Page 1 of 53 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460 **OFFICE OF CHEMICA** **L SA FETY**  **AND POLLUTION PREVENTION**  **MEMORANDUM Date:**  15 - May- 201 4 **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 0 5

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 a ggregate exposure assessments, as n eeded, 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 )hydrazinecarbox yl ate)]. 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 charac terization and endpoint selection by Anwar Dunbar (RAB1); the occupational and residential exposure assessment by Lata Venkateshwara (RAB1) ; and theBifenazate Human - Health Risk Assessment DP # 388228

Page 2 of 53 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. , D 371783 ).Bifenazate Human - Health Risk Assessment DP # 388228

Page 3 of 53 **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)**  ........................... 16 7 **4.2.1 Dermal Absorption**  ................................ ................................ ................................ . 17 8 **4.3 Toxicological Effects**  ................................ ................................ ................................ .... 18 **4.3.1 Summary of Toxicological Effects**  ................................ ................................ ........... 18 **4.4 Safety Factor for Infants and Children (FQPA Safety Factor)**  ............................. 18 9 **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**  .......................... 22 2 **4.5.4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk**  **Assessment** ................................ ................................ ................................ ............................... 22 **5.0 Dietary Exposure and Risk Assessment**  ................................ ................................ ....... 22 4 **5.1 Residues of Concern Summary and Rationale**  ................................ .......................... 24 **5.2 Food Residue Profile**  ................................ ................................ ................................ .... 25 **5.3 Water Residue Profile**  ................................ ................................ ................................ .. 26 **5.4 Dietary Risk**  **Assessment** ................................ ................................ .............................. 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**  ................................ .. 2 9 **6. 3**  **Spray Drift** ................................ ................................ ................................ ........................ 30 **6 .4**  **Residential Bystander Post**  **- Application Inhalation Exposure**  ................................ .... 30 **6 .**  **5 Residential Risk Estimates for Use in Aggregate Assessments**  ................................ .... 31Bifenazate Human - Health Risk Assessment DP # 388228

Page 4 of 53 **7.0 Aggregate Exposure/Risk Characterization**  ................................ ................................ .. 30 **7.1 Acute Aggregate Risk**  ................................ ................................ ................................ ... 31 **7.2 Short**  **- Term**  **Aggregate Risk** ................................ ................................ ........................ 32 1 **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 Calc**  **ulations 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**Bifenazate Human - Health Risk Assessment DP # 388228

Page 5 of 53 **1.0 Executive Summary**  **Background:** Bifenazate is a selective miticide/insecticide that controls the motile stage of mites either b y direct contact or through contact with foliar residues. There is conf licting evidence in the literature for bifenazate being a mitochondrial inhibitor or a GABA (gamma - aminobuty ric acid) channel modulator. Bifenazate is currently

registered for application to ornamental plants, pome fruit, fruiting vegetables, cucurbit v egetables, 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 ha s also been established for application of bifenazate to timothy with tolerances ranging from 5 0 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 by products 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 [diazinecarbox yl ic 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 group s 11 - 10 and 8 - 10. Additionally , IR - 4 proposes the establishment of tolerances with regional registrations for residues of bifenazate and its metabolite D3598 in/on the following RACs:

**Commodity Proposed Tolerance**  Timothy, forage 140 ppm Timothy, hay 120 ppm The end - use products (EPs) relevant to th ese registration request s are Acramite ® 50WS (EPA Reg. No. 400 - 503), a 50% by weight wettable - powder (WP) in water - soluble bags (WSP), and Acramite ® 4SC (EPA Reg. No. 400 - 514), a 4 lb/gal suspension - concentrate (SC) formulation [equivalent to a flowable - concentrate (FlC) f ormulation]. IR - 4 has proposed one foliar spray application to herbs and timothy by ground or aerial (timothy only) equipment at a rate of 0.38 to 0.50 lb ai/A to herbs and 0.43 to 0. 75 lb ai/A for timothy . The proposed pre - harvest intervals (PHIs) are 0 day s for timothy forage, 7 day s for timothy hay , and 3 day s for herbs. The established use pattern for pome fruit and fruiting v egetables is oneBifenazate Human - Health Risk Assessment DP # 388228

Page 6 of 53 application using ground equipment at a maximum rate of 0.38 to 0.50 lb ai/A with PHI s of 3 and 7 day s for f

ruiting vegetables and pome fruit, respectivel y. 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 sy stem (spleen and bone marrow with associated hematological findings) are the primary target organs in these species. A dditional 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 sy stem toxicity in several studies. In the rat developmental toxicity study , increases in earl y 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 hindl imb 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 sy stem. 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 “n ot 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 1 x for all exposure scenarios, as discussed in Section 4.4. For purposes of the current risk assessment, PODs were selected for acute and chronic dietary , short - and intermediate - term incidental oral, and both residential and occupational short - and 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 (NOAE L) 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 LOAELof 100 mg/kg/day based on maternal effects including clinical signs, decreased absolute body weight s and food consumption during the dosing period. At the same dose, there wa s 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 , respectivel y). 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, andBifenazate Human - Health Risk Assessment DP # 388228

Page 7 of 53 kidney . A similar LOAEL of 15.4 mg/kg/day was also established in the mouse carcinogeni city 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 interme diate - 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 sy stem . For short - and intermediate - term inhalation exposures, the route - specific 28 - day inhalation study

was chosen which generated a NOAEL of 0.03 mg/Land 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 bo th 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) d evelopmental toxicity studies in rats and rabbits; (2) two - generation reproducti ve study in rats; and (3) acute and subchronic neurotoxicity

studies. **Food Residue Profile:** The qualitative nature of the residue in plants and livestock are adequatel y 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 assessm ent purposes, the residues of concern in crops are bifenazate and its metabolite D3598 (calculated as the stoichiometric equivalent of bifenazate). L ivestock feedstuffs are not derived from the proposed crops of the subject petition with the exception of timothy . The proposed use on timothy is for a regional use in two counties of Nevada (Eureka and Humboldt Counties). Applications can onl y be made t o timothy that is intended for use as horse feed. The use on timothy was discussed and approved by the Chemistry

Science Advisory

Council (ChemSAC, meeting of 0 1/12/2011). Thus, secondary residues of bifenazate in livestock tissues are not of concern for this petition. The existing poultry

metabolism study

is adequate to conclude that tolerances for poultry tissues and eggs are not needed for the purpose of this petition (Category 3 of 40 CFR §180.6). There is no reasonable expectation of finite residue s in poultry matrices. This decision will be revisited in the future if additional crops with poultry feed stuffs are proposed for registration. The qualitative nature of the residue in rotational crops is adequatel y understood based on an acceptable con fined rotational crop metabolism study . The MARC concluded that a 30 - day plantback interval (PBI) is appropriate based on the available data. Appropriate PBI s appear on the product labels for Acramite ® 4SC and Acramite ® 50WS. IR - 4 has submitted adequate field trial data for bifenazate on basil. Four field trials were conducted in the 2008 growing season. At each trial, basil was treated with a single foliar application of Acramite ® 50 WS, at the approximate rate of 0.75 lb ai/A (1.5x the proposedBifenazate Human - Health Risk Assessment DP # 388228

Page 8 of 53 appli cation rate). The maximum residues of bifenazate and its metabolite D3598 on fresh basil following a single foliar application at the approximate rate of 0.75 lb ai/A. and a 3 - day pre harvest interval ranged from 3.4 to 15 ppm. For the trial that include d dried basil, the maximum combined residues of bifenazate and D3598 were 9.5 ppm in fresh basil and 91 ppm in dried basil which represents a concentration factor of 9.6 x for residues in dried basil. The residue data for basil from the submitted crop fiel d 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 timo thy forage and hay . Thirteen field trials were conducted in the United States during the 2004 growing season. At each trial, grasses received one foliar application of Acramite ® 4SC at a rate of approximately 0.75 lb ai/A. Grass forage samples were coll ected 4 hours after application and grass hay samples at 6 to 7 day s after application. The maximum combined residues of bifenazate and D3598 in/on grass forage and hay were 83.5 and 76.3 ppm, respectivel y . The residue data for grass forage and hay from the submitted crop field trials were anal yz ed 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. D rinking water estimates were directl y i ncorporated into the analy sis . The acute anal ys is for the general population, including infants and children, was unrefined and used tolerance - level residues and 100% crop - treated (PCT). The acute analy sis for females 13 to 49 years old was highl y refined and incorporated data from the U.S. Department of Agriculture (USDA’s ) Pesti cide 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 anal ys i s also included the acute surface water point estimate generated using the FQPA Index Reservoir Screening Tool (FIRST) and the dry bean application scenario (highest registered/proposed use rate). The chronic dietary

exposure anal ys is 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 jui ce, and wine/sherry . The processing factors for these commodities were reduced to 1.0 based on data from processing studies. The anal ys es 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 “n ot l ikely” to b e c arcinogenic to humans .Bifenazate Human - Health Risk Assessment DP # 388228

Page 9 of 53 **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 Procedure s (SOPs). A total aggregated risk index (ARI) approach was used since the level s of concern (LOC s ) for dermal exposure (100) and inhalation exposure (30) are different. The dermal and inhalation exposure risk estimates for residential handlers are not of concern at baseline for all scenarios. All the ARI s 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 “no t likely” to be carcinogenic to humans; therefore, a cancer assessment was not conducted. The label for Acramite ® 50WS only requires protective eyewear, long - sleeved shirt , long pants , and shoes plus socks. The label does not require gloves. The label for Acramite ® 4SC requires long - sleeved shirt , long pants, and shoes plus socks. It includes a statement that “when not using a closed sy stem, wear apron and chemicall y resistant gloves made of any wat erproof 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 (M OEs ≥ 100). All ARI s are greater than 1 except for the following scenarios that require single layer of gloves:  Mixing/loading liquids for aerial and chemigation applications and  Mixing/loading/application of liquids via mechanically pressurized handgun (foliar). **Occupational Post**

**- application Exposure:**  Post - application dermal exposure will occur since bifenazate is applied post - emergence as a foliar spray . Chemical - specific dislodgeable - foliar residue (DFR

t) data are available and used for bifenazate. The short - and intermediate - term risk estimates are not of concern (i.e., MOEs ≥ 100) on the day of treatment (d ay

0 ) for the post application exposure activities. Based on the Agency's current practices, a quantitativ e occupational post - application inhalation exposure assessment was not performed for bifenazate at this time. I f new policies or procedures are put into place, the Agency may revisit the need for a quantitative occupational post - application inhalation exp osure assessment for bifenazate. The 12 - hour restricted - entry interval (REI) listed on the label is adequate to protect agricultural workers from post - application exposures to bifenazate. **Review of Human Research:** This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. These data, which include Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1); the Agricultural Handler Exposure Task Force (AHETF) datab ase; the Outdoor Residential Exposure Task Force (ORETF) database; the Agricultural Reentry Task Force (ARTF), and the Residential SOPs (Gardens/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 b y the Human Studies Review Board. De scriptions of data sources, as well as guidance on their use, can be found at the Agency website 1

. 1 http://www.epa.gov/pesticides/science/handler - exposure - data.html and http://www.epa.gov/pesticides/science/post - app - exposure - data.htmlBifenazate Human - Health Risk Assessment DP # 388228

