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

Page 1 of 29Bifenazate HED Human-Health Risk Assessment DP#: D371783

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### aspects of the risk assessment which are a ffected 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 ASSESSMEN TS 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. ............................................29Bifenazate HED Human-Health Risk Assessment DP#: D371783

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### 1.0 EXECUTIVE SUMMARY

Bifenazate (1-methylethyl 2-(4-methoxy[1,1’-b iphenyl]-3-yl) hydrazinecarboxylate) is a selective miticide/insecticide which controls the motile stage of mites either by direct contact orthrough 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-m ethoxy-[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 equipmentBifenazate 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 ga in, 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 st udies 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 dimet hyl 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 N 2 

### and CO 2 

### 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 Co rporation 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),Bifenazate HED Human-Health Risk Assessment DP#: D371783

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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 consider ations 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 ba sed on common endpoints (changes in body weights and body-weight gains, and hematological effect s). Exposure assessments were conducted for the specific scenarios listed below.

Table 1.0. Summary of Toxicological Endpo ints used in the Cu rrent Risk Assessment 1

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

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

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

Short-term inhalation oral NOAEL = 10 mg/kg/day 2 LOC for MOEs ≤ 100 (occupational/residential) 1

Intermediate-term inhalation oral NOAEL = 0.9 mg/kg/day 2 LOC for MOEs ≤ 100 (occupational/residential) 1

1 NOAEL = no-observable-adverse-effect-level; RfD = refe rence dose = NOAEL ÷ 100; PAD = population-adjusted dose = RfD ÷ FQPA SF; LOC = level of con cern; 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 ornament als 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)). Th e 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-FCID TM 

### , ver. 2.03).

DEEM-FCID TM 

### 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) informationBifenazate HED Human-Health Risk Assessment DP#: D371783

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### provided by the Biological Economic Anal ysis Division (BEAD; 09/18/2008). DEEM TM 

### (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-termduration (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 Categor y 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 usesBifenazate 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. Whenev er 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 deficien t 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-met hoxy[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 residue s. 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 CH 3

O CH 3 CH 3

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 CH 3

O CH 3 CH 3

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

Page 9 of 29Bifenazate HED Human-Health Risk Assessment DP#: D371783

Page 10 of 29 Table 2.2. Physicochemical Properties of the Technical Grade of Bifenazate.

Melting range 124-125 oC

pH 6.78

Density 1.19 g/cm 3

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, pK

a 12.94 at 23 °C

Octanol/water partition coefficient, Log(K OW ) 3.4

UV/visible absorption spectrum Max 264 nm in water MRID 46064101



### 3.0 HAZARD CHARACTERIZATION

A detailed hazard characterization for bifenazat e 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 determ ine 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 immunotoxic ity 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 increasedBifenazate HED Human-Health Risk Assessment DP#: D371783

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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 histopathologi cal 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 (UF DB 

### ) 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 20-30 0 

### 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 25 0 

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

Page 12 of 29 T able 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

Page 13 of 29 

### 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 pr oceed 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 pare nt) 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 determined 1 Could not be determined 1

Drinking Water D1989 Not applicable

1 Based on the results of the confined rotational crop study conduc ted 0.5 lb ai/acre and the application rate for the registere d 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

Page 14 of 29 

### 4.0 EXPOSURE ASSESSMENT AND CHARACTERIZATION

Residue Chemistry Memo, pe nding, W.D. Wassell, D371943. Residue chemistry Memo, pending, W.D. Wassell, D380061 Dietary Exposure Memo, pe nding, W.D. Wassell, D371941 Dietary Exposure Memo, pe nding, 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 assessmen t), 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 fu zzy kiwifruit: grape, Amur river grape, gooseberry, hardy kiwifruit, maypop, schisandra berry; and cu ltivars, 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, be arberry, 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 bife nazate 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 fr om Crop Field Trials with Bifenazate. Residue Levels (ppm) 1
Commodity Total Applic.

