Document ID: EPA-HQ-OPP-2010-0904-0005
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2014-08-06T04:00Z

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
                            WASHINGTON, D.C.  20460
                                                                      OFFICE OF
                                                            CHEMICAL SAFETY AND
\* MERGEFORMAT
                                                           POLLUTION PREVENTION

MEMORANDUM

Date:		15-May-2014

SUBJECT:	Bifenazate.  Human-Health Risk Assessment.  Section 3 Registration Request to Add New Uses on Timothy Forage and Hay; Herb, Subgroup 19A; and to Expand Existing Uses on Pome Fruit, Group 11, and Fruiting Vegetables, Group 8.

PC Code: 
000586
DP Barcode:  
D388228
Decision No.:  
446177
Registration Nos.:
400-503, 400-514
Petition No.:  
1E7847
Regulatory Actions:
Section 3 Registration
Risk Assessment Type:  
Single Chemical/Aggregate
Case No.:
 7609
TXR No.:
NA
CAS No.:
149877-41-8
MRID No.:
None
40 CFR:
§180.572

FROM:	William D. Wassell, Chemist 
		Anwar Y. Dunbar, Ph.D., Pharmacologist
		Lata Venkateshwara, Environmental Scientist 
      Risk Assessment Branch 1 (RAB1)
		Health Effects Division (HED; 7509P)

THROUGH:	Charles W. Smith III, Branch Chief
      George F. Kramer, Ph.D., Senior Chemist 
		RAB1/HED (7509P)

         TO:		Barbara Madden, RM 05
	Registration Division (RD, 7505P) 

The HED of the Office of Pesticide Programs (OPP) is charged with estimating the risk to human health from exposure to pesticides.  The RD of OPP has requested that HED evaluate hazard and exposure data and conduct dietary, occupational, residential, and aggregate exposure assessments, as needed, to estimate the risk to human health that will result from the registered and proposed uses of the miticide/insecticide bifenazate [1-methylethyl 2-(4-methoxy[1,1'-biphenyl]-3-yl)hydrazinecarboxylate)].  

A summary of the findings and an assessment of human-health risk resulting from the proposed and registered uses of bifenazate are provided in this document.  The risk assessment, dietary exposure assessment, and residue chemistry assessment were provided by William Wassell (RAB1); the hazard characterization and endpoint selection by Anwar Dunbar (RAB1); the occupational and residential exposure assessment by Lata Venkateshwara (RAB1); and the drinking water exposure assessment by J. Hetrick of the Environmental Fate and Effects Division (EFED).  

The most-recent human-health risk assessment for bifenazate was for a Section 3 registration and tolerances to support a proposed use on tropical fruits and berries (Memo, 07/14/2010, W. Wassell, et al., D371783).  

                               Table of Contents
1.0	Executive Summary	5
2.0	HED Recommendations	10
2.1	Data Deficiencies	10
2.2	Tolerance Considerations	11
2.2.1	Enforcement Analytical Method	11
2.2.2	Recommended Tolerances	12
2.2.3	Revisions to Petitioned-For Tolerances	12
2.2.4	International Harmonization	13
2.3	Label Recommendations	13
3.0	Introduction	13
3.1	Chemical Identity	13
3.2	Physical/Chemical Characteristics	14
3.3	Pesticide Use Pattern	14
3.4	Anticipated Exposure Pathways	16
3.5	Consideration of Environmental Justice	16
4.0	Hazard Characterization and Dose-Response Assessment	16
4.1	Toxicology Studies Available for Analysis	16
4.2	Absorption, Distribution, Metabolism, and Excretion (ADME)	167
4.2.1	Dermal Absorption	178
4.3	Toxicological Effects	18
4.3.1	Summary of Toxicological Effects	18
4.4	Safety Factor for Infants and Children (FQPA Safety Factor)	189
4.4.1	Completeness of the Toxicology Database	19
4.4.2	Evidence of Neurotoxicity	19
4.4.3	Evidence of Sensitivity/Susceptibility in the Developing or Young Animal	19
4.4.4	Residual Uncertainty in the Exposure Database	20
4.5	Toxicity Endpoint and Point of Departure Selections	20
4.5.1	Dose-Response Assessment	20
4.5.2	Recommendation for Combining Routes of Exposures for Risk Assessment	22
4.5.3	Cancer Classification and Risk Assessment Recommendation	222
4.5.4	Summary of Points of Departure and Toxicity Endpoints Used in Human Risk Assessment	22
5.0	Dietary Exposure and Risk Assessment	224
5.1	Residues of Concern Summary and Rationale	24
5.2	Food Residue Profile	25
5.3	Water Residue Profile	26
5.4	Dietary Risk Assessment	26
5.4.1	Description of Residue Data Used in Dietary Assessment	26
5.4.2	Percent Crop Treated Used in Dietary Assessment	27
5.4.3	Acute Dietary Risk Assessment	27
5.4.4	Chronic Dietary Risk Assessment	28
5.4.5	Cancer Dietary Risk Assessment	28
5.4.6	Summary Table	28
6.0	Residential (Non-Occupational) Exposure/Risk Characterization	28
6.1	Residential (Non-Occupational) Exposure/Risk Characterization	28
6.2	Residential Post-Application Exposure/Risk Characterization	29
6.3	Spray Drift	30
6.4	Residential Bystander Post-Application Inhalation Exposure	30
6.5	Residential Risk Estimates for Use in Aggregate Assessments	31
7.0	Aggregate Exposure/Risk Characterization	30
7.1	Acute Aggregate Risk	31
7.2	Short-Term Aggregate Risk	321
7.3	Chronic Aggregate Risk	32
8.0	Cumulative Exposure/Risk Characterization	32
	8.1  Occupational Exposure/Risk Characterization	32
9.0	Occupational Handler Exposure/Risk Characterization	33
	9.1  Post-application Exposure/Risk	33
	9.2  Post-application Exposure/Risk	33
10.0	References	37
Appendix A.  Toxicology Profile and Executive Summaries	40
Appendix B.  Methodologies for Human-Equivalent Concentration Calculations 45
Appendix C.  Residential Handler and Post-application Algorithms	48
Appendix D.  Summary of Occupational and Residential Non-cancer Algorithms	51
Appendix E.  Summaries of Dislodgeable Foliar Residue Studies and Proposed Use in Assessment			51
Appendix F.  Physical/Chemical Properties		53

1.0	Executive Summary

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

Bifenazate is currently registered for application to ornamental plants, pome fruit, fruiting vegetables, cucurbit vegetables, tree nuts, tuberous and corm vegetables, legume vegetables, berries, tropical fruits, stone fruits, grape, strawberry, cotton, hops, okra, peppermint, and spearmint with tolerances ranging from 0.1 to 35 ppm (40 CFR §180.572(a)(1)).  A Section 18 registration has also been established for application of bifenazate to timothy with tolerances ranging from 50 to 150 ppm (40 CFR §180.572(b)).  Tolerances, as a result of secondary residues, are established for residues in milk, ruminant meat, ruminant fat, and ruminant meat byproducts at 0.02 to 0.10 ppm (40 CFR §180.572(a)(1) and (a)(2)).  

The Interregional Research Project No. 4 (IR-4) has submitted a petition proposing the establishment of permanent tolerances for residues of the acaricide bifenazate and its metabolite D3598 [diazinecarboxylic acid, 2-(4-methoxy-[1,1'biphenyl]-3-yl, 1-methylethyl ester], (expressed as bifenazate) in/on the following raw agricultural commodities (RACs):

Commodity
Proposed Tolerance
Herb Subgroup 19A, fresh leaves
30 ppm
Herb Subgroup 19A, dried leaves, except chervil, dried, and chive, dried
140 ppm
Fruit, Pome, Group 11-10
0.75 ppm
Vegetable, Fruiting, Group 8-10
2.0 ppm

Note:  Bifenazate tolerances are established for residues in/on pome fruit (group 11) and fruiting vegetables (group 8) at the requested levels.  IR-4 has proposed expanding the existing tolerances to cover additional commodities that are included in the revised crop groups 11-10 and 8-10.  

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

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

The end-use products (EPs) relevant to these registration requests are Acramite[(R)] 50WS (EPA Reg. No. 400-503), a 50% by weight wettable-powder (WP) in water-soluble bags (WSP), and Acramite[(R)] 4SC (EPA Reg. No. 400-514), a 4 lb/gal suspension-concentrate (SC) formulation [equivalent to a flowable-concentrate (FlC) formulation]. 

IR-4 has proposed one foliar spray application to herbs and timothy by ground or aerial (timothy only) equipment at a rate of 0.38 to 0.50 lb ai/A to herbs and 0.43 to 0.75 lb ai/A for timothy.  The proposed pre-harvest intervals (PHIs) are 0 days for timothy forage, 7 days for timothy hay, and 3 days for herbs.  The established use pattern for pome fruit and fruiting vegetables is one application using ground equipment at a maximum rate of 0.38 to 0.50 lb ai/A with PHIs of 3 and 7 days for fruiting vegetables and pome fruit, respectively.  Application by aerial equipment is permitted for fruiting vegetables.  

Hazard Assessment:  The toxicological database for bifenazate is complete and adequate for Food Quality Protection Act Safety Factor (FQPA SF) evaluation, selection of points of departure (PODs) for the various routes of exposure, and for dose-response evaluation.  Bifenazate was categorized as having low acute toxicity (Toxicity Category IV) for the oral, dermal, and inhalation routes of exposure for this duration.  For subchronic oral exposures, the dog is the most sensitive species.  For chronic oral exposures, the dog and the rat are equally sensitive.  Subchronic and chronic studies in rats and dogs indicate that the liver and hematopoietic system (spleen and bone marrow with associated hematological findings) are the primary target organs in these species.  Additional toxicity was seen in the kidney (dogs following chronic exposure) and adrenal cortex (male rats following subchronic exposure).  Decreases in body weight, body-weight gain, and food consumption were also associated with liver and hematopoietic system toxicity in several studies.  In the rat developmental toxicity study, increases in early fetal resorptions occurred at the same doses that caused maternal toxicity.  In the rabbit developmental toxicity study, there were no maternal or developmental effects up to the highest-dose tested (HDT).  In the two-generation rat reproduction study, there were no reproductive or offspring effects up to the HDT.  In both of the neurotoxicity screening batteries, effects were seen only at the HDT and consisted of decreased landing foot splay, decreased fore- and hindlimb grip strength, and decreased motor activity measurements (center times and rearing activity).  There were no effects in the immunotoxicity study.  In the 21-day dermal toxicity study in rats, adverse effects occurred at the mid-dose manifested as decreased body weight in females, decreased food consumption in both sexes, altered kidney parameters, and effects on the hematopoietic system.  In the 28-day inhalation study, effects included dried-red material around the nose in females and minimal to mild degeneration of the olfactory epithelium within nasal levels III, IV, and V in both sexes, lower body weights and body-weight gains, decreased food consumption, decreased heart and thymus weights in females, and increased incidences of mild brown pigmentation of the spleen.  Bifenazate is classified as "not likely" to be carcinogenic to humans.

Consistent with previous risk assessments for bifenazate (Memo, 07/14/2010, W. Wassell, et al., D371783), the bifenazate risk assessment team recommends that the 10x FQPA SF be reduced to 1x for all exposure scenarios, as discussed in Section 4.4.

For purposes of the current risk assessment, PODs were selected for acute and chronic dietary, short- and intermediate-term incidental oral, and both residential and occupational short- and intermediate-term dermal and inhalation exposures.  For the acute dietary exposure for the general population, the acute neurotoxicity study in rats established a no-observed adverse-effect level (NOAEL) of 600 mg/kg/day and a lowest-observed adverse-effect level (LOAEL) of 2000 mg/kg based on decreased motor activity measurements.  For the acute dietary exposure for females 13-49 years of age, the prenatal developmental toxicity study in rats was chosen which established a NOAEL of 10 mg/kg/day and a LOAEL of 100 mg/kg/day based on maternal effects including clinical signs, decreased absolute body weights and food consumption during the dosing period.  At the same dose, there was an increased incidence of early fetal resorptions.  For the chronic dietary exposure, co-critical studies with similar NOAELs (1 and 1.5 mg/kg/day) were selected (chronic dog and mouse carcinogenicity, respectively).  Specifically, the chronic dog study established a LOAEL at 8.9 mg/kg/day based upon changes in hematological and clinical chemistry parameters and histopathological changes in the bone marrow, liver, and kidney.  A similar LOAEL of 15.4 mg/kg/day was also established in the mouse carcinogenicity study based on changes in hematological parameters and kidney weights.  

For short- and intermediate-term incidental oral exposures, endpoints were derived from the 90-day dog study where the NOAEL was 0.9 mg/kg/day.  The LOAEL was 10.4 mg/kg/day based on changes in hematologic parameters.  For short- and intermediate-term dermal exposures, endpoints were derived from the 21-day dermal rat study where the NOAEL was 80 mg/kg/day.  The LOAEL was 400 mg/kg/day based upon decreased body weight in females, decreased food consumption in both sexes, as well as altered kidney parameters, and effects on the hematopoietic system.  For short- and intermediate-term inhalation exposures, the route-specific 28-day inhalation study was chosen which generated a NOAEL of 0.03 mg/L and a LOAEL of 0.075 mg/L for both sexes based upon portal-of-entry effects (dried red material around the nose in females and minimal to mild degeneration of the olfactory epithelium within nasal levels III, IV, and V in both sexes).  Using the reference concentration (RfC) methodology, human-equivalent concentrations (HECs), and human-equivalent doses (HEDs) were generated for residential and occupational inhalation risk assessments.  

The risk assessment team has concluded that the FQPA SF should be reduced to 1x.  The following acceptable studies are available for FQPA consideration:  (1) developmental toxicity studies in rats and rabbits; (2) two-generation reproductive study in rats; and (3) acute and subchronic neurotoxicity studies.

Food Residue Profile:  The qualitative nature of the residue in plants and livestock are adequately understood based on acceptable studies with apple, orange, cotton, radish, lactating goats, and laying hens.  A briefing document, summarizing the salient features of the studies was presented to the Metabolism Assessment Review Committee (MARC) (Memo, 07/31/2001, T. Bloem et al., D276623).  The MARC concluded that for tolerance expression and risk assessment purposes, the residues of concern in crops are bifenazate and its metabolite D3598 (calculated as the stoichiometric equivalent of bifenazate).

Livestock feedstuffs are not derived from the proposed crops of the subject petition with the exception of timothy.  The proposed use on timothy is for a regional use in two counties of Nevada (Eureka and Humboldt Counties).  Applications can only be made to timothy that is intended for use as horse feed.  The use on timothy was discussed and approved by the Chemistry Science Advisory Council (ChemSAC, meeting of 01/12/2011).  Thus, secondary residues of bifenazate in livestock tissues are not of concern for this petition.

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

The qualitative nature of the residue in rotational crops is adequately understood based on an acceptable confined rotational crop metabolism study.  The MARC concluded that a 30-day plantback interval (PBI) is appropriate based on the available data.  Appropriate PBIs appear on the product labels for Acramite[(R)] 4SC and Acramite[(R)] 50WS.

IR-4 has submitted adequate field trial data for bifenazate on basil.  Four field trials were conducted in the 2008 growing season.  At each trial, basil was treated with a single foliar application of Acramite[(R)] 50 WS, at the approximate rate of 0.75 lb ai/A (1.5x the proposed application rate).  The maximum residues of bifenazate and its metabolite D3598 on fresh basil following a single foliar application at the approximate rate of 0.75 lb ai/A. and a 3-day pre-harvest interval ranged from 3.4 to 15 ppm.  For the trial that included dried basil, the maximum combined residues of bifenazate and D3598 were 9.5 ppm in fresh basil and 91 ppm in dried basil which represents a concentration factor of 9.6x for residues in dried basil.  The residue data for basil from the submitted crop field trials were analyzed using the Organization for Economic Co-operation and Development (OECD) tolerance-calculation procedures.  Based on the data set, the recommended tolerance for residues of bifenazate and D3598 (calculated as the stoichiometric equivalent of bifenazate) is 30 ppm in/on fresh herbs (subgroup 19A) and 300 ppm in/on dried herbs (subgroup 19A).