Page 10 of 53 **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 anal ytical - grade standards at the EPA National Pesticide Standards Rep ository (see below), there are no residue chemistry or toxicological data deficiencies that would preclude the establishment of permanent tol erances for residues of bifenazate and its metabolites as outlined in Table 2.2.2. 860.1550 Proposed 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 )hydrazinecarbox yl ate) and diazinecarbox yl ic 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 diazinecarbox yl ic acid, 2 - (4 - methoxy- [1,1’biphenyl] - 3 - yl , 1 - methylethyl ester (D3598, expressed as bif

enazate), A1530 (1,1’ - biphenyl , 4 - ol) and A1530 - sulfate (expressed as A1530; 1,1’biphenyl , 4 - oxysulfonic acid). The proposed tolerance expressions need to be modified to comply

with the interim guidance on tolerance expressions (Memo, 5/27/2008, S. 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 . Specificall y, 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 t he 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 stoichi om**  **etric 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:Bifenazate Human - Health Risk Assessment DP # 388228

Page 11 of 53 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 an d 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 commoditi es: 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 a nd 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 -

y l) , 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 Analy tical Reference Standards Analy tical 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, Anal ytic al Chemistry

Branch (ACB), 01/25/2012). However, the standard for metabolites D23 - 15 and D23 - 16 expire d on 6/30/2012 and 05/31/2012, respective ly . Additionally , the Repository

does not have standards for bifenazate metabolite D23 - 22. The registrant must either recertify

the lots in the repository

and send in an updated certificate of anal ys is (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 Anal ytical Chemistry Lab, which is located at Fort Meade, to the attention of either Theresa Cole at the following address: USEPA National Pesti cide Standards Repository /Anal ytical 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 anal ytical methods for tolerance enforcement. For plants, high - performance liquid chromatography with oxidative coulometric electrochemical detector (HPL C/ELCD) Method UCC - D2341 is available as a primary enf orcement 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 Analy tical Manual,Bifenazate Human - Health Risk Assessment DP # 388228

Page 12 of 53 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 s ys tem with tandem mass spectrometers (LC - MS/MS) method (NCL ME 245) was recentl y 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 matri ces. The methods have undergone a successful validation by the Agency

and have been forwarded to FDA for inclusion in PAM II. In addition, the L C MS/MS Method NCLME 259 was recentl y submitted as a confirmatory method, and this method was also forwarded to FDA. The validated L OQ was 0.01 ppm for each anal yt e. 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 Bi**  **fenazate .**  **Comm odity**  **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 anal yz ed using the OECD tolerance - calculation procedures. The recommended tolerance for residues of bifenazate and its metabolite are 30 ppm in/on basil (translated to h erb , s ubgroup 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 ( c orrespond ence 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 level s , correct proposed commoditie s, and to change the tolerance expression (see Recommended Tolerances section).Bifenazate Human - Health Risk Assessment DP # 388228

Page 13 of 53 **2.2.4 International Harmonization**  There are currently

no established Codex, Canadian, or Mexican MRL s for bifenazate in/on herbs, and timothy

forage and hay . The tolerance expression s for plant commodities are harmonized between the U.S. and Canada, but not with Codex. Canadian MRL s 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 fruiti ng vegetables is harmonized with Canada (see above). The Canadian MRLfor residues in apples is not harmonized with the U.S. tolerance levels for residues in pome fruits. Codex MRL s 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 MRL s for residues in pome fruits, peppers, and tomato are not harmonized with the U.S. tolerance levels. **2.3 Label Recommendations**  The proposed use directions for Acramite ® 50WS (EPA Reg. No. 400 - 503) and Acramite ® 4SC (EPA Reg. No. 400 - 514) on herbs and timothy grass are sufficient to allow for evaluation of the submitted residue data. Bifenazate is currently registered for use on pome fruits and fruiting vegetables. The available field trial data support the proposed use directions for bifenazate on herbs, subgroup 19A, timothy , pome fruits, and fruiting vegetables . **3.0 Introduction**  **3.1 Chemical Identity**  **Table 3.1. Test Com pound Nom**  **enclature.** Com pound

Common name Bifenazate Com pany 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 num

ber 149877 - 41 - 8 End - use products (EPs) Acramite ® 50WS (EPA Reg. No. 400 - 503) Acramite ® 4SC (EPA Reg. No. 400 - 514) O N H N H O C H 3 O C H 3 C H 3Bifenazate Human - Health Risk Assessment DP # 388228

Page 14 of 53 **Table 3.1. Test Com pound Nom**  **enclature.** Com pound

Common name None Com pany 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 Com pound O H Common name None Com pany experimental name A1530 IUPAC name 1,1’ -biphenyl, 4 - ol CAS name p - hydroxybiphenyl CAS registry number 92 - 69 - 3 Com pound O S O 3 H Common name None Com pany 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 b y 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 hydroly sis , direct aqueous photoly sis , and aerobic degradation in soil (Memo, 10/17/2011, J . Hetrick, et al ., D388230 ) . A table of the phys icochemical properties of bifenazate can be found in Appendix E . **3.3 Pesticide Use Pattern**  The proposed use directions are presented in Table 3 .3 , below. The information presented in Table 3 .3 was obtained from undated draft labels for Acramite ® 50WS (EPA Reg. No. 400 - 503) and Acramite ® 4SC (EPA Reg. No. 400 - 514). O N N O C H 3 O C H 3 C H 3Bifenazate Human - Health Risk Assessment DP # 388228

Page 15 of 53 **Table 3 .3**  **. Summ ary of Proposed and Registered Directions for Use of Bifenazate.**  **Applic. Timing,**  **Type, and Equip.**  **Form ulation** 

**[Reg. No.] Applic.** 

**Rate (lb ai/A)**  **Max. No.**

**Applic. per Season**  **Max.**

**Seasonal Applic. Rate**  **(lb ai/A) PHI** 

**(days) Use Directions and** 

**Limitations Herb, Subgroup 19A (Except Chervil and Chive, Proposed Use)**  Ground Application Acramite ®

50WS [400 - 503] 0.38 to

0.50 1 0.50 (implied) 3 Application is to be made in a minimum of 50 gal/A using ground equipment. For maximum control, applications must be made as soon as mites appear. **Pom e Fruit, Group 8**  **- 10 (Registered Use)**  Ground Application Acramite ® 4SC

[400 - 514] Acramite ® 50WS [400 - 503] 0.38 to

0.50 1 0.50 (implied) 7 Application is to be made in a minimum of 50 gal/A using ground equipment. For maximum control, applications must be made as soon as mites appear. **Fruiting Vegetables, Group 8 -**  **10 (Registered Use)** 

Ground Application Acramite ® 4SC

[400 - 514] Acramite ® 50WS [400 - 503] 0.38 to

0.50 1 0.50 (implied) 3 Application is to be made in a minimum of 50 gal/A using ground equipment or 10 gal/A using aerial equipment. For maximum control, applications must be made as soon as mites appear. **Timothy (Proposed Use)** Ground or Aerial Application Acramite ® 4SC

[400 - 514] 0.43 to

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

made in a minimum of 20 gal/A using ground equipment or 10 gal/A by air. For maximum control, applications must be made as soon as mites appear. The following rotational crop restriction is specified: “This product has a plantback restriction of 30 day s. Do not plant another crop within 30 day s after last Acramite ® application due to chances of bifenazate residues showing up in rotational crops.” Conclusions: The propo sed use directions are adequate to allow evaluation of the residue data relative to the proposed use.Bifenazate Human - Health Risk Assessment DP # 388228

Page 16 of 53 **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 application s 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 pathway s 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 Environment**  **al 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 L ow - 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 w ith OPP policy , HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water consumption, and ac tivities in and around the home that involve pesticide use in a residential setting. Exten sive 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; 20 03 - 2008) and are used in pesticide risk assessments for all registered food uses of a pesti cide. These data are anal yz ed and categorized by subgroups based on age, season of the ye ar, ethnic group, and region of the country . Additionally , OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are perf ormed when conditions or circumstances warrant. Whenever appropriate, non - dietary exposures based on home use of pesticide products and associated risks for adult a pplicators and for toddlers, yo uths, 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 b y 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 deficienciesBifenazate Human - Health Risk Assessment DP # 388228

Page 17 of 53 consisted of an immunotoxicity study as well as the neurot oxicity screening battery

tests as specified in the revi sed 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 Coun cil (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 earl y resorptions at all doses tested); 2) specific effects on the nervous s ystem in both neurotoxicity screening battery tests; and 3) a neurotoxic pesti cidal mechanism of action. Sy ngenta provided comments regarding the Agency ’s conclusions ( MRID 48997401) and subsequentl y s ubmitted the raw historical control data (MRID 49271101) for the developmental rat study , which ultimatel y removed the Agency’s conc ern for an increased fetal sensitivity ( Memo, 02/20/2014 , A. Dunbar et al ., D416994). The Agency further conducted i ts own statistical analyses in the neurotoxicity screening batteries, and determined that the effects observed were not neurotoxic in nature but instead those indicative of overt s ys temic toxicity . Finall y, a rigorous literature search by the Agency and S yn genta revealed conflicting evidence concerning the pesticidal mechanism of action (EPA HQ - OPP - 2012 - 0633; Weiland and Rao, Feb 11, 20 13: Response to “Anticipated Data Needs” for bifenazate and DNT Guideline 870.6300 requirement). **4.2 Absorption, Di**  **stribution, Metabolism, and Excretion (ADME)** Recovery of bifenazate was >93% of the administered dose and was recovered within 72 hours of treatment for both the low - and high - dose groups. Lo w - dose male and female rats absorbed ~85% of the administered dose as indicated b y 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 hi ghest 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 mo st of the test material was carried in the plasma. The feces was the primary elimination route for low - dose rats with ~66% of the administered dose recovered in this media. Radioactivity in the feces was greater for the high - dose rats due to saturated absorption that resulted in subsequentl y 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 notabl y lower (<10% of the administered dose) due to saturated absorption. C max was reached earlier following a 10 mg/kg dose (5 - 6 hours) than the 1000 mg/kg dose (18 - 24 hours). In addition, the half - life was slightl y 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 highl y metabolized with eight primary metabol ites identified in the feces of both sexes for both low - and high - doses. These metabolites, as well as those identified in the urineBifenazate Human - Health Risk Assessment DP # 388228

Page 18 of 53 and bile, were due to metabolic reactions including hydrazine oxidation, demethylation, ring hydrox yl ation, and molecular scission with loss of the hydrazine carbox yl ic 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 th e 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 meta

bolic 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

L OAEL = 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 Toxi**  **cological 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 subchroni c oral exposures , the dog is the most sensitive species. For chronic oral exposures, the dog and the rat are equally sensitive. Subchronic and chronic studies in rats and dogs indicate that the liver and hematopoietic sy stem (spleen and bone marrow with associated hematological findings) are the primary target organs in these species . Additional toxicity was seen in the kidney (dogs following chronic exposure) and adrenal cortex (male rats following subchronic exposure). Decreases in body weight , bodyweight gain, and food consumption were also associated with liver and hematopoietic sy stem 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 onl y at the HDT , and consisted of decreased motor activity (rearing in females; center time in both sexes). In the subchronic neurotoxicity

study , effects were also only seen at the HDT (34.5 mg/kg/day) and consisted of dec reased landing foot splay (males) , decreased fore - and hindlimb grip strength (males), decreased motor activity measurements consisting of center times (females) and rearing activity (both sexes). There were no effects in the immunotoxicity study up to the HDT .Bifenazate Human - Health Risk Assessment DP # 388228

