### Tolfenp yrad Human Health Risk Assessment DP No. 383820

Page 1 of 65 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460 **OFFICE OF CHEMICA** **L SA FETY**  **AND POLLUTION PREVENTION**  

### MEMORANDUM **Date :**  1 2 April 2012 **SUBJECT:** Tolfenp yrad

– Aggregate Human Health Risk Assessment Evaluating the First

Food Uses on Multiple Commodities . PC Code: 090111 DP Barcode: D383820 Decision No.: 440578 Registration No. : 71711 - 31, 71711 - GA Petition No.: 0F7791 Regulatory Action: Section 3 Assessment Type: Single Chemical Registration Case No.: NA T XR No.: None CAS No.: 129558 - 76 - 5 MRID No s .: See Bibliography 40 CFR 180 : N one (first food use request) 

### FROM: Michael A. Doherty, Ph.D., Senior Chemist

Zaida Figueroa, Industrial Hygienist Karl yn Middleton, Toxicologist Risk Assessment Branch II Health Effects Division (7509P) **THROUGH:** Elizabeth Holman, Chemist

Suku Oonni than, Biologist Edward Scollon, Ph.D., Toxicologist Christina Swartz, Branch Chief Risk Assessment Branch II Health Effects Division (7509P) Christine L . Olinger, Senior Chemist Deborah Smegal, MPH, Toxicologist Dana Vogel, Branch Chief Risk Assessment Review Committee Health Effects Division (7509P) **TO:** Dris s Benmhend/Mark Suarez (Team 13) Insec ticide Branch Registration Division (7505P)

### Tolfenp yrad Human Health Risk Assessment DP No. 383820

Page 2 of 65 **1.0 Executive Summary**  ................................ ................................ ................................ ........... 4 **2.0 HED Recommendations**  ................................ ................................ ................................ .... 5 **2.1 Da**  **ta Deficiencies** ................................ ................................ ................................ ............ 5 **2.2 Tolerance Considerations**  ................................ ................................ .............................. 5 **2.2.1 Enforcement Analytical Method**  ................................ ................................ ............... 6 **2.2.2 International Harmonization**  ................................ ................................ ..................... 6 **2.2.3 Recommended Tolerances**  ................................ ................................ ......................... 6 **2.2.4 Revisions to Petitioned**  **- For Tolerances**  ................................ ................................ .... 8 **2.3 Label Recommendations**  ................................ ................................ ................................ 8 **2.3.1 Label Recommendations from Residue Reviews**  ................................ ..................... 8 **2.3.2 Label Recommendations from Occupational As**  **sessment** ................................ ...... 9 **3.0 Introduction**  ................................ ................................ ................................ ........................ 9 **3.1 Chemical Identity**  ................................ ................................ ................................ ........... 9 **3.2 Physical/Chemical Characteristics**  ................................ ................................ ............. 10 **3.3 Pesticide Use Pattern**  ................................ ................................ ................................ .... 10 **3.4 Anticipated Exposure Pathways**  ................................ ................................ ................. 13 **3.5 Consideration of Environmental Justice**  ................................ ................................ .... 14 **4.0 Hazard Characterization and Dose**  **- Response Assessment**  ................................ .......... 14 **4.1 Toxicology Studies Available for Analysis**  ................................ ................................ . 14 **4.2 Absorption, Distribution, Metabolism, & Eliminat** **ion (ADME)** ............................. 15 **4.2.1 Dermal Absorption**  ................................ ................................ ................................ ... 15 **4.3 Toxicological Effects**  ................................ ................................ ................................ .... 16 **4.4 Safety factor for Infants and Children (FQPA Safety Factor)**  ................................ 17 **4.4.1 Completeness of the Toxicology Database**  ................................ .............................. 17 **4.4.2 Evidence of Neurotoxicity**  ................................ ................................ ........................ 18 **4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal**  ........ 18 **4.4.4 Residual Uncertainty in the Exposure Database**  ................................ ................... 18 **4.5 Toxicity Endpoint and Point of Departure Selections**  ................................ .............. 18 **4.5.1 Dose**  **- Response Assessment**  ................................ ................................ ...................... 18 **4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment**  ..... 19 **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** ................................ ................................ ................................ ............................... 20 **5. 0**  **Dietary Exposure and Risk Assessment** ................................ ................................ ......... 21 **5.1 Metabolite/Degradate Residue Profile**  ................................ ................................ ....... 21 **5.1.1 Summary of Plant and Animal Metabolism Studies**  ................................ ............. 21 **5.1.2 Summary of Environmental Degradation**  ................................ .............................. 22 **5.1.3 Comparison of Metabolic Pathways**  ................................ ................................ ....... 23 **5.1.4 Residues of Concern Summary and Rationale**  ................................ ...................... 23 **5.2 Food Residue Profile**  ................................ ................................ ................................ .... 24 **5.3 Water Residue Profile**  ................................ ................................ ................................ .. 27 **5.4 Dietary Risk Assessment**  ................................ ................................ .............................. 28 **5.4.1 Description of Residue Data Used in Dietary Assessment**  ................................ .... 28 **5.4.2 Percent Crop Treated Used in Dietary Assessment**  ................................ .............. 30 **5.4.3 Acute Dietary Risk Assessment**  ................................ ................................ ............... 30 **5.4.4 Chronic Dietary Risk Assessment**  ................................ ................................ ........... 31

### Tolfenp yrad Human Health Risk Assessment DP No. 383820

Page 3 of 65 **5.4.5 Cancer Dietary Risk Assessment**  ................................ ................................ ............. 31 **5.4.6 Summary Table**  ................................ ................................ ................................ ......... 31 **6.0 Resi**  **dential (Non -**  **Occupational) Exposure/Risk Characterization** ............................. 32 **6.1 Residential Bystander Post**  **- Application Inhalation Exposure**  ................................ 32 **6.2 Spray Drift**  ................................ ................................ ................................ .................... 32 **8.0 Cumulative Exposure/Risk Characterization**  ................................ ............................... 33 **9.0 Occupational Exposure/Risk Characterization**  ................................ ............................ 33 **9.1 Short** **- and Intermediate**  **- Term Handler Risk**  ................................ ........................... 34 **9.2 Short** **- and Intermediate**  **- Term Post** **- Application Risk**  ................................ ............. 37 **9.2.1 Dermal Post**  **- Application Risk**  ................................ ................................ ................. 37 **9.2.2 Inhalation Post** **- Application Risk**  ................................ ................................ ............ 37 **10.0 References**  ................................ ................................ ................................ ......................... 38 **Appendix A. Toxicology Profile and Executive Summaries** ................................ .................. 39 **A.1 Toxicology Data Requirements**  ................................ ................................ ................... 39 **A.3 Triple**  **- Pack Analysis for Tolfenpyrad**  ................................ ................................ ....... 47 **A.4 Toxicological Doses and Endpoints for Use in Human**  **Risk Assessments** .............. 49 **Appendix B. Metabolism Summary Table** ................................ ................................ ............... 51 **Appendix C. Physical/Chemical Properties** ................................ ................................ ............. 56 **Appendix D. Review of Human Research** ................................ ................................ ................ 57 **Appendix E. Bibliography of Submitted Studies** ................................ ................................ .... 58

### Tolfenp yrad Human Health Risk Assessment DP No. 383820

Page 4 of 65 **1.0 Executive Summary**  Nichino America, Inc. has petitioned the Agency for Section 3 registration of end - use products containing the pesticide active ingredient tolfenp yr ad for use on a large number of food and feed crops as well as an increase in the maximum application rate for the registered use on cut flowers in greenhouses . Concomitant with the registration on food and feed crops, the petitioner has requested the estab lishment of tolerances for residues of tolfenpy rad . Tolfenp yrad shows broad insecticidal activity against target pests through the egg, larval, nymph, and adult stages. The proposed use s are for insect control on the following fourteen crops or crop groups: potato; leafy vegetables, except Brassica ; Brassica leafy vegetables; fruiting vegetables; cucurbit vegetables; citrus fruits; pome fruits; stone fruits ; persimmon ; pomegranate; grape; tree nuts (including pistachio ) ; and cotton . In addition, Nichin o America is requesting a tolerance for residues of tolfenpy rad in/on tea , without a U.S. registration . Tolfenp yrad was first assessed b y HED in June of 2010 in conjun ction with non - food uses on ornamental plants in greenhouses. In developing this human health risk assessment, the Health Effects Division has examined the available hazard and exposure information regarding tolfenp yr ad as it relates to its registered and requested uses. A variety of toxic effects were noted in the toxicology database for tolfenp yrad. However, the most consistent finding across species and studies was decreased body weight and

/or body weight gain , which were observed in adults of all species (rat, mice, rabbit, and dog) in the majority of the subchronic oral and dermal tox icity studies, and all chronic toxicity studies. With regard to exposure level, the rat is the species most sensitive to body weight changes . Although the body weight changes observed in other species were similar in magnitude to those in rats, they were observed at higher doses. Additional toxic effects observed were clinical signs and liver and kidney

effects. For dietary

and inhalation exposure scenarios, risk assessment s are based on the most sensitive endpoints and points of departure. N o hazard c oncern was identified from the available dermal toxicity and dermal penetration data; therefore, a dermal risk assessment was not conducted. Toxicological testing indicates that tolfenp yr ad is not neurotoxi c or immunotoxic, and it is classified as “not likel y to be carcinogenic to human s . ” After considering the completeness of the toxicological database, the overall hazard profile o f tolfenp yrad, the doses and endpoints selected for risk assessment, and the characteristics of the exposure assessment, HED is recommending that the FQPA Safety Factor to account for potential increased sensitivity of infants and children be reduced to 1X. Exposure to tolfenpy

rad may occur from consuming tolfenp yr ad - treated crops or their processed commodities . HED has used modeling to assess acute and chronic dietary exposure to tolfenpy rad. The modeling uses health -protective assumptions regarding residues of tolfenpy rad and its breakdown products in foods and drinking water in combination with an extensive database of fo od consumption patterns for the U.S. population and population subgroups. In the case of the acute assessment, screening - level assumptions were made, including tolerance - level

### Tolfenp yrad Human Health Risk Assessment DP No. 383820

Page 5 of 65 residues and 100% of crops treated. The chronic assessment includes significant refinements in the form of average residue levels and estimated percent of crops treated for oranges, apples, table grapes, and spinach. For both acute and chronic risk assessments, highl y conservative assumptions about potential residues in drinking water were included. The maximum dietary risk estimates are 76% and 69% of the acute and chronic population - adjusted dose s ( aPAD , cPAD ) , respectivel y. These estimates are below HED’s level of concern for the US population and population subgroups, including those of infants and children. Exposure s may

also occur during activities associated with using tolfenp yr ad - containing products and from activities in areas treated with this insecticide . At this time, there are no registered or requested uses for thes e products that involve a residential setting ; therefore, aggregate exposure and risk estimates are equivalent to those described above for food and water, and are not of concern. In an occupational setting, exposures have been assessed for occupational h andlers mixing, loading, and appl ying tolfenpy rad . P ost - application activities in treated areas have also been assessed . All occupational exposure assessments , including re - assessment of the registered use on ornamental plants to incorporate new endpoints, policies, and procedures , result in MOEs ranging from 550 to 85,000 . For tolfenp yr ad, MOEs of less than 100 are considered to be of concern. As no dermal endpoint was identified for tolfenpy rad, the occupational MOEs reflec t inhalation exposure only . This risk assessment is based, in part, o n data from studies in which adult human subjects were intentionally

exposed to a pesticide or other chemical. These studies are compliant with applicable ethics requirements . Although no special quantitative assessments have been conducted , HED has, to the extent possible, taken environmental justice consideration into account (see Section 3). **2.0 HED**  **Recommendations** HED is recommending in favor of registration of tolfenpy rad on the requested crops and establishment of permanent tolerances as summarized in Table 2.2.3. There are a number of issues that should be resolved prior to registration , including submittal of a reference standard for the PT - CA metabolite (see Section 2.1 ) , submittal of a revised Section F of the petition (see Section 2.2), and revisions to the proposed labels (see Section 2.3 ) . **2.1 Data Deficiencies**  P rior to registration , a reference standard for PT - CA should be submitted to the EPA National Pesticide Stan dards Repository . **2.2 Tolerance Considerations**  A revised Section F should be submitted reflecting the tolerances and commodity definitions that appear in Table 2.2.3, below.

### Tolfenp yrad Human Health Risk Assessment DP No. 383820

Page 6 of 65 **2.2.1 Enforcement Analytical Method**  Nichino has submitted an acceptable high performance liquid chromatography method with tandem mass spectrometry detection (LC/MS/MS) for enforcement of tolfenpy rad residue tolerances in/on plant commodities (Morse Laboratories Anal ytical Method #Meth - 183, Revision #2). The method limit of quanti tation ( LO Q ; based on the lowest level of method validation, LLMV) is 0.01 ppm. The method has been adequately validated and has undergone acceptable independent laboratory

validation (ILV). For livestock, the petitioner has submitted a method describe d in PTRLWest Study No. 1841W. The livestock method adequatel y determines residues of tolfenp yr ad and its metabolites, PT - CA, OH - PT - CA , and PCA in milk, bovine meat, kidney, liver and fat . Residues are determined by LC/MS/MS analy sis. The validated LOQ (based on the LLMV) was 0.01 ppm for all anal yt es in all matrices. The method has been adequatel y validated and has undergone acceptable independent laboratory

validation (ILV). Acceptable multiresidue methods test data have been submitted for tolfenpyrad per se . The data indicate that multiresidue methods are not suitable for determination of tolfenpy rad . The submitted data will be forwarded to the U.S. Food and Drug Administration (FDA) for further evaluation. M etabolite PT - CA is the major residue in livestock matrices and has been identified as a residue of concern for tolerance enforcement in livestock commodities . This metabolite was not tested through the appropriate FDA multiresidue PAM I method protocols as required . However, b ased on the str uctural similarity

between tolfenpy

rad and PT - CA, HED does not expect the FDA multiresidue method protocols to be suitable for anal ys is of PT - CA and recommends that the requirement for testing of PT - CA through these methods be waived. **2.2.2 International**  **Harmonization** At this time, no maximum residue limits (MRL s) for tolfenpy rad have been established by Canada, Mexico, or Codex; therefore, there are no issues associated with international harmonization of tolerances. **2.2.3 Recommended Tolerances**  Nichino America has proposed that tolerances for tolfenpy rad in/on plant and livestock commodities be expressed in terms of residues of tolfenpy rad: 4 - chloro - 3 - ethyl - 1 - methyl -N - [4 - ( p - tolyloxy)benzyl]py

razole - 5 - carboxamide . HED has determined that the residues of concern for tolerance enforcement are tolfenp yr ad in/on crop commodities and tolfenpy rad + metabolite PT - CA in livestock commodities. The tolerance expressions for plant and livestock commodities should be revised as follow s : For crop commodi ties: Tolerances are established for residues of th e insecticide tolfenp yrad , including its metabolites and degradates, in or on the commodities in the table below. Compliance with the tolerance levels specified below is to be determined b y measuring only tolfenpy rad, 4 - chloro - 3 - ethyl - 1 - methyl -N - [4 - ( p - tolyloxy)benzyl]py

razole - 5 - carboxamide .

### Tolfenp yrad Human Health Risk Assessment DP No. 383820

Page 7 of 65 For livestock commodities: Tolerances are established for residues of the insecticide tolfenp yrad , including its metabolites and degradates, in or on the commodities in the table below. Compliance with the tolerance levels specified below is to be determined b y measuring only the sum of tolfenp yrad, 4 - chloro - 3 - ethyl - 1 - methyl -N - [4 - ( p - tolyloxy)benz yl ]py

razole - 5 - carboxamide , and its metabolite 4 - [4 - [(4 - chloro - 3 - ethyl - 1 - methylpy razol - 5 - yl )carbonyl amino - methyl]phenoxy] - benzoic acid , calculated as the stoichiometric equivalent of tolfenp yr ad . The proposed and recommended tolerances are presented in Table 2.2.3. Table 2.2.3. Tolerance Summary for Tolfenpyrad. Commodity Tolerance (ppm) Comments (correct commodity definition) Proposed Recommended **Tolerances for residues of tolfenpyrad** Almond hulls 5.0 6.0 Almond, hulls Leaf lettuce 30 30 Vegetable, leafy, except Brassica, group 4 Head lettuce 5 Spinach 24 Celery subgroup 4B leaf petioles 12.5 Head and stem Brassica, subgroup 5A 3.6 5.0 Brassica, head and stem, subgroup 5A Leafy Brassica, subgroup 5B 44 40 Brassica, leafy greens, subgroup 5B Fruiting Vegetables, crop group 8 0.6 0.70 Vegetable, fruiting, group 8 - 10 Cucurbit vegetables crop group 9 0.8 0.70 Vegetable, cucurbit, group 9 Citrus crop group 10 1.0 1.5 Fruit, citrus, group 10 - 10 Citrus pulp dried 2.0 8.0 Citrus, dried pulp Citrus oil 16.0 70 Citrus, oil Pome fruit crop group 11 0.6 0.70 Fruit, pome, group 11 - 10 Apple pomace, wet 5.0 2.5 Apple, wet pomace Stone Fruit, crop group 12 3.0 2.0 Fruit, stone, group 12 Prunes 3.0 3.0 Plum, prune Persimmons 3.0 2.0 Persimmon Pomegranates 3.0 2.0 Pomegranate Potatoes 0.04 0.01 Potato Tree nuts, crop group 14 0.04 0.05 Nut, tree, group 14 Pistachio 0.04 0.05 Grapes 2.0 2.0 Grape Raisins 5.0 6.0 Grape, raisin Cottonseed, undelinted 0.6 0.70 Cotton, undelinted seed Cotton gin trash 9.0 15 Cotton, gin byproducts Tea 20.0 30 Tea **Tolerances for com bined residues of tolfenpyrad and PT**  **- CA**  Milk 0.03 0.03 Fat, cattle, goat, horse, sheep 0.01 0.01 Cattle, fat Goat, fat Horse, fat Sheep, fat

### Tolfenp yrad Human Health Risk Assessment DP No. 383820

Page 8 of 65 Table 2.2.3. Tolerance Summary for Tolfenpyrad. Commodity Tolerance (ppm) Comments (correct commodity definition) Proposed Recommended Kidney, cattle, goat, horse, sheep 0.3 0.35 Cattle, meat byproducts Goat, meat byproducts Liver, cattle, goat, horse, sheep 0.7 Horse, meat byproducts Sheep, meat byproducts Muscle, cattle, goat, horse, sheep 0.02 0.01 Cattle, meat Goat, meat Horse, meat Sheep, meat 

### 2.2.4 **Revisions to Petitioned -**  **For Tolerances**  Nearl y all of the commodity definitions for the petitioned - for tolerances are inconsistent with the current Agency

definitions and must be revised. No numerical revisions relative to the petitioned - for tolerances are necessary for prune, grape , milk, and cattle, goat, horse, and sheep fat. For leaf lettuce, head lettuce, spinach, and celery subgroup 4B leaf petioles, HED has concluded that a group tolerance of 30 ppm for v egetable, leafy , except Brassica , group 4 is appropriate. I f the petiti oner wishes to establish separate tolerances for the individual crop commodities, then additional crop field trial data will be required. For all remaining RACs, the adjustment in tolerance values is likel y the result of HED ’s use of the Organization for Economic Cooperation and Development (OECD) tolerance calculation procedures to establish tolerances rather than the North American Free Trade Agreement (NAFTA) tolerance calculation procedures that were used b y the petitioner. Because onl y limited inform ation was included in the administrative materials concerning establishment of tolerances in processed commodities, HED cannot determine the cause of the differences in the proposed tolerances for apple wet pomace, citrus dried pulp and oil, and raisin. D ifferences in the proposed livestock tolerances for meat by products and muscle are attributed to differences in the dietary

burden calculation generated by the petitioner and that generated b y the Agency . HED notes that based on data from the metabolism s tudy and on the calculated dietary burden for poultry , tolerances for poultry commodities are not needed at this time [see 40 CFR 180.6(a)(3)]. Should future uses of tolfenp yrad be proposed on significant poultry feed items, then a poultry

feeding study

w ill be required and an acceptable tolerance enforcement method for poultry commodities may

also be necessary . **2.3 Label Recommendations**  **2.3.1 Label**  **Recommendations from Residue Reviews**

### Tolfenp yrad Human Health Risk Assessment DP No. 383820

Page 9 of 65 Labeled Crops :  The available data in support of the proposed uses on fruiting vegetable crop group 8, citrus fruit crop group 10, and apple and pear will support uses on all crops listed under the current crop group definitions for vegetable, fruiting, group 8 - 10 ; fruit, citrus, group 10 - 10 , and fruit, pome, group 11 - 10. If the petitioner desires, the labels may be revised to reflect the current definitions for these groups .  White sapote is included in the list of crops under citrus fruit group 10. This commodity was originally

intended to be added to the citrus fruit c rop group when it was updated; however, per Bernie Schneider (communication 11/21/11), it will instead be placed in a tropical fruits group when those groups are established. White sapote should be removed from the label (crop group 10). Adjuvants : Because onl y one adjuvant ty pe was tested for each crop or crop group, the labels should be revised to specify

use of a n on - ionic surfactant (NI S ) as adjuvant for applications to potato, leafy

vegetables, Brassica vegetables, fruiting vegetables, cucurbit vegetables, citrus fruits, pome fruits, grape, and cotton; and use of a crop oil concentrate ( COC ) as adjuvant for applications to stone fruits and tree nuts. **2.3.2 Label**  **Recommendations from Occupational Assessment**

 RD should ensure that the proper amount of lbs ai/gal is consistently included throughout each label. Page 3 of each label should be changed to reflect the lb ai/gal l isted in the front page (i.e., 1.29 lbs ai/gal for Tolfenp yr ad 15EC and 1.31 lb ai/gal for T olfenp yrad 15 S C ) .  HED is not recommending specific changes to personal protective equipment (PPE ) based on risk concerns ; baseline clothing (i.e., long - sleeved shirt, long pants, socks and shoes) is adequate protection for handlers and other occupational workers. H owever, sinc e the 15EC and 15SC products are very similar and have identical use patterns for crops listed on both proposed labels , HED encourages RD to work with the petitioner to have similar PPE requirements on the two labels . F urthermore, RD should ensure that th e proper personal protective equipment (PPE ) is listed on both labels according to the use patterns , the acute toxicity profile, and the formulation for each product. **3.0 Introduction**  **3.1 Chemical Identity** 

### Tolfenp yrad Human Health Risk Assessment DP No. 383820

Page 10 of 65 Table 3.1 . Test Compound Nomenclature : Tolfenpyrad . Chemical structure

Common name Tolfenpyrad Com pany experimental name OMI - 88 IUPAC name 4 - chloro - 3 - ethyl - 1 - methyl -N - [4 - ( p - tolyloxy)benzyl]pyrazole - 5 - carboxamide CAS name 4 - chloro - 3 - ethyl - 1 - methyl -N - [[4 - (4 - methylphenoxy)phenyl]methyl] - 1 Hpyrazole - 5 - carboxamide CAS registry number 129558 - 76 - 5 End - use product/EP 15% EC formulation containing 1.29 lb ai/gal (Tolfenpyrad 15EC Insecticide; EPA Reg. No. 71711 - 31) 15% SC formulation of tolfenpyrad containing 1.31 lb ai/gal (Tolfenpyrad 15SC Insecticide, EPA Reg. No. 71711 - GA) 

### 3.2 **Physical/Chemical Characteristics** The available metabolism data and information regarding ph ys icochemical properties (Appendix C) do not indicate that there are any special concerns with this chemical in terms of bioaccumulation, exposure, or other risk assessment considerations. T olfenpy rad and its transformation products are expected to moderately degrade in the environment. In soil, t olfenpy rad is expected to be immobile ; whereas the breakdown products PCA and PT - CA are expected to be highly mobile . **3.3 Pesticide Use Pattern**  The proposed use pattern on agricultural crops, as well as the proposed amended use pattern on greenhouse ornamentals, is summarized in Table 3.3. Use of a spray

adjuvant is recommended. Applications may be made alone or as a tank mix with other registered pesticides for use on labeled crops or sites, in accordance with the most restrictive use di rections and precautions. The proposed labels specify that tolfenp yr ad is classified by the Insecticide Resistance Action Committee (IRAC) as a Group 21A - mitochondrial electron transport inhibitor. For resistance management, no more than two consecutive applications of Tolfenp yr ad 15EC Insecticide or Tolfenp yrad 15SC Insecticide should be made before alternating with an insecticide that has an alternate mode of action (not in Group 21A).