IR-4 has submitted adequate field trial data for bifenazate on grasses.  These data are intended to satisfy requirements for residue data for timothy forage and hay.  Thirteen field trials were conducted in the United States during the 2004 growing season.  At each trial, grasses received one foliar application of Acramite[(R)] 4SC at a rate of approximately 0.75 lb ai/A.  Grass forage samples were collected 4 hours after application and grass hay samples at 6 to 7 days after application.  The maximum combined residues of bifenazate and D3598 in/on grass forage and hay were 83.5 and 76.3 ppm, respectively.  The residue data for grass forage and hay from the submitted crop field trials were analyzed using the OECD tolerance-calculation procedures.  Based on the data set, the recommended tolerances for residues of bifenazate and D3598 (calculated as the stoichiometric equivalent of bifenazate) are 200 ppm in/on timothy forage and 150 ppm in timothy hay.

Exposure/Risk Assessment Characterization:  Acute and chronic dietary (food plus drinking water) exposure and risk assessments were conducted using the Dietary Exposure Evaluation Model - Food Consumption Intake Database (DEEM-FCID), Version 3.16.  The assessments were conducted for dietary exposure based on the existing and proposed uses.  Drinking water estimates were directly incorporated into the analysis.  

The acute analysis for the general population, including infants and children, was unrefined and used tolerance-level residues and 100% crop-treated (PCT).  The acute analysis for females 13 to 49 years old was highly refined and incorporated data from the U.S. Department of Agriculture (USDA's) Pesticide Data Program (PDP), crop field trial data, and PCT estimates.  DEEM, ver. 7.81, default processing factors were assumed for all commodities excluding apple juice, grape juice, and wine/sherry.  The processing factors for these commodities were reduced to 1.0, based on data from processing studies.  The analysis also included the acute surface water point estimate generated using the FQPA Index Reservoir Screening Tool (FIRST) and the dry bean application scenario (highest registered/proposed use rate).  

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

The acute and chronic exposure and risk estimates were not of concern.  A cancer dietary assessment was not conducted because bifenazate is classified as "not likely" to be carcinogenic to humans.

Residential Exposure/Risk: The proposed uses will not result in residential exposure; however, the currently registered garden and ornamental use has been reassessed in this document to reflect updates to HED's 2012 Residential Standard Operating Procedures (SOPs).  A total aggregated risk index (ARI) approach was used since the levels of concern (LOCs) for dermal exposure (100) and inhalation exposure (30) are different.  The dermal and inhalation exposure risk estimates for residential handlers are not of concern at baseline for all scenarios.  All the ARIs are above 1 and do not exceed HED's LOC for all scenarios.  All adult and children (6 <= 11 years) dermal post-application risk estimates for exposure to treated trees and gardens are not of concern (margins of exposure or MOEs) >= 100).  

Occupational Handler Exposure:  Occupational handler short- and intermediate-term exposure is anticipated from the proposed uses.  Chronic exposure is not expected for the proposed uses.  Bifenazate is classified as "not likely" to be carcinogenic to humans; therefore, a cancer assessment was not conducted.  The label for Acramite[(R)] 50WS only requires protective eyewear, long-sleeved shirt, long pants, and shoes plus socks.  The label does not require gloves.  The label for Acramite[(R)] 4SC requires long-sleeved shirt, long pants, and shoes plus socks.  It includes a statement that "when not using a closed system, wear apron and chemically resistant gloves made of any waterproof material for mixing/loading activities."

Inhalation risk estimates were not of concern for all scenarios.  MOEs ranged from 100 to 12,000 (MOEs >= 30).  Dermal risk estimates were not of concern for all scenarios.  MOEs ranged from 110 to 33,000 (MOEs >= 100).  All ARIs are greater than 1 except for the following scenarios that require single layer of gloves:
   * Mixing/loading liquids for aerial and chemigation applications and 
   * Mixing/loading/application of liquids via mechanically pressurized handgun (foliar). 

Occupational Post-application Exposure:  Post-application dermal exposure will occur since bifenazate is applied post-emergence as a foliar spray.  Chemical-specific dislodgeable-foliar residue (DFRt) data are available and used for bifenazate.  The short- and intermediate-term risk estimates are not of concern (i.e., MOEs >= 100) on the day of treatment (day 0) for the post-application exposure activities.  Based on the Agency's current practices, a quantitative occupational post-application inhalation exposure assessment was not performed for bifenazate at this time.  If new policies or procedures are put into place, the Agency may revisit the need for a quantitative occupational post-application inhalation exposure assessment for bifenazate.

The 12-hour restricted-entry interval (REI) listed on the label is adequate to protect agricultural workers from post-application exposures to bifenazate. 

Review of Human Research:  This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical.  These data, which include Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1); the Agricultural Handler Exposure Task Force (AHETF) database; the Outdoor Residential Exposure Task Force (ORETF) database; the Agricultural Reentry Task Force (ARTF), and the Residential SOPs (Gardens/Trees), are (1) subject to ethics review pursuant to 40 CFR §26, (2) have received that review, and (3) are compliant with applicable ethics requirements.  For certain studies, the ethics review may have included review by the Human Studies Review Board.  Descriptions of data sources, as well as guidance on their use, can be found at the Agency website.  

2.0	HED Recommendations

2.1	Data Deficiencies

Provided the petitioner submits revised Sections F (see below) and that the petitioner resolves the deficiency pertaining to the availability of analytical-grade standards at the EPA National Pesticide Standards Repository (see below), there are no residue chemistry or toxicological data deficiencies that would preclude the establishment of permanent tolerances for residues of bifenazate and its metabolites as outlined in Table 2.2.2.   
   
860.1550 Proposed Tolerances

In the subject petition, the proposed tolerance expression is in terms of the combined residues of bifenazate (1-methylethyl 2-(4-methoxy[1,1'-biphenyl]-3-yl)hydrazinecarboxylate) and diazinecarboxylic acid, 2-(4-methoxy-[1,1'-biphenyl]-3-yl, 1-methylethyl ester (expressed as bifenazate).  The established tolerance expression for livestock commodities is in terms of the combined residues of bifenazate and diazinecarboxylic acid, 2-(4-methoxy-[1,1'biphenyl]-3-yl, 1-methylethyl ester (D3598, expressed  as bifenazate), A1530 (1,1'-biphenyl, 4-ol) and A1530-sulfate (expressed as A1530; 1,1'biphenyl, 4-oxysulfonic acid).  The proposed tolerance expressions need to be modified to comply with the interim guidance on tolerance expressions (Memo, 5/27/2008, S. Knizner).  

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

Tolerances are established for residues of bifenazate (1-methylethyl 2-(4-methoxy[1,1'-biphenyl]-3-yl)hydrazinecarboxylate) including its metabolites and degradates, in or on the commodities listed in the following table. Compliance with the tolerance levels specified are to be determined by measuring only the sum of bifenazate and its metabolite, diazinecarboxylic acid, 2-(4-methoxy-[1,1'-biphenyl]-3-yl), 1-methylethyl ester, (expressed as bifenazate) in or on the following food commodities:

The tolerance expression should be changed to conform to current HED policy.  Specifically, the tolerance expression for 40 CFR §180.572(a)(1) should be as follows:

Tolerances are established for residues of the insecticide bifenazate (1-methylethyl 2-(4-methoxy[1,1'-biphenyl]-3-yl)hydrazinecarboxylate) including its metabolites and degradates, in or on the commodities listed in the following table.  Compliance with the tolerance levels specified are to be determined by measuring only the sum of bifenazate and its metabolite, diazinecarboxylic acid, 2-(4-methoxy-[1,1'-biphenyl]-3-yl), 1-methylethyl ester, (calculated as the stoichiometric equivalent of bifenazate) in or on the following food commodities:

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

Tolerances are established for residues of bifenazate (1-methylethyl 2-(4-methoxy[1,1′-biphenyl]-3-yl) hydrazinecarboxylate) including its metabolites and degradates, in or on the commodities listed in the following table. Compliance with the tolerance levels specified are to be determined by measuring only the sum of bifenazate and its metabolites diazinecarboxylic acid, 2-(4-methoxy-[1,1′-biphenyl]-3-yl), 1-methylethyl ester (expressed as bifenazate); 1,1′-biphenyl, 4-ol; and 1,1′-biphenyl, 4-oxysulfonic acid (expressed as 1,1′-biphenyl, 4-ol) in or on the following food commodities:

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

Tolerances are established for residues of the insecticide bifenazate (1-methylethyl 2-(4-methoxy[1,1′-biphenyl]-3-yl) hydrazinecarboxylate) including its metabolites and degradates, in or on the commodities listed in the following table.  Compliance with the tolerance levels specified are to be determined by measuring only the sum of bifenazate and its metabolites diazinecarboxylic acid, 2-(4-methoxy-[1,1′-biphenyl]-3-yl), 1-methylethyl ester; 1,1′-biphenyl, 4-ol; and 1,1′-biphenyl, 4-oxysulfonic acid (calculated as the stoichiometric equivalent of bifenazate) in or on the following food commodities:

860.1650 Submittal of Analytical Reference Standards

      Analytical reference standards for bifenazate and its metabolites D23-06 (D3598), D23-15, D23-16 (A1530) and D23-19 (A1530) are currently available at the EPA National Pesticide Standards Repository (personal communication with Theresa Cole, Analytical Chemistry Branch (ACB), 01/25/2012).  However, the standard for metabolites D23-15 and D23-16 expired on 6/30/2012 and 05/31/2012, respectively.  Additionally, the Repository does not have standards for bifenazate metabolite D23-22.  The registrant must either recertify the lots in the repository and send in an updated certificate of analysis (COA), or submit new standards (different lot #) if the previous lots will not be recertified.

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

         	USEPA
         	National Pesticide Standards Repository/Analytical Chemistry Branch/OPP
         	701 Mapes Road
         	Fort George G. Meade, MD  20755-5350

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

2.2	Tolerance Considerations

2.2.1	Enforcement Analytical Method

Plant Commodities:  There are adequate residue analytical methods for tolerance enforcement.  For plants, high-performance liquid chromatography with oxidative coulometric electrochemical detector (HPLC/ELCD) Method UCC-D2341 is available as a primary enforcement method for the combined residues of bifenazate and its metabolite D3598.  The method has been forwarded to the Food and Drug Administration (FDA) for inclusion in the Pesticides Analytical Manual, Volume II (PAM II).  The limit of quantification (LOQ) and limit of detection (LOD) of Method UCC-D2341 are 0.01 and 0.005 ppm, respectively.  In addition, a liquid chromatographic system with tandem mass spectrometers (LC-MS/MS) method (NCL ME 245) was recently submitted as a confirmatory method and has been forwarded to FDA.  

Livestock Commodities:  For livestock, HPLC methods with fluorescence detection or ELCD are available as primary methods for the enforcement of tolerances for residues of bifenazate and its regulated metabolites in livestock matrices.  The methods have undergone a successful validation by the Agency and have been forwarded to FDA for inclusion in PAM II.  In addition, the LC-MS/MS Method NCL ME 259 was recently submitted as a confirmatory method, and this method was also forwarded to FDA.  The validated LOQ was 0.01 ppm for each analyte.  The LOD was reported as 0.005 ppm.  

2.2.2	Recommended Tolerances

In accordance with the most recent guidance concerning tolerance expressions, HED recommends that the tolerance expression for 40 CFR §180.572 be changed as indicated above (see 860.1550 Proposed Tolerances).  A revised Section F specifying the new tolerance expression, HED-recommended tolerances, and correct commodities should be submitted.  

Table 2.2.2.  Tolerance Summary for Bifenazate.
Commodity
                           Proposed Tolerance (ppm)
                          Recommended Tolerance (ppm)
Correct Commodity Definition/Comments
To be established under 40 CFR §180.572 (a) General. (1)
Herb, subgroup 19A, fresh leaves
                                      30
                                      30
Herb, subgroup 19A, fresh leaves, except chervil and chive
Herb, subgroup 19A, dried leaves, except chervil, dried and chive, dried
                                      140
                                      300

Timothy, forage
                                      140
                                      200
Tolerance with regional registrations
Timothy, hay
                                      120
                                      150
Tolerance with regional registrations
Fruit, pome, group 11-10
                                     0.75
                                     0.75

Vegetable, fruiting, group 8-10
                                      2.0
                                      4.0
Tolerance level for harmonization with PMRA

2.2.3	Revisions to Petitioned-For Tolerances

The residue data for bifenazate and D3598 in/on basil, grass forage, and grass hay were analyzed using the OECD tolerance-calculation procedures.  The recommended tolerance for residues of bifenazate and its metabolite are 30 ppm in/on basil (translated to herb, subgroup 19A, fresh leaves, except chervil and chive), 200 ppm in/on grass forage (translated to timothy, forage), and 150 ppm in/on grass hay (translated to timothy, hay).  The recommended tolerance level of 300 ppm for herb, subgroup 19A, dried leaves, except chervil, dried, and chive, dried is based on residue data that examined residue levels in fresh and dried basil.  The tolerance level for pome fruit is based on the currently established tolerance.  The recommended-tolerance level for fruiting vegetables is based on comments from the Pest Management Regulatory Agency (PMRA) of Health Canada (correspondence from M. Thomas, PMRA to D. Vogel, EPA, dated:  02/24/2014).  PMRA has proposed a maximum residue limit (MRL) for bifenazate on fruiting vegetables at 4.0 ppm.  A revised Section F is required to adjust the tolerance levels, correct proposed commodities, and to change the tolerance expression (see Recommended Tolerances section).

2.2.4	International Harmonization

There are currently no established Codex, Canadian, or Mexican MRLs for bifenazate in/on herbs, and timothy forage and hay.  The tolerance expressions for plant commodities are harmonized between the U.S. and Canada, but not with Codex.  Canadian MRLs are established for residues in/on apples, but not for other crops in the pome fruit crop group.  The tolerance level for residues in/on fruiting vegetables is harmonized with Canada (see above).  The Canadian MRL for residues in apples is not harmonized with the U.S. tolerance levels for residues in pome fruits.  Codex MRLs are established for pome fruits, and for peppers and tomato (but not for the other members of the fruiting vegetables crop group).  Additionally the Codex MRLs for residues in pome fruits, peppers, and tomato are not harmonized with the U.S. tolerance levels.

2.3	Label Recommendations

The proposed use directions for Acramite[(R)] 50WS (EPA Reg. No. 400-503) and Acramite[(R)] 4SC (EPA Reg. No. 400-514) on herbs and timothy grass are sufficient to allow for evaluation of the submitted residue data.  Bifenazate is currently registered for use on pome fruits and fruiting vegetables.  The available field trial data support the proposed use directions for bifenazate on herbs, subgroup 19A, timothy, pome fruits, and fruiting vegetables.  

3.0	Introduction

3.1	Chemical Identity

Table 3.1.  Test Compound Nomenclature.
Compound
                                       
Common name
Bifenazate
Company experimental name
D2341
IUPAC name
isopropyl 3-(4-methoxybiphenyl-3-yl)carbazate or
isopropyl 2-(4-methoxybiphenyl-3-yl)hydrazinoformate
CAS name
1-methylethyl 2-(4-methoxy[1,1′-biphenyl]-3-yl)hydrazinecarboxylate
CAS registry number
149877-41-8
End-use products (EPs)
Acramite[(R)] 50WS (EPA Reg. No. 400-503)
Acramite[(R)] 4SC (EPA Reg. No. 400-514)

Compound
                                       
Common name
None
Company experimental name
D3598
IUPAC name
isopropyl-(4-methoxy-[1,1'-biphenyl]-3-yl)diazenecarboxylate
CAS name
diazenecarboxylic acid, 2-(4-methoxy-[1,1'-biphenyl]-3-yl), 1-methylethyl ester
CAS registry number
149878-40-8
                                       
Compound
                                       
Common name
None
Company experimental name
A1530
IUPAC name
1,1'-biphenyl, 4-ol
CAS name
p-hydroxybiphenyl
CAS registry number
92-69-3
                                       
Compound

                                       
Common name
None
Company experimental name
A1530 sulfate, biphenyl-4-ol-sulfate
IUPAC name
Unknown
CAS name
Unknown
CAS registry number
Unknown

3.2	Physical/Chemical Characteristics
BIFENAZATE IS A SELECTIVE MITICIDE/insecticide that controls the motile stage of mites either by direct contact or through contact with foliar residues.  Bifenazate is expected to be slightly mobile, but not persistent in the environment.  Bifenazate is expected to rapidly dissipate in soil and aquatic environments as a result of aqueous hydrolysis, direct aqueous photolysis, and aerobic degradation in soil (Memo, 10/17/2011, J. Hetrick, et al., D388230).  

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

3.3	Pesticide Use Pattern

The proposed use directions are presented in Table 3.3, below.  The information presented in Table 3.3 was obtained from undated draft labels for Acramite[(R)] 50WS (EPA Reg. No. 400-503) and Acramite[(R)] 4SC (EPA Reg. No. 400-514).

