Fluopy

ram Human Health Risk Assessment DP No. D385636

Page 1 of 105 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460 **OFFICE OF CHEMICA** **L SA FETY**  **AND POLLUTION PREVENTION**  **MEMORANDUM Date**  **:** November 23 , 2011 **SUBJECT: Fluopyram:**  Human Health Risk Assessment for Proposed Uses on Apple s , Banana s (Import only), Cherries (Sweet and Tart) , Dried Bean s , P eanut s , Potato es , Strawberries , Sugar Beet s , Tree Nuts , Watermelon and Wine Grape s . **PC Code:** 080302 **DP Barcode:** D385636 **Decision No.:** 402628 **Registration No. :**  264 - RNTI **Petition No .:**  8F7463 **Regulatory Action:** Section 3 **Risk A**  **ss essment Typ**  **e :**  Single Chemical/Aggregate **Case No.:** NA **T XR No.:**  NA **CAS No.:** 658066 - 35 - 4 **MRID No.:** NA **40 CFR:** 180.xxx(pending) **FROM:** Sheila Heal y, Risk Assessor

Leung Cheng, Chemist Barry O’Keefe, Biologist Whang Phang, Toxicologist Risk Assessment Branch III Health Effects Division (7509P) **THROUGH:** Paula Deschamp , Chief

Risk Assessment Branch III Health Effects Division (7509P) AND Ray Kent, Designated Reviewer Richard Loranger, Designated Reviewer Risk Assessment Review Committee **TO:** Shaja Joy

ner/Lisa Jones , Risk Management Team #20 Fungicide Branch Registration Division (7505P)Fluopy

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Page 2 of 105 **1.0 Executive Summary**  ................................ ................................ ................................ ........... 4 **2.0 HED Recommendations**  ................................ ................................ ................................ .... 7 **2.1 Data Deficiencies/Conditions of Registration**  ................................ .............................. 7 **2.2 Tolerance Considerations**  ................................ ................................ .............................. 8 **2.2. 1**  **Enforcement Analytical Method** ................................ ................................ ............... 8 **2.2.2 International Harmonization**  ................................ ................................ ..................... 9 **2.2.3 Recommended Tolerances**  ................................ ................................ ......................... 9 **2.2.4 Revisions to Petitioned**  **- For Tolerances**  ................................ ................................ .. 12 **2.3 Label Recommendations**  ................................ ................................ .............................. 13 **2.3.1 Recommendations from Residue Reviews**  ................................ .............................. 13 **2.3.2 Recommendations from Occupational Exposure Assessment**  .............................. 13 **3.0 Introduction**  ................................ ................................ ................................ ...................... 13 **3.1 Chemical Identity**  ................................ ................................ ................................ ......... 14 **3.2 Physical/Chemical Characteristics**  ................................ ................................ ............. 14 **3.3 Pesticide Use Pattern**  ................................ ................................ ................................ .... 14 **3.4 An**  **ticipated Exposure Pathways** ................................ ................................ ................. 16 **3.5 Consideration of Environmental Justice**  ................................ ................................ .... 16 **4.0 Hazard Characterization and Dose**  **- Response Assessment**  ................................ .......... 17 **4.1 Toxicology Studies Available for Analysis**  ................................ ................................ . 17 **4.2 Absorption, Distribution, Metabolism, & Elimination (A** **DME)** ............................. 17 **4.2.1 Dermal Absorption**  ................................ ................................ ................................ ... 18 **4.3 Toxicological Effects**  ................................ ................................ ................................ .... 18 **4.4 Sa**  **fety Factor for Infants and Children (FQPA Safety Factor)** ............................... 19 **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 Unc**  **ertainty in the Exposure Database** ................................ ................... 19 **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** ..... 20 **4.5.3 Cancer Classification and Risk Assessment**  **Recommendation** ............................ 20 **4.5.4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk**  **Assessment** ................................ ................................ ................................ ............................... 21 **4.6 Endocrine Disruption**  ................................ ................................ ................................ ... 23 **5.1 Metabolite/Degradate Residue Profile**  ................................ ................................ ....... 23 **5.1.1 Summary of Plant and Animal Metabolism Studies**  ................................ ............. 24 **5.1.2 Summary of Environmental Degradation**  ................................ .............................. 25 **5.1.3 Comparison of Metabolic Pathways**  ................................ ................................ ....... 25 **5.1.4 Residues of Concern Summary and Rationale**  ................................ ...................... 26 **5.2 Food Residue Profile**  ................................ ................................ ................................ .... 29 **5.3 Wate**  **r Residue Profile** ................................ ................................ ................................ .. 31 **5.4 Dietary Risk Assessment**  ................................ ................................ .............................. 31 **5.4.1 Description of Residue Data Used in Dietary Assessment**  ................................ .... 31 **5.4.2 Percent Crop Treated Used in Dietary Assessment**  ................................ .............. 32 **5.4.3 Acute Dietary Risk Assessment**  ................................ ................................ ............... 32 **5.4.4 Chronic Dietary Risk Assessment**  ................................ ................................ ........... 32Fluopy

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Page 3 of 105 **5.4.5 Cancer Dietary Risk Assessment**  ................................ ................................ ............. 33 **5.4.6 Summary Table**  ................................ ................................ ................................ ......... 33 **6.0 Residential (Non**  **- Occupational) Exposure/Risk Characterization**  ............................. 35 **6.1 Residential Handler Exposure**  ................................ ................................ .................... 35 **6.2 Residential Bystander Post**  **- application Inhalation Exposure**  ................................ . 35 **6.3 Spray Drift**  ................................ ................................ ................................ .................... 35 **7.0 Aggregate Exposure/Risk Characterization**  ................................ ................................ .. 35 **7.1 Acute Aggregate Risk**  ................................ ................................ ................................ ... 36 **7.2 Shor** **t -**  **and Intermediate -**  **Term Aggregate Risk** ................................ ........................ 36 **7.3 Chronic Aggregate Risk**  ................................ ................................ .............................. 36 **7.4 Cancer Aggregate Risk**  ................................ ................................ ................................ 36 **8.0 Cumulative Exposure/Risk Characterization**  ................................ ............................... 36 **9.0 Occupational Exposure/Risk Characterization**  ................................ ............................ 36 **9.1 Short** **- /Intermediate**  **- /Cancer Handler Risk**  ................................ .............................. 36 **9.2 Short** **- /Intermediate**  **- /Cancer Post** **- Application Risk**  ................................ ................ 37 **9.2.2 Inhalation Post** **- application Risk**  ................................ ................................ ............. 38 **10.0 References**  ................................ ................................ ................................ ......................... 39 **Appendix A. Toxicology Profile and Executive Summaries** ................................ .................. 40 **A.1 Toxicology Data Requirements**  ................................ ................................ ................... 40 **A.2 Toxicity Profiles**  ................................ ................................ ................................ ............ 41 **A.3 Hazard Identification and Endpoint Selection**  ................................ .......................... 47 **A.4 Executive Summaries**  ................................ ................................ ................................ ... 50 **Appendix B. Metabolism Summary Table**  ................................ ................................ ............... 81 **Appendix C. Physical/Chemical Properties** ................................ ................................ ............. 94 **Appendix D. Review of Human Research** ................................ ................................ ................ 95 **Appendix E. Occupational Exposure/Risk Summary Tables** ................................ ................ 96 **Appendix F. International Residue Limit Status Sheet** ................................ ........................ 104Fluopy

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Page 4 of 105 **1.0 Executive Summary**  Fluopy ram, ( N - [2 - [3 - chloro - 5 - (trifluoromethyl) - 2 - py ridinyl]ethyl] - 2 - (trifluoromethyl )benzamide) is a new broad - spectrum sy stemic fungicide of the py ridinyl - ethyl benzamide group. It acts by inhibiting succinate dehydrogenase in the cell respiration of fungi. The mech anism of toxicity in mammals is not clearly defined . Bayer CropSciences (BCS) submitted fluopy

ram as a Global Joint Review to USEPA, Canada (PMRA) and Germany (BVL) in 2008 . BCS initially proposed tolerances on practically all crop groups, hops, and glob e artichoke . Independent hazard evaluations in the US and Canada both yi elded the conclusion that fluopy

ram is a likely human carcinogen and the resulting lifetime cancer risks from the proposed array

of crop uses were of concern. Consequently , BCS withdrew a majority of the primary crops initially

proposed for this registration action and expanded the original rotatable crops of alfalfa and cotton to include canola, so yb ean, and cereals grains except rice. **Use Profile** : The proposed uses of fluop yr am addressed in this document are: a pples, bananas (no US registration), cherries ( s weet and t art), dried b eans (selected) , p eanut s , p otato es , strawberries , s ugar b eets, tree nuts , watermelon , and w ine grapes . The proposed formulated end - use prod uct is Fluopy

ram 500 SC Fungicide, a liquid formulation containing 41.5 % ai (4.16 lb /gal) fluop yr am . Applications of fluopy ram may be applied to agricultural crops using ground (chemigation, groundboom sprayers, airblast sprayers, low pressure hand wand sprayer s, and backpack sprayers) or aerial equipment at maximum single rates ranging from 0.092 to 0.22 lb ai/A. Multiple applications may be made per season, up to a maximum of 0.45 lb ai/season. Applications may be made in greenhouses of 10 acres or larger fo r strawberries and watermelon . Preharvest intervals (PHI s) range from 0 to 14 day s and the restricted entry

interval (REI) is 12 hours. These actions will be the first registrations in the US . Registration is pending in the European Union and concurrent petitions are being reviewed in Canada. **Human Health Risk Assessment** The l iver was the target organ across specie s and duration of exposure . Treatment - related thy roid effects were also observed at dose levels causing adverse liver perturbations in rats and mice. Decreased body weight w as a common clinical finding throughout the toxicology database. Liver tumors were observed in female rats and thyroid tumors , in male mice in chronic feeding studies. Fluopy ram is classified as “ Like ly to be Carcinogenic to Humans ” and a unit risk factor , Q 1 * , of 1.55 x 10 - 2 (mg/kg/day) - 1 was used for the linear low dose extrapolation of cancer risk based on liver tumors in female rats . Fluopy ram is not genotoxic or mutagenic. An acute endpoint for the general population (including infants and children) was selected from the acute neurotoxicity

study in rats based on decreased motor and locomotor activity (NOAEL = 50 mg/kg). Because this effect was reversible within 48 hours and attributed to generalized sy stemic toxicity , fluop yram is not considered a neurotoxicant . An acute endpoint attributable toFluopy

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Page 5 of 105 a single dose was not identified for females aged 13 - 49 years. The chronic endpoint (N OAEL = 1.2 mg/kg/day) was based primarily on liver and thy roid effects in the chronic toxicity /carcinogenicity s tudy

in rats. Short - and intermediate - term dermal endpoints were chosen from a dermal toxicity study in rats in which liver effects were seen at the limit dose (NOAEL = 300 mg/kg/day). Inhalation endpoints, s hort - and intermediate - term , were selected from the multigeneration reproduction study based on liver effects in the parental generation; inhalation and oral absorption equivalency is assumed ( 100% ). Fluopy ram has low acute toxicity via the oral, dermal and inhalation routes of exposure. Fluopy ram is not a skin or eye irritant or sensitizer under the conditions of the murine ly mph node assay . **Dietary Exposure ( F**  **ood and**  **W ater)**  Th e residue chemistry

data and environmental fate data are adequate to assess human exposure. The acute dietary

food exposure assessment is conservative/unrefined, the chronic dietary assessment is partially

refined, and the cancer dietary assessment, highl y refined. The assessments are based on reliable data and will not underestimate exposure/risk. Acute: The estimated acute dietary exposure to fluopy

ram from food and drinking water is below HED’s level of concern (<100%) for all population subgroups. Tolerance level residues and 100% crop treated values were utilized in the exposure estimates. Empirical or DEEMTM default processing factors were used . Combined dietary exposure from food and drinking water at the 95 th percentile of exposure is estimated to be 0.021 mg/kg/day for the overall US population, equivalent to 4. 2 % of the aPAD. The population subgroup with the highest estimated acute dietary

exposure to fluopy

ram is children 1 - 2 y

rs old , with an estimated exposure at the 95 th percentile of 0. 04 2 mg/kg/day , equivalent to 8. 4 % of the aPAD. Chronic : A partially

refined chronic dietary

assessment was conducted. The assumptions of this dietary assessment included average field trial residues for all propos ed crops and 100% crop treated (CT). Empirical or DEEMTM default processing factors were used . The surface water estimated drinking water concentration ( EDWC ) of 4.90 μ g/L was incorporated directl y into the dietary a ssessment . The results of the aggregate chronic dietary anal ys is for food and drinking water are below the Agency ’s level of concern (<100% cPAD) for all population subgroups. Chronic dietary

exposure was estimated at 0. 00042 mg/kg/day for the US population ( 3.5 % of the cPAD) and 0. 0012 mg/kg/day ( 10 % of the cPAD) for the most high ly exposed population subgroup (children 1 - 2 yrs old). Cancer: The cancer dietary (food and drinking water) exposure estimate for the general US population is 2.9 x 10 - 6 , with water contributing approximately 30% of the risk . The cancer dietary anal ys is included average residue levels, projected percent crop treated (PP CT) estimates based on the Market Leader and processing factors (empirical and default, commercial and household). Estimates were based on the maximum amount of acreage available for rotation following application to dry beans and potato . The DEEM anal ys is also assumed that all drinking water will contain fluopy ram at the highest EDWC levels modeled by EFED for ground water or surface water . For these reasons it can be concluded that the cancer dietary anal ys isFluopy

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Page 6 of 105 does not underestimate risk from chronic exposure to fluopy ram. **Residential Exposure** : No residential uses for fluopy ram have been proposed. **Aggregate Risk:** Acute: Aggregate a cute risk is equivalent to the acute dietary risk. There is potential acute exposure (~ 4.2 % aPAD) via the diet (food and drinking water) as determined in Section 5.4. Chronic: Aggregate chronic risk is equivalent to chronic dietary risk. There is potenti al chronic exposure ( 3.5 % cPAD) via the diet (food and drinking water) as determined in Section 5.4 . There are no proposed residential uses so short - or intermediate - term residential exposures are not likely to occur. Therefore neither short - nor inter mediate - term aggregate risks were assessed. The aggregate cancer risk (food and drinking water) is 2.9 x 10 - 6 (Table 5.4). The unit risk for fluopy ram, Q 1 * , is 1.55x10 - 2 (mg/kg/day) - 1 . The Q 1 * is based upon liver tumor s in female rats and is expressed in human equivalents. **Occupational Exposure/Risk:** Agricultural Handlers: Occupational short - term (1 - 30 day s) and intermediate - term (1 - 6 months) dermal and inhalation exposures are expected f or fluop yr am handler activities associated with the proposed agricultural uses . A Margin of Exposure (MOE) greater than 100 for the inhalation and dermal route s of exposure is deemed adequate to protect occupational fluopyram handlers. Non - cancer occupational risk estimates for dermal (with gloves) and inhalation short - and intermediate - term exposure durations all resulted in MOEs considerabl y greater than 100, and therefore, do not exceed HED’s level of concern (Table E1). MOEs for dermal (with gloves ) exposure ranged from 180,000 to 7,300 and MOE s for inhalation exposure ranged from 1,300,000 to 7,700 . Handler cancer risks for private growers and commercial applicators were calculated for different exposure scenarios at different levels of personal protection. Handler cancer risk estimates for combined inhalation and dermal (with gloves) exposures for private growers ranged from 1. 4 x 10 - 8 to 5.6 x 10 - 7 and for commercial workers ranged from 3.1 x 10 - 8 to 8.8 x 10 - 7

. Agricultural Post - application: The occupational post - application non - cancer MOEs do not exceed HED’s level of concern (MOEs ≥100) with dermal MOEs ranging from 530 to 5,600 on the day of application (12 hours post - application). Occupational post - application exposure scenarios for cancer risk estimates were assessed for individuals employed b y multiple establishments (i.e., commercial or migratory farm workers) and were assumed to be exposed 30 day s per year. The cancer risk estimates ranged from 5.1 xFluopy

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Page 7 of 105 10 - 7 to 4.0 x 10 - 6

. These estimates are considered conservative since the max imum application rate and shortest retreatment intervals were used to calculate the estimates. Restricted Entry

Interval: When postapplication risks are not a concern on day 0 (12 hours following application), the restricted entry interval (REI) is based on the acute toxicity of fluopy ram technical material. Fluop yram is classified as T oxicity C ategory III by the acute oral and dermal route s of exposure , and Toxicity Category IV for acute inhalation, eye irritation potential, and skin irritation potential. Under the WPS for Agricultural Pesticides, active ingredients classified as acute toxicity categories III or IV for these routes are assigned a 12 - h our REI . Therefore, the 12 - hour REIthat appears on the proposed label would be adequate. **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 oth er chemical. These studies (Appendix D ) have been determined to require a review of their ethical conduct, and one of these studies is also subject to review b y the Human Studies Review Board. All of the listed studies have received the appropriate review. **2.0 HED**  **Recommendations** Pending submission of a revised Section B (see 2.3 L abel Recommendations ) and a revised Section F (see 2.2.3 Recommended Tolerances), and anal ytical reference standards (see requirements under Submittal of Analy tical Reference Standards), there are no other issues that would preclude granting conditional Section 3 registration for the requested uses of fluopy ram, or establi sh ing tolerances for residues of fluopy ram. **2.1 Data Deficiencies/Conditions of Registration**  **The following data are required as a condition of registration:**  860.1900 Field Accumulation in Rotational CropsFluopy

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Page 8 of 105  The petitioner must submit extensive field rotational crop field trials conducted on canola, cereal grains (except rice), and so ybean , and submit a repeat cotton trial due to crop failure. In 2008, the Agency

received data in support of the registrant’s proposed registrations and tolerances for a wide variety of primary

crops in nearl y all crop groups . These data included extensive rotational field trial data for alfalfa and cotton to support inadvertent tolerances and limited rotational field trial data for wheat, turnip, and mustard greens. Subs equent to the 2008 petition, the re gistrant submitted a letter withdrawing their request for uses on numerous primary crops . Thus, the Agency has concluded that extensive field rotational crop studies are required as a condition of registration to support the rotation to canola, cereal grains except rice, corn, and soy bean following application of fluopy ram to potato and dry

beans. In addition, a repeat cotton trial is required as a condition of registration because of crop failure. 870.3465 90 - Day

Inhalation Toxicity

 The registrant must submit a subchronic inhalation study . Prior to 2010, the Agency frequentl y relied on oral toxicity studies to conduct inhalation risk assessments. In December 2009, the Agency sought expert advice and input from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) on issues related to this route to route extrapolation approach in the absence of an inhalation toxicity study (i.e., the use of oral toxicity

studies for inhalation ri sk assessment). Based on the SAP’s recommendations in the March 2, 2010 Final Report (http://www.epa.gov/scipoly /SAP/meetings/2009/120109meeting.html ), the Agency has increased its focus on the uncertainties associated with route - to - route extrapolation and is presentl y requiring inhalation toxicity studies more frequently . The Agency has concluded that an inhalation toxicity

study is required as a condition of registration to f ully characterize the risk from inhalation exposure to fluopy ram. **The following data should be submitted with future uses:** 875.2100 Foliar Dislodgeable Residue Dissipati on  Dislodgeable foliar residue (DFR), or turf transferable residue (TTR), studies may be required in the future if the use profile is expanded. **2.2 Tolerance Considerations**  **2.2.1 Enforcement Analytical Method**  The German multiresidue method DFG Method S 19, a gas chromatography with mass selective detection (GC/MSD) method, has been p roposed for the enforcement of tolerances for fluopy ram residues in/on crop commodities, and a high performance liquid chromatography method with tandem mass spectrometry detection (HPL C/MS/MS), Method 01079, has been proposed for theFluopy

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Page 9 of 105 enforcement of tolerances for residues of fluop yram and its metabolite, AE C656948 - benzamide , in livestock commodities. The validated limit of quantitation (L OQ) is 0.01 ppm for each anal yt e in each matrix. The proposed enforcement method for plant commodities (DFG Method S1 9) and livestock commodities (Method 01079) are deemed adequate as enforcement methods. Adequate HPLC/MS/MS methods were used for data collection for crop and livestock commodities. The FDA multiresidue methods of PAM Vol. Iare suitable for the determin ation of fluopy ram in non - fatty matrices (using Section 302), but are not suitable for detection of AE C656948 - benzamide residues. **2.2.2 International Harmonization**  Codex Maximum Residue Limits (CXLs) have been established for grape at 2 mg/kg and dried grapes (raisins) at 5 mg/kg , milk at 0.07 mg/kg , mammalian meat at 0.15 mg/kg , and edible offal mammalian (meat b yproducts) at 0.7 mg/kg . For the purpose of international harmonization, HED is recommending establishment of US tolerances for wine grape at 2.0 ppm (raised from 1.4 ppm), milk at 0.07 ppm (raised from 0.06 ppm), and hog meat b yproducts at 0.70 ppm (raised from 0.45 ppm). An International Residue Limit Status sheet is attached (Appendix F). The Codex MRLfor grapes is based on field trials conducted in Europe, and is calculated by rounding up of the statistically determined 1.3 mg/kg to 2 mg/kg . A US tolerance for dried grapes (raisins) is not needed as the tolerance request is for wine - ty pe grapes only , which are not converted to raisins. Harmonization of recommended US tolerances for meat and meat by products (other than hog) with Codex MRL s cannot be achieved. The Codex MRLfor livestock is calculated on the basis of the diets listed in Annex 6 of the 2009 JMPR Report (OECD Feed stuffs Derived from Field Crops) and the use of a reasonable worst case diet/feed approach (RWCF) . The dietary burden was calculated using only grape pomace residue and 20% contribution to the Australian dairy and beef cattle diets. The US tolerance was based on guidance “Revisions of Feedstuffs in Table 1 of OPPTS Test Guideline 860.1000 ” and “ Guidance on Constructing Maximum Reasonably Balanced Diets (MRBD)”. Based on the US livestock diets (which does not include grape pomace) and the cattle feeding s tudy , the meat byproduct (cattle, goat horse, sheep) tolerances need to be set at 1.1 ppm, a higher level than the 0.7 mg/kg Codex MRLfor edible offal. Similarly, the US meat tolerances for these animals need to be set higher than the Codex MRL (0.15 ver sus 0.1 ppm). **2.2.3 Recommended Tolerances**  HED recommends that tolerances be established in/on the following commodities as indicated in Table 2.2.3.Fluopy

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Page 10 of 105 **Table 2.2.3**  **. Tolerance Summary for**  **Fluopyram .**  Commodity Proposed Tolerance (ppm) Recommended/

Harmonized Tolerance (ppm) Comments; Correct Commodity Definition (a)(1) It is recommended that tolerances be established for residues of the fungicide fluopyram (N - [2 - [3 - chloro - 5 - (trifluoromethyl) - 2 -py

ridinyl]ethyl] - 2 - (trifluoromethyl)benzamide), including its metabolites and degradates, in or on the commodities below. Compliance with the tolerance levels specified below is to be determined by measuring only fluopyram in or on the commodity. Almond, hulls 8.0 8.0 Almond, hull Apple 0.5 0.30 Apple, wet pomace 2.5 0.60 Banana (Import Tolerance) 1.0 1.0 Tolerance must include a footnote stating “No US registrations as of [date of FR notice].” Beet, sugar, roots 0.10 0.04 Beet, sugar, root Beet, sugar, tops 30 Remove Tolerance is not required. Cherry 1.5 0.60 Grape, wine 2.0 2.0 Excludes grapes such as Thompson Seedless and Concord which may be used for purposes other than for wine. Nut, tree, group 14 and pistachio 0.05 0.05 Nut, tree, group 14 A separate tolerance is needed for pistachio; see below Peanut 0.05 0.02 Pistachio 0.05 A separate tolerance is needed for pistachio. Potato 0.05 0.02 Potato, processed potato waste 0.15 0.08 Straw berry 2.0 1.5 Watermelon 1.0 1.0 Vegetable, bean, dried, shelled (except soy

bean) 0.50 0.09 Bean, dry (a)(2) It is recommended that tolerances be established for residues of the fungicide fluopyram ( N - [2 - [3 - chloro - 5 - (trifluoromethyl) - 2 -py

ridinyl]ethyl] - 2 - (trifluoromethyl)benzamide), including its metabolites and degradates, in or on the commodities below. Compliance with the tolerance levels specified below is to be determined by measuring only the sum of fluopyram and its metabolite 2 - (trifluoromethyl)benzamide, calculated as the stoichiometric equivalent of fluopyram, in or on the commodity . Cattle, fat 0.10 0.11 Cattle, meat 0.10 0.15 Cattle , meat byproducts, except liver 0.10 1.1 Cattle, meat byproducts Cattle, liver 1.2 Eggs 0.10 0.25 Egg Goat , fat 0.10 0.11 Goat, meat 0.10 0.15Fluopy

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Page 11 of 105 **Table 2.2.3**  **. Tolerance Summary for**  **Fluopyram .**  Commodity Proposed Tolerance (ppm) Recommended/

Harmonized Tolerance (ppm) Comments; Correct Commodity Definition Goat , meat byproducts, except liver 0.10 1.1 Goat, meat byproducts Goat, liver 1.2 Hog, fat 0.01 0.05 Hog, meat 0.01 0.05 Hog , meat byproducts, except liver 0.01 0.70 H og , meat byproducts Hog, liver 0.15 Horse, fat 0.10 0.11 Horse, meat 0.10 0.15 Horse , meat byproducts, except liver 0.10 1.1 H o rse, meat byproducts Horse, liver 1.2 Milk 1.2 0.0 7 Poultry, fat 0.05 0.20 Poultry, meat 0.03 0.15 Poultry, meat byproducts 0.20 0.60 Sheep, fat 0.10 0.11 Sheep, meat 0.10 0.15 Sheep , meat byproducts, except liver 0.10 1.1 Sheep, meat byproducts Sheep , liver 1.2 (d) It is recommended that tolerances be established for indirect or inadvertent residues of fungicide fluopyram (N - [2 - [3 - chloro - 5 - (trifluoromethyl) - 2 -py ridinyl]ethyl] - 2 - (trifluoromethyl)benzamide), including its metabolites and degradates, in or on the commodities below . Compliance with the tolerance levels specified below is to be determined by measuring only fluopyram in or on the commodity. Alfalfa, forage 0.25 0.45 Alfalfa, hay 0.80 1.1 Canola 5.0 1.8 Corn, sweet, kernel plus cob with husk removed 0.10 Remove Tolerance is covered under Grain, cereal, group 15, except rice; see below Cotton, gin byproducts 0.05 0.05 Cotton, undelinted seed 0.10 0.01 Grain, cereal, forage, fodder and straw, group 16, except rice; forage 8.0 4.0 Grain, cereal, forage, fodder and straw, group 16, except rice; hay, straw and stover 14 7.0 Grain, cereal, forage, fodder and straw, group 16, except rice; aspirated fractions 50 Remove Tolerance is not applicable.Fluopy

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Page 12 of 105 **Table 2.2.3**  **. Tolerance Summary for**  **Fluopyram .**  Commodity Proposed Tolerance (ppm) Recommended/

Harmonized Tolerance (ppm) Comments; Correct Commodity Definition Grain, cereal, group 15, except rice and sweet corn 3.0 1.5 Grain, cereal, group 15, except rice Soy bean, forage 8.0 4.0 Soy bean, hay 30 15 Soy bean, hulls 0.40 Remove Tolerance is not applicable. Soy bean, seed 0.30 0.10 **2.2.4 Revisions to Petitioned**  **- For Tolerances**  Subsequent to the petition for establishment of tolerances and registration of uses on a wide variety of primary

crops in nearl y all crop groups, the petitioner submitted a letter withdrawing their request for certain crops. The petitioner also submitted a revised label specifying uses onl y on the following crops: apple; banana (no US registration); bean, dry ; beet, sugar, root; cherry (sweet and tart); grape,wine; nut tree crop group 14; peanut; pistachio, potatoe s; strawberry ; and watermelon. Therefore, HED is recommending revisions to the following proposed tolerance s because of use pattern revision s , use of primary crop residue data in place of field rotational crop data, harmonization with Codex MRL s and/or results from the NAFTA MRL calculator:

 Apple wet pomace (0.60 ppm), peanut (0.02 ppm), processed potato waste (0.08 ppm), sugar beet root (0.04 ppm), and cotton undelinted seed (0.01 ppm) .  Separate tolerances are recommended for the following commodities: apple (0.30 ppm), cherry (0.06 ppm), dried beans (0.09 ppm), pistachio (0.05 ppm), potato (0.02 ppm) and strawberry

(1.5 ppm).

  olerances for alfalfa and cotton commodities must be revised to be specified in terms of indirect or inadvertent residues of fluopyram. In addition, the recommended tolerances for alfalfa forage and hay are 0.45 ppm and 1.1 ppm, respectivel y.  Separate indirect or inadvertent residues of fluopyram are recommended for the following commodities : canola seed (1.8 ppm), grain, cereal, group 15 except rice (1.5 ppm), grain, cereal, forage, fodder and straw, group 16, except rice; forage (4.0 ppm), grain, cereal, forage, fodder and straw, group 16, except rice; hay , straw and stover (7.0 ppm), soy be an, seed (0.10 ppm), soy bean, forage (4.0 ppm), and soy bean, hay (15 ppm).

 For the purpose of harmonization with established Codex Maximum Residue Limits (CXL s), HED is recommending establishment of US tolerances for wine grape at 2.0 ppm , milk at 0.07 ppm , and hog meat by products at 0.70 ppm.

 Based on the maximum reasonable balanced dietary burdens, the following tolerances are recommended for the combined residues of fluopy ram and AE C656948 - benzamide in livestock commodities: For cattle, goat, hor se, and sheep fat (0.11ppm), meat (0.15Fluopy

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Page 13 of 105 ppm), and meat b yproducts (1.1 ppm) ; for hog fat and meat (0.05 ppm), for hog meat by products (0.70 ppm) ; for poultry fat (0.20 ppm), poultry

meat (0.15 ppm), poultry meat by products (0.60 ppm) ; eggs (0.25 ppm) and milk ( 0.07 ppm) .  A tolerance need not be established for beet, sugar, tops as this commodity is no longer considered an animal feed item. **2.3 Label Recommendations**  **2.3.1 Recommendations from Residue Reviews** 

 The petitioner must submit proposed labels (with English translations if needed) for fluopy ram uses on bananas in any countries from which the treated bananas may be imported into the US . The available data would support an application pattern of six applications of an SC fo rmulation at 0.100 kg ai/ha/application (0.089 lb ai/A/application) with a 7 - day retreatment interval (RTI) and a 0 - day PHI.

 The proposed label must be amended to specify minimum spray application volumes for wine grapes of 50 gallons per acre ( GPA) f or ground equipment.

 For wine grapes, the proposed label should be amended to include a statement stating “Do not treat grapes such as Thompson Seedless and Concord which may be used for purposes other than for wine.”

 The proposed labels must be am ended to clarify that the unit for application rates is fluid ounces per acre.  Also, with the exception of the banana field trials and one grape field trial, no spray adjuvants were used in any of the crop field trials. However, HED has recently revie wed bridging field trials conducted on strawberry , grape, cucumber, bulb onion, potato, lettuce, tomato, peach, apple and almond with and without addition of 0.125% v/v of a non - ionic surfactant (Induce®) and concluded that the addition of the NI S had no s ignificant effect on the residue level concentration on these crops. Therefore, the product label must be amended to specify that non - ionic surfactants at a maximum of 0.125% v/v may

be added to spray

mixtures.

 The label, under the rotational crop restrictions, must be amended to specify that canola, cereal grains (except rice) and so ybean may be replanted 30 day s following fluopy ram application on dry

beans and potato only , and that other crops not specified on the label may not be replanted following fluop yr am - treated crops. **2.3.2 Recommendations**  **from Occupational Exposure**  **Assessment** None **3.0 In**  **troduction**Fluopy

ram Human Health Risk Assessment DP No. D385636

Page 14 of 105 Fluopy ram (AE C656948) is a new fungicide with a broad spectrum of activity against numerous fungal diseases, including Ascomycetes, leaf spots, molds, sc a b, Alternaria, Septoria, Monlinia, Botry tis, Sclerotinia, and powdery mildews in a wide range of crops and plants. Fluopy ram represents a new class of chemistry (py ridyl ethyl amide) and its biochemical mode of action has been shown to rel y on the inhibition of the enzy me succinate dehydrogenase (complex II) within the fungal mitochondrial respiratory chain, thus blocking electron transport. Fluopy ram is a Group 7 fungicide. **3.1 Chemical Identity**  **Ta ble3.1.**  **Fluopyram Nomenclature**  . Chemical structure

Common name Fluopyram Com pany experimental name AE C656948 IUPAC name N - [2 - [3 - c hloro - 5 - (trifluoromethyl) - 2 -pyridyl]ethyl] - α,α,α - trifluoro - o - toluamide CAS name N - [2 - [3 - c hloro - 5 - (trifluoromethyl) - 2 -pyridinyl]ethyl] - 2 - (trifluoromethyl)benzamide CAS registry number 658066 - 35 - 4 End - use product (EP) Fluopyram 500 SC Fungicide (4.16 lb/gal SC formulation; EPA File Symbol No. 264 - RNTI) **3.2 Physical/Chemical Characteristics**  Fluopy ram is not a highly

lipophilic molecule (log KOW = 3.3) and is not expected to pass the dermal barrier, pass through human milk or bioaccumulate in significant quantity. Emp irical dermal absorption data estimate that less than 2% is absorbed via thi s route of exposure in humans and metabolism data in rats demonstrate rapid absorption with ~98% elimination with 72 hours of administration. Fluopy ram is persistent in soil (t 1⁄2 = 464 day s) w ith very little (a)biotic degradation . Fluopy ram , the major environmental residue and only compound modeled for drinking water exposure, is mobile , soluble and stable in water . **3.3 Pesticide Use Pattern**  CF 3 N H O N

Cl CF 3Fluopy

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Page 15 of 105 **Table 3.3. Summary of Directions for Use of Fluopyram**  Applic. Timing; Ty pe ; and Equip me nt Form ulation [EPA File Symbol No.] Applic.

Rate (lb ai/A) Max. No.

Applic. per Season Max.

Seasonal Applic. Rate (lb ai/A) PHI

(days) Use Directions and

Limitations 1 **Apple** Postemergence; Foliar spray; Ground, or chemigation 4.16 lb/gal SC [264 - RNTI] 0.078 -

0.222 NS 0.445 7 The proposed RTI is 7 - 14 days. **Cherry** Postemergence; Foliar spray; Ground, aerial , or chemigation 4.16 lb/gal SC [264 - RNTI] 0.092 NS 0.183 0 The proposed RTI is 5 - 7 days. **Dried shelled beans**  : b ean ( Lupinus spp., includes grain lupin, sweet lupin, white lupin, and white sweet lupin) , b ean (Phaseolus spp., includes field bean, kidney bean, lima bean (dry) , navy bean, pinto bean, tepary bean) , b ean ( Vigna spp., includes adzuki bean, blackeyed pea, cat jang, co w pea, Crowder pea, moth bean, mung bean, rice bean, southern pea, urd bean) , other beans (b road b ean (dry), c hickpea , guar , l ablab b ean , l entil ) Postemergence; Foliar spray; Ground , aerial , or chemigation 4.16 lb/gal SC [264 - RNTI] 0.134 NS 0.268 14 The proposed RTI is 7 - 14 days. Do not feed hay or threshings or allow livestock to graze in treated areas. **Peanut** Postemergence; Foliar spray; Ground, aerial , or chemigation 4.16 lb/gal SC [264 - RNTI] 0.182 -

0.222 NS 0.445 7 The proposed RTI is 14 days. Do not feed hay or threshings or allow livestock to graze in treated areas. **Potato** Postemergence; Foliar spray; Ground, aerial , or chemigation 4.16 lb/gal SC [264 - RNTI] 0.130 -

0.178 (ground, chemiga tion) 0.092 (aerial) NS 0.356

(ground, chemiga tion) 0.275 (aerial) 7 The proposed RTI is 5 - 7 days. The grazing of livestock in treated areas within 7 days of application is prohibited. **Strawberry** Postemergence; Drip/ chemigation, greenhouse spray 4.16 lb/gal SC [264 - RNTI] 0.222 NS 0.445 0 (drip appli cation) 1 (green house uses) The proposed RTI is 5 - 7

days. Applications may be made to straw

berries grown in a greenhouse of 10 acres or larger. **Sugar beet** Postemergence; Foliar spray; Ground, or chemigation 4.16 lb/gal SC [264 - RNTI] 0.111 NS 0.222 7 The proposed RTI is 5 - 7 days.Fluopy

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Page 16 of 105 **Table 3.3. Summary of Directions for Use of Fluopyram**  Applic. Timing; Ty pe ; and Equip me nt Form ulation [EPA File Symbol No.] Applic.