### Tolfenp yrad Human Health Risk Assessment DP No. 383820

Page 11 of 65 The following rotational crop restrictions are specified: 0 days f ollowing application for all labeled crops, and 14 days following application for all other crops. A reentry interval (REI) of 12 hours is proposed. No use pattern information was provided for tea; however, information in the submitted administrative mat erials indicates application rates of 0.401 - 0.535 lb ai/A (450 - 600 g ai/ha) and a 14 - day PHI. Recommended r evisions to the proposed label are specified in Section 2.3. Table 3.3. Summary of Proposed Directions for Use of Tolfenpyrad. Applic. Timing, Type, and Equip. Formulation

(EPA Reg. No.) † Use Sites Max. Single Applic. Rate ‡ Max.

Seasonal Applic. Rate PHI

(days) Use Directions and Limitations E Foliar application by air or ground equipment; airblast equipment for citrus, apple, pear, stone fruit and tree nuts; chemigation use in potatoes and vegetables crops only. Tolfenpyrad

15EC Insecticide

- Emulsifiable concentrate (15% a.i.) For Commercial use EPA Reg. No. 71711 - 31 (1.29 lb ai/gal) C itrus F ruit

(Crop Group 10) 0.27 lb ai/A

(27 fl oz product/A) 0.54 lb ai/A

per growing season 14 Do not apply more than 0.54 lb ai/A per growing season. 12 -hour REI; 14 - day interval between apps; For ground applications, do not use less than 100 gallons of water per acre. For high - air- velocity, low- volume or air- curtain sprayers, do not use less than 30 gallons of water per acre. For aerial applications, do not use less than 5 gallons of water per acre . Grapes (raisin, table, wine), Pome Fruit (Crop Group 11) 0.41 lb ai/A per growing season 7 - 14 12 -hour REI; 14 - day interval between apps; For ground applications, do not use less than 50 gallons of water per acre for grapes and 60 gallons of water per acre for apples and pears. For aerial applications, do not use less than 10 gallons of water per acre. Leafy Vegetables (Crop Group 4), Cucurbit Vegetables (Crop Group 9), P otatoes, Brassica (cole) Leafy Vegetables (Crop Group 5), Fruiting V egetables (Crop Group 8 plus Okra), C otton 0.21 lb ai/A

(21 fl oz product/A) 0.42 lb ai/A

per growing season For cucurbits vegetables, do not apply more than 0.85 lb ai/A per growing season. 1 - 14 12 -hour REI; 14 - day interval between apps; For ground applications, do not use less than 20 gallons of water per acre (10 gallons of water per acre for cotton). For air applications, do not use less than 5 gallons of water per acre. For aerial applications for cotton, do not use less than 3 gallons of water per acre.

### Tolfenp yrad Human Health Risk Assessment DP No. 383820

Page 12 of 65 Table 3.3. Summary of Proposed Directions for Use of Tolfenpyrad. Applic. Timing, Type, and Equip. Formulation

(EPA Reg. No.) † Use Sites Max. Single Applic. Rate ‡ Max.

Seasonal Applic. Rate PHI

(days) Use Directions and Limitations S tone F ruit (Crop Group 12), Tree Nuts (Crop Group 14) 0.28 lb ai/A

(28 fl oz product/A) 0.56 lb ai/A

per growing season 14 12 -hour REI; 10 - day interval between apps for stone fruit; 14 - day interval between apps for tree nuts; For ground applications, do not use less than 50 gallons of water per acre. For aerial applications, do not use less than 10 gallons of water per acre. T ea * Not

Specified Not

Specified Not

Specified Foliar application using ground equipment Ornamental plants (including cut flowers) in greenhouses, lath and shadehouses, nurseries, landscape ornamentals, ground covers, field - and container- grown ornamentals, non - bearing fruit and nut trees, vines in nurseries and Christmas trees 1.36 lb ai/A 2.72 lb ai/A per crop cycle 1 Apply no more than 10 gal of spray solution per 1,000 ft2 per application (100 gal per 20,000 ft2 typically cover greenhouse or nursery stock). Apply no more than 2 applications per crop cycle (64 fl oz). Allow at least 10 days between applications.

Foliar application by air or ground equipment; airblast equipment for citrus, apple, pear, stone fruit and tree nuts; chemigation use in potatoes and vegetable crops only. Tolfenpyrad

15SC Insecticide

- Soluble concentrate (15% a.i.) For Commercial use EPA Reg. No. 71711 - GA (1.31 lb ai/gal) C itrus F ruit

(Crop Group 10) 0.28 lb ai/A

(27 fl oz product/A) 0.55 lb ai/A

per growing season 14 12 -hour REI; 14 - day interval between apps; For ground applications, do not use less than 10 0 gallons of water per acre. For high - air- velocity, low- volume or air- curtain sprayers, do not use less than 30 gallons of water per acre. For air applications, do not use less than 10 gallons of water per acre. Grapes (raisin, table, wine), Pome Fruit (Crop Group 11) 0.42 lb ai/A per growing season 7 - 14 12 -hour REI; 14 - day interval between apps; For ground applications, do not use less than 50 gallons of water per acre for grapes and 60 gallons of water per acre for apples and pears. For air applications, do not use less than 10 gallons of water per acre.

### Tolfenp yrad Human Health Risk Assessment DP No. 383820

Page 13 of 65 Table 3.3. Summary of Proposed Directions for Use of Tolfenpyrad. Applic. Timing, Type, and Equip. Formulation

(EPA Reg. No.) † Use Sites Max. Single Applic. Rate ‡ Max.

Seasonal Applic. Rate PHI

(days) Use Directions and Limitations Leafy Vegetables (Crop Group 4), Cucurbit Vegetables (Crop Group 9), P otatoes, Brassica (cole) Leafy Vegetables (Crop Group 5), Fruiting V egetables (Crop Group 8 plus Okra), C otton 0.21 lb ai/A

(21 fl oz product/A) 0.43 lb ai/A

per growing season For cucurbits vegetables, do not apply more than 0.86 lb ai/A per growing season. 1 - 14 12 -hour REI; 14 - day interval between apps; For ground applications, do not use less than 20 gallons of wat er per acre (10 gallons of water per acre for cotton). For air applications, do not use less than 5 gallons of water per acre. For air applications for cotton, do not use less than 3 gallons of water per acre.

S tone F ruit (Crop Group 12), Tree Nuts (Crop Group 14) 0.29 lb ai/A

(28 fl oz product/A) 0.57 lb ai/A

per growing season 14 12 -hour REI; 10 - day interval between apps for stone fruit; 14 - day interval between apps for tree nuts; For ground applications, do not use less than 50 gallons of water per acre. For aerial applications, do not use less than 10 gallons of water per acre. Tea * Not

Specified Not

Specified Not

Specified Foliar application using ground equipment Ornamental plants in greenhouses, lath and shadehouses, nurseries, landscape ornamentals, ground covers, field - and container- grown ornamentals, non - bearing fruit and nut trees, vines in nurseries and Christmas trees 1.36 lb ai/A 2.72 lb ai/A per crop cycle 1 Apply no more than 10 gal of spray solution per 1,000 ft2 per application (100 gal per 20,000 ft2 typically cover greenhouse or nursery stock). Apply no more than 2 applications per crop cycle (64 fl oz). Allow at least 10 days between applications.

† For Tolfenpyrad 15EC I nsecticide (EPA Reg . No. 71711 - 31) - The proposed label has PPE requirements for early entry into treated areas which include: coveralls worn over short - sleeved shirt and short pants, socks, protective eyewear, chemical - resistant gloves and footwear. For Tolfenpyrad 15SC I

ns ecticide (EPA Reg . No. 71711 - GA) - The proposed label has PPE requirements for early entry into treated areas which include: long - sleeved shirt and long pants, shoes plus socks, protective eyewear and waterproof gloves. **‡** Max single application rate f or T olfenpyrad 15EC I

nsecticide (EPA Reg . No. 71711 - 31) = (28.0 fl oz/A) (1.29 lb ai/gal) (1.0 gal/128 fl oz) = 0.28 lb ai/A. Max single application rate f or Tolfenpyrad 15SC I

nsecticide (EPA Reg . No. 71711 - GA) = (28.0 fl oz/A) (1.31 lb ai/gal) (1.0 gal/128 fl oz) = 0.29 lb ai/A. * A label including the proposed use on tea is not available. HED has assumed the proposed use pattern is for application at 0 .401 - 0.535 lb ai/A (450 - 600 g ai/ha) and a 14 - day PHI based on information in the administrative materials submitted with the petition. 

### 3.4 **Anticipated Exposure Pathways**

### Tolfenp yrad Human Health Risk Assessment DP No. 383820

Page 14 of 65 As a result of the registered and proposed uses of tolfenpy rad, humans may experience dietary exposure to tolfenpy

rad residues via their food and drinking water. At this time, there are no registered or proposed uses of tolfenp yr ad that are likely to result in other exposures in a non occupational setting. In occupational setting s , exposure may occur during pesticide handling the pesticide prior to and during application. Furthermore, there is potential for postapplication exposure to workers who enter treated fields or greenhouses after the pesticide has been applied . These exposures occur via dermal and/or inhalation routes. For both occupational and non - occupational settings, this risk assessment considers all of the relevant exposure pathway s, combining them as appropriate, to estimate overall exposure and risk. **3.5 Consideration of Environmental Justice**  In accordance with U.S. Executive Order 12898 1 

### , p otential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment . As a part of every pesticide risk assessment, OPP considers a large variety of consumer subgroup s according to well - established procedures. In line with OPP policy, HED estimates risks from pesticide exposures to population subgroups that are based on patterns of that subgroup’s food and water consumption . Extensive data on food consumption pattern s 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 b y 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 when conditions or circumstances warrant. For pesticides used in a residential or public setting, exposure s from those uses are evaluated for adult applicators and for toddlers, youths, and adults entering treated areas after application . Techniques and policies are currently in development to address exposure to by standers and farm workers as well as unique exposures associated with lifestyle s and traditional dietary patterns among specific subgroups. **4.0 Hazard Characterization and Dose**  **- Response Assessment**  **4.1 Toxicology Studies Available for Analysis**  Based on the proposed use pattern, all require d studies for tolfenpy rad have been submitted. Since the last risk assessment (K. Middleton, D354437), the Registrant has submitted additional data for tolfenp yr ad , including a comparative in vitro dermal absorption study using human and rat skin (MRID4823 3401) and a range - finding inhalation toxicity study in rats (MRID 48250484). These studies have been reviewed and considered in the current risk assessment. The available toxicology

database is sufficient for assessing the toxicity and characterizing the hazard of the chemical. The available toxicology studies for tolfenpy

rad include subchronic and chronic oral toxicity

studies in rats, mice, and dogs, dermal studies (28 - day dermal toxicity, in 1 "Federal Actions to Address Environmental Justice in Minority Populations and Low - Income Populatio ns " (http://epa.gov/compliance/ej/resources/policy/exec_order_12898.pdf )

### Tolfenp yrad Human Health Risk Assessment DP No. 383820

Page 15 of 65 vivo dermal penetration, comparative in vitro dermal penetration in human and rat skin), carcinogenicity

studies in rats and mice, an inhalation toxicity study , developmental studies in rats and rabbits and a reproduction study in rats, acute and subchronic neurotoxicity studies in rats, immunotoxicity

(developmental), rat metabolism and a complete mutagenicity battery. A literature search did not reveal information that would impact the hazard or risk assessment. **4.2 Absorption, Distribution, Metabolism, & Elimination (ADME)**  Several metabolism studies were conducted with radiolabeled tolfenpy rad in rats (MRIDs 47447837, 47447836, 47447834). Overall, absorption, excretion, and metabolism of the test compound were rapid. Following a single oral dose, radioactivity was detected in the blood 0.5 h after administration. Blood concentrations of radioactivity plateaued after the third day in the multiple dose study, suggesting there was no bioaccumulation following repeated administration. The highest concentrations of radioactivity were observed in the liver, kidn ey , brown fat and heart, with a redistribution that also included white fat, bone marrow and skin over time. Radioactivity

concentrations dropped substantially from 12 to 168 h post - dosing. Tolfenp yrad was excreted in a rapid and dose - dependent manner following a single exposure. After a 1 mg/kg single dose, approximately 67% of the administered dose (AD) was eliminated during the first 24 h post - dosing, increasing to 85% AD at 48 h. In the 20 mg/kg single dose groups, excretion was somewhat slower, with up to 30% AD eliminated during the first 24 h post - dosing, increasing to up to 70% AD at 48 h. Feces were the predominant route of excretion, accounting for up to 93% AD; residues in urine, expired air, and cage wash were negligible. Administration o f repeated daily doses had no effect on the route of excretion or the extent of recovery . Tolfenp yr ad was metabolized by oxidation to form a number of hydrox yl ated metabolites (Pt - CA, OH - PT and OH - PT - CA), followed by conjugation (glucuronide, sulfate, asp aragines or taurine). The primary metabolite, PT - CA was found in plasma, liver, kidney , and fat (<5%), along with taurine - conjugated and hydrox yl ated forms, in the bile at 4.6 - 22.3%. Higher levels of PT - CA were found in the feces (9.0 - 36.2% AD); however , it was stated in the study that the additional PT - CA is likely formed by

the action of the enterobacteria in the gut. Parent was identified in the feces at onl y at 0.3 - 14.8% AD, and the amount decreased with time. There were no significant differences observed in the blood pharmacokinetic parameters between the [PY 14 

### C] - and [TO 14 

### C] - label positions in the single or multiple dose studies. However, in animals given multiple doses of py razole - labled ( 14 

### C) tolfenpy rad, blood levels of radioactivity were a pproximately

2 - to 3 - fold higher in females than in males. Females also had more radioactivity

remaining in the gastrointestinal tract, and the amount remaining increased with dose. Conversel y, absorption (defined as radioactivity found in the bile, urin e, cage wash, and carcass) was greater in males (72.8 - 77.8% AD) than in females (57.9 - 69.4% AD ). **4.2.1 Dermal Absorption**  An in vivo dermal absorption study in rats is available for tolfenpy rad. After 24hrs, in the 1 g/L group, the absorbable and absorbed dose accounted for 39.8% of the applied dose. Additi onally , in vitro dermal absorption data have been recently submitted and demonstrate s

### Tolfenp yrad Human Health Risk Assessment DP No. 383820

Page 16 of 65 that tolfenpy

rad absorption in human skin is significantly (10x) lower than in rat skin. (see section A. 3 ) . **4.3 Toxicological Effects**  A variety of toxic effects were noted in the toxicology database for tolfenp yrad. However, the most consistent finding across species and studies was effects on body weight and body

weight gain. Decreases in body

weight and/or body weight gain were observed in adults of all species (rat, mice, rabbit, and dog) in the majority of the subchronic oral and dermal toxicity studies, and all chronic toxicity

studies. The rat is the species most sensitive to body weight changes, wi th effects observed at much lower doses than in other species. In rats, significant decreases in body weight and body weight gain were observed in subchronic oral and acute and subchronic neurotoxicity studies. Decreases in body weight and body weight gain were also seen in chronic rat studies but at lower doses than observed in the other rat studies. A lthough seen at lower doses, the body weight decrements noted in the chronic study were not as pronounced as seen after subchronic exposure or in the neurotoxicity

studies. Decreases in body weight and body

weight gain were also observed in reproduction, developmental toxicity, and developmental immunotoxicity studies at doses comparable to the chronic studyBody weight changes observed in other species were similar in magnitude to those in rats, but were observed at higher doses. Significant decreases in body weight and body

weight gain were seen in both mice and dogs after subchronic exposure; these effects were also noted in rabbits in a developmental toxicity study . Chronic exposure resulted in body

weight and body

weight gain decreases in mice and do gs at lower doses. The severity of body weight changes increased with dose in mice while body weight effects in dogs were seen onl y at the highest dose tested (HDT). The body weight changes observed in the database were most often seen in the presence o f decreased food consumption and in some studies, additional toxicity including liver/kidney effects and clinical signs. Increased liver and kidney weights, liver and kidney hy pertrophy , hyaline droplets in the kidney , and color change in the kidney were seen after subchronic exposure in rats. Chronic exposure resulted in similar effects along with color changes in the liver and liver histopathology at slightl y lower doses than in the subchronic studies. Other effects noted in rats were effects on the harderian gland and ly mph nodes. In dogs, both liver and kidney

histopathology , along with testicular atrophy and clinical signs (emaciation, decreased movement, and staggering gait) were seen in short- term studies. Long - term exposure resulted in histopatho logy in the liver onl y, along with increased liver enzymes. No treatment related effects were noted in the liver or kidney in mice. However, rough coats, hunched posture, ataxia, and hypoactivity were seen in subchronic studies. Missing ears and ear lesi ons (scabs, sores, ulceration, and inflammation) were seen in a chronic toxicity study . The ear lesions observed were likely self inflicted since the mice in the study were individually

caged. No explanation was given to why the lesions occurred and the toxicological significance of this finding is unclear. Moribundity

and/or mortality

were noted in at least one study in all species at ≥ 3 mg/kg/day . Moribundity

and mortality

were noted in two dams in a rat reproduction study , and mortality was

### Tolfenp yrad Human Health Risk Assessment DP No. 383820

Page 17 of 65 noted in one dam in a rabbit developmental toxicity study. Mortality was also observed in two animals in an inhalation toxicity study (range - finding onl y). In mice and dogs, mortality was observed in both subchronic and chronic toxicity studies. In all cases, effects were observed in the presence of body weight changes and the points of departure (POD) are protective of the observed mortality . There is n o evidence of increased quantitative or qualitative susceptibility in the guideline rat and rabbit developmental s tudies , or the rat reproduction study . Although s everal adverse effects were noted in young animals in these studies , the effects were observed in the presence of significant maternal toxicity (significant body weight changes and/or moribundity /m ortality). In a non - guideline rat developmental immunotoxicity (DI T) study , a potential increase in qualitative susceptibility

was seen. In the study, decreased survival, body weight, body weight gain, increased blackish abdominal cavity, and dark green abnormal intestinal contents were observed in offspring animals at 3 mg/kg/day . At the same dose, decreased body weight (up to 10%), body weight gain (up to 36%) and food consumption were seen in maternal animals. There was no evidence of immunotoxicity observed in the study . No evidence of neurotoxicity was observed in acute and subchronic neurotoxicity studies for tolfenpy rad. Although hunched posture, ataxia, and hy poactivity

were seen in mice in a 28 day toxicity study , these effects were not seen in a 90 day study or after chronic exposure. In dogs, decreased spontaneous movement, and staggering gait were observed after 13 weeks. In rats, decreased motor activity

and prone position (lying face down) prior to death were noted in a reproduction study . Overall, the effects noted in the database were agonal effects mainly seen at high doses, not associated with neuropathology , and not noted in long - term studies. The effects observed are consistent with the mode of action for tolfenp yrad (mitochondrial inhibitor) and are not considered evidence of neurotoxicity . No evidence of carcinogenicity was observed in cancer studies with mice and rats. Therefore, in accordance with EPA’s Final Guidelines for Carcinogen Risk Assessment (March, 2005), tolfenpy rad is classified as “not likely to be carcinogenic to humans. ” **4.4 Safety factor for Infants and Children (FQPA Safety Factor)**  HED recommends that the required 10x FQPA safety factor be reduced to 1x. This recommendation is based on the following considerations: 1) the toxicological database is complete , and includes acceptable developmental and reproductive toxicity studies ; 2) while there was evidence of qualitative susceptibility in one study , HED ’s concern for the susceptibility

is low because it was not observed in other studies with tolfenpy rad, there was a clear NOAEL/LOAEL, and because endpoints and doses selected for risk assessment are protective of the susceptibility ; 3) there is no evidence of neurotoxicity in the submitted neurotoxicity studies, and a developmental neurotoxicity study is not required; and 4) the exposure assessment, although it includes some level of refinement, does not underestimate potential dietary

exposure to tolfenpy

rad ; there are no residential exposures at this time . **4.4.1 Completeness**  **o f**  **the Toxicology Database** 

### Tolfenp yrad Human Health Risk Assessment DP No. 383820

Page 18 of 65 The toxicology

database is complete for tolfenpy rad. The toxicity

profile can be characterized for all effects, including potential developmental and reproductive toxicity , immunotoxicity and neuroto xicity . Acceptable studies for developmental toxicity in rats and rabbits, developmental immunotoxicity, 2 - generation reproduction in rats, and neurotoxicity are available. **4.4.2 Evidence of N**  **eurotoxicity** The level of concern for neurotoxicity is low for tolfenpy

rad . N o neurotoxic effects were observed in the acute or subchronic neurotoxicity studies in rats. Although clinical signs were seen in dogs and mice , the effects are well characterized with clear NOAELs and LOAELs. Additionally , the effects were agonal, mainl y seen at high doses, not associated with neuropathology , and not noted in long - term studies . Based on the weight of the evidence, a developmental neurotoxicity study is not warranted at this time. **4.4.3 Evidence**  **o f Sensitivity/Su**  **s ceptibility in the Developing o**  **r Young Animal** Although there seems to be increased qualitative susceptibility in the young in the developmental immunotoxicity

study (DIT) in rats, there is low concern and there are no residual uncertainties regarding increased quantitative or qualitative pre - and/or postnatal susceptibility for tolfenpy rad . When the DIT study is considered along with the r eproduction study , the offspring toxicity in the DIT study w as observed at the same dose as comparable maternal toxic ity (moribundity

/mortality) in the reproduction study . Therefore, HED does not consider the isolated incident in the DIT a true indicator of qualitative susceptibility . Additionally, the effects observed in the DIT study are well characterized, a clear NOAEL was identified , and the endpoints chosen for risk assessment are protective of potential offspring effects. **4.4.4 Residual**  **Uncertainty in the Exposure Datab ase**  There are no residual uncertainties with regard to the exposure assessment . The acute dietary exposure assessment i s based on high - end health protective residue levels (that account for parent and metabolites of concern), processing factors, and percent crop treated assumptions (100%). The chronic dietary assessment incorporates some refinement in that average residue values were used and projected percent crop treated estimates were used for a few crops. For both the acute and chronic dietary exposure, a ctual exposure s to tolfenpy rad will likely

be lower than the estimated exposures . Furthermore, conservative, upper - bound assumptions were used to determine exposure through drinking water, such that these exposures have not been underestimated . There are no residential exposure scenarios at this time. **4.5 Toxicity Endpoint and Point of**  **D eparture Selections**  **4.5.1 Dose**  **- Response Assessment**  The detailed descriptions of the toxicity studies used for selecting toxicity endpoints and points of departure for various exposure scenarios are presented in section A. 4 of Appendix A.

