

(expressed as bifenazate) in/on subgroup 13-07F at 0.75 ppm. Thus, a revised Section F is 

required. 

Low-Growing Berry (Subgroup 13-07G):

No residue data were submitted to support the proposed use on subgroup 13-07G; however, 

strawberries are the representative commodity for this subgroup. Residue data for bifenazate and 

its metabolite in/on strawberries were submitted and reviewed in conjunction with a previous 

petition, PP# 0F6108 (Memo, 08/16/01, T. Bloem, D277089). Based upon these data, HED has 

recommended for the establishment of a tolerance for bifenazate and its metabolite (expressed as 

bifenazate) in/on strawberry at 1.5 ppm. IR-4 has proposed the establishment of a tolerance for 

residues of bifenazate and its metabolite (expressed as bifenazate) in/on subgroup 13-07G at 1.5 

ppm. 
Bifenazate HED Human-Health Risk Assessment DP#: D371783 

Page 17 of 29

Conclusions: The submitted residue data for sugar apple are adequate and support the 

recommended tolerance for residues of bifenazate and its metabolite (expressed as bifenazate) 

in/on sugar apple, cherimoya, atemoya, custard apple, ilama, soursop, and biriba at 1.6 ppm. The 

residue data for sugar apple were entered into the Agency’s tolerance spreadsheet as specified by 

the Guidance for Setting Pesticide Tolerances Based on Field Trial Data SOP to determine an 

appropriate tolerance level. The results of this determination indicate that a tolerance level of 

1.6 ppm is adequate for residues of bifenazate and its metabolite (expressed as bifenazate) in/on 

sugar apple, cherimoya, atemoya, custard apple, ilama, soursop, and biriba. A revised Section F 

is required. 

IR-4 has proposed the establishment of a tolerance for residues of bifenazate and its metabolite 

(expressed as bifenazate) in/on avocado at 7.0 ppm. This level is the highest tolerance level for 

residues in/on the commodities lychee, guava, sugar apple, and papaya and is supported by 

residue data for these commodities. 

IR-4 has proposed the establishment of a tolerance for residues of bifenazate and its metabolite 

(expressed as bifenazate) in/on small vine climbing fruit (subgroup 13-07F), except fuzzy 

kiwifruit at 0.75 ppm. This level is based upon the established tolerance level for residues in/on 

the representative commodity of this subgroup (grapes) at 0.75 ppm. However, HED has 

revaluated the reside data for grapes and determined that the tolerance for residues on grapes 

should be harmonized with the Canadian MRL of 1.0 ppm. Thus, a revised Section F is 

required. 

IR-4 has proposed the establishment of a tolerance for residues of bifenazate and its metabolite 

(expressed as bifenazate) in/on low-growing berries (subgroup 13-07G) at 1.5 ppm. This level is 

based upon the established tolerance level for residues in/on the representative commodity of 

this subgroup (strawberries) at 1.5 ppm. 

International Harmonization of Tolerances: 

There are currently no established Codex or Mexican maximum residue limits (MRLs) for 

bifenazate on the commodities included in the subject petition; however, Canadian MRLs are 

established for residues of bifenazate and its metabolite diazinecarboxylic acid, 2-(4-methoxy-

[1,1’-biphenyl]-3-yl, 1-methylethyl ester in or on strawberry at 1.5 ppm, grapes at 1.0 ppm and 

raisins at 1.2 ppm. Thus, the tolerance expression is harmonized; the MRL/tolerance level for 

residues in strawberry and raisins are harmonized; and the current MRL/tolerance level for 

residues in grapes is not harmonized. However, HED has revaluated the residue data for grapes 

data and determined that the tolerance for residues on grapes should be harmonized with the 

Canadian MRL of 1.0 ppm. 

Tolerance Summary: 
Bifenazate HED Human-Health Risk Assessment DP#: D371783 

Page 18 of 29

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 proposed tolerance expression is consistent with the bifenazate tolerances 

established in 40 CFR §180.572(a)(1) and reflect the residues of concern as determined by HED 

MARC and the bifenazate review team. The proposed and recommended tolerance levels are 

summarized in Table 4.3.2. A revised Section F is required. 

Table 4.3.2. Tolerance Summary for Bifenazate. 

Commodity Proposed Tolerance 

(ppm) 

Recommended 

Tolerance (ppm) 

Comments; Correct Commodity 

Definition

Sugar Apple 1.5 1.6 Revised Section F required. 