Page 19 of 53 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

weight s in females, and decreased food consumption in both sexes were associated with the t arget organ effects. In the 28 - day

inhalation study , there were statistically significant decreased thy mus 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 (3 0% of males and 40 - 50% of females). There was also an increased incidence of brown pigment in the spleen in females (80% at the mid - concentration and 90% at the high - concentration). At the highest concentration tested, there were also decreased lung weights in both sexes ( ↓14%). In the mouse carcinogenicity study , males and females were tested up to 225 ppm and 175 ppm, respectivel y. 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 b y pair- wise comparison. There also was no progression of the adenomas to carcinomas in males in this study . In addition, benign hep atocellular 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) d evelopmental toxic ity 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 onl y 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 Deve**  **loping or Young Animal** There is no evidence of increased susceptibility of offspring following pre - or postnatal exposure to bifenazate in rats or rabbits.Bifenazate Human - Health Risk Assessment DP # 388228

Page 20 of 53 **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 anal ys es are unlikely to underestimate exposure as they incorporated tolerance - level residues, 100% CT (acute) , PCT (chronic), and modeled drinking water estimates. For acute anal ys is for females 13 to 49 years, the dietary analy sis 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 rea sonable worst - case assumptions and are not expected to underestimate risk. **4.5 Toxicity Endpoint**  **and Point of Departure Selections 4.5.1**  **Dose -**  **Response Assessment** Acute Dietary

Endpoint for All Populations: The endpoint used for establishing the acute population - adjusted dose ( aPAD ) for the general population was selected from the acute neurotoxici ty

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

Endpoint for the General Population: The chronic diet ary endpoint for the general population was selected from co - critical studies with similar NOAEL s ( 1 and 1.5 mg/kg/day). Specificall y, 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 . Th e 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.Bifenazate Human - Health Risk Assessment DP # 388228

Page 21 of 53 Short - and Intermediate - Term Incidental Oral Endpoints: The short - and intermediate - term incidental oral endpoints were based upon the results from the subchronic 90 - day dog study where the NOAEL is 0.9 mg/kg/day . The LOAEL is 10.4 mg/kg/day based on changes in hematologic parameters. The LOC is 100 based upo n a 10x UF for inter- species extrapolations, 10x UF for intra - species variations, and a 1x FQPA SF. This study is appropriate for the durations of exposure and the population of concern, children in residential settings. It is noted that the effects and PODs seen in this study are consistent with the longer- term dog and mouse studies used to set the chronic dietary endpoint. Short - (1 - 30 day s) and Intermediate - (1 - 6 months) Term Dermal Endpoints: The short - and intermediate - t erm 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 urin ary 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 1 0x UF fo r intra - species variations. This study

protects for the earl y 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 day s) 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 weight s and body- weight gains, decreased food consumption, decreased heart and thy mus 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 co nsidered 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 s ys temic effects observed through the inhalation route. This study is thus appropriate for the route and d uration 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 N OAEL for use in MOE cal culations. 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 al ong the respiratory tract. The RDDR is also based on interspecies differences in ventilation and respiratory- tract surface areas. Thus, the RDDR can be used to adjust an observ ed inhalation particulate exposure of an animal to the predicted inhalation exposure for a human. For the 4 - week inhalation study with bifenazate, an RDDR wa s estimated at 2. 8 based on the reported MMAD of 2.20 μm and standard deviation (  g) of 2.78 and the 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 day s/week, the onl y exposure adjustment made was in the assumption of 8 hrs/day for human occupational exposures. The resulting HEC s are 0.0009 mg/L and 0. 0 039 mg/L for residential and oc cupational exposures. The LOC is 30 which includes interspecies (3 x) , and intraspeciesBifenazate Human - Health Risk Assessment DP # 388228

Page 22 of 53 (10x ) uncertainty factors. The interspecies factor was reduced from 10x to 3x due to the HEC calculation accounting for pharmacokinetic (not pharmacodyn am ic) interspecies differences. **4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment**  Based upon common effects (histopathology of the spleen and hematological parameters) between the two routes, dermal and inhalation exposures can be combined. **4.5.3 Cancer Classification and Risk Assessment Recommendation**  The available data show no evi dence of carcinogenicity in rats at adequate dose levels, and no evidence of carcinogenicity in mice at adequate doses. In the mouse , there was an increase in the incidence of adenomas only , which, while being slightly above historical control levels, was not statistically

significant. There was also no progression of time for mouse adenomas to carcinomas. In accordance with the proposed Draft Guidelines for Carcinogen Risk Assessment (1996), the Hazard Identification Assessment Review Committee (HIARC) classified bifenazate as “n ot likely” to be carcinogenic to humans ( Memo, 05/30/2001, J. Rowland, et al. , TXR# 0014576 ) . **4.5.4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk**  **Assessment Table 4.5.4.1**  **. Summ**  **ary of Toxicological Doses and Endpoints for Bifenazate for Use in Dietary and Non**   ** Occupational** **Hum an**  **- Health Risk Assessments**  **. Exposure/**  **Scenario P**  **O D**  **Uncertainty/FQPA SFs**  **RfD, PAD,**

**Level of Concern for**  **Risk Assessment**  **Study and Toxicological Effects** Ac ute Dietary (General Population, including Infants and Children) NOAEL =

600 mg/kg/day UF A = 10x

UF H = 10x FQPA SF = 1x Ac ute RfD =

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

** Rats** LOAEL = 200 0 mg/kg/day based on decreased motor activity (rearing in females) . Ac ute Dietary (Females 13 - 49 years of age) NOAEL =

10 mg/kg/day UF A = 10x

UF H = 10x FQPA SF = 1x Ac ute RfD =

0.1 mg/kg/day aPAD = 0.1 mg/kg/day **Prenatal Developm ental Toxicity**  **- Rats** 

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

Chronic Dietary (All Populations) NOAEL =

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

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

= 0.01 mg/kg/day cPAD = 0.01 mg/kg/day **Chronic Toxicity -**  **Dogs**

LOAEL = 8.9/10.4 mg/kg/day [M/F] based on changes in hematological and clinical chemistry parameters, and histopathology in bone marrow, liver, and kidney in the one - year dog feeding study. **Carcinogenicity Study -**  **Mouse** LOAEL = 15.4 (M) mg/kg/day based on hematology parameters and possibly kidney weights .Bifenazate Human - Health Risk Assessment DP # 388228

Page 23 of 53 **Table 4.5.4.1 .**  **Summ ary of Toxicological Doses and Endpoints for Bifenazate for Use in Dietary and Non**  **** **Occupational Hum**  **an -**  **Health Risk Assessments .**  **Exposure/ Scenario**  **P O**  **D Uncertainty/FQPA**  **SFs RfD, PAD,** 

**Level of Concern for**  **Risk Assessment**  **Study and Toxicological Effects** Incidental Oral Short Term (1

- 30 days) and Intermediate Term NOAEL =

0.9 mg/kg/day UF A = 10x

UF H = 10x FQPA SF = 1x Residential

LOC for MOE = 100 **90 -**  **Day Subchronic -**  **Dogs**

LOAEL = 10.4 mg/kg/day based upon changes in hematological parameters in both sexes, increased bilirubin in the urine in males, increased absolute and relative liver weight in females and liver histopathologic al effects in both sexes. Dermal Short and Intermediate Term (1 - 30 days and 1 - 6 mo nths) LOAEL =

80 mg/kg/day UF A = 10x

UF H = 10x FQPA SF = 1x Residential

LOC for MOE = 100 **21 -**  **Day D**  **erm al**  **T oxicity**  **- Rat** 

LOAEL = 400 mg/kg/day based on decreased body weight in females, decreased food consumption in both sexes, increased urinary ketones, increased urinary protein, increased urinary specific gravity, and decreased urinary volume in both sexes, and increased incidence of extramedullary hematopoiesis in the spleen in both sexes. Inhalation Short - and Intermediate Term (1 - 30 days, and 1 - 6 mo nths) Rat

NOAEL = 0.03 mg/L UF A = 3 x

UF H = 10x FQPA SF = 1x Residential

LOC for MOE = 30 **28 -**  **Day I**  **nhalation T**  **oxicity -**  **Rat**

LOAEL = 0.075 mg/L [M/F] on dried red material around the nose in females, lower body weight s and body - we ight gains, decreased food consumption, decreased heart and thymus weights in females, increased incidences of mild brow n pigmentation of the spleen, and minimal to mild degene ration of the olfactory epithelium within nasal levels III, IV, and V. HEC= 0.0009 mg/L HED = 0.14 mg/kg bw /day Cancer (oral, dermal, inhalation) Bifenazate is classified as "not likely to be a human carcinogen” . a = 25% dermal - absorption factor . Point of d eparture (POD) = a data point or an estimated point that is derived from observed dose - response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no - ob served adverse - effect level. LOAEL = lowest observed adverse - effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). UF L = use of a LOAEL to extrapolate a NOAEL. FQPA SF = FQPA Safety Factor. PAD = population - adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern. N/A = not applicable.Bifenazate Human - Health Risk Assessment DP # 388228

Page 24 of 53 **Table 4.5.4.2 Summa ry of Toxicological Doses and Endpoints for Bifenazate for Use in Occupational Hum**  **an 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 mo nths) LOAEL =

80 mg/kg/day UF A = 10x

UF H = 10x Occupational

LOC for MOE = 100 **21 -**  **Day D**  **erm al**  **T oxicity**  **- Rat** 

LOAEL = 400 mg/kg/day based on decreased body weight in females, decreased food consumption in both sexes, increased urinary ketones, increased urinary protein, increased urinary specific gravity, and decreased urinary volume in both sexes, and incre ased incidence of extramedullary hematopoiesis in the spleen in both sexes. Inhalation Short - and Intermediate Term (1 - 30 days, and 1 - 6 mo nths) Rat NOAEL

= 0.03 mg/L UF A = 3 x

UF H = 10x Occupational

LOC for MOE = 30 **28 -**  **Day I**  **nhalation T**  **oxicity -**  **Rat**

LOAEL = 0.075 mg/L [M/F] based on dried red material around the nose, lower body weight s and body - we ight gains, decreased food consumption, mild brown pigmentation of the spleen, and minimal to mild degeneration of the olfactory epithelium within nasal levels III, IV, and V in both sexes. HEC = 0.0039 mg/L HED = 0.19 mg/kg bw /day Cancer (oral, dermal, inhalation) Bifenazate is classified as "not likely ” to be a human carcinogen . a = 25% dermal - absorption factor . Point of departure (POD) = a data point or an estimated point that is derived from observed dose - response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no - observed adverse - effect level. LOAEL = lowest observed adverse - effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). MOE = margin of exposure. LOC = level of concern. **5.0 Dietary Exposure and Risk Assessment**  An overview of the metabolism of bifenazate can be found in the most recent residue chemistry assessment (Memo, pending, W. Wassell, D 388800 ). **5.1 Residues of Concern Summary and Rationale**  **Plant Commodities:** The qualitative nature of the residue in plants is adequately understood based on acceptable studies with 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 (calculate d 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 bifenaza te and D3598 (calculated as the stoichiometric equivalent of bifenazate).Bifenazate Human - Health Risk Assessment DP # 388228