### Tolfenp yrad Human Health Risk Assessment DP No. 383820

Page 19 of 65 For acute diet ary

exposure, an acute reference dose (aRfD) of 0.1 mg/kg/day was selected for assessment of the general population, based on a NOAEL of 10 mg/kg/day in an acute neurotoxicity

study in rats. At the L OAEL of 20 mg/kg/day , decreased body weight, body weight gain, and food consumption were seen. The effects were observed after a single dose exposure in a dietary

study and are considered appropriate for acute dietary exposure. No separate endpoint was identified for acute dietary exposure for females 13 - 49 years of age. For chronic dietary

exposure, a chronic reference dose (cRfD) of 0.006 mg/kg/day was selected for assessment of all populations, based on a NOAELof 0.6 mg/kg/day from a combined chronic/carcinogenicity s tudy in rats. D ecreased body weight, body weight gain and food consumption, changes in the harderian glands (found in the eye), histopathological changes in liver, kidney

and l ymph nodes were observed at the LOAEL of 1.5 mg/kg/day . Chronic mouse and dog studies were also considered f or chronic dietary

exposure; however, the chronic rat study provided the most sensitive endpoint for chronic dietary risk assessment. Previously , short - , intermediate - , and long - term dermal risk assessments were done for tolfenpy rad. For dermal exposures , a route - specific 21 - day dermal toxicity

study in rats was used for endpoint selection. Although no s ys temic toxicity was seen in the study , the NOAEL of 200 mg/kg/day

was used as a POD since the study did not test up to the limit dose of 1000 mg/kg/day . Additionally , an extra 3x uncertainty factor (subchronic to chronic) was applied to long - term dermal risk assessments since a short - term (21 - day) dermal study was used to assess long - term dermal exposure ( > 6 months) . Recently , the registrant submitted additional dermal data for tolfenp yr ad. Based on the anal ys is of the newly submitted data (Appendix A.3) and the lack of toxicity in the dermal study , HED concluded that no dermal hazard is identified for tolfenpy rad. Therefore, short - , and intermediate - t erm dermal risk assessments were not performed . A long - term dermal risk assessment was not performed since long - term exposure is not expected from the proposed use pattern. For short - and intermediate - term inhalation exposures, a 4 - week inhalation study wa s selected. No toxic effects were observed up to the NOAEL of 10 mg/m 3 

### and the LOAELwas not determined. However, body weight changes and mortality were observed in a range - finding study at 26 mg/m 3 

### (6.8 mg/kg/day). A clear NOAELwas identified at the next lowest dose of 10.9 mg/m 3 

### , which is comparable to the dose in the definitive study where no effects were seen ( 10 mg/m 3 

### ). HED used the NOAEL of 10 mg/m 3 

### ( EPA calculated dose = 2.6 mg/kg/day) from the definitive 4 - w eek inhalation study and the LOAELof 26 mg/m 3 

### ( 6.8 mg/kg/day) from the range - finding inhalation study for inhalation risk assessment. Based on the proposed use pattern for tolfenp yr ad, long - term inhalation exposure is not anticipated **4.5.2 Recommendation**  **for Combining Routes of Exposures for Risk Assessment** HED has considered oral, and inhalation routes of exposure in its assessment of tolfenpy rad. It is appropriate to combine routes of exposures when such exposures result in the same toxicological effe cts. In the case of tolfenp yrad, the PODs were based on different toxicological effects following oral and inhalation routes of exposure, and thus, these exposures were not combined in determining aggregate risks from exposure to tolfenpy rad.

### Tolfenp yrad Human Health Risk Assessment DP No. 383820

Page 20 of 65 **4.5.3 Cancer Classification and Risk Assessment Recommendation**  There was no evidence of carcinogenicity in cancer studies with mice and rats. Therefore, in accordance with EPA’s Final Guidelines for Carcinogen Risk Assessment (March, 2005), tolfenpy rad is clas sified as “not likely to be carcinogenic to humans. ” **4.5.4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk**  **Assessment** Table 4.5.4a Summary of Toxicological Doses and Endpoints for Tolfenpyrad for Use in Dietary and Non Occupational Human 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= 10

mg/kg/day UF A= 10 x

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

0.1 mg/kg/day aPAD = 0.1 mg/kg/day LOAEL=20 mg/kg/day from an acute

neurotoxicity study in rats, based on decreased body weight body weight gain and food consumption. Chronic Dietary (All Populations) NOAEL= 0.6

mg/kg/day UF A= 10 x

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

0.006 mg/kg/day cPAD = 0.006 mg/kg/day LOAEL = 1.5 mg/kg/day from a

combined chronic/carcinogenicity in rats, based on decreased body weight, body weight gain, and food consumption of females, gross changes in the Harderian glands of males, and histopathological changes in the liver, kidney and mesenteric lymph nodes of females and the kidney of males. Cancer (oral, dermal, inhalation) Classification: “Not likely to be Carcinogenic to Humans” based on the absence of significant

tumor increases in two adequate rodent carcinogenicity studies. 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). UF S = use of a short - term study for long - term risk assessment. FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. Table 4.5.4b Summary of Toxicological Doses and Endpoints for Tolfenpyrad for Use in Occupational Human Health Risk Assessments. Exposure/ Scenario Point of Departure Uncertainty

Factors Level of

Concern for Risk Assessment Study and Toxicological Effects Dermal Short - Term

And Intermediate - Term (Up to 6 months of exposure) A quantitative d ermal risk a ssessment was not conducted based on a lack of dermal toxicity. Dermal Long - Term

(>6 mo nths) Long - term dermal exposure is not expected based on use pattern .

### Tolfenp yrad Human Health Risk Assessment DP No. 383820

Page 21 of 65 Table 4.5.4b Summary of Toxicological Doses and Endpoints for Tolfenpyrad for Use in Occupational Human Health Risk Assessments. Exposure/ Scenario Point of Departure Uncertainty

Factors Level of

Concern for Risk Assessment Study and Toxicological Effects Inhalation Short - Term And Intermediate - Term (Up to 6 months of Exposure) NOAEL= 2.6 mg/kg/day UF A= 10 x

UF H=10 x Occupational

LOC for MOE = 100 LOAEL=6.8 mg/kg/day, based on

body weight changes and mo rtality observed in a range - finding inhalation study. NOAEL = 2.6 mg/kg/day. Cancer (oral, dermal, inhalation) Classification: “Not likely to be Carcinogenic to Humans” based on the absence of significant tumor increases in two adequate rodent carcino genicity studies. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). MOE = margin of exposure. LOC = level of concern. 

### 5.0 **Dietary Exposure and Risk Assessment 5.1**  **Metabolite/Degradate Residue Profile 5.1.1**  **Summary of Plant and Animal Metabolism Studies**  The petitioner has submitted acceptable studies depicting the metabolic fate of tolfenp yrad in target crops, rotational crops, and livestock. All studies were conducted in a manner appropriate for the proposed uses and consi sted of two sets of data. In the first set, tolfenpyrad was radiolabeled in the tol ylmoiety (TO) ; in the second set, the radiolabel was in the py razole ring (PY). The target - crop studies were conducted with radish, eggplant, peach, and cabbage; the rotational - crop studies with radish , lettuce, and wheat (each at plant - back intervals of 30, 120, and 365 day s) ; and the livestock studies with laying hens and lactating goats. In the primary

crop metabolism studies, tolfenpy rad was the major identified resid ue in all primary crops. The metabolic pathway for tolfenpy

rad was generally

similar in all primary crops, with the most extensive metabolism observed in cabbage. Based on the submitted studies, the petitioner proposed that tolfenpy rad is metabolized via : hydroxylation of the ethyl side chain of the py razole ring; hydroxylation of the methylgroup of the tolyloxy benzyl moiety; carbox yl ation; oxidative degradation of the py razole ring and tolyloxy

benzyl moiety (probabl y via hydrox yl ation of the benzyl m ethyl ene moiety); hydrol ys is of the amide bond; and oxidation of the alkylgroup of the tolyl benzyl moiety following cleavage . Cleavage near the amide bond appeared to be a more predominant metabolic pathway in radish root. Two metabolites, PT - CA2 

### and OH - PT - OH were identified in all primary crops; metabolites OH PT, PT - OH, PT - CHO, and CO - PT were identified in all crops except radish; and metabolites OH - PAM and PAM were identified in all crops except eggplant. Metabolites were generally minor (< 10% to tal radioactive residue; TRR) residue components, with the following exceptions: PT - CA (free and conjugated) at up to 17% TRR in peach leaves and 22% TRR in radish root, CA - T - CA (free and conjugated) at up to 11% TRR and OH - PAM at up to 9% TRR in peach l eaves, and PAM at up to 10% TRR in radish root. 2 See Appendix B for structures of the parent com pound and metabolites.

### Tolfenp yrad Human Health Risk Assessment DP No. 383820

Page 22 of 65 The metabolism studies with peach, eggplant , and cabbage included components to assess translocation of tolfenp yr ad. The results of these studies indicate that translocation of residues is very limited and that radioactivity moves onl y to the edge of the treated leaves , likely as a result of transpiration . In rotational crops, tolfenpy rad was ext ensively

metabolized and was not identified in any crop except at trace levels only (<0.001 ppm) in TO - label 120 - day lettuce and 30 - day

radish tops . The only metabolite identified in both PY - and TO - label crops was PT - CA (in radish tops) . In PY - label crops, OH - PAM and OH - PCA (free and conjugated) were major residues in nearl y all matrices at nearl y all PBIs . P AM was also a major residue in PY - label radish tops and roots, and PT - CA was a major residue in TO - label lettuce and radish tops . Based on the confined rotational crop study , the petitioner concluded that most of the residues in rotational crops result from cleavage of the amide bond, resulting in p yrazole and diphenylether fragments . The diphenyl ether portion produces minimal residues . The more polar p yr azole portion is initially present as the amide (PAM) which is generall y a minor metabolite . PAM i s hydrolyzed to the corresponding acid (PCA) or oxidized to the major metabolite OH - PAM . PCA is also oxidized to major metabolite OH - PCA . With increasing time, both OH - PCA and OH - PAM are present as conjugates . Tolfenp yrad was extensively metabolized in livestock and was a minor residue in livestock matrices, except fat. The major residue in all matrices was PT - CA. OH - PT - CA was also a major residue in goat liver and kidney , and PCA was a major residue in milk, eggs, and fat. We note that PCA was not d etected in the ruminant feeding study . Based on the submitted studies, metabolism of tolfenpy

rad in goat and hen proceeds initially by oxidation of tolfenpy

rad at the tolyl methyl group to form PT - CA , and PT - CA undergoes further oxidation at the py razole ethyl group to produce OH - PT - CA . The secondary metabolic routes differ in goat and hen. In goat, PT - CA may

also undergo hydrol ys is to produce metabolites PCA and CA - T -NH 2 

### ; PT - CA and these hydrolysis metabolites are then bound to nonpolar lipids in milk and fat. In hen, tolfenpy rad may also undergo oxidation at the methylene group next to the amide bond to produce the intermediate PAM, followed by hydrolysis to produce OH - PAM. PT - CA may undergo hydrol ys is to form PCA, and these metabolites are bound to nonpolar lipids in eggs and fat. **5.1.2 Summary of Environmental Degradation**  Drinking Water Exposure Assessment for Proposed New Uses of Tolfenpyrad on a Variety of Agricultural Crops, Nurseries, and Christmas Trees, L. Liu, D383822, 23 January 2012 

### Bas ed on the submitted environmental fate data and reported phys ic o chemical properties, tolfenpy rad and its transformation products are expected to moderatel y degrade in the environment. In the laboratory , tolfenpy rad degraded to PAM, PCA, PT(A) - 4OH, PT - CA , PT - CHO, PT - OH, OH - PAM, and OH - PT - OH . These breakdown products occurred under conditions to investigate aqueous and soil photolyis, aerobic and anaerobic soil dissipation, and aerobic and anaerobic aquatic dissipation. In these s ys tems, half - lives range d from approximately two weeks to over

### Tolfenp yrad Human Health Risk Assessment DP No. 383820

Page 23 of 65 one year. The longest half - lives are associated with anaerobic conditions and the shortest with aerobic conditions; photolysis driven dissipation had half lives on the order of three to six weeks. Tolfenp yrad has a propensity to bind to soil/sediments and is expected to be essentiall y immobile. Therefore, it is not expected to leach to ground water. However, t olfenpy rad does have the potential to contaminate surface water via spray drift and runoff of residues sorb ed to sediment. Under terrestrial field conditions, tolfenpy rad rapidl y degraded to PCA and PT - CA (half - lives = 1.8 - 6.6 days). PCA and PT - CA are expected to be highl y mobile. **5.1.3 Comparison of Metabolic Pathways**  In treated crops, metabolism of tolfenpy rad can be expected to be quite minimal, with parent compound comprising the majority of the residue. As evidenced by the confined rotational crop study and the environmental fate studies, once tolfenpy rad reaches the soil, it can be expected to undergo extensive degradation, with portions of the molecule ultimately forming CO 2 

### or being tied up as bound residue. The available data from studies with rats, goats, and hens indicates that tolfenpy rad is rapidl y taken up following oral exposure and then metabolized by oxidation to form a number of hydroxylated metabolites (principally P T - CA, OH - PT and OH - PT - CA), followed b y conjugation (glucuronide, sulfate, asparagines or taurine) . Of the major metabolites identified in plant, liv estock, rotational crop, and environmental fate studies, only

PT(A) - 4OH was not observed in the rat study . **5.1.4 Residues of Concern Summary and Rationale**  The toxicological and residue chemistry databases for tolfenpy

rad have been examined to determine r esidue definitions for tolerance - setting and risk - assessment purposes. The residue definitions are summarized in Table 5. 1 .4 and are in keeping with the recommendations of the Residues of Concern Knowledgebase Subcommittee (ROCKS; D395592, 18 January 2012 ). Table 5.1.4 Residue Definitions for Tolfenpyrad. Matrix Risk Assessment Tolerance Expression Plants Primary Crop Tolfenpyrad + PT - CA 1 (root crops only) Tolfenpyrad

Rotational Crop -- 2

-- Livestock Ruminant Tolfenpyrad + PT - CA + OH - PT - CA 3 Tolfenpyrad + PT - CA

Poultry Tolfenpyrad + PT - CA + PCA Tolfenpyrad + PT - CA Drinking Water Tolfenpyrad + PT - CA + PCA + PAM + PT(A) - 4 - OH Not Applicable 1 The metabolite abbreviations used here (i.e. "PCA" and "PAM") are specific for the metabolites depicted in the table. These abbreviations are not intended to represent other chemicals with similar, but not identical, structures containing other groups su bstituted using similar abbreviations. 2 Residues of concern in rotational crops are not expected as a result of the proposed use patterns. 3 OH - PT - CA should be limited to ruminant liver, kidney and other meat byproducts. 

### The above residue definitions are based on the following rationale: Plants (Primary Crops) . With the exception of root crops, the only major residue observed in target - crop metabolism studies is parent tolfenpy rad. In radish root, the PT - CA metabolite was observed at 10 and 21% TRR (PY and TO labels, respectivel y). Tolfenp yr ad alone is sufficient

### Tolfenp yrad Human Health Risk Assessment DP No. 383820

Page 24 of 65 for tolerance enforcement in all crops. PT - CA is structurall y similar to tolfenpyrad and is assumed to have similar toxicity to the parent compound; therefore, it is included in risk assessments for root crops. Plants (Rotational Crops). Parent tol fenp yr ad was not observed at any plant - back interval in rotated crops in either the confined rotational crop study (lettuce, radish, and wheat) or the limited field rotational crop study (lettuce, radish, and sorghum). Major metabolites observed in rotati onal crops in the confined study were OH - PAM, OH - PCA (free and conjugated), PAM in radish root, and PT - CA in lettuce and radish tops (not at all time points). Samples from the limited rotational crop study were anal yz ed for tolfenp yrad, PAM, OH - PAM (conjugates and hydrol ys is products), and OH - PCA (conjugates and hydrol ys is products). No residues of these compounds were observed (LOQ = 0.01 ppm) in the limited field rotational crop study at any plant - back interval of 14 days or greater. Therefore, no resi dues were selected for this scenario. However, if the use pattern changes in the future, this scenario may need to be reassessed. Livestock. In lactating goat and laying hen metabolism studies, parent compound was a major residue in fat, PT - CA was a maj or residue in all matrices, OH - PT - CA was a major residue in most lactating goat matrices, and PCA was a major residue in milk, eggs, and fat. However, PCA was not detected in the ruminant feeding study , so it can be excluded from the ruminant dietary risk assessment. Furthermore, OH - PT - CA need onl y be considered in the dietary risk assessment for ruminant liver, kidney , and other meat by products. The analy

tical method has been validated for parent, PT - CA, OH - PT - CA, and PCA (milk and fat only), and includ es a hydrol ys is step to convert conjugated forms of these metabolites to the free form. In the absence of toxicity

data, PT - CA and OH - PT - CA are included in the dietary risk assessment since they are structurally

similar to the parent compound. PCA, altho ugh structurally different from the parent compound and not likely

to be more toxic than the parent, is also included in the dietary risk assessment in the absence of any toxicity data. The residues to be included in the tolerance expression are p arent an d PT - CA, since parent residues alone would not be an adequate marker for misuse. Water . The major transformation products resulting from the degradation of tolfenpy rad are PAM, PCA, PT - OH, PT - CHO, PT(A) - 4OH and PT - CA . Of these six major degradates, ther e is more concern for PCA, PT - CA, PT(A) - 4OH, and PAM due to their high residue levels. Concern is reduced for PT - CHO and PT - OH because they were onl y formed via aqueous photolysis, which is not likely

to be the dominant route of degradation. As noted previously , PT - CA and PCA are included in the dietary risk assessment in the absence of any toxicity data. Although PT(A) - 4OH and PAM are structurall y different from the parent compound, in the absence of toxicity data they are also be ing included in the dietary assessment. **5.2 Food**  **Residue Profile**  The petitioner has submitted acceptable crop field trial data on potato, leafy vegetables (head and leaf lettuce, celery , and spinach), Brassica leafy vegetables (cabbage, cauliflower, and mustard greens), fruiting vegetables (tomato and bell and non - bell pepper), cucurbit vegetables (cucumber, cantaloupe, and summer squash), citrus fruits (orange, grapefruit, and lemon), pome fruits (apple and pe ar), stone fruit (cherry , peach, and plum), grape, tree nuts (almond and

### Tolfenp yrad Human Health Risk Assessment DP No. 383820

Page 25 of 65 pecan), cotton, and tea. Quantifiable residues were observed in/on all crop commodities except potato and pecan nutmeat (Table 5.2.1) . Residue data indicate that residues generall y declined or did not increase with increasing pre - harvest interval in all crops tested. The available data are adequate for risk assessment and tolerance assessment. In addition to the target crop field trials, the petitioner also submitted limited field rotational crop studies. Following the last of two applications of a 1.25 lb ai/gal EC formulation of tolfenpy rad to a primary

crop of mustard greens at a total rate of 0.5 4 lb ai/A, residues of tolfenp yrad , PAM, OH - PAM, and OH - PCA were below the LOQ ( < 0.01 ppm) in/on all samples of lettuce (leaf), radish (roots and tops), or sorghum (forage, grain, and stover) at the 14 - and 28 - to 30 - day PBI s, and in/on radish top an d lettuce leaf samples at the 58 - to 60 - day PBI. Residues are not expected in rotational crops. Adequate processing studies were submitted for apple, cotton, grape, orange, plum, potato, and tomato. The studies reflected application of tolfenpy rad at ~5 x exaggerated rates, and the raw agricultural commodities (RACs) were processed into the appropriate processed commodities. The data indicate that residues do not increase in any juice commodity

but do tend to concentrate in dried commodities (Table 5.2.2 ) . Table 5.2.1. Summary of Residues from Field Trials Conducted with Tolfenpyrad. Commodity Total App.

