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

MEMORANDUM

	Date:	12 April 2012

	SUBJECT:	Tolfenpyrad  -  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 TXR No.:  None CAS No.:  129558-76-5 MRID Nos.:  See Bibliography  40 CFR 180:  None (first food use request)

	FROM:	Michael A. Doherty, Ph.D., Senior Chemist 		Zaida Figueroa, Industrial Hygienist 		Karlyn Middleton, Toxicologist 		Risk Assessment Branch II 		Health Effects Division (7509P)

	THROUGH:	Elizabeth Holman, Chemist 		Suku Oonnithan, 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:	Driss Benmhend/Mark Suarez (Team 13) 		Insecticide Branch 		Registration Division (7505P)

1.0	Executive Summary	4 2.0	HED Recommendations	5 2.1	Data Deficiencies	5 2.2	Tolerance Considerations	5 2.2.1	Enforcement Analytical Method	5 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	9 2.3.2	Label Recommendations from Occupational Assessment	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, & Elimination (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	18 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	19 4.5	Toxicity Endpoint and Point of Departure Selections	19 4.5.1	Dose-Response Assessment	19 4.5.2	Recommendation for Combining Routes of Exposures for Risk Assessment	20 4.5.3	Cancer Classification and Risk Assessment Recommendation	20 4.5.4	Summary of Points of Departure and Toxicity Endpoints Used in Human Risk Assessment	20 5.0	Dietary Exposure and Risk Assessment	22 5.1	Metabolite/Degradate Residue Profile	22 5.1.1	Summary of Plant and Animal Metabolism Studies	22 5.1.2	Summary of Environmental Degradation	23 5.1.3	Comparison of Metabolic Pathways	24 5.1.4	Residues of Concern Summary and Rationale	24 5.2	Food Residue Profile	25 5.3	Water Residue Profile	28 5.4	Dietary Risk Assessment	29 5.4.1	Description of Residue Data Used in Dietary Assessment	29 5.4.2	Percent Crop Treated Used in Dietary Assessment	31 5.4.3	Acute Dietary Risk Assessment	31 5.4.4	Chronic Dietary Risk Assessment	32 5.4.5	Cancer Dietary Risk Assessment	32 5.4.6	Summary Table	32 6.0	Residential (Non-Occupational) Exposure/Risk Characterization	33 6.1	Residential Bystander Post-Application Inhalation Exposure	33 6.2	Spray Drift	33 8.0	Cumulative Exposure/Risk Characterization	34 9.0	Occupational Exposure/Risk Characterization	34 9.1	Short- and Intermediate-Term Handler Risk	35 9.2	Short- and Intermediate-Term Post-Application Risk	38 9.2.1	Dermal Post-Application Risk	38 9.2.2	Inhalation Post-Application Risk	39 10.0	References	39 Appendix A.  Toxicology Profile and Executive Summaries	41 A.1	Toxicology Data Requirements	41 A.3	Triple-Pack Analysis for Tolfenpyrad	49 A.4	Toxicological Doses and Endpoints for Use in Human Risk Assessments	51 Appendix B. Metabolism Summary Table	54 Appendix C.  Physical/Chemical Properties	59 Appendix D.  Review of Human Research	60 Appendix E.  Bibliography of Submitted Studies	61

1.0	Executive Summary

Nichino America, Inc. has petitioned the Agency for Section 3 registration of end-use products containing the pesticide active ingredient tolfenpyrad 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 establishment of tolerances for residues of tolfenpyrad.

Tolfenpyrad shows broad insecticidal activity against target pests through the egg, larval, nymph, and adult stages.  The proposed uses 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, Nichino America is requesting a tolerance for residues of tolfenpyrad in/on tea, without a U.S. registration.  Tolfenpyrad was first assessed by HED in June of 2010 in conjunction 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 tolfenpyrad as it relates to its registered and requested uses.

A variety of toxic effects were noted in the toxicology database for tolfenpyrad.  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 toxicity 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 assessments are based on the most sensitive endpoints and points of departure.  No hazard concern was identified from the available dermal toxicity and dermal penetration data; therefore, a dermal risk assessment was not conducted.