Page 25 of 53 **Rotational Crops:** The qualitative nature of the residue in rotational crops is adequatel y 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. **D rinking Water:**  The HED MARC determined that the residue of concern in water is D1989 . **Table 5.1. Summ ary of Metabolites and Degradates to be**  **I ncluded in Risk Assessment and Tolerance**  **Expression. Matrix**  **Residues Included in Risk Assessment Residues Included in Tolerance Expression**  Pla nts 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 , S ubgroup 19A . IR - 4 has submitted data for bifenazate and its metabolite D3598 on basil from a total of four crop field trials conducted during the 2008 growing season. The field trials were conducted in C A , SC, and 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 h erb, subgroup 19A, fresh leaves , exc ept 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 anal yz ed 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 . T imothy is used as horse feed . The proposed use on timothy

is for a regional use in two counties of Nevada (Eureka and Humboldt Counties). Applications can onl y be made to timothy that is intended for use as horse feed. The use on timothy was discussed and approved b y the ChemSAC (meeting of 1/12/11). Tolerances are established for residu es of bifenazate and its metabolites in/on horse fat, meat , and meat by product.Bifenazate Human - Health Risk Assessment DP # 388228

Page 26 of 53 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 upo n establishment of the uses and tolerances for residues in/on pome fruit, group 11 - 10. Residue data for the use on pome fruit w ere submitted and reviewed in conjunction with PP#0F6108 (Memo, 8/16/2001, T. Bloem, D277089). Bifenazate is currently

register ed 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 w ere submitted and reviewed in conjunction with PP# 3E6517 ( Memo, 5 /29 /200 3 , T. Bloem, D 290053 ). Poultry feed items are not derived from herbs, timothy , pome fruit , and fruiting vegetables. A poultry metabolism study was previousl y submitted. Based on this study and the dietary

burden , HED concludes that there i s 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 b y EFED (Memo , 10/17/2011 , J. Hetrick , et al ., D 388230 ; and Memo, 7/25/2012 , J. Hetrick , et al ., D 402952 ). Surface and ground water- 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 b y EFED using computer models. Bifenazate is expected to be slightl y mobile, but not persistent in the environment. Bifenazate is expected to rapidly dissipate in soil and aquatic environments as a result of aqueous hydroly sis, direct aqueous photoly sis, and aerobic degradation in soil. EFED provided estimates of drinking water concentrations (EDWC s ) for bifenazate using the FQPA FIRST model and the dry bean application scenario (highest registered/proposed use rate). The resulting chronic EDWCs in ground and surface water were 0.000014 ppm (30 - ye ar- annual average) and 0.0112 ppm (annual average), respectively . The resulting acute EDWC (daily peak) was 0.0373 ppm. **Table 5.3. Bifenazate EDWCs**  **.**

**Exposure Scenario EDWC (ppm)**  30 - year Annual Average (not used) 0.000014 Annual Average (used in chronic analysis) 0.0112 Daily Peak (used in acute analysis) 0.0373 **5.4 Dietary Risk Assessment**  **5.4.1 Description of Residue Data Used in Dietary Assessment**  A cute and chronic dietary (food plus drinking water) risk assessment s were conducted using the DEEM - FCID, Version 3.16, which uses food consumption data from the USD A’s NHANES/WWEIA. This dietary survey was conducted from 2003 to 2008. The anal ys es were conducted in support of a human - health risk assessment for the proposed to lerances forBifenazate Human - Health Risk Assessment DP # 388228

Page 27 of 53 bifenazate and D3598 on timothy and h erb, s ubgroup 19A; and to expand existing uses on p ome f ruit, group 11, and f

ruiting v egetables, group 8. The acute anal ys is for the general population, including infants and children, was unrefined and used tolerance - level residues and 100% PCT. The acute anal ys is for females 13 to 49 years old was highl y refined and incorporated data from the USDA’s PDP data , crop field trial data, and PCT estimates. DEEM (ver. 7.81 ) default processing factors were as sumed for all commodities excluding apple juice, grape juice, and wine/sherry . The processing factors for these commodities were reduced to 1.0, based on data from processing studies. The anal ys es also included the acute surface water point estimate (0.0 373 ppm) generated using the FIRST model. The chronic dietary

exposure anal ys is 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 anal ys es also included the chronic surface water point estimate (0.0112 ppm) generat ed using the FIRST model. **5.4.2 Percent Crop Treated Used in Dietary Assessment**  The acute anal ys is for general population, including infants and children, used 100% PCT estimates. The acute analy sis for females 13 to 49 years old and the chronic anal y sis use d PCT estimates provided b y 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%; grapefr uit: 5%; grapes: 10%; nectarines: 5%; oranges: 1%; peaches: 10%; pears: 15%; pecans: 1%; peppers: 5%; pistachios: 2.5%; plums/prunes: 5%; potatoes: 5%; pumpkins: 2.5%; squash: 1%; strawberries: 45%; tomatoes: 5%; walnuts: 2.5%; and watermel on: 1%. **5.4.3 Acute Dietary Risk Assessment**  The acute risk estimate utilizes <1% (0.040436 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 wh ich 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.Bifenazate Human - Health Risk Assessment DP # 388228

Page 28 of 53 **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 highl y exposed population subgroup was chil dren 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**  **(m g/kg/day)**  **% aPAD Dietary Exposure**  **(m g/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

chang es for body

we ight assumptions. **6.1 Residential (Non**  **- Occupational) Exposure/Risk Characterization**  The residential handler exposure assessment estimates dermal and inhalation exposures for individuals using bifenazate on residential ornamentals. The quantitative exposure/risk assessment developed for residential handlers is based on the following scenarios: (1) mixing/loading/appl ying liquids with manually- pressurized handwand, (2) mixing/loading/appl ying liquids with hose - end sprayer, (3) mixing/loading/ appl ying liquids with backpack, and (4) mixing/loading/appl ying liquids with sprinkler can. Unit exposure values and estimates for area treated were taken from HED’s 2012 Residential SOPs: Gardens and Trees. An ARIwas used since the LOCs for dermal exposure (100) andBifenazate Human - Health Risk Assessment DP # 388228

Page 29 of 53 inhalation exposure (30) are different. The target ARIis 1; therefore, ARIs of less than 1 result in risk estimates of concern. The ARI was calculated as follows. Aggregate Risk Index (ARI) = 1÷ [(Dermal LOC ÷ Dermal MOE) + (Inhalati on LOC ÷ Inhalation MOE) ] Short - term risk estimates for residential handlers are presented in Table 6.1. Intermediate - term exposures are not likel y because of the intermittent nature of applications by homeowners. Short - term dermal and inhalation risk e stimates to residential handlers do not exceed HED’s LOC for all scenarios. All the ARI s 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 (m** **g/k g/day)**  **Baseline MOE 5**  **ARI 6**  **Dermal 3**  **Inhalation 3**  **Dermal Inhalation**  **Dermal (LOC = 100)**  **Inhalation**

**(LOC = 30) Mi** **xer/Loader/Applicator for Soluble Concentrates( Liquids)**  Manuallypressurized handwand 0.00125 lb

ai/gal 5 gal 63 0.018 0.00 49 0.0000014 1 6,000 100,000 150 Hose - end sprayer 0.00125 lb

ai/gal 11 gal 58 0.0014 0.0 10 0.00000024 8 ,000 580,000 80 Backpack 0.00125 lb

ai/gal 5 gal 130 0.14 0.0 10 0.000011 7,9 00 13,000 66 Sprinkler can 0.00125 lb

ai/gal 5 gal 58 0.0014 0.00 45 0.00000011 18,000 1,300,000 180 1. Application rates based on communication between the registrant and EPA regarding the maximum rates allowed on the labels for the residential use sites. From label 400 - 508: 2.0 lb ai/gal/128 fl oz gal * 8 fl oz/100 gal = 0.00125 lb ai/gal . 2. Based on H ED’s SOPs: Gardens and Trees (HED’s 2012 Residential SOPs) . 3. Baseline Dermal: long - sleeve shirt, long pants, shoes, socks, and no gloves . Baseline I nhalation: 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; I nhalation = 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 ye ars old) selected for each post - application scenario are based on an anal ys is provided as an Appendix in the 2012 Residential SOPs. These lifestages are not the only lifestages that could be potentially exposed for these post - application scenarios; how ever, the assessment of these lifestages is health protective for the exposures and risks for any other potentially exposed lifestages. **Residential Post**

**- application Exposure Data and Assumptions:**  A series of assumptions and exposure factors served as 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/pesticide s/science/residential - exposure - sop.html ). **Residential Post**

**- application Non**  **- Cancer Exposure and Risk Equations:**  The algorithms used to estimate residential post - application exposure and dose can be found in the 2012 ResidentialBifenazate Human - Health Risk Assessment DP # 388228

Page 30 of 53 SOPs (http://www.epa.gov/pesticides/science/residential - exposure - sop.html ). For this assessment a chemical - specific dislodgeable foliar residue (DFRt) value of 0.161 μg/cm2 was us ed ( MRID 44859701 **)** . Table 6.2 lists the updated assessments of currently registered residential post - application exposures and risk estimates . All adult and children dermal post - application risk estimates for exposure to treated trees and to treated gardens are not of concern (MOEs ≥ 10 0). **Table 6.2. Short**  **- and Intermediate**  **- Term Residential Post**  **- application Exposure and Risk**  **Estimates for Bifenazate.**  **Liquid Formulations Lifestage**  **Post -**  **application Exposure Scenario**  **Dose a**  **MOEs b**  **(LOC = 100)**  Adult Garden - sprays 0.0 37 2,2 00 Child 6 < 11 years old 0.0 25 3,1 00 Adult Tree

– sprays 0.00 34 23, 000 Child 6 < 11 years old 0.00 23 34, 000 a . Dermal Dose (mg/kg/day) = DFRt (0.161 μg/cm 2 ) x 0.001 (mg/μg) x short - term TC (cm2/hr) x ET (hr/day) x Dermal Absorption (100%) BW (kg) . b. Dermal MOE = NOAEL ( 80 mg/kg/day) / Dermal Dose (mg/kg/day) . **6.3 Spray Drift**  Spray drift is a potential source of exposure to those nearby pesticide applications. This is particularl y 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) emplo yed 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 - Inissued by

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

. The Agency is also taking means to qualitatively and quantitati vely

address spray

drift as a potential source of exposure in risk assessments for pesticides through existing programs such as AgDrift® and chemical spe cific properties of pesticides. The potential for spray drift will be quantitatively evaluated for each 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 - appli cation inhalation exposure assessment was not performed for bifenazate at this time primarily because of the low acute inhalation toxicity

(To xicity C ategory IV), low vapor pressure , and the low proposed use rate. However, volatilization of pesticides may be a source of post - application inhalation exposure to individuals nearb y pesticide applications. The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 (http://www.epa.gov/scipoly /SAP/meetings/2009/120109meeting.html ). The A gency is in the process of evaluating the SAP report and may , as appropriate, develop policies and procedures to identify the need for and, subsequently , the way to incorporate post application inhalation exposure into the Agency's risk assessments. If ne w policies or 2 Available: http://www.epa.gov/opp00001/factsheets/spraydrift.htmBifenazate Human - Health Risk Assessment DP # 388228