Rate (lb ai/A) EP 1 PHI

(days) Residue Levels (ppm) 2 n Min. Max. HAFT 3 Median Mean Std. Dev. **POTATO (proposed use = 0.42 lb ai/A total application rate; 14**  **- day PHI)**  Potato Tuber 0.403 - 0.426 EC 13 - 14 16 <0.01 <0.01 0.01 0.01 0.01 NA 4 **LEAFY VEGETABLES CROP GROUP 4 (proposed use = 0.42 lb ai/A total application rate; 1 -**  **day PHI)** Leaf Lettuce 0.403 - 0.412 SC 1 6 0.873 13.3 13.3 4.46 5.45 4.15 Head Lettuce 0.399 - 0.420 SC 1 6 0.1 3.43 3.43 1.52 1.53 1.08

0.399 - 0.419 EC 1 6 0.143 3.74 3.74 1.73 1.65 1.22 Celery 0.403 - 0.413 SC 1 6 0.279 5.33 5.33 2.4 2.71 2.27 Spinach 0.400 - 0.417 SC 1 6 4.96 14.2 14.2 10.9 9.88 3.53 **BRASSICA LEAFY VEGETABLES CROP GROUP 5 (proposed use = 0.42 lb ai/A total application rate; 1**  **- day PHI)**  Cauliflower 0.394 - 0.422 SC 1 6 <0.01 0.521 0.521 0.216 0.247 0.257

0.406 - 0.416 EC 1 6 <0.01 0.441 0.441 0.015 0.15 0.214 Cabbage 0.409 - 0.415 SC 1 6 0.817 2.08 2.08 1.365 1.427 0.551 Mustard Greens 0.409 - 0.415 SC 1 5 1.84 18.6 18.6 7.01 8.62 6.16 **FRUITING VEGETABLES CROP GROUP 8 (proposed use = 0.42 lb ai/A total application rate; 1 -**  **day PHI)** To mato 0.404 - 0.428 SC 1 12 0.064 0.502 0.502 0.108 0.152 0.121

0.405 - 0.421 EC 1 11 0.049 0.175 0.175 0.079 0.096 0.046 Bell Pepper 0.407 - 0.413 SC 1 6 0.046 0.158 0.158 0.078 0.09 0.04 Non - bell Pepper 0.411 - 0.415 SC 1 3 0.125 0.289 0.289 0.284 0.233 0.093 **CUCURBIT VEGETABLES CROP GROUP 9 (proposed use = 0.85 lb ai/A total application rate; 1**  **- day PHI)**  Cucumber 0.818 - 0.841 EC 1 6 0.023 0.241 0.241 0.119 0.12 0.08 Cantaloupe 0.816 - 0.833 EC 1 6 0.077 0.34 0.34 0.249 0.23 0.101 Summer Squash 0.815 - 0.834 EC 1 5 0.019 0.077 0.077 0.044 0.047 0.023

**CITRUS FRUITS CROP GROUP 10 (proposed use = 0.54 lb ai/A total application rate; 14**  **- day PHI)**  Orange 0.525 - 0.547 EC 14 8 0.24 0.828 0.828 0.436 0.453 0.199

0.529 - 0.543 SC 14 10 0.189 0.56 0.56 0.355 0.364 0.12 Grapefruit 0.526 - 0.546 EC 14 - 15 6 0.073 0.339 0.339 0.194 0.205 0.117

0.540 - 0.547 SC 14 3 0.123 0.323 0.323 0.241 0.229 0.101 Lemon 0.533 - 0.538 EC 14 2 0.411 0.412 0.412 0.412 0.412 NA

0.527 - 0.535 SC 14 5 0.319 0.539 0.539 0.473 0.461 0.086 **POME FRUIT CROP GROUP 11 (proposed use = 0.41 lb ai/A total application rate; 14**  **- day PHI)** 

### Tolfenp yrad Human Health Risk Assessment DP No. 383820

Page 26 of 65 Table 5.2.1. Summary of Residues from Field Trials Conducted with Tolfenpyrad. Commodity Total App.

Rate (lb ai/A) EP 1 PHI

(days) Residue Levels (ppm) 2 n Min. Max. HAFT 3 Median Mean Std. Dev. Apple 0.397 - 0.404 SC 13 - 14 16 0.102 0.316 0.316 0.203 0.206 0.064 Pear 0.396 - 0.411 SC 14 6 0.068 0.355 0.355 0.177 0.197 0.104 Pear 0.397 - 0.412 EC 14 6 0.029 0.357 0.357 0.207 0.201 0.113

**STONE FRUIT CROP GROUP 12 (proposed use = 0.56 lb ai/A total application rate; 14**  **- day PHI)**  Sweet Cherry 0.542 - 0.550 SC 14 6 0.267 0.896 0.896 0.524 0.551 0.238 Peach 0.489 - 0.568 SC 13 - 14 9 0.14 0.689 0.689 0.329 0.362 0.177 Plum 0.546 - 0.558 SC 14 6 0.124 0.929 0.929 0.323 0.402 0.311 **GRAPE (proposed use = 0.41 lb ai/A total application rate; 7 -**  **day PHI)** Grape 0.395 - 0.409 SC 7 12 0.211 1.51 1.51 0.373 0.53 0.389

**TREE NUTS CROP GROUP 14 (proposed use = 0.56 lb ai/A total application rate; 14 -**  **day PHI)** Al mond Nutmeat 0.540 - 0.551 SC 13 - 14 5 <0.01 0.027 0.027 0.01 0.013 0.008 Al mond Hulls 0.540 - 0.551 SC 13 - 14 5 <0.01 3 3 1.69 1.628 1.087 Pecan Nutmeat 0.545 - 0.552 SC 13 - 14 5 <0.01 <0.01 0.01 0.01 0.01 NA **COTTON (proposed use = 0.42 lb ai/A total application rate; 14 -**  **day PHI)** Cotton, undelinted seed 0.405 - 0.420 EC 13 - 14 12 0.012 0.411 0.411 0.181 0.172 0.112 Cotton gin byproducts 0.405 - 0.420 EC 13 - 14 6 1.05 5.4 5.4 3.66 3.62 1.55 **TEA (proposed use = 0.401**  **- 0.535 lb ai/A**  **; 14**  **- day PHI**  **; assumed based on information in the administrative**  **materials )**  Tea (1997 Study) 0.267 EC 7 1 22 22 22 22 22 -- 14 1 7.06 7.06 7.06 7.06 7.06 -- 21 1 0.65 0.65 0.65 0.65 0.65 -- 30 1 0.14 0.14 0.14 0.14 0.14 -- 0.401 EC 7 1 17.3 17.3 17.3 17.3 17.3 --

14 1 4.29 4.29 4.29 4.29 4.29 -- 21 1 0.79 0.79 0.79 0.79 0.79 -- 30 1 0.15 0.15 0.15 0.15 0.15 -- Tea (2005 Study) 0.535 EC 7 2 31.4 67.6 67.6 49.5 49.5 -- 14 2 3.77 12.1 12.1 7.94 7.94 -- 28 2 0.07 0.18 0.18 0.13 0.13 -- 1 EP = End -use Product. SC = 15% SC formulation (1.25 lb ai/gal) and EC = 15% EC formulation (1.25 lb ai/gal). 2 Values reflect per trial averages; n = no. of field trials. 3 HAFT = Highest Average Field Trial. 4 NA = Not applicable. Table 5.2.2. Residue Data from the Processing Studies with Tolfenpyrad. Raw Agricultural C ommodity Processed Commodity Total Rate (lb ai/A) Average

Residue (ppm) Processing

Factor 1 Apple Fruit (RAC) 2.02 2.02 -- Wet pomace 14.6 7.2x Juice <0.01 <0.01x Cotton Undelinted seed (RAC) 2.08 1.04 -- Meal <0.01 <0.01x Hulls 0.027 0.03x Refined Oil 0.0523 0.05x Grape Fruit (RAC) 2.04 1.33 -- Juice 0.0397 0.03x Raisins 4.95 3.7x Orange Fruit (RAC) 2.66 0.905 -- Juice 0.0166 0.02x Dried Pulp 8.03 8.9x Citrus Oil 74.4 82x

### Tolfenp yrad Human Health Risk Assessment DP No. 383820

Page 27 of 65 Table 5.2.2. Residue Data from the Processing Studies with Tolfenpyrad. Raw Agricultural C ommodity Processed Commodity Total Rate (lb ai/A) Average

Residue (ppm) Processing

Factor 1 Plum (Trial CA - 3) Fruit (RAC) 2.7445 1.7 -- Prune 5.3 3.1x Plum (Trial CA - 4) Fruit (RAC) 2.7381 0.859 -- Prune 2.35 2.7x Plum Average processing factor 2.9x Potato Tuber (RAC) 2.09 <0.01 -- Flakes <0.01 NC Chips <0.01 NC 1 Processing Factor = Residue in the processed fraction ÷ Residue in the RAC. NC = Not calculated ; residues were below the LOQ in the RAC and the processed fraction. 

### 5.3 **Water Residue Profile** Drinking Water Exposure Assessment for Proposed New Uses of Tolfenpyrad on a Variety of Agricultural Crops, Nurseries, and Christmas Trees . L. Liu, D383822, 23 January 2012 . 

### As previously

noted , tolfenpy

rad and its transformation products are expected to moderatel y degrade in the environment. Insoil, tolfenpy rad is expected to be essentially immobile ; however, the degradates PCA and PT - CA are expected to be highl y mobile . A total residue approach was used to model residues in drinking water, with the residues of concern being PCA, PT - CA, PT(A) - 4OH, and PAM . Tolfenp yrad was modeled in this assessment as stable to metabolism and degradation because only limited studies were submitted by the registrant. As a result, the metabolic half - lives used in modeling were multiplied by 3. If additional metabolism studie s become available, EECs could be lowered. Assessment modeling relied on maximum labeled use patterns and a default national percent cropped area value (87%) . Where actual use patterns are less than the labeled maximum and location - specific PCAs are less than assumed in this assessment, actual environmental exposures may be lower. The EDWCs resulting from these input assumptions should be considered to be very conservative. Drinking water exposure estimates for the proposed uses of tolfenp yr ad are represented by the use pattern of maximum tolfenpy rad exposure, nurseries and Christmas trees ( Table 5.3 ). Maximum acute, chronic , and cancer EDWCs in surface water are 2 6.9 , 1 2.2 , and 4.8 μg/L, respectivel y. The maximum exposure estimate for ground water is 11 μg/L . Monitoring and drinking water treatment data on tolfenp yr ad are not available . The model and its description are available at the EPA internet site: http://www.epa.gov/oppefed1/models/water/ . Table 5.3 . Tolfenpyrad EDWCs in Surface Water and Ground Water for Use in Dietary Risk Assessment Based on the Use Pattern of Maximum Exposure, Nurseries and Christmas Trees. * Use (maximum rate) Source † Cropped Area, % 1 - in - 10 - year Conc., ppb

Peak (Acute) Mean

(Chronic) 30 - year Daily Average

(Cancer) Ornamental plants and Christmas trees (2.72 lbs a.i./A/year) Surface water 87 26.9 12.2 4.8

### Tolfenp yrad Human Health Risk Assessment DP No. 383820

Page 28 of 65 Table 5.3 . Tolfenpyrad EDWCs in Surface Water and Ground Water for Use in Dietary Risk Assessment Based on the Use Pattern of Maximum Exposure, Nurseries and Christmas Trees. * Use (maximum rate) Source † Cropped Area, % 1 - in - 10 - year Conc., ppb

Peak (Acute) Mean

(Chronic) 30 - year Daily Average

(Cancer) Ornamental plants and Christmas trees (2.72 lbs a.i./A/year) Ground water N/A 11.0

* EDWCs were calculated based on total residues of concern (a summation of tolfenpyrad, PAM, PT - CA, PCA and PT(A) - 4OH) and a percent cropped area of 87%. † Surface water estimates were derived using PRZM - EXAMS. Ground water estimates were derived using SCI GROW. 

### The estimated drinking water concentrations (EDWCs) were incorporated directly into the dietary assessment described in Section 5.4. **5.4 Dietary Risk Assessment**  Tolfenpyrad Acute and Chronic Aggregate Dietary Exposure and Risk Assessments. M. Doherty, D398817, 1 2 April 2012 . 

### Acute and chronic aggregate dietary (food and drinking water) exposure and risk assessments were conducted using the Dietary Exposure Evalu ation Model DEEM - FCIDTM (v. 2.03). This model uses food consumption data from the U.S. Department of Agriculture’s (USDA’s) Continuing Survey s of Food Intakes by Individuals (CSFII) from 1994 - 1996 and 1998. **5.4.1 Description of Residue Data Used in Dietar** **y Assessment** The residue data used in the acute and chronic dietary assessment are derived from field trials conducted with tolfenp yr ad on representative target crops. The trials were designed to maximize potential residues in/on crops treated according to the proposed use patterns [i.e., maximum proposed application rates and minimum proposed pre - harvest intervals (PHI s)]. The proposed uses include a number of commodities that are significant livestock feeds. Data from feeding studies in which lactating cattle and laying hens were fed tolfenp yr ad were combined with estimates of tolfenp yrad residues in livestock feed to derive estimates of tolfenp yrad livestock commodities (e.g., meat, milk, eggs). The residue estimates and their translation scheme (chronic assessment only) are summarized in Table 5.4.1. The crop field trials and cattle feeding study did not measure all of the residues of concern for risk assessment purposes. Therefore, residues of PT - CA in root crops and residues of OH - PT - CA in ruminant liver, kidney , and other meat by products are accounted for b y using ratios of these residues relative to the measured residues from the crop and livestock metabolism studies. A factor of 1.41 has been used in the dietary exposure model input files to c onvert tolfenpy rad to tolfenpy

rad + PT - CA for potato commodities (the only root crop in the current request) and a factor of 1.47 was used for all livestock liver, kidney , and meat - by product entries in the assessments.

### Tolfenp yrad Human Health Risk Assessment DP No. 383820

Page 29 of 65 Table 5.4.1. Summary of Crop Field Trial Residue Data Used in the Dietary Exposure and Risk Assessment for Tolfenpyrad. Commodity Residue, ppm Translated to Tolerance Mean Potato (Factor of 1.41 to account for PT - CA metabolite is not shown) Potato Tuber 0.01 0.01 -- Potato Processed Commodities (Processing Factor = 1) -- 0.01 -- Leafy Vegetables Crop Group 4 Leaf Lettuce 30 5.45 -- Head Lettuce (w

/ wrapper leaves) 30 1.59 -- Celery 30 2.71 Cardoon, Celtuce, Florence Fennel, Rhubarb , Swiss Chard Spinach 30 9.88 Head and Stem Brassica Vegetables Crop Subgroup 5A Cauliflower 5 0.199 Broccoli, Chinese Broccoli , Chinese Mustard Cabbage Cabbage w/ wrapper leaves 5 1.43 Brussels Sprouts, Chinese Napa Cabbage, Kohlrabi Leafy Brassica Vegetables Crop Subgroup 5B Mustard Greens 40 8.62 Broccoli Raab, Bok Choy, Collards, Kale, Rape Greens, Turnip Greens Fruiting Vegetables Crop Group 8 - 10 Tomato 0.7 0.124 Groundcherry, Pepino, Tomatillo , Tree Tomato Tomato Puree (Processing Factor = 0.3) -- 0.124 -- Tomato Paste (Processing Factor = 1.02) -- 0.124 -- Bell Pepper 0.7 0.09 Eggplant Non -bell Pepper 0.7 0.233 Okra Cucurbit Vegetables Crop Group 9 Cucumber 0.7 0.12 Waxgourd, Balsam Pear, Bitter Melon Cantaloupe 0.7 0.23 Citron Melon, Watermelon , Casaba, Honeydew Melon Summer Squash 0.7 0.047 Pum pkin, Winter Squash, Chayote Citrus Fruits Crop Group 10 - 10 Orange 1.5 0.409 Citrus Citron, Tangerine , Kumquat Grapefruit 1.5 0.217 Pummelo Lemon 1.5 0.437 Lime Orange Juice (Processing Factor = 0.02) -- See Above Grapefruit Juice, Lemon Juice,

Lime Juice, Tangerine Juice Citrus Oil (Processing Factor = 82) 70 0.409 -- Pome Fruits Crop Group 11 - 10 Apple 0.7 0.206 Crabapple Apple Juice (Processing Factor = <0.01) -- 0.206 Processing factor applied to pear juice Pear 0.7 0.199 Loquat, Quince Stone Fruit Crop Group 12 Sweet Cherry 2 0.551 Persimmon, Pomegranate Peach 2 0.362 Apricot, Nectarine Plum 2 0.402 -- Plum, Dried (Processing Factor = 2.9) 3 0.402 --

### Tolfenp yrad Human Health Risk Assessment DP No. 383820

Page 30 of 65 Table 5.4.1. Summary of Crop Field Trial Residue Data Used in the Dietary Exposure and Risk Assessment for Tolfenpyrad. Commodity Residue, ppm Translated to Tolerance Mean Tree Nuts Crop Group 14 Almond Nutmeat 0.05 0.013 Chestnut, Pistachio Pecan Nutmeat 0.05 0.01 Brazil Nut, Butternut, Cashew, Filbert, Hickory Nut, Macadamia Nut, Walnut Other Cotton, Undelinted Seed 0.7 0.172 -- Cotton, refined oil (Processing Factor = 0.05) -- 0.172 -- Grape 2 0.53 -- Grape Juice (Processing Factor = 0.03) -- 0.53 Processing factor applied to all juices not otherwise listed. Grape, Raisins (Processing Factor = 3.7) 6 0.53 -- Tea 30 7.06 -- Cattle, Horses, Goats, and Sheep (Factor of 1.47 to account for OH - PT - CA metabolite in kidney, liver, and meat byproducts is not shown) Meat 0.01 -- -- Fat 0.01 -- -- Kidney 0.35 -- -- Liver 0.35 -- -- Meat Byproducts 0.35 -- -- Milk 0.03 -- -- 

### 5.4.2 **Percent Crop Treated Used in Dietary Assessment** D393941, S. Haddad, 6 February 2012. Percent Crop Treated for Tolfenpyrad (PC# 090111) on Proposed New Uses for Oranges, Apples, Table Grapes, and Spinach. 

### The acute assessment assumed 100% crop treated for all crops with proposed uses of tolfenpy rad. As a refinement to the chronic assessment, the follow ing four new - use percent crop treated (PCTn) estimates were used: 40% for oranges; 60 % for apples ; 65 % for table grapes ; and 50 % for spinach. **5.4.3 Acute Dietary Risk Assessment**  The acute assessment is a screening - level, highly conservative assess ment. Inputs to the anal ys is are tolerance - level residues for the above - listed foods and modeled estimates of residues in drinking water. The acute assessment assumes that all crops with proposed uses are treated (i.e., 100% crop treated). For the acute assessment, the dietary risk for the U.S. population is estimated to be 62% of the aPAD. Children 3 - 5 years old are the highest - exposed population subgroup, with an estimated exposure at the 95 th 

### percentile of 0.076 mg/kg/day , which corresponds to 76% of the aPAD . Ty pically HED has concerns when estimated exposures exceed 100% of the acute or chronic population - adjusted dose (aPAD or cPAD). Acute dietary risk estimates are below HED’s level of concern for all population subgroups. For the acute assessm ent, the inputs to the analy sis can be characterized as highl y health protective. While the application of the juice processing factor from grapes to other juices

### Tolfenp yrad Human Health Risk Assessment DP No. 383820

Page 31 of 65 provides some refinement relative to a strict screening - level assessment, the conservatism in the other input parameters results in exposure estimates that are likel y to overestimate actual dietary exposure. The results of the acute dietary assessment are shown in Table 5.4.6. **5.4.4 Chronic Dietary Risk Assessment**  The chronic assessment is significantl y refined. Inputs to the chronic assessment include average residue levels from crop field trials; use of percent crop treated estimates for foods which were shown to have a high contribution to the overall dietary exposure; liberal translation o f juice processing factors; and reduction of residues from removal of head lettuce and cabbage wrapper leaves. Although refined, the chronic dietary analysis is not expected to underestimate dietary exposures. For the chronic assessment, the dietary risk for the U.S. population is estimated to be 28% of the cPAD. The highest chronic dietary exposure estimate is 0.0041 mg/kg/day for children 1 - 2 years old , which corresponds to 69% of the cPAD. As with the acute assessment, the chronic estimates are below HED’s level of concern for all population subgroups. As previously

noted, the chronic assessment includes significant refinements. Nevertheless, the overall chronic exposure estimates still retain a rather high level of conservatism due to the source and scope of the refinements. The average residue values are from field trials which are designed to produce worst - case residue levels (maximum application rate, shortest PHI). The residue levels make no allowance for lower applications rate, longer PHI, or dissipation of residues during storage and transportation to market. It is quite likel y that monitoring data, which take these issues into account, would show significantl y lower residues than those used in this assessment. Although the crop field trial data did not measure all residues of concern, HED made conservative assumptions to account for this deficiency . Furthermore, the use of percent of crop treated estimates was limited to only a few crops and, in the case of grapes, to only a particular typ e (table grapes). For all other crops, it was assumed that 100% of the planted acreage would be treated

– a situation which is highly unlikel y. Overall, the chronic risk estimates are likel y to be overestimates of actual chronic dietary risk. **5.4.5 Canc**  **er Dietary Risk Assessment** A quantitative cancer assessment was not conducted. Tolfenp yr ad is classified as “not likel y to be carcinogenic to humans;” therefore, there is no cancer risk associated with tolfenpy rad. **5.4.6 Summary Table**  Table 5.4.6. Summary of Acute and Chronic Dietary Exposure Analyses for Tolfenpyrad. Population Subgroup Ac ute (95 th Percentile) Chronic Cancer Estimated Exposure (mg/kg/day) Estimated

Risk, % aPAD E stimated

E xposure (mg/kg/day) Estimated

Risk, % c PAD Exposure

(mg/kg/day) Estimated

Risk U.S. Population 0.0618 62 0.00169 28 Not Applicable All infants 0.0397 40 0.00309 52 **Children 1 -**  **2 yrs** 0.0727 73 **0.00413 69**  **Children 3 -**  **5 yrs 0.0757**  **76** 0.00328 55 Children 6 - 12 y

rs 0.0637 64 0.00190 32 Youth 13 - 19 y

rs 0.0559 56 0.00130 22

### Tolfenp yrad Human Health Risk Assessment DP No. 383820

Page 32 of 65 Adults 20 - 49 y

rs 0.0605 61 0.00133 22 Adults 50+ yrs 0.0612 61 0.00173 29 Females 13 - 49 y

rs 0.0648 65 0.00139 23 Entries with the highest acute and chronic risk estimates are **bolded** . 

### 6.0 **Residential (Non -**  **Occupational) Exposure/Risk Characterization**  At this time, there are no existing or proposed uses of tolfenp yrad that are defined as residential uses ( i.e. , (1) directl y on humans or pets; (2) In, on, or around any structure, vehicle, article, surface, or area associat ed with the household, including but not limited to areas such as non agricultural outbuildings, non - commercial greenhouses, pleasure boats and recreational vehicles; or (3) in or around any preschool or daycare facility . **6.1 Residential Bystander Post**  **- A** **p plication Inhalation Exposure**  Based on the Agency's current practices, a quantitative post - application by stander inhalation exposure assessment was not performed for tolfenpy rad at this time primarily

because of the low acute inhalation toxicity

( Toxicity Category), low vapor pressure ( 3.0 x 10 - 8 

### mm Hg), and the proposed use rate ( 1.36 lb ai/A). However, volatilization of pesticides may be a source of post application inhalation exposure to individuals nearby pesticide applications. The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010. 3 

### 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. I f new policies or procedures are developed, the Agency may revisit the need for a quantitative post - application inhalation exposure assessment for tolfenpy rad . **6. 2**  **Spray Drift** Spray drift is always a potential source of exposure to residents nearby to spraying operati ons. This is particularly

the case with aerial application, but, to a lesser extent, could also be a potential source of exposure from the ground application method employed for tolfenp yr ad . The Agency has been working with the Spray Drift Task Force, EP A Regional Offices and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices 4 

### . On a chemical b y chemical basis, the Agency is now requiring interim mitigation measures for aerial applications that must be placed on product labels/labeling. The Agency has completed its evaluation of the new database submitted by the Spray

Drift Task Force, a membership of U.S. 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 pesticides applied b y 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 o ff - target drift with specific products with significant risks associated with drift.