Toxicological testing indicates that tolfenpyrad is not neurotoxic or immunotoxic, and it is classified as "not likely to be carcinogenic to humans."  After considering the completeness of the toxicological database, the overall hazard profile of tolfenpyrad, 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 tolfenpyrad may occur from consuming tolfenpyrad-treated crops or their processed commodities.  HED has used modeling to assess acute and chronic dietary exposure to tolfenpyrad.  The modeling uses health-protective assumptions regarding residues of tolfenpyrad and its breakdown products in foods and drinking water in combination with an extensive database of food 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 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, highly 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 doses (aPAD, cPAD), respectively.  These estimates are below HED's level of concern for the US population and population subgroups, including those of infants and children.

Exposures may also occur during activities associated with using tolfenpyrad-containing products and from activities in areas treated with this insecticide.  At this time, there are no registered or requested uses for these 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 handlers mixing, loading, and applying tolfenpyrad.  Post-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 tolfenpyrad, MOEs of less than 100 are considered to be of concern.  As no dermal endpoint was identified for tolfenpyrad, the occupational MOEs reflect inhalation exposure only.

This risk assessment is based, in part, on 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 tolfenpyrad 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

Prior to registration, a reference standard for PT-CA should be submitted to the EPA National Pesticide Standards 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.

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 tolfenpyrad residue tolerances in/on plant commodities (Morse Laboratories Analytical Method #Meth-183, Revision #2).  The method limit of quantitation (LOQ; 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 described in PTRL West Study No. 1841W.  The livestock method adequately determines residues of tolfenpyrad 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 analysis.  The validated LOQ (based on the LLMV) was 0.01 ppm for all analytes in all matrices.  The method has been adequately 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 tolfenpyrad.  The submitted data will be forwarded to the U.S. Food and Drug Administration (FDA) for further evaluation.  Metabolite 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, based on the structural similarity between tolfenpyrad and PT-CA, HED does not expect the FDA multiresidue method protocols to be suitable for analysis 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 (MRLs) for tolfenpyrad 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 tolfenpyrad in/on plant and livestock commodities  be expressed in terms of residues of tolfenpyrad:  4-chloro-3-ethyl-1-methyl-N-[4-(p-tolyloxy)benzyl]pyrazole-5-carboxamide.  HED has determined that the residues of concern for tolerance enforcement are tolfenpyrad in/on crop commodities and tolfenpyrad + metabolite PT-CA in livestock commodities.  The tolerance expressions for plant and livestock commodities should be revised as follows:

For crop commodities:       Tolerances are established for residues of the insecticide tolfenpyrad, 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 by measuring only tolfenpyrad, 4-chloro-3-ethyl-1-methyl-N-[4-(p-tolyloxy)benzyl]pyrazole-5-carboxamide.

For livestock commodities:       Tolerances are established for residues of the insecticide tolfenpyrad, 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 by measuring only the sum of tolfenpyrad, 4-chloro-3-ethyl-1-methyl-N-[4-(p-tolyloxy)benzyl]pyrazole-5-carboxamide, and its metabolite 4-[4-[(4-chloro-3-ethyl-1-methylpyrazol-5-yl)carbonylamino-methyl]phenoxy]-benzoic acid, calculated as the stoichiometric equivalent of tolfenpyrad.

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 combined 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 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

Nearly 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 vegetable, leafy, except Brassica, group 4 is appropriate.  If the petitioner 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 likely 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 by the petitioner.

Because only limited information 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.

Differences in the proposed livestock tolerances for meat byproducts and muscle are attributed to differences in the dietary burden calculation generated by the petitioner and that generated by the Agency.

HED notes that based on data from the metabolism study 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 tolfenpyrad be proposed on significant poultry feed items, then a poultry feeding study will 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 	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 crop 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 only one adjuvant type was tested for each crop or crop group, the labels should be revised to specify use of a non-ionic surfactant (NIS) 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 Listed in the front page (i.e., 1.29 lbs ai/gal for Tolfenpyrad 15EC and 1.31 lb ai/gal for Tolfenpyrad 15SC).