Table 3.3.  Summary of Proposed and Registered Directions for Use of Bifenazate.
Applic. Timing, Type, and Equip.
                                  Formulation
                                  [Reg. No.]
                                 Applic. Rate 
                                   (lb ai/A)
                          Max. No. Applic. per Season
                          Max. Seasonal Applic. Rate
                                   (lb ai/A)
                                      PHI
                                    (days)
                        Use Directions and Limitations
          Herb, Subgroup 19A (Except Chervil and Chive, Proposed Use)
Ground Application
                          Acramite[(R)] 50WS [400-503]
                                 0.38 to 0.50
                                       1
                                0.50 (implied)
                                       3
Application is to be made in a minimum of 50 gal/A using ground equipment.  For maximum control, applications must be made as soon as mites appear.  
                    Pome Fruit, Group 8-10 (Registered Use)
Ground  Application 
                               Acramite[(R)] 4SC
                                   [400-514]
                          Acramite[(R)] 50WS [400-503]
                                 0.38 to 0.50
                                       1
                                0.50 (implied)
                                       7
Application is to be made in a minimum of 50 gal/A using ground equipment.  For maximum control, applications must be made as soon as mites appear.  
               Fruiting Vegetables, Group 8-10 (Registered Use)
Ground Application
                               Acramite[(R)] 4SC
                                   [400-514]
                          Acramite[(R)] 50WS [400-503]
                                 0.38 to 0.50
                                       1
                                0.50 (implied)
                                       3
Application is to be made in a minimum of 50 gal/A using ground equipment or 10 gal/A using aerial equipment.  For maximum control, applications must be made as soon as mites appear.  
                            Timothy (Proposed Use)
Ground or Aerial Application
                               Acramite[(R)] 4SC
                                   [400-514]
                                       
                                 0.43 to 0.75
                                       1
                                0.75 (implied)
                                  0 (forage)
                                    7 (hay)
Application is to be made in a minimum of 20 gal/A using ground equipment or 10 gal/A by air.  For maximum control, applications must be made as soon as mites appear.  

The following rotational crop restriction is specified:  "This product has a plantback restriction of 30 days.  Do not plant another crop within 30 days after last Acramite[(R)] application due to chances of bifenazate residues showing up in rotational crops."

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

3.4	Anticipated Exposure Pathways
RD HAS REQUESTED AN ASSESSMENT OF HUMAN-HEALTH RISK TO SUPPORT THE IR-4 PROPOSED TOLERANCES FOR RESIDUES OF BIFENAZATE AND ITS METABOLITE D3598 IN/ON HERBS, SUBGROUP 19A, DRIED AND FRESH, timothy hay and forage, fruiting vegetables, group 8-10 and pome fruit, group 8-10.  Humans may be exposed to bifenazate in food and drinking water, since bifenazate may be applied directly to growing crops and applications may result in bifenazate reaching surface and ground water sources of drinking water.  In an occupational setting, applicators may be exposed while handling the pesticide prior to application, as well as during application.  In addition, adults and children may be exposed to bifenazate in residential settings due to the currently registered uses.  This risk assessment considers all of the exposure pathways based on the proposed new uses of bifenazate, but also considers the existing registered uses as well, particularly for the dietary and residential exposure assessment.

3.5	Consideration of Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and Low-Income Populations," (http://epa.gov/compliance/ej/resources/policy/exec_order_12898.pdf).  As a part of every pesticide risk assessment, OPP considers a large variety of consumer subgroups according to well-established procedures.  In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup's food and water consumption, and activities in and around the home that involve pesticide use in a residential setting.  Extensive data on food consumption patterns are compiled by the USDA under the National Health and Nutrition Examination Survey, What We Eat in America, (NHANES/WWEIA; 2003-2008) and are used in pesticide risk assessments for all registered food uses of a pesticide.  These data are analyzed and categorized by subgroups based on age, season of the year, ethnic group, and region of the country.  Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant.  Whenever appropriate, non-dietary exposures based on home use of pesticide products and associated risks for adult applicators and for toddlers, youths, and adults entering or playing on treated areas postapplication are evaluated.  Further considerations are currently in development as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.

4.0	Hazard Characterization and Dose-Response Assessment

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

4.1	Toxicology Studies Available for Analysis

The toxicological database for bifenazate is complete and adequate for FQPA evaluation, selection of PODs for the various routes of exposure, and for dose-response evaluation.  Appendix A is a summary of the bifenazate toxicological database.  In the previous human health risk assessment for bifenazate (Memo, 07/14/2010, W. Wassell, et al., D371783), the toxicity database deficiencies consisted of an immunotoxicity study as well as the neurotoxicity screening battery tests as specified in the revised 40 CFR §158 requirements.  A 90-day inhalation toxicity study was also requested.  Since that last risk assessment, all four studies have been submitted and reviewed, and are included in this hazard characterization.

The Hazard and Science Policy Council (HASPOC) concluded that a developmental neurotoxicity (DNT) study is not required for bifenazate (TXR# 0056728).  The HASPOC's original decision to require a DNT was based upon what was thought to be the presence of the three triggers necessary for the study including; 1) an increased fetal sensitivity in the developmental rat study (treatment related early resorptions at all doses tested); 2) specific effects on the nervous system in both neurotoxicity screening battery tests; and 3) a neurotoxic pesticidal mechanism of action.  Syngenta provided comments regarding the Agency's conclusions (MRID 48997401) and subsequently submitted the raw historical control data (MRID 49271101) for the developmental rat study, which ultimately removed the Agency's concern for an increased fetal sensitivity (Memo, 02/20/2014, A. Dunbar et al., D416994).  The Agency further conducted its own statistical analyses in the neurotoxicity screening batteries, and determined that the effects observed were not neurotoxic in nature but instead those indicative of overt systemic toxicity.  Finally, a rigorous literature search by the Agency and Syngenta revealed conflicting evidence concerning the pesticidal mechanism of action (EPA-HQ-OPP-2012-0633; Weiland and Rao, Feb 11, 2013: Response to "Anticipated Data Needs" for bifenazate and DNT Guideline 870.6300 requirement).   

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

Recovery of bifenazate was >93% of the administered dose and was recovered within 72 hours of treatment for both the low- and high-dose groups.  Low-dose male and female rats absorbed ~85% of the administered dose as indicated by the amount of radiolabel recovered in the urine, cage wash, tissues/carcass, and bile.  However, absorption was saturated at the high dose in male and female rats, as 57-64% of the administered dose was recovered in the feces in the biliary study.  

There was no significant tissue accumulation of the test material observed.  The highest tissue levels were found in the liver and whole blood, although the concentration of the test material represented <3% of the administered dose 6 hours after treatment.  Comparison of the whole blood and red blood cell concentrations suggests that most of the test material was carried in the plasma.  

The feces was the primary elimination route for low-dose rats with ~66% of the administered dose recovered in this media.  Radioactivity in the feces was greater for the high-dose rats due to saturated absorption that resulted in subsequently greater unabsorbed test material.  Urinary excretion was a relatively minor route with ~25% of the administered dose recovered in this media for both male and female low-dose rats.  For the high-dose male and female rats urinary excretion was notably lower (<10% of the administered dose) due to saturated absorption.  Cmax was reached earlier following a 10 mg/kg dose (5-6 hours) than the 1000 mg/kg dose (18-24 hours).  In addition, the half-life was slightly longer at the 1000 mg/kg dose (12-16 hours) than at the 10 mg/kg dose (12-13 hours).  No apparent sex-related differences in the pharmacokinetics of bifenazate were observed.  

Bifenazate was highly metabolized with eight primary metabolites identified in the feces of both sexes for both low- and high-doses.  These metabolites, as well as those identified in the urine and bile, were due to metabolic reactions including hydrazine oxidation, demethylation, ring hydroxylation, and molecular scission with loss of the hydrazine carboxylic acid portion with subsequent glucuronide or sulfate conjugation with glucuronic acid or sulfate.  The parent compound represented <7.2% of the administered dose of low-dose male and female rats, and >48% of the dose in high-dose rats, consistent with the saturation of absorption observed for the high-dose rats.  Six metabolites were identified in the bile of both sexes; however variations in their concentrations between bile and feces may represent further metabolic attack by intestinal bacteria.

4.2.1	Dermal Absorption

No studies are available to directly provide a dermal-absorption factor.  However, when the results of a 21-day dermal rat study LOAEL = 400 mg/kg/day) were considered along with the results of the oral developmental toxicity rat study (LOAEL = 100 mg/kg/day), the ratio provided an estimated 25% dermal-absorption factor (100 mg/kg/day  400 mg/kg/day) (Memo, 05/20/2001, J. Rowland, TXR #0014576).

4.3	Toxicological Effects

4.3.1	Summary of Toxicological Effects

Bifenazate was categorized as having low acute toxicity (Toxicity Category IV) for the oral, dermal and inhalation routes of exposure for this duration.  For subchronic oral exposures, the dog is the most sensitive species.  For chronic oral exposures, the dog and the rat are equally sensitive.  

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

In the rat developmental toxicity study, the maternal effects consisted of clinical signs of toxicity, decreased body weight and body-weight gains, and reduced food consumption at the mid-dose.  Increases in early fetal resorptions occurred at the same doses that caused maternal toxicity.  In the rabbit developmental toxicity study, there were no maternal or developmental effects up to the HDT.  In the two-generation rat reproduction study, the parental effects occurred at the mid-dose and consisted of decreased body weight and body-weight gains.  There were no reproductive or offspring effects up to the HDT.

In the acute neurotoxicity study, treatment related effects were seen only at the HDT, and consisted of decreased motor activity (rearing in females; center time in both sexes).  In the subchronic neurotoxicity study, effects were also only seen at the HDT (34.5 mg/kg/day) and consisted of decreased landing foot splay (males), decreased fore- and hindlimb grip strength (males), decreased motor activity measurements consisting of center times (females) and rearing activity (both sexes).  

There were no effects in the immunotoxicity study up to the HDT.

In the 21-day dermal toxicity study in rats, adverse effects occurred at the mid-dose of 400 mg/kg/day and manifested as kidney effects (↑urinary ketones, ↑urinary protein, ↑urinary specific gravity, and ↓urinary volume in both sexes), and hematotoxic effects (↑incidences of extramedullary hematopoiesis in the spleen in both sexes).  Similar to oral exposure studies, decreased body weights in females, and decreased food consumption in both sexes were associated with the target organ effects.  

In the 28-day inhalation study, there were statistically significant decreased thymus weights (↓21-32%) in females at all of the concentrations tested.  Starting at the mid-concentration (0.075 mg/L), there were clinical signs in females (dried-red material around the nose), and decreased heart weights in females.  There was a concentration-dependent increased incidence of slight to mild olfactory epithelial degeneration in nasal levels III, IV, and V (30% of males and 40-50% of females).  There was also an increased incidence of brown pigment in the spleen in females (80% at the mid-concentration and 90% at the high-concentration).  At the highest concentration tested, there were also decreased lung weights in both sexes (↓14%).  

In the mouse carcinogenicity study, males and females were tested up to 225 ppm and 175 ppm, respectively.  Dosing was considered adequate based on decreased body weight and body-weight gains in females.  In male mice, there was an increase in the incidence of liver adenomas only, which, while being slightly above historical control levels, was not statistically significant by pair-wise comparison.  There also was no progression of the adenomas to carcinomas in males in this study.  

In addition, benign hepatocellular adenomas and hepatocellular carcinomas had low occurrences in high-dose females and were within historical control ranges.  In rats, the HDT was 200 ppm in males and 160 ppm in females (9.7 mg/kg/day, each).  Toxicity at the high-dose level was mild, and consisted mainly of small decreases in body weight, body-weight gain, and food consumption during weeks 52-77 of the study.  A full battery of mutagenicity studies were negative for mutagenic or clastogenic activity. 

4.4	Safety Factor for Infants and Children (FQPA SF)

4.4.1	Completeness of the Toxicology Database

The risk assessment team has concluded that the FQPA SF should be reduced to 1x.  The following acceptable studies are available for FQPA consideration:  (1) developmental toxicity studies in rats and rabbits; (2) two-generation reproductive study in rats; and (3) acute and subchronic neurotoxicity studies.

4.4.2	Evidence of Neurotoxicity

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

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

There is no evidence of increased susceptibility of offspring following pre- or postnatal exposure to bifenazate in rats or rabbits.

4.4.4	Residual Uncertainty in the Exposure Database

The exposure databases are sufficient to determine the nature/magnitude of the residue in food and water.  For acute exposure for the general population and chronic exposure, the dietary exposure analyses are unlikely to underestimate exposure as they incorporated tolerance-level residues, 100% CT (acute), PCT (chronic), and modeled drinking water estimates.  For acute analysis for females 13 to 49 years, the dietary analysis is unlikely to underestimate exposure as PDP data, crop field trial data, PCT estimates and modeled drinking water estimates were utilized.  The residential handler and post-application exposure assessments are based upon the residential SOPs.  The residential SOPs are based upon reasonable worst-case assumptions and are not expected to underestimate risk.  

4.5	Toxicity Endpoint and Point of Departure Selections

4.5.1	Dose-Response Assessment

Acute Dietary Endpoint for All Populations:  The endpoint used for establishing the acute population-adjusted dose (aPAD) for the general population was selected from the acute neurotoxicity study in rats.  An aPAD of 6 mg/kg/day was derived from a NOAEL of 600 mg/kg/day and a 100-fold uncertainty factor (UF) that included a 10x UF for inter-species extrapolations, 10x UF for intra-species variations, and a 1x FQPA SF.  Effects at the LOAEL of 2000 mg/kg included decreased motor activity (rearing in females; center time in both sexes).  This study is appropriate for the duration of exposure and it is protective for the general population.

Acute Dietary Endpoint for Females 13-49 Years of Age:  The endpoint for establishing the aPAD for females 13-49 years of age was selected from the prenatal developmental toxicity study in rats.  An aPAD of 0.1 mg/kg/day was derived from a NOAEL of 10 mg/kg/day and 100-fold UF that included a 10x UF for inter-species extrapolations, 10x UF for intra-species variations, and a 1x FQPA SF.  At the LOAEL of 100 mg/kg/day, maternal effects included clinical signs, decreased absolute body weights, and food consumption during the dosing period.  At the same dose, there was an increased incidence of early fetal resorptions.  This study is appropriate for the duration of exposure as well as protective for pregnant females ages 13-49 years of age.

Chronic Dietary Endpoint for the General Population:  The chronic dietary endpoint for the general population was selected from co-critical studies with similar NOAELs (1 and 1.5 mg/kg/day).  Specifically, the chronic dog study established a LOAEL at 8.9 mg/kg/day based upon changes in hematological and clinical chemistry parameters and histopathological changes in the bone marrow, liver, and kidney.  A similar LOAEL of 15.4 mg/kg/day was also established in the mouse carcinogenicity study based on changes in hematological parameters and kidney weights.  The endpoint used for deriving the chronic PAD (cPAD) was selected from the chronic toxicity study in dogs.  The cPAD of 0.01 mg/kg/day was derived from a NOAEL of 1 mg/kg/day and a 100-fold UF that included a 10x UF for inter-species extrapolations, 10x UF for intra-species variations, and a 1x FQPA SF.  The endpoint of concern was seen following repeated oral exposure in the most sensitive species and thus is appropriate for assessing potential risk via chronic dietary exposure to bifenazate.  This study is appropriate for the duration of exposure and is protective of the general population.

Short- and Intermediate-Term Incidental Oral Endpoints:  The short- and intermediate-term incidental oral endpoints were based upon the results from the subchronic 90-day dog study where the NOAEL is 0.9 mg/kg/day.  The LOAEL is 10.4 mg/kg/day based on changes in hematologic parameters.  The LOC is 100 based upon a 10x UF for inter-species extrapolations, 10x UF for intra-species variations, and a 1x FQPA SF.  This study is appropriate for the durations of exposure and the population of concern, children in residential settings.  It is noted that the effects and PODs seen in this study are consistent with the longer-term dog and mouse studies used to set the chronic dietary endpoint.

Short- (1-30 days) and Intermediate- (1-6 months) Term Dermal Endpoints:  The short- and intermediate-term dermal endpoints were derived from the 21-day dermal rat study where the NOAEL is 80 mg/kg/day.  The LOAEL is 400 mg/kg/day based upon decreased body weight in females, decreased food consumption in both sexes, increased urinary ketones, increased urinary protein, increased urinary specific gravity, and decreased urinary volume in both sexes, and increased incidences of extramedullary hematopoiesis in the spleen in both sexes.  The LOC is 100 based upon a 10x UF for inter-species extrapolations, and a 10x UF for intra-species variations.  This study protects for the early resorptions in the developmental rat study where the maternal and fetal effects occur at the same dose.  This study is appropriate for the route as well as the durations of exposure, in both residential and occupational settings.