3 See http://www.epa.gov/scipoly/sap/meetings/2009/120109meeting.html for the referenced SAP report. 4 S ee http://www.epa.gov/opp00001/factsheets/spraydrift.htm for more information on spray drift.

### Tolfenp yrad Human Health Risk Assessment DP No. 383820

Page 33 of 65 Although a quantitative residential post - application inhalation exposure assessment was not performed as a result of pesticide drift from neighboring treated agricultural fields, an inhalation exposure assessment was performed for flaggers (see Table 9.1) . This exposure scenario is representative of a worse case inhalation (drift) exposure and may be considered protective of most outdoor agricultural and commercial post - a pplication inhalation exposure scenarios. **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 exposu res. In an aggregate assessment, exposures from relevant sources are added together and compared to quantitative estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can be aggregated. When aggregating exposures and risks from various sources, HED considers both the route and duration of exposure. As tolfenpy

rad has no residential uses at this time, aggregate exposures and risks are equivalent to the dietary

exposures and risks discussed in Section 5.4. All risk estimates are below HED’s level of concern. **8.0 Cumulative Exposure/Risk Characterization**  Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding linking tolfenp yrad to any other substances no r does tolfenpy rad appear to produce a toxic metabolite produced b y other substances. For the purposes of this tolerance action, therefore, EPA has not assumed that tolfenpy rad has a common mechanism of toxicity with other substances. For information regarding EPA’s efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by

EPA’s Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative. **9.0 Occupational Exposure/Risk Characterization**  This section of the assessment addresses exposure and risk associated with the proposed end use product s ( EPA Reg . No s . 71711 - 31 and 71711 - GA) for tolfenp yr ad when used as directed by commercial applicators . There is a potential for occupational exposure associated with handl er activities ( i.e., mixing, loading, and applying) as well as with post - application activities (i.e., re - entering treated areas). Based on the use pattern s , the duration of exposure for the proposed uses on crops is expected to be short - term (1 to 3 0 days) and intermediate - term (1 to 6 months) . In a previous assessment, long - term exposures (greater than 6 months) were considered; however, based on the proposed use pattern and resistance - management information on the proposed labels, long - term exposures are not anticipated at this time .

### Tolfenp yrad Human Health Risk Assessment DP No. 383820

Page 34 of 65 In addition to the newly

proposed uses, HED reassessed the currently registered use of tolfenpy rad on ornamental plants based on current policies and change s in dermal toxicological endpoints. This reassessment was triggered b y Nichino’s request to increase the maximum application rate on cut flowers and other ornamentals grown in greenhouses. **9.1 Short** **- and**  **Intermediate -**  **Term Handler Risk** Based upon the proposed use pattern, HED expects the most highly exposed occup ational pesticide handler scenarios to be: 1) mixing/loading liquids for aerial applications; 2) mixing/loading liquids for airblast applications; 3) mixing/loading liquids for chemigation; 4) mixing/loading liquids for ground applications; 5) applying sprays via air equipment (enclosed cockpit); 6) applying sprays via air blast equipment; 7) applying sprays via open cab groundboom equipment; and 8) flagging for aerial spray applications. Handler exposure is expected to be short - or intermediate - term in duration based on information provided on the proposed labels. Since the same endpoint and point of departure were selected for short - and intermediate - term durations, short - term exposure and risk estimates are considered to be protective of intermediate - term exposure and risk. Lo ng - term exposures are not expected; therefore, a long - term assessment was not conducted. No handler exposures are expected from applying sprays via chemigation s ys tems. HED notes that there is no toxicity associated with dermal exposure to tolfenpy rad for short - and intermediate - term durations, and therefore onl y inhalation exposure and risk were assessed for occupational handlers. In addition to the food uses, Nichino is requesting an increase in the maximum application rate for the registered use on cut flowers in greenhouses. HED rea ssessed the use of tolfenpy rad on ornamental plants in greenhouses (i.e., cut flowers) at the maximum proposed application rate based on current policies and change s in dermal toxicological endpoints . For the use on ornamentals, HED expects occupational p esticide handlers to be exposed to the following scenarios: 1) mixing/loading/appl ying sprays with m echanically -pressurized handgun sprayer; 2) mixing/loading/appl ying sprays with b ackpack sprayer; and 3) mixing/loading/appl ying sprays with m anually- pressurized handwand. In the past, HED has considered greenhouse uses to have the potential for long - term dermal exposure, especiall y for crops such as cut flowers, which have significant repeated postapplication foliar contact. However, in the case of tolfenp yr ad, lo ng - term dermal exposure is not expected to occur. The pests that are target s for tolfenp yrad have biological and life - stage properties that provide for short windows of opportunity for control. T o avoid development of tolfenpy rad - resistant pests, the tolfenpy rad label requires switching periodically to another insecticide. Therefore, b ased on the proposed use pattern and directions, resistance management

### Tolfenp yrad Human Health Risk Assessment DP No. 383820

Page 35 of 65 strategies (i.e., onl y two consecutive applications of tolfenp yrad) and the retreatment interv al (i.e., minimum of 10 days), only short - and intermediate - term exposures are expected for handlers. Table 9.1 presents the estimated short - and intermediate - term inhalation risk estimate s for workers. The MOEs shown in the table are all greater than 100, with the lowest MOE of 550 identified for handlers conducting mix er /loader and appl icator activities with mechanicallypressurized handgun sprayer for ornamental plants. All non - aerial application scenarios were assessed assuming a single layer of clothing and no respirator [i.e., baseline levels of personal protective equipment (PPE) ] . For aerial applications, an engineering control (i.e., enclosed cockpit) was assumed and incorporated as part of the description of the scenario . All occupational handler scenarios for the proposed and existing uses resulted in risk estimates that are not of concern (i.e., MOEs are all greater than 100) . Table 9.1 . Tolfenpyrad: Short - and Intermediate - Term Exposure and Risk Estimates for Occupational Handlers. † Exposure Scenario Crops or Target Max Single Application Rate a Area or

Amount Treated Inhalation Unit

Exposure b (mg/lb) (Mitigation Level) Inhalation

Dose c (mg/kg/day) MOE d Mixer/Loader

Aerial - Liquids Citrus (Crop Group 10), grapes

(raisin, table, wine), apple, crabapple, loquat, mayhaw, quince, pear, oriental pear 0.28 lb ai/A 350 A 0.000219 (Baseline) (AHETF) 0.0002683 9,700 Leafy vegetables (Crop Group 4), cucurbit vegetables (Crop Group 9), potatoes, brassica (cole) leafy vegetables (Crop Group 5), fruiting vegetables (Crop Group 8 plus okra) 0.21 lb ai/A 350 A 0.0002011 13,000 Stone fruit (Crop Group 12), tree nuts (Crop Group 14) 0.29 lb ai/A 350 A 0.0002778 9,400 Cotton 0.21 lb ai/A 1,200 A 0.0006897 3,800 Airblast - Liquids Citrus (Crop Group 10), grapes

(raisin, table, wine), apple, crabapple, loquat, mayhaw, quince, pear, oriental pear 0.28 lb ai/A 40 A 0.000219 (Baseline) (AHETF) 0.00003065 85,000 Stone fruit (Crop Group 12), tree nuts (Crop Group 14) 0.29 lb ai/A 40 A 0.00003175 82,000 Chemigation - Liquids Potatoes; vegetable crops 0.21 lb ai/A 350 A 0.000219 (Baseline) (AHETF) 0.00020110 13,000

Ground - Liquids Leafy vegetables (Crop Group

4), cucurbit vegetables (Crop Group 9), potatoes, brassica (cole) leafy vegetables (Crop Group 5), fruiting vegetables (Crop Group 8 plus okra) 0.21 lb ai/A 80 A 0.000219 (Baseline) (AHETF) 0.00004570 57,000 Cotton 0.21 lb ai/A 200 A 0.00011420 23,000 Applicator Aerial

– Liquids Citrus (Crop Group 10), grapes

(raisin, table, wine), apple, crabapple, loquat, mayhaw, quince, pear, oriental pear 0.28 lb ai/A 350 A 0.000068 (Engineering Control; Enclosed Cockpit) (PHED) 0.0000833 31,000

### Tolfenp yrad Human Health Risk Assessment DP No. 383820

Page 36 of 65 Table 9.1 . Tolfenpyrad: Short - and Intermediate - Term Exposure and Risk Estimates for Occupational Handlers. † Exposure Scenario Crops or Target Max Single Application Rate a Area or

Amount Treated Inhalation Unit

Exposure b (mg/lb) (Mitigation Level) Inhalation

Dose c (mg/kg/day) MOE d Leafy vegetables (Crop Group 4), cucurbit vegetables (Crop Group 9), potatoes, brassica (cole) leafy vegetables (Crop Group 5), fruiting vegetables (Crop Group 8 plus okra) 0.21 lb ai/A 350 A 0.000068 (Engineering Control) (PHED) 0.0000625 42,000 Stone fruit (Crop Group 12), tree nuts (Crop Group 14) 0.29 lb ai/A 350 A 0.000068 (Engineering Control) (PHED) 0.0000863 30,000 Cotton 0.21 lb ai/A 1,200 A 0.000068 (Engineering Control) (PHED) 0.0002137 12,000

Airblast - Liquids Citrus (Crop Group 10), grapes

(raisin, table, wine), apple, crabapple, loquat, mayhaw, quince, pear, oriental pear 0.28 lb ai/A 40 A 0.00471 (Baseline) (AHETF) 0.0006594 3,900 Stone fruit (Crop Group 12), tree nuts (Crop Group 14) 0.29 lb ai/A 40 A 0.0006829 3,800 Open Cab Groundboom Leafy vegetables (Crop Group

4), cucurbit vegetables (Crop Group 9), potatoes, brassica (cole) leafy vegetables (Crop Group 5), fruiting vegetables (Crop Group 8 plus okra) 0.21 lb ai/A 80 A 0.00034 (Baseline) (AHETF) 0.0000709 37,000 C otton 0.21 lb ai/A 200 A 0.0001779 15,000 Other Handlers

Flagger for Aerial Applications Citrus (Crop Group 10), grapes

(raisin, table, wine), apple, crabapple, loquat, mayhaw, quince, pear, oriental pear 0.28 lb ai/A 350 A 0.00035 (Baseline) (PHED) 0.0004273 6,100 Leafy vegetables (Crop Group 4), cucurbit vegetables (Crop Group 9), potatoes, brassica (cole) leafy vegetables (Crop Group 5), fruiting vegetables (Crop Group 8 plus okra) 0.21 lb ai/A 350 A 0.0003180 8,200 Stone fruit (Crop Group 12), tree nuts (Crop Group 14) 0.29 lb ai/A 350 A 0.0004470 5,800 Cotton 0.21 lb ai/A 1,200 A 0.0011031 2,400 Mixer/Loader/Applicator Mechanicallypressurized Handgun Sprayer Ornamentals 0.00313 lb ai/gal 1,000

gal/day 0.120

(Baseline) (PHED) 0.004691 550 Backpack Sprayer Ornamentals 0.00313 lb ai/gal 40 gal/day 0.140 (Baseline) (AHETF) 0.000219 12,000 Manuallypressurized Handwand Ornamentals 0.00313 lb ai/gal 40 gal/day 0.030 (Baseline) (PHED) 0.000049 53,000 † . Only the exposure and risk estimates using the max. single application rates f rom Tolfenpyrad 15SC Insecticide (EPA Reg . No. 71711 - GA) are shown in the table above . MOEs for the proposed uses listed on Tolfenpyrad 15EC Insecticide (EPA Reg . No. 71711 - 31) label were greater than or equal to those presented above. a. Per the proposed label s : For food crops, the maximum s ingle application rate for Tolfenpyrad 15SC Insecticide (EPA Reg . No. 71711 - GA) = (28.0 fl oz/A) (1.31 lb ai/gal) (1.0 gal/128 fl oz) = 0.29 lb ai/A. For ornamentals, the maximum s ingle

### Tolfenp yrad Human Health Risk Assessment DP No. 383820

Page 37 of 65 a pplication rate (Higher Spray Volume) = 1.36 lb ai/A (at 10 gal/1000 ft2 = 436 gal/A) 0.00313 lb ai/gal * 436 gal/A = 1.36 lb ai/A . b. Occupational Pesticide Handler Unit Exposure Surrogate Reference Table (September 26, 2011). c. Inhalation Dose (mg/kg/day) = Inhalation Unit Exposure (mg/lb ai) *A pplication Rate * Acres Treated or Amount Handled / Body Weight ( 80 kg). d. Inhalation MOE = NOAEL (2.6 mg/kg/day) / Inhalation Dose (mg/kg/day). 

### 9.2 **Short -**  **an d**  **Intermediate -**  **Term Post -** **Application Risk 9.2.1**  **Dermal Post -** **A pplication Risk**  For occupational exposure scenarios involving dermal exposure, no hazard was identified, and thus a quantitative dermal post - application exposure assessment w as not performed . HED does not anticipate risks resulting from dermal exposure to tolfenpy rad . The Restricted Entry

Interval specified on the proposed label is based on the acute toxicity of tolfenpy rad technical material, which is classified as Category III for acute dermal and Category IVfor dermal and eye irritation. Based on the acute toxicity profile of tolfenpy

rad, the 12 - hour REIappearing on the proposed label is appropriate. **9.2.2 Inhalation Post** **- A** **pplication Risk** Based on the Agency's current practices, a qu antitative post - application inhalation exposure assessment was not performed for tolfenp yr ad at this time primarily because of the acute inhalation toxicity

(Toxicity Category III), low vapor pressure (3.0 x 10 - 8 

### mm Hg), and the proposed use rate s . 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 receive d the SAP’s final report on March 2, 2010 (http://www.epa.gov/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 policies and procedures, to identify the need for and, subsequently , the way to incorporate occupational post - application inhalation exposure into the Agency's risk assessments. If new polic ies or procedures are put into place, the Agency may revisit the need for a quantitative occupational post - application inhalation exposure assessment for tolfenp yr ad. Although a quantitative occupational post - application inhalation exposure assessment was not performed, an inhalation exposure assessment was performed for agricultural occupational/commercial handlers (see Table 9.1) . Handler exposure resulting from application of pesticides outdoors is likely to result in higher exposure than post - application exposure. Therefore, it is expected that these handler inhalation exposure estimates would be protective of most occupational post - application inhalation exposure scenarios. Furthermore, the Worker Protection Standard for Agricultural Pesticides contains requirements for protecting workers from inhalation exposures during and after greenhouse applications

### Tolfenp yrad Human Health Risk Assessment DP No. 383820

Page 38 of 65 through the use of ventilation requirements [40 CFR 170.110, (3) (Restrictions associated with pesticide applications)]. **10.0 References**  Doherty, M. 1 2 April 2012 . D384995. Tolfenp yr ad Petition for the Establishment of Permanent Tolerances and Registration for Use on Potato; Leafy Vegetables, Except Brassica; Brassica Leafy Vegetables; Fruiting Vegetables; Cucurbit Vegetables; Citrus Fruits; Pome Fruits; Stone Fruits, Persimmon, and Pomegranate; Grape; Tree Nuts and Pistachio; Cotton; and Tea. Summary

of Analy tical Chemistry

and Residue Data. Doherty, M. 1 2 April 2012 . D398817. Tolfenp yr ad Acute and Chronic Aggregate Dietary Exposure and Risk Assessments Figueroa, Z. 1 2 April 2012 . D 386087 . Tolfenp yr ad. Occupational and Residential Exposure and Risk Assessment to Support Registration for the Proposed First Food Uses on a Variety of Crops and for an Increased Application Rate for Ornamental Plants. Irwin, W. 18 January

2012. D395592. Tolfenpy rad. Report of the Residues of Concern Knowledgebase Subcommittee (ROCKS). Liu, L. 23 January

2012. D383822. Drinking Water Exposure Assessment for Proposed New Uses of Tolfenp yr ad on a Variety of Agricultural Crops, Nurseries, and Christmas Trees. Haddad, S. 6 February

2012. D393941. Percent Crop Treated for Tolfenpy rad (PC# 090111) on Proposed New Uses for Oranges, Apples, Table Grapes, and Spinach.

### Tolfenp yrad Human Health Risk Assessment DP No. 383820

Page 39 of 65 **A ppendix**  **A . Toxicology Profile and**  **Executive Summaries A.1**  **Toxicology Data Requirements** The requirements (40 CFR 158.340) for food use for tolfenpy rad are in Table A1. Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used. **Table A.1 Test**  **Technical Required**  **Satisfied** 870.1100 Ac ute Oral Toxicity ................................ ........................ 870.1200 Ac ute Dermal Toxicity ................................ ................... 870.1300 Ac ute 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 21/28 - Day Dermal ................................ .......................... 870.3250 90 - Day

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

Inhalation ................................ ........................... yes yes yes ye s yes yes

yes yes ye s * yes # 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

yes yes yes yes 870.5100 Mutagenicity

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

—Gene Mutation - mammalian ................. 870.5375 Mutagenicity

— Structural Chromosomal Aberrations .... 870.5395 Mutagenicity

—Mammalian Erythrocyte Micronucleus . 870.5550 Mutagenicity

— Unscheduled DNA Synthesis ................ 870.5915 Mutagenicity

— In Vivo Sister Chromatid Exchange yes yes yes yes yes yes yes

yes yes yes yes yes 870.6100a Ac ute Delayed Neurotox. (hen) ................................ ...... 870.6100b 90 - Day

Neurotoxicity (hen) ................................ ........... 870.6200a Ac ute Neurotox. Screening Battery (rat) ........................ 870.6200b 90 Day Neurotox. Screening Battery (rat) ...................... 870.6300 Develop. Neuro ................................ .............................. no no yes yes no ---

--- yes yes

--- 870.7485 General Metabolism ................................ ....................... 870.7600 Dermal Penetration ................................ ......................... yes no yes

yes 870.7800 Immunotoxicity................................................ yes yes * Requirement fulfilled by 21/28 day dermal toxicity study and dermal absorption data. # Requirement fulfilled by 21/28 day inhalation toxicity study.

### Tolfenp yrad Human Health Risk Assessment DP No. 383820

Page 40 of 65 **A.2 Toxicity Profiles**  Table A.2.1. Ac ute Toxicity Profile - Tolfenpyrad Guideline No. Study T ype MRID(s) Results Toxicity Category 870.1100 Ac ute Oral - Rat 47457501 LD 50 Males => 386 mg/kg bw LD 50 Females =>150 mg/kg bw LD 50 Com

bined =>239 mg/kg bw II

870.1200 Ac ute Dermal - Rat 47457503 LD 50 Males > 2000 mg/kg bw LD 50 Females > 3000 mg/kg bw LD 50 Com

bined > 2500 mg/kg bw III

870.1300 Ac ute Inhalation - Rat 47447734 LC 50 Males >2.21 mg/L LC 50 Females >1.50 mg/L LC 50 Com

bined >1.82 mg/L III

870.2400 Ac ute Eye Irritation - Rabbit 47457505 Mildly irritating III 870.2500 Ac ute Dermal Irritation - Rabbit 47457507 Slightly irritating IV 870.2600 Skin Sensitization - Guinea Pig 47447740 Not Sensitizing - Table A.2.2 Subchronic, Chronic and Other Toxicity Profile for Tolfenpyrad Ty pe of Study/Guide line Study Title MRID Results 870.3100 90 - Day

Oral Toxicity, Rat w/4 week recovery 47447743 Levels tested: 0, 15, 80, 160 ppm or 0/0, 0.9/1, 4.8/5.2, 9.3/9.3 mg/kg/day in males/females NOAEL (M/F) =15 ppm or 0.9/1 mg/kg/day LOAEL (M/F) = 80 ppm or 4.8/5.2 mg/kg/day, based on decreased body weight (5 - 9%), body weight gain (8 - 13%), and food consumption in both sexes; increased relative liver and kidney weight, hepatoce llular hypertrophy and kidney hypertrophy, hyaline droplets in the kidney, brown color change in the liver , brown color change in the harderian gland along with hypersecretion. Additionally at 160 ppm, decreased body weight (8 - 26%), body weight gain (35 - 41%) and food consumption; small sex organs (seminal vesicle, ovary, uterus, and vagina; ovarian and uterine atrophy and decreased ovarian weight. 870.3100 90 - Day

Oral Toxicity, 47463702 and Levels tested: 0, 15, 100, 300 pm or 0/0, 2.4/3.0,

### Tolfenp yrad Human Health Risk Assessment DP No. 383820

Page 41 of 65 Table A.2.2 Subchronic, Chronic and Other Toxicity Profile for Tolfenpyrad Ty pe of Study/Guide line Study Title MRID Results

Mouse 47447801 15.9/20.2, 46.2/57.9 mg/kg/day in males/females NOAEL (M/F) - 300 ppm

or 46.2/57.9 mg/kg/day LOAEL (M/F) - not determined in main study; 600 ppm (104/126 mg/kg/day) based on decreased body weights, body weight gains, clinical signs (rough coat s, hunched posture, ataxia, hypoactivity), and mo ribundity/mortality seen in 28 day oral study. Note: Decreased Body weight gain (42%) was observed at 300 ppm in the range - finding study; however, 600 ppm (the HDT) was selected as the LOAEL for the 90 day mo use study since no effects on body weight gain were seen in this study at 300 ppm. 870.3150 4 - week Oral Toxicity,

Dog (capsule) 47447805 Levels tested: 0, 1, 5, 10 mg/kg/day NOAEL (M/F) = 5 mg/kg/day LOAEL (M/F) = 10 mg/kg/day, based on abnormal feces and liver and kidney histopathology. 870.3150 13 - we ek Oral Toxicity,

Dog (capsule) 47447803 Levels tested: 0, 1, 5, 10 mg/kg/day NOAEL (M/F) = 10 mg/kg/day LOAEL (M/F) = Not determined 870.3150 13 - we ek Oral Toxicity,

Dog (capsule) 47447804 Levels tested: 0, 10, 30, 100 mg/kg/day NOAEL (M/F) = 10 mg/kg/day LOAEL (M/F) = 30 mg/kg/day, based on mortality (1/4 males); clinical signs (no defecation/watery feces, emaciation, decrease in spontaneous mo vement, and staggering gait); decreased body weights, body

weight gains, and food consumption; and effects on the liver (increased cytoplasmic eosinophilia and centrilobular vacuolation in the hepatocytes) and in males, testes (atrophy) and kidney (vacuolization of tubular epithelium). 870.3200 21 - Day Dermal 47447806 Levels tested: 0, 10, 50, 200 mg/kg/day NOAEL (M/F) = 200 mg/kg/day LOAEL (M/F) = not determined At ≥ 50 mg/kg/day, decreased body weight gain and food consumption observed. 870.3250 90 - Day