   * 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.  However, since 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.  Furthermore, RD should ensure that the 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

Table 3.1.  Test Compound Nomenclature: Tolfenpyrad.  Chemical structure                                                                                Common name Tolfenpyrad Company 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]-1H-pyrazole-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 physicochemical 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.  Tolfenpyrad and its transformation products are expected to moderately degrade in the environment.  In soil, tolfenpyrad 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 directions and precautions.

The proposed labels specify that tolfenpyrad 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 Tolfenpyrad 15EC Insecticide or Tolfenpyrad 15SC Insecticide should be made before alternating with an insecticide that has an alternate mode of action (not in Group 21A).

The following rotational crop restrictions are specified:  0 days following 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 materials indicates application rates of 0.401-0.535 lb ai/A (450-600 g ai/ha) and a 14-day PHI.

Recommended revisions 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) Citrus Fruit  (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), Potatoes, Brassica (cole) Leafy Vegetables (Crop Group 5), Fruiting Vegetables (Crop Group 8 plus Okra), Cotton 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.

Stone Fruit (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.

Tea[*] 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 ft[2] per application (100 gal per 20,000 ft[2] 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) Citrus Fruit  (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 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 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.

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), Cotton 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 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 air applications for cotton, do not use less than 3 gallons of water per acre.

Stone Fruit (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 ft[2] 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 Insecticide (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 Insecticide (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 for Tolfenpyrad 15EC Insecticide (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 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. * 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

As a result of the registered and proposed uses of tolfenpyrad, humans may experience dietary exposure to tolfenpyrad residues via their food and drinking water.  At this time, there are no registered or proposed uses of tolfenpyrad that are likely to result in other exposures in a non-occupational setting.

In occupational settings, 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 pathways, combining them as appropriate, to estimate overall exposure and risk.

3.5	Consideration of Environmental Justice

In accordance with U.S. Executive Order 12898, potential 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 subgroups 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 patterns 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 analyzed and categorized by subgroups based on age, season of the year, ethnic group, and region of the country.  Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups when conditions or circumstances warrant.  For pesticides used in a residential or public setting, exposures 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 bystanders and farm workers as well as unique exposures associated with lifestyles 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 required studies for tolfenpyrad have been submitted. Since the last risk assessment (K. Middleton, D354437), the Registrant has submitted additional data for tolfenpyrad, including a comparative in vitro dermal absorption study using human and rat skin (MRID48233401) 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 tolfenpyrad include subchronic and chronic oral toxicity studies in rats, mice, and dogs, dermal studies (28-day dermal toxicity, in 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 tolfenpyrad 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, kidney, 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.

Tolfenpyrad 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 of repeated daily doses had no effect on the route of excretion or the extent of recovery.  Tolfenpyrad was metabolized by oxidation to form a number of hydroxylated metabolites (Pt-CA, OH-PT and OH-PT-CA), followed by conjugation (glucuronide, sulfate, asparagines or taurine).  The primary metabolite, PT-CA was found in plasma, liver, kidney, and fat (<5%), along with taurine-conjugated and hydroxylated 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 only 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 pyrazole-labled ([14]C) tolfenpyrad, blood levels of radioactivity were approximately 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.  Conversely, 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).

4.2.1	Dermal Absorption

An in vivo  dermal absorption study in rats is available for tolfenpyrad.  After 24hrs, in the 1 g/L group, the absorbable and absorbed dose accounted for 39.8% of the applied dose.   Additionally, in vitro dermal absorption data have been recently submitted and demonstrates  that tolfenpyrad 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 tolfenpyrad.  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, with 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.  Although 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 dogs at lower doses.  The severity of body weight changes increased with dose in mice while body weight effects in dogs were seen only at the highest dose tested (HDT).

The body weight changes observed in the database were most often seen in the presence of decreased food consumption and in some studies, additional toxicity including liver/kidney effects and clinical signs.  Increased liver and kidney weights, liver and kidney hypertrophy, 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 slightly lower doses than in the subchronic studies.  Other effects noted in rats were effects on the harderian gland and lymph 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 histopathology in the liver only, 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 lesions (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 noted in one dam in a rabbit developmental toxicity study.  Mortality was also observed in two animals in an inhalation toxicity study (range-finding only).  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 no evidence of increased quantitative or qualitative susceptibility in the guideline rat and rabbit developmental studies, or the rat reproduction study.  Although several 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/mortality).  In a non-guideline rat developmental immunotoxicity (DIT) 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 tolfenpyrad.  Although hunched posture, ataxia, and hypoactivity 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 tolfenpyrad (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), tolfenpyrad 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 tolfenpyrad, 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 tolfenpyrad; there are no residential exposures at this time.