Short- (1-30 days) and Intermediate- (1-6 months) Term Inhalation Endpoints:  The short- and intermediate-term inhalation endpoints were derived from the route-specific 28-day inhalation study in rats where the NOAEL is 0.030 mg/L.  The LOAEL is 0.075 mg/L for both sexes based on dried red material around the nose in females, lower body weights and body-weight gains, decreased food consumption, decreased heart and thymus weights in females, increased incidences of mild brown pigmentation of the spleen, and minimal to mild degeneration of the olfactory epithelium within nasal levels III, IV, and V in both sexes.  HECs were derived from this study based upon this degeneration of the olfactory epithelium which is considered a portal-of-entry effect.  For residential exposure, the HEC is 0.0009 mg/L, and for occupational exposure, the HEC is 0.0039 mg/L.  HEDs were subsequently calculated (0.14 mg/kg/day for residential exposure and 0.19 mg/kg/day for occupational exposure).  For details regarding the calculation of the HECs and HEDs, see Appendix B.  These HEDs are protective of the systemic effects observed through the inhalation route.  This study is thus appropriate for the route and duration of exposure, and is protective of adults in occupational and residential settings.

The methods and dosimetry equations described in EPA's RfC guidance (1994) are suited for calculating HECs based on the inhalation toxicity NOAEL for use in MOE calculations.  The regional deposited-dose ratio (RDDR), which accounts for the particulate diameter (mass median aerodynamic diameter [MMAD] and geometric standard deviation [g] of aerosols), can be used to estimate the different dose fractions deposited along the respiratory tract.  The RDDR is also based on interspecies differences in ventilation and respiratory-tract surface areas.  Thus, the RDDR can be used to adjust an observed inhalation particulate exposure of an animal to the predicted inhalation exposure for a human.  For the 4-week inhalation study with bifenazate, an RDDR was estimated at 2.8 based on the reported MMAD of 2.20 um and standard deviation (g) of 2.78 and the respiratory-tract surface area of the rat relative to the human (see Appendix B for detailed calculations).  Since the rat inhalation study was carried out for 6 hr/day for 5 days/week, the only exposure adjustment made was in the assumption of 8 hrs/day for human occupational exposures.  The resulting HECs are 0.0009 mg/L and 0.0039 mg/L for residential and occupational exposures.  The LOC is 30 which includes interspecies (3x), and intraspecies (10x) uncertainty factors.  The interspecies factor was reduced from 10x to 3x due to the HEC calculation accounting for pharmacokinetic (not pharmacodynamic) interspecies differences.

4.5.2	Recommendation for Combining Routes of Exposures for Risk Assessment

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

4.5.3	Cancer Classification and Risk Assessment Recommendation

The available data show no evidence of carcinogenicity in rats at adequate dose levels, and no evidence of carcinogenicity in mice at adequate doses.  In the mouse, there was an increase in the incidence of adenomas only, which, while being slightly above historical control levels, was not statistically significant.  There was also no progression of time for mouse adenomas to carcinomas.  In accordance with the proposed Draft Guidelines for Carcinogen Risk Assessment (1996), the Hazard Identification Assessment Review Committee (HIARC) classified bifenazate as "not likely" to be carcinogenic to humans (Memo, 05/30/2001, J. Rowland, et al., TXR# 0014576).

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

Table 4.5.4.1.  Summary of Toxicological Doses and Endpoints for Bifenazate for Use in Dietary and Non-Occupational Human-Health Risk Assessments.
                              Exposure/ Scenario
                                      POD
                             Uncertainty/FQPA SFs
                RfD, PAD, Level of Concern for Risk Assessment
                        Study and Toxicological Effects
Acute Dietary (General Population, including Infants and Children)
NOAEL = 600 mg/kg/day
                                   UFA = 10x
                                   UFH = 10x
                                 FQPA SF = 1x
Acute RfD = 6 mg/kg/day
aPAD = 6 mg/kg/day
Acute Neurotoxicity Screening Battery-Rats
LOAEL = 2000 mg/kg/day based on decreased motor activity (rearing in females).
Acute Dietary (Females 13-49 years of age)
NOAEL = 10 mg/kg/day
                                   UFA = 10x
                                   UFH = 10x
                                 FQPA SF = 1x
Acute RfD = 0.1 mg/kg/day
aPAD = 0.1 mg/kg/day
Prenatal Developmental Toxicity-Rats
Developmental LOAEL = 100 mg/kg/day based upon clinical signs, decreased body weight and food consumption during the dosing period.
Chronic Dietary (All Populations)
NOAEL = 1.0 mg/kg/day
Co-critical Study
NOAEL = 1.5 mg/kg/day
                                   UFA = 10x
                                   UFH = 10x
                                 FQPA SF = 1x
Chronic RfD = 0.01
mg/kg/day
cPAD = 0.01 mg/kg/day
Chronic Toxicity-Dogs
LOAEL = 8.9/10.4 mg/kg/day [M/F] based on changes in hematological and clinical chemistry parameters, and histopathology in bone marrow, liver, and kidney in the one-year dog feeding study.
Carcinogenicity Study-Mouse
LOAEL = 15.4 (M) mg/kg/day based on hematology parameters and possibly kidney weights.
Incidental Oral Short Term (1 -30 days) and Intermediate Term
NOAEL = 0.9 mg/kg/day
                                   UFA = 10x
                                   UFH = 10x
                                 FQPA SF = 1x
Residential LOC for MOE = 100
90-Day Subchronic- Dogs
LOAEL = 10.4 mg/kg/day based upon changes in hematological parameters in both sexes, increased bilirubin in the urine in males, increased absolute and relative liver weight in females and liver histopathological effects in both sexes.
Dermal Short- and Intermediate-Term (1-30 days and 1-6 months)
LOAEL = 80 mg/kg/day
                                   UFA = 10x
                                   UFH = 10x
                                 FQPA SF = 1x
Residential LOC for MOE = 100
21-Day Dermal Toxicity-Rat
LOAEL = 400 mg/kg/day based on decreased body weight in females, decreased food consumption in both sexes, increased urinary ketones, increased urinary protein, increased urinary specific gravity, and decreased urinary volume in both sexes, and increased incidence of extramedullary hematopoiesis in the spleen in both sexes.
Inhalation Short- and Intermediate-Term (1-30 days, and 1-6 months)
Rat NOAEL = 0.03 mg/L 
                                   UFA = 3x
                                   UFH = 10x
                                 FQPA SF = 1x
                         Residential LOC for MOE = 30
28-Day Inhalation Toxicity-Rat
LOAEL = 0.075 mg/L [M/F] on dried red material around the nose in females, lower body weights and body-weight gains, decreased food consumption, decreased heart and thymus weights in females, increased incidences of mild brown pigmentation of the spleen, and minimal to mild degeneration of the olfactory epithelium within nasal levels III, IV, and V.

HEC= 0.0009 mg/L
HED = 0.14 mg/kg bw/day

Cancer (oral, dermal, inhalation)
Bifenazate is classified as "not likely to be a human carcinogen".
a = 25% dermal-absorption factor.  Point of departure (POD) = a data point or an estimated point that is derived from observed dose-response data and  used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures.  NOAEL = no-observed adverse-effect level.  LOAEL = lowest-observed adverse-effect level.  UF = uncertainty factor.  UFA = extrapolation from animal to human (interspecies).  UFH = potential variation in sensitivity among members of the human population (intraspecies).  UFL = use of a LOAEL to extrapolate a NOAEL.  FQPA SF = FQPA Safety Factor.  PAD = population-adjusted dose (a = acute, c = chronic).  RfD = reference dose.  MOE = margin of exposure.  LOC = level of concern.  N/A = not applicable.

Table 4.5.4.2 Summary of Toxicological Doses and Endpoints for Bifenazate for Use in Occupational Human Health Risk Assessments
                              Exposure/ Scenario
                                      POD
                              Uncertainty Factors
                     Level of Concern for Risk Assessment
                        Study and Toxicological Effects
Dermal Short- and Intermediate-Term (1-30 days and 1-6 months)
LOAEL = 80 mg/kg/day 
                                   UFA = 10x
                                   UFH = 10x
                                       
Occupational LOC for MOE = 100
21-Day Dermal Toxicity- Rat
LOAEL = 400 mg/kg/day based on decreased body weight in females, decreased food consumption in both sexes, increased urinary ketones, increased urinary protein, increased urinary specific gravity, and decreased urinary volume in both sexes, and increased incidence of extramedullary hematopoiesis in the spleen in both sexes.
Inhalation Short- and Intermediate-Term (1-30 days, and 1-6 months)
Rat NOAEL = 0.03 mg/L 
                                   UFA = 3x
                                       
                                   UFH = 10x
                                       
Occupational LOC for MOE = 30
28-Day Inhalation Toxicity-Rat
LOAEL = 0.075 mg/L [M/F] based on dried red material around the nose, lower body weights and body-weight gains, decreased food consumption, mild brown pigmentation of the spleen, and minimal to mild degeneration of the olfactory epithelium within nasal levels III, IV, and V in both sexes.

HEC = 0.0039 mg/L
HED = 0.19 mg/kg bw/day

Cancer (oral, dermal, inhalation)
Bifenazate is classified as "not likely" to be a human carcinogen.
a = 25% dermal-absorption factor.  Point of departure (POD) = a data point or an estimated point that is derived from observed dose-response data and  used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures.  NOAEL = no-observed adverse-effect level.  LOAEL = lowest-observed adverse-effect level.  UF = uncertainty factor.  UFA = extrapolation from animal to human (interspecies).  UFH = potential variation in sensitivity among members of the human population (intraspecies).  MOE = margin of exposure.  LOC = level of concern.  

5.0	Dietary Exposure and Risk Assessment 

An overview of the metabolism of bifenazate can be found in the most recent residue chemistry assessment (Memo, pending, W. Wassell, D388800).

5.1	Residues of Concern Summary and Rationale

Plant Commodities:  The qualitative nature of the residue in plants is adequately understood based on acceptable studies with apple, orange, cotton, and radish.  Based upon these studies, the HED MARC concluded that for tolerance expression and risk assessment purposes, the residues of concern in crops are bifenazate and its metabolite D3598 (calculated as the stoichiometric equivalent of bifenazate).  

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

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

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

Table 5.1.  Summary of Metabolites and Degradates to be Included in Risk Assessment and Tolerance Expression.
Matrix
Residues Included in Risk Assessment
Residues Included in Tolerance Expression
Plants
bifenazate, D3598 (expressed as parent)
bifenazate, D3598 (expressed as parent)
Livestock (excluding fat)
bifenazate, D3598 A1530, A1530-sulfate (expressed as parent),
bifenazate, D3598, A1530, A1530-sulfate (expressed as parent)
Livestock  -  fat
bifenazate, D3598 (expressed as parent)
bifenazate, D3598 (expressed as parent)
Rotational Crops
could not be determined[1]
could not be determined[1]

Drinking Water
D1989
Not applicable
1.  Based on the results of the confined rotational crop study conducted at 0.5 lb ai/acre (the application rate for the registered crops which are likely to be rotated), HED concluded that residues in rotated crops were unlikely and that tolerances were unnecessary.

5.2	Food Residue Profile

The submitted magnitude of the residue data for basil will support the proposed use pattern for Herbs, Subgroup 19A.  IR-4 has submitted data for bifenazate and its metabolite D3598 on basil from a total of four crop field trials conducted during the 2008 growing season.  The field trials were conducted in CA, SC, and GA.  The residue data were analyzed using the OECD tolerance-calculation procedures.  The tolerance worksheet recommended a tolerance for residues of bifenazate and D3598 at 30 ppm in/on basil (translated to herb, subgroup 19A, fresh leaves, except chervil and chive).  The recommended tolerance level of 300 ppm for herb, subgroup 19A, dried leaves, except chervil, dried, and chive, dried, is based on residue data that examined residue levels in fresh basil and dried basil.  

The submitted magnitude of the residue data for grass forage and hay will support the proposed use patterns for timothy.  IR-4 has submitted data for bifenazate and its metabolite D3598 on grass forage and hay from thirteen crop field trials conducted during the 2004 growing season.  The field trials were conducted in MD (2 trials), NC (1 trial), NJ (1 trial), TN (1 trial), FL (2 trials), TX (1 trial), CO (1 trial), CA (1 trial), ID (1 trial), WA (1 trial), and OR (1 trial).  The residue data were analyzed using the OECD tolerance-calculation procedures.  The tolerance worksheet recommended a tolerance for residues of bifenazate and D3598 at 200 ppm in/on grass forage (translated to timothy, forage) and 150 ppm in/on grass, hay (translated to timothy, hay).  

Livestock feed items are not derived from herbs.  Timothy is used as horse feed.  The proposed use on timothy is for a regional use in two counties of Nevada (Eureka and Humboldt Counties).  Applications can only be made to timothy that is intended for use as horse feed.  The use on timothy was discussed and approved by the ChemSAC (meeting of 1/12/11).  Tolerances are established for residues of bifenazate and its metabolites in/on horse fat, meat, and meat byproduct.  

Bifenazate is currently registered for use on pome fruit (group 11).  IR-4 has proposed expanding the existing tolerances to cover additional commodities that are included in the revised crop group 11-10.  The petitioner further states that the established tolerances for residues in/on pome fruit, group 11 may be deleted upon establishment of the uses and tolerances for residues in/on pome fruit, group 11-10.  Residue data for the use on pome fruit were submitted and reviewed in conjunction with PP#0F6108 (Memo, 8/16/2001, T. Bloem, D277089).

Bifenazate is currently registered for use on fruiting vegetables (group 8).  IR-4 has proposed expanding the existing tolerances to cover additional commodities that are included in the revised crop group 8-10.  The petitioner further states that the established tolerances for residues in/on fruiting vegetables, group 8 may be deleted upon establishment of the uses and tolerances for residues in/on fruiting vegetables, group 8-10.  Residue data for the use on fruiting vegetables were submitted and reviewed in conjunction with PP#3E6517 (Memo, 5/29/2003, T. Bloem, D290053).

Poultry feed items are not derived from herbs, timothy, pome fruit, and fruiting vegetables.  A poultry metabolism study was previously submitted.  Based on this study and the dietary burden, HED concludes that there is no reasonable expectation of finite residues of bifenazate in poultry commodities [Category 3 of 40 CFR §180.6(a)]; therefore, tolerances for secondary residues in poultry tissues and eggs are not required.  

5.3	Water Residue Profile

The information concerning the environmental fate and drinking water assessment of bifenazate were provided by EFED (Memo, 10/17/2011, J. Hetrick, et al., D388230; and Memo, 7/25/2012, J. Hetrick, et al., D402952).  Surface and ground water-monitoring data are not available for bifenazate.  Since water-monitoring data are not available, estimates of bifenazate levels in surface and ground water were provided by EFED using computer models.  Bifenazate is expected to be slightly mobile, but not persistent in the environment.  Bifenazate is expected to rapidly dissipate in soil and aquatic environments as a result of aqueous hydrolysis, direct aqueous photolysis, and aerobic degradation in soil.  EFED provided estimates of drinking water concentrations (EDWCs) for bifenazate using the FQPA FIRST model and the dry bean application scenario (highest registered/proposed use rate).  The resulting chronic EDWCs in ground and surface water were 0.000014 ppm (30-year-annual average) and 0.0112 ppm (annual average), respectively.  The resulting acute EDWC (daily peak) was 0.0373 ppm.

Table 5.3.  Bifenazate EDWCs.
                               Exposure Scenario
                                  EDWC (ppm)
                       30-year Annual Average (not used)
                                   0.000014
                   Annual Average (used in chronic analysis)
                                    0.0112
                      Daily Peak (used in acute analysis)
                                    0.0373

5.4	Dietary Risk Assessment

5.4.1	Description of Residue Data Used in Dietary Assessment

Acute and chronic dietary (food plus drinking water) risk assessments were conducted using the DEEM-FCID, Version 3.16, which uses food consumption data from the USDA's NHANES/WWEIA.  This dietary survey was conducted from 2003 to 2008.  The analyses were conducted in support of a human-health risk assessment for the proposed tolerances for bifenazate and D3598 on timothy and herb, subgroup 19A; and to expand existing uses on pome fruit, group 11, and fruiting vegetables, group 8.  