Rate (lb ai/A) Max. No.

Applic. per Season Max.

Seasonal Applic. Rate (lb ai/A) PHI

(days) Use Directions and

Limitations 1 **Tree nuts :**  almond, b eech nut, Brazil nut, b utternut, c ashew, c hestnut, c hinquapin, f ilbert (hazelnut), h ickory nut, macadamia nut (bush nut), p ecan, p istachio, walnut [including black and English (Persian) walnuts] Postemergence; Foliar spray; Ground, aerial , or chemigation 4.16 lb/gal SC [264 - RNTI] 0.104 -

0.222 NS 0.445 14 The proposed RTI is 7 - 14 days. **Waterm elon**  : watermelon (includes hybrids and/or varieties of Citrullus lanatus ) Postemergence; Foliar spray; Ground, or drip/chemigation 4.16 lb/gal SC [264 - RNTI] 0.078 -

0.222 NS 0.445 0 (spray uses) 3 (green house uses) 7 (drip appli cations) The proposed RTI is 5 - 14

days. Applications may be made to cucurbits grown in a greenhouse of 10 acres or larger. **Wine Grape**  **s:** varieties only such as but not limited to these varieties: Chardonnay, Cabernet sauvignon, Syrah, Merlot, Pinot Noir, and Zinfandel Postemergence; Foliar spray; Ground, or chemigation 4.16 lb/gal SC [264 - RNTI] 0.078 -

0.222 NS 0.445 7 The proposed RTI is 12 - 21 days.

**3.4 Anticipated Exposure Pathways**  The Registration Division has requested an assessment of human health risk to support the proposed new use of fluopy ram on apples, cherries (sweet and tart), dried beans, peanut s , potato es , strawberries , sugar beets, tree nuts, watermelon and wine grapes. Humans may be exposed to fluopy

ram in food and drinking water, since fluopy ram may be applied directl y to growing crops and application may result in fluopy

ram reaching surface and ground water sources of drinking water. There are no residential uses of fluop yram, so exposure in residential or non - occupational settings is not likely . In an occupational setting, applicators may be exposed while handling the pesticide prior to application, as well as during application. There is a potential for post - application exposure for workers re - entering treated fields . **3.5 Consideration of Environmental Justice**  Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with US Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and L ow - Income Populations," (http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf . As a part of every

pesticide risk assessment, OPP considers a large variety of consumer subgroups according to well - establishedFluopy

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Page 17 of 105 procedures. In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water consumption, and activities in and around the home that involve pesticide use in a residential setting. Extensive data on food consumption patter ns are compiled by

the USDA under the Continuing Survey of Food Intake by Individuals (CSFII) and are used in pesticide risk assessments for all registered food uses of a pesticide. These data are anal yz ed and categorized by subgroups based on age, season of the year, ethnic group, and region of the country . Additionally , OPP is able to assess dietary

exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant. Whenever appropriate, non - dietary exposures based on home use of pesticide products and associated risks for adult applicators and for toddlers, youths, and adults entering or playing on treated areas post - application are evaluated. Further considerations are currentl y in development a s 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 Characteriza** **tion and Dose -**  **Response Assessment 4.1**  **Toxicology Studies Available for Analysis** The toxicology

database for fluop yram is complete for risk assessment. There are acceptable studies available for toxicity endpoint selection ; they include: 1) subchronic oral toxicity studies in rats, mice, and dogs; 2) chronic oral toxicity studies in rats and dogs , 3) carcinogenicity studies in rats and mice; 4 ) developmental studies in rats and rabbits , 5) a reproduction study in rats ; 6 ) acute and subchronic neurotoxic ity studies in rats; 7 ) subchronic dermal toxicity and dermal penetration studies in rats ; and 8 ) immunotoxicity study in rats . There is also a complete mutagenicity study battery , metabolism studies in rats, and several mechanistic studies related to the mode of action for tumor formation. The submitted mechanistic studies are , however, insufficient to support the proposed mode of action for tumor formation. Further MOA studies are ongoing . **4.2 Absorption, Distribution, Metabolism, & Elimination (ADME**  **)** With oral dosing, fluopy

ram was rapidl y absorbed from the GI tract of male and female rats. Based on the results obtained in bile duct cannulated male rats, the percentage absor b ed was approximately 93% of the administered dose. The max imal plasma concentration was reached at 15 h ours in males and 11 h ours in females post dosing (5 mg/kg) . Kinetics were influenced b y the dose level as Tmax ≥ 35 hours in animals receiving 250 mg/kg. The absorbed fluop yram was quickl y distributed within the central compartments of the body (e.g. blood, liver, and kidney) and showed a distinctive preference towards the liver and to a small er extent to the kidneys. The major part of the dosed radioactivity ( 53 - 65%) was eliminated via feces ; 32 - 41 % w as eliminated via the urine. After 72 hours, the fecal excretion was nearl y completed. In both sexes, the urinary excretion showed a slightly different behavior , as a clear plateau level was not reached during the sampling period of seven day s and renal excretion was still ongoing on a low level. Less than 0.07 - 0.09 % of the administered dose was expired . AfterFluopy

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Page 18 of 105 168 hrs post dosing 91 - 99% of the administered radioactivity was eliminated via urine and feces. Residue anal ys is showed that the highest radioactivity level was found in the liver (0.4 to 1.0% of the administered radioactivity) . Fluop yram was extensively metabolized and more than 29 metabolites were identified. Three major groups of metabolites were formed in the liver (fluopy ram - 7 - OH - GA, 8 - OH - GA and enol - glucouronic acid) . Bioaccumulation was not observed. **4.2.1 Dermal Absorption**  I n vivo dermal absorption studies o f F luopy ram SC 500 neat formulation (500 mg fluopy ram/ml) and the spray

dilution (0.5 mg/ml) were conducted in rats . The results showed that the dermal penetration , as a percentage of the administered dose , was 4.5% for the neat formulation and 12.8% for the spray

dilution . Refinement of the dermal absorption factors for the neat formulation and spray

dilution was achieved by cond ucting a study under similar conditions in vitro using rat skin and human skin. A parallelogram approach was used to estimate the dermal absorption factor in human skin by using a proportional relationship: rat in vivo /rat in vitro = human in vivo /human in vitro . The refined dermal absorption values for human skin were calculated to be 0.2% for the neat formulation and 1.9% for the spray dilution. **4.3 Toxicological Effects**  D ecreased body weight and liver effects were the common and frequent findings in the subchronic and chronic oral toxicity studies in rats, mice, and dogs , and they appeared to be the most sensitive effects. L iver effect s were characterized by increased liver weight, hepatocellular hy pertrophy , hepatocellular vacuolation, increased mitosis and hepatocellular necrosis . In female rats of the carcinogenicity study , increased liver tumors were also observed. Liver effects in rodent s were seen at lower dose levels than those in the dogs. Thyroid effects were found at dose levels similar to those that produced liver effects in rats and mice; effects consisted of follicular cell hypertrophy, increased thyroid weight and hy perplasia at dose levels ≥ 100 mg/kg/day . C hanges in thy roid hormon e level s (T 3 & T 4 ) and increased TSH were also seen in rats in a subchronic toxicity study where these parameters were measured . In male mice, there was an increased incidence of thyroid adenomas. In the genotoxicity battery , fluopy

ram was shown to have no genotoxic potential. The registrant is currentl y c onducting mechanistic studies to demonstrate a mode of action for tumor formation. Fluopy ram is not a developmental toxicant, nor did it adversel y affect reproductive parameters. No evidence of qualitative or quantitative susceptibility w as observed in these studies . In an acute neurotoxicity

study , transient decreased motor activity was seen only

on the day

of treatment, but no other finding demonstrating neurotoxic i ty was found. In addition, no neurotoxicity

was observed in the subchronic neurotoxicity study in the presence of other sy stemic adverse effects. Fluopy ram did not produce treatment - related effects on the immune sy stem.Fluopy

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Page 19 of 105 F luopy ram plant metabolites , fluopy ram - py ridyl - carbox yl ic acid and fluopy ram methyl sulfoxide , demonstrate d less acute toxic potential than the parent compound. Mutagenicity tests on these two metabolites were negative. **4.4 Safety**  **F actor for Infants and Children (FQPA Safety Factor)**  **4.4 .1**  **Completeness o**  **f the**  **Toxicology Database** As described in Section 4.1, the toxicology database for fluop yr am is complete and includes the immunotoxicity

study and neurotoxicity

screening battery . The available studies are adequate to characterize potential pre - and/or post - natal risk for infants and children **4.4.2 Evide**  **nce of N eurotoxicity**  The fluop yram toxicology database did not demonstrate evidence of neurotoxicity . Although transient decreases in motor and locomotor activities in the acute neurotoxicity study on the day of treatment and limited use of hind - limbs an d reduced motor activity in the rat chronic/carcinogenicity s tudy were seen, there were no other associated neurobehavioral or histopathology

changes found in other studies in the fluopy ram toxicity

database. The effects seen in the chronic/carcinogenicity study were in the presence of increased mortality and morbidity such as general pallor and emaciated appearance. Therefore, the reduced motor activity and limited use of hind - limbs seen in these two studies were judged to be the consequence of the s ys te mic effects and not direct neurotoxicity . **4.4.3 Evidence**  **o f Sensitivity/Su**  **sceptibility in the Developing o r Young Animal**  As mentioned in Section 4.3, the available developmental toxicity studies in rats and rabbits and the multi - generation reproduction in rats demonstrate no evidence of increased susceptibility in the developing or young animals which were exposed during pre - or post - natal periods. **4.4.4 Residual**  **Uncertainty in the Exposure Datab ase**  There are no residual uncertainties in the exposure database. Although extended field rotational crop studies are required as a condition of registration, the rotational crop tolerances used in the dietary risk assessment are not expected to underestimate exposure because they are based on direct foliar tr eatment crop residue data as opposed to residues taken up by plants through roots from treated soil. The acute dietary exposure assessment was performed using toleran ce level residues for all crops whereas the chronic dietary assessment included average fi eld trial residue levels for all crops . Both acute and chronic assessments assumed 100% crop treated and incorporated empirical or default processing factors. The dietary exposure assessment also assumed that all drinking water will contain fluopyram at the highest EDWC levels modeled by EFED for ground or surface water. Residential exposures are not expected. Therefore, it can be concluded that the dietary exposure anal ys is does not underestimate risk from acute and chronic dietary exposure to fluopy

ram .Fluopy

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Page 20 of 105 **4.5 Toxicity Endpoint and Point of**  **D eparture Selections**  **4.5.1 Dose**  **- Response Assessment**  The details for selecting toxicity endpoints and points of departure for various exposure scenarios are presented in the Appendix A. For fluop yr am, HED has selected the most sensitive and protective endpoints from the database to establish points of departure for the risk assessment. For example, for acute oral exposure, an acute neurotoxicity

study in rats has been used to select the dose and endpoint for es tablishing the aRfD ( 0. 5 mg/kg/day) for the general population. The LOAEL of 100 mg/kg is based on decreased motor and locomotor activity in females . The effect is attributable to general toxicity . For chronic dietary

exposure, a combined chronic/carcinogenicity study in rats was used to select the dose (NOAEL=1.2 mg/kg/day) and endpoint for establishing the chronic reference dose ( cRfD ; 0.012 mg/kg/day) . The toxicity endpoint was based on follicular cell hy pertrophy in the thy roid and increased liver weight with liver gross pathological and histopathological findings at 6.0 mg/kg/day . The point of departure derived from this study is protective of the adverse thy roid effects observed in the mouse carcinogenicity study seen at 1 05 mg/kg/day . A 2 - generation reproduction study in rats was used to select the dose (NOAEL = 14.5 mg/kg/day) and endpoint for short - and intermediate - term incidental oral exposure (though these endpoints are not necessary

for this risk assessment since no residential uses are proposed) . The LOAEL of 82. 8 mg/kg/day was based on c linical pathology changes, increased liver weight , centrilobular hy pertrophy in parents, and decreased body weight ( - 8.1%, p<0.05) and body weight gain ( - 8.6% p<0.05) with secondary decreases in spleen and thymus weights and secondary slight delay

in preputial separation in offspring . This study was also chosen for short - and intermediate - term inhalation exposure scenarios, assuming inhalation and oral absorption equivalency (100%). A 2 8 - day dermal toxicity

study was used to select the point of departure (NOAEL= 300 mg/kg/day) and endpoint (liver toxicity ) for short - and intermediate term dermal exposure. **4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment**  P er FQPA, 1996, when there are potential residential exposures to a pesticide, aggregate risk assessment must consider exposures from three major sources: oral, dermal , and inhalation exposures. There are no residential exposures expected with the currently proposed uses for fluopy ram . C ommon toxicological effect s w ere not observed at the L OAELs of studies selected for the assessment of short - and intermediate - term exposures by the dermal and inhalation routes ; liver toxicity was the dermal endpoint whereas the inhalation endpoint was based on clinical spleen and thy mus effects accompanied by clinical pathology

and body weight changes. Therefore, it is not appropriate to combine these routes of exposure for risk assessment . **4.5.3 Cancer Classification**  **and Risk Assessment Recommendation** In accordance with the EPA’s Final Guidelines for Carcinogen Risk Assessment (March, 2005), the Cancer Assessment Review Committee (CARC) classified fluop yram as **“Likely to be**Fluopy

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Page 21 of 105 **Carcinogenic to Humans”** based on tumors in two species and two sexes: a treatment - related increase in thy

roid follicular cell adenomas in high dose male mice and liver tumors in female rats at the high dose, with incidences exceeding that of the laboratory ’s historical controls (CARC Report, Nov. 25, 2009). There is no mutagenic concern for fluop yr am. The available mechanistic data are insufficient to support the proposed modes of action for the thy roid or liver tumors. The CARC recommended the use of a linear low dose extrapol ation model applied to the animal data (Q1*) for quantitative estimation of human risk. The unit risk, Q 1 * (mg/kg/day) - 1 , of f luopy ram based upon female rat liver combined adenoma and carcinoma tumor rates is 1.55 x 10 - 2 in human equivalents. **4. 5**  **. 4**  **Summary of Points of Departure and Toxicity Endpoints Used in Human Risk Assessment**  **Table 4 .5.**  **4 .**  **1 Summary of Toxicological Doses and Endpoints for**  **Fluopyram for Use in Dietary and Non**  **** **Occupational Hum an Health Risk Assessments**  **Exposure/ Scenario**  **Point of** 

**Departure Uncertainty/FQPA** 

**Safety Factors RfD, PAD,** 

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

50 mg/kg/day UF A= 10 X

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

0. 50 mg/kg/day aPAD = 0. 50 mg/kg/day Ac ute Neurotoxicity Study in Rats.

The LOAEL of 100 mg/kg in females is based on decreased motor and locomotor activity in females. The LOAEL in males wa s 125 mg/kg/day. Ac ute Dietary (Females 13 - 49 years of age) An endpoint attributable to a single dose exposure has not been identified for this subpopulation

Chronic Dietary (All Populations) NOAEL=

1.2 mg/kg/day UF A= 10 X

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

= 0.0 12 mg/kg/day cPAD = 0.0 12 mg/kg/day Com

bined Chronic/Carcinogenicity in Rats The LOAEL of 6.0 mg/kg/day is based on follicular cell hypertrophy in the thyroid, and increased liver weight with gross pathological and histopathological findings. Incidental Oral Short - Term (1 - 30 days) and Intermediate Term (1 - 6 mo nths) NOAEL=

14.5 mg/kg/day UF A= 10 X

UF H=10 X FQPA SF= 1 X Residential

LOC for MOE = 100 Reproduction study in rats

The LOAEL of 82.8 mg/kg/day is based clinical pathology changes, decreased spleen and thymus weights, increased liver weight and centrilobular hypertrophy in parents, and decreased body weight and body weight gain with decreases in spleen and thymus weights and slight delay in preputial separation in offspring.Fluopy

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Page 22 of 105 **Table 4 .5.**  **4 .**  **1 Summary of Toxicological Doses and Endpoints for**  **Fluopyram for Use in Dietary and Non**  **** **Occupational Hum an Health Risk Assessments**  **Exposure/ Scenario**  **Point of** 

**Departure Uncertainty/FQPA** 

**Safety Factors RfD, PAD,** 

**Level of Concern for**  **Risk Assessment**  **Study and Toxicological Effects** Dermal Short Term (1 - 30 days) and Intermediate Term (1 - 6 mo nths) NOAEL=

300 mg/kg/day UF A= 10 X

UF H=10 X FQPA SF=1 X Residential

LOC for MOE = 100 A 28 - day dermal study in rats The LOAEL of 1000 mg/kg/day is based on increased cholesterol (F), increased prothrombin time (M), and increased liver weights (M, F) associated with hepatocellular hypertrophy. Inhalation Short - Term (1 - 30 days) and Intermediate Term (1 - 6 mo nths) NOAEL=

1 4 .5 mg/kg/day UF A= 10 X

UF H=10 X FQPA SF=1 X Residential

LOC for MOE = 100 Reproduction study in rats

The LOAEL of 82.8 mg/kg/day is based clinical pathology changes, decreased spleen and thymus weights, increased liver weight, and centrilobular hypertrophy in parents, and decreased body weight and body weight gain with decreases in spleen and thymus weights and slight delay in preputial separation in offspring . Cancer (oral, dermal, inhalation) Based on the liver tumor in female rats and thyroid tumor in male mice , the CARC classified

fluopyram as a “Likely to be Carcinogenic to Human” and recommended the use of linear low dose extrapo lation model for risk assessment using a unit risk, Q 1 * =1.55x10 - 2 (mg/kg/day) - 1

. 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). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern. **Table 4.5.**  **4 .2 Summary of Toxicological Doses and Endpoints**  **for Fluopyram**  **for Use in Occupational Hum an**  **Health Risk Assessments Exposure/**  **Scenario Point of** 

**Departure Uncertainty** 

**Factors Level of Concern** 

**for Risk Assessment**  **Study and Toxicological Effects** Dermal Short Term (1 - 30 days) and Intermediate Term (1 - 6 mo nths) NOAEL=

300 mg/kg/day UF A= 10 X

UF H=10 X Occupational

LOC for MOE = 100 A 28 - day dermal study in rats The LOAEL of 1000 mg/kg/day is based on increased cholesterol (F), increased prothrombin time (M), and increased liver weights (M, F) associated with hepatocellular hypertrophy . Inhalation Short - Term

(1 - 30 days) and Intermediate term (1 - 6 mo nths) NOAEL=

1 4 .5 mg/kg/day UF A= 10 X

UF H= 10 X Occupational

LOC for MOE = 100 A 2 - generation reproduction study in rats.

The LOAEL of 82.8 mg/kg/day is based clinical pathology changes, increased liver weight, and centrilobular hypertrophy in parents, and decreased body weight and body weight gain with secondary decreases in spleen and thymus weights and sec ondary slight delay in preputial separation in offspring.Fluopy

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Page 23 of 105 **Table 4.5.**  **4 .2 Summary of Toxicological Doses and Endpoints**  **for Fluopyram**  **for Use in Occupational Hum an**  **Health Risk Assessments Exposure/**  **Scenario Point of** 

**Departure Uncertainty** 

**Factors Level of Concern** 

**for Risk Assessment**  **Study and Toxicological Effects** Cancer (oral, dermal, inhalation) Based on the liver tumor in female rats and thyroid tumor in male mice , the CARC classified

fluopyram as a “Likely to be Carcinogenic to Human” and recommended the use of linear low dose extrapolation model for risk assessment using a unit risk, Q 1 * =1.55x10 - 2 (mg/kg/day) - 1 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. N/A = not applicable. **4.6 Endocrine Disruption**  As required under FFDCA section 408(p), EPA has developed the Endocrine Disruptor Screening Program (EDSP) to determine whether certain substances (including pesticide active and other ingredients) may have an effect in humans or wildlife similar to an eff ect produced b y a “naturally

occurring estrogen, or other such endocrine effects as the Administrator may designate.” The EDSP employ s a two - tiered approach to making the statutorily required determinations. Tier 1 consists of a battery of 11 screening as say s to identify the potential of a chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal sy stems. Chemicals that go through Tier 1 screening and are found to have the potential to interact with E, A, or T hormonal s ys tems will proceed to the next stage of the EDSP where EPA will determine which, if any , of the Tier 2 tests are necessary based on the available data. Tier 2 testing is designed to identify any adverse endocrine related effects caused by the substance, and establish a dose - response relationship between the dose and the E, A, or T effect. Between October 2009 and February 2010, EPA issued test orders/data call - ins for the first group of 67 chemicals, which contains 58 pesticide active ingredients and 9 in ert ingredients. This list of chemicals was selected based on the potential for human exposure through pathways such as food and water, residential activity , and certain post - application agricultural scenarios. This list should not be construed as a list of known or likely endocrine disruptors. Fluopy ram is not among the group of 58 pesticide active ingredients on the initial list to be screened under the EDSP. Under FFDCA sec. 408(p) the Agency must screen all pesticide chemicals. Accordingl y, EPA anticipates issuing future EDSP test orders/data call - ins for all pesticide active ingredients . For further information on the status of the EDSP, the policies and procedures, the list of 67 chemicals, the test guidelines and the Tier 1 screening battery , p lease visit our website: http://www.epa.gov/endo/ . **5.0 Dietary Exposure and Risk Assessment**  **5.1 Metabolite/Degradate Residue Profile** Fluopy

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Page 24 of 105 **5.1.1 Summary of Plant and Animal Metabolism Studies**  P RIMARY CROPS: Adequate m etabolism studies were conducted in grape , bean , potato and red pepper labeled in the phenyl ring or py ridine ring . Positions of the radiolabel are indicated below.

[phenyl - UL 14 C]AE C656948 [pyridyl - 2,6 - 14 C]AE C656948 The results indicate that the parent is the major residue and that met abolism of fluopy ram is similar within the submitted studies which represent three dissimilar crop group s . The metabolism of fluopy

ram in plants appears to proceed via hydrox yl ation of parent compound leading to AE C656948 - 7 - hydroxy and AE C656948 - 8 - hydrox y, conjugation of the hydrox yl ated parent compound mainl y with sugars, and cleavage of the molecule leading to AE C656948 - benzamide, AE C656948 - PAA, and AE C656948 - PCA. Further conjugation of AE C656948 - 7 - hydro xy- glucose with malonic acid was observed in bean and red pepper; in addition, cleavage of the molecule yi elded glycoside conjugates and AE C656948 - hydroxyethyl conjugates in bean and red pepper . ROTATIONAL CROPS : Inconfined rotational crop studies, parent fluop yr am also accounted for the majority of residue. However, AE C656948 - 7 - hydrox y (up to 39% TRR, plus its conjugate (up to 16% TRR) ) was found in Swiss chard at all rotation intervals, and the methylsulfoxide metabolite was predominant in wheat grain at longer rotation intervals. The latter metabolite was detected up to 0.10 ppm in field rotational wheat trials and the AE C656948 - 7 - hydroxy compound was found onl y in wheat straw at 0.10 ppm level. AE C656948 - Benzamide (u

p to 39% TRR) was also present in Swiss chard. POULTRY: The major component in all the edible matrices was the metabolite AE C656948 - benzamide, at 68.6% to 98.6% TRR. Other metabolites identified were AE C656948 - Z - olefine (25.9% TRR in fat and ≤1.2% T RR in egg, muscle, and liver), AE C656948 - E - olefine (≤2.3% TRR in fat and liver), and AE C656948 - benzoic acid (0.3% TRR, in liver only). Parent compound was detected as a minor component only in eggs and fat at ≤2.5% TRR. Id entification rates in the organs and tissues ranged from 93% to 99% TRR. RUMI NANTS: An adequate metabolism study was conducted on lactating goats with fluop yr am labeled on the phenyl or py ridine ring . When goats were orally dosed with [phenyl - UL 14 C]fluopy

ram, the major component detected in all the edible matrices was the metabolite AE C656948 - benzamide (49.1% to 97.6% TRR). Other major compounds identified were AE C656948 - Z - olefine and the parent compound, which were found at 13.1% and 18.2% TRR, respectivel y, in fat. AE C656948 - Z - olefine was identified as a minor residue (<1% TRR) in milk and liver and was not found in muscle and kidney . The parent compound was identified as

N H O N

Cl C F 3 C F 3

* N H O N

Cl C F 3 C F 3 * *Fluopy

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Page 25 of 105 a minor component in milk, liver, and kidney , at ≤1.7% TRR, and was not detected in muscle. When animals were dosed with [py ridyl - 2,6 - 14 C]fluopyram, the parent compound was identified as a major component in milk, muscle, and fat (27.3 - 46.4% TRR) but was only found as a minor residue in liver (7.7% TRR) and was not found in kidney . The metabolite AE C656948 - Z olefine was identified as a major metabolite in milk, muscle, and fat, at 12.9 - 33.7% TRR; it was found at 5.7% TRR in liver and was not found in kidney . The other isomer AE C656948 - E olefine was found at <5% TRR in milk, muscle, fat, and liver. AE C65 6948 - 7 - hydrox y was also found to be a major component of milk, muscle, and fat, at 12.8 - 21.6% TRR, but a minor residue (≤6% TRR) in liver and kidney . **5.1.2 Summary of Environmental Degradation**  Environmental fate studies indicate that the parent fluopy ram is stable under environmental conditions. Reported half - lives range from 89 days in field and aqueous photoly sis studies to >1000 days in aerobic/anaerobic water/sediment systems. Fluopy ram is mobile in soil and can therefore , be expected to occur in surface water runoff and/or in ground water leachate. Four metabolites were identified in aerobic soil metabolism studies : AE C656948 - 7 - hydrox y, AE C656948 - benzamide , AE C656948 - py ridylcarboxylic acid (PCA) , and lactame. None of the metabolites exceeded 10% of applied radioactivity nor were any of the metabolites considered more toxic than the parent. AE C656948 - 7 - hydrox y , AE C656948 - benzamide, and AE C656948 - PCA were also tracked in field dissipation studies. AE C65694 8 - 7 - hydrox y , though structurally similar to the parent, was only found at 1 - 3% of the fluopy ram levels. AE C656948 - PCA (1.2 - 18%) and AE C656948 - benzamide (0.2 - 16.2%) were more abundant but showed rapid declines. Lactame, a proposed metabolite of parent f

luopy ram, was present at low levels in the soil sy stem (1.2%) and as a major metabolite in the aqueous photoly sis study (13%). Lactame is structurally dissimilar from parent fluop yr am but would only be expected to form at significant levels in clear, shal low water . Based upon the low abundance of the metabolites in the soil studies and their rapid dissipation in the field studies , minimal exposure is expected through drinking water. Furthermore, none of the metabolites are considered more toxic than the parent. Therefore, these metabolites are not considered of concern. **5.1.3 Comparison of Metabolic Pathways**  In representative plants, the metabolism is limited and parent accounts for the majority of the residue. In legumes, however, metabolites AE C656948 - benzamide or AE C656948 - py ridyl acetic acid and p yridylcarbox yl ic acid also become major residues. The metabolic pathways begin with hydroxylation at the ethylene bridge, conjugation with sugars, and cleavage leading to the benzamide, py ridyl acetic acid and py

ridylcarboxylic acid. Fluopy ram is the major residue in rotational crops. In livestock the metabolis m is more extensive. The metabolic profiles in poultry and ruminants are similar. In poultry

(phenyl label), very

little parent was present in eggs, muscle, liver or fat, and benzamide is the major residue in these matrices. A second major residue in poultry is theFluopy

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Page 26 of 105 Z - olefin. In lactating goats (phenyl label), parent was only present as a major residue in fat and the predominant residue is the benzamide in milk and tissues. In addition to Z - olefin, the 7 - hydrox y m etabolite is a major residue in milk, mu scle and fat. In the rat, the metabolism is also very extensive leading to numerous excreted metabolites with very little parent detected. The metabolic pathway in the rat is very similar to those in plants and livestock, namely , hydroxylation in the ethyl ene bridge (and the phenylring), conjugation, and cleavage of the ethylene bridge to form benzamide, py ridyl acetic acid and py

ridyl carbox yl ic acid. Z - and E - Olefins are also present as metabolites. **5.1.4 Residues of Concern Summary and Rationale**  Primary and Rotational Crops The metabolism in plants is relatively limited . In plant metabolism studies, unchanged parent accounted for >90% of the residues in grapes, beans (immature) , and potatoes and 70% of the residue in red bell peppers. While several metabolites were quantified (most <1% TRR), only AE C656948 - benzamide exceeded 10% TRR in succulent and dry beans (52 - 64%). Measurable quantities of parent and metabolites ( AE C656948 - py ridyl - acetic acid (PAA), AE C656948 -py

ridyl - carboxylic acid (PCA) and AE C656948 - benzamide ) were also found in succulent (at full maturity) and dry beans during European field trials. These metabolites were not measured in US field trials. Of the major metabolites, AE C656948 - benzamide, PAA and PCA result from hydrol ys is of the ethylene bridge; AE C656948 - benzamide is a phenyl cleavage product and PPA and PCA are py ridylcleavage products. AE C656948 - methyl - sulfoxide results from the substitution of the chlorine atom in PCA. None of the metabolites or their conjugate s is expected to be more toxic than the parent fluopy

ram. Furthermore, inclusion of both phenyl and py ridyl metabolites as fluopy ram equivalents for either risk assessment or tolerance expression, would overestimate total exposure to fluopy

ram. Parent fluopy

ram b y itself is expected to be an adequate measure of misuse in primary

crops. In addition, parent fluopy ram can be measured by some of the FDA multiresidue methods (MRM) while the benzamide metabolite does not lend itself to MRM anal ys is. Therefore , HED recommends fluopy ram only for tolerance expression. For risk assessment, HED recommends fluopy ram only , except for legumes and oil seeds. For these commodities, HED recommends fluopy ram + AE C656948 - benzamide due to the high levels of the latter in the bean metabolism studies. Livestock Commodities The metabolism in livestock is more extensive than was found in plant studies . The major residues identified at varyingsampling intervals include parent, AE C656948 - benzamide, AE C656948 - 7 - hydrox y, and AE C656948 E - and Z - olefines. In the egg and poultry metabolism studies, AE C656948 - benzamide (up to 99% TRR) accounted for the majority of residue in egg, muscle, fat, and liver. Parent fluop yram (18%) was found in eggs and AE C656948 - olefines ( 14% ) in the liver. Similarly in the goat, AE C656948 - benzamide accounted for the majority of residue (up to 99% TRR) in milk, muscle, fat, liver, and kidney . Fluopy ram (46%), AE C656948 - 7 - hydrox y (22%), and AE C656948

–E - olefines (33%) were found at lower l evels in milk, muscle, and fat. The phenylmetabolite, AE C656948 - benzamide , was a majorFluopy

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Page 27 of 105 metabolite in both plant and livestock metabolism studies. However, the p yridyl metabolites, AE C656948 -py

ridyl - acetic acid (PAA) and AE C656948 - py ridyl - carbox yl ic acid (PCA) , were not present in the livestock studies. While the fate of the py ridylportion of the molecule is unknown, HED determined tolerance expression and risk assessment decisions could be made without fully

elucidating the livestock metabolic pathw ay . Calculating the benzamide residues in terms of parent equivalents would likely account for the unknown py ridyl metabolites. Feeding studies confirmed the rapid transformation of parent fluop yr am; AE C656948 - benzamide was the onl y major residue in edible poultry matrices while fluopy

ram, AE C656948 - benzamide and AE C656948 - olefines were measured in the milk and meat of dairy cattle. In the cattle study , the levels of benzamide metabolite were significantl y higher than the parent in many samples. Therefore, HED recommends fluopy ram + AE C656948 - benzamide for tolerance enforcement in ruminant and poultry

commodities; fluopy

ram + AE C656948 - benzamide + AE C656948 - 7 - hydrox y fluopy

ram + AE C656948 E - and Z - olefines for risk assessments in ruminant commodi ties; and fluopyram + AE C656948 - benzamide + AE C656948 E - and Z - olefines for risk assessment in poultry. The US, EU, and Canada are in agreement on parent fluopy ram + AE C656948 - benzamide for purposes of tolerance enforcement in livestock. The US, EU, a nd Canada are also in agreement regarding which compounds to include for risk assessment of poultry commodities. However, consistent with their decisions for plants, the EU has proposed the inclusion of the conjugated metabolites, AE C656948 - 7 - OH - GA and AE C656948 - 8 - OH - GA , for risk assessments in ruminants (see Table 5.1.4).Fluopy

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Page 28 of 105 **Table 5.1.4. Summary of Metabolites and Degradates to be included in the Risk Assessment and Tolerance Expressions.**  Matrix US EU Canada Risk Assessment Tolerance Expression Risk Assessment Tolerance Expression Risk Assessment Tolerance Expression Plant s Primary Crop Fluopyram (Fluopyram + benzamide for legumes and oil seed crops) Fluopy ram Fluopyram +

benzamide (M25) + 7 - OH - fluopyram (M08) + 7 - OH - Glc (M11) + 7 - OH - Glc MA(M12) Fluopyram Fluopyram + (Fluopyram + benzamide for legumes and oil seed crops) F luopyram

Rotational Crop Fluopyram

(Fluopyram + benzamide for legumes and oil seed crops) Fluopyram Fluopyram + benzamide (M25) + 7 - OH - fluopyram (M08) + 7 - OH - Glc (M11) + 7 - OH - Glc MA(M12) Fluopyram Fluopyram (Fluopyram + benzamide for legumes and oil seed crops) Fluopyram

Livestock Ruminant Fluopyram + benzamide + 7 - OH fluopyram + olefins (E, Z) Fluopyram +

benzamide Fluopyram +

benzamide + 7 - OH fluopyram (M08)+ olefins (E, Z) + 7 - OH - GA (M09) + 7 - OH - GA (M20b) Fluopyram +

benzamide Fluopyram +

benzamide + 7 - OH fluopyram + olefins (E, Z) Fluopyram +

benzamide Poultry Fluopyram +

benzamide + olefins (E, Z) Fluopyram +

benzamide Fluopyram +

benzamide + olefins (E, Z) Fluopyram +

benzamide Fluopyram +

benzamide + olefins (E, Z) Fluopyram +

benzamide Drinking Water Fluopyram Not Applicable Not Applicable Not Applicable Not Applicable Not ApplicableFluopy