4.4.1	Completeness of the Toxicology Database

The toxicology database is complete for tolfenpyrad.   The toxicity profile can be characterized for all effects, including potential developmental and reproductive toxicity, immunotoxicity and neurotoxicity. 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 Neurotoxicity

The level of concern for neurotoxicity is low for tolfenpyrad.  No 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, mainly 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 of Sensitivity/Susceptibility in the Developing or 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 tolfenpyrad.   When the DIT study is considered along with the reproduction study, the offspring toxicity in the DIT study was observed at the same dose as comparable maternal toxicity (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 Database

There are no residual uncertainties with regard to the exposure assessment.  The acute dietary exposure assessment is 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, actual exposures to tolfenpyrad 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 Departure 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.

For acute dietary 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 LOAEL 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 NOAEL of 0.6 mg/kg/day from a combined chronic/carcinogenicity study in rats.  Decreased body weight, body weight gain and food consumption, changes in the harderian glands (found in the eye), histopathological changes in liver, kidney and lymph nodes were observed at the LOAEL of 1.5 mg/kg/day.  Chronic mouse and dog studies were also considered for 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 tolfenpyrad.  For dermal exposures, a route-specific 21-day dermal toxicity study in rats was used for endpoint selection.  Although no systemic 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 tolfenpyrad.  Based on the analysis 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 tolfenpyrad.  Therefore, short-, and intermediate-term 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 was selected. No toxic effects were observed up to the NOAEL of 10 mg/m3 and the LOAEL was 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 NOAEL was identified at the next lowest dose of 10.9 mg/m3, which is comparable to the dose in the definitive study where no effects were seen (10 mg/m3).  HED used the NOAEL of 10 mg/m3 (EPA calculated dose = 2.6 mg/kg/day) from the definitive 4-week inhalation study and the LOAEL of 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 tolfenpyrad, 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 tolfenpyrad.  It is appropriate to combine routes of exposures when such exposures result in the same toxicological effects.  In the case of tolfenpyrad, 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 tolfenpyrad.

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), tolfenpyrad is classified 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 Acute Dietary (General Population, including Infants and Children) NOAEL= 10 mg/kg/day UFA= 10 x UFH=10 x FQPA SF=1x

Acute 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 UFA= 10 x UFH=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.  UFA = extrapolation from animal to human (interspecies).  UFH = potential variation in sensitivity among members of the human population (intraspecies). UFS = 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 dermal risk assessment was not conducted based on a lack of dermal toxicity.   Dermal Long-Term (>6 months) Long-term dermal exposure is not expected based on use pattern. Inhalation Short-Term And Intermediate-Term (Up to 6 months of Exposure) NOAEL= 2.6 mg/kg/day UFA= 10 x UFH=10 x Occupational LOC for MOE = 100 LOAEL=6.8 mg/kg/day, based on body weight changes and mortality 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 carcinogenicity studies. NOAEL = no observed adverse effect level.  LOAEL = lowest observed adverse effect level.  UF = uncertainty factor.  UFA = extrapolation from animal to human (interspecies).  UFH = potential variation in sensitivity among members of the human population (intraspecies).  MOE = margin of exposure.  LOC = level of concern.

5.0	Dietary Exposure and Risk Assessment

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 tolfenpyrad in target crops, rotational crops, and livestock.  All studies were conducted in a manner appropriate for the proposed uses and consisted of two sets of data.  In the first set, tolfenpyrad was radiolabeled in the tolyl moiety (TO); in the second set, the radiolabel was in the pyrazole 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 days); and the livestock studies with laying hens and lactating goats.