Page 31 of 53 p rocedures are developed, the Agency may revisit the need for a quantitative post - application inhalation exposure assessment for bifenazate. **6.5 Residential Risk Estimates for Use in Aggregate Assessments**  Table 6.5 reflects the residential risk estimates that are recommended for use in the aggregate assessment for bifenazate.  The recommended residential exposure for use in the adult aggregate assessment reflects dermal post - application exposure to treated gardens.  The recommended residential exposure for use in the children 6 to 11 ye ars old aggregate assessment reflects dermal post - application exposure to treated gardens. **Table 6.5. Short**  **- Term** **Residential Exposures for the Bifenazate Com bined Residential Risk**  **Calculations .**  **Population Handler Exposure** 

**(m g/kg/day)**  **1 Post**  **- application Exposure**  **(m g/kg/day)**  **2 Recommended Post**  ****

**application Exposure for Aggregate**  **(m g/kg/day)**  **3 Derm**  **al Inhalation**  **Derm al**  **Inhalation Oral**  Adult 0.0045 0.000011 0.0 37 N/A N/A 0.037 Children 6 < 11 yrs old N/A N/A 0.0 25 N/A N/A 0.025 1 . Handler exposure represents high - end handler exposure, where the appropriate duration is appropriate to assess. 2 . Postapplication exposure represents high - end dermal, inhalation and/or incidental oral exposure for the relevant exposure duration. 3 . The highest estimated total residential exposure (for adults and child populations) should be used as the basis of the aggreg ate assessments. **7.0 Aggregate Exposure/Risk Characterization**  In accordance with the FQPA, HED must consider aggregate pesticide exposures and risks from three major sources: food, drinking water, and residential exposures. In an aggregate assessment, exposures from relevant sources are added together and compared 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 ris k assessments were performed for acute, short - and interm ediate - term, and chronic exposure . Bifenazate is classified as "not likely " to be a human carcinogen and thus no cancer aggregate risk assessment is required. **7.1 Acute Aggregate Risk**  The acute aggregate risk assessment takes into account acute exposure estimates from dietary consumption of bifenazate (food and drinking water). The acute dietary exposure estimates are not of concern to HED (<100% aPAD) for the general U.S. population and all population subgroups (see Table 5.4.6). **7.2 Short** **- Term Aggregate Risk**  The short - and intermediate - term toxicological POD s for bifenazate are the same for each route of exposure. Therefore, for residential exposure scenarios, onl y short - term exp osures were assessed, and are considered to be protective of intermediate - term exposure and risk.Bifenazate Human - Health Risk Assessment DP # 388228

Page 32 of 53 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 - 1 2 years old were used in the aggregate risk estimate for adults and children 6 ≤ 11 years old, respectively . All of the adult and children 6 ≤ 11 years old chronic dietary + dermal aggregate risk estimates do not exceed HED’s LOC (MOEs ≥ 100) . The results of the adult and children’s aggregate risk determinations are presented in Table 7.2. **Table 7.2 Short -**  **Term and/or Intermediate Term Aggregate Risk Calculations**  **(Option 2: 1/MOE Approach –**  **All Levels of Concern are Identical) .**  **Population Short**  **- or Interm**  **ediate -**  **Term Scenario**

**LOC for Aggregate**  **Risk 1**  **Dietary**

**MOE 2**  **MOE Oral**

**Residential Exposure**  **MOE**

**Derm al**  **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 Aggr egate 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 produ ce a toxic metabolite produced b y other substances. For the purposes of this tolerance action, therefore, EPA has not assumed that imazapic has a common mechanism of toxicity with other substances. For information regarding EPA’s efforts to determine whi ch chemicals have a common mechanism of toxicity

and to evaluate the cumulative effects of such chemicals, see the policy statements released b y EPA’s Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating eff ects from substances found to have a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/.Bifenazate Human - Health Risk Assessment DP # 388228

Page 33 of 53 **8.1 Occupational Exposure/Risk Characterization**  The proposed uses are on agri cultural crops; therefore, there is potential for occupational handler and post - application exposure. **9 .**  **0 Occupational Handler Exposure/Risk Estimates**  The proposed uses are on agricultural crops; therefore, there is potential for occupational handler an d post - application exposure. **9 .**  **1 Post**  **- application Exposure/Risk**  HED uses the term handlers to describe those individuals who are involved in the pesticide application process. HED believes that there are distinct job functions or tasks related to appli cations and exposures can vary depending on the specifics of each t ask. Job requirements (amount of chemical used in each application), the kinds of equipment used, the target being treated, and the level of protection used b y 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/L oader: 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 spray s via aerial application; 8. application of spray s via groundboom equipment; 9. application of spray s via airblast application; and 10. application of spray s via chemigation; Mixer/L oader/Applicator: 11. application of liquids via mechanically pressurized handgun (foliar); 12. application of wettable - powder in water- soluble bags via mechanicall y pressurized handgun (foliar); Flagger: 13. flagging to support aerial spray applications.Bifenazate Human - Health Risk Assessment DP # 388228

Page 34 of 53 **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 ARIis 1; therefore, ARIs of less than 1 result in risk estimates of concern. The ARI was calculated as follows. Aggregate Risk Index (ARI) = 1÷ [(Dermal LOC ÷ Dermal MOE) + (Inhalation LOC ÷ Inhalation MOE) ] **Summary of Occupational Handler Non**  **- Cancer Exposure and Risk Estimates:**  Table 9.1 provides a summary

of the estimated exposures and risks to occupational pesticide handlers. An MOE ≥ 100 is adequate to protect occupational pesticide handlers from dermal exposures and an MOE ≥ 30 from inhalation exposures . Inhalation and dermal risk estimates were not of concern for all scenarios . All ARIs are greater than 1 and are not risks of concern , except for the following scenarios that require single layer of gloves:  Mixing/loading liquids for aerial and chemigation applications and  Mixing/loading/application of liquids via mechanically pressurized handgun (foliar).Bifenazate Human - Health Risk Assessment DP # 388228

Page 35 of 53 **Table 9.1. Short**  **- /Interm**  **ediate -**  **Term Occupational Exposure and Risk Estim**  **ates for Bifenazate.** Exposure Scenario Dermal Unit

Exposure (ug/lb ai) 1 Inhalation Unit

Exposure (ug/lb ai) 1 Application

Rate 2 Amount

Treated Daily3 Dose (mg/kg/day) 4,5 MOE 6,7 Total

Dermal Inhalation Dermal (LOC = 100) Inhalation (LOC = 30) ARI 9 **Mi xer/Loader Wettable Powder in Water Soluble Bags**  Aerial Application Eng Control 8 :

9.8 Eng Control 8 :

0.24 0.5 lb ai/A 350 A EC : 0.0 215 EC : 0.00053 EC : 3, 700 EC : 360 EC : 9.1 Airblast Applications 0.5 lb ai/A 40 A EC : 0.00 245 EC : 0.00006 EC : 33 ,000 EC : 3,200 EC : 81 Groundboom applications 0.5 lb ai/A 80 A EC : 0.00 49 EC : 0.00012 EC : 16 ,000 EC : 1,600 EC : 40 **Mi xer/Loader Liquids**  Aerial Application Base: 220 Base: 0.219 0.75 lb ai/A 350 A Base: 0. 723 SL/G: 0.123 Base: 0.00072 Base: 110 SL/G: 650 Base: 260 Base: 0.98 SL/G: 3.7 Chemigation Applications 0.75 lb ai/A 350 A Base: 0. 723 SL/G: 0.123 Base: 0.00072 Base: 110 SL/G: 650 Bas e: 260 Base: 0.98 SL/G: 3.7 Groundboom applications 0.75 lb ai/A 80 A Base: 0. 165 Base: 0.000 16 Base: 480 Base: 1,200 Base: 4.3 **Applicator** Applicator, Aerial EC: 2.08 EC: 0.0049 0.75 lb ai/A 350 A EC: 0.00 683 EC : 0 .0000161 EC: 12,000 EC : 12,000 EC : 92 Applicator, Open Cab Groundboom Base: 78.6 Base: 0.34 0.75 lb ai/A 80 A Base : 0 .0 0365 Base: 0.443 Base : 180 Base: 750 Base: 1.3 Applicator, Open Cab, Airblast Base: 1770 Base: 4.71 0.5 lb ai/A 40 A Base : 0 . 00383 Base: 0.059 Base: 1,400 Base: 160 Base: 9 **Mi xer/Loader/Applicator**  Mixing/Loading Applying Liquids with Mechanically Pressurized Handgun (foliar) Base: 1,300

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

Gallons Base : 0.61 Base : 0.00183 Base : 130

SLw/G: 440 Base: 100 Base : 0 .94 SLw/G + Base: 1.9 Mixing/Loading Applying Water Soluble Packets with Mechanically Pressurized Handgun (foliar) Base: 1,300 Base: 3.9 0.01 lb ai/gallon 1,000

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

11 Base: 0.35 0.75 lb ai/A 350 A Base : 0.0361 Base: 0.0011 Base : 2,200 Base: 170 Base: 4.5 1. Based on “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (March 2013); includes data from PHED /AHETF (level of mitigation: Baseline, PPE, Eng. Controls): Base = single layer and no gloves; no respirator; SL w/G = single layer w/glove; EC = Engineering control; PF5 = dust/mist respirator. 2 . Based on proposed labels for bifenazate (see Table 3.3). 3 . Exposure Science Advisory Council Policy #9.1. 4 . Dermal Dose = Dermal Uni t Exposure (ug/lb ai) x CF (0.001 mg/ug) x Application Rate (lb ai/acre) x Area Treated (A/day) x % Absorption (100% dermal) / Body weight (80 kg). 5 . Dermal MOE = Dermal NOAEL (80 mg/kg/day)/Dermal Dose (mg/kg/day). 6 . Inhalation Dose = Inhalation Unit Exposure (ug/lb ai) x CF (0.001 mg/ug) x Application Rate (lb ai/acre) x Area Treated (A/day) /BW (80 kg). 7 . Inhalation MOE = Inhalation NOAEL ( 0.19 mg/kg/day)/ Inhalation Dose (mg/kg/day). 8 . Engineering controls for the wettable - powder scenario. 9 . AR I = Aggregate Risk I ndex = 1÷ [(Dermal LOC ÷ Dermal MOE ) + (I nhalation LOC ÷ I

nhalation MOE)]. **9.2 Post -**  **application Exposure/Risk Dermal:**  HED expects that post - application dermal exposure wi ll occur since bifenazate is applied post - emergence as a foliar spray to upper and lower leaf surfaces. Post - application exposure is expected to be short - and intermediate - term based on information provided onBifenazate Human - Health Risk Assessment DP # 388228