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Page 29 of 105 **5 .2**  **Food Residue**  **Profile** Adequate residue data are available to support dietary risk assessment as well as the proposed tolerances of the fungicide fluopy ram in/on apple, banana (import), cherry (sweet and tart), dry beans, watermelon , wine grapes, peanut, potato, stone fruit, strawberry , sugar beet, and tree nuts (including pistachio). Crop field trial studies were conducted in North America and Europe. Residues are quantifiable in all crops. Residues tend to be surface residues and generally decline with increasing PHI. Processing studies indicate that residues concentrate substantially in wet appl e pomace and potato wet peel and slightly in dried sugar beet pulp and refined sugar. Livestock feeding studies indicate low transfer of residues to meat, milk, poultry and eggs with the highest transfer in liver. Rotational crop data show uptake of finite residues in forage/leaf, hay and straw but very

low residues in grain, seed and root. Residue chemistry

studies are supported b y adequate storage stability data which demonstrate that fluopy

ram and its major metabolites are stable for at least 24 or 36 months in water- starch - , protein - , oil - , and acid - containing materials under frozen conditions. **Table 5 .2.**  **Summ ary of Residues from the Crop Field Trials with**  **Fluopyram Crop Matrix**  **Applic. Rate (lb ai/A)**  **PHI**

**(days) Residues (ppm** **)**

**Me an**  **Std.**

**Dev. HAFT**  **1 Min.**  **Max. POME FRUIT**  **(proposed use = 0.445**  **lb ai/A total application rate, 0**  **- day PHI**  **; 7 -**  **day revised PHI** ) **Two Applications; Concentrate Spray** Apple 0.440 - 0.461 7 0.120 0.063 0.242 0.040 0.247 **Two Applications; Dilute**  **Spray** Apple 0.440 - 0.461 7 0.105 0.055 0.255 0.057 0.262 **Four Applications; Concentrate Spray** Apple 0.477

– 0.479 7 0.084 0.021 0.101 0.061 0.107 **DRIED BEANS (proposed use =**  **0.445 lb ai/A total application rate,**  **0 -**  **day PHI ; revised use = 0.268 lb ai/A**  **total application rate, 14**  **- day PHI**  ) Dried bean seed 0.441

– 0.452 0 2 , 13 - 14 0.024 0.021 0.068 <0.01 0.076 **GRAPE (proposed use =**  **0.44 5**  **lb ai/A total application rate, 7 -**  **day PHI ; revised to wine grapes only**  ) Grape 0.439 - 0.458 6 - 7 0.401 0.229 0.948 0.096 0.950

**PEANUT (proposed use = 0.44**  **5 lb ai/A total application rate,**  **7 -**  **day PHI)**  Peanut 0.438 - 0.455 6 - 7 0.011 <0.01 0.017 <0.01 0.018 Peanut, hay 0.438 - 0.455 6 - 7 8.72 6.78 20.66 1.0 8 21.8 8 **POTATO (proposed use = 0.44**  **5 lb ai/A total application rate,**  **7 -**  **day PHI**  **; revised to 0.356 lb ai/A for** 

**ground applications and 0.275 lb ai/A for aerial applications )**  Potato, tuber 0.437 - 0.454 6 - 7 0.01 0.002 0.017 <0.01 0.017 **STRAWBERRY (proposed use = 0.44 5**  **lb ai/A total application rate, 0**  **- day PHI**  **for spray uses and drip**

**application and 1 -**  **day PHI greenhouse uses; revised to delete field spray use )**  Straw berry - drip irrigation field 0.442 - 0.468 0 0.026 0.028 0.10 <0.01 0.112 Straw berry - greenhouse 0.446 1 0.35 0.26 0.79 0.12 0.79Fluopy

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Page 30 of 105 **Table 5 .2.**  **Summ ary of Residues from the Crop Field Trials with**  **Fluopyram Crop Matrix**  **Applic. Rate (lb ai/A)**  **PHI**

**(days) Residues (ppm** **)**

**Me an**  **Std.**

**Dev. HAFT**  **1 Min.**  **Max.** spray (European data) **SUGAR BEET (proposed use = 0.44**  **5 lb ai/A total application rate,**  **7 -**  **day PHI**  **; revised to 0.222 lb ai/A )**  Sugar beet, root 0.439

– 0.456 5 - 7 0.029 0.011 0.040 0.013 0.050 Sugar beet, tops 0.439

– 0.456 5 - 7 3.30 4.89 16.5 0.273 18.7 **CUCURBIT VEGETABLES**  **(proposed use = 0.44 5**  **lb ai/A total application rate, 0**  **- day**  **PHI spray uses, 3**  **-**

**day PHI greenhouse uses, and 7 -**  **day PHI drip applications )**  **Foliar Spray Applications** Cucumber 0.432 - 0.45 4 0 0.094 0.045 0.144 0.037 0.189 Muskmelon 0.445 - 0.469 0 0.217 0.156 0.439 0.069 0.529 Summer squash 0.443 - 0.445 0 0.099 0.047 0.173 0.047 0.179 **Drip Line Irrigation** Cucumber 0.446 - 0.456 7 0.022 0.017 0.057 <0.01 0.058 Muskmelon 0.446 - 0.455 5 - 7 0.015 0.008 0.027 <0.01 0.029 Summer squash 0.446 6 - 7 0.012 0.002 0.015 <0.01 0.017 **Greenhouse Application**  **s** Cucumber (European data) 0.535 2 - 4 0.15 0.09 0.29 0.04 0.29 Muskmelon (European data) 0.535 3 3 0.12 0.05 0.19 0.04 0.19 **STONE FRUIT (proposed use = 0.44**  **5 lb ai/A total application rate,**  **0 -**  **day PHI**  **; revised cherry use = 0.183** 

**lb ai/A, revised stone fruit use other than cherry = 0.367 lb ai/A )**  **Concentrate Spray** Cherry 0.447

– 0.460 0 0.425 0.223 0.639 0.066 0.641 Peach 0.436

– 0.456 0 0.29 0.105 0.44 0.126 0.457 Plum 0.429

– 0.445 0 0.082 0.085 0.257 0.022 0.286 **Dilute Spray** Cherry 0.444

– 0.457 0 0.516 0.349 1.174 0.147 1.229 Peach 0.441

– 0.457 0 0.34 0.121 0.548 0.175 0.588 Plum 0.442

– 0.454 0 0.083 0.095 0.283 0.021 0.292

**TREE NUT (proposed use = 0.44**  **5 lb ai/A total application rate,**  **14 -**  **day PHI)**  Concentrate Spray Almond 0.437 - 0.449 14 0.01 0.01 0.018 <0.01 0.019 Almond, hulls 0.437 - 0.449 14 3.18 1.09 4.25 1.93 4.45 Pecan 0.445 - 0.455 12 - 14 0.01 0.01 0.018 <0.01 0.021 **Dilute Spray** Almond 0.439 - 0.462 14 0.01 0.01 0.015 <0.01 0.016 Almond, hulls 0.439 - 0.462 14 2.97 1.57 5.43 1.22 6.12 Pecan 0.448 - .458 12 - 14 0.01 0.014 0.031 <0.01 0.045

**BANANA -**  **Latin Am**  **erica (**  **no proposed use**  **inform ation was provided for banana** **)**Fluopy

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Page 31 of 105 **Table 5 .2.**  **Summ ary of Residues from the Crop Field Trials with**  **Fluopyram Crop Matrix**  **Applic. Rate (lb ai/A)**  **PHI**

**(days) Residues (ppm** **)**

**Me an**  **Std.**

**Dev. HAFT**  **1 Min.**  **Max.** Banana, whole f

ruit , bagged 0.587 - 0624 0 0.01 8 0.0 09 0.038 <0.01 0.040 Banana, whole f

ruit , unbagged 0.587 - 0624 0 0.164 0.140 0.510 0.018 0.526 1 HAFT = Highest Average Field Trial. 2 At one trial (n=2), the bean plants were cut from the ground at a 0 - day PHI and the seed was sampled 14 days later, after drying in the field. Sample residues from this trial were not the maximum residue or HAFT for the study 3 The data include results from one trial with a PHI of 1 day (no sample collected at 3 - day PHI) and one trial with a PHI of 7 days (residues were higher than those at the 3 - day PHI). **5.3 Water Residue Profile**  Estimated drinking water concentrations (EDWCs) for ground and surface water are presented in Table 5.3. Upper- bound ground water estimates were derived using the Tier I SCI - GROW model. Surface water concentrations were estimated using the Tier II PRZM/EXAMS model. The available data allowed for refinement of the estimates beyond our standard modeling approach b y incorporating a 90 th percentile foliar degradation rate of 0.131 day- 1 (half - life = 5.29 days). The foliar decay

rate was calculated from two plant residue field trial studies c in which residues were determined at various intervals following foliar application; no rain or irrigation occurring during the study period. All other inputs reflect high - end assumptions regarding application rates and percent cropped area (PCA = 0.87 ) in the watershed. **Table 5. 3**  **Summary of Estimated Surface Water and Groundwat er Concentrations** 

**for Fluopyram .**  Scenario Surface Water Conc., ppb a Groundwater Conc., ppb b Ac ute 12.97 0.319 Chronic (non - cancer) 4.90 Chronic (cancer) 3.487 a From the Tier II PRZM - EXAMS - Index Reservoir model. Input parameters are based on FL cucumber and ME potato (chronic) scenarios using the maximum application rate, maximum num ber of applications and minimum intervals stated in the labels for fluopyram . b From the SCI - GROW model. C GM090 (2007) conducted on leaf lettuce (Crop Group 4: leafy vegetables) in Sanger, CA. Bayer report number RAGMP085; GM230 (2007) conducted on mu stard green leaves (Crop Subgroup 5B: leafy Brassica greens) in Sycamore, GA. Bayer Report Number: RAGMP063. Shamim, M., 7/8/2011, D353319, D363812, D363820, D363821, D363822, D363824, and D369773 **5.4 Dietary Risk Assessment**  **5.4.1 Description of Residue**  **Data Used in Dietary Assessment**Fluopy

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Page 32 of 105 For the acute dietary

analysis: tolerance residue levels, 100% crop treated assumption and processing factors (empirical and default) were used . The EDWC was incorporated directl y into the dietary

assessment ( 1 in 10 y

r annual peak of 13 μg/L) based on application rate of cucumber . For the chronic dietary

analysis: average residues, 100% CT and processing factors (empirical and default) were used. The EDWC was incorporated directl y into the dietary assessment ( 1 in 10 y r annual mean of 4.9 μg/L) based on application rate of potato . For the cancer dietary

assessment: average residues, projected percent crop treated, and empirical processing factors were used. The EDWC was incorporated directl y into the dietary as sessment ( 1 in 30 y r annual mean of 3.5 μg/L) based on application rate of potato . **5.4.2 Percent Crop Treated Used in Dietary Assessment**  The following average percent crop treated estimates (J. Alsadek and C. Chen , 0 5/23 /20 11, D387227) were used in the cancer dietary risk assessment for the following crops that are the subject of this petition for residues of fluopy ram: almonds : 33%; apples: 40%; barley : 22%; cherry : 49%; cotton : 7 %; dry beans: 2.5%; grapes: 79%; oats: 23%; peanuts : 67 %; potatoes : 64 %; rapeseed: 73%; rye: 63%; sorghum: 12%; soy beans: 1%; strawberries: 71% ; sugar beets: 48 % ; w atermelon : 54 % ; and wheat: 1% . One hundred percent of the crops were assumed to have been treated for the acute and chronic dietary exposure assessments. To calculate these projected percent crop treated values, BEAD used recent data from the National Agricultural Statistics Service (NASS) 2002 - 2006, and recent proprietary data (2006 - 2010). The estimates for the primary crops are based on the market leader approach involving several registered fungicides, and the estimates for the rotational crops are based on acres of wheat, corn, sorghum, barley , oats, rye, millet, soy beans, canola, cotton, and alfalfa grown relative to the total acreage of dry beans and potato treated with fluopy ram . **5.4.3 Acute Dietary Risk Assessment**  The acute dietary

anal ys is included tolerance residue levels, 100% crop treated assumption and processing factors (empirical and default) . Estimated drinking water concentration (EDWC) was incorporated directl y into the dietary assessment ( 1 in 10 y r annual peak of 13 μg/L) and was calculate d based on a maximum application rate of 0.446 lb ai/A/season (cucumber). Estimated acute dietary

exposure to fluopy

ram from food and drinking water is below HED’s level of concern for all population subgroups (<100% (aPAD) acute Population Adjusted Dose) . Combined dietary

exposure from food and drinking water at the 95 th percentile of exposure is estimated to be 0.021 mg/kg/day for the overall US population, equivalent to 4. 2 % of the aPAD. The population subgroup with the highest estimated acute dietary exposure to fluopy ram is children 1 - 2 years, with an estimated exposure at the 95 th percentile of 0. 042 mg/kg/day , equivalent to 8. 4 % of the aPAD (see Table 5.4.6). **5.4.4 Chronic Dietary Risk Assessment** Fluopy

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Page 33 of 105 The chronic dietary

analysis us ed average residue levels, 100% crop treated assumption, and processing factors (empirical and default) . EDWC was incorporated directly into the dietary assessment ( 1 in 10 y

r annual mean of 4.9 μg/L) and was calculated based on a maximum application rate of 0.356 lb ai/A/season (potato). Chronic dietary

exposure estimates for food and drinking water are well below HED’s level of concern (<100% (cPAD) chronic Population Adjusted Dose) for all population subgroups. The dietary exposure is estimated at 0. 0004 2 mg/kg/day for the general US population ( 3.5 % of the cPAD) and 0. 0012 mg/kg/day ( 10 % of the cPAD) for children 1 - 2 year olds, the population subgroup with the highest estimated chronic dietary exposure to fluopy

ram (see Table 5.4.6). **5.4.5 Cancer Diet**  **ary Risk Assessment** The HED Cancer Peer Review C ommittee (CARC) classified fluop yram as “Likely to be Carcinogenic to Human” and recommended the use of linear low dose extrapolation model for risk assessment using a unit risk, Q 1 * = 1.55x10 - 2 (mg/kg/day) - 1

. The cancer dietary anal ys is included average residue levels, projected percent crop treated (PP CT) estimates and processing factors (empirical and default) . EDWC was incorporated directly into the dietary

assessment ( 1 in 3 0 y r annual mean of 3.5 μg/L) and was calculated based on a maximum application rate of 0.356 lb ai/A/season (potato). The cancer dietary (food and drinking water) risk estimate for the general US population is 2.9 x 10 - 6 (Table 5.4.6). Water, direct and indirect sources, contributes approximately

30% to the risk estimate, or 1.1 X 10 - 6

. **5.4.6 Summary Table**  **Table 5.4.6. Summary of Dietary** (Food and Drinki ng Water) **Exposure and Risk for Fluopyram**  **Population Subgroup Acute Dietary**  **( 95**  **th Percentile)**  **Chronic Dietary Cancer**  **Dietary Exposure**  **(m g/kg/day)**  **%**

**aPAD*** **Dietary**

**Exposure (m**  **g/kg/day) %** 

**cPAD*** **Dietary**

**Exposure (m**  **g/kg/day) Risk**  General US Population 0. 020741 4. 2 0. 000423 3.5 0. 000 188 2.9 x 10 - 6 All Infants (< 1 year old) 0. 038195 7.6 0. 000800 6.7 N/A N/A Children 1 - 2 years old **0. 04**  **2156 8.**  **4 0.**  **001239 10**  Children 3 - 5 years old 0. 035136 7. 0 0. 001017 8.5 Children 6 - 12 years old 0. 024081 4.8 0. 000574 4.8 Youth 13 - 19 years old 0. 015398 3. 1 0. 000315 2.6 Adults 20 - 49 years old 0. 013032 2. 6 0. 000320 2.7Fluopy

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Page 34 of 105 **Table 5.4.6. Summary of Dietary** (Food and Drinki ng Water) **Exposure and Risk for Fluopyram**  **Population Subgroup Acute Dietary**  **( 95**  **th Percentile)**  **Chronic Dietary Cancer**  **Dietary Exposure**  **(m g/kg/day)**  **%**

**aPAD*** **Dietary**

**Exposure (m**  **g/kg/day) %** 

**cPAD*** **Dietary**

**Exposure (m**  **g/kg/day) Risk**  Adults 50+ years old 0. 011141 2. 2 0. 000353 2.9 Females 13 - 49 years old 0. 012844 2. 6 0. 000326 2.7 * The population subgroup with the highest estimated acute and chronic dietary (food + drinking water) exposure and risk is indicated by bold text. NA = not applicableFluopy

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Page 35 of 105 **6.0 Residential (Non**  **- Occupational) Exposure/Risk Characterization**  **6.1 Residential Handler Exposure**  Based on product label, the product is not intended for use b y homeowners, or by occupational handlers in residential settings. Therefore, non - occupational/residential risk assessments have not been conducted . **6.2 Residential Bystander**  **Post -**  **application Inhalation Exposure**  Based on the Agency's current practices, a quantitative post - application inhalation exposure assessment was not performe d for fluop yr am at this time primarily because of the low acute inhalation toxicity

(Toxicity Category IV), low vapor pressure (1.2x10 - 6 Pa at 20 o C), and the low proposed use rate (0.22 lb ai/A). However, volatilization of pesticides may be a source of po st application inhalation exposure to individuals nearby pesticide applications. The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory P anel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 (http://www.epa.gov/scipoly /SAP/meetings/2009/120109meeting.html ). The Agency is in the process of evaluating the SAP report and may , as appropriate, develop policies and procedures to identify the need for and, subsequently , the way to incorporate post - application inhalation exposure into the Agency's risk assessments. If new policies or procedures are developed, the Agency may revisit the need for a quantitative post - appli cation inhalation exposure assessment for fluop yram. **6. 3**  **Spray Drift** S pray drift is always a potential source of exposure to residents nearby to spraying operations. This is particularly

the case with aerial application , but to a lesser extent, could also be a potential source of exposure from the airblast and groundboom application method s additionally employed for fluop yr am . The Agency has been working with the Spray Drift Task Force, EPA Regional Offices , and State Le ad Agencies for pesticide regulation and other parties to develop the best spray

drift management practices. The Agency is now requiring interim mitigation measures for aerial applications that must be placed on product labels/labeling. The Agency has co mpleted its evaluation of the new database submitted by the Spray

Drift Task Force, a membership of US pesticide registrants, and is developing a policy on how to appropriatel y apply the data and the AgDRIFT computer model to its risk assessments for pesti cides applied by air, orchard airblast , and ground hydraulic methods. After the policy is in place, the Agency may impose further refinements in spray drift management practices to reduce off - target drift and risks associated with aerial as well as other application ty pes where appropriate. **7.0 Aggregate Exposure/Risk Characterization**  In accordance with the FQPA, HED must consider and aggregate (add) 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 quantitativeFluopy

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Page 36 of 105 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. **7.1 Acute Aggregate Risk**  There is potential acute exposure via the diet (food and drinking water). Refer to Section 5.4.3. **7.2 Short** **- and Intermediate**  **- Term Aggregate Risk**  There are no proposed residential uses so short - or intermediate - ter m residential exposures are not likely to occur. Therefore neither short - nor intermediate - term aggregate risks were not assessed. **7.3 Chronic Aggregate Risk**  There is potential chronic exposure via the diet (food and drinking water). Refer to Section 5.4.4. **7.4 Cancer Aggregate Risk**  The aggregate cancer risk (food and drinking water) is 2.9 x 10 - 6 (Table 5.4 ) . The unit risk for fluopy ram , Q 1 * , is 1.55x10 - 2 (mg/kg/day) - 1 . Th e Q 1 * is based upon liver tumor in female rats and is expressed in human equivalents. **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 toxici ty finding as to fluopy ram and any other substances and fluop yr am does not appear to produce a toxic metabolite produced b y other substances. For the purposes of this tolerance action, therefore, EPA has not assumed that fluopy ram has a common mechanism of toxicity with other substances. For information regarding EPA’s efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy stat ements released by

EPA’s Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/. **9.0 Occupati**  **onal Exposure/Risk Characterization 9.1**  **Short -** **/Intermediate -**  **/Cancer Handler Risk** Fluopy ram can be applied to agricultural crops using aerial, chemigation, groundboom, airblast, backpack, and low - and high -pressure sprayer application equipment. Broadcast foliar applications of fluop yram may be applied to agricultural crops at maximum single rates rangingFluopy

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Page 37 of 105 from 0.092 to 0.22 lb ai/A. Multiple applications may be made per season, up to a maximum of 0.45 lb ai/season. Applications may be made in gr eenhouses of 10 acres or larger for strawberries, or watermelons . The proposed label requires handlers to wear chemical resistant gloves. Handler exposure is expected to be short - or intermediate - term in duration based on information provided on proposed labels No chemical - specific handler exposure data were submitted in support of this Section 3 registration. To assess handler exposures for regulatory actions when chemical - specific monitoring data are not available, HED relies on the most scientifically- reliable surrogate data currentl y available from various sources such as the Pesticide Handler Exposure Database (PHED), the Agricultural Handler Exposure Task Force (AHETF), and the Outdoor Residential Exposure Task Force (ORETF). Some of this data, such as the industry task force data, is compensatory , subject to the data protection provisions of FIFRA. HED policy on use of surrogate data is described in more detail on the Agency's website (http://www.epa.gov/pesticides/science/handler- exposure - data.html). Scenario - specific surrogate exposure data, including their sources, are presented in the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (http://www.epa.gov/pesticides/science/handler- exposure - table.pdf ). HED has developed a series of tables of standard unit exposure values for many occupational scenarios that can be utilized to ensure consistency in exposure. Non - cancer occupational risk estimat es for dermal (with gloves) and inhalation short - and intermediate - term exposure durations all resulted in MOEs considerabl y greater than 100, and therefore, do not exceed HED’s level of concern (Table E1). MOEs for dermal (with gloves ) exposure ranged from 180,000 to 7,300 and MOEs for inhalation exposure ranged from 1,300,000 to 7,700. Handler cancer risks for private growers and commercial applicators were calculated for different exposure scenarios at different levels of personal protection. Handler cancer risk estimates for combined inhalation and dermal (with gloves) exposures for private growers ranged from 1. 4 x 10 - 8 to 5.6 x 10 - 7 and for commercial workers ranged from 3.1 x 10 - 8 to 8.8 x 10 - 7 (Tables E2 and E3, respectively). **9.2 Short** **- /Intermed**  **iate -** **/Cancer Post** **- Application**  **Risk 9.2.1**  **Dermal Post**  **- application**  **Risk** Short - and intermediate - term dermal post - application exposures and risks to occupational workers were estimated using standard values established by HED since no chemical - specific data were submitted. The transfer coefficients (TC) used for all post - application activities were the TCs established by the Sc ience Advisory Council for Exposure Policy Number 3 (http://www.epa.gov/pesticides/science/exposac_policy3.pdf). This policy reflects adoption of all Agricultural Re - Entry Task Force (ARTF) data. Use of the data in this policy requires compensation to th e ARTF under FIFRA. The transfer coefficients (TCs) used in this assessment were taken from the Agency ’s revised Agricultural Transfer Coefficient SOP. Many of the TCs in this SOP are based on work of the ARTF . The dislodgeable foliar residue (DFR)Fluopy

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Page 38 of 105 leve ls for agricultural crops were estimated using HED standard values where it is assumed that the initial residue on treated foliage is 20% of the application rate and the residues degrade at a rate of 10% per day . The occupational post - application non - canc er MOEs do not exceed HED’s level of concern (MOEs ≥100) with dermal MOEs ranging from 5,600 to 530 (Table E4). Restricted Entry

Interval **:** Since postapplication risks were not a concern on day 0 (12 hours following application), the REIis based on the a cute toxicity of fluop yr am technical material. Fluopy ram is classified as T oxicity C ategory I II by the acute oral and dermal route s of exposure and Toxicity

Category IV for acute inhalation, eye irritation potential and skin irritation potential. Under the WPS for Agricultural Pesticides, active ingredients classified as acute toxicity categories III or IV for these routes are assigned a 12 - hour REI. Therefore, the 12 - hour REIthat appears on the proposed label is adequate. Worker post - application canc er risk estimates were asses sed for individuals employed b y multiple establishments (i.e., commercial or migratory farm workers) and were assumed to be exposed 30 day s per year. DFRs were estimated using the method described above in the non cancer post - a

pplication section (i.e., assuming 20% of the active ingredient is available initially and a dissipation of 10% per day thereafter). HED used the average DFR residue (μg/cm 2 ) over the minimum re - treatment interval for each crop or crop group to estimate cancer risk. The post application cancer risks estimates ranged from 5.1 x 10 - 7 to 4 . 0 x 10 - 6 (Table E5). These estimates are considered conservative, since the maximum application rate and shortest retreatment intervals were used to calculate the estimates. **9.2.2 Inhalation**  **Post -**  **application Risk**  Occupational post - application exposure can occur via the inhalation route. Based on the Agency's current practices, a quantitative post - application inhalation exposure assessment was not performed for fluop yram at this time primarily because of the low acute inhalation toxicity (Toxicity Category IV), low vapor pressure (1.2x10 - 6 Pa at 20 o C), and the low proposed use rate (0.22 lb ai/A). However, there are multiple potential sources of post - application inhalation exposure to individuals performing post - application activities in previously treated fields. 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 Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory

Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 (http://www.epa.g ov/scipol y/ SAP/meetings/2009/120109meeting.html ). The Agency is in the process of evaluating the SAP report as well as available post - application inhalation exposure data generated by the Agricultural Reentry Task Force and may , as appropriate, develop po licies 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, the Agency may revisit the ne ed for a quantitative occupational post - application inhalation exposure assessment for fluop yr am. Proposed uses include applications in greenhouses. The WPS for Agricultural Pesticides contains requirements for protecting workers and bystanders from inhalation exposures during and after greenhouse applications through the use of ventilation requirements. For these reasons,Fluopy

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Page 39 of 105 post - application inhalation exposures and risks were not quantitatively assessed for the proposed greenhouse uses. **10.0 References**  O’ Keefe, B., 8 / 30 /201 1 **,** D389135 . **Fluopyram :**  Occupational and Residential Exposure Assessment for Proposed Uses on A pples, Cherry (Sweet and Tart), Dried Beans, Peanut, Potato, Strawberry, Sugar Beets, Tree Nuts, Wa termelon and Viniferous Variety Grap es. Cheng, L., 9 /23 /2011, D387587 and D 389081. **Fluopyram** . Application for Section 3 Registration for Use on Apple, Banana (Import only), Dried Beans, Cherry, Grape (W ine Production only), Peanut, Pistachio, Potato, Sugar Beet, Strawberry, Tree Nuts Crop Group 14, Watermelon, and Rotational Crops Alfalfa, Canola, Cotton, Cereal Grains Crop (Except Rice) Group 15, and Forage, Fodder, and Straw of Cereal Grains Crop (Except Rice) Group 16. Summary of Analytical Chemistry and Residue Data. Cheng, L., 9 /29 /2011, D 389122. **Fluopyram:** Acute, Chronic, and Cancer Aggregate Dietary Exposure and Risk Assessments for Section 3 Registration for Use on Apple, Banana (Import only), Dried Beans, Cherry , Grape (Wine Production only) , Peanut, Pistachio, Potato, Sugar Beet, Strawberry, Tree Nuts Crop Group 14, Wa termelon and Rotational Crops Alfalfa, Canola, Cotton, Cereal Grains (Except Rice) Crop Group 15, and Forage of Cereal Grains (Except Rice) Crop Group 16 . Scollon, E., 7/16/2009, D367115. **Fluopyram** . Report of the Residues of Concern Knowledgebase Subcommittee (ROCKS). Shamim, M., 7/8/2011, D 353319, D 363812, D 363820, D 363821, D 363822, D 363824, and D 369773 . Estimated Drinking W ater Concentrations of the new chemical Fluopyram from Apples, Beans (dry), Cherries, Cucurbits, Grapes (wine), Peanut, Potato, Stone Fruits, Strawberry, Sugar beet, and Tree Nuts for the Use in Human Health Risk Assessment. Kidwell, J., 12/23/2009. **Fluopyram -**  ToxSAC Meeting on July 16, 2009 : A ddendum 1/13/2010 Kidwell, J., 11/25/2009, TXR0055261 . **Fluopyram** : Report of the Cancer Assessment Review Committee . Alsadek, J., 5/23/2011, D387227. Percent Crop Treated for New Uses of Fluopyram on Cantaloupe, Cucumber, Dry Beans, Peanuts, Potatoes, Pumpkin, Squash, Sugar Beet, and Watermelon. Analysis of the Bayer Crop Science Percent Crop Treated Estimates for Rotated Crops (Wheat, Corn, Sorghum, Barley, Oats, Rye, Millet, Soybeans, Canola, Cotton, and Alfalfa) from the Combined Acreage of Dry Beans and Potatoes.Fluopy

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Page 40 of 105 **A ppendix**  **A .**  **Tox icology Profile and Executive Summaries**  **A.1 Toxicology Data Requirements**  The requirements (40 CFR 158.500 ) for food use for fluopyram are in Table 1. Use of the new guideline numbers does not imply that the ne w (1998) guideline protocols were used. **Study Technical**  **Required Satisfied**  870.1100 Acute Oral Toxicity ................................ ....................... 870.1200 Acute Dermal Toxicity ................................ .................. 870.1300 Acute Inhalation Toxicity ................................ .............. 870.2400 Primary Eye Irritation ................................ .................... 870.2500 Primary Dermal Irritation ................................ .............. 870.2600 Dermal Sensitization ................................ ...................... yes yes yes yes yes yes yes

yes yes yes yes yes 870.3100 Oral Subchronic (rodent) ................................ ............... 870.3150 Oral Subchronic (nonrodent) ................................ ......... 870.3200 21 - Day

Dermal ................................ .............................. 870.3250 90 - Day

Dermal ................................ .............................. 870.3465 90 - Day

Inhalation ................................ .......................... yes yes yes no yes yes

yes yes

- no 870.3700a Developmental Toxicity (rodent) ................................ ... 870.3700b Developmental Toxicity (nonrodent) ............................. 870.3800 Reproduction ................................ ................................ . yes yes yes yes

yes yes 870.4100a Chronic Toxicity (rodent) ................................ .............. 870.4100b Chronic Toxicity (nonrodent) ................................ ........ 870.4200a Oncogenicity (rat) ................................ .......................... 870.4200b Oncogenicity (mouse) ................................ .................... 870.4300 Chronic/Oncogenicity ................................ .................... - yes

- yes yes -

yes

- yes yes 870.5100 Mutagenicity

—Gene Mutation - bacterial ..................... 870.5300 Mutagenicity

—Gene Mutation - mammalian ................ 870.5xxx Mutagenicity

— Structural Chromosomal Aberrations ... 870.5xxx Mutagenicity

—Other Genotoxic Effects ....................... yes yes yes yes yes

yes yes yes 870.6100a Acute Delayed Neurotox icity (hen) ............................... 870.6100b 90 - Day

Neurotoxicity (hen) ................................ ........... 870.6200a Acute Neurotox icity Screening Battery (rat) ................. 870.6200b 90 - Day

Neuro toxicity Screening Battery (rat) ............... 870.6300 Develop. Neuro toxicity ................................ ................. no no yes yes no -

- yes yes

- 870.7485 General Metabolism ................................ ...................... 870.7600 Dermal Penetration ................................ ........................ 870.7800 Immunotoxicity ................................ ............................. yes yes yes yes

yes yesFluopy

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Page 41 of 105 **A.2 Toxicity Profile**  **s Table A.2.1**  **Acute Toxicity Profile -**  **Fluopyram Guideline**  **No. Study Type**  **MRID Results**  **Toxicity Category**  870.1100 Ac ute oral - rat 47372430 No mortalities observed at 2000 mg/kg III 870.1200 Ac ute dermal - rat 47372432 LD 50 > 2000 mg/kg III 870.1300 Ac ute inhalation - rat 47372435 47372434 LC 50 at 4 hours > 5112 mg/m 3

LC 50 > 5.1 mg/L IV 870.2400 Ac ute eye irritation - rabbit 47723701 Non - irritating IV 870.2500 Ac ute dermal irritation - rabbit 47372436 Non - irritating IV 870.2600 Skin sensitization - mo use 47372440 Non - sensitizing Not Applicable **Table A.2.2 Subchronic, Chronic and Other Toxicity Profile**  **Guideline No. Study Type**  **MRID No. (year)/ Classification /Doses**  **Results** Non - guideline 28 - day dietary rat

study (exploratory) 47372516; (2004)

Acceptable 50, 400, 3200 ppm (4., 31, & 254 mg/kg/day ♂ 4.6, 36, & 263 mg/kg/day ♀) NOAEL = 31 mg/kg/day LOAEL = 254 mg/kg/day based on  platelet count and prothrombin time (M),  cholesterol and triglycerides (M/F),  aspartate aminotransferase and alkaline phosphatase  liver weight with hepatocellular hypertrophy (M/F)  thyroid weight with follicular cell hypertrophy (M) Non - guideline 28 - day rat study

(dietary) (preliminary) AE C657188 (PCA), a soil metabolite of AE C638206 47372521; (2003)

Acceptable 20; 200; 2,000, & 20,000 ppm (1.5; 15; 149; & 1,574 mg/kg/day for ♂ 1.6; 16; 162; & 1,581 mg/kg/day for ♀) NOAEL=1574 mg/kg (HDT) no compound related effects were seen.