In the primary crop metabolism studies, tolfenpyrad was the major identified residue in all primary crops.  The metabolic pathway for tolfenpyrad was generally similar in all primary crops, with the most extensive metabolism observed in cabbage.  Based on the submitted studies, the petitioner proposed that tolfenpyrad is metabolized via:  hydroxylation of the ethyl side chain of the pyrazole ring; hydroxylation of the methyl group of the tolyloxy benzyl moiety; carboxylation; oxidative degradation of the pyrazole ring and tolyloxy benzyl moiety (probably via hydroxylation of the benzyl methylene moiety); hydrolysis of the amide bond; and oxidation of the alkyl group 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-CA 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% total 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 leaves, and PAM at up to 10% TRR in radish root.

The metabolism studies with peach, eggplant, and cabbage included components to assess translocation of tolfenpyrad.  The results of these studies indicate that translocation of residues is very limited and that radioactivity moves only to the edge of the treated leaves, likely as a result of transpiration.

In rotational crops, tolfenpyrad was extensively 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 nearly all matrices at nearly all PBIs.  PAM 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 pyrazole and diphenyl ether fragments.  The diphenyl ether portion produces minimal residues.  The more polar pyrazole portion is initially present as the amide (PAM) which is generally a minor metabolite.  PAM is 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.

Tolfenpyrad 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 detected in the ruminant feeding study.  Based on the submitted studies, metabolism of tolfenpyrad in goat and hen proceeds initially by oxidation of tolfenpyrad at the tolyl methyl group to form PT-CA, and PT-CA undergoes further oxidation at the pyrazole ethyl group to produce OH-PT-CA.   The secondary metabolic routes differ in goat and hen.  In goat, PT-CA may also undergo hydrolysis to produce metabolites PCA and CA-T-NH2; PT-CA and these hydrolysis metabolites are then bound to nonpolar lipids in milk and fat.   In hen, tolfenpyrad 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 hydrolysis 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

Based on the submitted environmental fate data and reported physicochemical properties, tolfenpyrad and its transformation products are expected to moderately degrade in the environment.

In the laboratory, tolfenpyrad 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 systems, half-lives ranged from approximately two weeks to over 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.  Tolfenpyrad has a propensity to bind to soil/sediments and is expected to be essentially immobile.  Therefore, it is not expected to leach to ground water.  However, tolfenpyrad does have the potential to contaminate surface water via spray drift and runoff of residues sorbed to sediment.  Under terrestrial field conditions, tolfenpyrad rapidly degraded to PCA and PT-CA (half-lives = 1.8-6.6 days).  PCA and PT-CA are expected to be highly mobile.

5.1.3	Comparison of Metabolic Pathways

In treated crops, metabolism of tolfenpyrad 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 tolfenpyrad reaches the soil, it can be expected to undergo extensive degradation, with portions of the molecule ultimately forming CO2 or being tied up as bound residue.  The available data from studies with rats, goats, and hens indicates that tolfenpyrad is rapidly taken up following oral exposure and then metabolized by oxidation to form a number of hydroxylated metabolites (principally PT-CA, OH-PT and OH-PT-CA), followed by conjugation (glucuronide, sulfate, asparagines or taurine).

Of the major metabolites identified in plant, livestock, 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 tolfenpyrad have been examined to determine residue 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 substituted 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 tolfenpyrad.  In radish root, the PT-CA metabolite was observed at 10 and 21% TRR (PY and TO labels, respectively).  Tolfenpyrad alone is sufficient for tolerance enforcement in all crops.  PT-CA is structurally 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 tolfenpyrad 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 rotational 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 analyzed for tolfenpyrad, PAM, OH-PAM (conjugates and hydrolysis products), and OH-PCA (conjugates and hydrolysis 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 residues 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 major 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 only be considered in the dietary risk assessment for ruminant liver, kidney, and other meat byproducts.  The analytical method has been validated for parent, PT-CA, OH-PT-CA, and PCA (milk and fat only), and includes a hydrolysis 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, although 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 parent and PT-CA, since parent residues alone would not be an adequate marker for misuse.