Page 36 of 53 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). Onl y short - term exposure was assessed, how ever the assessment is protective of intermediate - term exposures since the dermal endpoints are the same. **Data and Assumptions for Post -** **application Exposure Scenarios : It is the policy of HED**  to use the best available data to assess post - application exposure. Sources of generic post application data, used as surrogate data in the absence of chemical - specific data, are derived from ARTF exposure - monitoring studies, and, as proprietary data, are subject to the data protection provisions of FIFRA. The standard values recommended for use in predicting post application exposure that are used in this assessment, known as “transfer 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 dat a were availabl e for bifenazate; however, the data were not for the currentl y proposed crops. Since DFR data are not available for the specific crops currentl y proposed for bif

enazate, the available data were used as surrogates. Based on a review of the available data, it was decided that the DFR data for Spathiphyllum (Peace Lily) in greenhouses would be used as a surrogate for the proposed field crops (fruiting vegetable , Group 8 - 10, herb S ubgroup 19 A, pome fruit Group 11 - 10, and timothy forage and hay). Even though the data are not for the specific crops, it is the only chemical - specific data submitted to HED. There are several limitations that were considered such as (1) the study represents DFR data collected in a greenhouse which may potentially

be a more conservative estimate of residue dissipation compared to field crops; (2) the formulation in the study is a wettable - powder packaged in a water- soluble bags whereas one of the proposed labels (EPA Reg.#400 - 514) is for a product that is a SC (liquid); (3) the application rate was lower in the study (0.29 lb ai/A) compared to the proposed labels (0.5 lb ai/A and 0.75 lb ai/A); and (4) the application was made with a calibrated hand - held boom sprayer. Tables 9.2.1 provide a summary of the data for use 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 Gre**  **enhouses with Bifenazate (MRID# 448597 -**  **01).**

**Input/Parameter Site: Florida**  **Bifenazate** Application Rate (lb ai/A) a Study Target Rate = 0.29 lb ai/A 0.29 lb ai/A Spray Volume (GPA) 5 gallons/1000 ft2 Measured Average Day 0 Residue (μg/cm2 ) 0.151 Predicted Day 0 Residue (μg/cm2 ) b 0.161 Slope - 0.07 Half - life (days) 9.9 R2 0.8433 a. The application was conducted using hand -held boom sprayer. b. Regressions are based on data collected after second application. HED has determined that short - and intermediate - term risk estimates are not of concern (i.e., MOEs <100) on the day

of treatment (day

0) for all the post - application exposure activities .Bifenazate Human - Health Risk Assessment DP # 388228

Page 37 of 53 Estimates were calculated for the highest transfer coefficients and are protective of all other activities. Table 9.2.2 presents the risk estimates for all crops for the highest transfer coefficient associated with that crop; this represents the activitie s with the highest estimated risk. **Table 9.2.2. Derm al 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** 

**Treat me**  **nt Daily Dose**  **2**

**(m g/k** **g/ day)**  **MOE 3**  Fruiting vegetable Group 8 - 10 0.5 1,900 (irrigation; hand set) 0.278 0 (12 hours) 0.0528 1,500 Herbs Subgroup 19A 0.5 1,900 (irrigation; hand - set) 0.278 0 (12 hours) 0.01528 1,500 Pome fruit Group 11 - 10 0.5 3,600 (thinning fruit) 0.278 0 (12 hours) 0. 10 800 Timothy forage and hay 0.75 1,900 (irrigation; hand set) 0.416 0 (12 hours) 0.079 1,000 1. Chemical - specific DFR = predicted chrysanthemum DFR data for Spathiphyllum (Peace Lily) in greenhouses for a surrogate for the proposed field crops (fruiting vegetable group 8 - 10, herb subgroup 19 A, pome fruit group 11 - 10, and timothy forage and hay) . Application rate in studies is less than the proposed application rate. 2. Dermal Dose = [DFR (ug/cm2 ) x TC (cm2/hr) x 0.001 mg/ug x 8 hrs/day xDA (25%)]  body weight (69 kg). 3 . MOE = NOAEL (Short - and I ntermedi ate - term NOAEL 80 mg/kg/day)/Daily Dose (LOC=100)). **Inhalation:** Based on the Agency's current practices, a quantitative occupational post application inhalation exposure assessment was not performed for bifenazate at this time primarily because it has a low acute inhalation toxicity (Toxicity Category IV), has a low vapor pressure, and is applied at a low use 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/s cipoly /SAP/meetings/2009/120109meeting.html ). The Agency is in the process of evaluating the SAP report as well as available post - application inhalation exposure data generated b y 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 occu pational post - application inhalation exposure assessment for bifenazate. **REI:** Bifenazate is classified in acute Toxicity Category IV for acute dermal, inhalation, and oral toxicity, primary

eye irritation, and primary skin irritation . Bifenazate is a dermal sensitizer by the Magnusson/Kligman method, but not the Buehler method. The 12 - hour REIlisted on the label is adequate to protect agricultural workers from post - application exposures to bifenazate. **10.0 References**  Previous Risk Assessment:

 Memo, 07/14/2010 , W. Wassell , et al. , D 371783.Bifenazate Human - Health Risk Assessment DP # 388228

Page 38 of 53 Registration Review Scoping Document:

 Memo, 11/15/2012, W. Wassell, et al. , D402278. HIARC:  Memo, 05/30/2001, J. Rowland, et al ., TXR# 0014576. Residue Chemistry:

 Memo, pending, W. Wassell, D38 8800 .  Memo, 08/16/2001, T. Bloem, et al ., D276801.  Memo, 0 8/16/2001, T. Bloem, D277089.  Memo, 0 5/29/2003, T. Bloem, D290053.  Memo, 07/31/2001, T. Bloem et al. , D276623 HASPOC Memo:

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

ater Memo:

 Memo, 1 0/1 7 /20 1 1, J. Hetrick , et al ., D 388230  Memo, 0 7 /25 /20 12 , J. Hetrick , et al ., D 402952 Dietary Memo:

 Memo, pending, W. Wassell, D384709. ORE Memo:  Memo, pending, L. Venkateshwara, D388802 **Attachments** Appendix A. Toxicology Profile and Executive Summaries Appendix B. Methodologies for Human - Equivalent Concentration Calculations. Appendix C. Residential Handler and Post - application Algorithms Appendix D. Summary

of Occupational and Residential Non - cancer Algorithms Appendix E. Summaries of Dislodgeable Foliar Residue Studies and Proposed Use in Assessment Appendix F. Phy sical/Chemical Properties RDI: RAB1 (04/09/2014) W. Wassell : S - 10958: Potomac Yard 1 (PY1): (703)305 - 6135): 7509P: RAB1Bifenazate Human - Health Risk Assessment DP # 388228

Page 39 of 53Bifenazate Human - Health Risk Assessment DP # 388228

Page 40 of 53 **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 ne w (1998) guide line protocols were used. **Study Technical**  **Required Satisfied**  870.1100 Acute Oral Toxicity ................................ ....................... 870.1200 Acute Dermal Toxicity ................................ .................. 870.1300 Acute Inhalation Toxicity ................................ .............. 870.2400 Acute Eye Irritation ................................ ....................... 870.2500 Acute Dermal Irritation ................................ ................. 870.2600 Skin Sensitization ................................ .......................... yes yes yes yes yes yes yes

yes yes yes yes yes 870.3100 90 - Day

Oral Toxicity in Rodents ................................ .. 870.3150 90 - Day

Oral Toxicity in Non - rodents ............................ 870.3200 21/28 - Day Dermal Toxicity ................................ ........... 870.3250 90 - Day

Dermal Toxicity ................................ ................ 870.3465 28 - Day Inhalation Toxicity ................................ ........... yes yes yes yes yes yes

no yes no yes 870.3700a Prenatal Developmental Toxicity (rodent) ..................... 870.3700b Prenatal Developmental Toxicity (non - rodent) ............. 870.3800 Reproduction and Fertility Effects ................................ . yes yes yes yes

yes yes 870.4100a Chronic Toxicity (rodent) ................................ .............. 870.4100b Chronic Toxicity (non - rodent) ................................ ....... 870.4200a Carcinogenicity (rat) ................................ ...................... 870.4200b Carcinogenicity (mouse) ................................ ................ 870.4300 Combined Chronic Toxicity/Carcinogenicity ................ no yes no yes yes no

yes no yes yes 870.5265 Mutagenicity

—Ames Assay ................................ .......... 870.5300 Mutagenicity

—Mammalian Cell Gene Mutation Test .. 870.5375 Mammalian Cytogenetics Assay (CHO - K1 Cells) ........ 870.5 385 Mouse Bone Marrow Micronucleus Assay .................. yes yes yes yes yes

yes yes yes 870.6200a Acute Neurotoxicity Screening Battery (rat) ................. 870.6200b 90 - Day

Neurotoxicity Screening Battery (rat) ............... 870.6300 Developmental Neurotoxicity ................................ ........ yes yes no yes

yes yes 870.7485 Metabolism and Pharmacokinetics ................................ 870.7600 Dermal Penetration ................................ ........................ 870.7800 Immunotoxicity ................................ ............................. yes no yes yes

no yesBifenazate Human - Health Risk Assessment DP # 388228

Page 41 of 53 **A.2 Toxicity Profiles**  **Guideline No.**  **Study Type MRID #**  **Results Toxicity Category**  870.1100 Ac ute Oral 44464934 LD 50 > 5,000 mg/kg IV 870.1200 Ac ute Dermal 44464936 LD 50 > 5000 mg/kg IV 870.1300 Ac ute Inhalation 44464937 LC 50 > 4.4 mg/L IV 870.2400 Primary Eye Irritation 44464938 slight irritation IV 870.2500 Primary Skin Irritation 44464939 slight irritation IV 870.2600 Dermal Sensitization 45385101 dermal sensitizer Magnusson/Kligman 870.2600 Dermal Sensitization 44464940 not a dermal sensitizer Buehler **Table A.2.2 .**  **Bifenazate Subchronic, Chronic,**  **and Other Toxicity Profile .**  **Guideline No.**  **Study Type MRID No. (year)/**  **Classification /Doses Results**  870.3100 90 - Day

oral toxicity (rat) 43214321 (1997)

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

oral toxicity (dog) 43214321 (1997)

Acceptable/Guideline 0, 200, 800, 400 ppm (0, 0.9/ 1.3, 10.4/ 10.7, 25/ 28.2 mg/kg/day [M/F] NOAEL = 0.3 /1.9 mg/kg/day [M/F] . LOAEL = 10.4/10.7 mg/kg/day based [M/F] based upon changes in hematological parameters in both sexes, increased bilirubin in the urine in males, increased absolute and relative liver weight in females and liver histopathological effects in both sexes. 870.3200 21 - Day

dermal toxicity (rat) 44778401 (1998)

Acceptable/Guideline 0, 80, 400, 1,000 mg/kg/day NOAEL = 80 mg/kg/day in males and females mg/kg/day . LOAEL = 400 mg/kg/day based on decreased body weight in females, decreased food consumption in both sexes, increased urinary ketones, increased urinary protein, increased urinary specific 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 i n females, increased incidences of mild brown pigmentation of the spleen, and minimal to mild degeneration of the olfactory epithelium within nasal levels III, IV, and V. 870.3700a Prenatal

developmental in (rat) 44464945 (1999)

Acceptable/Guideline 0, 10, 100, 500 mg/kg/day **Maternal** NOAEL = 10 mg/kg/day . LOAEL = 100 mg/kg/day based on increased clinical signs, and decreased body weight, body- weight gain , and food consumption. **Developm ental**  NOAEL = not established LOAEL = 10 mg/kg/day based upon an increased incidence of early resorptions .Bifenazate Human - Health Risk Assessment DP # 388228