Cherimoya 1.5 1.6 

Atemoya 1.5 1.6 

Custard Apple 1.5 1.6 

Ilama 1.5 1.6 

Soursop 1.5 1.6 

Biriba 1.5 1.6 

Revised Section F required. Data 

translated from sugar apple. 

Avocado 7.0 7.0 Data translated from lychee, guava, 

papaya and sugar apple. 

Fruit, Small, Vine 

Climbing, Subgroup 13-

07F, 

Except Fuzzy Kiwifruit 

0.75 1.0 Data translated from grapes. 

Berry, Low-Growing, 

Subgroup 13-07G 

1.5 1.5 Data translated from strawberries. 

4.4 Water Exposure/Risk Pathway

Memo (drinking water), 09/30/08, A. Al-Mudallal, D349290 

Memo (drinking water), 01/28/10, M. Corbin, et al. D371784 

Surface and ground water estimated drinking water concentrations (EDWCs) were generated 

using the FIRST and screening concentration in ground water (SCI-GROW) models, 

respectively. Both models were run using the dry bean application scenario (2 x 0.75 lb ai/acre; 

14-day RTI; highest registered/proposed rate). The resulting chronic EDWCs in ground and 

surface water were 0.044 ppb and 11.2 ppb, respectively (EFED Memo; A. Al-Mudallal, 

9/30/08, D349290). Since the surface water concentration was the highest, the chronic dietary 

run was conducted assuming a residue of 0.0112 ppm for all water sources (direct and indirect). 

EFED has completed a more recent estimate of EDWCs (EFED Memo, 1/28/2010. M. Corbin, et 

al., D371784); however, the EDWCs of this assessment are lower than that of the 2008 

assessment. Thus, the EDWCs from the 2008 assessment were used in this analysis. 

4.5 Dietary Exposure Analysis

Chronic dietary risk assessments were conducted using the DEEM-FCIDTM, ver. 2.03. DEEMFCIDTM incorporates the food consumption data from the USDA’s CSFII (1994-1996 and 1998). 

The chronic analyses incorporated tolerance-level residues for all commodities excluding 

squash, peach, and tomato (average field-trial residues were assumed) and milk (the tolerance 
Bifenazate HED Human-Health Risk Assessment DP#: D371783 

Page 19 of 29

level was adjusted upward to account for all of the residues of concern for risk assessment). The 

chronic analyses incorporated average %CT information which were provided by the BEAD 

(Memo, A. Grube, 10/06/2008). The percent crop-treated information used in the dietary 

analysis was as follows: pepper, tomato, watermelon cucumber, apricot, cherry, pecan, 

pistachio, and walnut utilized 1% crop-treated; apple, nectarine, plum, almond, and grapes 

utilized 5% crop treated; pear and peach utilized 10% crop treated; and strawberry utilized 30% 

crop treated. DEEMTM (ver. 7.81) default processing factors were assumed for all commodities 

excluding apple juice, grape juice, raisins, wine/sherry, tomato paste, and tomato puree. The 

processing factors for these commodities were reduced to 0.23, 0.17, 1, 0.17, 1, and 1, 

respectively, based on data from processing studies. The analyses also included the chronic 

surface water point estimate generated using the FIRST and the dry bean application scenario (2 

x 0.75 lb ai/acre; 14-day RTI; highest registered/proposed rate). The chronic exposure estimates 

are ≤81% cPAD and are, therefore, not of concern. The most highly-exposed population 

subgroup was children 1 to 2 years old. Based on a critical-commodity contribution analysis 

conducted in DEEM-FCIDTM, the major contributors to the risk for children 1 to 2 years old were 

Crop Group 6 commodities (legume vegetables, succulent or dried), Crop Subgroup 6A 

commodities (edible-podded legume vegetables) and other commodities (denoted with group 

“O” in the residue files; includes water, tropical fruits, grape, and cranberry). Table 4.5 is a 

summary of the chronic dietary exposure estimates. 

Table 4.5. Summary of Chronic Dietary Exposure and Risk for Bifenazate (Drinking Water Exposure Included). 