870.3100 90 - day dietary rat

study 47372441; (2005)

Acceptable/guideline 0, 50, 200, 1000, 3200 ppm ♂: 3, 13, 61, & 204 mg/kg/day ♀: 4, 15, 70, & 230 mg/kg/day NOAEL = 13 mg/kg/day LOAEL = 61 mg/kg/day based on ↓ body weight & food consumption, hematology parameters affected. ↑ cholesterol conc &  - glutamyltransferase activity. Slight ↑ in TSH, T3 & T4. Target organs were liver and thyroid gland (M/F) & kidney (M). ↑ liver, thyroid gland & kidney weights. Liver: centrilobular hypertrophy & periportal to midzonal hepatocellular macrovacuolation. Thyroid gland: follicular cell hypertrophy.Fluopy

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Page 42 of 105 **Table A.2.2 Subchronic, Chronic and Other Toxicity Profile**  **Guideline No. Study Type**  **MRID No. (year)/ Classification /Doses**  **Results** Non - guideline 28 - day dietary

study in the mouse (preliminary) 47372517; (2004)

Acceptable 150; 1,000; 5,000 ppm ♂: 25, 162, & 747 mg/kg/day ♀: 31, 162, & 954 mg/kg/day NOAEL = 25 mg/kg/day LOAEL = 162 mg/kg/day based on ↓ body weight gain (M), ↑ ALT (M), ↑ liver weights, 27 - 49% (M/F) associated with : centrilobular hypertrophy, single cell and focal necrosis, hepatocellular eosinop hilia and bile duct/oval cell hyperplasia (M/F). Adrenal gland: hypertrophy of zona fasciculata (F) . 870.3100 90 - day dietary

study in the mouse 47372442; (2005)

Acceptable/guideline 30, 150, 1000 ppm ♂ : 5, 27, & 188 mg/kg/day ; ♀: 7, 32, & 216 mg/kg/day NOAEL = 27 mg/kg/day LOAEL = 188 mg/kg/day based on ↑ ALT & ↓ albumin conc. (M/F), ↓ cholesterol conc & ↑ alkaline phosphatase (M), ↑ liver weights , 34 - 45% (M/F), ↑ adrenal gland weights, 87 - 92% (M) Liver: centrilobular hypertrophy and focal necrosis (M/F) Adrenal gland: ↓ ceroid pigment (M), ↑ cortical vacuolation (F) . Non - guideline 28 - day oral

toxicity s tudy

in dogs (gavage) 47372515; (2004)

Acceptable 30, 150, & 750 mg/kg/day NOAEL = 150 mg/kg/day LOAEL = 750 mg/kg/day based on ↓ erythrocyte count, hemoglobin, hematocrit (M), ↑ alkaline phosphatase (M/F), ↓ albumin conc. (M/F), ↑  - glutamyltransferase activity and triglyceride concentration (F). ↑ liver weights associated with hepatocellular hypertrophy (M/F). 870.3150 90 - day dietary

toxicity s tudy

in the dog 47372443; (2006 )

Acceptable/guideline 800; 5,000, & 20,000/10,000 ppm (at day 15, the high dose group dietary concentration was reduced due to lack of palatability) ♂: 29, 171, & 332 mg/kg/day ♀: 33, 184, & 337 mg/kg/day NOAEL = 29 mg/kg/day LOAEL = 171 mg/kg/day based on liver effects characterized by ↑ alkaline phosphatase ,  - glutamyltransferase activity, ALT & AST; ↓ albumin conc and bilirubin; ↑ liver weights associated with hepatocellular hypertrophy, intracytoplasmic eosinophilic droplets and single cell necrosis. Both sexes were affected. 870.3200 28 - day dermal

toxicity study in the rat 47372444; (2007)

Acceptable/guideline 100; 300; & 1,000 mg/kg/day NOAEL = 300 m/kg/day LOAEL = 1,000 mg/kg/day based on ↑ cholesterol (F), and ↑ liver weights associated with hepatocellular hypertrophy 870.3700 Developmental

toxicity in the rat 47372445; (2008, Report)

(Study conducted in 2006) Acceptable/guideline Maternal NOAEL = 30 mg/kg/day Maternal LOAEL = 150 mg/kg/day based on decreased body weight gains and food consumption, higher liver weights and diffused centrilobular hepatocellular hypertrophy. Developmental NOAEL= 150 mg/kg/day Developmental LOAEL = 450 mg/kg/day based De creased fetal body weight (5%), increased incidence of two minor variations at both the visceral and skeletal evaluation .Fluopy

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Page 43 of 105 **Table A.2.2 Subchronic, Chronic and Other Toxicity Profile**  **Guideline No. Study Type**  **MRID No. (year)/ Classification /Doses**  **Results** 870.3700 Developmental

toxicity study in the rabbit 47372446; (2006)

Acceptable/guideline 10, 25, & 75 mg/kg bw/day (gavage, GD 6 - 28) Maternal NOAEL = 25 mg/kg/day Maternal LOAEL = 75 mg/kg/day based on reduced body weight gain and food consumption. Developmental NOAEL = 25 mg/kg/day Developmental LOAEL = 75 mg/kg/day based on d ecreased fetal body weight ( - 11%). Non - guideline D ose range - finding

reproduction study in the rat 47372448; (2008) (Report)

(This study was conducted in 2006) Acceptable 30; 150; 750; & 1,500 ppm ♂: 2,10, 50, & 102 mg/kg/day ♀: 2, 12, 58, & 118 mg/kg/day . Parental NOAEL = 10 mg/kg/day Parental LOAEL = 50 mg/kg/day b ased on increased liver and kidney weights Offspring NOAEL = 118 mg/kg/day (HDT) Reproductive NOAEL = 118 mg/kg/day (HDT) No effect was seen in any of reproductive parameters examined. 870.3800 2 - Generation

reproduction study in the rat 47372447; (2008, Report)

(Study was conducted in 2006) Acceptable/guideline 40; 220; & 1, 200 ppm ♂: 3, 15, 83 mg/kg/day (premating) ♀: 3., 18, & 96 mg/kg/day (premating) . Parental NOAEL = 15 mg/kg/day Parental LOAEL = 83 mg/kg/day based on increased creatinine, total protein, and albumin. Increase d kidney and liver weights. Increased incidence of liver hypertrophy. Offspring NOAEL = 15 mg/kg/day Offspring LOAEL= 83 mg/kg/day based on d ecreased body weight and body weight gain with secondary decreases in spleen and thymus weights and secondary slight delay in preputial separation. Reproductive NOAEL = 96 mg/kg/day (HDT). No effect was seen in any of reproductive parameters examined. 870.4100 1 - ye ar toxicity study

in dogs (dietary) 47372449; (2007)

Acceptable/guideline 100; 400; & 2,000 ppm ♂: 3, 13, & 68 mg/kg/day ♀: 4, 14, & 66 mg/kg/day. NOAEL = 13 mg/kg/day LOAEL = 66 mg/kg/day based on ↓ body weight & food consumption (M/F), ↑ alkaline phosphatase (M/F), Liver: centrilobular hypertrophy. 870.4200 Carcinogenicity

study in the mouse 47372450; (2007)

Acceptable/guideline 30, 150, & 750 ppm ♂: 4, 21, & 105 mg/kg/day ♀: 5, 27, & 129 mg/kg/day. NOAEL = 4 mg/kg/day LOAEL = 21 mg/kg/day b a sed on treatment - related follicular cell hyperplasia in the thyroid gland, centrilobular to panlobular hypertrophy and hepatocellular single cell degeneration /necrosis in the liver. Thyroid gland follicular cell adenomas in high dose males.Fluopy

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Page 44 of 105 **Table A.2.2 Subchronic, Chronic and Other Toxicity Profile**  **Guideline No. Study Type**  **MRID No. (year)/ Classification /Doses**  **Results** 870.4300 Chronic

/carcino genicity study in the rat 47372501; (2008)

Acceptable/guideline 30 , 150 & 750/375 ppm for ♂; 30 , 150 and 1,500 ppm for ♀. ♂: 1.2, 6.0, & 29 mg/kg/day ♀: 1.7, 8.6, & 89 mg/kg/day (Due to high mortality in 750 ppm males, this concentration was reduced to 375 ppm from week 85 onward) NOAEL = 1.2 mg/kg/day LOAEL = 6.0 mg/kg/day based on treatment - related marked liver toxicity, nephropathy, and follicular cell hypertrophy in the thyroid gland. Liver cell tumors (carcinoma and adenoma) in high dose females.

870.5100 Ames test 47372502; (2006) Acceptable/guideline Doses: 16 to 5000 μg/plate +/ - metabolic activation Negative

870.5100 Ames test 47372503; (2008) Acceptable/guideline Doses: 5 to 1581 μg/plate 16 to 5000 μg/plate +/ - metabolic activation Negative

870.5300 In - vitro

chromosome aberration (V79 cells). 47372505; (2005)

Acceptable/guideline Concentrations: 30, 60, 120, 180, & 240 μg/ml. Negative

870.5300 HPRT Test (V79

cells). 47372504; (2006)

Acceptable/guideline Concentrations: 4 to 256 μg/ml +/ - metabolic activation. Negative

870.5385 In - vivo micro nucleus test in male mice 47372506; (2005)

Acceptable/guideline Doses: 250, 500, & 1000 mg/kg. Negative 870.6200a Ac ute

neurotoxicity screening battery 47372507; (2007)

Acceptable/guideline Initial study 125; 500; and 2,000 mg/kg/day Follow- up study using only female rats 25, 50 and 100 mg/kg/day . NOAEL = 125 for males ; <125 for females Based on ↓ motor and locomo tor activity, clinical signs and ↓ body temperature LOAEL for male = 500 mg/kg/day based on ↓ motor and locomotor activity. NOAEL = 50 mg/kg/day LOAEL = 100 mg/kg/day based on ↓ motor and locomotor activity .Fluopy

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Page 45 of 105 **Table A.2.2 Subchronic, Chronic and Other Toxicity Profile**  **Guideline No. Study Type**  **MRID No. (year)/ Classification /Doses**  **Results** 870.6200b Subchronic

neurotoxicity screening battery 47372508; (2008, Report)

(The study was conducted in 2007) Acceptable/guideline 100; 500; & 2,500 ppm ♂: 7, 33, & 164 mg/kg/day ♀: 8, 41, & 197 mg/kg/day NOAEL = 33 mg/kg/day LOAEL = 164 m/kg/day based on a host of effects which included increases in cholesterol and triglyceride levels, decrease in glucose level, decreases in hemoglobin and hematocrit, and deceases in body weight and food consumption . No evidence of neurotoxic ity in either neurobehavioral parameter or histopathology . 870.7485 ADME study in rats 47372509; (2008) Acceptable/guideline 5 & 250 mg/kg (single dose by gavage )( 14 C on phenyl ring) 5 mg/kg (radiola

beled fluopyram) after 14 days pre treatment With oral dosing, fluopyram was rapidly absorbed (93.2 % of administered radioactivity) from the GI tract of male and female rats. The max. plasma concentration was reached at 15 hrs in males and 11 hrs in females post dosing with 5 mg/kg. After 168 hrs p ost dosing 91 - 99 % of the administered radioactivity was eliminated via urine and feces. The ratio of renal and fecal elimination was comparable (45% via urine and 47% via feces). The organ which contained the highest radioactivity was the liver (0.4 to 1. 0 % of the administered radioactivity. ) Considerable enterohepatic circulation was demonstrated by the results. Fluopyram was extensively metabolized and 29 metabolites were identified. It was proposed that three main metabolite groups were formed in the l iver (fluopyram- 7 - OH - GA, 8 - OH - GA and enol - GA) (GA=glucuronic acid) . 870.7485 ADME in the rat 47372511; (2008) Acceptable/guideline Single oral dose, 5 mg/kg (gavage) ( 14 C in position s 2 & 6 of the pyridyl ring) With oral dosing, fluopyram was absorbed rapidly and efficiently eliminated from the body (>98% of the administered radioactivity was eliminated) after 72 hrs post dosing. No significant residues remained in the body. Considerable enterohepatic circulation occurred. Three main metabolite groups were formed in the liver (fluopyram- 7 - OH - GA, 8 - OH - GA and enol - GA) (GA= glucuronic acid) . 870.7485 Distribution of total

radioactivity in male & female rats 47372513; (2008)

Acceptable/non - guideline Single dose 14 C in the phenyl ring of fluopyram at 3 mg/kg . Distribution occurred in almost all organs with liver reaching the maximal concentration first, and most of the tissue reaching the peak concentration at approximately 24 hr post - dosing. By 136 hr post dosing little of the radioactivity was present in most organs except nasal mucosa. 870.7485 Distribution of 14 C

labeled fluopyram . 47372512; (2008)

Acceptable/non - guideline 3 mg/kg for ♂ & 4.5 mg/kg for ♀ (Single oral dose; 14 C on pyridyl ring of f luopyram. ) Fluopyram was readily absorbed from the GI tract and distributed among almost all organs. The data indicated that peak value was reached at approximately 1 hr after dosing in most organs with liver having the higher concentration than other organs. From peak values, a continuous but slo w decline of radioactivity concentrations was observed for all organs. 870.7485 Metabolism in

organs and tissues in rats 473725 09 ; (2008)

Acceptable/non - guideline 5 mg/kg (Single oral dose; 14 C in the 2 & 6 p osition of the pyridyl ring of fluopyram) . AE C656948 was extensively metabolized, and more than 20 metabolites were identified. The report concluded that the major metabolic transformation was oxidation and took place mainly at the ethylene bridge of the molecule. The major metabolites were AE C65694 8 - 7 -hydroxy and AE C656948 -pyridyl - acetic acid.Fluopy

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Page 46 of 105 **Table A.2.2 Subchronic, Chronic and Other Toxicity Profile**  **Guideline No. Study Type**  **MRID No. (year)/ Classification /Doses**  **Results** 870.7600 In - vitro dermal

absorption study with human and rat skin 47372514 (2007)

Acceptable 500 mg AE C656948 & 0.5 mg AE C656948 (spray dilution) Dermatomed skin membranes from human and rat were examined. The report stated that over a period of 24 hrs the potentially absorbable [ 14 C]

–AE C656948 was 1.8% and 12.4 % for human and rat skin, respectively. This results in approximately 6x difference between dermatomed human and rat skin. Rat skin being more p ermeable. In - vivo dermal absorption 47567201 (2008)

Acceptable/guideline 0, 60 μg (spray dilution) and 60 mg (neat) The maximal dermal absorption rates for neat formulation and spray dilution we re 4.5% and 12.8% of the applied dose, respectively . 870.7800 28 - Day

immunotoxicity study in rats 48239930; (2010)

Acceptable/guideline 0, 200, 600, 1800 ppm 0, 17.2, 53.6, 156.3 mg/kg/day. Immunotoxicity NOAEL for anti - SRBC IgM response = 156.3 mg/kg/day (HDT). Non - guideline 7 - Day mechanistic

study in female rats (dietary administration) 47372520; (2008)

Acceptable/non - guideline 3,000 ppm (193 mg/kg/day). Feeding fluopyram at 193 mg/kg/day in the diet to female rats did not affect body weight, clinical signs or food or water consumption. Mean absolute and relative liver weights were increased (40 to 43%) relative to the controls. This increase was associated with enlarged and dark livers in 13/15 females. At histological examination, minimal to slight centrilobular to panlobular hepatocellular hypertrophy was found in all treated animals. There was a 4x increase in mean BrdU labeling index in both the perilobular and centrilobular areas of the hepatic lobule in treated animals relative to the controls. A slight increase in total P - 450 content and in mean EROD activity, a moderate increase in mean PROD and BROD activities and a marked increase in mean UDPGT activity (all statistically different from the control group (p ≤0.01)) were seen. The report concluded that AE C656948 has the ability to induce moderately phenobarbital - inducible hepatic enzymes (total cytochrome P - 450, BROD and PROD and UDPGT) as well as liver hypertrophy and cell proliferation in the liver.Fluopy

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Page 47 of 105 **Table A.2.2 Subchronic, Chronic and Other Toxicity Profile**  **Guideline No. Study Type**  **MRID No. (year)/ Classification /Doses**  **Results** Non - guideline 7 - Day mechanistic

study with Phenobarbital Reduction in activity in all treated animals & slight reduction in body weight gain. Mean absolute and relative liver weights were increased ( ≈ 22%) relative to the controls. Dark liver was found in 5/14 females and enlarged liver in 3/14 females. Minimal to slight centrilobular to panlobular hepatocellular hypertrophy was found in all treated animals. A 2x increase in mean BrdU labeling index in the perilobular and centrilobular areas in the treated animals. A moderate increase in total P - 450 content and in mean PROD, BROD and UDPGT activities (all statistically different from the control group p ≤0.01). The report states that phenobarbital has the ability to induce hepatic enzymes like total cytochrome P - 450, PROD, BROD and UDPGT activities as well as liv er hypertrophy and cell proliferation in the liver. Non - guideline 14 - Day dietary

administration to the mice (hepato - toxicity and thyroid hormone investigations) 47372519; (2008

Acceptable/non - guideline 2,000 ppm 308 and 314 mg/kg for 3 or 14 days, respectively. After 3 days of exposure, mean T3 level was not changed, whereas mean T4 level was decreased ( - 30%) while mean TSH level was increased (+18%) relative to the controls. Mean absolute and relative liver weights were increased by approximately 60%. Enlarged liver was found in all the treated animals. Diffuse centrilobular to panlobular hepatocellular hypertrophy and an increased number of mitoses were observed in all examined treated animals. In addition, hepatocellular single cell necrosis was observed in 1/5 treated animals. No significant microscopic change was observed in the thyroid gland. Total cytochrome P - 450 content was markedly increased (+116%) by the treatment. EROD activities were marginally increased (+235%), whereas PROD and BROD activities were markedly increased (respectively +2890% and +8717%) relative to controls. No significant changes were observed in UDPGT. Non - guideline Phenobarbital 14 -

day mechanistic study in the mouse (gavage) (hepato toxicity and thyroid hormone investigations) 47372522; (2008)

Acceptable/non - guideline 80 mg/kg for 3 or 14 days by gavage. The report stated that phenobarbital administration at a dose level of 80 mg/kg body weight/day in the mouse for 3 and 14 days induced significant liver change s including increases in hepatic total cytochrome P - 450, PROD and BROD activities. Phenobarbital also induced a modification of the normal thyroid hormone balance (in particular by a decrease in T4 and/or T3 after 3 and/or 14 days of exposure together with a concomitant increase in TSH level after 14 days. ) Non - guideline In - vitro studies on

the potential interactions with thyroid peroxid a se catalyzed reactions 47372518; (2008)

Acceptable/non - guideline 300 μM Fluopyram at 300 μM did not affect thyroid peroxidase ( TP O) - catalyzed guaiacol oxidation and TP O - catalyzed iodine formation. Therefore, the data show that fluopyram does not affect thyroid hormone synthesis at the level of TPO. **A.3 Hazard Identification and Endpoint Selection**  **A.3.1 Acute Reference**  **Dose (aRfD) -**  **Females age 13 -**  **49**Fluopy

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Page 48 of 105 **Study Selected:** None **MRID No:** N/A **Dose and Endpoint for Risk Assessment** : None **Uncertainty Factor:** Not applicable **Comments about Study/Endpoint/Uncertainty Factors:** An endpoint attributable to a single dose was not identified. **A.3.2 Acute Reference Dose (aRfD)**  **- General Population**  **Study Selected:** Acute Neurotoxicity Studies in Rats **MRID No:** 47372507 **Dose and Endpoint for Risk Assessment** : NOAEL= 50 mg/kg/day **Uncertainty Factor:** 100x (10x interspecies extrapolation, 10x intraspecies variability) **Acute RfD** = )

( 100 / / 50 UF day kg mg = **0.50 m g/kg/day**  **Comments about Study/Endpoint/Uncertainty Factors:** An acute neurotoxicity

study in rats was used to select the dose and endpoint for establishing the general population aRfD of 0.5 mg/kg/day . The LOAEL of 100 mg/kg is based on decreased motor and locomotor activity in females. The LOAELin males was 125 mg/kg/day . This acute endpoint is appropriate for the route and duration of exposure as well as for the population of concern. **A.3.3 Chronic Reference Dose (cRfD**  **) `**  **Study Selected:** Combined Chronic Toxicity /Carcinogenicity Study in Rats **MRID No:** 47372501 **Dose and Endpoint for Risk Assessment** : NOAEL= 1.20 mg/kg/day **Uncertainty Factor:** 100x (10x interspecies extrapolation, 10x intraspecies variability) **Chronic RfD** = ) ( 100 / / 20 . 1 UF day

kg mg = **0.012 m g/kg/day**  **Comments about Study/Endpoint/Uncertainty Factors:** A combined chronic/carcinogenicity study in rats was used to select the dose and endpoint for establishing the cRfD of 0.012 mg/kg/day . The LOAEL of 6.0 mg/kg/day is based on nephropathy, follicular cell hy pertrophy in the thyroid, and increased liver we ight with gross pathological and histopathological findings. The selection of the point of departure and toxicity endpoint from this study

endpoint is appropriate for the duration and population of concern. In addition it will be protective of thy roid eff ects (thyroid hyperplasia and thyr oid follicular cell tumors) seen in mice at 750 ppm (105 mg/kg/day).Fluopy

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Page 49 of 105 **A.3.4 Incidental Oral Exposure (Short** **- and Intermediate**  **- Term)**  **Study Selected:** 2 - Generation Reproduction - Rat **MRID No:** 47342447 **Dose and Endpoint fo r Risk Assessment:**  NOAEL= 14.5 mg/kg/day **Uncertainty Factor:** 100x (10x interspecies extrapolation, 10x intraspecies variability) **Comments about Study/Endpoint/Uncertainty Factors:** A 2 - generation reproduction study in rats was used to select the dose and endpoint for short - and intermediate - term incidental oral exposure. The LOAEL of 82.8 mg/kg/day is based on clinical pathology changes, increased liver weight, protein droplet nephropathy (M) and centrilobular hy pertrophy in parents, and decreased body weight ( - 8.1%, p<0.05) and body weight gain ( - 8.6% p<0.05) with secondary

decreases in spleen and thy mus weights and secondary slight delay

in preputial separation in offspring. This endpoint is appropriate for the population of concern (children) since this body weight/body weight gain effect occurred post - natally and is not an in utero effect. **A.3.5 Dermal Exposure (Short** **- , Intermediate**  **- and Long**  **- Term** **)** Dermal absorption studies of Fluop yram SC 500 neat formulation (500 mg fluopyram/ml) or the spray dilution (0.5 mg/ml) were conducted in rats in vivo. **The conservative estimates of the percentage of the administered dose absorbed**  **were 4.5% for the neat fo**  **rmulation and 12.8% for the spray dilution.**  Refinement of the dermal absorption factors for the neat formulation and spray

dilution was achieved by conducting in vitro studies under similar conditions (e.g. same material, same times, similar treatment of the skin including tape stripping) using rat skin and human skin. With the results from both in vivo and in vitro studies, a parallelogram (also called a "Triple Pack") approach was used to calculate the dermal absorption factor in human skin b y using a proportional relationship: rat in vivo /rat in vitro =human in vivo /human in vitro . **The refined dermal absorption values for human skin were 0.2% for the neat formulation and 1.9% for the spray dilution.**  **Short -**  **and Intermediate -**  **Term Dermal Exposure Study S**  **elected:** 28 - day

Dermal -- Rat **MRID No:** 47567201 **Dose and Endpoint for Risk Assessment:** Dermal NOAEL= 300 mg/kg/day **Uncertainty Factor:** 100x (10x interspecies extrapolation, 10x intraspecies variability) **Comments about Study/Endpoint/Uncertainty Facto rs:**  A 28 - day dermal study

was selected for the dose and endpoint for short and intermediate term dermal exposure. The LOAEL of 1000 mg/kg/day (oral equivalent = 45 mg/kg/day) is based on increased cholesterol (females), increased prothrombin time (males) and increased liver weights (males & females) associated with hepatocellular hy pertrophy . The 28 - day dermal toxicity study in rats is the appropriate route of exposure and measures all endpoints of concern. An oral study was not chosen for a derm al endpoint since no increased sensitivity was seen in theFluopy

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Page 50 of 105 developmental rat or rabbit studies or in the 2 - generation reproduction study in rats. The dermal endpoint is protective of effects from any in utero exposure. In addition, this 28 - day dermal toxi city study is appropriate for both the short - and intermediate - term exposures. Since dermal absorption is so low (<1% in humans for the concentrate), it is unlikely that the internal dose would lead to a progression of toxicity . **A.3.6 Inhalation Exposure**  **(Short -**  **, Intermediate -**  **and Long -**  **Term) Short**  **- and Intermediate** **- Term Inhalation Exposure**  See Incidental Oral exposure ( A 3.4). The assumed inhalation absorption factor is 100%. **Long -**  **Term Inhalation Exposure** Long - term Inhalation exposure is not anticipated. **A.4 Executive Summaries**  **A.4.1 Subchronic Toxicity**  **870.3100 90**  **- Day Oral Toxicity**  **– Rat**  In a subchronic oral toxicity study (MRID 47372441), fluopy ram (99.0% a.i., L ot/Batch PFI 0304) was administered in the diet to ten Wistar (Rj:WI[I OPS HAN]) rats/sex/dose group at dose levels of 0, 50, 200, 1000, or 3200 ppm (equivalent to 0/0, 3.06/3.63, 12.5/14.6, 60.5/70.1, and 204/230 mg/kg/day

in males/females) for at least 90 days . Additionally , groups of ten rats/sex/dose group were administered the test substance in the diet at dose levels of 0 or 3200 ppm for at least 90 days and then maintained on basal diet for a minimum of 28 days to examine the reversib ility

of any treatment - related effects. In addition to the customary parameters, animals of the main treatment group were assessed for neurotoxicity on Study Weeks 11 and 12 by observers who were “blind” to the dose groups of the animals. Motor activity , sensor reactivity, and grip strength were recorded. Additionally , during Weeks 3 and 13 of the treatment period, and Week 5 of the recovery period, blood samples were collected and T3, T4, and TSH levels were measured. There were no effects of treatment observed on clinical signs, motor activity , sensor reactivity , grip strength, or ophthalmoscopic examinations. There were no treatment - related deaths. One 1000 ppm male was euthanized on Day 37 having had a distended abdomen between Day s 22 and 37 and general pallor between Days 27 and 37. This animal was noted to have a pale appearance and an enlarged, irregular, and red mottled liver at necrops y; a cause of death was not reported. One 50 ppm male was killed on Day 57 having been noted to have labore d and nois y respiration, a wasted appearance, piloerection, and ocular discharge from both eyes on the day of termination, together with a body weight loss of 8.2 g/day and reduced food consumption during the week prior to sacrifice. The condition of thisFluopy

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Page 51 of 105 animal was attributed to accidental trauma, as soiled fur around both eyes and a fracture of the nasal cavity were discovered at necrops y. All other animals survived to scheduled termination. At 3200 ppm, the liver toxicity findings observed at 1000 pp m were increased in severity and magnitude and more frequently noted in both sexes. In addition to the findings in the liver noted above, triglycerides were increased in the females and higher mean prothrombin times were noted in the males. In the thy roi d, a bsolute and relative weights were increased in both sexes, with minimal to slight diffuse follicular cell hypertrophy noted in the majority (8/10) of the males; minimal diffuse follicular cell hypertrophy was noted in one female. TSH was increased in both sexes at Week 3, and in the males at Week 13. T3 was increased in the females at Week 3, and in the males at Week 13. T4 was increased in the females at Week 3. Additionally at this dose, body

weights were slightly

decreased throughout the study , resulting in a decrease in overall body weight gains in both sexes. Food consumption was slightly decreased from Day 29 - 90 in the females. Treatment - related liver toxicity was observed at 1000 ppm. Absolute and relative (to body) liver weights were incre ased by 20 - 27% in both sexes. Total cholesterol was increased by 45 - 48% in both sexes, and gamma glutamyltransferase was increased by 480% in the females. At necrops y, obviously large liver was observed in 6/9 males and 7/10 females, dark liver was noted in 2/9 males, and prominent liver lobulation was observed in 4/9 males. Minimal to slight diffuse centrilobular hepatocellular hy pertrophy was noted in 9/9 males and 7/10 females, and minimal focal/multifocal periportal to midzonal hepatocellular macrovacuolation was observed in 6/10 females. Additionall y at 1000 ppm, minimal to slight diffuse follicular cell hypertrophy was noted in 4/9 males and 2/10 females, and TSH and T4 were increased b y 54% and 43%, respectivel y, in the males. At 200 ppm, certain effects (such as increased total cholesterol, increased g amma glutamyltransferase in females only , enlarged liver, minimal diffuse centrilobular hepatocellular hy pertrophy and minimal focal/multifocal periportal to midzonal hepatocellular macrovacuolation) were found in a small number of test animals. The severity and magnitude of effect were minimal relative to the effects seen in 1000 ppm group. These minor findings were considered to represent an adaptive response of the liver to exposure to the test compound and were not considered adverse. Kidney toxicity

was noted in the males at 1000 ppm and above. Absolute and relative kidney weights were increased by 25 - 34%. Obviously large kidney

and pale kidney

were noted in the majority of the 1000 ppm and above males at necropsy , and in 1 - 3 males at 50 and 200 ppm. The increased weights were associated with microscopic changes of hyaline droplet nephropathy (hyaline droplets in the proximal tubule, focal/multifocal basophilic tubules, granular casts in the medulla, and focal/multifocal hyaline casts) observed in all dose groups, increasing in severity and frequency

with increasing dose. Cellular casts in the urine were also noted at all dose levels in the males. This nephropathy was considered to be due t o accumulation of 2u - globulin, a common toxicological finding in young male rats following exposure to toxicants. Therefore, these findings were not considered relevant to human health considerations.Fluopy

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Page 52 of 105 During the recovery

period, there was a tendency tow ards reversibility

in the majority

of the animals treated with 3200 ppm of the test compound. The findings in the male kidney tended to be the most persistent. **The LOAEL is 1000 ppm (equivalent to 60.5/70.1 mg/kg/day in males/females), based on liver tox**  **icity as described above and diffuse follicular cell hypertrophy**  **in both sexes, and**  **increased TSH and T4 in the males.**  **The NOAEL is 200 ppm (equivalent to 12.5/14.6 mg/kg/day in males/females).**  This study is considered **acceptable /guideline**  and satisfies the requirements (OPPTS 870.3100; OECD 408) for a subchronic toxicity study in rodents. **870.3100 90**  **- Day Oral Toxicity**  **– Mouse**  In a subchronic oral toxicity study (MRID 47372442), fluopy ram (99.0% a.i., L ot/Batch PFI 0304) was administered in the diet to ten C57BL/6J mice/sex/dose group at dose levels of 0, 30, 150, or 1000 ppm (equivalent to 0/0, 5.4/6.8, 26.6/32.0, and 188/216 mg/kg/day in males/females) for at least 90 day s . There were no effects of treatment observed on clinical signs, body weights, body

weight gains, or food consumption. There were no treatment - related deaths. One 30 ppm male was found dead on Day 30 after a body weight loss of 6.9 g between Day s 15 - 29 and reduced food consumption between Days 9 - 29. Clinical signs included reduced motor activity on Day s 22 - 23 together with wasted appearance and hunched posture during Days 22 - 29. Spontaneous hydrocephalus was observed at necrops y and confirmed microscopicall y. This was considered to be the cause of death for this animal. One control male was killed for humane reasons on Day 69 after an accidental trauma. All other mice survived to scheduled termination. Treatment - related liver toxicity was observed at 1000 ppm. Alanine aminotransferase was increased b y 109 - 205% in both sexes, and alkaline phosphatase and aspartate aminotransferase were increased b y 21% and 46%, respectively, in males. Absolute and relative (to body) liver weights were increased by 36 - 45% in both sexes, corresponding to enlarged liver in 8/10 mal es and 9/10 females. Dark liver was noted in 5/10 males and 10/10 females. Microscopicall y, centrilobular hepatocellular hy pertrophy was observed in 10/10 males (moderate severity) and 10/10 females (minimal to moderate severity). Focal necrosis was not ed in 3/10 males (minimal severity) and 6/10 females (minimal to slight severity). Additionally

at 1000 ppm, absolute and relative adrenal gland weights were increased b y 87 - 92% in the males. Microscopically in the adrenal glands, there was a lower incidence of cortical ceroid pigment in the males, and a greater incidence of minimal to slight cortical vacuolation in the females. At 150 ppm, absolute and relative liver weights were increased b y 14 - 28% in both sexes. Centrilobular hepatocellular hy pertrop hy was observed in 10/10 males (minimal to slightFluopy

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Page 53 of 105 severity) and 5/10 females (minimal severity). These minor findings were considered to represent an adaptive response of the liver to exposure to the test compound and were not considered adverse. **The LOA EL is 1000 ppm (equivalent to 188/216 mg/kg/day in males/females), based on**  **liver toxicity as described above in both sexes, increased adrenal gland weights and lower**  **incidence of adrenal gland cortical ceroid pigment in males, and a greater incidence of c**  **ortical vacuolation of the adrenal gland in females .**  **The NOAEL is 150 ppm (equivalent to 26.6/32.0 mg/kg/day in males/females).**  This study is considered **acceptable /guideline**  and satisfies the requirements (OPPTS 870.3100; OECD 408) for a subchronic toxicity study in rodents. **870.3150 90**  **- Day Oral Toxicity**  **– Dog**  In a subchronic oral toxicity study (MRID 47372443), fluopy ram (94.6% a.i., Batch 08528/0002) was administered in the diet to four beagle dogs/sex/dose group at dose levels of 0, 800, 5000, or 20,000 ppm (equivalent to 0/0, 28.5/32.9, 171/184, and 332/337 mg/kg/day in males/females) for at least 90 days . The highest dietary concentration was reduced to 10,000 ppm on Day 15 due to body weight losses and decreased food consumption during the first two weeks, which were attributed to a lack of palatability of the test substance in the diet. There were no effects of treatment observed on mortality , during the ophthalmosc opic examinations, or on urinaly sis. All dogs survived to scheduled euthanasia. Treatment - related liver toxicity was observed at 5 000 ppm. Absolute and relative (to body) liver weights were increased by 59 - 69% in the males and by 35 - 49% in the females . The following changes in clinical chemistry parameters were observed in both sexes at Weeks 8 and 13: (i) alkaline phosphatase was increased b y 169 - 300%; (ii) gamma glutamyltransferase was increased by 50 - 200%; (iii) albumin was decreased by 17 - 22%; and (iv) albumin/globulin ratio was decreased b y 21 - 34%. The changes generall y increased in magnitude with time. At necrops y, enlarged liver was noted in 1/4 males and females. The following microscopic findings were noted in the liver (all compared to 0 co ntrols): (i) minimal to slight diffuse hepatocellular hy pertrophy in 4/4 males and females; (ii) multifocal intracy toplasmic eosinophilic droplets in 3/4 males (minimal to slight severity) and 4/4 females (minimal to moderate severity); and (iii) focal/multifocal hepatocellular single cell necrosis in 2/4 males (minimal severity). Additionally

at 5000 ppm, overall (Weeks 1 - 13) food consumption was decreased by 7% in males and b y 22% in females. This decrease was also attributed to a lack of palatability of the dietary formulations. Thy

mic involution (decreased size of cortex) was increased in severity (minimal to slight) in all males and females compared to controls (minimal); however, this finding was considered to be secondary to the decreased food con sumption. At 20,000/10,000 ppm, the findings observed at 5000 ppm were increased in severity and magnitude and more frequently noted in both sexes. In addition to the findings in the liver noted above, increases in aspartate aminotransferase (incr. 54 - 75 %) and alanine aminotransferase (incr.Fluopy

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Page 54 of 105 259 - 594%) were noted in the males at Weeks 8 and 13. Additional findings of toxicity included a wasted appearance noted for one male and two females. This observation was noted in correlation with body

weight loss and corresponding marked reduction in food consumption in both sexes during Weeks 1 and 2. These findings were attributed to a lack of palatability of the test diets at this concentration. Overall (Weeks 1 - 13) body weight losses of 0.8 kg in males and 1.1 kg in females were noted (compared to gains of 1.0 kg in controls), corresponding to decreases in overall food consumption of 25% and 46% in males and females, respectively . Platelet counts were increased b y 30 - 56% in both sexes during Weeks 8 and 13. Also at 20,000/10,000 ppm, absolute and relative thy mus weights were decreased b y 61 - 71% in the females, and 4/4 females were in anestrus compared to 1/4 controls. These findings were considered to be secondary to the reductions in body weight gains and f

ood consumption. At 800 ppm, absolute and relative liver weights were increased b y 25 - 39% in both sexes. This finding was considered to represent an adaptive response of the liver to exposure to the test compound, and was not considered adverse. **The LOAEL is 5000 ppm (equivalent to 171/184 mg/kg/day in males/females), based on**  **liver toxicity as described above in both sexes .**  **The NOAEL is 800 ppm (equivalent to 28.5/32.9 mg/kg/day in males/females).**  This study is considered **acceptable /guideline**  and s atisfies the requirements (OPPTS 870.3150; OECD 409) for a subchronic toxicity study in dogs. **870.3200 21/28**  **- Day Dermal Toxicity**  **– Rat**  In a 28 - day

dermal toxicity

study (MRID 47372444), fluopy ram (94.7% a.i., Batch 08528/0002) was applied to the shaved (intact) dorsal and lateral skin of ten Wistar rats/sex/dose group at dose levels of 0, 100, 300, and 1000 mg/kg/day for a minimum of six hours/day , five consecutive days/week, for four weeks . There were no effects of treatment observed on mortality , clinical signs, body weights, food consumption, or gross pathology . At 1000 mg/kg/day , treatment - related effects were observed on the liver . Relative (to body) liver weights were increased in the males, and absolute and relative liver weights were increased in the females. Microscopically , increased incidence of centrilobular and mid - zonal hy pertrophy were observed in the liver of males and females. Additionally , prothrombin time was increased in the males, and total cholesterol was increased in the females . **The LOAEL for systemic toxicity is 1000 mg/kg/day, based on liver toxicity as described above**  **. The NOAEL is 300 mg/kg/day.**  There were no local effects observed on the skin at any dose level. **The LOAEL for dermal toxicity was not observed. The NOAEL is 1000 mg/kg/day.** Fluopy