Water.  The major transformation products resulting from the degradation of tolfenpyrad are PAM, PCA, PT-OH, PT-CHO, PT(A)-4OH and PT-CA.  Of these six major degradates, there 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 only 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 structurally different from the parent compound, in the absence of toxicity data they are also being 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 pear), stone fruit (cherry, peach, and plum), grape, tree nuts (almond and 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 generally 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 tolfenpyrad to a primary crop of mustard greens at a total rate of 0.54 lb ai/A, residues of tolfenpyrad, 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 PBIs, and in/on radish top and 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 tolfenpyrad at ~5x 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) Tomato                                   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) 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) Almond Nutmeat                                   0.540-0.551 SC 13-14 5 <0.01 0.027 0.027 0.01 0.013 0.008 Almond 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 Commodity 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 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, tolfenpyrad and its transformation products are expected to moderately degrade in the environment.  In soil, tolfenpyrad is expected to be essentially immobile; however, the degradates PCA and PT-CA are expected to be highly 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.

Tolfenpyrad 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 studies 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 tolfenpyrad are represented by the use pattern of maximum tolfenpyrad exposure, nurseries and Christmas trees (Table 5.3).  Maximum acute, chronic, and cancer EDWCs in surface water are 26.9, 12.2, and 4.8 ug/L, respectively.  The maximum exposure estimate for ground water is 11 ug/L.  Monitoring and drinking water treatment data on tolfenpyrad 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 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, 12 April 2012.

Acute and chronic aggregate dietary (food and drinking water) exposure and risk assessments were conducted using the Dietary Exposure Evaluation Model DEEM-FCID(TM) (v. 2.03).  This model uses food consumption data from the U.S. Department of Agriculture's (USDA's) Continuing Surveys of Food Intakes by Individuals (CSFII) from 1994-1996 and 1998.

5.4.1	Description of Residue Data Used in Dietary Assessment

The residue data used in the acute and chronic dietary assessment are derived from field trials conducted with tolfenpyrad 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 (PHIs)].  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 tolfenpyrad were combined with estimates of tolfenpyrad residues in livestock feed to derive estimates of tolfenpyrad 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 byproducts are accounted for by 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 convert tolfenpyrad to tolfenpyrad + 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-byproduct entries in the assessments.

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 Pumpkin, 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 -- 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 tolfenpyrad.  As a refinement to the chronic assessment, the following 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 assessment.  Inputs to the analysis 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.  Typically 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 assessment, the inputs to the analysis can be characterized as highly health protective.  While the application of the juice processing factor from grapes to other juices provides some refinement relative to a strict screening-level assessment, the conservatism in the other input parameters results in exposure estimates that are likely 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 significantly 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 of 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 likely that monitoring data, which take these issues into account, would show significantly 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 type (table grapes).  For all other crops, it was assumed that 100% of the planted acreage would be treated  -  a situation which is highly unlikely.  Overall, the chronic risk estimates are likely to be overestimates of actual chronic dietary risk.

5.4.5	Cancer Dietary Risk Assessment

A quantitative cancer assessment was not conducted.  Tolfenpyrad is classified as "not likely to be carcinogenic to humans;" therefore, there is no cancer risk associated with tolfenpyrad.

5.4.6	Summary Table

Table 5.4.6.  Summary of Acute and Chronic Dietary Exposure Analyses for Tolfenpyrad. Population Subgroup                            Acute (95[th] Percentile)                                     Chronic                                     Cancer

                        Estimated Exposure (mg/kg/day)                             Estimated Risk, % aPAD                         Estimated Exposure (mg/kg/day)                             Estimated Risk, % cPAD                                                                      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 yrs 0.0637 64 0.00190 32

Youth 13-19 yrs 0.0559 56 0.00130 22

Adults 20-49 yrs 0.0605 61 0.00133 22

Adults 50+ yrs 0.0612 61 0.00173 29

Females 13-49 yrs 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 tolfenpyrad that are defined as residential uses (i.e., (1) directly on humans or pets; (2) In, on, or around any structure, vehicle, article, surface, or area associated 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-Application Inhalation Exposure

Based on the Agency's current practices, a quantitative post-application bystander inhalation exposure assessment was not performed for tolfenpyrad 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.  The Agency is in the process of evaluating the SAP report and may, as appropriate, develop policies and procedures to identify the need for and, subsequently, the way to incorporate post-application inhalation exposure into the Agency's risk assessments.  If new policies or procedures are developed, the Agency may revisit the need for a quantitative post-application inhalation exposure assessment for tolfenpyrad.