The acute analysis for the general population, including infants and children, was unrefined and used tolerance-level residues and 100% PCT.  The acute analysis for females 13 to 49 years old was highly refined and incorporated data from the USDA's PDP data, crop field trial data, and PCT estimates.  DEEM (ver. 7.81) default processing factors were assumed for all commodities excluding apple juice, grape juice, and wine/sherry.  The processing factors for these commodities were reduced to 1.0, based on data from processing studies.  The analyses also included the acute surface water point estimate (0.0373 ppm) generated using the FIRST model.  

The chronic dietary exposure analysis for all population subgroups was partially refined and used tolerance-level residues and PCT estimates.  DEEM (ver. 7.81) default processing factors were assumed for all commodities excluding apple juice, grape juice, and wine/sherry.  The processing factors for these commodities were reduced to 1.0 based on data from processing studies.  The analyses also included the chronic surface water point estimate (0.0112 ppm) generated using the FIRST model.  

5.4.2	Percent Crop Treated Used in Dietary Assessment

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

The following maximum PCT estimates (Memo, 5/16/12, C. Doucoure, D401788) were used in the acute dietary risk assessment:  almonds:  10%; apples:  5%; apricots:  10%; beans, green:  2.5%; caneberries:  30%; cantaloupes:  2.5%; cherries:  5%; cucumbers:  5%; grapefruit:  5%; grapes:  20%; nectarines:  10%; oranges:  2.5%; peaches:  20%; pears:  30%; pecans:  2.5%; peppers:  10%; pistachios:  2.5%; plums/prunes:  20%; potatoes:  5%; pumpkins:  5%; squash:  2.5%; strawberries:  65%; tomatoes:  10%; walnuts:  5%; and watermelon:  2.5%.  

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

5.4.3	Acute Dietary Risk Assessment

The acute risk estimate utilizes <1% (0.040436 mg/kg/day) of the aPAD for the U.S. population at the 95[th] percentile of exposure.  The most highly exposed population subgroup was children 1 to 2 years old which utilized 1.9% (0.113582 mg/kg/day) of the aPAD at the 95[th] percentile of exposure.  The acute risk estimate utilizes 9.9% (0.009941 mg/kg/day) of the aPAD for females 13 to 49 years old at the 99.9[th] percentile of exposure.  Thus, acute dietary exposure to bifenazate for all population subgroups is not of concern.  

5.4.4	Chronic Dietary Risk Assessment

The chronic risk estimate utilizes 24% (0.002360 mg/kg/day) of the cPAD for the U.S. population.  The most highly exposed population subgroup was children 1 to 2 years old that utilized 74% (0.007438 mg/kg/day) of the cPAD.  Thus, chronic dietary exposure to bifenazate for all population subgroups is not of concern.  

5.4.5	Cancer Dietary Risk Assessment

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

5.4.6	Summary Table

 Table 5.4.6.  Summary of Dietary (Food and Drinking Water) Exposure Risk for Bifenazate[1].
                              Population Subgroup
                       Acute Dietary (95[th] Percentile)
                                Chronic Dietary
                                        
                          Dietary Exposure (mg/kg/day)
                                     % aPAD
                                Dietary Exposure
                                  (mg/kg/day)
                                     % cPAD
 General U.S. Population
                                    0.040436
                                     <1
                                   0.002360
                                      24
 All Infants (<1 year old)
                                    0.079571
                                      1.3
                                   0.003713
                                      37
 Children 1-2 years old
                                    0.113582
                                      1.9
                                   0.007438
                                      74
 Children 3-5 years old
                                    0.098092
                                      1.6
                                   0.005635
                                      56
 Children 6-12 years old
                                    0.055662
                                     <1
                                   0.003053
                                      31
 Youth 13-19 years old
                                    0.031028
                                     <1
                                   0.001858
                                      19
 Adults 20-49 years old
                                    0.031220
                                     <1
                                   0.002106
                                      21
 Adults 50-99 years old
                                    0.028073
                                     <1
                                   0.001681
                                      17
 Females 13-49 years old
                                  0.009941[2]
                                      9.9
                                   0.001950
                                      20
 1.  The values for the highest exposed population for each type of risk assessment are bolded.
 2.  The acute exposure data for females 13 to 49 years is from 99.9[th] percentile.

6.0 Residential (Non-Occupational) Exposure/Risk Characterization

The proposed uses do not involve applications by homeowners or commercial applicators in residential settings.  Therefore, no new residential exposure is expected.  However, there are existing residential uses that have been reassessed in this document to reflect updates to HED's 2012 Residential SOPs (http://www.epa.gov/pesticides/science/residential-exposure-sop.html) along with policy changes for body weight assumptions.  

6.1	Residential (Non-Occupational) Exposure/Risk Characterization

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

(1) mixing/loading/applying liquids with manually-pressurized handwand,  
(2) mixing/loading/applying liquids with hose-end sprayer,
(3) mixing/loading/applying liquids with backpack, and
(4) mixing/loading/applying liquids with sprinkler can.

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

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

Short-term risk estimates for residential handlers are presented in Table 6.1.  Intermediate-term exposures are not likely because of the intermittent nature of applications by homeowners.  Short-term dermal and inhalation risk estimates to residential handlers do not exceed HED's LOC for all scenarios.  All the ARIs are above 1 and do not exceed HED's LOC for all scenarios.

Table 6.1.  Residential Handler Exposure and Risk Estimates for Bifenazate Applications to Ornamentals.
                               Exposure Scenario
                              Application Rate[1]
                             Area Treated Daily[2]
                      Baseline Unit Exposures (mg/lb ai)
                         Baseline Dose[4] (mg/kg/day)
                                 Baseline MOE[5]
                                    ARI[6]
                                       
                                       
                                       
                                   Dermal[3]
                                 Inhalation[3]
                                    Dermal
                                  Inhalation
                                    Dermal
                                  (LOC = 100)
                             Inhalation (LOC = 30)
                                       
          Mixer/Loader/Applicator for Soluble Concentrates( Liquids)
                                       
Manually-pressurized handwand
                               0.00125 lb ai/gal
                                     5 gal
                                      63
                                     0.018
                                    0.0049
                                   0.0000014
                                    16,000
                                    100,000
                                      150
                               Hose-end sprayer
                               0.00125 lb ai/gal
                                    11 gal
                                      58
                                    0.0014
                                     0.010
                                  0.00000024
                                     8,000
                                    580,000
                                      80
                                   Backpack
                               0.00125 lb ai/gal
                                     5 gal
                                      130
                                     0.14
                                     0.010
                                   0.000011
                                     7,900
                                    13,000
                                      66
                                 Sprinkler can
                               0.00125 lb ai/gal
                                     5 gal
                                      58
                                    0.0014
                                    0.0045
                                  0.00000011
                                    18,000
                                   1,300,000
                                      180
1.  Application rates based on communication between the registrant and EPA regarding the maximum rates allowed on the labels for the residential use sites.  From label 400-508: 2.0 lb ai/gal/128 fl oz gal * 8 fl oz/100 gal = 0.00125 lb ai/gal.
2.  Based on HED's SOPs: Gardens and Trees (HED's 2012 Residential SOPs).
3.  Baseline Dermal:  long-sleeve shirt, long pants, shoes, socks, and no gloves.  Baseline Inhalation:  no respirator.  
4.  Dose (mg/kg/day) = daily unit exposure (mg/lb ai) x application rate (lb ai/gal) x gal treated x % Absorption (100% dermal and 100% inhalation assumed) / Body weight (80 kg).
5.  MOE = NOAEL (Dermal = 80 mg/kg/day; Inhalation = 0.14 mg/kg/day) / daily dose (mg/kg/day).  
6.  ARI = Aggregate Risk Index = 1/ [(Dermal LOC / Dermal MOE) + (Inhalation LOC/ Inhalation MOE)].

6.2	Residential Post-Application Exposure/Risk Characterization

Non-cancer Exposure/Risk Estimates:  Short-term dermal exposure and risk estimates have been assessed for bifenazate.  The scenarios, routes of exposure and lifestages assessed include:

   * Gardens and Trees:  adults (dermal) and children 6 <= 11 years old (dermal).

The lifestages (i.e., adults and children 6 <= 11 years old) selected for each post-application scenario are based on an analysis provided as an Appendix in the 2012 Residential SOPs.  These lifestages are not the only lifestages that could be potentially exposed for these post-application scenarios; however, the assessment of these lifestages is health protective for the exposures and risks for any other potentially exposed lifestages.  

Residential Post-application Exposure Data and Assumptions:  A series of assumptions and exposure factors served as the basis for completing the residential post-application risk assessment.  Each assumption and factor is detailed in the 2012 Residential SOPs (http://www.epa.gov/pesticides/science/residential-exposure-sop.html).

Residential Post-application Non-Cancer Exposure and Risk Equations:  The algorithms used to estimate residential post-application exposure and dose can be found in the 2012 Residential SOPs (http://www.epa.gov/pesticides/science/residential-exposure-sop.html).  For this assessment a chemical-specific dislodgeable foliar residue (DFRt) value of 0.161 ug/cm[2] was used (MRID 44859701).

Table 6.2 lists the updated assessments of currently registered residential post-application exposures and risk estimates.  All adult and children dermal post-application risk estimates for exposure to treated trees and to treated gardens are not of concern (MOEs >= 100).

Table 6.2.  Short- and Intermediate-Term Residential Post-application Exposure and Risk Estimates for Bifenazate.
                              Liquid Formulations
                                   Lifestage
                      Post-application Exposure Scenario
                                    Dose[a]
                                    MOEs[b]
                                  (LOC = 100)
                                     Adult
                                       
                                Garden - sprays
                                       
                                     0.037
                                     2,200
                           Child 6 < 11 years old
                                       
                                     0.025
                                     3,100
                                     Adult
                                Tree  -  sprays
                                    0.0034
                                    23,000
                           Child 6 < 11 years old
                                       
                                    0.0023
                                    34,000
a.  Dermal Dose (mg/kg/day) = DFRt (0.161 ug/cm[2]) x 0.001 (mg/ug) x short-term TC (cm[2]/hr) x ET (hr/day) x Dermal Absorption (100%) 
                                          BW (kg). 
b.  Dermal MOE = NOAEL (80  mg/kg/day) / Dermal Dose (mg/kg/day).

6.3	Spray Drift

Spray drift is a potential source of exposure to those nearby pesticide applications.  This is particularly the case with aerial application, but, to a lesser extent, spray drift can also be a potential source of exposure from the ground application methods (e.g., groundboom and airblast) employed for bifenazate.  The Agency has been working with the Spray Drift Task Force (a task force composed of various registrants which was developed as a result of a Data Call-In issued by EPA), EPA Regional Offices and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices (see the Agency's Spray Drift website for more information) .  The Agency is also taking means to qualitatively and quantitatively address spray drift as a potential source of exposure in risk assessments for pesticides through existing programs such as AgDrift[(R)] and chemical specific properties of pesticides.  The potential for spray drift will be quantitatively evaluated for each pesticide during the Registration Review process that ensures that all uses for that pesticide will be considered concurrently. 

6.4	Residential Bystander Post-Application Inhalation Exposure

Based on the Agency's current practices, a quantitative post-application inhalation exposure assessment was not performed for bifenazate at this time primarily because of the low acute inhalation toxicity (Toxicity Category IV), low vapor pressure, and the low proposed use rate.  However, volatilization of pesticides may be a source of post-application inhalation exposure to individuals nearby pesticide applications.  The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) Scientific Advisory Panel (SAP) in December 2009, and received the SAP's final report on March 2, 2010 (http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html).  The Agency is in the process of evaluating the SAP report and may, as appropriate, develop policies and procedures to identify the need for and, subsequently, the way to incorporate post-application inhalation exposure into the Agency's risk assessments.  If new policies or procedures are developed, the Agency may revisit the need for a quantitative post-application inhalation exposure assessment for bifenazate. 

6.5	Residential Risk Estimates for Use in Aggregate Assessments

Table 6.5 reflects the residential risk estimates that are recommended for use in the aggregate assessment for bifenazate.     
   * The recommended residential exposure for use in the adult aggregate assessment reflects dermal post-application exposure to treated gardens.
   * The recommended residential exposure for use in the children 6 to 11 years old aggregate assessment reflects dermal post-application exposure to treated gardens.  
      
Table 6.5.  Short-Term Residential Exposures for the Bifenazate Combined Residential Risk Calculations.
                                  Population
                        Handler Exposure (mg/kg/day)[1]
                   Post-application Exposure (mg/kg/day)[2]
      Recommended Post-application Exposure for Aggregate (mg/kg/day)[3]
                                       
                                    Dermal
                                  Inhalation
                                    Dermal
                                  Inhalation
                                     Oral
                                       
Adult 
                                    0.0045
                                   0.000011
                                     0.037
                                      N/A
                                      N/A
                                     0.037
Children 6 < 11 yrs old
                                      N/A
                                      N/A
                                     0.025
                                      N/A
                                      N/A
                                     0.025
1.  Handler exposure represents high-end handler exposure, where the appropriate duration is appropriate to assess. 
2.  Postapplication exposure represents high-end dermal, inhalation and/or incidental oral exposure for the relevant exposure duration.
3.  The highest estimated total residential exposure (for adults and child populations) should be used as the basis of the aggregate assessments.

6.0 Aggregate Exposure/Risk Characterization

In accordance with the FQPA, HED must consider aggregate pesticide exposures and risks from three major sources: food, drinking water, and residential exposures.  In an aggregate assessment, exposures from relevant sources are added together and compared to quantitative estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can be aggregated.  When aggregating exposures and risks from various sources, HED considers both the route and duration of exposure.

For bifenazate, aggregate exposure risk assessments were performed for acute, short- and intermediate-term, and chronic exposure.  Bifenazate is classified as "not likely" to be a human carcinogen and thus no cancer aggregate risk assessment is required.  

7.1	Acute Aggregate Risk

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

7.2	Short-Term Aggregate Risk
 
 The short- and intermediate-term toxicological PODs for bifenazate are the same for each route of exposure.  Therefore, for residential exposure scenarios, only short-term exposures were assessed, and are considered to be protective of intermediate-term exposure and risk.

 There are two aggregate risk scenarios that are of interest to HED:  1) adult dermal postapplication exposure to gardens and ornamentals, and 2) children 6 <= 11 years old dermal postapplication exposure to gardens and ornamentals.  Exposure from these two scenarios is aggregated with chronic dietary exposure that is considered to be background exposure.
 
 For the adult and children 6 <= 11 years old short- and intermediate-term aggregate risk assessment, the MOE approach was used to estimate aggregate exposures as the there are different PODs for oral and dermal routes of exposure but the LOC are the same.  The chronic dietary exposure estimate for Adults 20-49 years old and Children 6-12 years old were used in the aggregate risk estimate for adults and children 6 <= 11 years old, respectively.
 
All of the adult and children 6 <= 11 years old chronic dietary + dermal aggregate risk estimates do not exceed HED's LOC (MOEs >= 100).  The results of the adult and children's aggregate risk determinations are presented in Table 7.2.

Table 7.2  Short-Term and/or Intermediate Term Aggregate Risk Calculations
(Option 2:  1/MOE Approach  -  All Levels of Concern are Identical).
                                  Population
                     Short- or Intermediate-Term Scenario
                                       
                           LOC for Aggregate Risk[1]
                                    Dietary
                                    MOE[2] 
                        MOE Oral Residential Exposure 
                      MOE Dermal Residential Exposure[3]
                      MOE Inhalation Residential Exposure
                Aggregate MOE (food, water, and residential)[4]
Adult 20 < 49
100
430
N/A
2,200
N/A
360
Children 6  11
100
290
N/A
3,100
N/A
270
1.  Indicate in this footnote the basis for the LOC (include the standard inter- and intra- species uncertainty factors totaling 100, as well as additional uncertainty factors/safety factors as appropriate.)
2.  MOE dietary = [(short- and intermediate-term oral NOAEL)/(chronic dietary exposure)] or [(0.9 mg/kg/day)/(0.002106 mg/kg/day)] for adults and  [(0.9 mg/kg/day)/(0.003053 mg/kg/day)] for children 6 < 11 years old. 
3.  MOE dermal = [(short- or intermediate-term dermal NOAEL)/(high-end dermal residential exposure)] or [(80 mg/kg/day)/(0.037 mg/kg/day)] for adults and [(80 mg/kg/day)/(0.025 mg/kg/day)] for children 6 < 11 years old.  
4.  MOE Aggregate = 1/[(1/MOE dietary) + (1/MOE dermal)].

7.3	Chronic Aggregate Risk

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

8.0	Cumulative Exposure/Risk Characterization

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

37.1      Occupational Exposure/Risk Characterization

The proposed uses are on agricultural crops; therefore, there is potential for occupational handler and post-application exposure. 