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Page 55 of 105 This study is considered **acceptable /**  **guideline** and satisfies the requirements (OPPTS 870.3200; OECD 410) for a 28 - day

dermal toxicity

study in rats. **A.4.2 Prenatal Developmental Toxicity**  **870.3700a Prenatal Developmental Toxicity Study –**  **Rat** In a developmental toxicity study (MRID 47372445 ), AE C656948 (Fluop yram, 94.6% a.i.; Lot/Batch # 08528/0002) in 0.5% aqueous methyl cellulose 400 was administered via dail y oral gavage in a dose volume of 10 mL/kg to 23 time - mated Sprague - Dawley rats/dose group at doses of 0, 30, 150, or 450 mg/kg/day from gestation day s (GD) 6 - 20 . On GD 21, all dams were euthanized; each dam’s uterus was removed via cesarean section and its contents examined. Fetuses were examined for external, visceral, and skeletal malformations and variations. No compound - related effects were observed on mortality , clinical signs of toxicity, or pregnancy rate. At 450 mg/kg/day , maternal body weight gain was decreased (p<0.01) b y 16% during GD 6 - 21, and food consumption was decreased b y 13 - 15% at all intervals from GD 6 - 14. Liver weights were increased (p<0.01) by 40% compared to controls and enlarged liver was also noted grossl y in 4/23 females at this dose (vs. 0/23 controls). Microscopic findings were limited to slight to marked diffuse centrilobular hepatocellular hypertrophy in all treated females at this dose (vs. 0/23 controls). At 150 mg/kg/day , maternal body weight gain was decreased by 6% during GD 6 - 21, and food cons umption was decreased by 10 - 18% at all intervals from GD 6 - 14. Liver weights were increased (p<0.01) b y 15% compared to controls. Microscopic findings were limited to minimal to moderate diffuse centrilobular hepatocellular hypertrophy in 20/23 females at this dose (vs. 0/23 controls). At 30 mg/kg/day , food consumption was decreased (p<0.01) b y 10% on GD 6 - 8; however, overall (GD 6 - 21) body weight gains were similar to controls. **The maternal LOAEL is 150 mg/kg/day based on decreased body weight gains and food consumption, and liver effects (increased liver weights and incidence of**  **diffuse centrilobular hepatocellular hypertrophy)**  **. The maternal NOAEL is 30 mg/kg/day.** There were n o treatment - related effects on abortions, premature deliveries, complete litter resorptions, or dead fetuses and no effects of treatment on the numbers of litters, live fetuses, earl y resorptions, or late resorptions. There were no treatment - related exter nal, visceral, or skeletal malformations, and no external variations. At 450 mg/kg/day , mean fetal body weight was decreased (p<0.05) b y 5% for both the combined and separate sexes. The incidence of the visceral variations “thy mic remnant presentFluopy

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Page 56 of 105 (unilateral/bilateral)” and “ureter (unilateral/bilateral); convoluted and /or dilated” was higher at the fetal and/or litter level than in the control group, and was outside the historical control range for both parameters. Additionally, there was a high er incidence of the skeletal variations “at least one thoracic centrum split/split cartilage” and “at least one thoracic centrum: dumbbell and/or bipartite/normal cartilage”, compared with the control group. The incidence was outside the historical control range at both the fetal and litter level for both findings. **The developmental LOAEL was 450 mg/kg/day based on decreased fetal body weights, and increased incidence of visceral and skeletal variations. The developmental NOAEL is 150**  **mg/kg/day.** This study

is classified **acceptable/guideline** and satisfies the guideline requirement for a developmental toxicity

study (OPPTS 870.3700; OECD 414) in rats . **870.3700b Prenatal Developmental Toxicity Study –**  **Rabbit** In a developmental toxicity study (MRID 4737244 6 ), AE C656948 (Fluop yram , 94.6% a.i.; Lot/Batch # 08528/0002) in 0.5% aqueous methylcellulose 400 was administered via daily oral gavage in a dose volume of 4 mL/kg to 23 time - mated New Zealand White rabbits/dose group at doses of 0, 10, 25, or 75 mg/kg/day from gestation day s (GD) 6 - 28 . On GD 29, all surviving females were euthanized; each doe’s uterus was removed via cesarean section and its contents examined. Fetuses were examined for external, visceral, and skeletal malformations and variations. No compound - related effects were observed on mortality , clinical signs of toxicity, pregnancy rate, macroscopic findings, or liver parameters (weight or pathology). On GD 21 one female at 75 mg/kg/day died and one control female was sacrificed due to accidental trauma on GD 15. Both deaths were attributable to a gavage error. The macroscopic observation showed hemorrhaging in the lung of both females together with hemorrhaging and foam in the trachea of one female and a trachea filled with fluid for the other female. In addition, one female was killed for humane reasons on GD 23 at 25 mg/kg/day , following a slight loss in body

weight and a reduction in food consumption between GD 20 and 22. Clinical signs in this female consisted of a limited use of the right hindlimb on GD 22 and 23. The macroscopic observation showed a severe fracture of the right hindlimb, in association with massive subcutaneous hemorrhaging and a distal epiphysal femoral disjunction. The condition of this animal was considered to be due to accidental trauma. At 75 mg/kg/day , mean body weight gain was decreased (p<0.01) between GD 14 - 18 (0.02 kg vs. 0.09 kg for controls) and between GD 18 - 22 (0.02 kg vs. 0.07 kg for controls). Thereafter, mean body weight gain was similar to the c ontrols, resulting in an overall (GD 6 - 29) decreased (not significant )body weight gain of 35% (0.20 kg treated vs. 0.31 kg controls). Maternal corrected body weight change was decreased (not statistically significant) by

47% ( - 0.25 kg treated vs. - 0.17 kg controls). M ean maternal food consumption was also reduced (p<0.01) b y 22 - 34% at all intervals between GD 14 - 26.Fluopy

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Page 57 of 105 **The maternal LOAEL was 75 mg/kg/day based on decreased body weight gains (absolute and corrected) and food consumption. The maternal NOAEL**  **is 25 mg/kg/day.** There were no treatment - related effects on abortions, premature deliveries, complete litter resorptions, or dead fetuses and no effects of treatment on the numbers of litters, live fetuses, earl y resorptions, or late resorptions. There were no treatment - related external, visceral, or skeletal variations or malformations. At 75 mg/kg/day , mean fetal body weight was decreased (p<0.05) b y 11% for both the combined and separate sexes. **The developmental LOAEL was 75 mg/kg/day based on decreased fetal body weights. The**  **developmental NOAEL is 25 mg/kg/day.** This study

is classified **acceptable/guideline** and satisfies the guideline requirement for a developmental toxicity

study (OPPTS 870.3700b; OECD 414) in rabbits . **A.4.3 Reproductive To**  **xicity 870.3800 Reproduction and Fertility Effects**  **– Rat**  In a two - generation reproduction toxicity study (MRID 47372447), AE C656948 (Fluopy ram, 94.7% a.i.; L ot/Batch # 08528/0002) was administered continuousl y in the diet at dose levels of 0, 40, 220, or 1200 ppm (equivalent to 0/0, 2.65/3.15, 14.5/17.2, and 82.8/96.0 mg/kg/day in males/females, respectively) for two consecutive generations. The P generation animals (30/sex/dose group) were fed the test diets for 10 weeks prior to mating to produce the F1 litters. F1 offspring selected to be parents of the next generation (30/sex/dose group) were fed the same test diet concentrations as their parents. F1 parents were fed the test diets for 10 weeks prior to mating to produce the F2 generation. The F2 offspring were terminated after weaning. There were no effects of treatment on mortality , clinical signs of toxicity , or food consumption in either sex in either generation during pre - mating. Furthermore, no treatment - related effects on body weight gain or food consumption were observed during gestation or lactation in either generation. No treatment - related gross necrops y findings were observed in either sex in either generation. During pre - mating (Weeks 1 - 10), body weight gains were decreased b y 20 and 10% in the 1200 ppm females of the P and F1 generations, respectively . Additionall y in the P generation females, decreases in body weight were observed at 1200 ppm during Days 0 - 13 of gestation (decr 5 - 6%) and on Day

0 of lactation (decr 5%). At 1200 ppm, treatment - related clinical chemistry findings were limited to increased creatinine, total protein, and albumin in the P - generation males, increased urea nitrogen and total protein in F1 males, and increased cholesterol in the F1 females. Additionally at this dose, hematology changes included decreased hemoglobin and hematocrit in the P - generation females, decreasedFluopy

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Page 58 of 105 hemoglobin in F1 females, and increased white blood cell and monocy te counts in the F1 females. In both the P - and F1 generations, test s ubstance - related increases were noted at 1200 ppm in absolute and relative kidney (right and left) weights in the males, and absolute and relative liver weights in both sexes. Additionally in the F1 females, absolute and relative spleen weights were decre ased at 1200 ppm and relative spleen weight was also decreased in 220 ppm. It was stated that the decreases in spleen weights (absolute and/or relative) in the F1 females were not associated with corresponding micropathology findings. However, as white bl ood cell parameters were changed in F1 animals and spleen weights were later found to be affected in F1 and F2 pups as well, this finding may be treatment related and further studies may be required to clarify reasons for this observation. In the P - generation, test substance - related micropathology findings noted at 1200 ppm included increased incidence of protein droplet nephropathy and l ymphocy tic infiltration in the kidneys of the males, and increased incidence of centrilobular hy pertrophy in the livers of both sexes. It was stated that these findings were in accordance with findings of other studies over a similar duration. **The LOAEL for parental toxicity is 1200 ppm (equivalent to 82.8/96.0 mg/kg/day in males/females, respectively) based on: decreases in body weight gain during pre**  **- mating in**  **the P -**  **and F1 generation females; decreased body weights during gestation and lacta tion in**  **P generation females; clinical chemistry effects (increased creatinine, total protein, albumin**  **and urea nitrogen in males and increased cholesterol in F1 females); hematology effects (decreased hemoglobin and hematocrit in the P**  **- generation females,**  **decreased hemoglobin in F1 females, and increased white blood cell and monocyte counts in the F1 females);**  **increased kidney weight associated with an increased incidence of protein droplet nephropathy and lymphocytic infiltration in P**  **- and F1 generation m**  **ales; and increased liver weights associated with an increased incidence of centrilobular hypertrophy**  **in both sexes. The NOAEL is 220 ppm (equivalent to 14.5/17.2 mg/kg/day in males/females,**  **respectively).** There were no treatment - related effects on: via bility , clinical signs, birth or live birth indices; lactation index, or pup sex ratio for either generation. Vaginal patency was similar to controls in the F1 females, and anogenital distance on PND 0 was unaffected b y treatment in the F2 pups. There were no treatment - related macroscopic or microscopic findings in the F1 or F2 pups. At 1200 ppm, F1 pup body weights (combined male and female) were decreased (not significant [NS]) by 5% on PND 14 and 21, resulting in a 5% decreased in overall (PND 0 - 21) body weight gain. F2 pup body

weights were decreased (NS, except p<=0.05 on PND 21) by 6 - 8% on PND 4 - 21. Overall body

weight gain throughout lactation was also decreased by 9% in these animals. At 1200 ppm, test substance - related decreases in organ weights in F2 generation pups were limited to decreased absolute and relative spleen and thy mus weights in males, females, and combined pups.Fluopy

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Page 59 of 105 A slight delay

in preputial separation in the 1200 ppm F1 males was observed (42.5 days) compared to controls. It wa s stated that although statistically significant, the number of days to criteria was within the range of historical controls (40.7 - 44.0 day s). Therefore, this finding was considered secondary

to the reduced body weight observed in the males during lactati on. **The LOAEL for offspring toxicity is 1200 ppm (equivalent to 82.8/96.0 mg/kg/day in males/females, respectively) based on decreased pup body weights and overall body weight**  **gains in the F1 and F2 generations, and decreased spleen and thymus weights in both sexes**  **in the F2 generation. The NOAEL is 220 ppm (equivalent to 14.5/17.2 mg/kg/day in males/females, respectively).**  There were no effects of treatment in either generation on: estrous cycle number or length, sperm parameters (motility , counts, or morphology), mating, fertility or gestation indices, day s to insemination, gestation length, or the median number of implants . Ovarian follicle counts in the F1 females were similar to controls. **The LOAEL for reproductive toxicity was not observed. The NOAEL is 1200 ppm**  **(equivalent to 82.8/96.0 mg/kg/day in males/females, respectively).** This study

is classified as **acceptable/guideline** and satisfies the guideline requirements (OPPTS 870.3800; OECD 416) for a two - generation reproduction study in the rat. **A.4.4 Chronic Toxicity**  **870.4100a (870.4300) Chronic Toxicity –**  **Rat** In a combined chronic toxicity / carcinogenicity study

(MRID 47372501), AE C656948 (94.5% a.i., Batch 08528/0002) was administered in the diet to 60 Wistar (Rj: WI[IOPS HAN]) rats/sex/dose group at dose levels of 0, 30, 150, 750 (males only), or 1500 (females onl y) ppm (equivalent to 0/0, 1.20/1.68, 6.0/8.6, 29 (males), and 89 (females) mg/kg day in males/females) for up to 24 months . In the 750 ppm males, the dose level was reduced to 375 ppm from Week 85 onward due to increased mortality . In addition, an interim sacrifice was performed at Week 52 on groups of 10 rats/sex/dose that were treated as above. At 1500 ppm (females only), increased incidence of hair loss and wasted appearance was noted. Mean body weights were significantl y reduced in both sexes. At 750/375 ppm (males only), there was a statistically significant increase in mortality at Week 52 and after 24 months , although no clear cause for these premature deaths could be established. Mean body weight was significantly reduced in both sexes at various time during the study.. Liver toxicity

became apparent by

an increase in organ weight at 150 ppm and above in male rats and at 1500 ppm in females that was s ometimes accompanied . Clinical chemistry findings suggesting hepatotoxicity were minor in nature and were observed at 750/375 and 1500 ppm. They comprised occasionally higher mean trigl yceride concentrations and slightly lower mean glucose concentrations in the female s. Activity of alkaline phosphatase was reduced in bothFluopy

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Page 60 of 105 sexes throughout the study but achieved statistical significance onl y occasionally . Histological changes included a higher incidence of altered hepatocy tes (eosinophilic foci) and hepatocellular brown pigments, focal or multifocal hepatocellular vacuolation, increased number of mitoses, centrilobular to panlobular hypertrophy and hepatocellular single cell necrosis , with females being much more affected. At 150 ppm, however, histopathol ogical finding (hy pertrophy) was confined to male rats corresponding to the increased organ weight noted at this dose. In the kidney , marked degenerative changes such as chronic progressive nephropathy or focal/multifocal (medullar or cortical) tubular di latation, together with an increased incidence of tubular golden/brown pigments (mainly in females) and collecting ducts hyperplasia , were observed at the high dose. Inaddition, a higher incidence of hyaline droplets and of renal cysts was noted in male rats . At the mid dose level of 150 ppm, male rats still displayed a higher frequency of tubular hyp ertrophy or dilatation. During the first year of treatment, but not thereafter, urinalysis revealed higher incidences of abnormal color of urine (orange to red) in females and a higher incidence and severity of cellular casts in males . This latter finding was also confirmed in male rats receiving the intermediate dose. Effects of AE C656948 on the thy roid gland were demonstrated by increased organ weights at the highest dose level in both sexes that were associated with histopathological changes ( follicular cell hy

perplasia and/or hy

pertrophy and colloid alteration/depletion). At 150 ppm, colloid alteration was noted in the females, and follicular cell hy p ertrophy was observed in the males. Both findings were reduced in frequency and severity compared to the high dose groups. The **eyes** were affected by long - term treatment was seen in treated animals at 150 ppm or above. Ophthalmologic examination revealed abnormal color of the retinal fundus in females after 12 months . At the 24 - month examination, this condition was observed in female s and males , together with small retinal vessels. In addition, hyper- reflectivity in the retina was noted in females and corneal opacity , edema of the cornea and nuclear opacity in males . These effects were more severe at the top dose level and less pronounced but still present after 2 ye ars in the male and female groups receiving 150 ppm. Histologicall y, bilateral retinal atrophy was noted at the highest dose level , together with a higher incidence of lens degeneration. A tendency

towards lower ery

throcy te parameters (hemoglobin concentration, mean corpuscular volume, hematocrit and/or mean corpuscular hemoglobin) was observed in the 1500 ppm female s throughout the study confirming evidence from short - term studies that th e red blood cells might be an additional target . The same tendency was observed in 750/375 ppm males at most time points; however, statistical significance was not achieved. The assumption of an effect on the blood was further substantiated b y a more fre quent occurrence of extramedullary hematopoiesis in the livers of high dose females. **The LOAEL is 150 ppm (6.0mg/kg/day) based on nephropathy, follicular cell hypertrophy in the thyroid, eye effect, and liver effect characterized by increased liver weight** **, gross and his**  **to pathological findings. The NOAEL is 30 ppm (1.2 mg/kg/day).**  At the doses tested, there was a treatment - related increase in tumor incidence compared to controls. At the end of the 2 - year carcinogenicity phase , the incidence of liver ce ll tumorsFluopy

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Page 61 of 105 (carcinoma and adenoma) was significantl y increased in females receiving 1500 ppm. The combined incidence of female rats with benign and malign liver tumors was 11 (including 3 animals with carcinoma) as compared to 2 in each of the control, low and mid dose groups. No such increment was seen in male rats but the very different actual compound intakes do not allow for a meaningful comparison. Dosing was considered adequate based on the findings of liver, kidney , thy

roid, and ocular toxicity

as described above. This study is considered **acceptable /**  **guideline** and satisfies the requirements (OPPTS 870.4300; OECD 453) for a combined chronic toxicity / carcinogenicity

study in rats. **870.4100b Chronic Toxicity –**  **Dog** In a chronic oral toxicity

study (MRID 47372449), fluopy ram (94.6% a.i., Batch 08528/0002) was administered in the diet to four beagle dogs/sex/dose group at dose levels of 0, 100, 400, or 2000 ppm (equivalent to 0/0, 3.0/3.8, 13.2/14.4, and 67.6/66.1 mg/kg/day in males/females) for at le ast 1 year . There were no effects of treatment observed on mortality , clinical signs, ophthalmoscopic examinations, hematology, urinal ys is, or gross pathology . At 2000 ppm, body

weight losses were observed in both sexes during Week 1 ( - 0.2 kg and

- 0.1 kg in males and females, respectivel y, compared to gains of +0.1 kg, and 0.0 kg in control males and females). These body weight losses corresponded to decreased food consumption (decr. 30% and 24% in males and females, respectively) during Week 1. The de crease in food consumption persisted in females until the end of the study . Additionall y at 2000 ppm, alkaline phosphatase was increased by 58 - 187% in males and females at Weeks 3, 6, and 12, and minimal diffuse centrilobular hepatocellular hypertrophy was observed microscopically in 3/4 males. No treatment - related effects were seen in 400 and 100 ppm groups. **The LOAEL was 2000 ppm (equivalent to 67.1/66.1 mg/kg/day in males/females) based decrease in food consumption and corresponding slight decrease i**  **n body weight, increases in alkaline phosphatase and centrilobular hepatocellular hypertrophy. NOAEL was 400**  **ppm (13.2/14.4 mg/kg/day in males/females).** This study is considered **acceptable /**  **guideline** and satisfies the requirements (OPPTS 870.4100b; OECD 452) for a subchronic toxicity study in dogs. **A.4.5 Carcinogenicity**  **870.4200a Carcinogenicity Study –**  **rat** See A.4.4 for Combined Chronic Toxicity /Carcinogenicity

Study in Rats (870.4300). **870.4200b Carcinogenicity (feeding) –**  **Mouse**Fluopy

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Page 62 of 105 In a carcinogenicity

study (MRID 47372450), AE C656948 (≥94.5% a.i., Batch 08528/0002) was administered in the diet to 50 C57BL/6J mice/sex/dose group at dose levels of 0, 30, 150, or 750 ppm (equivalent to 0/0, 4.2/5.3, 20.9/26.8, and 105/129 mg/kg day in males/females) for up to 78 weeks . In addition, an interim sacrifice was performed at Week 52 on groups of 10 mice/sex/dose that were treated as above. There were no unscheduled deaths or clinical signs occur ring during the study

that could be attributed to treatment. The survival rate was not different among the control and dose groups. Body weight gain was decreased onl y in the 150 ppm and above males and only during the second trimester of the study (weeks 26 to 54). Afterwards, some compensatory growth was observed resulting in a mean final body weight that was similar to the control group value. Mean absolute and relative liver weights were markedly increased in the 150 ppm and above males and females at interim sacrifice as well as at study termination. The increment exhibited a clear dose response. At these dose levels, gross necrops y findings such as dark and enlarged livers were corroborated by an increase in non - neoplastic histopathological lesions such as centrilobular to panlobular hypertrophy , hepatocellular cholestasis, single cell degeneration/necrosis or eosinophilic foci. A few of these non - neoplastic effects on the liver were observed onl y in males pointing to a higher vulnerability of this sex with regard to hepatotoxicity . Toxic effects on the thy

roid were noted at 750 ppm in both males and females and in the 150 ppm males. The main non - neoplastic finding, follicular cell hy perplasia, was apparent in male mice at the interim sacrifice. M ean absolute and relative kidney weights were decreased at the 750 ppm dose level in both sexes. Inaddition, a higher incidence and/or severity of bilateral cortical basophilic tubules, hyaline casts(s) and interstitial mononuclear cell infiltrate s , glomerular congestion/ hemorrhage(s), and more pronounced amyl oid deposition (mainly in the glomerular interstitium) was noted at this dose but only in females. At 30 ppm, mean absolute and relative liver weight was higher in the males than in the control group, but b y less than 10 % although the difference was statisticall y significant. More important, this organ weight increase was not accompanied by liver cell hy

pertrophy . The onl y histopathological finding in the liver at this dose level was diffuse centrilobular vacuolation. Therefore, these minor findings were not considered adverse. **The LOAEL is 150 ppm (equivalent to 20.9/26.8 mg/kg/day in males/females), based on liver and thyroid toxicity as described above**  **. The NOAEL is 30 ppm (equivalent to**  **4.2/5.3 mg/kg/day in males/females).**  At the doses tested, there was a treatment - related increase in tumor incidence compared to controls. A higher incidence (p<=0.05) of follicular cell adenoma was observed in the 750 ppm males (7/50) as compared to the control s (1/50) . Dosing was considered adequate based on the findings of liver and thyroid toxicity as described above.Fluopy

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Page 63 of 105 This study is considered **acceptable /**  **guideline** and satisfies the requirements (OPPTS 870.4200b; OECD 451)for a combined chronic toxicity / carcinogenicity study

in rats. **A.4.6 Mutagenicity**  **Gene Mutation** Guideline 870.5100 , In vitro Bacterial Gene Mutation (Salmonella typhimurium/ E. coli) / mammalian activation gene mutation assay . MRID 47372503 Acceptable/Guideline In a reverse gene mutation a ssay in bacteria , Salmonella typhimurium strains TA98, TA100, TA102, TA1535, and TA1537 were expose d to AE C656948 in dimethylsulfoxide (DMSO) at concentrations of 0, 16, 50, 158, 500, 1581, or 5000 μg/plate (initial trial) and 0, 5, 16, 50, 158, 500, or 15 81 μg/plate both in the presence and absence of S9 - activation . Standard strain - specific mutagens served as positive controls. AE C656948 was tested up to cy totoxic concentrations. There were no marked increases in the mean number of revertants/plate in any

strain in either trial in the presence or absence of S9. The positive controls induced the appropriate respo nse in all strains in the presence and absence of S9 - activation. **There was no evidence of induced mutant colonies over background**  Guideline 870.53 00, V79 Cells /Mammalian Activation Gene Forward Mutation Assay

at the HGPRT Locus . MRID 4 7372504 Acceptable/Guideline In a mammalian cell gene mutation assay at the HGPRT locus , V79 lung fibroblast cells cultured in vitro were expos ed to AE C656948 in DMSO at concentrations of 0, 4, 8, 16, 32, 64, 128, or 256 μg/mL (+/ - S9) for 5 hours. The positive c ontrols were ethyl methanesulfonate ( - S9) and dimethylbenzanthracene (+S9). AE C656948 was tested up to the limit of solubility . No marked increase in mutant frequency was observed in the presence or absence of S9 - activation. The positive controls induc ed the appropriate response (+/ - S9). **There was no evidence of induced mutant colonies over background in the presence or absence of S9**  **- activation.**  **Cytogenetics** Guideline 870.5375 , In Vitro Chromosomal Aberration Assay in Chinese Hamster V79 Cells . MRID 47372505 Acceptable/Guideline In a mammali an cell cytogenetics assay, Chinese hamster V79 cell cultures w ere exposed to AE C656948 in DMSO at concentrations of 0, 30, 60, 120, 180, or 240 μg/mL for 4 hours (with a 14 - or 26 - hour recovery period) in the presence of S9 and 18 hours of continuous exposure in the absence of S9. Cells were harvested at 18 or 30 hours after initiation of dosing ( +S9) and 18 hours after initiation of dosing ( - S9). The positive controls were mitomycin C ( - S9) and cyclophosphamide (+S9). AE C656948 was tested up to the limit of solubility and cytotoxicity . No biologically relevant or statistically significant increases in the number of metaphases with aberrations were observed at any

concentration at any

harvest time in the presence or absence of S9. The positive controls induced the appropriate response in the presence and absence of S9. **There was no evidence of chromosome aberrations**  **induced over background in the presence or absence of S9 -**  **activation.**Fluopy

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Page 64 of 105 Guideline 870.5395, Micronucleus Assay in Mice. MRID 47372506 Acceptable/Guideline In a bone marrow mi cronucleus assay, young adult male NMRI mice were treated with AE C656948 in 0.5% aqueous Cremophor at doses of 0, 250, 500, or 1000 mg/kg , i.p . Bone marrow cells were harvested at 24 hours after final dosing. Cyclophosphamide served as the positive control. All animals survived to scheduled sacrifice. Clinical signs including apathy, semi anesthetized state, roughened fur, weight loss, sternal recumbency, spasm, body stretching, and difficulty in breathing were observed at all dose levels until sacrifice. There was an increase in the number of n ormochromatic erythrocytes in all fluopy ram treated groups compare to controls although the difference was only

statistically significant at 1000 mg/kg. This demonstrated a relevant and sufficient systemic exposure of the animals to the test substance. The MPCE (micronucleated polychromatic erythrocy tes) frequency was comparable between vehicle controls and all treated groups. The positive control induced the appropriate response. **There was no significant increase in the frequency of micronucleated poly**  **chromatic erythrocytes in bone marrow.**  **A.4.7 Neurotoxicity**  **870.6200 Acute Neurotoxicity Screening Battery** In an acute neurotoxicity

study (MRID 47372507), groups of 12 non - fasted young adult Wistar rats/sex/dose were given a single oral gavage dose (10 mL/kg) of Fluopy ram (94.7% a.i.; Lot/Batch # 08528/0002) in aqueous 2% (v/v) Cremophor ELat dose levels of 0 , 125, 500, or 2000 mg/kg (limit dose) and were observed for 14 days. Neurobehavioral assessment (functional observational battery

[FOB] and motor activity testing) was performed in all rats at one week prior to dosing and on Day s 0 (approximately 1 hour post - dosing), 7, and 14. At study termination, all animals were necropsied, and 6 rats/sex/dose were euthanized and perfused in situ for neuropathological examination. The brain and peripheral nervous system tissues collected from the perfused animals in the control and 2000 mg/kg groups were subjected to histopathological evaluation. Because motor and locomotor activity were impaired in females even at the lowest dose level of 125 mg/kg, a follow - up study was initiated in order to establish a clear NOAE L. For this purpose, 12 females/group were treated in the same manner as in the initial study

at dose levels of 0, 25, 50, or 100 mg/kg. In - life observations were limited to FOB and motor activity

measurements at one week prior to dosing and on Day 0 (app roximately

1 hour post - dosing). The animals were sacrificed at 2 or 3 days post - dosing and were discarded without further examinations. Positive control data were not provided. There were no compound - related effects on mortality , body weight, brain weight (absolute and relative), and gross or neuropathology observed at any

dose. In the initial study , compound - related clinical signs were limited to urine stain in 4/12 males at 2000 mg/kg. In the FOB on Day 0, mean body temperature was decreased in the 5 00 and 2000 mg/kg females (37.4°C and 36.9°C, respectivel y vs. 37.9°C for controls). At 500 and 2000 mg/kg, total session motor and locomotor activity were decreased b y 51 - 72% and 49 - 77%, respectivel y, in both sexes on Day 0. Additionally in the 125 mg/kg females, total session motor and locomotor activity

were decreased by

26 - 31% on Day

0.Fluopy

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Page 65 of 105 In the follow - up study , total session motor and locomotor activity were decreased b y 38% each in the 100 mg/kg females on Day 0. **The LOAEL is 100 mg/kg, based on d ecreased motor and locomotor activity in the females.**  **The NOAEL is 50 mg/kg.** The initial study

is considered to be acceptable whereas the follow - up study in females is only supplementary . However, because a full study in both sexes is available, the information obtained from both experiments, when taken together, is considered com plete and sufficient to address this annex point. This study is classified as **acceptable/guideline** and satisfies the guideline requirement (OPPTS 870.6200a; OECD 424) for an acute neurotoxicity study in the rat. **870.6200 Subchronic Neurotoxicity Screeni ng Batter** **y** In a subchronic neurotoxicity study (MRID 47372508), groups of 12 young adult Wistar rats/sex/dose were exposed to Fluop yram (94.7% a.i.; Lot/Batch # 08528/0002) in the diet at nominal concentrations of 0, 100, 500, or 2500 ppm (equivalent to 0 /0, 6.69/8.05, 33.2/41.2, and 164.2/197.1 mg/kg/day , M/F) for 13 weeks. Neurobehavioral assessment (functional observational battery

[FOB] and motor activity testing) was performed in all rats at one week prior to dosing and during Weeks 2, 4, 8, and 13. At study termination, all rats were necropsied, and 6 rats/sex/dose were euthanized and perfused in situ for neuropathological examination. The brain and peripheral nervous system tissues collected from the perfused animals in the control and 2500 ppm groups were subjected to histopathological evaluation. Positive control data were not provided; however, it was stated that previous studies conducted at this laboratory had demonstrated the sensitivity of the test s ys tem and the methods used, as well as th e adequacy of training of technical personnel. There were no compound - related effects on mortality , clinical signs of toxicity , ophthalmoscopic examinations, FOB parameters, motor or locomotor activity , brain weight (absolute and relative), and gross or neuropathology observed at any

dose. At 2500 ppm, body

weights were decreased b y 4 - 7% in males and 5 - 12% in females from Day 21 throughout the remainder of the study. Overall (Day s 0 - 91) body weight gains were decreased b y 10% in males and 26% in females. Additionally at this dose, food con sumption was decreased b y 15% in the males on Day 21 and by 13 - 24% in the females from Day 21 throughout the remainder of the study . Compound - related increases in clinical chemistry parameters included: (i) cholesterol (incr 44 - 69%) in both sexes; (ii) triglycerides (incr 90%) in females; (iii) protein (incr 9%) in females; (iv) globulin (incr 16%) in females; and (v) albumin (incr 10%) in males. Additionally, glucose levels were decreased b y 6 - 15% in both sexes at this dose. The findings in clinical chemistry were likely

due to changes in liver function induced by Fluopy ram, as well known from other studies with this compound at comparable dose levels. In the 2500 ppm females, compound - related decreases in hematology parameters included: (i) hemoglobin (decr 10%); (ii) mean corpuscular hemoglobin (MCH, decr 14%); (iii) mean corpuscular volume (MCV, decr 13%); and (iv) hematocrit (decr 9%). Additionally, hemoglobin distribution width (HDW) was increased b y 28% in females at this dose.Fluopy

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Page 66 of 1 05 At 500 ppm, decre ased food consumption (decr 7 - 12%) was observed in females on Day s 21 - 42, 63 - 70, and 91. However, these decreases did not result in significant decreases in body weights or body weight gain in this group. **No evidence of neurotoxicity was observed in eithe r sex at any dose.**  **The LOAEL is 2500 ppm (164.2/197.1 mg/kg/day, M/F), based on decreases in body weight, body weight gain, and food consumption, and differences in clinical chemistry and**  **hematology parameters. The NOAEL is 500 ppm (equivalent to 33.2/41 .2 mg/kg/day, M/F).**  This study

is classified as **acceptable/guideline** and satisfies the guideline requirement (OPPTS 870.6200b; OECD 424) for a subchronic neurotoxicity study in the rat. **A.4.8 Metabolism**  **870.7485 Metabolism**  **– Rat**  In a metabolism study (MRID 47 372509 ), [ phenyl - UL 14 C] - AE C656948 (Batch/L ot No. not provided; radiochemical purity >98%) in aqueous 0.5% Tragacanth was administered by oral gavage to groups of Wistar [Hsd/Cpb: WU] rats for the following experiments: (i) a single 5 mg/kg dose administered to five bile duct cannulated males; (ii) a single 5 mg/kg dose administered to four rats/sex; (iii) a single 250 mg/kg dose administered to four rats/sex; and (iv) 5 mg/kg doses of non - radiolabeled test material administered daily for 14 days to four males, followed b y one dose of radiolabeled test material at 5 mg/kg . All animals were killed 168 hours after the final dose was administered except the bile duct- cannulated animals, which were terminated at 48 hours post - dosing. Metabolite prof iles were determined for pooled urine, feces, and bile (where applicable) samples collected from all of the experimental groups . [Phenyl - UL 14 C] - AE C656948 was rapidl y absorbed from the gastrointestinal tract in all test groups. Absorption commenced immediatel y after oral dosing as shown by the plasma curves and the values calculated for the absorption half - lives (0.1

– 0.5 h). Based on the results obtained in bile duct cannulated male rats, the absorption rate accounted for more than 93% . The test material was widel y distributed in the body with highest organ/tissue concentrations found in liver, kidney , ery

throcy tes and adrenals. In the experiments in non - cannulated rats, the majority of the administered dose had been excreted 168 h post dosing wi th fecal excretion accounting for 47 % - 64% and urinary

excretion accounting for 35% - 45% of the administered dose. Nonetheless , total residues in body (GIT excluded) were still found in the range between 2 and 6%. The high values in the excretory organs li ver and kidney

suggest that excretion was still ongoing. Despite these observations, the experiment with repeated administration did not provide indications of a relevant potential for bioaccumulation since excretion and residues patterns were not altered . Considerable enterohepatic circulation was proven by high biliary (78.5% within 48 hours in males) and low renal excretion in the bile fistulation test . The test compound was extensively metabolized, with a high number of metabolites occurring of which 9 to 22 could be structurall y identified and quantified in the different groups and matrices.Fluopy