Page 42 of 53 **Table A.2.2 .**  **Bifenazate Subchronic, Chronic,**  **and Other Toxicity Profile .**  **Guideline No.**  **Study Type MRID No. (year)/**  **Classification /Doses Results**  870.3700b Prenatal

developmental in (rabbit) 44464943, 44464944

(1997) Acceptable/Guideline 0, 10, 50, 200 mg/kg/day **Materna** l NOAEL = 200 mg/kg/day . LOAEL = **not established** ; doses for the main study were selected based on a range - finding study in which groups of 5 rabbits each received 0, 125, 250, 500, 750, or 1,000 mg/kg/day during gestation days 6 - 19 by gavage . Maternal toxicity was seen as increased deaths and decreased body weight at 7 50 mg/kg/day and above. A treatment - related increase in the number of does aborting was seen at 250 mg/kg/day and above . **Developm enta**  l NOAEL = 200 mg/kg/day . LOAEL = **not established** ; due to only one or two litters available in each of the treated groups i n the range finding stu dy, a clear assessment of developmental toxicity was not possible. Based on these results, doses of 10, 50, and 200 mg/kg/day were selected for the main study . 870.3800 Reproduction

and fertility effects (rat) 45076503 (1999)

Acceptable/Guideline 0, 20, 80, or 200 ppm (0/0, 1.5/1.7, 6.1/6.9, and 15.3/17.2 mg/kg/day in the P animals [M/F], and 0/0, 1.7/1.9, 6.9/7.8, and 17.4/19.4 mg/kg/day in F 1 animals [M/F], respectively) **Parental/System ic**  NOAEL = 20 ppm (1.6/1.8 mg/kg/day [M/F]) . LOAEL = 80 ppm

(equivalent to 6.5/7.4 mg/kg/day [M/F]) based on decreased body weights and cumulative body - weight gain s in males and females . **Reproductive** NOAEL  2 00 ppm (16.4/18.3 mg/kg/day [M/F]) . LOAEL = not o bserved. **Offspring** NOAEL  200 ppm (16.4/18.3 mg/kg/day [M/F]) . LOAEL = not observed . 870.4100b Chronic toxicity

(dog) 45052221 (1999)

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

(mouse) 45052222 (1999)

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

Carcinogenicity (rat) 45076504 (1999)

Acceptable/Guideline 0, 20, 80, or 200 ppm (M) and 160 ppm (F) (0/0, 1.0/1.2, 3.9/4.8, and 9.7/9.7 mg/kg/day [M/F], respectively) NOAEL = 80 ppm ( 3.9 /4.8 [M/F]) mg/kg/day . LOAEL = 200 ppm ( 9.7 mg/kg/day ([M/F]) based on decreased body weight, body - weight gain , and food consumption in both sexes . **No evidence of carcinogenicity .** Bifenazate Human - Health Risk Assessment DP # 388228

Page 43 of 53 **Table A.2.2 .**  **Bifenazate Subchronic, Chronic,**  **and Other Toxicity Profile .**  **Guideline No.**  **Study Type MRID No. (year)/**  **Classification /Doses Results**  Gene Mutation 870. 5265 Ames Assay 44464947 (1996) Acceptable/Guideline 0, 10, 33, 100, 333, 1000, 3333, 5000 μg/plate (±S9) Non - mutagenic when tested up to 5000 ug/plate, in presence and absence of activation, in S. typhimurium strains TA98, TA100, TA 1535 and TA1537 and E. coli strain WP2uvra. Gene Mutation 870.5300 Mammalian Cell

Gene Mutation Assay 44464949 (1996)

Acceptable/Guideline 0, 15, 20, 25, 30, 40, 50 μg/ml ( - S9) 0, 25, 50, 100, 150, 250, 350 μg/ml (+S9) 0,100, 150, 200, 250, 350, 500 μg/ml (+S9) Non - mutagenic at the TK locus in L5178Y mo use lymphoma cells tested up to cytotoxic concentrations or limit of solubility, in presence and absence of S - 9 activation. Cy togenetics 870.5375 Mammalian

Cy togenetics Assay (CHO - K1 Cells) 44464950 (1996)

Acceptable/Guideline 0, 12, 24, 47, 94, 188, 375 μg/ml ( - S9) 0, 20, 40,79,157, 313, 625, 1250 μg/ml (+S9) 0,12,24, 36, 47, 71, 94 μg/ml ( - S9) 0, 20, 40, 79, 119, 157, 236 μg/ml (+S9) Did not induce structural chromosome aberration in CHO - K1 cell cultures in the presence and absence of activation up to cy totoxic 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 Ac ute

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 mo tor activity (rearing in females) . 870.6200b Subchronic

neurotoxicity screening battery 48526101 (2010)

Acceptable/Guideline 0, 80, 200, or 600 ppm (0, 5.2 / 5.8, 13.4 / 14.9, or 34.5 / 40.3 mg/kg bw/day [M/F] ) NOAEL = 13.4 / 14.9 mg/kg/day . LOAEL = 34.5 /40.3 mg/kg/day based on decreased landing foot splay (males) , decreased fore - and hindlimb grip strength (males), decreased motor activity [center time (females) and rearing activity (both sexes) .Bifenazate Human - Health Risk Assessment DP # 388228

Page 44 of 53 **Table A.2.2 .**  **Bifenazate Subchronic, Chronic,**  **and Other Toxicity Profile .**  **Guideline No.**  **Study Type MRID No. (year)/**  **Classification /Doses Results**  870.7485 Metabolism and

pharmacokinetics (Rat) 45052223 (1998)

10 mg/kg or 1000 mg/kg acceptable/guideline Absorption, distribution, and metabolism of bifenazate wa s rapid, with > 93% of the administered dose being recovered within 72 hours of treatment for both the low - and high dose groups. As a result of this rapid turnaround, no signi ficant tissue accumulation of the test material wa s 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 c arried in the plasma. The feces were the primary elimination route for low - dose rats with ~66% of the administered dose recovered in this media. Radioactivity i n the feces was greater for the high - dose rats (823%) due to saturated absorption that resulted in subsequently greater unabsorbed test material. Urinary excretion wa s a relatively minor route with ~25% of the administered dose recovered in this media for both male and female low - dose rats. For the high - dose male and female rats urinary excretion was notably lower (<10% of the administered dose) due to saturated absorption. C max was reached earlier following a 10 mg/kg dose (5 - 6 hours) than the 1000 mg/kg dose (18 - 24 hours). In addition, t 1⁄2 wa s 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]) Sy stemic 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 phy sicochemical properties o f the inhaled compound, the ty

pe of toxicity

observed ( e.g. sy stemic vs. port of entry) and the pharmacokinetic (PK) **but not pharmacodynamic** (PD) differences between animals and humans. Based on the EPA’s RfC guidance (1994), the methodology for RfCs deri vation is an estimate of the quantitative dose - response assessment of chronic non - cancer toxicity for individual inhaled chemicals and includes dosimetric adjustment to account for the species - specific relationships of exposure concentration to deposited/delivered dose. This adjustment is influenced b y theBifenazate Human - Health Risk Assessment DP # 388228

Page 45 of 53 phy sicochemical properties of the inhaled compound as well as the type of toxicity observed ( e.g. sy stemic vs. port - of

- entry), and takes into consideration the PK differences between animals and humans. Though the RfC methodology was developed to estimate toxicity of inhaled chemicals over a lifetime, it can be used for other inhalation exposures ( e.g . acute and short - term exposures) since the dosimetric adjustment incorporates mechanistic determinants o f disposition that can be applied to shorter duration of exposures provided the assumptions underlying the methodology

are still valid. These assumptions, in turn, vary depending on the ty

pe of toxicity observed. Thus , the derivation of a HEC for inhaled gases is described b y the following equation: Where: POD study : Point of departure identified in the critical toxicology study . D animal exposure : Duration of animal exposure (hrs/day; day s/wk) . D anticipated exposure : Anticipated human duration of exposure (hrs/day ; days/wk) . RGDR: Regional Gas Dose Ratio . Calculations used to estimate the inhalation risk to humans from aerosols are dependent not on the RGDR as for gases, but on the regional deposited dose ratio (RDDR). Inhalation studies using aerosols characterize particulate exposure by defining the particulate diameter (mass median aerodyn amic diameter [MMAD]) and the geometric standard deviation (σ g), which is then used to determine the RDDR. The RDDR is a multiplicative factor used to adju st an observed inhalation particulate exposure concentration of an animal (A) to the predicted inhalation particulate exposure concentration for a human (H) that would be associated with the same dose delivered to the rth region or target tissue. RDDR

r = (RDD r /Normalizing Factor) A (RDD r /Normalizing Factor) H As with calculations for gases, the r regions and potential target tissues are the three respiratory regions (ET, TB, PU). The RDDR is easily calculated by

using a software program designed specificall y for computing the RDDR from the MMAD and σ g defined from an aerosol inhalation study . The values for the species - specific parameters used to calculate the RDDR are provided in the EPA document “Methods for Derivation of Inhalation Reference C oncentrations and Application of Inhalation Dosimetry .” **Regional Deposited Dose Ratio (RDDR) for B**  **ifenazate :**  MMAD = 2.20 Sigma g = 2.78

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

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

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

Extrathoracic 

## HEC = POD * D

D * W

W * RGDR study animal exp

osure (hrs / day) human expo

sure (hrs / day) animal exp osure (day s / wk) human expo

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

Page 46 of 53 SA (m^2) deposited fraction

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

------- ------------------------------------------------------------------------- RATIO 0.075 0.740 RDDR = (VE/SA) animal/(VE/SA) human * deposited fraction animal/deposited 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 Res**  **idential Exposure:** Assume residents will be exposed for 24 hrs/day and 7 day s/week: HEC = NOAEL study * (daily duration of exposure animal/daily duration of exposure human) * (day s/week of exposure animal/days/week of exposure human) * RDDR HEC = 0.03 mg/L * (6/24) * (5/7) * 0.175 = 0.00094 mg/L. **Table B.1. HEC Array for Residental**  **Risk Assessment.**

Relevant Study LOAEL (mg/L) NOAEL

(mg/L) Da Dh Wa Wh RDDR HEC (mg/L) inter intra UF Short - & Intermediate - Term Exposure Inhalation

– Rat (MRID 48723301 ) 28 - day ET 0.075 0.03 6 24 5 7 0.175 0.00094 3 10 NA Long - Term Exposure: 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 forBifenazate Human - Health Risk Assessment DP # 388228

Page 47 of 53 default body

weight s 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/Lto 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 w hich 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 day s/week: HEC = NOAEL study * (daily duration of exposure animal/daily duration of exposure human) * (day s/week of exposure animal/days/week of exposure human) * RDDR HEC = 0.03 mg/L * (6/8) * (5/5) * 0.175 = 0.00394 mg/L. **Table B. 2**  **. HEC Array for Occupational Risk Assessment.** 

Relevant Study LOAEL (mg/L) NOAEL

(mg/L) Da Dh Wa Wh RDDR HEC (mg/L) inter intra UF Short - & Intermediate - Term Exposure Inhalation