9.0	Occupational Handler Exposure/Risk Estimates

The proposed uses are on agricultural crops; therefore, there is potential for occupational handler and post-application exposure. 

9.1	Post-application Exposure/Risk

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

Based on the anticipated use patterns, current labeling, and types of equipment that can potentially be used, occupational handler exposure is expected from the proposed uses.  The quantitative exposure/risk assessment developed for occupational handlers is based on the following scenarios:
 
Mixer/Loader:
   1. mixing/loading water-soluble bags (engineering controls for the wettable-powder scenario) for aerial application; 
   2. mixing/loading water-soluble bags (engineering controls for the wettable-powder scenario) for groundboom application;
   3. mixing/loading water-soluble bags (engineering controls for the wettable-powder scenario) for airblast application;
   4.  open mixing/loading liquids for aerial application;
   5. open mixing/loading liquids for groundboom application; and
   6. open mixing/loading liquids for chemigation;
       
Applicator:
   7. application of sprays via aerial application;
   8. application of sprays via groundboom equipment; 
   9. application of sprays via airblast application; and
   10. application of sprays via chemigation; 

Mixer/Loader/Applicator:
   11. application of liquids via mechanically pressurized handgun (foliar);
   12. application of wettable-powder in water-soluble bags via mechanically pressurized handgun (foliar);

Flagger:
   13. flagging to support aerial spray applications.

Occupational Handler Exposure Data and Assumptions:  A series of assumptions and exposure factors served as the basis for completing the occupational handler risk assessments.  Each assumption and factor is detailed in pending memo L. Venkateshwara, D388802.  The algorithms used to estimate non-cancer exposure and dose for occupational handlers can be found in Appendix C.  A total ARI was used since the LOC values for dermal exposure (100) and inhalation exposure (30) are different.  The target ARI is 1; therefore, ARIs of less than 1 result in risk estimates of concern.  The ARI was calculated as follows.

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

Summary of Occupational Handler Non-Cancer Exposure and Risk Estimates:  Table 9.1 provides a summary of the estimated exposures and risks to occupational pesticide handlers.  An MOE >= 100 is adequate to protect occupational pesticide handlers from dermal exposures and an MOE >= 30 from inhalation exposures.  Inhalation and dermal risk estimates were not of concern for all scenarios.  All ARIs are greater than 1 and are not risks of concern, except for the following scenarios that require single layer of gloves:
   * Mixing/loading liquids for aerial and chemigation applications and 
   * Mixing/loading/application of liquids via mechanically pressurized handgun (foliar). 

Table 9.1.  Short-/Intermediate-Term Occupational Exposure and Risk Estimates for Bifenazate.  
                               Exposure Scenario
                             Dermal Unit Exposure
                                 (ug/lb ai)[1]
                           Inhalation Unit Exposure
                                 (ug/lb ai)[1]
                              Application Rate[2]
                                       
                            Amount Treated Daily[3]
                                       
                             Dose (mg/kg/day)[4,5]
                                   MOE[6,7]
                                     Total
                                       
                                       
                                       
                                       
                                       
                                    Dermal
                                  Inhalation
                                    Dermal
                                  (LOC = 100)
                                  Inhalation
                                  (LOC = 30)
                                    ARI[9]
              Mixer/Loader Wettable Powder in Water Soluble Bags
                                    Aerial 
                                  Application
                               Eng Control[8]: 
                                      9.8
                             Eng Control[8]: 0.24
                                  0.5 lb ai/A
                                     350 A
                                  EC: 0.0215
                                  EC: 0.00053
                                   EC: 3,700
                                    EC: 360
                                    EC: 9.1
                                   Airblast 
                                 Applications
                                       
                                       
                                  0.5 lb ai/A
                                     40 A
                                  EC: 0.00245
                                  EC: 0.00006
                                  EC: 33,000
                                   EC: 3,200
                                    EC: 81
                            Groundboom applications
                                       
                                       
                                  0.5 lb ai/A
                                     80 A
                                  EC: 0.0049
                                  EC: 0.00012
                                  EC: 16,000
                                   EC: 1,600
                                    EC: 40
                             Mixer/Loader Liquids
                                    Aerial 
                                  Application
                                   Base: 220
                                  Base: 0.219
                                 0.75 lb ai/A
                                     350 A
                                  Base: 0.723
                                  SL/G: 0.123
                                 Base: 0.00072
                                   Base: 110
                                   SL/G: 650
                                   Base: 260
                                  Base: 0.98
                                   SL/G: 3.7
                                 Chemigation 
                                 Applications
                                       
                                       
                                 0.75 lb ai/A
                                     350 A
                                  Base: 0.723
                                  SL/G: 0.123
                                 Base: 0.00072
                                   Base: 110
                                   SL/G: 650
                                   Base: 260
                                  Base: 0.98
                                   SL/G: 3.7
                            Groundboom applications
                                       
                                       
                                 0.75 lb ai/A
                                     80 A
                                  Base: 0.165
                                 Base: 0.00016
                                   Base: 480
                                  Base: 1,200
                                   Base: 4.3
                                  Applicator
                              Applicator, Aerial 
                                   EC: 2.08
                                  EC: 0.0049
                                 0.75 lb ai/A
                                     350 A
EC: 0.00683
EC: 0.0000161
                                  EC: 12,000
                                  EC: 12,000
                                    EC: 92
                        Applicator, Open Cab Groundboom
                                  Base: 78.6
                                  Base: 0.34
                                 0.75 lb ai/A
                                     80 A
Base: 0.00365
Base: 0.443
                                   Base: 180
                                   Base: 750
                                   Base: 1.3
                        Applicator, Open Cab, Airblast
                                  Base: 1770
                                  Base: 4.71
                                  0.5 lb ai/A
                                     40 A
Base: 0.00383

Base: 0.059
Base: 1,400
                                   Base: 160
                                    Base: 9
                            Mixer/Loader/Applicator
Mixing/Loading Applying Liquids with Mechanically Pressurized Handgun (foliar)
                                  Base: 1,300
                                  SLw/G: 390
                                   Base: 3.9
                              0.0375 lb ai/gallon
                                 1,000 Gallons
                                  Base: 0.61
                                   Base   : 
                                    0.00183
                                   Base: 130
                                  SLw/G: 440
                                       
                                   Base: 100
                                       
                                  Base: 0.94
                               SLw/G + Base: 1.9
                                       
Mixing/Loading Applying Water Soluble Packets with Mechanically Pressurized Handgun (foliar)
                                  Base: 1,300
                                   Base: 3.9
                               0.01 lb ai/gallon
                                 1,000 Gallons
                                  Base: 0.163
                                     Base:
                                   0.000488
                                   Base: 490
                                   Base: 390
                                   Base: 3.6
                                    Flagger
                                    Flagger
                                    Base: 
                                      11
                                  Base: 0.35
                                 0.75 lb ai/A
                                     350 A
                                 Base: 0.0361
                                 Base: 0.0011
                                  Base: 2,200
                                   Base: 170
                                   Base: 4.5
1.  Based on "Occupational Pesticide Handler Unit Exposure Surrogate Reference Table" (March 2013); includes data from PHED /AHETF (level of mitigation: Baseline, PPE, Eng. Controls): Base = single layer and no gloves; no respirator; SL w/G = single layer w/glove; EC = Engineering control; PF5 = dust/mist respirator.
2.  Based on proposed labels for bifenazate (see Table 3.3).
3.  Exposure Science Advisory Council Policy #9.1.
4.  Dermal Dose = Dermal Unit Exposure (ug/lb ai) x CF (0.001 mg/ug) x Application Rate (lb ai/acre) x Area Treated (A/day) x% Absorption (100% dermal) / Body weight (80 kg).
5.  Dermal MOE = Dermal NOAEL (80 mg/kg/day)/Dermal Dose (mg/kg/day).
6.  Inhalation Dose = Inhalation Unit Exposure (ug/lb ai) x CF (0.001 mg/ug) x Application Rate (lb ai/acre) x Area Treated (A/day) /BW (80 kg). 
7.  Inhalation MOE = Inhalation NOAEL (0.19 mg/kg/day)/ Inhalation Dose (mg/kg/day).
8.  Engineering controls for the wettable-powder scenario.
9.  ARI = Aggregate Risk Index = 1/ [(Dermal LOC / Dermal MOE) + (Inhalation LOC / Inhalation MOE)].

9.2  Post-application Exposure/Risk

Dermal:  HED expects that post-application dermal exposure will occur since bifenazate is applied post-emergence as a foliar spray to upper and lower leaf surfaces.  Post-application exposure is expected to be short- and intermediate-term based on information provided on proposed labels (e.g., according to the label there is a maximum of 1 spray per season at a maximum rate of 0.75 lb ai/A).  Only short-term exposure was assessed, however the assessment is protective of intermediate-term exposures since the dermal endpoints are the same.    

Data and Assumptions for Post-application Exposure Scenarios:  It is the policy of HED to use the best available data to assess post-application exposure.  Sources of generic post-application data, used as surrogate data in the absence of chemical-specific data, are derived from ARTF exposure-monitoring studies, and, as proprietary data, are subject to the data protection provisions of FIFRA.  The standard values recommended for use in predicting post-application exposure that are used in this assessment, known as "transfer coefficients," are presented in the ExpoSAC, Policy 3 (http://www.epa.gov/pesticides/science/exposac_policy3.pdf), which, along with additional information about the ARTF data, can be found at http://www.epa.gov/pesticides/science/post-app-exposure-data.html.

Chemical-specific DFR data were available for bifenazate; however, the data were not for the currently proposed crops.  Since DFR data are not available for the specific crops currently proposed for bifenazate, the available data were used as surrogates.  Based on a review of the available data, it was decided that the DFR data for Spathiphyllum (Peace Lily) in greenhouses would be used as a surrogate for the proposed field crops (fruiting vegetable, Group 8-10, herb Subgroup 19 A, pome fruit Group 11-10, and timothy forage and hay).  

Even though the data are not for the specific crops, it is the only chemical-specific data submitted to HED.  There are several limitations that were considered such as (1) the study represents DFR data collected in a greenhouse which may potentially be a more conservative estimate of residue dissipation compared to field crops; (2) the formulation in the study is a wettable-powder packaged in a water-soluble bags whereas one of the proposed labels (EPA Reg.#400-514) is for a product that is a SC (liquid); (3) the application rate was lower in the study (0.29 lb ai/A) compared to the proposed labels (0.5 lb ai/A and 0.75 lb ai/A); and (4) the application was made with a calibrated hand-held boom sprayer. 

Tables 9.2.1 provide a summary of the data for use in the post-application exposure and risk calculations.  See L. Venkateshwara, pending, D388802 for summaries of the studies and references.  

Table 9.2.1.  Summary of DFR Values and Regression Analysis Results for Treated Spathiphyllum (Peace Lily) in Greenhouses with Bifenazate (MRID# 448597-01).
                                Input/Parameter
                                 Site: Florida
                                  Bifenazate
Application Rate (lb ai/A) [a] Study Target Rate = 0.29 lb ai/A
0.29 lb ai/A
Spray Volume (GPA) 
5 gallons/1000 ft[2]
Measured Average Day 0 Residue (ug/cm[2])
0.151
Predicted Day 0 Residue (ug/cm[2]) [b]
0.161
Slope
-0.07
Half-life (days)
9.9
R[2]
0.8433
a.  The application was conducted using hand-held boom sprayer. 
b.  Regressions are based on data collected after second application. 

HED has determined that short- and intermediate-term risk estimates are not of concern (i.e., MOEs <100) on the day of treatment (day 0) for all the post-application exposure activities.  Estimates were calculated for the highest transfer coefficients and are protective of all other activities.  Table 9.2.2 presents the risk estimates for all crops for the highest transfer coefficient associated with that crop; this represents the activities with the highest estimated risk. 

Table 9.2.2.  Dermal Post-application Exposure and Risk for Bifenazate Using Chemical-Specific DFR Data.
                                     Crop
                               Application Rate
                                   (lb ai/A)
               Highest Transfer Coefficient for Crop (cm[2]/hr) 
                            and Associated Activity
                               DFR[1] (ug/cm[2])
                             Days After Treatment
                                 Daily Dose[2]
                                    (mg/kg/
                                     day)
                                    MOE3  
                         Fruiting vegetable Group 8-10
                                      0.5
                                     1,900 
                             (irrigation; hand-set)
                                     0.278
                                 0 (12 hours)
                                    0.0528
                                     1,500
                              Herbs Subgroup 19A
                                      0.5
                          1,900 (irrigation; hand-set)
                                     0.278
                                 0 (12 hours)
                                    0.01528
                                     1,500
                            Pome fruit Group 11-10
                                      0.5
                                     3,600
                                (thinning fruit)
                                     0.278
                                 0 (12 hours)
                                     0.10
                                      800
                            Timothy forage and hay
                                     0.75
                                     1,900
                             (irrigation; hand-set)
                                     0.416
                                 0 (12 hours)
                                     0.079
                                     1,000
1.  Chemical-specific DFR = predicted chrysanthemum DFR data for Spathiphyllum (Peace Lily) in greenhouses for a surrogate for the proposed field crops (fruiting vegetable group 8-10, herb subgroup 19 A, pome fruit group 11-10, and timothy forage and hay).  Application rate in studies is less than the proposed application rate.  
2.  Dermal Dose = [DFR (ug/cm[2]) x TC (cm[2]/hr) x 0.001 mg/ug x 8 hrs/day xDA (25%)]  body weight (69 kg).
3.  MOE = NOAEL (Short- and Intermediate-term NOAEL 80 mg/kg/day)/Daily Dose (LOC=100)).  

Inhalation:  Based on the Agency's current practices, a quantitative occupational post-application inhalation exposure assessment was not performed for bifenazate at this time primarily because it has a low acute inhalation toxicity (Toxicity Category IV), has a low vapor pressure, and is applied at a low use rate.  However, there are multiple potential sources of post-application inhalation exposure to individuals performing post-application activities in previously treated areas.  These potential sources include volatilization of pesticides and resuspension of dusts and/or particulates that contain pesticides.  The Agency sought expert advice and input on issues related to volatilization of pesticides from its FIFRA SAP in December 2009, and received the SAP's final report on March 2, 2010 (http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html).  The Agency is in the process of evaluating the SAP report as well as available post-application inhalation exposure data generated by the ARTF and may, as appropriate, develop policies and procedures, to identify the need for and, subsequently, the way to incorporate occupational post-application inhalation exposure into the Agency's risk assessments.  If new policies or procedures are put into place, then the Agency may revisit the need for a quantitative occupational post-application inhalation exposure assessment for bifenazate.

REI:  Bifenazate is classified in acute Toxicity Category IV for acute dermal, inhalation, and oral toxicity, primary eye irritation, and primary skin irritation.  Bifenazate is a dermal sensitizer by the Magnusson/Kligman method, but not the Buehler method.  The 12-hour REI listed on the label is adequate to protect agricultural workers from post-application exposures to bifenazate.

10.0	References

Previous Risk Assessment:  

   * Memo, 07/14/2010, W. Wassell, et al., D371783.

Registration Review Scoping Document:

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

HIARC:

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

Residue Chemistry:

   * Memo, pending, W. Wassell, D388800.
   * Memo, 08/16/2001, T. Bloem, et al., D276801.
   * Memo, 08/16/2001, T. Bloem, D277089.
   * Memo, 05/29/2003, T. Bloem, D290053.
   * Memo, 07/31/2001, T. Bloem et al., D276623

HASPOC Memo:  

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

Drinking Water Memo:  

   * Memo, 10/17/2011, J. Hetrick, et al., D388230
   * Memo, 07/25/2012, J. Hetrick, et al., D402952

Dietary Memo:  

   * Memo, pending, W. Wassell, D384709.