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Page 67 of 105 The ethyllinking group of the molecule was the preferred site for metabolism. The metabolic transformations detected were hydrox yl ation of the ethyllinking group of the parent compound forming AE C656948 - 7 - hydrox y and 8 - hydrox y metabolites. Further oxidation of AE C656948 - 7 - hydroxy

and 8 - hydroxy

metabolites resulted in AE C656948 - enol which was further conjugated with glucuronic acid. Hydrox yl ation of the phenyl ring led to AE C656948 - phenol and AE C656948 - 7 - OH - phenol. All of the hydroxylated metabolites were conjugated mainl y with glucuronic acid and , to a lower extent, with sulfate. The cleavage of the molecule yi elded AE C656948 - benzamide that was one of the most abundant metabolites. T his molecule was further metaboli z ed via oxidation, hydrox yl ation and conjugation to AE C656948 - benzoic acid and various AE C656948 - benzamide - and AE C656948 - hydroxy benzamide - conjugates. The phenyl ring mo iety was also conjugated with glutathione followed by further degradation to AE C656948 - 7 - OH - methyl - sulfone, AE C656948 - BA - methyl - sulfoxide , and AE C656948 - BA methyl - sulfone. This study

is classified **acceptable/guideline** and satisfies the requirements [O PPTS 870.7485, OECD 417] for a metabolism study in rats. In a metabolism study (MRID 47 372511 ), [ py ridyl - 2,6 - 14 C] - AE C656948 (Batch/Lot No. not provided; radiochemical purity >99%) in aqueous 0.5% Tragacanth was administered by oral gavage to groups of W istar [Hsd/Cpb: WU] rats for the following two experiments: a single 5 mg/kg dose administered to six bile duct cannulated males; and a single 5 mg/kg dose administered to four rats/sex . All animals were killed 168 hours after the final dose was administ ered except the bile duct - cannulated animals, which were terminated at 48 hours post dosing. Metabolite profiles were determined for pooled urine, feces, and bile (where applicable) samples collected from all of the experimental groups . [Py ridyl - 2,6 - 14 C] - AE C656948 was rapidl y absorbed from the gastrointestinal tract in all test groups. The absorption commenced immediatel y after oral dosing as shown by the plasma curves and the values calculated for the a bsorption half

- lives (0.3

– 0.4 h). Based on the results obtained in bile duct cannulated male rats, the absorption rate accounted for 97.7 % of the recovered radioactivity and, thus, the administered dose may be considered to be virtually completely

absorbed and sy stemicall y bioavailable. The test material was widely distributed in the body

with highest organ/tissue concentrations found in liver and ery

throcy tes. Excretion was almost completed 72 h after administration. At this time, males and females had excreted more than 98 % of the administered dose via urine and feces with some minor sex related differences . In b ile duct - cannulated male rats , the major part of radioactivity ( 86.8 % ) was eliminated via bile proving, together with the low renal excretion in the bile fistulation experiment , the significant enterohepatic circulation of this compound. At 168 h after oral administration , residues in most of the organs and tissues of male and females rats were very low (<0.1 % of the dose) and, thus, retention or accumulation of AE C656948 or its metabolites are not expected.Fluopy

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Page 68 of 105 Metabolism was extensive with up to 25 metabolites in the different groups and matrices that could be identified and quantified. The ethyllinking group of the molecule was the preferred site for metabolism. The met abolic transformations detected were hydroxylation of the ethyl linking group of the parent compound forming AE C656948 - 7 - hydroxy and - 8 - hydrox y metabolites. Further oxidation of AE C656948 - 7 - hydrox y and 8 - hydrox y metabolites resulted in AE C656948 - enol, which was conjugated with glucuronic acid. Hydrox yl ation of the phenyl ring of AE C656948 led to AE C656948 - phenol and AE C656948 - 7 - OH - phenol. All of the hydrox yl ated metabolites were conjugated mainl y with glucuronic acid and , to a lesser extent, with s ulfate. Hydrol ytic cleavage and subsequent oxidation mainly led to AE C656948 - py

ridyl acetic acid (PAA), AE C656948 - ethyl - diol , and - py ridyl - carbox yl ic acid (PCA). This study

is classified **acceptable/guideline** and satisfies the requirements [OPPTS 870.74 85, OECD 417] for a metabolism study in rats. **870.7600 Dermal Absorption**  **– Rat**  In an in vitro dermal absorption study (MRID 47372514) where dermatomed rat and human skin membranes maintained in flow through diffusion cells at approximately 32 ° C. The der

matomed skin membranes were exposed to [ 14 C] - AC C56948 at two concentrations: one was a neat formulation (500 mg AE C656 948/ml formulation) and the other was the spray dilution (0.5 mg AE C656948/ml formulation). The two formulations were applied at a rate of 10 μ L/cm2 to the mounted skin samples. Receptor fluid samples were collected at hourl y interval for the duration of the study

(24 hours). Eight hours post - application, epidermal membranes were washed. At the end of the study, the skin samples were sw abbed and tape - stripped to remove residual test material from the skin surface. The results demonstrated the recovery to be 100.7% to 103.1% of the applied concentration for both high and low concentrations. For the neat formulation , majority of the radio activity

was found in the skin swab (100.9% & 100.1% of the applied concentration in human skin and rat skin, respectivel y) and tap - stripes (0.707% and 0.728% of the applied concentrations for human and rats skin, respectively). The percentages of the test material found in the receptor fluid from 0 - 24 hours were 0.004% and 0.077% of the applied concentrations for human and rat skin, respectivel y. For the spray dilution, The mean percentages of the applied concentrations considered to be potentially absorb able (directl y absorbed plus remaining at the application site) were 0.101% and 2.097% for human and rat skin, respectivel y. The results of the neat formation experiment yielded a factor of difference of 21 between human and rat skin. For the spray

diluti on **,** the majority

of the applied radioactivity was again found in the skin swab (97.6% and 86.2% of the applied concentrations in human and rat skin swabs, respectivel y), and tap - stripes contained 1.12% and 2.33% of the applied concentrations in human and rat skin, respectivel y. The percentages of the test material found in the receptor fluid from 0 - 24 hours were 1.23% and 8.56% of the applied concentrations for human and rat skin, respectivel y. The mean percentages of the applied concentrations considered to be potentiall y absorbable (directl y absorbed plus remaining at the application site) were 1.77% and 12.43% for human skin and rat skin, respectivel y. The results of spray dilution experiment showed that there was a factor of difference of 7 between human and skin.Fluopy

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Page 69 of 105 This study is considered **acceptable** and provides information regarding in vitro dermal absorption of fluop yram. In a dermal absorption study , 8 groups of four male Wistar Rj:WI(IUPS HAN) rats ( 7 to 9 weeks old , body

weights ranging from 240 to 377 g) were exposed for eight hours either to a neat formulation containing 500 mg [ 14 C] - fluopy ram/mLor to a 1:1000 spray dilution (0.5 mg/mL) (radiolabeled at the phenylring) . Twenty - four hours prior to dosing, an area of dorsal skin was shaved. Approximately 120 μL of each dose formulation in total (divided into two portions) was applied to the shaved area of ca 2 x 6 cm2 resulting in a final amount of nearl y 60 mg fluop yr am/animal (56.4

– 59.4 mg) in the high dose and of nearl y 60 μg fluop yr am/animal in the low dose experiment. The topical concentrations per cm2 skin ranged from 4.7 to 4.95 mg/cm2 for the concentrate and from 5.08 to 5.28 μg/cm2 for the dilution. Rounding of the applied concentrations to 5 or 0.005 mg/cm2 , respectivel y, seems app ropriate. When dose application was complete, the treated skin was semi - occluded with a perforated plastic cover that prevented loss of test substance but allowed air circulation. At termination of the eight - hour exposure period, the cover was removed an d the skin swabbed with 1 % Tween 80 in phosphate buffered saline (PBS) until no more radioactivity was detectable on the swabs. Subsequently , animals of the first high and low dose groups were sacrificed whereas the other three groups per dose level were terminated at 24, 72, or 168 hours after dosing. Urine and faeces were collected separatel y at 0 - 8, 8

– 24, and, thereafter, at 24 - hour intervals until sacrifice. At termination, cardiac blood was taken and tape stripping was performed to remove the Stra tum corneum . Up to 15 or 20 tape strips were taken until a “shiny” appearance of the epidermis became evident. The excreta (including cage wash), cardiac blood, carcass, samples of untreated skin, fur from the dose site, application site skin and samples o f the skin directly

surrounding the treated sites, individual tape strips, cover dressings, and swabs were anal yz ed for radioactivity by liquid scintillation counting. The results showed no clinical signs in the treated rats. The mean total recovery in all four groups was slightl y above 100 % with mean values ranging from 100.5 to 103.2 % for the neat formulation. Most of the radioactivity was detected in skin swabs immediately after dosing suggesting poor absorption. The distribution of radioactivity in the different compartments is summarized in Table 1 for neat formulation. Estimation of dermal absorption is based on the amount that is considered potentially absorbable for the individual groups . For neat formulation, a maximum potential dermal absorpti on was 4 .5 % a fter 24 hours post dosing. After single topical application of [ 14 C] - fluopy ram in the 1:1000 spray

dilution ( 0.5 mg/mL) , total recoveries in the different groups were slightly less than in the high dose experiment but, with mean values ranging from 89.7 to 98.8 % . Again, the major portion of radioactivity was found in skin swabs immediately

after treatment but the total percentage of dermal absorption was higher. Th e highest mean value for the potentially absorbable amount was at 8 hrs (at the end of the treatment period : 8 hours); the dermal absorption rate was 12.8 %.Fluopy

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Page 70 of 105 In summary , under the conditions of this study, the maximal dermal absorption rates for neat formulation and spray

dilution are 4.5% and 12.8% of the applied dose, respectively . This study is considered **acceptable /**  **guideline** and satisfies the requirements for in vivo dermal absorption study

in rats (Guideline 870.7600). **A.4.9 Immunotoxicity**  **870.7800 Immunotoxicity**  In an immunotoxicity

study (MRID 48239930 ) Fluop yr am (94.7% a.i., batch number: Mix Batch: 08528/0002) was administered to female Wistar Rj:WI(IOPS HAN) rats (10/dose) through diet at dose levels of 0, 200, 600, or 1800 ppm (0, 17.2, 53.6, or 156.3 mg/kg/day , respectivel y) for 28 day s. The positive control group consisting of 10 female Wistar Rj:WI (IOPS HAN) rats were administered 3.5 mg/kg/day cyclophosphamide daily via gavage for 28 days. On Day

26, all test animals received a 0.5 mL intravenous injection of sheep red blood cells (SRBCs) at a conc entration of 5x10 8 cells/mL. On Day 30, blood samples (0.5 mL) were taken from all groups b y puncture of the retro - orbital venous plexus. The level of anti - SRBC Ig M in response to SRBC antigen administration was determined with an Enzy me - Linked Immunosorbent Assay

(ELISA). Other parameters evaluated were: clinical condition, mortality, body weight, body weight gain, food consumption, spleen weight, and thymus weight. In the treated animals there were no treatment - related effects on clinical signs of toxici ty, body weight, body weight gain, food consumption, gross pathology , and spleen or thy mus weights. The anti - SRBC IgM ELISA results showed that there were no statistical differences in quantity of anti - SRBC IgM in any treatment group when compared with the vehicle controls. A high inter- individual variability was noted in all the treatment groups as well as in the control group. Evaluation of individual animal data did not show any trend or distribution that would demonstrate significant suppression of anti - SRBC antibody response. The Natural Killer (NK) cells activity assay was not performed in this study . The toxicology database for fluop yr am does not show any evidence of treatment - related effects on the immune sy stem. The overall weight of evidence suggests that this chemical does not dire ctly target the immune system. Under HED guidance, NK cells activity assay is not required at this time. **The immunotoxicity NOAEL for anti**  **- SRBC IgM response is 1800 ppm (156.3 mg/kg/day)**  **and the LOAEL was not estab**  **lished.** This immunotoxicity

study is classified acceptable / guideline and satisfies the guideline requirement for an immunotoxicity study (OPPTS 870.7800) in rats . **A.4.9 Special/Other Studies**  **Non -**  **Guideline: Mode of Action**Fluopy

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Page 71 of 105 In a non - guideline, mechanistic study (MRID 4737252 3 ), phenobarbital (9 9.6 % a.i., Lot/Batch 06100228 ) in 0.5% aqueous methylcellulose 400 was administered by oral gavage to groups of 15 female Wistar (Rj: WI [I OPS HAN]) rats /dose group at dose levels of 0 or 80 mg/kg day for seven day s . An 80 mg/100 mLaqueous solution of bromodeoxy uridine (BrdU) was provided as drinking water during the treatment period to allow evaluation of liver cell proliferation . The rats were observed regularly for changes in mortality, clinical signs of toxicity , body weight, and food and water consumption. On the day of necropsy , the rats were exsanguinated and necropsied. Brain and liver were weighed, and duodenum and two central sections of the left and medial lobes of the liver were removed and fixed in neutral buffered 10% formalin. BrdU incorporation was determined by immunohistochemical staining, and labeling indices were calculated for the centrilobular and periportal zones. The remaining portions of the liver from 10 females from each grou

p were taken, and microsomal preparations were made and anal yz ed for total cy tochrome P - 450 content and activities of ethoxy resorufin - O - deethylase (EROD), benzoxy resorufin - O - dealkylase (BROD), pentox yresorufin - O - deethylase (PROD), and UDP glucuronosyltran sferase (UDPGT). The purpose of this study was to confirm the ability of phenobarbital to induce enhanced activity of hepatic enzy

mes and to cause hepatocellular hy pertrophy and proliferation when administered at 80 mg/kg/day for seven day s. There were n o treatment - related deaths. One treated female was found dead on Day 5; however, a cause of death was not determined. All treated rats displayed reduced motor activity . Treated rats had no mean body weight gain during treatment, while control rats gaine d 7 g. Food and water consumption were similar to controls. In the treated females, absolute and relative (to body) liver weights were increased by 19 - 22%. The weight increase was associated with enlarged (3/14) and dark (5/14) livers observed at necrop sy , and diffuse centrilobular to panlobular hepatocellular hy pertrophy observed microscopicall y in all treated females. BrdU labeling indices were approximately 2 - fold higher in treated females compared to controls, and the centrilobular labeling index wa s higher than the periportal labeling index. Total cy tochrome P - 450 content was increased by 57%, EROD activity was increased b y 24%, UDPGT activity was increased b y 93%, PROD activity was increased b y 439%, and BROD activity was increased b y 1823%. Thes e data demonstrated the ability of phenobarbital to induce enhanced activity of hepatic enzy mes and to cause hepatocellular hy pertrophy and proliferation when administered at 80 mg/kg/day

for seven days. This study is considered **acceptable /non**  **- guideline**  and provides information regarding the effects of oral gavage administration of the test compound on rat liver. In a non - guideline, mechanistic study (MRID 473725 19 ), AE C656948 (9 4.7 % a.i., Lot/Batch 08528/0002 ) was administered in the diet to groups of 15 male C57BL/6J mice/dose group at dose levels of 0 or 2000 ppm (equivalent to 0 and 311 mg/kg day) for either three or fourteen days . The rats were observed regularl y for changes in mortality, clinical signs of toxicity, body weight, and fo od consumption. On the days of necrops y (Days 4 or 15), blood samples were taken from all animals for determination of TSH, T3, and T4 hormone levels. The mice wereFluopy

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Page 72 of 105 then exsanguinated and necropsied. Brain and liver were weighed, and pieces of the left and medial lobes of the liver from five mice/group were removed and fixed in neutral buffered 10% formalin. The remaining portions of the liver from these mice and the whole livers from the other ten males from each group were pooled (two whole livers poo led with one remaining portion) to generate five liver samples. Microsomal preparations were made from these five pooled samples and analyzed for total cy tochrome P - 450 content and activities of ethox yr esorufin - O - deethylase (EROD), benzoxy resorufin - O - dealkylase (BROD), pentox yr esorufin - O - deethylase (PROD), and UDP - glucuronos yltransferase (UDPGT). No mortalities were observed, and there were no clinical signs of toxicity . Body weights and body weight gains were unaffected by treatment. There was a slight decrease in food consumption noted in the 3 - day treatment group (decr. 12.5%) and in the 14 - day treatment group after 1 week of exposure (decr. 5.1%). T4 levels were decreased by 30% after 3 days and b y 27% after 14 days of treatment; TSH levels were increased by 18% after 3 days and by

7% after 14 days of treatment. These results were consistent with the known feedback regulation mechanism of thy roid hormone homeostasis. No relevant changes in gross or microscopic pathology were observed in the thyroid gland. Absolute and relative (to body) liver weights were increased by 59 - 61% at Day s 4 and 15. The weight increases were associated with enlarged and/or dark livers observed at necrops y, and centrilobular to panlobular hepatocellular hypertrophy observe d microscopically in all treated males (5/5 mice at Days 4 and 15). Additionally , an increased number of mitoses was observed in 5/5 males on Day

4, and single cell necrosis was noted in 4/5 males on Day 15. Total cy tochrome P - 450 content was increased b y 71 - 116%, EROD activity was increased by

165 - 235%, PROD activity

was increased b y 2163 - 2890%, and BROD activity was increased b y 8717 - 9061% on Day s 4 and 15. Incontrast, UDPGT activity was unaffected by

treatment. AE C656948 demonstrated the ability to induce total cy

tochrome P - 450, PROD, BROD, and EROD activities in mouse liver after 3 and/or 14 days of dietary exposure at the high dose level of 2000 ppm. Hepatotoxicity became further apparent by liver weight increases and concomitant histological les ions. Rapid onset of these changes was noted in the 3 - day experimental group. Furthermore, exposure to the test compound resulted in disturbance of thyr oid hormone balance in male mice b y causing a decrease in T4 levels with a concomitant increase in TSH . However, there were no microscopic findings of thy roid toxicity , perhaps due to the relatively short exposure period. This study is considered **acceptable /non**  **- guideline**  and provides information regarding the effects of dietary

administration of the test compound on mouse liver and thy roid. In a non - guideline, mechanistic study (MRID 47372520), AE C656948 (94.7% a.i., Batch 08528/0002) was administered in the diet to groups of 15 female Wistar (Rj: WI[I OPS HAN]) rats /dose group at dose levels of 0 or 300 0 ppm (equivalent to 0 and 193 mg/kg day) for seven days . An 80 mg/100 mL aqueous solution of bromodeoxy uridine (BrdU) was provided as drinking water during the treatment period to allow evaluation of liver cell proliferation . The rats were observed regularly for changes in mortality, clinical signs of toxicity , body weight, andFluopy

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Page 73 of 105 food and water consumption. On the day of necropsy , the rats were exsanguinated and necrops ied. Brain and liver were weighed, and duodenum and two central sections of the left and medial lobes of the liver were removed and fixed in neutral buffered 10% formalin. BrdU incorporation was determined by immunohistochemical staining, and labeling in dices were calculated for the centrilobular and periportal zones. The remaining portions of the liver from 10 females from each group were taken, and microsomal preparations were made and anal yz ed for total cy tochrome P - 450 content and activities of etho xy resorufin - O - deethylase (EROD), benzoxy resorufin - O - dealkylase (BROD), pentox yresorufin - O - deethylase (PROD), and UDP glucuronosyltransferase (UDPGT). The purpose of this study was to investigate the effects of the test compound on the liver, particularl y hepatocellular hy pertrophy and proliferation and induction of hepatic xenobiotic metabolizing enzymes. There were no deaths or clinical signs observed in either group during treatment. Body weight and food and water consumption were similar to controls. In the 3000 ppm females, absolute and relative (to body) liver weights were increased by 40 - 43%. The weight increase was associated with enlarged livers in nearl y all treated females at necrops y, and diffuse centrilobular to panlobular hepatocellular hyp ertrophy was seen microscopicall y in all treated females. BrdU labeling indices were approximately 4 - fold higher in treated females compared to controls. Total cy tochrome P - 450 content was increased b y 35%, EROD activity

was increased by

115%, PROD acti vity

was increased b y 329%, UDPGT activity was increased b y 378%, and BROD activity was increased b y 1066%. These data demonstrated that the test compound, when administered at 3000 ppm for seven days, induced xenobiotic metabolizing enzy mes in female rat liver, and caused hepatocellular hy pertrophy and proliferation. This study is considered **acceptable /non**  **- guideline**  and provides information regarding the effects of dietary

administration of the test compound on rat liver. In a non - guideline, mechanistic study (MRID 4737252 2 ), phenobarbital (9 9.6 % a.i., Lot/Batch 06100228 ) in 0.5% aqueous methylcellulose 400 was administered by daily oral gavage to groups of 15 male C57BL/6J mice/dose group at dose levels of 0 or 80 mg/kg day for either three o r fourteen day s . The rats were observed regularly for changes in mortality , clinical signs of toxicity, body

weight, and food consumption. On the days of necrops y (Days 4 or 15), blood samples were taken from all animals for determination of TSH, T3, and T4 hormone levels. The mice were then exsanguinated and necropsied. Brain and liver were weighed, and pieces of the left and medial lobes of the liver from five mice/group were removed and fixed in neutral buffered 10% formalin. The remaining portions of the liver from these mice and the whole livers from the other ten males from each group were pooled (two whole livers pooled with one remaining portion) to generate five liver samples. Microsomal preparations were made from these five pooled samples an d anal yz ed for total cytochrome P - 450 content and activities of ethox yr esorufin - O - deethylase (EROD), benzoxy resorufin - O - dealkyl ase (BROD), pentox yr esorufin - O - deethylase (PROD), and UDP - glucuronos yltransferase (UDPGT).Fluopy

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Page 74 of 105 No mortalities were observed, and the re were no clinical signs of toxicity . In the 3 - day exposure group, an overall mean body weight loss of 0.6 g was observed compared to a 0.3 g gain in the controls. Similarly

in the 14 - day

exposure group, a mean body weight loss of 0.3 g was noted on Day 7 compared to a 0.4 g gain in the controls. A slight decrease in food consumption was noted in the 14 - day

treatment group at the beginning of treatment. T4 levels were decreased by 27% after 3 days and by

19% after 14 days of treatment; TSH levels were increased by

9% after 14 days of treatment. No relevant changes in gross or microscopic pathology were observed in the thy roid gland. Absolute and relative (to body) liver weights were increased by 5 - 23% at Day s 4 and 15. The weight increases were associ ated with enlarged and/or dark livers observed at necrops y, and centrilobular to panlobular hepatocellular hypertrophy observed microscopically (4/5 mice at Day 4; 5/5 mice at Day

15). Additionally , an increased number of mitoses was observed in 3/5 males on Day

4. Total cy

tochrome P - 450 content was increased b y 36 - 146%, EROD activity was increased b y 297 - 375%, PROD activity was increased b y 1345 - 1381%, and BROD activity was increased b y 2844 - 4930% on Day s 4 and 15. Incontrast, UDPGT activity was unaffe cted by treatment. In summary , the results of this study demonstrated that phenobarbital administration (by gavage) at 80 mg/kg produced liver toxicity in male C57BL/6J mice by induction of hepatic xenobiotic metabolizing enzy

mes and causing gross and microscopic pathological changes in the liver. Furthermore, it had the potential to modify thy roid hormone balance by

causing a decrease in T4 and a concomitant increase in TSH levels. This study is considered **acceptable /non**  **- guideline**  and provides informati on regarding the effects of oral gavage administration of phenobarb ital on mouse liver and thy roid. **Non -**  **Guideline: ADME**  In a non - guideline study (MRID 47 372510 ), [ py ridyl - 2,6 - 14 C] - AE C656948 (Batch/Lot No. not provided; radiochemical purity > 99%) in aqueous 0.5% Tragacanth was administered by oral gavage to three groups of four Wistar [Hsd/Cpb: WU] rats /sex at a nominal doses of 5 mg/kg. Groups were terminated at 1, 4, or 24 hours post - dosing, and urine, feces, and plasma were collected. Radioactivity

was measured in urine, plasma, carcass, kidneys, liver, gastrointestinal tract (with feces), skin, and perirenal fat. Metabolic profiles were determined for plasma, urine pools, and extracts of liver, kidney , and fat for each time point. The o verall recovery

accounted for 97.2 - 98.8% of the administered dose in males and 97.8 - 99.7% of the administered dose in females. The majority of radioactivity was detected in the gastrointestinal tract (with feces) in the males at all time points; in female s, the majority of radioactivity

was detected in the body without the gastrointestinal tract at 1 hour post - dosing, then in the gastrointestinal tract (with feces) at 4 and 24 hours post - dosing. The highest TRR (total radioactive residues) were detected in the organs and tissues as well as in the combined GIT plus feces at one hour after administration. The distribution of the radioactivity

within the central compartments of the body (e.g. blood, liver, and kidney) was fastFluopy

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Page 75 of 105 and showed a distinctive preference towards the liver as the main organ responsible for metabolism and to a small er extent to the kidney . Residues decreased significantly towards study termination . In comparison to the male rats, the TRR values of organs and tissues from female rats w ere higher at nearl y all points in time. [ Py ridyl - 2,6 - 14 C] - AE C656948 was extensively metabolized and more than 20 metabolites were identified. Molecular cleavage occurred at least in a range of 23 - 34% of the administered dose in both sexes represented by numerous label - specific metabolites. In the various samples, some sex differences were observed with regard to the ratio of py ridyllabel - specific and common metabolites which contained the intact molecular structure. The metabolic transformation of the parent compound was generall y more pronounced in male rats. This was obvious from somewhat higher findings of unchanged parent compound in tissues of female rats compared to male rats. The metabolism of [ py ridyl - 2,6 - 14 C] - AE C656948 in male and female rats was principally

oxidative and took place mainl y at the ethylene bridge of the molecule. The metabolic transformations detected were hydrox yl ation of the ethyllinking group of the parent compound forming AE C656948 - 7 - hydrox y and - 8 - hydroxy metabolite s and one di hydrox yl ated metabolite. Hydroxylation of the phenyl ring of AE C656948 led to AE C656948 - phenol and - 7 - OH -phenol. Hydrol ytic cleavage led to AE C656948 - py ridyl - hydrox ye thyl and - py ridyl - carbox yl ic acid (PCA). Subsequent oxidation of AE C65 6948 - py ridyl - hydrox ye thyl led to mainly AE C656948 -py ridyl - acetic acid (PAA) and to a lesser extent to AE C656948 - ethyl diol, and - hydroxy- PAA. Elimination of water from compounds hydrox yl ated in the ethylene bridge afforded the AE C656948 - Z - olefine and E - olefine (E - and Z - olefine can isomerise into each other). As the double bond of the olefine may be a target for epoxidation and a dihydroxymetabolite which could result from hydroly sis of an epoxid e by epoxid e hydroxylase was observed, the olefine was c onsidered to be of potential toxicological relevance. Several hydrox yl ated metabolites were conjugated with glucuronic acid and , to a lesser extent , with sulfate. This study

is classified **acceptable/non -**  **guideline** and provides information regarding the di stribution, excretion, and metabolism of the test compound following oral dosing in rats. In a non - guideline study (MRID 47 372513 ), [ phenyl - UL 14 C] - AE C656948 (Batch/L ot No. not provided; radiochemical purity >98%) in aqueous 0.5% Tragacanth was administered by oral gavage to eight Wistar [Hsd/Cpb: WU] rats /sex at a nominal dose of 3 mg/kg. Urine and feces were collected at regular intervals up to 168 hours post - dosing. Carbon dioxide and other volatiles from expired air were trapped and sampled at 24 and 48 hours post - dosing. The distribution of total radioactivity in organs and tissues was determined at regular intervals by means of quantitative whole - body autoradiography . Groups of one male and one female each were killed at 1, 4, 8, 24, 48, 72, 120, and 168 hours post - dosing. The animals were fixed in a stretched position and immediately frozen at approximately - 70°C. The frozen carcass was then embedded in a slurry

of carboxy

methylcellulose (7 - 8%), and the slurry was deep frozen. Sections were then cut from the block using a microtome; the sections were attached to adhesive tape and freeze - dried overnight. Four sections from each animal showing the relevant organs and tissues were exposed using imaging plates, and the exposed plates w ere scanned. A controlFluopy

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Page 76 of 105 animal of each sex was similarly dosed, and prepared as above four hours post - dosing to correct for possible chemographic effects. The distribution and elimination of radioactivity in males and females was very similar. In both se xes, [phenyl - UL 14 C ] - AE C656948 was readily absorbed from the gastrointestinal tract and distributed to almost all organs and tissues. The major part of the dosed radioactivity ( 53 - 65%) was excreted with feces ; 32 - 41 % was excreted via the urine. After 72 hours, the fecal excretion was nearly

completed. In the males, o nly a very minor part of the dose was excreted between 72 and 168 hours after dosing. In both sexes, the urinary excretion showed a slightly different behavior , as a clear plateau level was not reached during the sampling period of seven day s and renal excretion was still ongoing on a low level. Less than 0.07 - 0.09 % of the administered dose was expired, demonstrating the stability of the 14 C - phenyl labeling position. For nearl y all organs and tissues, the highest concentration equivalents ( CEQ max) w ere reached during the first day after administration. Infemales, the CEQ max for the nasal mucosa and glandula preputialis peaked after 48 hours. For most organs of the central compartment (e. g. liver, kidney) as well as p eripheral tissues such as fat, muscle, some glands (e.g. adrenal, thyroid, Harderian) and nasal mucosa , the CEQ max was higher than in blood at the times of tmax and t 168 h suggesting a rapid clearance from blood and distribution to organs and tissues of the animals. In the females, the higher values for the organs at t 168 h indicate a still ongoing degradation (liver) and excretion (kidney) and a delayed depletion of test compound related radioactivity from the other organs. The equivalent concentrations in blood and all organs and tissues declined up to the end of the study (168 h post - dosing ) . In males, the highest value was detected in the nasal mucosa (52.1% of the maximum equivalent concentration) . In females, the highest values were detected in the glandula preputialis (24% of the maximum equivalent concentration) and in the nasal mucosa (55%) . In both sexes, the lowest was in the pineal body . This study

is class ified **acceptable/non -**  **guideline** and provides information regarding the distribution and excretion of the test compound following oral dosing in rats. **Non -**  **Guideline** : **Range -**  **Finding, Oral Toxicity** In a range - finding oral toxicity study (MRID 47372515), fluopy ram (99.0% a.i., L ot/Batch PFI 0304) in aqueous 0.4% methylcellulose 400 was administered by dail y oral gavage (5 mL/kg) to two beagle dogs/sex/dose group at dose levels of 0, 30, 150, or 750 mg/kg/day for at least 28 days . Mortality , clinical signs of toxicity, body weights, and food consumption were recorded at regular intervals. Ophthalmoscopic examinations, hematology and clinical chemistry measurements, and urinaly sis were performed prior to administration of the test compound and approximately at the end of treatment. On Day s 29 and 30, all animals were euthanized and subjected to a gross necropsy . Histopathological examinations were also performed (organs/tissues not specified). There were no effects of treatment on mortality , clinical sign s, body weights, body

weight gains, food consumption, ophthalmoscopic examinations, or urinal ys is. At 750 mg/kg/day , diffuse centrilobular to panlobular hepatocellular hypertrophy was observed in 2/2 males (minimal to slight severity) and 2/2 females (sli ght severity), and focal/multifocalFluopy

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Page 77 of 105 eosinophilic inclusion bodies were noted in 1/2 males (minimal severity) and 2/2 females (minimal to slight severity). Additionally at this dose, it was stated that the two males demonstrated decreased ery throcy te count s, hemoglobin, and hematocrit, and a high alkaline phosphatase activity

was observed in one male and one female. The female also exhibited high gamma - glutamyltransferase activity and increased trigl ycerides. It was further stated that absolute and relative (to body) liver weights were clearl y increased in both sexes at 750 mg/kg/day . As no data regarding the magnitude of these changes were presented, the reviewers cannot be certain as to the severity and adverse nature of these findings. At 150 mg/kg/day and below, the only finding reported was a slight increase in liver weights in both sexes at 150 mg/kg/day and in males at 30 mg/kg/day . This finding was considered to be an adaptive response of the liver to exposure to the test compound. **The LOAEL is 750 mg/kg/day, based on liver toxicity as described above in both sexes, and**  **hematology findings in males. The NOAEL is 150 mg/kg/day.** This study is classified **acceptable /non**  **- guideline**  and provides sufficient data to aid in dose level selection for the definitive subchronic oral toxicity study in dogs. In a range - finding oral toxicity study (MRID 47372516), fluopy ram (98.6% a.i., L ot/Batch FLH 999) was administered in the diet to five Wistar (Rj:WI [I OPS HAN]) rats/sex/dose group at dose levels of 0, 50 , 400, or 3200 ppm (equivalent to 0/0, 4.0/4.6, 31.0/36.1, and 254/263 mg/kg/day

in males/females) for 28 day s . Mortality , clinical signs of toxicity , body weights, and food consumption were recorded at regular intervals. On Day 29, blood samples were co llected for measurement of hematology and clinical chemistry

parameters, and all animals were then subjected to a gross necropsy . Histopathological examinations were performed on the adrenal gland, brain, liver, kidney, lung, ovary , pituitary , spleen, tes tis, and thy roid (with parathy

roid). Additionally , microsomal preparations were made from the livers of all rats and anal yz ed for total cy tochrome P - 450 content and activities of ethoxy resorufin - O - deethylase (EROD), benzoxy resorufin - O - dealkylase (BROD), and pentoxy resorufin - O - deethylase (PROD). All animals survived to scheduled termination. There were no effects of treatment on clinical signs. Treatment - related s ys temic effects were observed at 3200 ppm. Body weight gains were decreased b y 12 - 28% in males (Weeks 1 and 3) and by 16 - 29% in females (Weeks 1, 3, and 4). Additionally

in the females, overall body weight gains were decreased b y 14%, and food consumption was reduced by 4 - 10% throughout the study . **L iver**  toxicity

was noted at 3200 ppm. Absolute and relative (to body) liver weights were each increased b y 54% in males, and b y 65% and 73%, respectivel y, in females. These weight increases were associated with enlarged and dark livers at necrops y, and minimal to moderate centrilobular hepatocellul ar hy pertrophy in most animals in both sexes. Total cy tochrome P - 450 levels were increased b y 37% and 41% in males and females, respectivel y, with increases in BROD (1831% in males, 3002% in females) and PROD (941% males, 1526% in females). Males exhibit ed a 30% increase in platelet count and increased prothrombin time (18.0 s treatedFluopy