Population Subgroup cPAD (mg/kg/day) Chronic 

Exposure (mg/kg/day) %cPAD 

General U.S. Population 0.003036 30 

All Infants (<1 year old) 0.006661 67 

Children 1-2 years old 0.008094 81 

Children 3-5 years old 0.006120 61 

Children 6-12 years old 0.003749 37 

Youth 13-19 years old 0.002164 22 

Adults 20-49 years old 0.002523 25 

Adults 50+ years old 0.002591 26 

Females 13-49 years old 

0.01 

0.002382 24 

4.6 Residential Exposure and Risk Assessment 

Memo, M. Dow and D. Vogel, 08/15/02, D284802 

HED previously reviewed a request for homeowner application of bifenazate to “all ornamental 

plants, including bedding plants, flowering plants, foliage plants, bulb crops, perennials, trees, 

and shrubs.” In conjunction with this request, labeling for Floramite SC (a formulation 2 lb 

ai/gal) was submitted and the assessment was conducted using the instructions on this label. 

HED noted that the petition indicated that Florimite, Floramite LS, Floramite GN, and Floramite 

SC/LS may also be applied to ornamentals. Copies of those product labels were not forwarded 

for review; therefore, HED is not aware of any differences in labels that might exist. 

HED anticipated only short-term dermal and inhalation exposure for residential handlers. The 

resulting dermal and inhalation MOEs were 4,200 and 430,000, respectively, and yielded a 

combined MOE of 4,200; therefore, residential exposure to bifenazate is not of concern. With 

respect to post-application residential exposures, current HED policy (see minutes to ExpoSAC 

meeting, 07/26/01) specifies that no significant post-application exposure is anticipated from 
Bifenazate HED Human-Health Risk Assessment DP#: D371783 

Page 20 of 29

landscape ornamentals, either by residents or professional applicators; therefore, no residential 

post-application assessment was conducted. 

4.7 Non-occupational Off-Target Exposure

Spray drift is always a potential source of exposure to residents nearby to spraying operations. 

This is particularly the case with aerial application, but, to a lesser extent, could also be a 

potential source of exposure from ground application. The Agency has been working with the 

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

other parties to develop the best spray drift management practices. On a chemical by chemical 

basis, the Agency is now requiring interim mitigation measures for aerial applications that must 

be placed on product labels/labeling. The Agency has completed its evaluation of the new data 

base submitted by the Spray Drift Task Force, a membership of U.S. pesticide registrants, and is 

developing a policy on how to appropriately apply the data and the AgDRIFT® computer model 

to its risk assessments for pesticides applied by air, orchard airblast and ground hydraulic 

methods. After the policy is in place, the Agency may impose further refinements in spray drift 

management practices to reduce off-target drift with specific products with significant risks 

associated with drift. 

5.0 AGGREGATE RISK ASSESSMENTS AND RISK CHARACTERIZATION

In general, HED conducts aggregate risk assessments by summing dietary (food and water) and 

residential exposures (residential or other non-occupational exposures). Based on the 

registered/proposed agricultural and residential uses and since a common toxicological endpoint 

has been identified for assessment of oral, dermal, and inhalation exposures (all durations; 

changes in body weights and body weight gains, and hematological effects), HED conducted 

short-term (food, water, residential dermal, and residential inhalation) and chronic (food and 

water) aggregate risk assessments are required. The HIARC did not select an acute dietary 

endpoint for the general U.S. population, infants, children, and females 13-50 years old and 

bifenazate has been classified as “not likely” to be a human carcinogen. Therefore, acute and 

cancer aggregate exposure analyses are not required for bifenazate. 

Short-Term Aggregate Risk Assessment: Since a common endpoint has been identified for 

assessment of short-term oral, dermal, and inhalation exposures (changes in body weights and 

body-weight gains, and hematological effects) the short-term aggregate risk assessment 

considered exposure from food, water, and residential sources. Since the doses corresponding to 

the identified oral, dermal, and inhalation endpoints were different but the level of concern for all 

three routes of exposure are identical, the short-term aggregate exposures were calculated using 

the 1 ÷ MOE approach. HED combines chronic dietary (food and water) exposure estimates with 

residential exposure estimates when conducting short-term aggregate risk assessments. Shortterm exposure has been defined as from 1 to 30 days and HED has concluded that chronic dietary 

exposure estimates will more accurately reflect actual dietary exposure over these time periods 

than will high-end acute-dietary exposures. The residential scenarios result in exposure to only 

adults. Therefore, short-term aggregate assessments were not conducted for infants and children. 

 Table 5.0 is a summary of the short-term aggregate exposures and risk estimates. Since the 

aggregate MOEs are ≥2200 for all population subgroups, short-term aggregate exposure to 

bifenazate is not of concern. 