Dermal No study Available: Waiver request submi tted 870.3465 4 - Week Inhalation

Toxicity, Rat 47447728 and 48250484 (range - finding) Levels tested: 0, 0.50, 2.0, 10 mg/m 3 or 0, 0.0005,

0.002, and 0.01 mg/L NOAEL = 10 mg/m 3 (EPA calculated 2.6 mg/kg/day) LOAEL = not determined Decreased body weight and mortality (2/6) observed at 26 mg/m 3 (EPA calculated 6.8 mg/kg/day) in range - finding study. No mortality seen at the next lowest dose of 10.9 mg/m 3 Range - finding levels tested 5, 10, 25,100 mg/m 3 (targeted); 3.6, 10.9, 26.0 , and 79.3 mg/m 3 (analyzed aerosol concentrations achieved)

### Tolfenp yrad Human Health Risk Assessment DP No. 383820

Page 42 of 65 Table A.2.2 Subchronic, Chronic and Other Toxicity Profile for Tolfenpyrad Ty pe of Study/Guide line Study Title MRID Results 870.3700a Developmental Toxicity,

Rat (Gavage) 47447809 Levels tested: 0, 1, 3, 4.5 mg/kg/day; GD 6 - 15) Maternal NOAEL =1 mg/kg/day Maternal LOAEL = 3 mg/kg/day, based on decreased body weight gains and food consumption Developmental NOAEL = 3 mg/kg/day Developmental LOAEL = 4.5 mg/kg/day, based on increased incidences of 14 th ribs, decreased fetal body weights, and decreased number of ossified metacarpals. 870.3700b Developmental Toxicity,

Rabbit (Gavage) 47447811 Levels tested: 0, 1, 3, 6 mg/kg/day GD 6 - 18 Maternal NOAEL = 6 mg/kg/day Maternal LOAEL = 9 mg/kg/day. The maternal LOAEL was not established in the current study but wa s 9 mg/kg/day in the preliminary study (MRID 47447810) based on a single mortality, em aciation, and on decreased body weights, body weight gains, and food consumption Developmental NOAEL = 6 mg/kg/day Developmental LOAEL = 9 mg/kg/day. The developmental LOAEL was not established in the current study but was 9 mg/kg/day in the preliminary s tudy

based on increased early resorption and incidences of supernumerary coronary orifices, fusion of the ossification centers of the caudal vertebral bodies, 13 th ribs, and delayed ossification of the manus 870.3800 2 Generation

Reproduction, Rat (feeding) 47447817 Levels tested: 0, 0.75, 1.5, or 3.0 mg/kg/day. Parental NOAEL  1.5 mg/kg/day Parental LOAEL = 3.0 mg/kg/day , based on decreased body weight and body weight gains, decreased motor activity, reddish tears, and prone position prior to death in two dams. Reproductive NOAEL 1.5 mg/kg/day Reproductive LOAEL= 3.0 mg/kg/day , based on decreased gestation index, incre ased gestation duration, abnormal parturition, and total litter loss Offspring NOAEL = 1.5 mg/kg/day Offspring LOAEL = 3.0 mg/kg/day , based on decreased pup viability and body weights, and delays in attainment of developmental landmarks (eye opening, pinna folding, surface righting reflex) 870.3800 1 Generation

Reproduction, Rat (feeding) 47447816 Levels tested: 0, 15, 50, 100 ppm or 0/0, 0.86/0.92, 2.7/2.9, 4.8/4.4 mg/kg/day. Parental NOAEL  15 ppm or 0.86/0.92 mg/kg/day Parental LOAEL = 50 ppm or 2.7 /2.9 mg/kg/day , based on decreased body weight gains and food consumption during pre - mating, and on decreased body weights during gestation and lactation in the females. Reproductive NOAEL 50 ppm Reproductive LOAEL= 100 ppm or 4.8/4.4, based

### Tolfenp yrad Human Health Risk Assessment DP No. 383820

Page 43 of 65 Table A.2.2 Subchronic, Chronic and Other Toxicity Profile for Tolfenpyrad Ty pe of Study/Guide line Study Title MRID Results on increased gestation duration Offspring NOAEL = 15 ppm Offspring LOAEL = 50 ppm , based on decreased body weights and body weight gains in both sexes. 870.4100 Chronic Toxicity- 1 Year,

Dog (feeding) 47442818 Levels tested: 0, 1, 5, 10 (reduced from 20) mg/kg/day NOAEL (M/F) 5 mg/kg/day LOAEL (M/F) 10 mg/kg/day, based on mortality, vomiting, decreased body weights, body weight gains, food consumption,, increased serum alanine aminotransferase in the males, and microscopic liver findings in males and females 870.42 00a Carcinogenicity, 18 -

Month Mouse (feeding) 47463703 Levels tested: 0, 15, 150 ppm or 0, 2.2/2.8, 20.8/27.1 mg/kg/day in males/females ; An additional group of 50 mice/sex/dose was treated similarly at a dose of 500 ppm for Weeks 1 - 12, 400 ppm for Weeks 13 - 19, and 300 ppm for Weeks 20 - 79 (60.9/75.9 mg/kg bw

/day in males/females). The dose for the high group was adjusted twice due to observed toxicity (mortality). NOAEL (M/F) 15 ppm or 2.2/2.8 mg/kg/day LOAEL (M/F) 150 ppm or 20.8/27.1 mg/kg/day, based o n moderate decreases in body weight (3 - 9%) and body weight gain (18%), food consumption, and clinical signs (increased incidence of ears missing in males and ear sores and scabs in females) 870.4200b Chronic/Oncogenicity, 2 -

Year, Rat (feeding) 47463704 Levels tested: 0, 15, 40, 80 ppm or 0/0, 0.6/0.7, 1.5/1.9, and 3.1/3.8 mg/kg/day in males/females NOAEL (M/F) 15 ppm or 0.6/0.7 mg/kg/day LOAEL (M/F) 40 ppm or 1.5/1.9 mg/kg/day , based on decreased body weight, body weight gain, and food consumption of females, gross changes in the Harderian glands of males, and histopathological changes in the liver, kidney and me senteric lymph nodes of females and the kidney of males . 870.5100 Technical (OMI - 88)

In vitro Bacterial Gene Mutation (S. typhimurium/ E. coli) / mammalian activation gene mutation assay 47463705 Negative. There was no evidence of induced mutant colonies over background.

870.5100 Metabolite (OH - PT)

In vitro Bacterial Gene Mutation (S. typhimurium/ E. coli) / mammalian activation gene mutation assay 47447822 Negative. There was no evidence of induced mutant colonies over background.

870.5300 Technical (OMI - 88) 47463706 Negative. There was no evidence of induced mutant colonies over background in the presence or absence of S9 - activation.

### Tolfenp yrad Human Health Risk Assessment DP No. 383820

Page 44 of 65 Table A.2.2 Subchronic, Chronic and Other Toxicity Profile for Tolfenpyrad Ty pe of Study/Guide line Study Title MRID Results

In Vitro Gene Mutation assay in mouse lymphoma cells 870.5375 Technical (OMI - 88)

In vitro Mammalian Cy togenetics (Chromosomal Aberration Assay in Chinese Hamster Lung (CHL) cells) 47447824 Negative. There was no evidence of structural chromosome aberrations induced over background in the presence or absence of S9 - activation. Note: cultures tr eated for 24 and 48 hours in the absence of S9 in Trial 2 resulted in a marked increase in the frequency of cells with numerical chromosome aberrations (predominantly polyploidy) that exceeded the historical control range. However, this effect decreased with an increase in dose. Similarly, a significant effect was only observed at the low - dose (10.1 μg/mL) during Trial 1 (24 hr, - S9). The biological significance of polyploidy in vitro is not completely understood at the present time. Therefore, this finding was not considered to be an adverse treatment - related effect. The positive controls induced the appropriate response in the presence and absence of S9 in both trials. 870.5375 Metabolite (OH - PT)

In vitro Mammalian Cy togenetics (Chromosomal Aberration Assay in Chinese Hamster Lung (CHL) cells) 47447826 Negative. There was no evidence of structural chromosome aberrations induced over background in the presence or absence of S9 - ac tivation.

870.5395 Technical (OMI - 88)

In Vivo Mammalian Cy togenetics - Erythrocyte Micronucleus Assay 47447827 Negative. T here was no significant increase in the frequency of micronucleated polychromatic erythrocytes in bone marrow after any treatment time. 870.5395 Technical (OMI - 88)

In Vivo Mammalian Cy togenetics - Erythrocyte Micronucleus Assay 47463708 Negative. T here was no significant increase in the frequency of micronucleated polychromatic erythrocytes in bone marrow after any treatment time. Non - guideline Technical (OMI - 88)

Cell Cycle Kinetics Assay 47463707 The purpose of this study was to explain the polyploidy observed in a previously conducted Chinese hamster lung chromosome aberration study (MRID 47447824). In the absence of S9 - activation, Tolfenpyrad caused cell cycle delay after exposure for as little as 3 hours and polyploidy after as little as 6 hours exposure. The polyploidy observed in the previous chromosome aberration study was likely due to the inhibition of cell cyc le progression. 870.6200a Ac ute Neurotoxicity, Rat 47447831 Levels tested: 0, 20, 40, 60 mg/kg/day in males and

### Tolfenp yrad Human Health Risk Assessment DP No. 383820

Page 45 of 65 Table A.2.2 Subchronic, Chronic and Other Toxicity Profile for Tolfenpyrad Ty pe of Study/Guide line Study Title MRID Results

(gavage) 0, 10, 20, or 40 mg/kg/day in females. NOAEL (M/F) = 10 mg/kg/day LOAEL (M/F) = 20 mg/kg/day, based on decreases in body weight, body we ight gain and food consumption in females. 870.6200b Subchronic Neurotoxicity,

Rat (feeding 47447830 0, 15, 40, 80 ppm or 0/0, 1/1.2, 2.7/3.2, 5.4/6 mg/kg/day NOAEL (M/F) =40 ppm or 2.7/3.2 mg/kg/day LOAEL (M/F) = 80 ppm or 5.4/6 mg/kg/day, based on decreased body weights, body weight gains, and food consumption 870.6300 Developmental

Neurotoxicity, Rat No t required 870.7485 Metabolism, Rat 47447837, 47447836, 47447834, 47447833, and 47447835 The test compound was rapidly absorbed and

excreted. Total recoveries ranged from 91.3 - 99.6% of the administered dose (AD) across all groups and in both sexes. Feces were the predominant route of excretion. Across all single dose groups, 88.2 - 93.2% AD was excreted in the feces and 1.7 - 3.0% AD was eliminated in the urine. Negligible amounts of radioactivity were recovered in the expired air and cage wash, both accounting for ≤0.1% AD. In the bile duct - cannulated rats at 48 h post - dosing, the majority of radioactivity was excreted in the bile (51.3 - 69.5% AD), with minor amounts eliminated in the feces (3.5 - 8.3% AD) and urine (0.7 - 3.0% AD), indicating that bile was the primary route of excretion for the absorbed test material. Absorption (defined as radioactivity found in the bile, urine, cage wash, and carcass) was greater in males (72.8 - 77.8% AD) than in females (57.9 - 69.4% AD). Females also had more radioactivity remaining in the gastrointestinal tract, and the amount remaining increased with dose. 870.7600 Dermal Penetration, Rat 47447839 At 24 hours in the 1 g/L group, the dermal absorption (absorbed + absorbable dose) is 39.8 %. Non guideline New data Com

parative in vitro dermal absorption study using human and rat skin 48233401 At 24 hrs, the total absorbed dose (absorbed + absorbable dose) at th e high dose was 1.12% in human skin and 26.78% in rats skin. At the low dose, the total absorbed dose was 6.49% in human skin and 67.02% in rat skin. 870.7800 Developmental

Immunotoxicity, Rat (feeding) 47447840 Levels tested: 0, 0.75, 3 mg/kg/day Maternal NOAEL = 0.75 mg/kg/day Maternal LOAEL = 3 mg/kg/day, based on decreased body weight (up to 10%), body weight gain (up to 36%), and food consumption in the P generation Offspring NOAEL = 0.75 mg/kg/day Offspring LOAEL = 3 mg/kg/day, based on decr eased survival, body weight, and body weight

### Tolfenp yrad Human Health Risk Assessment DP No. 383820

Page 46 of 65 Table A.2.2 Subchronic, Chronic and Other Toxicity Profile for Tolfenpyrad Ty pe of Study/Guide line Study Title MRID Results gains; increased incidence of blackish abdominal cavity and dark green abnormal intestinal content; and decreased thymus and spleen weights in the F1 and/or F2 generations Note: No treatment - related effects no ted on the immune system. Non guideline In vitro metabolism 47447838 Total recovery was 91.0 - 108.1% of the radioactivity added to the incubations, of which the parent compound accounted for 10.2 - 12.4%. Only 1.4 - 1.9% of the radioactive residues were found in unidentified compounds; the remaining approximately 88% of the isolated metabolites were identified. In addition to the parent, a total of 17 metabolites were identified. The primary metabolite wa s OH - PT - CA (24.5 - 32.4%); other major metabolites included PT - CA (13.4 - 16.2%), CO - PT CA (9.3 - 13.2%), OH - PT (7.6 - 8.4%), PT - OH (6.7 - 7.7%), and OH - PT - OH (3.8 - 5.3%). The other metabolites were present at <5% of the total incubation dose. The main metabolic pathways included the oxidations of the methyl moiety of T - CH 3 and ω - 1 carbon of CH 3 CH 2 - P. The oxidation of these two carbons resulted in the formation of the hydroxylated metabolites PT - OH, OH - PT, and OH PT - OH. Further oxidation leads to the metabolites PT - CHO, PT - CA, OH - PT - CA, CO - PT, CO - PT - OH, and CO - PT - CA. Other metabolic pathways include the bond cleavage of the amide and methylene mo ieties, the demethylation of N - CH 3 , or the formation of the vinyl group after hydroxylation of CH 3 CH 2 - P.

### Tolfenp yrad Human Health Risk Assessment DP No. 383820

Page 47 of 65 **A.3 Triple**  **- Pack Analysis for Tolfenpyrad**  The dermal abso rption data and dermal toxicity data for tolfenp yr ad were used to calculate a refined dermal equivalent dose (RDD) for short and intermediate term dermal risk assessment. To calculate a RDD, in vitro results using rat skin are corrected for any differenc es between in vitro and in vivo absorption rates (rats) and species differences seen between rats and humans. This refinement in dermal absorption is important since absorption b y human skin is usually lower than that by rat skin. Accordingl y, the combin ed use of data from the three studies and two testing s ys tems offers greater precision in estimating human dermal absorption which strengthens the reliability of the dermal risk assessment. **Short -**  **and Intermediate -**  **Term Exposure -** **Dermal POD and Dermal Absorp tion Data**  For dermal exposure scenarios, no hazard was identified. This is based on the lack of dermal toxicity at 200 mg/kg/day

in a rat 2 1 - day

dermal toxicity

study , and analyses of the newl y submitted dermal absorption data. U sing the available dermal data for tolfenpy rad, a refined dermal equivalent dose (RDD) for human skin of 2065 mg/kg/day was calculated. POD = dermal NOAEL = 200 mg/kg/day DAF ( in vivo rat) = 39.8% In Vitro Human dermal absorption = 6.49% In Vitro Rat dermal absorption = 67.02% **Refined Dermal Equivalent Dose(RDD)=**DED x (animal in vitro /human in vitro ) **POD=DED RDD=**  200mg/kg/day

x 67.02% ÷ 6.49%= **2065 mg/kg/day Long**  **- Term Exposure**  **- Oral POD and Dermal Absorptio**  **n Data** Based on the use pattern of tolfenpy rad, long - term exposure is not anticipated. **Tolfenpyrad Triple Pack Data for Short and Intermediate Term Dermal exposure Param**  **eters In Vivo**  **Rat In Vitro**  **Rat In Vitro**  **Human Comments**  **Study ID** MRID No. 47447839

TXR No. 0054937 MRID No.48233401 TXR No.0055527 MRID No.48233401 TXR No.0055527 Same formulation products were tested in all three studies. Lo w dose is identical in the in vitro rat and human studies Identical **Test Material EC Formulation**  **(15%) EC Formulation**  **(15%) EC Formulation (15%)**  **Exposure (hours)**  0.5, 1, 2, 4, 10 and 24 24 24 **Doses tested** Lo w Mid Hi Lo w High Lo w High

0.91 μ g/c m2 8.41 μ g/c m2 99.9 μ g/c m2 1μ g/cm

2 1500 μ g/cm2 1μ g/cm 2 1500 μ g/cm2 **% Absorbed (+ absorbable)**  **at 24 hrs**  **39.8** 44.5 22.09 **67.02** 26.78 **6.49** 1.12

### Tolfenp yrad Human Health Risk Assessment DP No. 383820

Page 48 of 65 **Risk Values** POD = 21 day dermal study - dermal NOAEL of 200 mg/kg/day (LOAEL not

determined) used to assess short - , intermediate, and long - term dermal exposure. Extra 3x was applied to long - term dermal exposure scenario to account for subchronic to chronic extrapolation . exposure periods Calculated a Refined Dermal Dose (RDD) to mo dify the dermal POD. **Derm al**  **Equivalent Dose (DED)**  For short - , and intermediate - term dermal exposures, **DED =POD=200 mg/kg/day**  , since route specific study used. For long - term dermal exposure, **DED = 1.5 m g/kg/day**  (POD (0.6 mg/kg/day) - oral study  DAF (39.8%) - in vivo rat) since an oral toxicity study with a NOAEL of 0.6 mg/kg/day was used. **Estimated Hum**  **an In Vivo**  **Derm al**  **Absorption Factor**  **EC formulation (low dose)**

DAF=in vivo rat absorption (39.8%) x in vitro human absorption (6.49%) in vitro rat absorption (67.02%) Estimated In Vivo Human Dermal Absorption= 3.85% **Refined Dermal Equivalent**  **Dose (RDD) -**  **Derm al Study**  **Short -**  **and Intermediate**  **** **Term Exposure** POD = dermal NOAEL = 200 mg/kg/day DAF ( In Vivo rat ) = 39.8% In Vitro Human dermal absorption = 6.49% In Vitro Rat dermal absorption = 67.02% **Refined Dermal Equivalent Dose(RDD)=**DED x (animal in vitro/human in vitro) **POD=DED RDD=** 200mg/kg/day x 67.02% ÷ 6.49% = **2065 m g/kg/day** 

### Tolfenp yrad Human Health Risk Assessment DP No. 383820

Page 49 of 65 **A. 4**  **Toxicological Doses and Endpoints for Use in Human Risk Assessments A.**  **4 .1**  **Acute Reference Dose (aRfD) –**  **All Populations Study Selected:**  Acute Neurotoxicity Study in Rats **MRID No:** 47447831 **Dose and Endpoint for Risk Assessment** : NOAEL= 10 mg/kg/day , based on decreased body weight, body weight gain and food consumption observed at the LOAEL of 20 mg/kg/day. **Uncertainty Factor:** 100x (10x interspecies extrapolation, 10x intraspecies variability)

**Acute RfD** = )

( 100 / / 10 UF day kg mg = **0.1 m g/kg/day**  

### Comments about Study/Endpoint/Uncertainty Factors: Although body weight changes are not usually the result of a single dose exposure, significant decreases in body weight (6 - 12%) and decreases in body weight gain (26%) were observed after a single dose exposure in a dietary study and are appropriate for acute dietary exposure. No separate endpoint was identified for acute dietary exposure for females 13 - 49 years of age. Resorptions seen in a range - finding developmental toxicity study in rabbits were considered for endpoint selection. However, the resorptions were seen in the presence of significant maternal effects (emaciation, body wei ght changes, and mortality) and are considered secondary to maternal toxicity

and not a result of a single exposure. Therefore, the endpoint is not applicable to acute dietary

risk assessment. **A. 4**  **.2 Chronic Reference Dose (cRfD** ) **Study Selected:** Combined Chronic Toxicity /Carcinogenicity Study in Rats **MRID No:** 47463704 **Dose and Endpoint for Risk Assessment** : NOAEL= 0.6 mg/kg/day , based on decreased body weight, body weight gain and food consumption of females, changes in the harderian glands (found in the eye) of males, histopathological changes in liver, kidney and ly mph nodes in females, and histopathologi cal changes in the kidney of males, observed at the L OAEL of 1.5 mg/kg/day . **Uncertainty Factor:** 100x (10x interspecies extrapolation, 10x intraspecies variability)

**Chronic RfD** = ) ( 100 / / 6 . 0 UF day kg mg = **0.006m g/kg/day**  

### Comments about **Study/Endpoint/Uncertainty Factors:** The study is appropriate for chronic dietary exposure due to the route (oral) and long - term duration of dosing. In addition, the dose selected is the lowest NOAEL in the toxicity database, and will therefore be protective of other observed toxic effects. Chronic mouse and dog studies

### Tolfenp yrad Human Health Risk Assessment DP No. 383820

Page 50 of 65 were also considered for chronic dietary exposure; however, the chronic rat study provided the most sensitive endpoint for chronic dietary risk assessment. **A. 4**  **.3 Occupational Short** **- and**  **Intermediate -**  **Term Dermal Exposure** For dermal exposure scenarios, no hazard was identified. A 21 - day dermal toxicity

study in rats is available for tolfenp yr ad. No treatment - related effects were observed in the study at doses up to and including the hi ghest dose tested of 200 mg/kg/day . For short - and intermediate term dermal exposure, a refined dermal dose (RDD), for human skin, was calculated using the dermal toxicity study in rats and in vivo (rat) and in vitro (human and rat skin) dermal absorption data. Using the data, a RDD of > 2000 mg/kg/day was calculated. S ince the RDD is significantl y higher than the limit dose, short - , and intermediate - term dermal risk assessments were not performed. **A. 4**  **.4 Occupation**  **al Long -**  **Term Dermal Exposure** Based on the proposed use pattern for tolfenp yr ad, long - term dermal exposure is not anticipated. **A. 4**  **.5 Occupational Short** **- and Intermediate**  **- Term Inhalation Exposure**  **Study Selected:** 4 week inhalation toxicity study in rats **MRID No:** 47447728 **Dose and Endpoint for Risk Assessment:** NOAEL= 10 mg/m 3 

### (2.6 mg/kg/day **Uncertainty Factor:** 100x (10x interspecies extrapolation, 10x intraspecies variability) **Comments about Study/Endpoint/Uncertainty Factors:** No toxic effects were observed up to 10 mg/m 3 

### (EPA calculated dose = 2.6 mg/kg/day) in the main study ; however, mortality was observed in a range - finding study at 26 mg/m 3 

### (6.8 mg/kg/day). No mortality was seen at the next lowest dose of 10.9 mg/m 3 

### in the range - finding study . The developmental toxic ity studies (rats and rabbits), the developmental immunotoxicity study in rats and the reproduction study in rats were all considered for short - and intermediate term inhalation risk assessment. However, the inhalation study was selected because it is a route specific study and considered more appropriate for inhalation risk assessment than the oral studies. There is no evidence of increased quantitative susceptibility between the young and the adult (i.e., developmental/offspring toxicity occurred at the same dose level as adult toxicity ) and the Agency

concluded that selecting points of departure from route - specific studies that are protective for adults would also be protective for developmental/offspring effects. Therefore, the inhalation study

it is p rotective of potential offspring effects since it adequately measured sy stemic toxicity

in adult animals. **A. 4.6**  **Occupational Long -**  **Term Inhalation**  **Exposure** Based on the proposed use pattern for tolfenp yr ad, long - term inhalation exposure is not anticipate d.