6.2	Spray Drift

Spray drift is always a potential source of exposure to residents nearby to spraying operations.  This is particularly the case with aerial application, but, to a lesser extent, could also be a potential source of exposure from the ground application method employed for tolfenpyrad.  The Agency has been working with the Spray Drift Task Force, EPA Regional Offices and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices.  On a chemical by chemical basis, the Agency is now requiring interim mitigation measures for aerial applications that must be placed on product labels/labeling.  The Agency has completed its evaluation of the new database submitted by the Spray Drift Task Force, a membership of U.S. pesticide registrants, and is developing a policy on how to appropriately apply the data and the AgDRIFT computer model to its risk assessments for pesticides applied by air, orchard airblast and ground hydraulic methods.  After the policy is in place, the Agency may impose further refinements in spray drift management practices to reduce off-target drift with specific products with significant risks associated with drift.

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-application 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 exposures.  In an aggregate assessment, exposures from relevant sources are added together and compared to quantitative estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can be aggregated.  When aggregating exposures and risks from various sources, HED considers both the route and duration of exposure.

As tolfenpyrad 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 tolfenpyrad to any other substances nor does tolfenpyrad appear to produce a toxic metabolite produced by other substances. For the purposes of this tolerance action, therefore, EPA has not assumed that tolfenpyrad 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 products (EPA Reg. Nos. 71711-31 and 71711-GA) for tolfenpyrad when used as directed by commercial applicators.  There is a potential for occupational exposure associated with handler activities (i.e., mixing, loading, and applying) as well as with post-application activities (i.e., re-entering treated areas).  Based on the use patterns, the duration of exposure for the proposed uses on crops is expected to be short-term (1 to 30 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.

In addition to the newly proposed uses, HED reassessed the currently registered use of tolfenpyrad on ornamental plants based on current policies and changes in dermal toxicological endpoints.  This reassessment was triggered by 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 occupational 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 airblast 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.  Long-term exposures are not expected; therefore, a long-term assessment was not conducted.  No handler exposures are expected from applying sprays via chemigation systems.   HED notes that there is no toxicity associated with dermal exposure to tolfenpyrad for short- and intermediate-term durations, and therefore only 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 reassessed the use of tolfenpyrad on ornamental plants in greenhouses (i.e., cut flowers) at the maximum proposed application rate based on current policies and changes in dermal toxicological endpoints.  For the use on ornamentals, HED expects occupational pesticide handlers to be exposed to the following scenarios:

   1) mixing/loading/applying sprays with mechanically-pressurized handgun sprayer;    2) mixing/loading/applying sprays with backpack sprayer; and    3) mixing/loading/applying sprays with manually-pressurized handwand.        In the past, HED has considered greenhouse uses to have the potential for long-term dermal exposure, especially for crops such as cut flowers, which have significant repeated postapplication foliar contact.  However, in the case of tolfenpyrad, long-term dermal exposure is not expected to occur.  The pests that are targets for tolfenpyrad have biological and life-stage properties that provide for short windows of opportunity for control.  To avoid development of tolfenpyrad-resistant pests, the tolfenpyrad label requires switching periodically to another insecticide.  Therefore, based on the proposed use pattern and directions, resistance management strategies (i.e., only two consecutive applications of tolfenpyrad) and the retreatment interval (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 estimates for workers.  The MOEs shown in the table are all greater than 100, with the lowest MOE of 550 identified for handlers conducting mixer/loader and applicator activities with mechanically-pressurized 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

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

Cotton                                  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 Mechanically-pressurized 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 Manually-pressurized 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 from 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 labels:  For food crops, the maximum single 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 single application rate (Higher Spray Volume) = 1.36 lb ai/A (at 10 gal/1000 ft[2] = 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) * Application 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- and Intermediate-Term Post-Application Risk

9.2.1	Dermal Post-Application Risk

For occupational exposure scenarios involving dermal exposure, no hazard was identified, and thus a  quantitative dermal post-application exposure assessment was not performed.  HED does not anticipate risks resulting from dermal exposure to tolfenpyrad.