Table 5.0. Short-Term Aggregate Exposure. 
Bifenazate HED Human-Health Risk Assessment DP#: D371783 

Page 21 of 29

Population Target Aggregate 

MOE1

Dietary 

MOE2

Dermal 

MOE3

Inhalation 

MOE4

Aggregate MOE 

(dietary and residential)5

General U.S. pop. 3,300 4,200 430,000 1,800 

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

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

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

Females 13-49 years old 

100 

4,200 4,200 430,000 2,100 1

 Total uncertainty factor for all routes of exposure is 100x; therefore, the target MOE is 100. 2

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

10 mg/kg/day. 3

 Adult dermal MOE = short-term dermal NOAEL ÷ dermal residential handler exposure (see Section 4.5). 4

 Adult inhalation MOE = short-term inhalation NOAEL ÷ inhalation residential handler exposure (see Section 4.5). 5

 Adult aggregate MOE (dietary and residential) = 1 ÷ ((1÷MOEdietary)+ (1÷MOEdermal) + (1÷MOEinhalation)). 

Chronic Aggregate Risk Assessment: Since there are no registered/proposed uses which result 

in chronic residential exposures, the chronic aggregate exposure assessment is concerned only 

with exposure from food and water. Since the dietary exposure analysis included drinking water, 

the discussion and exposure estimates presented in Section 4.5 represent aggregate chronic 

exposure. 

6.0 CUMULATIVE RISK

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 for 

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 assumed that bifenazate does not have 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 OPP 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/.

7.0 OCCUPATIONAL EXPOSURE AND RISK ASSESSMENT

Memo, 01/12/2010, M. Clock-Rust, DP# 371944 

7.1 Handler Exposure and Risk Assessment

All exposure scenarios based on the proposed uses have already been assessed by HED in 

previous risk assessments for the same chemical, product and use rate (for strawberries and 

grapes a higher rate was assessed for handlers, resulting in a more conservative assessment). 

Avocados can be grouped with tropical fruit since the application method is the same (airblast) 

and post-application activities are similar to those for tropical fruits. 

Based on the proposed use pattern, HED anticipated the most highly exposed occupational 

handlers will be: 
Bifenazate HED Human-Health Risk Assessment DP#: D371783 

Page 22 of 29

Mixer/Loaders 

(1) Mixing/loading WPs in WSB for groundboom (strawberries and caneberries) and airblast 

application (avocados, tropical fruit and grapes). 

Applicators 

(1) Applying sprays using groundboom equipment (strawberries and caneberries). 

(2) Applying sprays using airblast equipment (avocado, tropical fruit and grapes). 

As can be seen below in the table, all potential exposure scenarios associated with the new uses 

have already been assessed previously by HED. For all use sites, only one to two applications 

are permitted per season, with the exception of strawberries, which are limited to one application 

per crop (minimum of 21 days between applications). Risk estimates are provided for the shortterm duration (1-30 days) and all handler MOEs are above 100 and not of concern. For postapplication, all MOEs are above 100 and not of concern with the exception of grapes, which 

result in an MOE for the high-exposure post-application activities (tying, turning and girdling). 

A REI of 5 days is necessary for grapes and is already on Acramite® 50WS labels. 

Table 7.1.1. Handler Exposure and Risk Assessment. 

Crop or Crop Group Representative Crop for 

Occupational Exposure 

Assessment 

Assessment Covering this Use Pattern 

for Purposes of Occupational 

Exposure 

Avocado N/A 

Tropical Fruit N/A 

Memo, K. Lowe, D337535, 7/24/2008. 

Note: Avocado use pattern very similar 

to tropical fruit. 

Small Vine Climbing 

Fruit (13-07F) 

Grape 

Low-Growing 

Berry(13-07G) 

Strawberry 

Memo, J. T. Swackhammer, D277204, 

8/21/2001 
HED Human-Health Risk Assessment DP#: D371783 

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Table 7.1.2. Risk Estimates for Proposed Uses of Bifenazate on Caneberry, Tropical Fruit, Strawberry, and Grape Based on Previous 

Use Site Product Formulation Application Rates Application Equipment and Area Treated Referenced Document Short-Term Handler MOEs Short-Te

Caneberry 

Groundboom 

80 Acres 

Dermal: 14,000 

Inhalation: 

73,000

D

(Activities: I

scouting, trai

Tropical 

Fruit and 

Avocado 

Airblast 

40 Acres 

K. Lowe, 

D337535 

7/24/08. 