### Tolfenp yrad Human Health Risk Assessment DP No. 383820

Page 51 of 65 O C l H 3 C O H N N C H 3 N H

O O O H 

### A**ppendix B. Metabolism Summary Table**  Summary of Metabolism of Tolfenpyrad in Target Crops, Livestock, and Rotational Crops. Values shown are maxima from studies with tolyl - and pyrazole - labeled tolfenpyrad. Com pound Matrix % TRR ppm Tolfenpyrad Radish Root 54 0.235 Radish Top 85 9.311 Peach Fruit (56 DAT) 78.4 0.808 Peach Leaves (56 DAT) 32.6 21.1 Peach Stems (56 DAT) 70.9 11.1 Eggplant Fruit (28 DAT) 93.6 0.8 Eggplant Foliage (28 DAT) 93.6 206 Cabbage 55 4.74 Goat Milk 6.5 0.011 Goat Fat 17.3 0.062 Goat Muscle 10.1 0.014 Hen Eggs 2.4 0.004 Hen Fat 14.7 0.063 Hen Liver 0.2 0.004 Hen Muscle 1.8 0.002 Rat Feces 14.8% AD -- PT - CA Radish Root 21.5 0.113 Peach Leaves (56 DAT) 17 10.95 Peach Stems (56 DAT) 2.3 0.23 Goat Milk 54.1 0.092 Goat Fat 34.1 0.111 Goat Liver 58.7 14.8 Goat Kidney 62.6 4.33 Goat Muscle 67.8 0.088 Hen Eggs 64.4 0.105 Hen Fat 49.5 0.218 Hen Liver 90.4 1.54 Hen Muscle 84.8 0.095 Rot. Lettuce 120 13.3 0.002 Rot. Radish Tops 30 5.7 0.002 Rot. Radish Tops 120 16.7 0.002 Rot. Wheat Hay 30 5.3 0.001 Rat Urine 1.9% AD -- Rat Bile (includes PT - CA glu) 22.3% AD -- Rat Feces 36.2% AD -- OH - PT - CA Peach Leaves (56 DAT) 3.2 2.06 Cabbage 3 0.28 Goat Milk 16.9 0.029 Goat Liver 27.7 6.98 Goat Kidney 19.3 1.34 Goat Muscle 8.9 0.008 Hen Liver 5.2 0.094

### Tolfenp yrad Human Health Risk Assessment DP No. 383820

Page 52 of 65 Summary of Metabolism of Tolfenpyrad in Target Crops, Livestock, and Rotational Crops. Values shown are maxima from studies with tolyl - and pyrazole - labeled tolfenpyrad. Com pound Matrix % TRR ppm Hen Muscle 2.7 0.003 Rat Bile 1.5% AD -- Rat Feces 7.4% AD -- Sul - OH - PT - CA Rat Bile 3.3% AD -- Rat Feces 9.2% AD -- PT - CA glu Peach Leaves (56 DAT) 7 3.6 Peach Stems (56 DAT) 6.3 0.8 PAM Radish Root 9.9 0.043 Radish Top 2.1 0.149 Peach Leaves (56 DAT) 2.2 1.4 Peach Stems (56 DAT) 3.4 0.34 Rot. Lettuce 30 5.1 0.004 Rot. Lettuce 120 8.3 0.004 Rot. Lettuce 365 8.8 0.003 Rot. Radish Root 30 25.4 0.015 Rot. Radish Root 120 30 0.018 Rot. Radish Root 365 27.3 0.003 Rot. Radish Tops 30 12 0.015 Rot. Wheat Forage 30 1.1 0.006 OH - PAM Radish Root 3.4 0.015 Peach Fruit (56 DAT) 3.9 0.03 Peach Leaves (56 DAT) 9 5.82 Hen Eggs 12.6 0.021 Hen Muscle 12.4 0.016 Rot. Lettuce 30 3.8 0.003 Rot. Lettuce 120 29.2 0.014 Rot. Lettuce 365 14.7 0.005 Rot. Radish Root 30 8.5 0.005 Rot. Radish Root 120 8.3 0.005 Rot. Radish Root 365 9.1 0.001 Rot. Radish Tops 30 14.4 0.018 Rot. Radish Tops 120 8.3 0.01 Rot. Radish Tops 365 6.5 0.003 Rot. Wheat Forage 30 5 0.027 Rot. Wheat Forage 120 8.4 0.022 Rot. Wheat Hay 30 6.8 0.045 Rot. Wheat Hay 120 5.5 0.041 Rot. Wheat Straw 30 11.5 0.142 Rot. Wheat Straw 120 8.2 0.064 OH - PAM conjugate Radish Root 6.4 0.028 Rot. Lettuce 30 24.1 0.019 Rot. Lettuce 120 16.7 0.008 Rot. Lettuce 365 32.4 0.011 Rot. Radish Tops 30 20 0.025 Rot. Radish Tops 120 11.6 0.014

### Tolfenp yrad Human Health Risk Assessment DP No. 383820

Page 53 of 65 Summary of Metabolism of Tolfenpyrad in Target Crops, Livestock, and Rotational Crops. Values shown are maxima from studies with tolyl - and pyrazole - labeled tolfenpyrad. Com pound Matrix % TRR ppm Rot. Radish Tops 365 15.2 0.007 Rot. Wheat Grain 30 7.1 0.004 Rot. Wheat Grain 120 19.6 0.009 Rot. Wheat Grain 365 12.5 0.001 Rot. Wheat Forage 30 29.7 0.16 Rot. Wheat Forage 120 19.5 0.051 Rot. Wheat Forage 365 77.1 0.148 Rot. Wheat Hay 30 38.4 0.255 Rot. Wheat Hay 120 31.6 0.233 Rot. Wheat Hay 365 16.4 0.043 Rot. Wheat Straw 30 32.1 0.397 Rot. Wheat Straw 120 25.4 0.199 Rot. Wheat Straw 365 19.7 0.059 PCA Cabbage 2.2 0.21 Goat Milk 12.2 0.021 Goat Fat 28.6 0.078 Hen Eggs 14.4 0.024 Hen Fat 11.2 0.048 Rot. Wheat Hay 30 0.2 0.001 Rot. Wheat Hay 120 0.1 0.001 Rot. Wheat Straw 30 0.2 0.002 Rot. Wheat Straw 120 0.3 0.002 OH - PCA Radish Root 1.8 0.008 Rot. Lettuce 30 20.3 0.016 Rot. Lettuce 120 27.1 0.013 Rot. Radish Root 30 1.7 0.001 Rot. Radish Tops 30 4 0.005 Rot. Radish Tops 120 2.5 0.003 Rot. Radish Tops 365 2.2 0.001 Rot. Wheat Grain 30 10.7 0.006 Rot. Wheat Grain 120 2.2 0.001 Rot. Wheat Forage 30 17.5 0.094 Rot. Wheat Forage 120 17.6 0.046 Rot. Wheat Forage 365 2.1 0.004 Rot. Wheat Hay

30 5.1 0.034 Rot. Wheat Hay 120 10.2 0.076 Rot. Wheat Hay 365 5.7 0.015 Rot. Wheat Straw 30 8.5 0.105 Rot. Wheat Straw 120 5.6 0.044 Rot. Wheat Straw 365 6.7 0.02 OH - PCA conjugate Rot. Lettuce 30 26.6 0.021 Rot. Radish Root 30 27.1 0.016 Rot. Radish Tops 30 24 0.03 Rot. Wheat Grain 30 14.3 0.008 Rot. Wheat Grain 120 23.9 0.011 O H O Cl

C H 3

N N H 3 C

### Tolfenp yrad Human Health Risk Assessment DP No. 383820

Page 54 of 65 Summary of Metabolism of Tolfenpyrad in Target Crops, Livestock, and Rotational Crops. Values shown are maxima from studies with tolyl - and pyrazole - labeled tolfenpyrad. Com pound Matrix % TRR ppm Rot. Wheat Grain 365 12.5 0.001 Rot. Wheat Forage 30 32.3 0.174 Rot. Wheat Forage 120 30.3 0.079 Rot. Wheat Hay 30 12.8 0.085 Rot. Wheat Hay 120 30.3 0.224 Rot. Wheat Hay 365 37.5 0.097 Rot. Wheat Straw 30 12.7 0.157 Rot. Wheat Straw 120 21.4 0.168 Rot. Wheat Straw 365 41.8 0.125 CA - T -NH2 Goat Milk 19.4 0.033 Goat Fat 5.3 0.019

OH - PT Cabbage 7.99 0.76 OH - PT - OH Peach Stems (56 DAT) 1.1 0.11 Cabbage 3.49 0.33 OH - PT - OH conjugate Radish Top 3.8 0.355 OH - T - CA Cabbage 3.9 0.33 OH - T - OH Cabbage 3.7 0.31 OH - T - AM Cabbage 1.9 0.16 CA - T - AM Cabbage 2.4 0.2 CO - PT Peach Stems (56 DAT) 1 0.1 Rat Bile 2.8% AD -- CO - PT - OH Cabbage 1.2 0.1 CA - T - CA Peach Leaves (56 DAT) 11.1 5.7 Rot. Radish Root 30 6.3 0.001 Rot. Radish Tops 30 2.9 0.001 T - CA Peach Leaves (56 DAT) 6.6 3.4 2OH - PAM Peach Fruit (56 DAT) 4.5 0.035 Peach Leaves (56 DAT) 1.5 0.95 * Included compounds are ≥ 1% TRR (% AD in rat) in at least one matrix. 

### Comparison of Radiolabeled Studies to Proposed Use Directions Radiolabeled Study Proposed Use ; PHI (days) in parenthesis Radish (48250449) 0.21 lb ai/A × 2 = 0.4 lb ai/A; PHI = 1 day 1X : grape (7) , pome fruit (14) , leafy veg. (1) , potato (14) , Brassica veg. (1) , fruiting veg. (1) , cotton (14 ) 0.7X : citrus (14) , stone fruit (14) , tree nuts (14 ) 0.47X : cucurbit veg. (1 ) O O H O

N H 2

### Tolfenp yrad Human Health Risk Assessment DP No. 383820

Page 55 of 65 Peach (4825045 - 46) 0.67 lb ai/A ** ; PHI = 0, 14, 28, and 56 days Eggplant (48250444) 0.67 lb ai/A ** ; PHI = 3, 7, 14, and 28 days Cabbage (4825047 - 48) 0.67 lb ai/A ** ; PHI = 0, 7, 14, and 28 days

** Assuming 20% of the application adheres to the plant. Actual application rate was 0.13 lb ai/A 1.6X : grape (7) , pome fr uit (14) , leafy veg. (1) , potato (14) , Brassica veg. (1) , fruiting veg. (1) , cotton (14 ) 1.2X : citrus (14) , stone fruit (14) , tree nuts (14 ) 0.79X : cucurbit veg. (1 )

Rot.Crops (48250476; Lettuce, radish, wheat) ~0.312 lb ai/A; PBI = 30, 120, 365 days 0.76 X : grape (7) , pome fruit (14) , leafy veg. (1) , potato (14) , Brassica veg. (1) , fruiting veg. (1) , cotton (14 ) 0.58X : citrus (14) , stone fruit (14) , tree nuts (14 ) 0.37X : cucurbit veg. (1 ) Livestock (48250450 - 51) ~ 12.5 ppm feeding level, all studies DRAFT Dietary Burdens: Beef Cattle = 3.7 ppm Dairy Cattle = 2.2 ppm Poultry = 0.12 ppm Rat (47447834, 36, 37) Metabolism Study: 1 mg/kg, single dose; 20 mg/kg single dose; 1 mg/kg daily for 14 days Not Applicable

### Tolfenp yrad Human Health Risk Assessment DP No. 383820

Page 56 of 65 **Appendix C. Physical/Chemical Properties**  Table 3 .2 . Physicochemical Properties of the Technical Grade Test Compound: Tolfenpyrad 1 Parameter Value Reference Molecular Weight 383.9 MRID 47447704 Melting point/range (PAI) 2 85.5 - 88.5° C MRID 47447705 pH 5.1 MRID 47447704 Density 1.25 g/cm3 Water solubility (PAI) 0.061 mg/L MRID 47447705 Solvent solubility (tem perature not specified) n - heptane 6.92 g/L Xylene 218 g/L 1,2 dichloroethane >250 g/L Methanol 50.8 g/L n - octanol 43.7 g/L Acetone 250 g/L Ethyl acetate 250 g/L MRID 47447704

Vapor pressure (PAI) 4 x 10 - 5 Pa at 25 °C (= 3.0 x 10 - 8 mm Hg) MRID 47447705 Dissociation constant, pKa No dissociation constant in the environmental pH range Partition coefficient, log 10 P OW (PAI) 4.3 MRID 47447705 Soil half - life 

### A erobic = 15.1 day s

Anaerobic = 216.6 day s Drinking Water Assessment (D383822) 1 Refer to D354437.mem, 6/3/10 2 PAI = Purified Active Ingredient

### Tolfenp yrad Human Health Risk Assessment DP No. 383820

Page 57 of 65 **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 or other chemical. These data, which include studies from the Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1) and the Agricultural Handler Exposure Task Force (AHETF) database are subject to ethics review pursuant to 40 CFR 26, have received that review, and are compliant with applicable ethics requirements. For certain studies that review may

have in cluded review b y the Human Studies Review Board. Descriptions of data sources as well as guidance on their use can be found at : http://www.epa.gov/pesticides/science/handler- exposure - data.html and http://www.epa.gov/pesticides/science/post - app - exposure - data.html .

### Tolfenp yrad Human Health Risk Assessment DP No. 383820

Page 58 of 65 **Appendix E. Bibliography of Submitted Studies** MRID Citation 47447728 Kelly, D. (2008) Tolfenpyrad: Four -Week Inhalation Toxicity Study in Rats. Project

Number: DUPONT/22217, 16846, 782. Unpublished study prepared by E.I. du Pont de Nemours & Co., Inc. 291 p. 47447731 Ikeya, M. (1999) Oral Acute Toxicity Study of OH - PT in Rats. Project Number: T/10106,

B/4162. Unpublished study prepared by Bozo Research Center, Inc. 65 p. 47447733 Moore, G. (2008) Acute Dermal Toxicity Study in Rats - Limit Test: NAI - 2302

(Tolfenpyrad) 15%EC. Project Number: P322/RAT, 24304, 080212/3R. Unpublished study prepared by Product Safety Laboratories. 14 p. 47447734 Wesson, C. (2006) Acute Inhalation Toxicity (Nose Only) Study in the Rat. Project

Number: 562/027, T/10007. Unpublished study prepared by Safepharm Laboratories, Ltd. 48 p. 47447740 Shibata, R. (1997) A Dermal Sensitization Study of OMI - 88 Technical in the Guinea Pig.

Project Number: T/10010, B/3513. Unpublished study prepared by Bozo Research Center, Inc. 32 p. 47447741 Moore, G. (2008) Dermal Sensitization in Guinea Pig s (Buehler Method): NAI - 2302

(Tolfenpyrad) 15% EC. Project Number: 24305, P328, 080212/3R. Unpublished study prepared by Product Safety Laboratories. 24 p. 47447742 Mutai, M. (1995) 4 -Week Subacute Toxicity Study of AP81088 by Dietary Administration

in Rats. Project Number: T/10011. Unpublished study prepared by Safety Laboratory, Pathology Group. 11 p. 47447743 Nishitomi, T. (1999) A 13 -Week Subacute Oral Toxicity Study of OMI - 88 Technical in Rats

by Dietary Administration, Followed by a 4 -Week Rec overy Period. Project Number: T/10012, 6L162. Unpublished study prepared by Mitsubishi Chemical Safety Institute, Ltd. 246 p. 47447801 Trutter, J. (1999) 4 -Week Dietary Range - Finding Study in Mice with OMI - 88 Technical.

Project Number: T/10014, CHV/62 87/102, 8270A. Unpublished study prepared by Covance Laboratories, Inc. 211 p. 47447803 Nagashima, Y. (1997) A 13 -Week Subacute Oral Toxicity Study of OMI - 88 Technical in

Beagle Dogs. Project Number: T/10018, BOZO/B/3352. Unpublished study prepared by Kannami Laboratory. 132 p. 47447804 Nagashima, Y. (2004) A 13 -Week Oral Subacute Toxicity Study of OMI - 88 Technical in

Beagle Dogs (A Supplementary Study): Final Report. Project Number: T/10019, BOZO/B/3644. Unpublished study prepared by Kannami Laboratory - Bozo Research Center, Inc. 168 p. 47447805 Nagashima, Y. (1997) A 4 -Week Oral Subacute Toxicity Study of OMI - 88 Technical in

Beagle Dogs (Dose Range Finding Study). Project Number: T/10017, B/3351. Unpublished study prepared by Bozo Research Center, Inc. 55 p. 47447806 Barnett, J. (2008) 21 - Day Dermal Toxicity Study of Tolfenpyrad in Crl:CD(SD) Rats.

Project Number: XTH00005, 824690, W05899. Unpublished study prepared by Charles River Laboratories. 361 p. 47447807 Maks, M. (2008) Waiver Re quest for 90 - Day Dermal Rat Study: Tolfenpyral. Project

Number: TOL/TOX/01. Unpublished study prepared by Nichino America, Inc. 5 p. 47447808 Maks, M. (2008) Waiver Request for 90 - Day Rat Inhalation Study: Tolfenpyral. Project

Number: TOL/TOX/02. Unpublished study prepared by Nichino America, Inc. 4 p. 47447809 Hoshino, N. (1999) A Teratogenicity Study of OMI - 88 Technical in Rats. Project Number:

T/10024, B031577, 6L611. Unpublished study prepared by Mitsubishi Chemical Safety Institute, Ltd. 156 p.

### Tolfenp yrad Human Health Risk Assessment DP No. 383820

Page 59 of 65 MRID Citation 47447810 Matsuura, I. (1996) A Preliminary Teratogenicity Study of AP81088 in Rabbits. Project

Number: T/10029, B031577, 5L485HEO. Unpublished study prepared by Mitsubishi Chemical Safety Institute, Ltd. 140 p. 47447811 Fuj ii, O. (1997) A Teratogenicity Study of OMI - 88 Technical in Rabbits. Project Number:

T10030, 6L612. Unpublished study prepared by Mitsubishi Chemical Safety Institute, Ltd. 126 p. 47447812 Hoshino, N. (1999) Additional Fetus Examination to "A Teratogenicity Study of OMI - 88

Te chnical in Rats". Project Number: 9L550, T/10028. Unpublished study prepared by Mitsubishi Chemical Safety Institute, Ltd. 91 p. 47447813 Hoshino, N. (2008) Addendum to the Study Entitled "Effects of OMI - 88 (Tolfenpyrad) on a

Teratogenicity Study in Rats" for Agrichemical Application to the U.S. EPA. Project Number: B071133, 6L611. Unpublished study prepared by Mitsubishi Chemical Safety Institute, Ltd. 17 p. 47447814 Hoshino, N. (2008) Addendum to the Study Entitled "Effects of OMI - 88 (Tolfenpyra d) on a

Teratogenicity Study in Rabbits" for Agrichemical Application to the U.S. EPA. Project Number: B071134, 6L612. Unpublished study prepared by Mitsubishi Chemical Safety Institute, Ltd. 16 p. 47447815 Maks, M. (2008) Addendum 2 to "Effects of OMI - 88 (Tolfenpyrad) on a Teratogenicity

Study on Rats". Project Number: 6L611. Unpublished study prepared by Nichino America, Inc. 6 p. 47447816 Matsuura, I. (1996) A Preliminary Reproduction Study of AP81088 in Rats. Project

Number: T/10021, 5L484KE O, 5L484. Unpublished study prepared by Mitsubishi Chemical Safety Institute, Ltd. 249 p. 47447817 Nishitomi, T. (1999) A Two - Generation Reproduction Toxicity Study of OMI - 88 Technical

in Rats. Project Number: T/10022, 7L027. Unpublished study prepare d by Mitsubishi Chemical Safety Institute, Ltd. 1123 p. 47447818 Nagashima, Y. (1999) A 52 -Week Oral Chronic Toxicity Study of OMI - 88 Technical in

Beagle Dogs. Project Number: T/10020, B/3949. Unpublished study prepared by Bozo Research Center, Inc. 183 p. 47447822 Ozaki, M. (1999) A Reverse Mutation Test of OH - PT Using Bacteria. Project Number:

T/10109, M/1016. Unpublished study prepared by Bozo Research Center, Inc. 28 p. 47447824 Riley, S. (1997) OMI - 88 Technical: Induction of Chromosome Aberrations in Cultured

Chinese Hamster Lung (CHL) Cells: Final Report. Project Number: 1509/2/1052, T/10034. Unpublished study prepared by Covance Laboratories, Ltd. 63 p. 47447826 Ozaki, M. (2001) A Chromosomal Aberration Test of OH - PT Using CHL Cells. Project

Number: T/10111, M/1090. Unpublished study prepared by Bozo Research Center, Inc. 45 p. 47447827 Saigo, K. (2000) A Micronucleus Test of OH - PT in Rats. Project Number: SBL/92/14,

T/10110. Unpublished study prepared by Shin Nippon Biomedical La boratories, Ltd. 28 p. 47447829 Maks, M. (2008) Waiver Request for Delayed Neurotoxicity (Acute) - Hen Study. Project

Number: TOL/TOX/04. Unpublished study prepared by Nichino America, Inc. 4 p. 47447830 Kilpatrick, H. (2003) OMI - 88 Technical Neurotoxi city Study by Dietary Administration to

CD Rats for 13 Weeks. Project Number: MUB/146/024442, T/10036. Unpublished study prepared by Huntingdon Life Sciences, Ltd. 356 p. 47447831 Barnett, J. (2008) Tolfenpyrad: Oral (Gavage) Acute Neurotoxicity Study in Crl: CD(SD)

Rats. Project Number: XTH00001. Unpublished study prepared by Charles River Laboratories. 745 p. 47447832 Maks, M. (2008) Waiver Request for Developmental Neurotoxicity Study. Project Number:

TOL/TOX/03. Unpublished study prepared by N ihon Nohyaku Co., Ltd. 5 p.