– Rat (MRID 48723301 ) 28 - day ET 0.075 0.03 6 8 5 5 0.175 0.00394 3 10 NA Long - Term Exposure: Not appropriate for bifenazate. **Key for Array Tables** LOAEL : Lowest observed adverse effect level NOAEL : No observed adverse effect level Da : Daily animal exposure (hrs/day) Dh : Anticipated daily human exposure (hrs/day) Wa : Weekly animal exposure (days/week) Wh : Anticipated weekly human exposure (days/week) RRDR : Regional Deposited Dose Ratio HEC : Human Equivalent Concentration inter : interspecies extrapolation UF intra : intraspecies variation UF UF: Other UF(s) ET: Extra thoracic region **Route -**  **to -**  **Route Extrapolation** More information and details see : Memo, “Route - to - Route Extrapolations” J. Whalen and H. Pettigrew, 10/10/98.Bifenazate Human - Health Risk Assessment DP # 388228

Page 48 of 53 HED’s route - to - route extrapolation converts human and animal values from mg/L concentrations to mg/kg oral - equivalent doses. The equation uses a single conversion factor to account for default body

weight s and respiratory

volumes. An activity

factor is u sed to account for increased exposure resulting from increased respiration. Using the HEC calculated (based upon terminal airway inflammation in males), a conversion of the inhalation concentration to a dose (mg/L to mg/kg/day) was conducted as follows: Human - Equivalent Dose (HED, mg/kg/day) = Dose (systemic HEC value, mg/L) x A x CF (L/hr/kg) x D (hours) x AF = mg/kg Where: A = absorption: ratio of deposition and absorption in respiratory tract compared to

absorption by the oral route. CF = conversi on Factor; a L/hr/kg factor w hich accounts for respiratory volume and body weight for a given species and strain (Table 1 of J. Whalen and H. Pettigrew , 10/10/98). D = duration; duration of daily animal or human exposure (hours). AF = activity Factor; ani mal default is 1. Therefore, the occupational human equivalent dose for bifenazate is calculated as follows: **Occupational HED:** (0.0039 mg/L) x 1 x 6 x 8 x 1 = 0.187 mg/kg/day Based on the current bifenazate label, HED believes exposures can be short - (1 - 30 day s) or intermediate - (1 to 6 months) term in duration. L ong - 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 sy stemic versus port - of - entry effects. Ty pically , HECs are calculated separatel y for s ys temic versus port - of - entry effect. For bifenazate, port - of

- entry irritation was observed and, therefore, onl y port - of - entry HECs were derived. 2. Time adjustments are traditionally needed for non - occupational (b ys tander) 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 day s/week. In comparison, the average workweek for an occupational worker is 8 hours/day and 5 day s/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 -Bifenazate Human - Health Risk Assessment DP # 388228

Page 49 of 53 application method - specific unit exposure by an estimate of the amount of active ingredient handled in a day , using the equation below: E = UE * AR * A where: E = exposure (mg/day); UE = unit exposure (mg/lb ai); AR = application rate (e.g., lb ai/ft2 , lb ai/gal); and A = area treated or amount handled (e.g., ft2 /day , gal/day). 1.2 Residential Handler Dose Calculations Dermal and/or inhalation absorbed doses normalized to body weight are calculated as: D = E *AF / BW where: D = dose (mg/kg - day); E = exposure (mg/day); AF = absorption factor (dermal and/or inhalation); and BW = body

weight (kg). **2.0 Residential**  **Post -**  **application 3.1**  **Gardens and Trees 3.2**  Post- application Dermal Exposure Algorithm Exposure resulting from contacting previousl y treated gardens and trees while performing phy sical 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 = DFR t * CF1 * TC * ET where : E = exposure (mg/day); DFRt = dislodgeable foliar residue on day "t" (μg/cm2 ); CF1 = weight unit conversion factor (0.001 mg/μg); TC = transfer coefficient (cm2 /hr); and ET = exposure time (hrs/day). In the absence of chemical - specific data, DFR t can be cal culated as follows: DFR t = AR * F

AR * (1 -F

D ) t * CF2 * CF3 where : DFRt = dislodgeable foliar residue on day "t" (μg/cm2 );Bifenazate Human - Health Risk Assessment DP # 388228

Page 50 of 53 AR = application rate (lbs ai/ft2 or lb ai/acre); F AR = fraction of ai as dislodgeable residue following application (unitless); F D = fraction of residue that dissipates daily (unitless); t = post - application day

on which exposure is being assessed; CF2 = weight unit conversion factor (4.54 x 10 8 μg/lb); and CF3 = area unit conversion factor (1.08 x 10 - 3 ft2 /cm2 or 2.47 x 10 - 8 acre/c m2 ). Absorbed dermal dose, normalized to body weight , is calculated as: BW AF E D *  where : D = dose (mg/kg - day); E = exposure (mg/day); AF = absorption factor (dermal and/or inhalation); and BW = body

weight (kg). **Table 3.**  **2. Gardens, Trees, and “Pick** **- your**  **- own” Farms**  **– Inputs for Residential Post**  **- application Derm**  **al Exposure**  **. Algorithm**  **Notation Exposure Factor**  **(units) Point Estimate(s)**  AR Application rate (mass ai per unit area) **[input]** F AR DFR following application, if chemical - specific is unavailable (fraction) 0.25 F D Daily residue dissipation, if chemical - specific is unavailable (fraction) 0.10

TC Transfer

Coefficient (cm 2/hr) Gardens a Adults 8 , 400 Children 6 ≤ 11 years old 4 , 600 Trees, Retail Plants (if applicable) a Adults 1 , 700 Children 6 ≤ 11 years old 930 Indoor Plants Adults 220 Children 6 ≤ 11 years old 120

ET Exposure

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

Children 6 ≤ 11 years old 0.50 Indoor Plants Adults 1.0

Children 6 ≤ 11 years old 0.50 “Pick - yo ur - own” Farm s (if applicable) Adults 5.0 Children 6 ≤ 11 years old 1.9 BW Body w eight (kg) Adults 69 Children 6 ≤ 11 years old 32 a Transfer coefficient point estimates from a composite distribution assuming equal proportion of time spent conducting various activities. See “Transfer Coefficient” section below . Children 6 ≤ 11 years old TC derived using surface area adjustment (see Section 2.3 ). b Activity time point estimates from a composite distribution assuming equal proportion of each respective activity. Time for children 6 < 11 years old derived using hrs/day ratio adju stment.Bifenazate Human - Health Risk Assessment DP # 388228

Page 51 of 53 **Appendix D. Summary of Occupational and Residential Non -**  **cancer Algorithms** Average Dail y Dose Potential daily

exposures for occupational handlers are calculated using the following formulas:

E=UE * AR * A * 0.001 mg/ug where: E = exposure (mg ai/day), UE = unit exposure (μg ai/lb ai), AR = maximum application rate according to proposed label (lb ai A or lb ai/gal), and A = area treated or amount handled (e.g., A/day , gal/day). The daily doses are calculated using the following formula: ADD= E * AF BW where: ADD = average dail y dose absorbed in a gi ven scenario (mg ai/kg/day), E = e xposure (mgai/day), AF = absorption factor (dermal and/or inhalation), and BW = body

weight (kg). Margin of Exposure (MOE) Non - cancer risk estimates for each application handler scenario are calculated using a n MOE that is a ratio of the toxicological endpoint to the daily dose of concern. The daily dermal and inhalation dose received by occupational handlers are compared to the appropriate POD (i.e., NOAEL) t o assess the risk to occupational handlers for each exposure route. All MOE values are calculated using the following formula: MOE= POD ADD where: MOE = margin of exposure: value used b y HED to represent risk estimates (unitless), POD = point of departure (mg/kg/day), and ADD = average dail y dose absorbed in a given scenario (mg ai/kg/day). **Appendix E. Summaries of Dislodgeable Foliar Residue Studies and Proposed Use in Assessment**  **.**

**Proposed Uses for Bifenazate .**  **Commodity Foliage Type**  **a Product**  **Name Application** 

**Equipment Applicatio** 

**n Rate (lb ai/A)**  **Ma xim**  **um**

**Number Applications**  **Per Season** Herbs subgroup 19 A (except chives, chervil) Unknown Florimite® 50WP Groundboom,

Aerial Airblast 0.5 1 Fruiting vegetable Group 8 - 10 smooth Pome fruit Group 11 - 10 smooth Timothy forage hay varied Airblast 0.75 1 a. Based on information in the ARTF/ORETF DFR Guidance **DFR Studies Available:** Florimite®

50WP on Spathiphyllum: Dislodgeable Foliar Residue Study (MRID 448597 - 01) . (HED Review: Memo, L. Venkateshwara, pending , D 388802 )Bifenazate Human - Health Risk Assessment DP # 388228

Page 52 of 53 This study

was designed to collect data to evaluate dislodgeable foliar residue (DFR) dissipation for the compound bifenazate from Spathiphyllum (Peace Li ly) foliage grown in a greenhouse at one site in Florida. One field trial was conducted in two greenh ouses, one containing treated Spathiphyllum (Peace Lil y) plants and the other containing untreated plants. Primary review of the study was conducted by

Versar In c., 07/07/2000 (MRID 448597 - 01). F lorimite® 50WP is a wettable - powder packaged in water- soluble bags that contains 50 % bifenazate as the active ingredient. Floramite ® 50W P 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 day s after the last treatment. Samples were anal yz ed 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 analy zed was 72 μ g/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 μ g/sample) within the 21 - day sampling period following the first two applications. DFR values did decline to <LOQ b y DAT - 35 after the third application. Assuming first order kinetics, HED modeled dissipation rates and estimated half - lives for bifenazate of 9.9 days in Florida (R2 = 0.8433). **Summary of DFR Values and Regression Analysis Results for Treated Spathiphyllum**  **(Peace Lily) in Greenhouses with Bifenazate (MRID# 448597**  **- 01).** 

Input/Parameter Site: Florida **Bifenazate** Application Rate (lb ai/A) a Study Target Rate = 0.29 lb ai/A 0.29 lb ai/A Spray Volume (GPA) 5 gallons/1000 ft2 Measured Average Day 0 Residue (μg/cm2 ) 0.151 Predicted Day 0 Residue (μg/cm2 ) b 0.161 Slope - 0.07 Half - life (days) 9.9 R2 0.8433 a. The application was conducted using hand -held boom sprayer. b. Regressions are based on data collected after second application. **Proposed use of DFR data:**

 Use the greenhouse Spathiphyllum (Peace Lily) DFR data to estimate post - application exposure for h erbs subgroup 19 A (except chives, chervil), fruiting vegetable group 8 - 10, pome fruit group 11 - 10, Timothy forage hay (use predicted values).Bifenazate Human - Health Risk Assessment DP # 388228

Page 53 of 53 Crop DFR Data Sites Proposed use of DFR Data Characterization

Herbs subgroup 19 A (except chives, chervil), Fruiting vegetable group 8 - 10, Pome fruit group 11 - 10, Timothy forage hay Spathiphyllum (Peace Lily) (Greenhouse) FL Predicted DFR values  DFR data collected in greenhouse; is a

conservative estimate.  The formulation in the study is a wettable - powder packaged in a 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/cm3 Water solubility (25 ± 1°C) 2.1 mg/L (20°C) Solvent solubility 102 mg/mL ethyl acetate (20°C) Vapor pressure at 25 ± 1°C <1 x 10 - 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.