Dermal: 15,000 

Inhalation: 

78,000

D

(Ac

Strawberry Groundboom 80 Acres 

Dermal: 2,700 

Inhalation: 

5,400 

(Rate used: 

0.75 lb ai/A) 

D

(Activities: Pr

Grape 

Acramite®

50WS 

50% ai 

EPA Reg. No. 

400-503 

Watersoluble bags 0.5 lb ai/A 

Airblast - 40 Acres 

and Specialized 

Groundboom – 80 

Acres 

Memo, J.T. 

Swackhammer, 

D277204 Dermal: 520 

Inhalation: 

4,400 

(Rate Used: 

0.75 lb ai/A) 

(Activities: 

1 All Post-application risks represent risks on day zero/day of application. MOE for tropical fruit is the lowest MOE (range: 210-620). 2. Post-application risk for workers tying, turning and girdling grapes resulted in risks of concern, requiring a 5-day REI. Bifenazate 
Bifenazate HED Human-Health Risk Assessment DP#: D371783 

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7.2 Postapplication Inhalation Exposure 

Based on the Agency's current practices, a quantitative postapplication inhalation exposure 

assessment was not performed for bifenazate at this time primarily because it has the chemical 

has very low vapor pressure (vapor pressure less than 1 x 10-7 mmHg). However, volatilization of 

pesticides may be a potential source of postapplication inhalation exposure to individuals nearby 

to pesticide applications. The Agency sought expert advice and input on issues related to 

volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific 

Advisory Panel (SAP) in December 2009. The Agency received the SAP’s final report on March 

2, 2010 (http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). The Agency is 

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

procedures to identify the need for and, subsequently, the way to incorporate postapplication 

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

place, the Agency may revisit the need for a quantitative postapplication inhalation exposure 

assessment for bifenazate. 

7.3 REI 

Bifenazate is classified in Acute Toxicity Category IV for acute dermal toxicity, acute inhalation 

toxicity, primary eye irritation, and primary skin irritation. It is not a dermal sensitizer. 

Therefore, the interim WPS REI of 12 hours is sufficient to protect agricultural workers from 

postapplication exposures to bifenazate. 

For post-application, all MOEs are above 100 and not of concern with the exception of grapes, 

which result in an MOE for the higher-exposure post-application activities (tying, turning and 

girdling). The interim WPS REI of 5 days is necessary for grapes and is already on Acramite®

50WS labels. 

8.0 DEFICIENCIES 

8.1 Toxicology 

• An immunotoxicity study is required as a condition of registration. 

• A 28-day inhalation study is required as a condition of registration. 

• Acute and subchronic neurotoxicity studies are required as a condition of registration. 

8.2 Residue Chemistry 

• The petitioner should submit a revised Section F reflecting the recommended tolerance 

presented in Table 4.3.2. 

8.3 Occupational/Residential

• None. 
Bifenazate HED Human-Health Risk Assessment DP#: D371783 

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Attachment 1: Chemical Structures. 

Attachment 2: Toxicology Profile Table. 

Attachment 3: Percent Crop-Treated Data used for Bifenazate. 

RDI: RAB1 Branch: 05/19/2010 

Petition Number: PP#9E7642 

DP Number: D371783 

PC Code: 000586 
Bifenazate HED Human-Health Risk Assessment DP#: D371783 

Attachment 1: Chemical Structures. 

Chemical Name Chemical Structure

bifenazate (D2341) 

hydrazinecarboxylic acid, 2-(4-methoxy-[1,1’-biphenyl]-3-yl), 1-

methylethyl ester 

O

N

H

N

H O CH3

O CH3

CH3

D3598 

diazinecarboxylic acid, 2-(4-methoxy-[1,1’-biphenyl]-3-yl), 1-

methylethyl ester 

O

N

N O CH3

O CH3

CH3

D1989 

1,1’-biphenyl, 4-methoxy 

OCH3

D9569 

[1,1’-biphenyl]-4,4’-diol 

HO OH

A1530 

1,1’-biphenyl, 4-ol 

OH

A1530-sulfate OSO3H

D23-14; 

biphenyl hydrazine; 

(4-methoxy-[1,1’-biphenyl]-3-yl)hydrazine 

OCH3

NH NH2

Page 26 of 29
Bifenazate HED Human-Health Risk Assessment DP#: D371783 

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Attachment 2: Toxicity Profile of Bifenazate Technical. 

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 

Guideline 

No. 

Study Type 

(All Studies 

Acceptable) 

Results 

870.3100 90-Day oral 

toxicity rodents-rat 

NOAEL = 13.8 mg/kg/day in males, 3.2 mg/kg/day in females.