### Tolfenp yrad Human Health Risk Assessment DP No. 383820

Page 60 of 65 MRID Citation 47447833 Okada, M. (1997) Fate of OMI - 88 in Rats - Preliminary Study. Project Number: T/10039,

6L190. Unpublished study prepared by Mitsubishi Chemical Safety Institute, Ltd. 44 p. 47447834 Nishitomi, T. (1999) Fate of OMI - 88 in Rats - Metabolism Study After a Single Oral

Administration. Project Number: T/10042, 7L366. Unpublished study prepared by Mitsubishi Chemical Safety Institute, Ltd. 88 p. 47447835 Kitazawa, K. (1998) Fate of OMI - 88 in Rats: Structural Identific ation of its Metabolites.

Project Number: T/10043, 7L367. Unpublished study prepared by Mitsubishi Chemical Safety Institute, Ltd. 86 p. 47447836 Okada, M. (1999) Fate of OMI - 88 in Rats - Absorption, Distribution, and Excretion by

Repeated Oral Administration. Project Number: 8L127, T/10065. Unpublished study prepared by Mitsubishi Chemical Safety Institute, Ltd. 112 p. 47447837 Miyagawa, M. (1998) Pharmacokinetic Study of OMI - 88 in Rats - Absorption, Distribution

and Excretion after a Single Oral A dministration - (Study No.: 7L365). Project Number: 7L365, T/10041. Unpublished study prepared by Mitsubishi Chemical Safety Institute, Ltd. 141 p. 47447838 Fuj ii, O. (1997) Metabolism Study of OMI - 88 in Rat Liver S - 9. Project Number: T/10040,

6L165. Unpublished study prepared by Mitsubishi Chemical Safety Institute, Ltd. 55 p. 47447839 Fasano, W. (2007) Tolfenpyrad 15% EC: In vivo Dermal Penetration in the Rat. Project

Number: 1643, 16846, DUPONT/21646. Unpublished study prepared by E.I. du Pont de Nemours & Co., Inc. 159 p. 47447840 Atai, H. (1999) Next Generation Immunotoxicity Study of OMI - 88 Technical in Rats.

Project Number: T/10037, 8L894. Unpublished study prepared by Mitsubishi Chemical Safety Institute, Ltd. 619 p. 47457501 Glaza, S . (1997) Acute Oral Toxicity Study of OMI - 88 Technical in Rats: Final Report.

Project Number: COVANCE/6649/108T/10. Unpublished study prepared by Covance Laboratories, Inc. 69 p. 47457502 Omori, M. (2000) An Acute Oral Toxicity Study of OMI - 88% Emulsio n in Rats. Project

Number: SBL13/61, T/10045. Unpublished study prepared by Shin Nippon Biomedical Laboratories, ltd. 98 p. 47457503 Glaza, S. (1997) Acute Dermal Toxicity Study of OMI - 88 Technical in Rats. Project

Number: CHW/6649/103, T/10006. Unpu blished study prepared by Corning Hazleton Inc. 49 p. 47457504 Omori, M. (2000) An Acute Inhalation Toxicity Study of OMI - 88 15% Emulsion in Rats.

Project Number: SBL13/60, T/10048. Unpublished study prepared by Shin Nippon Biomedical Laboratories, ltd . 84 p. 47457505 Glaza, S. (1996) Primary Eye Irritation Study of OMI - 88 Technical in Rabbits: Final Report.

Project Number: CHW/6649/105, T/10009. Unpublished study prepared by Corning Hazleton Inc. 38 p. 47457506 Sato, M. (2000) A Primary Eye Irritation Study of OMI - 88 15% Emulsion in Rabbits.

Project Number: SBL13/65, T/10050. Unpublished study prepared by Shin Nippon Biomedical Laboratories, ltd. 29 p. 47457507 Glaza, S. (1996) Primary Dermal Irritation Study of OMI - 88 Technical in Rabbit s: Final

Report. Project Number: CHW/6649/104, T/10008. Unpublished study prepared by Corning Hazleton Inc. 30 p. 47457508 Sato, M. (2000) A Primary Dermal Irritation Study of OMI - 88 15% Emulsion in Rabbits.

Project Number: SBL13/66, T/10049. Unpubli shed study prepared by Shin Nippon Biomedical Laboratories, ltd. 21 p.

### Tolfenp yrad Human Health Risk Assessment DP No. 383820

Page 61 of 65 MRID Citation 47463702 Trutter, J. (1999) 13 - Week Dietary Toxicity Study in Mice with OMI - 88 Technical: Final

Report. Project Number: 6287/104, T/10015. Unpublished study prepared by Covance Lab oratories, Inc. 346 p. 47463703 Ivett, J. (1999) 78 - Week Dietary Oncogenicity Study in Mice with OMI - 88 Technical: Final

Report. Project Number: 6287/110, T/10016. Unpublished study prepared by Covance Laboratories, Inc. 1562 p. 47463704 Chida, T. (1999) A Chronic Toxicity/ Carcinogenicity Study of OMI - 88 Technical in Rats

by Dietary Administration. Project Number: T/10013, 6L792, B031577. Unpublished study prepared by Kashima Chemical Company, Ltd. 1315 p. 47463705 Ballantyne (1997) OMI - 88 Technical: Reverse Mutation in Five Histidine - Requiring Strains

of Salmonella typhimurium and One Tryptophan - Requiring Strain of Escherichia coli: Final Report. Project Number: 1509/1/1052, T/10031. Unpublished study prepared by Covance Laboratories, Ltd. 7 4 p. 47463706 Cifone, M. (2007) L5178Y TK +/ - Mouse Lymphoma Forward Mutation Assay with a

Confirmatory Assay: Final Report. Project Number: 7883/100, 28781/0/431OECD. Unpublished study prepared by Covance Laboratories, Inc. 84 p. 47463707 Murli, H. ( 2007) Cell Cycle Kinetics in Chinese Hamster Lung (CHL)Cells: Final Report.

Project Number: 7883/102, 28781/0/443. Unpublished study prepared by Covance Laboratories, Inc. 53 p. 47463708 Xu, Yong (2007) In vivo Mouse Bone Marrow Micronucleus Assay: Fin al Report. Project

Number: 7883/101, 28781/0/455OECD. Unpublished study prepared by Covance Laboratories, Inc. 67 p. 47904801 Arce, G. (2009) Nichino America, Inc. Rebuttal to the Tolfenpyrad Briefing Document

(August 8, 2009) and the Draft DER: Developmental Immunotoxicity Study in Rats and the Draft DER: Multigeneration Reproduction Study in Rats. Project Number: TOL/TOX/05. Unpublished study prepared by Nichino America, Inc. 37 p. 47904802 Maks, M. (2009) Supplement 1 to: A Teratogenicity Study of OMI - 88 Technical in Rats

(Study Number 6L611 (MRID No. 47447815) and Next Generation Immunotoxicity Study of OMI - 88 Technical Rats (Study Number 8L894) (MRID No. 47447840). Project Number: T/10037, T/10024. Unpublished study prepared by Nichino Americ a, Inc. 20 p. 48233401 Citation: Jones, A. (2010) Tolfenpyrad: Comparative in vitro Dermal Absorption Study

Using Human and Rat Skin. Project Number: LMS00014, T/10160. Unpublished study prepared by Huntingdon Life Sciences, Ltd. 68 p. 48233402 Maks , M. (2010) Additional Data to Support 90 - Day Dermal Rat Requirement for

Greenhouse Use Pattern for Tolfenpyrad 15EC Insecticide. Project Number: TOL/TOX/13. Unpublished study prepared by Nichino America, Inc. 8 p. 48250444 Kunihiko, O. (1998) Metabolism Study of OMI - 88 on Eggplants. Project Number: R/10005,

6L191. Unpublished study prepared by Mitsubishi Chemical Safety Institute, Ltd. 202 p. 48250445 Ogawa, K. (1998) Metabolism Study of OMI - 88 [TO - (Carbon 14)] on Peach Plants. Project

Num ber: R/10003, 7L336. Unpublished study prepared by Mitsubishi Chemical Safety Institute, Ltd. 61 p. 48250446 Ogawa, K. (1999) Metabolism Study of OMI - 88 [PY - Carbon 14] on Peach Plants. Project

Number: R/10004, 8L123. Unpublished study prepared by Mitsubishi Chemical Safety Institute, Ltd. 52 p. 48250447 Ogawa, K. (1998) Metabolism Study of OMI - 88 [TO - Carbon 14] on Cabbage. Project

Number: R/10001, 7L170. Unpublished study prepared by Mitsubishi Chemical Safety Institute, Ltd. 55 p.

### Tolfenp yrad Human Health Risk Assessment DP No. 383820

Page 62 of 65 MRID Citation 48250448 Ogawa, K. (1999) Metabolism Study of OMI - 88 [PY - Carbon 14] on Cabbage. Project

Number: R/10002, 8L122. Unpublished study prepared by Mitsubishi Chemical Safety Institute, Ltd. 43 p. 48250449 Quistad, G.; Kovatchev, A. (2008) A Metabolism Study with [Pyrazole (Carbon 14)] and

[Tolyl Ring -U - (Carbon 14)]Tolfenpyrad in Radish. Project Number: 1740W. Unpublished study prepared by PTRL West, Inc., and Excel Research Services, Inc. 176 p. 48250450 Quistad, G.; Kovatchev, A. (2007) The Metabolism of (Carbon 14)Tolfenpyrad (2

Radiolabels) in the Lactating Goat. Project Number: R/10160, 1556W. Unpublished study prepared by PTRL West, Inc. and Genesis Midwest Laboratories. 245 p. 48250451 Quistad, G.; Kovatchev, A. (2007) The Metabolism of (Carbon 14)Tolfenp yrad (2

Radiolabels) in Laying Hens. Project Number: R/10161, 1557W. Unpublished study prepared by PTRL West, Inc., and Genesis Midwest Laboratories. 243 p. 48250452 Boatwright, M. (2007) Independent Laboratory Validation of Morse Laboratories, Inc.

An alytical Method "Determination of Tolfenpyrad and its OH - PT Metabolite in Crops (Raw Agricultural and Processed Commodities)". Project Number: 070269. Unpublished study prepared by Golden Pacific Laboratories, LLC. 81 p. 48250453 Reed, R. (2007) Validation of the Residue Analytical Method: "Determination of

Tolfenpyrad and its OH - PT Metabolite in Crops (Raw Agricultural Commodities)". Project Number: MLI/07/1, ML07/1350/NAI, A/10037. Unpublished study prepared by Morse Laboratories, Inc. 237 p. 48250454 Brookey, F. (2009) Validation of the Analytical Method: "Determination of Tolfenpyrad

(Including its PT - CA and PCA Metabolites) in Soil". Project Number: A/10040, MLI/07/03, ML07/1375/NAI. Unpublished study prepared by Morse Laboratories, Inc. 166 p. 48250455 Class, T.; Gocer, M. (2010) Independent Laboratory Validation of an Analytical Method for

the Determination of Tolfenpyrad and It's Metabolites PT - CA, OH - PT - CA and PCA in Foodstuffs of Animal Origin, Using LC/MS/MS. Project Number: P/17 50/G, A/10042. Unpublished study prepared by PTRL Europe Gmbh. 79 p. 48250456 Arndt, T. (2009) Independent Laboratory Validation of the Analytical Method for

Tolfenpyrad and its Metabolites PT - CA and PCA in Soil. Project Number: A/10041, 1934W. Unpubl ished study prepared by PTRL West, Inc. 91 p. 48250457 Brooks, M. (2010) Waiver Request for Multi - Residue Method for Tolfenpyrad and Crop

Uses. Project Number: TOL/RES/01. Unpublished study prepared by Nichino America, Inc. 5 p. 48250458 Arndt, T. (2 010) Magnitude of Tolfenpyrad Residues in Bovine Tissues and Milk from a 28 -

Day Feeding Study. Project Number: 1841/W, 1841/W/1, 213/013/10. Unpublished study prepared by PTRL West, Inc., and Genesis Midwest Laboratories. 923 p. 48250459 Chisolm, K. (2010) Tolfenpyrad: Request for Waiver of: Magnitude of the Residue in

Poultry Meat and Egg Commodities. Project Number: TOL/RES/02. Unpublished study prepared by Nichino America, Inc. 6 p. 48250460 Carringer, S. (2009) Magnitude of the Residue of Tolf enpyrad and its Metabolite in or on Grape Raw Agricultural and Processed Commodities Following Two Foliar Applications of NAI - 2303 15SC: Final Report. Project Number: TCI/08/195/01, TCI/08/195, TCI/08/195/02. Unpublished study prepared by Morse Laboratories, Inc., University of Idaho, Cooperative Extension and Reality Research. 275 p. 48250461 Wyatt, D. (2008) Magnitude of the Residue of Tolfenpyrad and its Metabolite in or on Apple

Raw Agricultural and Processed Commodities Followinng Two Applications of NAI - 2303 15SC: Final Report. Project Number: TCI/07/166. Unpublished study prepared by University of Idaho, Cooperative Extension, Morse Laboratories, Inc. and Reality Research. 367 p.

### Tolfenp yrad Human Health Risk Assessment DP No. 383820

Page 63 of 65 MRID Citation 48250462 Carringer, S. (2008) Magnitude of the Residue of Tolfen pyrad and its Metabolite in or on Potato Raw Agricultural and Processed Commodities Following Two Foliar Applications of NAI - 2302 15EC. Project Number: TCI/07/163, TCI/07/163/01, TCI/07/163/02. Unpublished study prepared by University of Idaho, Cooperative Extension, Morse Laboratories, Inc. and Reality Research. 342 p. 48250463 Carringer, S. (2008) Magnitude of the Residue of Tolfenpyrad and its Metabolite in or on

Fruiting Vegetable Raw Agricultural and Processed Commodities Following Two Foliar Appli cations of NAI - 2302 15EC or NAI - 2303 15SC: Final Report. Project Number: TCI/07/164, TCI/07/164/01, TCI/07/164/02. Unpublished study prepared by Morse Laboratories, Inc., National Food Laboratory, and Crop Management Strategies, Inc. 462 p. 48250464 St ewart, E. (2008) Tolfenpyrad Residues on Leafy Vegetables (Leaf Lettuce, Head Lettuce,

Celery and Spinach) from trials Conducted in the United States in 2007: Final Report. Project Number: SARS/07/03, SARS/07/04, SARS/07/05. Unpublished study prepared by Stewart Agricultural Research Services, Inc. 328 p. 48250465 Stewart, E. (2008) Tolfenpyrad Residues on Brassica (Cole) Leafy Vegetables (Cauliflower,

Cabbage and Mustard Greens) from Trials Conducted in the United States in 2007. Project Number: SARS/07/07, SARS/07/08, SARS/07/09. Unpublished study prepared by Stewart Agricultural Research Services, Inc. 273 p. 48250466 Greenland, R. (2009) Tolfenpyrad Residues on Tree Nuts (Almond and Pecan) from Trials

Conducted in the United States in 2008: Final Report. Project Number: SARS/08/01, SARS/08/02, R/10178. Unpublished study prepared by Stewart Agricultural Research Services, Inc. 227 p. 48250467 Greenland, R. (2009) Tolfenpyrad Residues on Stone Fruit (Cherry, Peach, Plum and the

Processed Co mmodity, Prune) from Trials Conducted in the United States in 2008: Final Report. Project Number: SARS/08/13, SARS/08/14, SARS/08/15. Unpublished study prepared by Stewart Agricultural Research Services, Inc. 306 p. 48250468 Wyatt, D. (2008) Magnitude of the Residue of Tolfenpyrad and its Metabolite in or on Citrus

Raw Agricultural and Processed Commodities Following Two Foliar Applications of NAI 2303 15SC or NAI - 2302 15EC: Final Report. Project Number: TCI/07/184, TCI/07/184/01, TCI/07/184/02. Unpub lished study prepared by Morse Laboratories, Inc., University of Idaho, Cooperative Extension and Florida Pesticide Research, Inc. 552 p. 48250469 Wyatt, D. (2008) Magnitude of the Residue of Tolfenpyrad and its Metabolite in or on

Cotton Raw Agricultural and Processed Commodities Following Two Foliar Applications of NAI - 2302 15EC: Final Report. Project Number: TCI/07/165, TCI/07/165/01, TCI/07/165/02. Unpublished study prepared by Morse Laboratories, Inc., GLP Technologies and Southeast Ag Research, Inc. 334 p. 48250470 Greenland, R. (2009) Tolfenpyrad Residues on Cucurbits (Cucumber, Cantaloupe and

Summer Squash) from Trials Conducted in the United States in 2008: Final Report. Project Number: SARS/08/10, SARS/08/11, SARS/08/12. Unpublished study prepared by Stewart Agricultural Research Services, Inc. 247 p. 48250471 Carringer, S. (2009) Magnitude of the Residue of Tolfenpyrad and its Metabolite in or on

Pear Raw Agricultural Commodities Following Two Foliar Applications of NAI - 2303 15SC or NAI - 2302 15EC: Final Report. Project Number: TCI/08/196, TCI/08/196/01, TCI/08/196/02. Unpublished study prepared by Morse Laboratories, Inc., Reality Research and Research for Hire. 234 p. 48250472 Komatsu, K.; Yabusaki, T. (1998) Residue of OMI - 88: Residue of OMI - 88 on/in Green Tea.

Project Number: R/10027. Unpublished study prepared by Japan Food Research Laboratories. 23 p.

### Tolfenp yrad Human Health Risk Assessment DP No. 383820

Page 64 of 65 MRID Citation 48250473 Hagio, S. (1998) Residue of OMI - 88 on/in Green Tea. Project Number: R/10028.

Unpublished study prepared by Mitsu bishi Chemical Safety Institute, Ltd. 20 p. 48250474 Yabusaki, T. (2005) Residue of Tolfenpyrad: Residue of Tolfenpyrad (Hachi - Hachi) on/in

Green Tea. Project Number: R/10097. Unpublished study prepared by Japan Food Research Laboratories. 21 p. 4825 0475 Otsubo, S. (2005) Residue of Tolfenpyrad: Residue of Tolfenpyrad (Hachi - Hachi) on/in

Green Tea. Project Number: R/10098. Unpublished study prepared by Japan Ecotech Company, Ltd. 18 p. 48250476 Quistad, G.; Kovatchev, A.; Hiler, R. (2008) A Confined Rotational Crop Study with

[Pyrazole - (Carbon 14)] and [Tolyl Ring -U - (Carbon 14)] Tolfenpyrad Using Radish, Lettuce, and Wheat. Project Number: 1550W, R/10171. Unpublished study prepared by PTRL West, Inc., and Research for Hire. 409 p. 48250477 Carringer, S. (2010) Field Accumulation of Tolfenpyrad and its OH - PAM, OH - PCA, and

PAM Metabolites in Rotational Crops: Final Report. Project Number: TCI/09/235, TCI/09/235/01, TCI/09/235/02. Unpublished study prepared by PTRL West, Inc., Agvise Laboratories, Inc. and South Texas Ag Research, Inc. 859 p. 48250478 Durando, J. (2010) NAI - 2303 15%SC (Tolfenpyrad 15SC): Acute Oral Toxicity Up and

Down Procedure in Rats. Project Number: 28303, P320/UDP, 090929/2D. Unpublished study prepared by Eurofins/Pro duct Safety Laboratories. 16 p. 48250479 Durando, J. (2010) NAI - 2303 15%SC (Tolfenpyrad 15SC): Acute Dermal Toxicity Study in

Rats - Limit Test. Project Number: T/10154, 28304, P322/RAT. Unpublished study prepared by Eurofins/Product Safety Laboratorie s. 15 p. 48250480 Durando, J. (2010) NAI - 2303 15%SC (Tolfenpyrad 15SC): Acute Inhalation Toxicity Study

in Rats. Project Number: T/10155, 28305, P330. Unpublished study prepared by Eurofins/Product Safety Laboratories. 35 p. 48250481 Durando, J. (201 0) NAI - 2303 15%SC (Tolfenpyrad 15SC): Primary Eye Irritation Study in

Rabbits. Project Number: T/10157, 28306, P324. Unpublished study prepared by Eurofins/Product Safety Laboratories. 16 p. 48250482 Durando, J. (2010) NAI - 2303 15%SC (Tolfenpyrad 15SC) : Primary Skin Irritation Study in

Rabbits. Project Number: T/10156, 28307, P326. Unpublished study prepared by Eurofins/Product Safety Laboratories. 16 p. 48250483 Durando, J. (2010) NAI - 2303 15%SC (Tolfenpyrad 15SC): Dermal Sensitization Study in

Guinea Pigs (Buehler Method). Project Number: T/10158, 28308, P328. Unpublished study prepared by Eurofins/Product Safety Laboratories. 25 p. 48250484 Arcee, G. (2010) Tolfenpyrad: Range - Finding Inhalation Toxicity Study in Rats:

Supplement 1 to Tolfenpyrad: Four -Week Inhalation Toxicity Study in Rats. Project Number: DUPONT/22217R, T/10159, 16846. Unpublished study prepared by Dupont Haskell Laboratory. 73 p. 48250485 Buxton, P. (2010) Method Validation to Support Analysis of Tolfenpyrad in Corn Oi l Dose

Formulations for Nihon Nohyaku Co., Ltd.. Project Number: XTH00010AX/07/384, A/10043. Unpublished study prepared by Charles River Laboratories. 36 p. 48250488 Wyatt, D. (2009) Dissipation of Dislodgeable Foliar Residues of Tolfenpyrad Following

Two Applications to Apple Trees: Final Report. Project Number: TCI/08/188, TCI/08/188/01, TCI/08/188/02. Unpublished study prepared by Carringers, Inc., Morse Laboratories, Inc. and Reality Research. 216 p. 48250489 Wyatt, D. (2009) Dissipation of Disl odgeable Foliar Residues of Tolfenpyrad Following

Two Applications to Cantaloupes: Final Report. Project Number: TCI/08/190, R/10182, TCI/08/190/01. Unpublished study prepared by Morse Laboratories, Inc., Carringers, Inc. and Southeast Ag Research, Inc. 214 p.

### Tolfenp yrad Human Health Risk Assessment DP No. 383820

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Two Applications to Grapes: Final Report. Project Number: R/10181, TCI/08/189, TCI/08/189/01. Unpublished study prepared by Morse Laboratories, Inc., Reality Research and Agsearch. 212 p.