ORE Memo:
   * Memo, pending, L. Venkateshwara, D388802

Attachments  

Appendix A.  Toxicology Profile and Executive Summaries
Appendix B.  Methodologies for Human-Equivalent Concentration Calculations.
Appendix C.  Residential Handler and Post-application Algorithms
Appendix D.  Summary of Occupational and Residential Non-cancer Algorithms
Appendix E.  Summaries of Dislodgeable Foliar Residue Studies and Proposed Use in Assessment
Appendix F.  Physical/Chemical Properties

RDI:  RAB1 (04/09/2014)
W. Wassell: S-10958: Potomac Yard 1 (PY1): (703)305-6135): 7509P: RAB1

Appendix A.  Toxicology Profile and Executive Summaries

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

                                     Study
                                   Technical

                                   Required
                                   Satisfied
870.1100    Acute Oral Toxicity	
870.1200    Acute Dermal Toxicity	
870.1300    Acute Inhalation Toxicity	
870.2400    Acute Eye Irritation	
870.2500    Acute Dermal Irritation	
870.2600    Skin Sensitization	
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
870.3100    90-Day Oral Toxicity in Rodents	
870.3150    90-Day Oral Toxicity in Non-rodents	
870.3200    21/28-Day Dermal Toxicity	
870.3250    90-Day Dermal Toxicity	
870.3465    28-Day Inhalation Toxicity	
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      no
                                      yes
                                      no
                                      yes
870.3700a  Prenatal Developmental Toxicity (rodent)	
870.3700b  Prenatal Developmental Toxicity (non-rodent)	
870.3800    Reproduction and Fertility Effects	
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
870.4100a  Chronic Toxicity (rodent)	
870.4100b  Chronic Toxicity (non-rodent)	
870.4200a  Carcinogenicity (rat)	
870.4200b  Carcinogenicity (mouse)	
870.4300    Combined Chronic Toxicity/Carcinogenicity	
                                      no
                                      yes
                                      no
                                      yes
                                      yes
                                      no
                                      yes
                                      no
                                      yes
                                      yes
870.5265    Mutagenicity -- Ames Assay	
870.5300    Mutagenicity -- Mammalian Cell Gene Mutation Test	
870.5375    Mammalian Cytogenetics Assay (CHO-K1 Cells)	
870.5385    Mouse Bone Marrow Micronucleus Assay 	
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
870.6200a  Acute Neurotoxicity Screening Battery (rat)	
870.6200b  90-Day Neurotoxicity Screening Battery (rat)	
870.6300    Developmental Neurotoxicity	
                                      yes
                                      yes
                                      no
                                      yes
                                      yes
                                      yes
870.7485    Metabolism and Pharmacokinetics	
870.7600    Dermal Penetration	
870.7800    Immunotoxicity	
                                      yes
                                      no
                                      yes
                                      yes
                                      no
                                      yes

A.2	Toxicity Profiles

                                   Guideline
                                      No.
                                  Study Type
                                    MRID #
                                    Results
                               Toxicity Category
                                   870.1100
                                  Acute Oral
                                   44464934
                             LD50 > 5,000 mg/kg
                                      IV
                                   870.1200
                                 Acute Dermal
                                   44464936
                             LD50 > 5000 mg/kg
                                      IV
                                   870.1300
                               Acute Inhalation
                                   44464937
                              LC50 > 4.4 mg/L
                                      IV
                                   870.2400
                            Primary Eye  Irritation
                                   44464938
                               slight irritation
                                      IV
                                   870.2500
                            Primary Skin Irritation
                                   44464939
                               slight irritation
                                      IV
                                   870.2600
                             Dermal Sensitization
                                   45385101
                               dermal sensitizer
                               Magnusson/Kligman
                                   870.2600
                             Dermal Sensitization
                                   44464940
                            not a dermal sensitizer
                                    Buehler

Table A.2.2.  Bifenazate Subchronic, Chronic, and Other Toxicity Profile.
                                Guideline No. 
                                  Study Type
                    MRID No. (year)/ Classification /Doses
                                    Results
870.3100

90-Day oral toxicity (rat)
43214321 (1997)
Acceptable/Guideline
0, 40, 200, 400 ppm
(0, 2.7/ 3.2, 13.8/ 16.3, 27.7/ 32.6  mg/kg/day [M/F])
NOAEL = 13.8/3.2 mg/kg/day [M/F].
LOAEL = 27.7/16.3 mg/kg/day based on  decreased body-weight gain in both sexes, decreased liver weight in males, increased spleen weight in females, and histopathology in liver in both sexes, and histopathological changes in the spleen and adrenal cortex in males.
870.3100

90-Day oral toxicity (dog)
43214321 (1997)
Acceptable/Guideline
0, 200, 800, 400 ppm
(0, 0.9/ 1.3, 10.4/ 10.7, 25/ 28.2 mg/kg/day [M/F]
NOAEL = 0.3/1.9 mg/kg/day [M/F].
LOAEL = 10.4/10.7 mg/kg/day based [M/F] based upon changes in hematological parameters in both sexes, increased bilirubin in the urine in males, increased absolute and relative liver weight in females and liver histopathological effects in both sexes.
870.3200

21-Day dermal toxicity (rat)
44778401 (1998)
Acceptable/Guideline
0, 80, 400, 1,000 mg/kg/day

NOAEL = 80 mg/kg/day in males and females mg/kg/day.
LOAEL = 400 mg/kg/day based on decreased body weight in females, decreased food consumption in both sexes, increased urinary ketones, increased urinary protein, increased urinary specific gravity, and decreased urinary volume in both sexes, and increased incidence of extramedullary hematopoiesis in the spleen in both sexes.
870.3465

28-Day inhalation toxicity (rat)
48723301 (2012)
Acceptable/Guideline
0, 0.03, 0.075, 0.15 mg/L (0, 30, 75, 150 mg/m[3])
 (0, 7.83, 19.58, 39.15 mg/kg/day [M/F])
NOAEL = 0.03 mg/L [M/F].
LOAEL = 0.075 mg/L [M/F] based on dried red material around the nose in females, lower body weights and weight gains, decreased food consumption, decreased heart and thymus weights in females, increased incidences of mild brown pigmentation of the spleen, and minimal to mild degeneration of the olfactory epithelium within nasal levels III, IV, and V.
870.3700a

Prenatal developmental in (rat)
44464945 (1999)
Acceptable/Guideline
0, 10, 100, 500 mg/kg/day
Maternal NOAEL = 10 mg/kg/day.
LOAEL = 100 mg/kg/day based on increased clinical signs, and decreased body weight, body-weight gain, and food consumption.
Developmental NOAEL = not established 
LOAEL = 10 mg/kg/day based upon an increased incidence of early resorptions.
870.3700b

Prenatal developmental in (rabbit)
44464943, 44464944 (1997)
Acceptable/Guideline
0, 10, 50, 200 mg/kg/day
Maternal NOAEL = 200 mg/kg/day.
LOAEL = not established; doses for the main study were selected based on a range-finding study in which groups of 5 rabbits each received 0, 125, 250, 500, 750, or 1,000 mg/kg/day during gestation days 6-19 by gavage.  Maternal toxicity was seen as increased deaths and decreased body weight at 750 mg/kg/day and above.  A treatment-related increase in the number of does aborting was seen at 250 mg/kg/day and above.
Developmental NOAEL = 200 mg/kg/day.
LOAEL = not established; due to only one or two litters available in each of the treated groups in the range finding study, a clear assessment of developmental toxicity was not possible.  Based on these results, doses of 10, 50, and 200 mg/kg/day were selected for the main study.
870.3800

Reproduction and fertility effects
(rat)
45076503 (1999)
Acceptable/Guideline
0, 20, 80, or 200 ppm
(0/0, 1.5/1.7, 6.1/6.9, and 15.3/17.2 mg/kg/day in the P animals [M/F], and 
0/0, 1.7/1.9, 6.9/7.8, and 17.4/19.4 mg/kg/day in F1 animals [M/F], respectively)
Parental/Systemic NOAEL = 20 ppm (1.6/1.8 mg/kg/day [M/F]).
LOAEL = 80 ppm (equivalent to 6.5/7.4 mg/kg/day [M/F]) based on decreased body weights and cumulative body-weight gains in males and females.
Reproductive NOAEL 2 00 ppm (16.4/18.3 mg/kg/day [M/F]).
LOAEL = not observed.
Offspring NOAEL 200 ppm (16.4/18.3 mg/kg/day [M/F]).
LOAEL = not observed.
870.4100b

Chronic toxicity (dog)
45052221 (1999)
Acceptable/Guideline
0, 40, 400, or 1000 ppm (0/0, 1.014/1.051, 8.949/10.422, 23.942/29.192 mg/kg/day [M/F])
NOAEL = 40 ppm (1.014/1.051 mg/kg/day [M/F]).
LOAEL = 400 ppm (8.949/10.422 mg/kg/day [M/F]) based on hematological and clinical chemistry parameters and histopathological changes in the bone marrow, liver, and kidney.
870.4200b

Carcinogenicity
(mouse)
45052222 (1999)
Acceptable/Guideline
0, 10, 100, or 225 ppm (M) and 175 ppm (F) 
(0/0, 1.5/1.9, 15.4/19.7, and 35.1/35.7 mg/kg/day [M/F], respectively)
NOAEL = 1.5 (M)/ 19.7 (F) mg/kg/day.
LOAEL = 15.4 (M) mg/kg/day based on hematology parameters and possibly kidney weights.
LOAEL = 35.7 (F) mg/kg/day based on decreased body weights and body-weight gains.
No evidence of carcinogenicity.
870.4300

Chronic/ Carcinogenicity
(rat)
45076504 (1999)
Acceptable/Guideline
0, 20, 80, or 200 ppm (M) and 160 ppm (F) 
(0/0, 1.0/1.2, 3.9/4.8, and 9.7/9.7 mg/kg/day [M/F], respectively)
NOAEL = 80 ppm (3.9/4.8 [M/F]) mg/kg/day.  
LOAEL = 200 ppm (9.7 mg/kg/day ([M/F]) based on decreased body weight, body-weight gain, and food consumption in both sexes.
No evidence of carcinogenicity.
Gene Mutation
870. 5265
Ames Assay
44464947 (1996)
Acceptable/Guideline
0, 10, 33, 100, 333, 1000, 3333, 5000 ug/plate (+-S9)
Non-mutagenic when tested up to 5000 ug/plate, in presence and absence of activation, in S. typhimurium strains TA98, TA100, TA1535 and TA1537 and E. coli strain WP2uvra.
Gene Mutation 
870.5300
Mammalian Cell Gene Mutation Assay
44464949 (1996)
Acceptable/Guideline
0, 15, 20, 25, 30, 40, 50 ug/ml (-S9)
0, 25, 50, 100, 150, 250, 350 ug/ml (+S9)
0,100, 150, 200, 250, 350, 500 ug/ml (+S9)
Non-mutagenic at the TK locus in L5178Y mouse lymphoma cells tested up to cytotoxic concentrations or limit of solubility, in presence and absence of S-9 activation.
Cytogenetics 
870.5375
Mammalian Cytogenetics Assay (CHO-K1 Cells)
44464950 (1996)
Acceptable/Guideline
0, 12, 24, 47, 94, 188, 375 ug/ml (-S9)
0, 20, 40,79,157, 313, 625, 1250 ug/ml (+S9)
0,12,24, 36, 47, 71, 94 ug/ml (-S9)
0, 20, 40, 79, 119, 157, 236 ug/ml (+S9)
Did not induce structural chromosome aberration in CHO-K1 cell cultures in the presence and absence of activation up to cytotoxic concentrations.
Micronucleus
870.5385
Mouse Bone Marrow Micronucleus Assay
44464948 (1996)
Acceptable/Guideline
0, 96/50, 192/100, 384/200 mg/kg [M/F]
Non-mutagenic in ICR mouse bone marrow micronucleus chromosomal aberrations assay up to cytotoxic concentrations.
870.6200a

Acute neurotoxicity screening battery
48395101 (2010)
Acceptable/Guideline
0, 200, 600, or 2000 mg/kg bw

NOAEL = 600 mg/kg/day.
LOAEL = 2000 mg/kg/day based on decreased motor activity (rearing in females).
870.6200b

Subchronic neurotoxicity screening battery
48526101 (2010)
Acceptable/Guideline
0, 80, 200, or 600 ppm (0, 5.2/5.8, 13.4/14.9, or 34.5/ 40.3 mg/kg bw/day [M/F])
NOAEL = 13.4/14.9 mg/kg/day.
LOAEL = 34.5/40.3 mg/kg/day based on decreased landing foot splay (males), decreased fore- and hindlimb grip strength (males), decreased motor activity [center time (females) and rearing activity (both sexes).
870.7485

Metabolism and pharmacokinetics
(Rat)
45052223 (1998)
10 mg/kg or 1000 mg/kg
acceptable/guideline
Absorption, distribution, and metabolism of bifenazate was rapid, with >93% of the administered dose being recovered within 72 hours of treatment for both the low- and high-dose groups.  As a result of this rapid turnaround, no significant tissue accumulation of the test material was found.  The highest tissue levels were found in the liver and whole blood, although the concentration of the test material represented <3% of the administered dose 6 hours after treatment.  Comparison of the whole blood and red blood cell concentrations suggests that most of the test material was carried in the plasma.
The feces were the primary elimination route for low-dose rats with ~66% of the administered dose recovered in this media.  Radioactivity in the feces was greater for the high-dose rats (823%) due to saturated absorption that resulted in subsequently greater unabsorbed test material.  Urinary excretion was a relatively minor route with ~25% of the administered dose recovered in this media for both male and female low-dose rats.  For the high-dose male and female rats urinary excretion was notably lower (<10% of the administered dose) due to saturated absorption.  Cmax was reached earlier following a 10 mg/kg dose (5-6 hours) than the 1000 mg/kg dose (18-24 hours).  In addition, t(1/2) was slightly longer at the 1000 mg/kg dose (12-16 hours) than at the 10 mg/kg dose (12-13 hours).  No apparent sex-related differences in the pharmacokinetics of bifenazate were observed. 
Eight primary metabolites were identified in the feces of male and female rats given oral doses of 10 mg/kg or 1000 mg/kg bifenazate.
870.7800
Immunotoxicity
(rat)
48305501 (2010)
Acceptable/Guideline
0, 20, 80, or 200 ppm 
(0, 5, 20, or 50 mg/kg/day [F])

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

Appendix B.  Methodologies for Human-Equivalent Concentration (HEC) Calculations.

The RfC methodology applies a dosimetric adjustment that takes into consideration not only the differences in ventilation rate (MV) but also the physicochemical properties of the inhaled compound, the type of toxicity observed (e.g. systemic vs. port of entry) and the pharmacokinetic (PK) but not pharmacodynamic (PD) differences between animals and humans.  Based on the EPA's RfC guidance (1994), the methodology for RfCs derivation is an estimate of the quantitative dose-response assessment of chronic non-cancer toxicity for individual inhaled chemicals and includes dosimetric adjustment to account for the species-specific relationships of exposure concentration to deposited/delivered dose.  This adjustment is influenced by the physicochemical properties of the inhaled compound as well as the type of toxicity observed (e.g. systemic vs. port-of-entry), and takes into consideration the PK differences between animals and humans.  Though the RfC methodology was developed to estimate toxicity of inhaled chemicals over a lifetime, it can be used for other inhalation exposures (e.g. acute and short-term exposures) since the dosimetric adjustment incorporates mechanistic determinants of disposition that can be applied to shorter duration of exposures provided the assumptions underlying the methodology are still valid.  These assumptions, in turn, vary depending on the type of toxicity observed.  Thus, the derivation of a HEC for inhaled gases is described by the following equation:

Where:
PODstudy:  Point of departure identified in the critical toxicology study.
Danimal exposure:  Duration of animal exposure (hrs/day; days/wk).
Danticipated exposure:  Anticipated human duration of exposure (hrs/day; days/wk).
RGDR:  Regional Gas Dose Ratio.

Calculations used to estimate the inhalation risk to humans from aerosols are dependent not on the RGDR as for gases, but on the regional deposited dose ratio (RDDR).  Inhalation studies using aerosols characterize particulate exposure by defining the particulate diameter (mass median aerodynamic diameter [MMAD]) and the geometric standard deviation (σg), which is then used to determine the RDDR.  The RDDR is a multiplicative factor used to adjust an observed inhalation particulate exposure concentration of an animal (A) to the predicted inhalation particulate exposure concentration for a human (H) that would be associated with the same dose delivered to the rth region or target tissue.

	RDDRr = (RDDr/Normalizing Factor)A
		     (RDDr/Normalizing Factor)H  

As with calculations for gases, the r regions and potential target tissues are the three respiratory regions (ET, TB, PU).  The RDDR is easily calculated by using a software program designed specifically for computing the RDDR from the MMAD and σg defined from an aerosol inhalation study.  The values for the species-specific parameters used to calculate the RDDR are provided in the EPA document "Methods for Derivation of Inhalation Reference Concentrations and Application of Inhalation Dosimetry." 