LOAEL = 27.7 mg/kg/day in males, 16.3 mg/kg/day in females 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. 

870.3150 

90-Day oral 

toxicity nonrodents-dog 

NOAEL = 0.9 mg/kg/day in males, 1.3 mg/kg/day in females.

LOAEL = 10.4 mg/kg/day in males, 10.7 mg/kg/day in females based on 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 

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

LOAEL = 400 mg/kg/day in males and females 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. 

870.3700a 

Prenatal 

developmental in 

rodents- rat 

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 = 500 mg/kg/day. 

LOAEL = not established.

870.3700b 

Prenatal 

developmental in 

non-rodents- rabbit 

Maternal NOAEL = 200 mg/kg/day. 

LOAEL = not established; doses for the main study were selected based on a rangefinding 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 

Parental/Systemic NOAEL = 1.6 mg/kg/day in males, 1.8 mg/kg/day in females. 

LOAEL = 6.5 mg/kg/day in males and 7.4 mg/kg/day in females based on decreased 

body weight, body-weight gain, and food consumption in both sexes. 

Reproductive NOAEL = 16.4 mg/kg/day in males, 18.3 mg/kg/day in females. 

LOAEL = not established. 

Offspring NOAEL = 16.4 mg/kg/day in males, 18.3 mg/kg/day in females. 

LOAEL = not established.
Bifenazate HED Human-Health Risk Assessment DP#: D371783 

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Guideline 

No. 

Study Type 

(All Studies 

Acceptable) 

Results 

870.4100b Chronic toxicity 

dogs 

NOAEL = 1.01 mg/kg/day in males, 1.05 mg/kg/day in females 

LOAEL = 8.95 mg/kg/day in males, 10.42 mg/kg/day in females based on changes 

in hematological and clinical chemistry parameters in both sexes and 

histopathological effects in bone marrow (compensatory hyperplasia), liver, and 

kidney in both sexes. 

870.4300 Chronic/Carcinogenicity rats 

NOAEL = 3.9 mg/kg/day in males, 4.8 mg/kg/day in females. 

LOAEL = 9.7 mg/kg/day in males and 9.7 mg/kg/day in females based on decreased 

body weight, body-weight gain, and food consumption in both sexes. 

No evidence of carcinogenicity.

870.4300 Carcinogenicity 

mice 

NOAEL = 1.5 mg/kg/day in males, 19.7 mg/kg/day in females. 

LOAEL = 15.4 mg/kg/day in males, 35.7 mg/kg/day in females based on decreased 

body weight and body-weight gain in females and hematological effects and 

decreased kidney weight in males. 

No evidence of carcinogenicity.

870.5265 Gene Mutation 

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. 

870.5300 Gene Mutation 

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. 

870.5375 Chromosome 

aberration 

Did not induce structural chromosome aberration in CHO-K1 cell cultures in the 

presence and absence of activation up to cytotoxic concentrations. 

870.5385 Chromosomal 

aberration 

Non-mutagenic in ICR mouse bone marrow micronucleus chromosomal aberrations 

assay up to cytotoxic concentrations. 

870.7485 

Metabolism and 

pharmacokinetics - 

rat 

Total recovery of the administered dose was >93% for all treatment groups. Fecal 

excretion was the major route of elimination (66-83% of the dose), with eight 

primary metabolites detected. These metabolites, as well as those identified in the 

urine and bile, were the result of metabolic reactions including hydrazine oxidation, 

demethylation, ring hydroxylation, and molecular scission with the loss of 

hydrazinecarboxylic acid portion with subsequent conjugation. 
Bifenazate HED Human-Health Risk Assessment DP#: D371783 

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Attachment 3: Percent Crop-Treated Data used for Bifenazate. 

Commodities Percent Crop-treated 

Almond Commodities 1.0% 

Apple Commodities 1.0% 

Apricot Commodities 1.0% 

Cucumber 1.0% 

Grape Commodities 5.0% 

Nectarine 5.0% 

Peach Commodities 5.0% 

Pear Commodities 10% 

Pecans 1.0% 

Peppers (bell and non-bell) 1.0% 

Plum and Prune Commodities 5.0% 

Strawberry Commodities 25% 

Tomato Commodities 5.0% 

Walnuts 1.0% 

Watermelon Commodities 1.0% 

Reference: BEAD Memorandum, A. Grube, 10/06/2008.