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Page 78 of 105 vs. 13.4 s controls), and total cholesterol and triglycerides were increased in males (82% and 148%, respectively) and females (84% and 152%, respectivel y). Also at 3200 pp m, absolute and relative thyroid weights were increased by 43% and 41%, respectivel y, in males, with hy pertrophy of the follicular cells noted in 3/5 males. At 400 ppm, absolute and relative liver weights were increased b y 12% and 7%, respectively, in mal es, and b y 16% and 15%, respectively, in females. These changes were not statistically significant. Goss examination showed enlarged and dark livers, and histological evaluation revealed centrilobular hepatocellular hypertrophy. However, the magnitude, in cidence, and severity were lower than those observed at 3200 ppm. Total cytochrome P - 450 levels were increased b y 20% and 15% in males and females, respectivel y, with increases in BROD (698% in males, 842% in females) and PROD (350% in males, 360% in females). The liver effects at 400 ppm were considered as an adaptive response of the liver to the exposure of the test compound and were not adverse. In creased absolute and relative kidney weights were observed in the 400 ppm and above males (19 - 20% absolut e weight; 15 - 18% relative weight). These increased weights were associated with microscopic changes of hyaline droplet nephropathy (basophilic tubules, hyaline droplets in the proximal tubule, and granular casts in the medulla). This nephropathy was cons idered to be due to accumulation of  2μ - globulin, a common toxicological finding in yo ung male rats following exposure to toxicants. Therefore, this finding was not considered relevant to human health considerations. **The LOAEL is 3200 ppm (equivalent to 254/263 mg/kg/day in males/females), based on**  **decreased body weight gains and liver toxicity as described above in both sexes, increased thyroid weights and hypertrophy of the follicular cells in males, and decreased overall body**  **weight gains and food cons umption in females. The NOAEL is 400 ppm (equivalent to**  **31.0/36.1 mg/kg/day in males/females).** This study is classified **acceptable /non**  **- guideline**  . Although it satisfies the majority of the requirements for a repeated dose 28 - day oral toxicity

study in rodents (OPPTS 870.3050; OECD 407), it was stated that as a range - finding study , it was not intended to meet guideline requirements. In a range - finding oral toxicity study (MRID 47372517), fluopy ram (99.4% a.i., L ot/Batch FLH 1046) was administered in the diet to five C57BL/6J mice/sex/dose group at dose levels of 0, 150, 1000, or 5000 ppm (equivalent to 0/0, 24.7/31.1, 162/197, and 747/954 mg/kg/day in males/females) for 28 days . Mortality, clinical signs of toxicity , body weights, and food consumption were recorded at regular intervals. On Day 29, blood samples were collected for measurement of clinical chemistry parameters, and all animals were then subjected to a gross necrops y. Histopathologic al examinations were performed on the adrenal gland, liver, kidney , lung, ovary , spleen, testis, and thy roid (with parathy

roid).Fluopy

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Page 79 of 105 At 5000 ppm, the maximum tolerated dose was exceeded. All males and 3/5 females were euthanized between Days 17 and 27. Thes e animals were observed with reduced motor activity, hunched posture, piloerection, wasted appearance, and/or coldness to the touch in both sexes, with labored respiration in 3/5 males and distended abdomen in 2/3 females, noted mainly on the day of euthan asia or for a few day s prior. A loss of body weight and reduced food intake accompanied these signs. At necrops y, a pale pancreas was observed in all males and in 2/3 females. Rounded borders were observed in the liver in 3/5 males and 1/3 females. Dar k liver was observed in 4/5 males and all females; enlarged liver was observed in 1/5 males and 2/3 females. Thymus size was clearly reduced in 4/5 males and 1/3 females and distended abdomen was noted in 3/5 males. Red liquid was noted in the thoracic c avity in all males. Treatment related effects were seen in the adrenal glands, liver, lungs, spleen, thy mus, and thy

roid gland. Hy pertrophy , vacuolation, and degeneration/necrosis of the zona fasciculata were seen in the adrenal glands in all animals, to gether with perivascular and intra- alveolar hemorrhage and degeneration/inflammation of pulmonary veins in the lungs and ery throid extramedullary hematopoiesis in the spleen. Focal hemorrhage was seen in the thyroid gland in 3/5 males, and decreased cellularity of the cortex and focal hemorrhage were seen in the thymus in all animals where examination was possible. In the liver, hy pertrophy of hepatocy

tes (mainly

centrilobular), hepatocellular eosinophilia, bile duct/oval cell hyp erplasia, focal necrosis and single hepatocellular necrosis were seen in all animals, and centrilobular degeneration/necrosis in 1/5 males. It was considered that premature sacrifice in all males and 1/3 females was associated with intrathoracic hemorrhage, as the majority of the decedents had areas of hemorrhage in the thoracic cavity , thy

roid gland, lungs, and thymus. In the two surviving females dosed at 5000 ppm, distended abdomen was noted between Day s 8 and 10 in one animal. Body weights, body weight gains, and food consumption were similar to controls. Total cholesterol was increased b y 118%, total protein was increased b y 16%, and alanine aminotransferase was increased b y 384%. Absolute and relative (to body) liver weights were increased b y 132 - 144%. Enlarged liver was observed in both females; dark liver was noted in 1/2 females. Hy

pertrophy of the zona fasciculata was seen in the adrenal glands in both females. The following microscopic findings were noted in the liver of both females: moderate hy pertrophy of centrilobular hepatocy tes, slight focal necrosis, minimal hepatocellular eosinophilia, and minimal bile duct/oval cell hy perplasia. Additionally , minimal single cell hepatocellular necrosis was observed in 1/2 females. At 1000 ppm and below, there were no eff ects of treatment on mortality , clinical signs, body weights, body weight gains, or food consumption. **Liver** toxicity

was noted at 1000 ppm. Alanine aminotransferase was increased by 259% in males. Absolute and relative liver weights were increased b y 41 - 46% in males, and by 27 - 38% in females. Enlarged liver was observed in all males and 4/5 females; dark liver was noted in 3/5 males and 2/5 females. The following microscopic findings were noted: hypertrophy of centrilobular hepatocy

tes in 5/5 males (m oderate severity) and 5/5 females (minimal to slight severity); minimal single cell hepatocellular necrosis in 5/5 males; minimal focal necrosis in 3/5 males and 2/5 females; and minimal bile duct/oval cell hy perplasia in 1/5 females.Fluopy

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Page 80 of 105 Additionally

at 1000 ppm, hy

pertrophy of the zona fasciculata was seen in the adrenal glands of 3/5 females. The following findings were observed at 150 ppm. Absolute and relative liver weights were increased b y 18 - 21% in males and 16 - 17% in females, and hy pertrophy of centrilobular hepatocy tes was noted in 5/5 males (minimal to slight severity) and 2/5 females (minimal severity). These minor findings were considered to represent an adaptive change of the liver to exposure to the test compound, and were not considered adverse. **The LOAEL is 1000 ppm (equivalent to 162/197 mg/kg/day in males/females), based on liver toxicity as described above in both sexes, and microscopic findings in the adrenal**  **glands in females. The NOAEL is 150 ppm (equivalent to 24.7/31.1 mg/kg/day in males/females).**  This study is classified **acceptable /non**  **- guideline**  . Although it satisfies the majority of the requirements for a repeated dose 28 - day oral toxicity

study in rodents (OPPTS 870.3050; OECD 407), it was stated that as a range - finding study , i t was not intended to meet guideline requirements.Fluopy

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Page 81 of 105 **A ppendix**  **B. Metabolism Summary Table**  **Table B.1 Tabular Summary of**  **Fluopyram and Metabolites**  **.** Chemical Name (other names in parentheses) and Structure Matrix Percent TRR (PPM) 1 Matrices - Major Residue (>10% TRR) Matrices - Minor Residue (<10% TRR) N - [2 - [3 - chloro - 5 - (trifluoromethyl) - 2 - pyridinyl]ethyl] - 2 - (trifluoromethyl) - benzamide (fluopyram; AE C656948) Grape Fruit: 97.6 (1.82) [PH] 95.8 (1.63) [PY] Leaves: 91.8 (44.11) [PH]

91.3 (39.00) [PY] Potato Tuber: 68.8 (0.006) [PH] 23.2 (0.003) [PY] Leaves: 98.0 (46.69) [PH]

98.1 (21.26) [PY] Bean Green bean: 93.9 (1.31) [PH] 99.3 (3.86) [PY] Foliage: 93.8 (34.39) [PH]

92.3 (35.53) [PY] Succulent bean:

11.4 (< 0.01) [PH] Succulent bean: 4.8 (<0.01) [PY] Dry bean: 12.6 (0.02) [PH] Dry bean: 5.7 (0.02) [PY] Straw: 90.2 (14.94) [PH]

87.1 (16.56) [PY] Pepper, bell Fruit: 48.9 (0.019) [PH] 16.2 (0.010) [PY] 32.8 (0.049) [PY; 4x] Foliage: 64.0 (2.27) [PH]

70.1 (1.64) [PY] Rotational Crops

- Swiss Chard 32.7 - 56.0 (0.055 - 0.302) [PH]

37.3 - 56.7 (0.081 - 0.323) [PY]

- Turnip Root 77.7 - 83.5 (0.010 - 0.054)

[PH; 30 - and 139 - day] 86.1 - 94.6 (0.010 - 0.031) [PY]

- Turnip Tops 54.3 - 68.4 (0.060 - 0.605) [PH]

59.9 - 70.6 (0.061 - 0.399) [PY]

- Wheat Forage 59.2 - 74.9 (0.075 - 0.588) [PH]

70.2 - 77.9 (0.113 - 0.442) [PY]

- Wheat Hay 57.5 - 76.9 (0.748 - 1.370) [PH]

66.9 - 78.9 (0.473 - 1.421) [PY]

- Wheat Straw 50.1 - 74.1 (0.516 - 4.557) [PH]

58.3 - 73.9 (0.945 - 4.926) [PY]

- Wheat Grain 28.4 - 61.9 (0.007 - 0.104) [PH]

20.4 - 33.4 (0.012 - 0.137) [PY] N H O N

Cl C F 3 C F 3Fluopy

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Page 82 of 105 **Table B.1 Tabular Summary of**  **Fluopyram and Metabolites**  **.** Chemical Name (other names in parentheses) and Structure Matrix Percent TRR (PPM) 1 Matrices - Major Residue (>10% TRR) Matrices - Minor Residue (<10% TRR) fluopyram (continued) Poultry (hen) Egg (days 1 - 6): 14.7 (0.023) [PY] Egg (days 1 - 6): 0.7 (0.024) [PH] Egg (days 7 - 14):

1.4 (0.026) [PH] 6.0 (0.017) [PY] Fat: 12.2 (0.061) [PY] Fat: 2.5 (0.042) [PH] Muscle: 1.0 (0.001) [PY] Ruminant (goat) Milk: 42.5 (0.023) [PY] Milk: 0.7 - 1.7 (0.002 - 0.004) [PH] Fat: 18.2 (0.073) [PH]

46.4 (0.173) [PY] Liver: 0.6 (0.047) [PH] 7.7 (0.110) [PY] Muscle: 27.3 (0.011) [PY] Kidney: 0.4 (0.009) [PH] N - {2 - [3 - chloro - 1 - oxido - 5 - (trifluoromethyl) pyridin 2 - yl]ethyl} - 2 - (trifluoromethyl) - benzamide (AE C656948 -N - oxide; M01) Pepper, bell Foliage: 2.9 (0.07) [PY]

N - {(E) - 2 - [3 - chloro - 5 - (trifluoromethyl)pyridin - 2 - yl]ethenyl} - 2 - (trifluoromethyl) - benzamide (AE C656948 - E - olefine; BCS - AA10627; M02) Poultry (hen) Egg (days 1 - 6): 1.0 (0.001) [PY] Egg (days 7 - 14):

1.0 (0.003) [PY] Muscle: 3.9 (0.002) [PY] Fat: 12.4 (0.062) [PY] Fat: 2.3 (0.037) [PH] Liver: 11.8 (0.063) [PY] Liver: 0.3 (0.028) [PH] Ruminant (goat) Milk: 2.0 (0.001) [PY] Muscle: 1.9 (0.001) [PY] Fat: 8.6 (0.034) [PH]

2.2 (0.008) [PY] Liver: 0.3 (0.021) [PH]

4.1 (0.058) [PY] N H O N +

Cl C F 3 C F 3 O

N H O N

Cl C F 3 C F 3Fluopy

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Page 83 of 105 **Table B.1 Tabular Summary of**  **Fluopyram and Metabolites**  **.** Chemical Name (other names in parentheses) and Structure Matrix Percent TRR (PPM) 1 Matrices - Major Residue (>10% TRR) Matrices - Minor Residue (<10% TRR) N - {(Z) - 2 - [3 - chloro - 5 - (trifluoromethyl)pyridin - 2 - yl]ethenyl} - 2 - (trifluoromethyl) - benzamide (AE C656948 - Z - olefine; BCS - AA10650; M03) Poultry (hen) Egg (days 7 - 14): 15.4 (0.044) [PY] Egg (days 1 - 6): 0.5 (0.010) [PH] 4.1 (0.006) [PY] Egg (days 7 - 14):

1.2 (0.044) [PH] Muscle: 33.0 (0.016) [PY] Muscle: 0.5 (0.015) [PH] Fat: 25.9 (0.425) [PH]

70.5 (0.350) [PY] Liver: 0.2 (0.016) [PH] 1.9 (0.010) [PY] Ruminant (goat) Milk: 12.9 (0.007) [PY] Milk: 0.7 (0.002) [PH]

Muscle: 21.6 (0.009) [PY] Liver: 0.2 (0.015) [PH] 5.7 (0.081) [PY] Fat: 13.1 (0.052) [PH]

33.7 (0.125) [PY]

AE C656948 -phenol - glc (M06) Rotational Crops

- Turnip tops 10.1 - 16.2 (0.010 - 0.092) [PH]

12.0 - 18.4 (0.014 - 0.068) [PY]

AE C656948 -phenol - GA (M07) Ruminant (goat) Liver: 0.8 (0.068) [PH] 2.0 (0.029) [PY] Kidney: 1.2 (0.027) [PH]

3.2 (0.013) [PY] N H O

N Cl

C F 3 C F 3

N O N

Cl C F 3 C F 3

O H O H O H O O H O

N H O N

Cl C F 3 C F 3

O O H O H O H O O H OFluopy

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Page 84 of 105 **Table B.1 Tabular Summary of**  **Fluopyram and Metabolites**  **.** Chemical Name (other names in parentheses) and Structure Matrix Percent TRR (PPM) 1 Matrices - Major Residue (>10% TRR) Matrices - Minor Residue (<10% TRR) N - {2 - [3 - chloro - 5 - (trifluoromethyl)pyridin - 2 - yl] - 2 - hydroxyethyl} - 2 - (trifluoromethyl) benzamide (AE C656948 - 7 - hydroxy; BCS - AA10065; M08) Grape Fruit: 0.3 (<0.01) [PH/PY] Leaves: 0.7 (0.35) [PH]

1.0 (0.43) [PY] Potato Tuber: 1.2 (<0.001) [PH] 1.1 (<0.001) [PY] Leaves: 0.8 (0.36) [PH]

0.6 (0.12) [PY] Bean Foliage: 0.7 (0.26) [PH] 1.6 (0.60) [PY] Succulent bean:

4.0 (<0.01) [PH/PY] Dry bean: 2.5 (<0.01) [PH] 4.0 (0.01) [PY] Straw: 0.7 (0.12) [PH]

1.1 (0.20) [PY] Pepper, bell Fruit: 9.0 (0.003) [PH] 3.7 (0.006) [PY; 4x] Foliage: 6.8 (0.24) [PH]

5.1 (0.12) [PY] Rotational Crops

- Swiss chard 20.9 - 35.4 (0.057 - 0.134) [PH]

28.0 - 38.6 (0.081 - 0.160) [PY]

- Turnip roots 3.6 - 4.1 (0.001 - 0.002) [PH; 30 - and 139 - day] 3.1 - 6.1 (≤0.001) [PY]

- Turnip tops 3.3 - 8.2 (0.007 - 0.029) [PH] 3.5 - 8.3 (0.005 - 0.020) [PY]

- Wheat forage 2.4 - 6.3 (0.002 - 0.030) [PH] 2.1 - 5.6 (0.003 - 0.018) [PY]

- Wheat hay 12.6 (0.193) [PH; 280 - day] 4.3 - 5.2 (0.059 - 0.077) [PH; 30 - and 139 - day] 3.8 - 8.6 (0.057 - 0.068) [PY]

- Wheat straw 12.3 (0.127) [PH; 280 - day]

10.1 (0.164) [PY; 280 - day] 5.6 - 6.0 (0.208 - 0.346) [PH; 30 - and 139 - day] 6.1 - 7.4 (0.156 - 0.494) [PY; 30 - and 139 - day]

- Wheat grain 1.3 - 3.4 (0.001 - 0.005) [PH] 0.8 - 2.3 (0.001 - 0.008) [PY] Poultry (hen) Egg (days 1 - 6): 3.9 (0.006) [PY] Egg (days 7 - 14):

0.9 (0.002) [PY] Liver: 0.8 (0.004) [PY] O H N H O N

Cl C F 3 C F 3Fluopy

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Page 85 of 105 **Table B.1 Tabular Summary of**  **Fluopyram and Metabolites**  **.** Chemical Name (other names in parentheses) and Structure Matrix Percent TRR (PPM) 1 Matrices - Major Residue (>10% TRR) Matrices - Minor Residue (<10% TRR) AE C656948 - 7 - hydroxy , continued Ruminant (goat) Milk: 16.2 (0.009) [PY] Milk: 0.8 - 1.8 (0.002 - 0.004) [PH] Muscle: 21.6 (0.009) [PY] Muscle: 0.3 (0.002) [PH] Fat: 12.8 (0.048) [PY] Fat: 7.7 (0.031) [PH] Liver: 0.9 (0.073) [PH]

6.1 (0.086) [PY] Kidney: 0.6 (0.014) [PH]

1.0 (0.004) [PY] 1 - [3 - chloro - 5 - (trifluoromethyl)pyridin - 2 - yl] - 2 - {[2 - (trifluoromethyl) - benzoyl]amino}ethyl beta D - glucopyranosiduronic acid (AE C656948 - 7 - OH - GA; M09) Ruminant (goat) Milk: 0.6 (0.002) [PH] 4.8 (0.003) [PY] Muscle: 11.7 (0.005) [PY] Muscle: 0.3 (0.002) [PH] Liver: 26.3 (0.375) [PY] Liver: 4.3 (0.363) [PH] Kidney: 51.4 (0.208) [PY] Kidney: 9.4 (0.216) [PH]

1 - [3 - chloro - 5 - (trifluoromethyl)pyridin - 2 - yl] - 2 - ({[2 - (trifluoromethyl)phenyl] - carbonyl}amino)ethyl hydrogen sulfate (AE C656948 - 7 - OH - SA; M10) Rotational Crops

- Swiss chard 12.1 - 15.6 (0.020 - 0.059)

[PH; 139 - and 280 - day] 13.5 - 16.8 (0.029 - 0.058) [PY; 139 - and 280 - day] 7.0 (0.038) [PH; 30 - day] 7.9 (0.045) [PY; 30 - day]

- Turnip tops 0.7 - 1.0 (0.001 - 0.006) [PH; 30 - and 139 - day] 0.4 - 0.7 (<0.001 - 0.004) [PY] O O H O H

O H O O H N H O N

Cl C F 3 C F 3

O

O

N H O N

Cl C F 3 C F 3

S O

O O HFluopy

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Page 86 of 105 **Table B.1 Tabular Summary of**  **Fluopyram and Metabolites**  **.** Chemical Name (other names in parentheses) and Structure Matrix Percent TRR (PPM) 1 Matrices - Major Residue (>10% TRR) Matrices - Minor Residue (<10% TRR) N - [2 - [3 - chloro - 5 - (trifluoromethyl)pyridin - 2 - yl] - 2 - (beta - D glucopyranosyloxy)ethyl] - 2 - (trifluoromethyl) benzamide (AE C656948 - 7 - hydroxy glc; M11) Grape Leaves: 0.7 (0.35) [PH] 0.8 (0.34) [PY] Bean Foliage: 0.4 (0.15) [PH] 0.6 (0.25) [PY] Succulent bean:

1.7 (<0.01) [PH] 1.4 (<0.01) [PY] Dry bean: 1.3 (<0.01) [PY] Straw: 0.4 (0.07) [PH]

0.7 (0.14) [PY] Pepper, bell Fruit: 3.9 (0.001) [PH] Foliage: 8.9 (0.31) [PH]

9.2 (0.22) [PY] Rotational Crops

- Swiss chard 1.0 - 1.8 (0.002 - 0.007) [PH] 0.9 - 1.8 (0.003 - 0.006) [PY]

- Turnip tops 0.4 - 0.9 (0.001 - 0.004) [PH; 30 - and 139 - day] 0.3 - 1.6 (0.001 - 0.002) [PY]

- Wheat forage 2.0 - 3.4 (0.002 - 0.016) [PH] 1.0 - 3.0 (0.002 - 0.005) [PY]

- Wheat hay 1.4 - 3.4 (0.023 - 0.052) [PH] 0.9 - 3.0 (0.016 - 0.024) [PY]

- Wheat straw 2.8 - 6.9 (0.071 - 0.169) [PH] 2.3 - 3.7 (0.059 - 0.203) [PY]

- Wheat grain 1.2 (0.002) [PH; 30 - day] O O H O H

O H O O H N H O N

Cl C F 3 C F 3Fluopy

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Page 87 of 105 **Table B.1 Tabular Summary of**  **Fluopyram and Metabolites**  **.** Chemical Name (other names in parentheses) and Structure Matrix Percent TRR (PPM) 1 Matrices - Major Residue (>10% TRR) Matrices - Minor Residue (<10% TRR) 1 - [3 - chloro - 5 - (trifluoromethyl)pyridin - 2 - yl] - 2 - {[2 - (trifluoromethyl) - benzoyl]amino}ethyl 6 - O - (carboxyacetyl) -beta - D glucopyranoside (AE C656948 - 7 - hydroxy glc - MA ; M12) Bean Foliage: 2.2 (0.82) [PH] 3.2 (1.22) [PY] Succulent bean:

2.2 (<0.01) [PH] Straw: 4.1 (0.68) [PH]

4.7 (0.90) [PY] Pepper, bell Foliage: 0.7 (0.02) [PH] Rotational Crops

- Swiss chard 0.3 (0.001) [PH; 30 - day]

- Turnip tops 2.0 - 2.9 (0.002 - 0.019) [PH] 2.5 - 4.0 (0.004 - 0.014) [PY]

- Wheat forage 3.2 - 9.7 (0.003 - 0.049) [PH] 3.3 - 8.6 (0.005 - 0.036) [PY]

- Wheat hay 11.1 (0.170) [PH; 280 - day]

10.7 (0.075) [PY; 280 - day] 6.1 - 6.8 (0.077 - 0.107) [PH; 30 - and 139 - day] 5.4 - 8.4 (0.081 - 0.097) [PY; 30 - and 139 - day]

- Wheat straw 11.8 (0.190) [PY; 280 - day] 5.5 - 9.2 (0.095 - 0.340) [PH] 6.0 - 6.7 (0.153 - 0.448) [PY; 30 - and 139 - day]

- Wheat grain 1.7 (0.003) [PH; 30 - day] O O H O H O H O N H O N

Cl C F 3 C F 3

O O O H OFluopy

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Page 88 of 105 **Table B.1 Tabular Summary of**  **Fluopyram and Metabolites**  **.** Chemical Name (other names in parentheses) and Structure Matrix Percent TRR (PPM) 1 Matrices - Major Residue (>10% TRR) Matrices - Minor Residue (<10% TRR) N - {2 - [3 - chloro - 5 - (trifluoromethyl)pyridin - 2 - yl] - 1 - hydroxyethyl} - 2 - (trifluoromethyl) benzamide (AE C656948 - 8 - hydroxy; M18) Grape Leaves: 0.6 (0.28) [PH] 0.8 (0.34) [PY] Bean Foliage: 0.3 (0.11) [PH] 0.5 (0.21) [PY] Succulent bean:

6.0 (<0.01) [PH] 2.7 (<0.01) [PY] Dry bean: 2.1 (<0.01) [PH] 1.6 (<0.01) [PY] Straw: 0.6 (0.09) [PH]

0.9 (0.17) [PY] Pepper, bell Foliage: 0.5 (0.02) [PH] Rotational Crops

- Swiss chard 0.7 - 1.4 (0.002 - 0.004) [PH] 0.9 - 1.3 (0.003 - 0.005) [PY]

- Turnip roots 0.9 - 2.3 (≤0.001) [PH; 30 - and 139 - day] 1.5 (0.001) [PY; 30 - day]

- Turnip tops 0.3 - 0.4 (<0.001 - 0.003) [PH] 0.3 - 0.5 (<0.001 - 0.002) [PY]

- Wheat forage 0.3 - 0.5 (<0.001 - 0.004) [PH] 0.7 (0.004) [PY; 139 - day]

- Wheat hay 0.6 - 1.1 (0.009 - 0.016) [PH] 0.4 - 0.7 (0.006 - 0.007) [PY; 30 - and 139 - day]

- Wheat straw 1.3 - 1.4 (0.014 - 0.087) [PH] 1.2 - 1.7 (0.028 - 0.087) [PY]

- Wheat grain 0.9 (0.001) [PH; 30 - day] 1 - [3 - chloro - 5 - (trifluoromethyl)pyridin - 2 - yl] - 1 - {[2 - (trifluoromethyl) - benzoyl]amino}ethyl 6 - O - (carboxyacetyl) -beta - D glucopyranoside (AE C656948 - 8 - hydroxy glc - MA ; M19) Rotational Crops

- Wheat forage 1.0 - 2.2 (0.001 - 0.009) [PH] 1.2 - 1.7 (0.003 - 0.007) [PY; 139 - and 280 - day]

- Wheat hay 0.8 - 1.4 (0.014 - 0.021) [PH] 0.6 - 1.7 (0.010 - 0.014) [PY]

- Wheat straw 0.7 - 1.2 (0.043 - 0.046) [PH; 30 - and 139 - day] 0.4 - 1.2 (0.019 - 0.028) [PY] N H O N

Cl C F 3 C F 3 O H

O O H O H O H O O O O H O

N H O N

Cl C F 3 C F 3Fluopy

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Page 89 of 105 **Table B.1 Tabular Summary of**  **Fluopyram and Metabolites**  **.** Chemical Name (other names in parentheses) and Structure Matrix Percent TRR (PPM) 1 Matrices - Major Residue (>10% TRR) Matrices - Minor Residue (<10% TRR) 2 - [3 - chloro - 5 - (trifluoromethyl)pyridin - 2 - yl] - 1 - {[2 - (trifluoromethyl) - benzoyl]amino}ethyl beta D - glucopyranosiduronic acid (AE C656948 - 8 - OH - GA; M20) Ruminant (goat) Milk: 1.1 (0.001) [PY] Muscle: 2.5 (0.001) [PY] Liver: 2.1 (0.174) [PH]

9.5 (0.136) [PY] Kidney: 17.7 (0.071) [PY] Kidney: 3.6 (0.082) [PH]

AE C656948 - di - OH - GA (M21) Ruminant (goat) Kidney: 0.7 (0.015) [PH] 1.7 (0.007) [PY] Liver: 1.0 (0.014) [PY]

AE C656948 - hydroxy glyc - gluc (M22) Bean Dry bean: 10.4 (0.01) [PH] Dry bean: 5.6 (0.02) [PY] Succulent bean:

6.7 (<0.01) [PH] 4.5 (<0.01) [PY] Straw: 0.2 (0.03) [PY] O H O H O H O O H

O O

N H O N

Cl C F 3 C F 3

O H

O H N H O N

Cl C F 3 C F 3

O H

O H O H O O H O O

- H 2 O

N H O N

Cl C F 3 C F 3

glyc = glycoside

gluc = glucuronic acid glyc - glucFluopy

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Page 90 of 105 **Table B.1 Tabular Summary of**  **Fluopyram and Metabolites**  **.** Chemical Name (other names in parentheses) and Structure Matrix Percent TRR (PPM) 1 Matrices - Major Residue (>10% TRR) Matrices - Minor Residue (<10% TRR) 2 - (trifluoromethyl) - benzamide (AE C656948 -benzamide; AE F148815; BCS AA10014; M25) Grape Fruit: 0.7 (0.01) [PH] Potato Tuber: 7.1 (0.001) [PH] Leaves: 0.5 (0.23) [PH] Bean Succulent bean: 51.6 (0.04) [PH] Foliage: 0.5 (0.17) [PH] Dry bean: 64.0 (0.08) [PH] Straw: 0.6 (0.10) [PH] Pepper, bell Fruit: 16.1 (0.006) [PH]

Foliage: 10.1 (0.36) [PH] Rotational Crops

- Swiss chard 10.3 - 11.1 (0.017 - 0.060)

[PH; 30 - and 280 - day] 7.4 (0.028) [PH; 139 - day]

- Turnip roots 4.0 - 5.8 (0.001 - 0.003) [PH; 30 - and 139 - day]

- Turnip tops 11.7 (0.012) [PH; 280 - day] 5.6 - 9.7 (0.006 - 0.086) [PH; 30 - and 139 - day]

- Wheat forage 3.5 - 8.0 (0.006 - 0.028) [PH]

- Wheat hay 3.7 - 6.2 (0.041 - 0.095) [PH]

- Wheat straw 2.8 - 6.6 (0.068 - 0.169) [PH]

- Wheat grain 3.3 - 5.9 (0.001 - 0.007) [PH] Poultry (hen) Egg (days 1 - 6): 95.8 (1.735) [PH] Egg (days 7 - 14):

96.3 (3.447) [PH] Muscle: 98.6 (3.233) [PH] Fat: 68.6 (1.126) [PH] Liver: 92.3 (8.737) [PH] Ruminant (goat) Milk: 88.4 - 89.2 (0.202 - 0.246) [PH] Muscle: 97.6 (0.719) [PH] Fat: 49.1 (0.196) [PH] Liver: 82.8 (6.941) [PH] Kidney: 77.1 (1.769) [PH] AE C656948 -benzamide SA (M31) Ruminant (goat) Milk: 4.3 (0.010 - 0.012) [PH] Muscle: 0.7 (0.005) [PH] Liver: 1.6 (0.133) [PH] Kidney: 2.5 (0.058) [PH] N H 2 O C F 3

N H 2

O C F 3 O S O O H OFluopy

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Page 91 of 105 **Table B.1 Tabular Summary of**  **Fluopyram and Metabolites**  **.** Chemical Name (other names in parentheses) and Structure Matrix Percent TRR (PPM) 1 Matrices - Major Residue (>10% TRR) Matrices - Minor Residue (<10% TRR) 2 - (trifluoromethyl) - benzoic acid (AE C656948 -benzoic acid; M33) Rotational Crops

- Turnip Root 3.7 (0.002) [PH; 30 - day]

- Turnip Tops 0.6 (0.005) [PH; 30 - day]

- Wheat Forage 0.4 - 1.7 (0.002 - 0.003) [PH; 30 - and 139 - days]

- Wheat Hay 0.3 - 0.6 (0.004 - 0.011) [PH; 30 - and 139 - days]

- Wheat Grain 13.0 - 13.6 (0.003 - 0.007)

[PH; 139 - and 280 - day] 6.9 (0.012) [PH; 30 - day] Poultry (hen) Liver: 0.3 (0.024) [PH] 2 - [3 - chloro - 5 - (trifluoromethyl)pyridin - 2 - yl]ethyl beta - D glucopyranoside (AE C656948 - hydroxyethyl - glc; M35) Bean Foliage: 0.2 (0.06) [PY] Succulent bean:

1.9 (<0.01) [PY] Dry bean: 3.1 (0.01) [PY]

2 - [3 - chloro - 5 - (trifluoromethyl)pyridin - 2 - yl]ethyl 6 - O -beta - D glucopyranosyl -beta - D glucopyranoside (AE C656948 - hydroxyethyl - di - glc; M36) Pepper, bell Foliage: 7.0 (0.16) [PY]

O H O C F 3

O H O H O H O O H O N Cl C F 3

O O H O H O H O

O H

O

O H O H O H O N

Cl C F 3Fluopy

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Page 92 of 105 **Table B.1 Tabular Summary of**  **Fluopyram and Metabolites**  **.** Chemical Name (other names in parentheses) and Structure Matrix Percent TRR (PPM) 1 Matrices - Major Residue (>10% TRR) Matrices - Minor Residue (<10% TRR) 2 - [3 - chloro - 5 - (trifluoromethyl)pyridin - 2 - yl]ethyl beta - D glucopyranosiduronic acid (AE C656948 - hydroxyethyl - GA; M37) Ruminant (goat) Kidney: 4.3 (0.017) [PY]

[3 - chloro - 5 - (trifluoromethyl)pyridin - 2 - yl]acetic acid (AE C656948 -pyridyl acetic acid (PAA) ; M40) Bean Succulent bean: 29.5 (0.05) [PY] Dry bean: 22.6 (0.07) [PY] Straw: 0.2 (0.04) [PY] Pepper, bell Fruit: 9.8 (0.015) [PY; 4x] Poultry (hen) Egg (days 1 - 6): 6.4 (0.010) [PY] Egg (days 7 - 14):

3.7 (0.011) [PY] Liver: 1.3 (0.007) [PY] Ruminant (goat) Kidney: 8.6 (0.035) [PY] AE C656948 - PAA glycoside (M42) Pepper, bell Fruit: 38.0 (0.023) [PY] 32.2 (0.048) [PY; 4x]

3 - chloro - 5 - (trifluoromethyl)pyridine 2 - carboxylic acid (AE C656948 -pyridyl carboxylic acid (PCA); M43) Grape Fruit: 0.9 (0.02) [PY] Leaves: 0.8 (0.33) [PY] Potato Tubers: 49.8 (0.006) [PY] Leaves: 0.5 (0.11) [PY] Bean Succulent bean: 31.0 (0.05) [PY] Foliage: 0.5 (0.19) [PY] Dry bean: 32.5 (0.10) [PY] Straw: 0.6 (0.11) [PY] Pepper, bell Fruit: 43.5 (0.026) [PY] 19.5 (0.029) [PY; 4x] Rotational Crops

- Swiss chard 0.2 - 1.8 (<0.001 - 0.010) [PY]

- Turnip roots 6.0 (0.002) [PY; 30 - day]

- Turnip tops 1.1 - 4.3 (0.001 - 0.024) [PY]

- Wheat forage 16.5 (0.026) [PY; 30 - day] 0.9 - 1.0 (0.002 - 0.006) [PY; 139 - and 280 - day]

- Wheat hay 0.5 - 4.9 (0.004 - 0.088) [PY]

- Wheat straw 0.9 (0.060) [PY; 30 - day]

- Wheat grain 16.4 - 55.9 (0.011 - 0.230) [PY] O O H O H O H O O H

N

Cl O C F 3

N Cl C F 3 O H O

N

Cl C F 3 O O g l yc

O H N Cl C F 3

OFluopy

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Page 93 of 105 **Table B.1 Tabular Summary of**  **Fluopyram and Metabolites**  **.** Chemical Name (other names in parentheses) and Structure Matrix Percent TRR (PPM) 1 Matrices - Major Residue (>10% TRR) Matrices - Minor Residue (<10% TRR) 3 - (methylsulfinyl) - 5 - (trifluoromethyl) pyridine 2 - carboxylic acid (AE C656948 - methyl sulfoxide; M45) Rotational Crops

- Swiss chard 0.4 - 0.5 (0.001 - 0.003) [PY]

- Wheat forage 2.0 - 2.2 (0.003 - 0.012) [PY; 139 - and 280 - day]

- Wheat hay 3.5 - 4.7 (0.025 - 0.046) [PY; 139 - and 280 - day]

- Wheat straw 1.2 (0.019 - 0.031) [PY; 139 - and 280 - day]

- Wheat grain 20.3 - 49.0 (0.008 - 0.035)

[PY; 139 - and 280 - day] 1.2 (0.005) [PY; 30 - day]

1 Fluopyram was radiolabeled in the phenyl ring [PH] or on the pyridyl ring [PY] . Grape; 47372524 - 47372525; three applications at total rate of 0.446 lb ai/A (500 g ai/ha); 1x label rate; postemergence (BBCH 17 - 19, 71, and 81); 18 - day PHI (fruit) and 19 - day PHI (leaves). Potato; 47372528 - 47372529; three applications at total rate of 0.446 lb ai/A (500 g ai/ha); postemergence (BBCH 16, 55, and 71) ; 51 - day PHI. Bean; 47372526 - 47372527; two applications at total rate of 0.446 lb ai/A (500 g ai/ha); postemergence (BBCH 51 and 75); 4 - day PHI for green bean and foliage (BBCH 75), and 29 - day PHI for mature succulent bean, dried bean, and straw. Pepper, b ell; 47372530 - 47372531; 5 mg ai/plant and 20 mg ai/plant, drip irrigation to plants grown on stone wool; x rate compared to label rate for tomato could not be determined; postemergence BBCH 15 - 17; fruit harvested at 55 to 96 days posttreatment and combined for analysis; 97 - day PHI for remaining plant material; results for fruit treated at exaggerated rate reported only for PY - label. Rotational Crops (turnip, Swiss chard & wheat); 47372631 - 32; 0.46 - 0.48 lb ai/A (514 - 534 g ai/ha); ~1x label rate; applied to b are soil; 30 - , 139 - and 280 - day PBIs ; metabolite levels across all PBIs are reported unless otherwise noted . Hen; 47372532 - 33; 25.96 - 26.42 ppm; 14 days dosing; 24 - hour PSI. Goat; 47372534 - 35; 44.62 - 46.26 ppm; 5 days dosing; 24 - hour PSI. For milk, result s represent morning and evening samples for PH study, and evening samples only for PY study.