Rate (lb ai/A) PHI (days) N Min. Max. HAFT 2 Mean Std. Dev 3

. 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 (expre ssed 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 a pple, 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 concentr ation 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 asse ssment 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-FCID TM 

### , ver. 2.03. DEEMFCID TM 

### 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 toleranceBifenazate 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. DEEM TM 

### (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 studi es. 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 c oncern. The most highly-exposed population subgroup was children 1 to 2 years old. Based on a critical-commodity contribution analysis

conducted in DEEM-FCID TM 

### , 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).

Chronic Population Subgroup cPAD (mg/kg/day)
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 Florim ite, Floramite LS, Floramite GN, and Floramite SC/LS may also be applied to ornamentals. C opies 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 pos t-application exposure is anticipated fromBifenazate HED Human-Health Risk Assessment DP#: D371783

Page 20 of 29 

### landscape ornamentals, either by residents or prof essional 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, St ate 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 ASSESSMEN TS 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 withresidential 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

MOE 1 Dietary

MOE 2 Dermal

MOE 3 Inhalation

MOE 4 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 e xposure 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 = s hort-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 ÷ MOE dietary )+ (1 ÷ MOE dermal ) + (1 ÷ MOE inhalation )).



### 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 di etary 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 th e 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 applicationper 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,

8/21/2001HED Human-Health Risk AssessmentDP#: D371783Page 23 of 29Table 7.1.2. Risk Estimates for Proposed Uses of Bifenazateon Caneberry, Tropical Fruit, Strawberry, and Grape Based on Previous HED ORE Assessments.Use SiteProductFormulationApplicationRatesApplicationEquipmentand AreaTreatedReferencedDocumentShort-TermHandler MOEsShort-Term Post-Appl MOEs1CaneberryGroundboom80 AcresDermal: 14,000Inhalation:73,000Dermal: 570(Activities: Irrigation, Hand weeding,scouting, training, hand pruning, tying)TropicalFruit andAvocadoAirblast40 AcresK. Lowe,D3375357/24/08.Dermal: 15,000Inhalation:78,000Dermal: 210(Activity: Thinning)StrawberryGroundboom80 AcresDermal: 2,700Inhalation:5,400(Rate used:0.75 lb ai/A)Dermal: 420(Activities: Pruning, training, harvesting)GrapeAcramite®50WS50% aiEPA Reg. No.400-503Watersoluble bags0.5 lb ai/AAirblast - 40 Acresand SpecializedGroundboom – 80AcresMemo, J.T.Swackhammer,D277204Dermal: 520Inhalation:4,400(Rate Used:0.75 lb ai/A)Dermal: 622(Activities: Tying, turning, girdling)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.BifenazateBifenazate HED Human-Health Risk Assessment DP#: D371783

Page 24 of 29 

### 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/SA P/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 Categor y 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

Page 25 of 29 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: 000586Bifenazate 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 CH 3

O CH 3 CH 3

D3598

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

N N O CH 3

O CH 3 CH 3

D1989

1,1’-biphenyl, 4-methoxy OCH 3

D9569

[1,1’-biphenyl]-4,4’-diol OH HO

A1530

1,1’-biphenyl, 4-ol OH

A1530-sulfate OSO 3 H

D23-14; biphenyl hydrazine; (4-methoxy-[1,1’-biphenyl]-3-yl)hydrazine OCH 3

NH NH 2

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

Page 27 of 29 

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

Guideline

No. Study Type MRID # Results Toxicity Category

870.1100 Acute Oral 44464934 LD 50 > 5,000 mg/kg IV

870.1200 Acute Dermal 44464936 LD 50 > 5000 mg/kg IV

870.1300 Acute Inhalation 44464937 LC 50 > 4.4 mg/L IV

870.2400 Primary Eye Irritation 44464938 slight irritation IV

870.2500 Primary Skin Irritation 44464939 slight irritation IV

870.2600 Dermal Sensitization 45385101 derm al 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, d ecreased liver weight in males, increased spleen weight in females, and histopa thology in liver in both sexes, and histopathological changes in the spl een and adrenal cortex in males.

870.3150 90-Day oraltoxicity 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 wei ght 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 urin ary specific gravity, and decreased urinary volume in both sexes, and increased incide nce 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

Page 28 of 29 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 chemis try 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 fe males 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 L 5178Y mouse lymphoma ce lls 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 elimin ation (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

Page 29 of 29 

### 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.