Regional Deposited Dose Ratio (RDDR) for Bifenazate:

MMAD    =  2.20
Sigma g    =  2.78

                 	 Body 	         Minute              
SPECIES  	 Weight (g)    Ventilation (VE, ml)    
-----------------------------------------------------------------------------
    rat          	204           	 171.5      
  human    	70000         	13800.0    
-----------------------------------------------------------------------------
                       Extrathoracic 
		 SA (m^2)    	        deposited fraction  
--------------------------------------------------------------------------------
    rat                        15     		0.413        
  human                   200     		0.391    
--------------------------------------------------------------------------------
 RATIO                0.075                     0.740

RDDR = (VE/SA)animal/(VE/SA)human     * deposited fractionanimal/deposited fractionhuman
	= (171.5/15)animal/(13800/200)human     * 0.413/0.391
	= 0.175

The magnitude of the UFs applied is dependent on the methodology used to calculate risk.  The RfC methodology takes into consideration the PK differences, but not the PD differences.  Consequently, the UF for interspecies extrapolation may be reduced to 3X (to account for the PD differences) while the UF for intraspecies variation is retained at 10X.  Thus, the UF when using the RfC methodology is customarily 30X.

B.1.  HEC Calculations for Short- and Intermediate-term Residential Exposure:

Assume residents will be exposed for 24 hrs/day and 7 days/week:
   
HEC = NOAELstudy * (daily duration of exposureanimal/daily duration of exposurehuman) * (days/week of exposureanimal/days/week of exposurehuman) * RDDR
            
HEC = 0.03 mg/L * (6/24) * (5/7) * 0.175 = 0.00094 mg/L.

Table B.1.  HEC Array for Residental Risk Assessment.
                                Relevant Study
                                     LOAEL
                                    (mg/L)
                                     NOAEL
                                    (mg/L)
                                      Da
                                      Dh
                                      Wa
                                      Wh
                                     RDDR
                                  HEC (mg/L)
                                     inter
                                     intra
                                      UF
                    Short-& Intermediate-Term Exposure
                              Inhalation  -  Rat
                            (MRID 48723301) 28-day
                                      ET
                                     0.075
                                     0.03
                                       6
                                      24
                                       5
                                       7
                                     0.175
                                    0.00094
                                       3
                                      10
                                      NA
Long-Term Exposure:  not appropriate for bifenazate.

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

Route-to-Route Extrapolation

More information and details see:  Memo, "Route-to-Route Extrapolations" J. Whalen and H. Pettigrew, 10/10/98.

HED's route-to-route extrapolation converts human and animal values from mg/L concentrations to mg/kg oral-equivalent doses.  The equation uses a single conversion factor to account for default body weights and respiratory volumes.  An activity factor is used to account for increased exposure resulting from increased respiration.  

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

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

Where: 
A	=	absorption: ratio of deposition and absorption in respiratory tract compared to 
      absorption by the oral route.
CF	=	conversion Factor; a L/hr/kg factor which accounts for respiratory volume and body 
            weight for a given species and strain (Table 1 of J. Whalen and H. Pettigrew, 10/10/98).
D	=	duration; duration of daily animal or human exposure (hours).
AF	=	activity Factor; animal default is 1.

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

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

B.2. HEC Calculations for Short- and Intermediate-term Occupational Exposure:

Assume workers will be in the field for 8 hrs/day and 5 days/week:
   
HEC = NOAELstudy * (daily duration of exposureanimal/daily duration of exposurehuman) * (days/week of exposureanimal/days/week of exposurehuman) * RDDR
            
HEC = 0.03 mg/L * (6/8) * (5/5) * 0.175 = 0.00394 mg/L.

      
Table B.2.  HEC Array for Occupational Risk Assessment.
                                Relevant Study
                                     LOAEL
                                    (mg/L)
                                     NOAEL
                                    (mg/L)
                                      Da
                                      Dh
                                      Wa
                                      Wh
                                     RDDR
                                  HEC (mg/L)
                                     inter
                                     intra
                                      UF
                    Short-& Intermediate-Term Exposure
                              Inhalation  -  Rat
                            (MRID 48723301) 28-day
                                      ET
                                     0.075
                                     0.03
                                       6
                                       8
                                       5
                                       5
                                     0.175
                                    0.00394
                                       3
                                      10
                                      NA
Long-Term Exposure:  Not appropriate for bifenazate.

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

Route-to-Route Extrapolation

More information and details see:  Memo, "Route-to-Route Extrapolations" J. Whalen and H. Pettigrew, 10/10/98.

HED's route-to-route extrapolation converts human and animal values from mg/L concentrations to mg/kg oral-equivalent doses.  The equation uses a single conversion factor to account for default body weights and respiratory volumes.  An activity factor is used to account for increased exposure resulting from increased respiration.  

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

Human-Equivalent Dose (HED, mg/kg/day) = Dose (systemic HEC value, mg/L) x A x CF (L/hr/kg) x D (hours) x AF = mg/kg
Where: 
A	=	absorption: ratio of deposition and absorption in respiratory tract compared to 
      absorption by the oral route.
CF	=	conversion Factor; a L/hr/kg factor which accounts for respiratory volume and body 
            weight for a given species and strain (Table 1 of J. Whalen and H. Pettigrew, 10/10/98).
D	=	duration; duration of daily animal or human exposure (hours).
AF	=	activity Factor; animal default is 1.

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

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

Based on the current bifenazate label, HED believes exposures can be short- (1-30 days) or intermediate- (1 to 6 months) term in duration.  Long-term exposures are not anticipated for bifenazate based on proposed labeled uses.  For the short- and intermediate-term scenarios, inhalation data from the 28-day inhalation rodent study was most appropriate for determining HECs.  In the RfC methodology, different HECs may be calculated for the same experimental NOAEL due to the following:

1. Different algorithms are used to derive HECs for systemic versus port-of-entry effects.  Typically, HECs are calculated separately for systemic versus port-of-entry effect.  For bifenazate, port-of-entry irritation was observed and, therefore, only port-of-entry HECs were derived.  
2. Time adjustments are traditionally needed for non-occupational (bystander) versus occupational exposure scenarios.  Traditionally, HECs for non-occupational exposure are based on the number of hours an individual may be at home.  Therefore, the most conservative estimate of hours spent at home would be 24 hours/day and 7 days/week.  In comparison, the average workweek for an occupational worker is 8 hours/day and 5 days/week.  The HEC array table reflects the time adjustment in the calculations.
3. 
Appendix C.  Residential Handler and Post-application Algorithms

1.0	Residential Handlers

1.1	Residential Handler Exposure Calculations

1.1.1	Turf, Gardens and Trees, Indoor Environments

Dermal and Inhalation Handler Exposure Algorithm
Daily dermal and inhalation exposure (mg/day) for residential pesticide handlers, for a given formulation-application method combination, is estimated by multiplying the formulation-application method-specific unit exposure by an estimate of the amount of active ingredient handled in a day, using the equation below:

                                E = UE * AR * A

where:

E = exposure (mg/day);
UE = unit exposure (mg/lb ai);
AR = application rate (e.g., lb ai/ft[2], lb ai/gal); and
A = area treated or amount handled (e.g., ft[2]/day, gal/day).

1.2	Residential Handler Dose Calculations

Dermal and/or inhalation absorbed doses normalized to body weight are calculated as:
                                       
                                D = E *AF / BW
where:

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

2.0	Residential Post-application

3.1 Gardens and Trees
3.2 
Post-application Dermal Exposure Algorithm
Exposure resulting from contacting previously treated gardens and trees while performing physical activities is calculated as shown below.  Residential post-application exposure assessment must include calculation of exposure on the day of application.  Therefore, though an assessment can present exposures for any day "t" following the application, it must include "day 0" exposure.

	E = DFRt * CF1 * TC * ET 	
where:

E = exposure (mg/day);
DFRt = dislodgeable foliar residue on day "t" (ug/cm[2]);
CF1 = weight unit conversion factor (0.001 mg/ug);
TC  = transfer coefficient (cm[2]/hr); and
ET  = exposure time (hrs/day).

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

	DFRt = AR * FAR * (1-FD)t * CF2 * CF3 	
where:

DFRt = dislodgeable foliar residue on day "t" (ug/cm[2]);
AR = application rate (lbs ai/ft[2] or lb ai/acre);
FAR = fraction of ai as dislodgeable residue following application (unitless);
FD = fraction of residue that dissipates daily (unitless);
t = post-application day on which exposure is being assessed;
CF2 = weight unit conversion factor (4.54 x 10[8] ug/lb); and
CF3 = area unit conversion factor (1.08 x 10[-3] ft[2]/cm[2] or 2.47 x 10[-8] acre/cm[2]).

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

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

Table 3.2.  Gardens, Trees, and "Pick-your-own" Farms  -  Inputs for Residential Post-application Dermal Exposure. 
                              Algorithm Notation
                                Exposure Factor
                                    (units)
                               Point Estimate(s)
                                       
                                      AR
                               Application rate
                            (mass ai per unit area)
                                    [input]
                                      FAR
        DFR following application, if chemical-specific is unavailable
                                  (fraction)
                                     0.25
                                      FD
        Daily residue dissipation, if chemical-specific is unavailable
                                  (fraction)
                                     0.10
                                      TC
                             Transfer Coefficient
                                  (cm[2]/hr)
                                  Gardens[a]
                                    Adults
                                     8,400
                                       
                                       
                                       
                          Children 6 <= 11 years old
                                     4,600
                                       
                                       
                    Trees, Retail Plants (if applicable)[a]
                                    Adults
                                     1,700
                                       
                                       
                                       
                          Children 6 <= 11 years old
                                      930
                                       
                                       
                                 Indoor Plants
                                    Adults
                                      220
                                       
                                       
                                       
                          Children 6 <= 11 years old
                                      120
                                      ET
                                 Exposure Time
                                (hours per day)
                              Home activities[b]
                                    Gardens
                                    Adults
                                      2.2
                                       
                                       
                                       
                                       
                          Children 6 <= 11 years old
                                      1.1
                                       
                                       
                                       
                     Trees, Retail Plants (if applicable)
                                    Adults
                                      1.0
                                       
                                       
                                       
                                       
                          Children 6 <= 11 years old
                                     0.50
                                       
                                       
                                       
                                 Indoor Plants
                                    Adults
                                      1.0
                                       
                                       
                                       
                                       
                          Children 6 <= 11 years old
                                     0.50
                                       
                                       
                   "Pick-your-own" Farms (if applicable)
                                    Adults
                                      5.0
                                       
                                       
                                       
                          Children 6 <= 11 years old
                                      1.9
                                      BW
                                  Body weight
                                     (kg)
                                    Adults
                                      69
                                       
                                       
                          Children 6 <= 11 years old
                                      32
[a] Transfer coefficient point estimates from a composite distribution assuming equal proportion of time spent conducting various activities.  See "Transfer Coefficient" section below.  Children 6 <= 11 years old TC derived using surface area adjustment (see Section 2.3).
[b] Activity time point estimates from a composite distribution assuming equal proportion of each respective activity.  Time for children 6 < 11 years old derived using hrs/day ratio adjustment.  

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

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

The daily doses are calculated using the following formula:
ADD=  E * AFBW
where:
ADD = average daily dose absorbed in a given scenario (mg ai/kg/day),
E = exposure (mg ai/day),
AF = absorption factor (dermal and/or inhalation), and
BW = body weight (kg).

Margin of Exposure (MOE)
Non-cancer risk estimates for each application handler scenario are calculated using an MOE that is a ratio of the toxicological endpoint to the daily dose of concern.  The daily dermal and inhalation dose received by occupational handlers are compared to the appropriate POD (i.e., NOAEL) to assess the risk to occupational handlers for each exposure route.  All MOE values are calculated using the following formula:
MOE= PODADD
where:
MOE = margin of exposure: value used by HED to represent risk estimates (unitless),
POD =	point of departure (mg/kg/day), and
ADD = average daily dose absorbed in a given scenario (mg ai/kg/day).

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

Proposed Uses for Bifenazate.
                                   Commodity
                                Foliage Type[a]
                                 Product Name
                             Application Equipment
                               Application Rate
                                   (lb ai/A)
                          Maximum Number Applications
                                  Per Season
                 Herbs subgroup 19 A (except chives, chervil)
                                    Unknown
                               Florimite(R) 50WP 
                          Groundboom, Aerial Airblast
                                      0.5
                                       1
                         Fruiting vegetable Group 8-10
                                    smooth
                                       
                                       
                                       
                                       
Pome fruit Group 11-10
                                    smooth
                                       
                                       
                                       
                                       
                              Timothy forage hay
                                    varied
                                       
                                   Airblast
                                     0.75
                                       1
a. Based on information in the ARTF/ORETF DFR Guidance

DFR Studies Available:

Florimite(R) 50WP on Spathiphyllum: Dislodgeable Foliar Residue Study (MRID 448597-01).
(HED Review:  Memo, L. Venkateshwara, pending, D388802)

      This study was designed to collect data to evaluate dislodgeable foliar residue (DFR) dissipation for the compound bifenazate from Spathiphyllum (Peace Lily) foliage grown in a greenhouse at one site in Florida.  One field trial was conducted in two greenhouses, one containing treated Spathiphyllum (Peace Lily) plants and the other containing untreated plants.  Primary review of the study was conducted by Versar Inc., 07/07/2000 (MRID 448597-01).  

      Florimite(R) 50WP is a wettable-powder packaged in water-soluble bags that contains 50 % bifenazate as the active ingredient.  Floramite(R) 50WP was applied with a hand-held boom sprayer at 0.29 lb ai/A.  Three applications were made with a 30-day application interval.  DFR samples were collected were up to 28 days after the first two treatments and up to 35 days after the last treatment.  Samples were analyzed for combined residues of bifenazate and a breakdown product UCC-D3598.
      
      Study results indicate that the range of DFR values quantified were quite similar after all three applications.  The maximum DFR analyzed was 72 μg/sample (after correction for 68 percent field recovery), found on DAT-1 after the first application.  DFR values did not decline to <LOQ (i.e. 2 μg/sample) within the 21-day sampling period following the first two applications.  DFR values did decline to <LOQ by DAT-35 after the third application.
      
      Assuming first order kinetics, HED modeled dissipation rates and estimated half-lives for bifenazate of 9.9 days in Florida (R[2] = 0.8433).  

Summary of DFR Values and Regression Analysis Results for Treated Spathiphyllum (Peace Lily) in Greenhouses with Bifenazate (MRID# 448597-01).
                                Input/Parameter
                                 Site: Florida
                                  Bifenazate
Application Rate (lb ai/A)[a] 
Study Target Rate = 0.29 lb ai/A
0.29 lb ai/A
Spray Volume (GPA) 
5 gallons/1000 ft[2]
Measured Average Day 0 Residue (ug/cm[2])
0.151
Predicted Day 0 Residue (ug/cm[2]) [b]
0.161
Slope
-0.07
Half-life (days)
9.9
R[2]
0.8433
a. The application was conducted using hand-held boom sprayer.
b. Regressions are based on data collected after second application.

Proposed use of DFR data:

   * Use the greenhouse Spathiphyllum (Peace Lily) DFR data to estimate post-application exposure for herbs subgroup 19 A (except chives, chervil), fruiting vegetable group 8-10, pome fruit group 11-10, Timothy forage hay (use predicted values).

                                     Crop
                                   DFR Data
                                     Sites
                           Proposed use of DFR Data
                               Characterization
Herbs subgroup 19 A (except chives, chervil), Fruiting vegetable group 8-10, Pome fruit group 11-10, Timothy forage hay 
                    Spathiphyllum (Peace Lily) (Greenhouse)
                                      FL
                                   Predicted
                                  DFR values
* DFR data collected in greenhouse; is a conservative estimate.
* The formulation in the study is a wettable-powder packaged in a water-soluble bag whereas in one of the proposed labels (EPA Reg#400-514) the formulation is a SC (liquid).  The second label (EPA Reg#400-503) the formulation is a wettable-powder in a water-soluble bag.
* The application rate was lower in the study (0.29 lb ai/A) compared to the proposed label (0.5 lb ai/A and 0.75 lb ai/A).
* Application method is not application method for proposed crops.

Appendix F.  Physical/Chemical Properties

TABLE B.  Physicochemical Properties of the Technical Grade of Bifenazate.  
Parameter
Value
Reference
Melting point/range
124-125ºC
MRID 46064101
pH
6.78

Density
1.19 g/cm[3]

Water solubility (25 +- 1°C)
2.1 mg/L (20°C)

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

Vapor pressure at 25 +- 1°C
<1 x 10[-8] atm M[3]/mole (25°C)

Dissociation constant (pKa)
12.94 at 23 C

Octanol/water partition coefficient Log(KOW)
3.4

UV/visible absorption spectrum
Max 264 nm in water

NA = not available.