C F 3 N S

O O H O C H 3Fluopy

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Page 94 of 105 **Appendix C. Physical/Chemical Properties**  **Table C1. Physicochemical Properties of Fluopyram**  **.** Parameter Value Reference Melting point 118 oC MRID 47372240 pH 6.6 (1% aqueous solution; pure substance) MRID 47372236 Density 1.53 MRID 47372242 Water solubility (20 °C) Distilled water (pH 6.7) = 16 mg/L pH 4 = 15 mg/L pH 7 = 16 mg/L pH 9 = 15 mg/L MRID 47372247 Solvent solubility (g/L at 20 °C) heptane 0.66 toluene 62.2 dichloromethane >250 methanol >250 acetone >250 ethyl acetate >250 dimethyl sulfoxide >250 MRID 47372248

Vapor pressure 1.2 x 10 - 6 Pa at 20 oC 3.1 x 10 - 6 Pa at 25 oC 2.9 x 10 - 4 Pa at 50 oC MRID 47372249 Dissociation constant (pKa) 0.5 (23 oC) MRID 47372243 Octanol/water partition coefficient Log(KOW) 3.3 MRID 47372245 UV/visible absorption spectrum Peak max at 270 nm MRID 47372237Fluopy

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Page 95 of 105 **Appendix D. 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 to determine their dermal and inhalation exposure. Many such studies, involving exposure to many different pesticides, comprise generic pesticide exposure databases such as PHED , ARTF, ORETF and AH ETF . EPA has reviewed all the studies supporting these multi -pesticide generic exposure databases, and has found no clear and convincing evidence that the conduct of any of them was either fundamentally unethical or significantl y deficient relative to the ethical standards prevailing at the time the research was conducted. All applicable requirements of EPA’s Rule for the Protection of Human Subjects of Research (40 CFR Part 26) have been satisfied, and there is no regulatory barrier to continued rel iance on these studies.Fluopy

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Page 96 of 105 **Appendix E**  **. Occupational Exposure/Risk Summary Tables Table**  **E1 . Non**  **- Cancer Occupational Short** **- and Intermediate**  **- Term**  **Dermal and Inhalation Exposures and Risk Estim**  **ates For Fluopyram** Exposure Scenario Crop or Target Application Rate a (lb ai/A) Ar ea

Treated Daily b (A/day) Unit Exposure d Daily Exposure e (mg/kg/day) MOE f

Baseline Dermal c (mg/lb ai) PPE - G

Dermal c (mg/lb ai) Baseline

Inhalation c (μg/lb ai) Baseline

Dermal PPE - G

Dermal Baseline

Inhalation Baseline

Dermal PPE - G

Dermal Baseline

Inhalation **Mixer/Loader** Mixing/Loading Liquid Concentrates for Aerial Applications Peanut, Strawberry, Tree Nuts 0.22 350 0.22 0.0376 0.219 0.242 0.0414 0.000241 1,200 7,300 60,000 Dried Beans 0.13 0.143 0.0244 0.000142 2,100 12,000 100,000 Cherry, Potato 0.092 0.101 0.0173 0.000101 3,000 17,000 140,000 Mixing/Loading Liquid Concentrates for Chemigation Applications Apples, Peanut, Strawberry, Tree Nuts , Watermelon (field and greenhouse), Viniferous variety Grapes 0.22 350 0.22 0.0376 0.219 0.242 0.0414 0.000241 1,200 7,300 60,000 Potato 0.18 0.198 0.338 0.000197 1,500 8,900 74,000 Dried Beans 0.13 0.143 0.0244 0.000142 2,100 12,000 100,000 Sugar Beet 0.11 0.121 0.0207 0.000120 2,500 15,000 120,000 Cherry 0.092 0.101 0.0173 0.000101 3,000 17,000 140,000 Mixing/Loading Liquids Concentrates for Gr oundboom Applications Apples, Peanut, Strawberry, Tree Nuts , Watermelon (field and greenhouse), Viniferous variety Grapes 0.22 80 0.22 0.0376 0.219 0.0553 0.00945 0.0000551 5,400 32,000 260,000 Potato 0.18 0.0452 0.00773 0.0000451 6,600 39,000 320,000 Dried Beans 0.13 0.0327 0.00559 0.0000325 9,200 54,000 450,000 Sugar Beet 0.11 0.0277 0.00473 0.0000275 11,000 63,000 530,000 Cherry 0.092 0.0231 0.00395 0.0000230 13,000 76,000 630,000 Mixing/Loading Liquids Concentrates for Airblast Applications Apples, Tree Nuts ,

Viniferous variety Grapes 0.22 40 0.22 0.0376 0.219 0.0277 0.00473 0.0000275 11,000 63,000 530,000 Cherry 0.092 0.0116 0.00198 0.0000115 26,000 150,000 1,300,000 **Applicator** Applying Sprays via Aerial Equipment Peanut, Strawberry, Tree Nuts 0.22 350 0.005 No Data 0.068 0.0055 0 No Data 0.0000748 5 5 ,000 No Data 190,000 Dried Beans 0.13 0.00 325 No Data 0.0000 442 92 ,000 No Data 190,000 Cherry, Potato 0.092 0.00 230 No Data 0.0000 313 130 ,000 No Data 190,000 Applying Sprays via Gr oundboom Equipment Apples, Peanut, Strawberry, Tree Nuts , Watermelon (field and greenhouse), Viniferous variety Grapes 0.22 80 0.0 786 0.01 61 0. 3 4 0.0198 0.00405 0.0000855 15,000 74,000 170,000 Potato 0.18 0.0162 0.00331 0.0000699 19,000 91,000 210,000 Dried Beans 0.13 0.0117 0.00239 0.0000505 26,000 130,000 290,000 Sugar Beet 0.11 0.00988 0.00202 0.0000427 30,000 150,000 340,000 Cherry 0.092 0.00826 0.00169 0.0000357 36,000 180,000 410,000Fluopy

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Page 97 of 105 **Table E1**  **. Non -**  **Cancer Occupational Short -**  **and Intermediate -**  **Term Dermal and Inhalation Exposures and Risk**  **Estim ates For Fluopyram**  Exposure Scenario Crop or Target Application Rate a (lb ai/A) Ar ea

Treated Daily b (A/day) Unit Exposure d Daily Exposure e (mg/kg/day) MOE f

Baseline Dermal c (mg/lb ai) PPE - G

Dermal c (mg/lb ai) Baseline

Inhalation c (μg/lb ai) Baseline

Dermal PPE - G

Dermal Baseline

Inhalation Baseline

Dermal PPE - G

Dermal Baseline

Inhalation Applying Sprays via Airblast Equipment Apples, Tree Nuts , Viniferous variety Grapes 0.22 40 0.36 0.24 4.5 0.0453 0.0302 0.000566 6,600 9,900 26,000 Cherry 0.092 0.0189 0.0126 0.000237 16,00 24,000 61,000 **Flagger** Flagging for Aerial Sprays Applications Peanut, Strawberry, Tree Nuts 0.22 350 0.011 NA 0.35 0.0121 NA 0.000385 25,000 NA 38,000 Dried Beans 0.13 0.00715 NA 0.000228 42,000 NA 64,000 Cherry, Potato 0.092 0.00506 NA 0.000161 59,000 NA 90,000 **Mixer/Loader/Applicator** Mixing/Loading/Applying Li quid Concentrates with Low Pressure Hand wand Gr eenhouse Only: Strawberries & Watermelon 0.22 5 100 0.43 30 1.57 0.00676 0.000471 190 44,000 31,000 Mixing/Loading/Applying Li quid Concentrates with High Pressure Hand wand Gr eenhouse Only: Strawberries & Watermelon 0.22 5 3.5 2.5 0.12 0.0550 0.0393 0.00189 5,500 7,600 7,700 Mixing/Loading/Applying Li quid Concentrates with a Backpack Gr eenhouse Only: Strawberries & Watermelon 0.22 5 2.51 2.5 30 0.0394 0.0393 0.000471 7,600 7,600 31,000 a. Application Rates are based on proposed uses from the fluopyram label s (Fluopyram 500 SC). b. Science Advisory Council Policy No. 9.1 . c. Baseline Dermal: Long - sleeve sh irt, long pants, and no gloves. PPE - G Dermal : Baseline plus chemical - resistant gloves. Baseline Inhalation: no respirator. Engineering control unit exposure for applying sprays via aerial equipment = enclosed cockpit. d. Unit Exposures are based on PHED Version 1.1. e . Daily Exposure (mg/kg/day) = Application Rate (lb ai/A) * Unit Exposure (mg/lb ai) * Area Treated or Amount Applied (acre/day) / 70 kg. f. MOE = NOAEL (mg/kg/day) / Daily Exposure (mg/kg/day); where dermal NOAEL = 300 mg/kg/day and inhalation NOAEL = 14.5 mg/kg/day.Fluopy

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Page 98 of 105 **Table E2**  **. Occupational Handler Estimated Cancer Risks for Private Growers.** Exposure Scenario Crop or Target Application Rate a (lb ai/A) Ar ea

Treated Daily b (acres/day) Unit Exposure d Average Daily Dose e (mg/kg/day) LADD f (mg/kg/day) Cancer Riskg

Baseline Dermal c (mg/lb ai) PPE - G

Dermal c (mg/lb ai) Baseline

Inhalation c (μg/lb ai) Baseline

Dermal PPE - G

Dermal Baseline

Inhalation Baseline

Dermal PPE - G

Dermal Baseline

Inhalation Baseline

Dermal + Inhalation PPE - G

Dermal + Inhalation **Mixer/Loader** Mixing/Loading Li quid Concentrates for Aerial Applicati ons Peanut, Strawberry, Tree Nuts 0.22 350 0.22 0.0376 0.219 4.60E - 3 7.87E - 4 2.41E - 4 6.30E - 5 1.08E - 5 3.30E - 6 1.1E - 6 2.2E - 7 Dried Beans 0.13 2.72E - 3 4.64E - 4 1.42E - 4 3.72E - 5 6.35E - 6 1.95E - 6 6.1E - 7 1.3E - 7 Cherry, Potato 0.092 1.92E - 3 3.29E - 4 1.01E - 4 2.63E - 5 4.50E - 6 1.38E - 6 4.3E - 7 9.1E - 8 Mixing/Loading Li quid Concentrates for Chemigation Applications Apples, Peanut,

Strawberry, Tree Nuts , Watermelon (field and greenhouse), Viniferous variety Grapes 0.22 350 0.22 0.0376 0.219 4.60E - 3 7.87E - 4 2.41E - 4 6.30E - 5 1.08E - 5 3.30E - 6 1.1E - 6 2.2E - 7 Potato 0.18 3.76E - 3 6.42E - 4 1.97E - 4 5.15E - 5 8.80E - 6 2.70E - 6 8.4E - 7 1.8E - 7 Dried Beans 0.13 2.72E - 3 4.64E - 4 1.42E - 4 3.72E - 5 6.35E - 6 1.95E - 6 6.1E - 7 1.3E - 7 Sugar Beet 0.11 2.30E - 3 3.93E - 4 1.20E - 4 3.15E - 5 5.39E - 6 1.64E - 6 5.1E - 7 1.1E - 7 Cherry 0.092 1.92E - 3 3.29E - 4 1.01E - 4 2.63E - 5 4.50E - 6 1.38E - 6 4.3E - 7 9.1E - 8 Mixing/Loading Li quids Concentrates for Gr oundboom Applications Apples, Peanut,

Strawberry, Tree Nuts , Watermelon (field and greenhouse), Viniferous variety Grapes 0.22 80 0.22 0.0376 0.219 1.05E - 3 1.80E - 4 5.51E - 5 1.44E - 5 2.46E - 6 7.55E - 7 2.3E - 7 5.0E - 8 Potato 0.18 8.59E - 4 1.47E - 4 4.51E - 5 1.18E - 5 2.01E - 6 6.18E - 7 1.9E - 7 4.1E - 8 Dried Beans 0.13 6.21E - 4 1.06E - 4 3.25E - 5 8.51E - 6 1.45E - 6 4.45E - 7 1.4E - 7 2.9E - 8 Sugar Beet 0.11 5.26E - 4 8.99E - 5 2.75E - 5 7.21E - 6 1.23E - 6 3.77E - 7 1.2E - 7 2.5E - 8 Cherry 0.092 4.39E - 4 7.51E - 5 2.30E - 5 6.01E - 6 1.03E - 6 3.15E - 7 9.8E - 8 2.1E - 8 Mixing/Loading Li quids Concentrates for Airblast Applications Apples, Tree Nuts ,

Viniferous variety Grapes 0.22 40 0.22 0.0376 0.219 5.26E - 4 8.99E - 5 2.75E - 5 7.21E - 6 1.23E - 6 3.77E - 7 1.2E - 7 2.5E - 8 Cherry 0.092 2.20E - 4 3.76E - 5 1.15E - 5 3.02E - 6 5.15E - 7 1.58E - 7 4.9E - 8 1.0E - 8 **Applicator** Applying Sprays via Aerial Equipment Peanut, Strawberry, Tree Nuts 0.22 350 0.005 (Eng. Control) No Data 0.068 (Eng. Control) 1.04E - 4

(Eng. Control) No Data 0.0000748 (Eng. Control) 1.43E - 6 No Data 1.02E - 6 3.8E - 8 No Data Dried Beans 0.13 6.18E - 5 No Data 0.0000 442 8.46E - 7 No Data 5.75E - 7 2.2E - 8 No Data Cherry, Potato 0.092 4.37E - 5 No Data 0.0000 313 5.99E - 7 No Data 4.29E - 7 1.6E - 8 No Data Applying Sprays via Gr oundboom Apples, Peanut,

Strawberry, Tree 0.22 80 0.0 786 0.01 61 0. 3 4 3.76E - 4 7.70E - 5 0.0000855 5.15E - 6 1.05E - 6 1.17E - 6 9.8E - 8 3.4E - 8Fluopy

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Page 99 of 105 **Table E2**  **. Occupational Handler Estimated Cancer Risks for Private Growers.** Exposure Scenario Crop or Target Application Rate a (lb ai/A) Ar ea

Treated Daily b (acres/day) Unit Exposure d Average Daily Dose e (mg/kg/day) LADD f (mg/kg/day) Cancer Riskg

Baseline Dermal c (mg/lb ai) PPE - G

Dermal c (mg/lb ai) Baseline

Inhalation c (μg/lb ai) Baseline

Dermal PPE - G

Dermal Baseline

Inhalation Baseline

Dermal PPE - G

Dermal Baseline

Inhalation Baseline

Dermal + Inhalation PPE - G

Dermal + Inhalation Equipment Nuts , Watermelon

(field and greenhouse), Viniferous variety Grapes Potato 0.18 3.08E - 4 6.29E - 5 6.99E - 5 4.22E - 6 8.62E - 7 9.58E - 7 8.0E - 8 2.8E - 8 Dried Beans 0.13 2.22E - 4 4.54E - 5 5.05E - 5 3.04E - 6 6.22E - 7 6.92E - 7 5.8E - 8 2.0E - 8 Sugar Beet 0.11 1.88E - 4 3.84E - 5 4.27E - 5 2.57E - 6 5.26E - 7 5.85E - 7 4.9E - 8 1.7E - 8 Cherry 0.092 1.57E - 4 3.21E - 5 3.57E - 5 2.15E - 6 4.40E - 7 4.89E - 7 4.1E - 8 1.4E - 8 Applying Sprays via Airblast Equipment Apples, Tree Nuts ,

Viniferous variety Grapes 0.22 40 0.36 0.24 4.5 8.61E - 4 5.74E - 4 5 . 66 E - 4 1.18E - 5 7.86E - 6 7.75E - 6 3.0E - 7 2.4E - 7 Cherry 0.092 3.59E - 4 2.39E - 4 2.37E - 4 4.92E - 6 3.28E - 6 3.25E - 6 1.3E - 7 1.0E - 7 **Flagger** Flagging for Aerial Sprays Applications Peanut, Strawberry, Tree Nuts 0.22 350 0.011 NA 0.35 2.30E - 4 NA 3 . 85 E - 4 3.15E - 6 NA 5.27E - 6 1.3E - 7 NA Dried Beans 0.13 1.36E - 4 NA 2.28E - 4 1.86E - 6 NA 3.12E - 6 7.7E - 8 NA Cherry, Potato 0.092 9.61E - 5 NA 1.61E - 4 1.32E - 6 NA 2.21E - 6 5.5E - 8 NA **Mixer/Loader/Applicator** Mixing/Loading/ Applying Liquid Concentrates with Low Pressure Hand wand Gr eenhouse Only:

Strawberries & Watermelon 0.22 5 100 0.43 30 2.98E - 2 1.28E - 4 4 . 71 E - 4 4.09E - 4 1.76E - 6 6.45E - 6 6.4E - 6 1.3E - 7 Mixing/Loading/ Applying Liquid Concentrates with High Pressure Hand wand Gr eenhouse Only: Strawberries & Watermelon 0.22 5 3.5 2.5 120 1.05E - 3 7.47E - 4 1 . 89 E - 3 1.43E - 5 1.02E - 5 2.59E - 5 6.2E - 7 5.6E - 7 Mixing/Loading/ Applying Liquid Concentrates with a Backpack Gr eenhouse Only:

Strawberries & Watermelon 0.22 5 2.51 2.5 30 7.49E - 4 7.47E - 4 4 . 71 E - 4 1.03E - 5 1.02E - 5 6.45E - 6 2.6E - 7 2.6E - 7 a. Application Rates are based on proposed uses from the fluopyram labels (Fluopyram 500 SC) . b. Science Advisory Council Policy No. 9.1 . c. Baseline Dermal: Long - sleeve shirt, long pants, and no gloves . PPE - G Dermal: Baseline plus chemical - resistant gloves. Baseline I nhalation: no respirator. Engineering control unit exposure for applying sprays via aerial equipment = enclosed cockpit. d. Unit Exposures are based on PHED Version 1.1, or AHETF data . e. Average Daily Dose (ADD) (mg/kg/day) = Application Rate (lb ai/A) * Unit Exposure (mg/lb ai ) * Area Treated or Amount Applied (acre/day) * Absorption Factor (1.9% dermal, 100% inhalation) / 70 kg . f. Lifetime Average Daily Dose (LADD) = ADD (mg/kg/day) x (10 days per year treated by Private Growers / 365 days per year) x (35 years working duration / 70 years per lifetime). g. Cancer Risk = Q1* (1.55E - 2 (mg/kg/day) - 1 ) x LADD mg/kg/day).Fluopy

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Page 100 of 105 **Table E3**  **. Occupational Handler Estimated Cancer Risks for Commercial Applicators**  **.** Exposure Scenario Crop or Target Application Rate a (lb ai/A) Ar ea

Treated Daily b (acres/day) Unit Exposure d Average Daily Dose e (mg/kg/day) LADD f (mg/kg/day) Cancer Riskg

Baseline Dermal c (mg/lb ai) PPE - G

Dermal c (mg/lb ai) Baseline

Inhalation c (μg/lb ai) Baseline

Dermal PPE - G

Dermal Baseline

Inhalation Baseline

Dermal PPE - G

Dermal Baseline

Inhalation Baseline

Dermal + Inhalation PPE - G

Dermal + Inhalation **Mixer/Loader** Mixing/Loading Li quid Concentrates for Aerial Applications Peanut, Strawberry, Tree Nuts 0.22 350 0.22 0.0376 0.219 4.60E - 3 7.87E - 4 2.41E - 4 1.89E - 4 3.23E - 5 9.90E - 6 3.1E - 6 6.5E - 7 Dried Beans 0.13 2.72E - 3 4.64E - 4 1.42E - 4 1.12E - 4 1.91E - 5 5.84E - 6 1.8E - 6 3.9E - 7 Cherry, Potato 0.092 1.92E - 3 3.29E - 4 1.01E - 4 7.89E - 5 1.35E - 5 4.15E - 6 1.3E - 6 2.7E - 7 Mixing/Loading Li quid Concentrates for Chemigation Applications Apples, Peanut,

Strawberry, Tree Nuts , Watermelon (field and greenhouse), Viniferous variety Grapes , 0.22 350 0.22 0.0376 0.219 4.60E - 3 7.87E - 4 2.41E - 4 1.89E - 4 3.23E - 5 9.90E - 6 3.1E - 6 6.5E - 7 Potato 0.18 3.76E - 3 6.42E - 4 1.97E - 4 1.55E - 4 2.64E - 5 8.10E - 6 2.5E - 6 5.3E - 7 Dried Beans 0.13 2.72E - 3 4.64E - 4 1.42E - 4 1.12E - 4 1.91E - 5 5.84E - 6 1.8E - 6 3.9E - 7 Sugar Beet 0.11 2.30E - 3 3.93E - 4 1.20E - 4 9.45E - 5 1.62E - 5 4.93E - 6 1.5E - 6 3.3E - 7 Cherry 0.092 1.92E - 3 3.29E - 4 1.01E - 4 7.89E - 5 1.35E - 5 4.15E - 6 1.3E - 6 2.7E - 7 Mixing/Loading Li quids Concentrates for Gr oundboom Applications Apples, Peanut,

Strawberry, Tree Nuts , Watermelon (field and greenhouse), Viniferous variety Grapes , 0.22 80 0.22 0.0376 0.219 1.05E - 3 1.8E - 4 5.51E - 5 4.32E - 5 7.38E - 6 2.26E - 6 7.1E - 7 1.5E - 7 Potato 0.18 8.59E - 4 1.47E - 4 4.51E - 5 3.53E - 5 6.04E - 6 1.85E - 6 5.8E - 7 1.2E - 7 Dried Beans 0.13 6.21E - 4 1.06E - 4 3.25E - 5 2.55E - 5 4.36E - 6 1.34E - 6 4.2E - 7 8.8E - 8 Sugar Beet 0.11 5.26E - 4 8.99E - 5 2.75E - 5 2.16E - 5 3.69E - 6 1.13E - 6 3.5E - 7 7.5E - 8 Cherry, Stone Fruit 0.092 4.39E - 4 7.51E - 5 2.30E - 5 1.80E - 5 3.08E - 6 9.45E - 7 2.9E - 7 6.2E - 8 Mixing/Loading Li quids Concentrates for Airblast Applications Apples, Tree Nuts ,

Viniferous variety Grapes 0.22 40 0.22 0.0376 0.219 5.26E - 4 8.99E - 5 2.75E - 5 2.16E - 5 3.69E - 6 1.13E - 6 3.5E - 7 7.5E - 8 Cherry 0.092 2.20E - 4 3.76E - 5 1.15E - 5 9.06E - 6 1.55E - 6 4.73E - 7 1.5E - 7 3.1E - 8 **Applicator** Applying Sprays via Aerial Equipment Peanut, Strawberry, Tree Nuts 0.22 350 0.005 (Eng. Control) No Data 0.068 (Eng. Control) 1.05E - 4

(Eng. Control) No Data 7 . 48 E - 5 (Eng. Control) 4.29E - 6 No Data 3. 07 E - 6 1.1E - 7 No Data Dried Beans 0.13 6.18E - 5 No Data 4.42E - 5 2.54E - 6 No Data 1.82E - 6 6.8E - 8 No Data Cherry, Potato 0.092 4.37E - 5 No Data 3.13E - 5 1.80E - 6 No Data 1.29E - 6 4.8E - 8 No Data Applying Sprays via Gr oundboom Equipment Apples, Peanut,

Strawberry, Tree Nuts , Watermelon 0.22 80 0.0 786 0.01 61 0. 3 4 3.76E - 4 7.70E - 5 8.55E - 5 1.55E - 5 3.16E - 6 3.51E - 6 2.9E - 7 1.0E - 7Fluopy

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Page 101 of 105 **Table E3**  **. Occupational Handler Estimated Cancer Risks for Commercial Applicators**  **.** Exposure Scenario Crop or Target Application Rate a (lb ai/A) Ar ea

Treated Daily b (acres/day) Unit Exposure d Average Daily Dose e (mg/kg/day) LADD f (mg/kg/day) Cancer Riskg

Baseline Dermal c (mg/lb ai) PPE - G

Dermal c (mg/lb ai) Baseline

Inhalation c (μg/lb ai) Baseline

Dermal PPE - G

Dermal Baseline

Inhalation Baseline

Dermal PPE - G

Dermal Baseline

Inhalation Baseline

Dermal + Inhalation PPE - G

Dermal + Inhalation (field and greenhouse), Viniferous variety Grapes , Potato 0.18 3.08E - 4 6.29E - 5 6.99E - 5 1.26E - 5 2.58E - 6 2.87E - 6 2.4E - 7 8.5E - 8 Dried Beans 0.13 2.22E - 4 4.54E - 5 5.05E - 5 9.14E - 6 1.87E - 6 2.08E - 6 1.7E - 7 6.1E - 8 Sugar Beet 0.11 1.88E - 4 3.84E - 5 4.27E - 5 7.71E - 6 1.58E - 6 1.75E - 6 1.5E - 7 5.2E - 8 Cherry 0.092 1.57E - 4 3.21E - 5 3.57E - 5 6.45E - 6 1.32E - 6 1.47E - 6 1.2E - 7 4.3E - 8 Applying Sprays via Airblast Equipment Apples, Tree Nuts , Viniferous variety Grapes 0.22 40 0.36 0.24 4.5 8.61E - 4 5.74E - 4 5 . 66 E - 4 3.54E - 5 2.36E - 5 2.3 3 E - 5 9.1E - 7 7.3E - 7 Cherry 0.092 40 0.36 0.24 4.5 3.59E - 4 2.39E - 4 2.37E - 4 1.48E - 5 9.84E - 6 9.74E - 6 3.8E - 7 3.0E - 7 **Flagger** Flagging for Aerial Sprays Applications Peanut, Strawberry, Tree Nuts 0.22 350 0.011 NA 0.35 2.30E - 4 NA 3 . 85 E - 4 9.45E - 6 NA 1. 58 E - 5 3.9E - 7 NA Dried Beans 0.13 1.36E - 4 NA 2.28E - 4 5.58E - 6 NA 9.34E - 6 2.3E - 7 NA Cherry, Potato 0.092 9.61E - 5 NA 1.61E - 4 3.95E - 6 NA 6.62E - 6 1.6E - 7 NA **Mixer/Loader/Applicator** Mixing/Loading/ Applying Liquid Concentrates with Low Pressure Hand wand Gr eenhouse Only:

Strawberries & Watermelon 0.22 5 100 0.43 30 2.98E - 2 1.28E - 4 4 . 71 E - 4 1.23E - 3 5.28E - 6 1.9 4 E - 5 1.9E - 5 3.8E - 7 Mixing/Loading/ Applying Liquid Concentrates with High Pressure Hand wand Gr eenhouse Only: Strawberries & Watermelon 0.22 5 3.5 2.5 120 1.05E - 3 7.47E - 4 1 . 89 E - 3 4.29E - 5 3.07 2.59E - 5 1.1E - 6 8.8E - 7 Mixing/Loading/ Applying Liquid Concentrates with a Backpack Gr eenhouse Only:

Strawberries & Watermelon 0.22 5 2.51 2.5 30 7.49E - 4 7.47E - 4 4 . 71 E - 4 3.08E - 5 3.07E - 5 1.9 4 E - 5 7.8E - 7 7.8E - 7 a. Application Rates are based on proposed uses from the fluopyram labels (Fluopyram 500 SC) . b. Science Advisory Council Policy No. 9.1 . c. Baseline Dermal: Long - sleeve shirt, long pants, and no gloves . PPE - G Dermal: Baseline plus chemical - resistant gloves. Baseline I nhalation: no respirator. Engineering control unit exposure for applying sprays via aerial equipment = enclosed cockpit. d. Unit Exposures are based on PHED Version 1.1, or AHETF data . e. Average Daily Dose (ADD) (mg/kg/day) = Application Rate (lb ai/A) * Unit Exposure (mg/lb ai) * Area Treated or Amount Applied (acre/day) * Absorption Factor (1.9% dermal, 100% inhalation)/ 70 kg . f. Lifetime Average Daily Dose (LADD) = ADD (mg/kg/day) x ( 3 0 days per year treated by Commercial Growers / 365 days per year) x (35 years working duration / 70 years per lifetime). g. Cancer Risk = Q1* (1.55E - 2 (mg/kg/day) - 1 ) x Dermal LADD mg/kg/day).Fluopy

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Page 102 of 105 **T able**  **E.4 . Summary of Occupational**  **Non -**  **Cancer Postapplication Risks**  **(Short -**  **and Intermediate**  **- Term)**  **with HED Default Assumptions .**  Crop Grouping Application

rate (lb ai/acre) Default DFR

on 0 day s (12 hrs) after application a ( μg/cm2 ) Work Activity & Maximum Transfer Coefficient

b (cm2/hr) Daily

Dose c (mg/kg/day) MOE d

(LOC = 100) Apples 0.22 0.493 3, 6 00 - Thinning 0.203 1,500 Cherry 0.092 0.206 3, 6 00 - Thinning 0.0848 3,500 Dried Beans 0. 13 0.292 1 , 9 00 - Irrigation 0.0634 4,700 Peanut s 0.22 0.493 1 , 9 00 - Irrigation 0.107 2,800 Potato es 0. 18 0.404 1 , 9 00 - Irrigation 0.0877 3,400 Strawberries 0.22 0 .493 1, 1 00

– Hand Harvest 0.0620 4,800 Sugar Beets 0.11 0.247 1 , 9 00 - Irrigation 0.0536 5,600 Tree Nuts 0.22 0.49 3 3 , 6 00 - Thinning 0.203 1,500 Watermelon 0.22 0.493 1 , 9 00 - Irrigation 0.107 2,800 Viniferous variety Grapes 0.22 0.493 10 , 1 00 - Harvest (hand), Training, Tying, Leaf Pulling 0. 569 530 a. Default DFR (μg/cm 2 ) = application rate (lb ai/A) x (1 - daily dissipation rate) t x 4.54E+8 μg/lb x 24.7E - 9 A/cm2 x 20% DFR after initial treatment. b. Crops were assessed using the highest transfer coefficient (TC) available. c. Daily Dose = DFR x TC x (1 mg/1000 μg) x ET (8 hr/d ay) / body weight (70 kg) d. MOE = NOAEL (300 mg/kg/day) / Daily Dose (mg/kg/day)Fluopy

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Page 103 of 105 **T able**  **E5 . Summary of Occupational Postapplication**  **Cancer Risks**  **with HED Default Assumptions .**  Crop Grouping Average DFR

after application a ( μg/cm2 ) Work Activity &

Maximum Transfer Coefficient b (cm2/hr) Dermal Average Daily Dose c (mg/kg/day) Dermal LADD d

(mg/kg/day) Cancer Riske Apples 0.351 3, 6 00 - Thinning 2.74E - 3 1.13E - 4 1.7E - 6 Cherry 0.161 3, 6 00 - Thinning 1.26E - 3 5.18E - 5 8.0E - 7 Dried Beans 0.208 1 , 9 00 - Irrigation 8.59E - 4 3.53E - 5 5.5E - 7 Peanut s 0.261 1 , 9 00 - Irrigation 1.08E - 3 4.44E - 5 6.9E - 7 Potato es 0.315 1 , 9 00 - Irrigation 1.30E - 3 5.34E - 5 8.3E - 7 Strawberries 0 .385 1, 1 00 - Hand Harvest 9.20E - 4 3.78E - 5 5.9E - 7 Sugar Beets 0.193 1 , 9 00 - Irrigation 7.96E - 4 3.27E - 5 5.1E - 7 Tree Nuts 0. 351 3 , 6 00 - Thinning 2.74E - 3 1.13E - 4 1.7E - 6 Watermelon 0 .385 1 , 9 00 - Irrigation 1.59E - 3 6.53E - 5 1.0E - 6 Viniferous variety Grapes 0. 283 10 , 1 00 - Harvest (hand), Training, Tying, Leaf Pulling 6.21E - 3 2.55E - 4 4.0E - 6 a. Average DFR residue averaged over the shortest number of re - treatment days for each crop or crop group (μg/cm2 ) . b. Crops were assessed using the highest transfer coefficient (TC) available. c. Dermal Average Daily Dose (ADD) = Average DFR x TC x (1 mg/100 0 μg) x ET (8 hr/day) x Dermal Absorption Factor (1.9%)/ body weight (70 kg). d. Dermal Lifetime Average Daily Dose (LADD) = Dermal ADD (mg/kg/day) x (30 days per year treated / 365 days per year) x (35 years working duration / 70 years per lifetime). e. C ancer Risk = Q1* (1.55E - 2 (mg/kg/day) - 1 ) x Dermal LADD mg/kg/day).Fluopy

ram Human Health Risk Assessment DP No. D385636

Page 104 of 105 **Appendix F. International Residue Limit Status Sheet**  Summary of US and International Tolerances and Maximum Residue Limits Residue Definition : US Canada Mexico 2 Codex 3 40 CFR 180.XXX: Plants: fluopyram (N - [2 - [3 - chloro - 5 - (trifluoromethyl) - 2 -py

ridinyl]ethyl] - 2 - (trifluoromethyl)benzamide). Livestock: sum

of fluopyram (N - [2 - [3 - chloro - 5 - (trifluoromethyl) - 2 -py ridinyl]ethyl] - 2 - (trifluoromethyl)benzamide) and its benzamide metabolite [2 - (trifluoromethyl) - benzamide], calculated as the stoichiometric equivalent of fluopyram Identical to US Plants: fluopyram. Animal commodities: Sum of fluopyram and 2 - (trifluoromethyl)benzamide, expressed as fluopyram.

Commodity 1 Tolerance (ppm) /Maximum Residue Limit (mg/kg) US Canada Mexico 2 Codex 3 Almond hull 8.0 Apple 0.30 Apple wet pomace 0.60 Banana (im

port) 1.0 B ean , dry 0.09 Cherry 0.60 Nut, tree, group 14 0.05 Peanut 0.02 Pistachio 0.05 Potato 0.02 Potato processed waste 0.08 Straw berry 1.5 Sugar beet 0.04 Watermelon 1.0 Wine Grapes 2.0 5 Dried grapes (=currants, raisins and sultanas) ; 2 Grapes (proposed) Alfalfa forage 0.45 Alfalfa hay 1.1 Canola 1.8 Cotton gin byproducts 0.05 Cotton undelinted seed 0.01 Grain, cereal, group 15, except rice 1.5 Grain, cereal, forage, fodder and straw , group 15, except rice ; forage 4.0 Grain, cereal, forage, fodder and straw , group 15, except rice ; hay, straw and stover 7.0 Soy bean forage 4.0 Soy bean hay 15 Soy bean seed 0.10Fluopy

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Page 105 of 105 Summary of US and International Tolerances and Maximum Residue Limits Residue Definition : US Canada Mexico 2 Codex 3 Cattle, fat 0.11 Cattle, meat 0.15 0.1 Meat (from mammals other than marine mammals) Cattle , meat byproducts 1.1 0.7 Edible offal (mammalian) Cattle, liver Eggs 0.25 Goat , fat 0.11 Goat, meat 0.15 Goat , meat byproducts 1.1 Hog, fat 0.05 Hog, meat 0.05 Hog , meat byproducts 0.70 Horse, fat 0.11 Horse, meat 0.15 Horse , meat byproducts 1.1 Milk 0.07 Milks 0.07 Poultry, fat 0.20 Poultry, meat 0.15 Poultry, meat byproducts 0.60 Sheep, fat 0.11 Sheep, meat 0.15 Sheep , meat byproducts 1.1

1 Includes only commodities of interest for this action. Tolerance values should be the HED recommendations and not those proposed by the applicant. 2 Mexico adopts US tolerances and/or Codex MRLs for its export purposes. 3 * = absent at the limit of quantitation; Po = postharvest treatment, such as treatment of stored grains. PoP = processed postharvest treated commodity, such as processing of treated store d wheat. (fat) = to be measured on the fat portion of the sample. MRLs indicated as proposed have not been finalized by the CCPR and the CAC.