The Restricted Entry Interval specified on the proposed label is based on the acute toxicity of tolfenpyrad technical material, which is classified as Category III for acute dermal and Category IV for dermal and eye irritation.  Based on the acute toxicity profile of tolfenpyrad, the 12-hour REI appearing on the proposed label is appropriate.

9.2.2	Inhalation Post-Application Risk

Based on the Agency's current practices, a quantitative post-application inhalation exposure assessment was not performed for tolfenpyrad 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 rates.  However, there are multiple potential sources of post-application inhalation exposure to individuals performing post-application activities in previously treated fields.  These potential sources include volatilization of pesticides and resuspension of dusts and/or particulates that contain pesticides.  The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP's final report on March 2, 2010 (http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html).  The Agency is in the process of evaluating the SAP report as well as available post-application inhalation exposure data generated by the 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 policies or procedures are put into place, the Agency may revisit the need for a quantitative occupational post-application inhalation exposure assessment for tolfenpyrad.

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 through the use of ventilation requirements [40 CFR 170.110, (3) (Restrictions associated with pesticide applications)].

10.0	References

Doherty, M.  12 April 2012.  D384995. Tolfenpyrad 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 Analytical Chemistry and Residue Data. Doherty, M.  12 April 2012.  D398817.  Tolfenpyrad Acute and Chronic Aggregate Dietary Exposure and Risk Assessments Figueroa, Z.  12 April 2012.  D386087. Tolfenpyrad.  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.  Tolfenpyrad.  Report of the Residues of Concern Knowledgebase Subcommittee (ROCKS). Liu, L.  23 January 2012.  D383822.  Drinking Water Exposure Assessment for Proposed New Uses of Tolfenpyrad on a Variety of Agricultural Crops, Nurseries, and Christmas Trees.  Haddad, S.  6 February 2012.  D393941.  Percent Crop Treated for Tolfenpyrad (PC# 090111) on Proposed New Uses for Oranges, Apples, Table Grapes, and Spinach. Appendix A.  Toxicology Profile and Executive Summaries

A.1	Toxicology Data Requirements

The requirements (40 CFR 158.340) for food use for tolfenpyrad 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	Acute Oral Toxicity	 870.1200	Acute Dermal Toxicity	 870.1300	Acute Inhalation Toxicity	 870.2400	Primary Eye Irritation	 870.2500	Primary Dermal Irritation	 870.2600	Dermal Sensitization

                                      yes                                       yes                                       yes                                       yes                                       yes                                       yes

                                      yes                                       yes                                       yes                                       yes                                       yes                                       yes

870.3100	Oral Subchronic (rodent)	 870.3150	Oral Subchronic (nonrodent)	 870.3200	21/28-Day Dermal	 870.3250	90-Day Dermal	 870.3465	90-Day Inhalation

                                      yes                                       yes                                       yes                                        yes                                       yes

                                      yes                                       yes                                       yes                                       yes*                                     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	Acute Delayed Neurotox. (hen)	 870.6100b	90-Day Neurotoxicity (hen)	 870.6200a	Acute 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.

A.2	Toxicity Profiles

Table A.2.1.	Acute Toxicity Profile -Tolfenpyrad                                   Guideline No. Study Type MRID(s)                                     Results                                Toxicity Category 870.1100 Acute Oral -Rat 47457501 LD50 Males => 386 mg/kg bw  LD50 Females =>150 mg/kg bw LD50 Combined =>239 mg/kg bw                                       II 870.1200 Acute Dermal-Rat 47457503 LD50 Males > 2000 mg/kg bw  LD50 Females > 3000 mg/kg bw LD50 Combined > 2500 mg/kg bw                                       III 870.1300 Acute Inhalation-Rat 47447734 LC50 Males >2.21 mg/L LC50 Females >1.50 mg/L  LC50 Combined >1.82 mg/L                                       III 870.2400 Acute Eye Irritation-Rabbit 47457505 Mildly irritating                                       III 870.2500 Acute 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                            Type 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, hepatocellular 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, Mouse 47463702 and 47447801 Levels tested: 0, 15, 100, 300 pm or 0/0, 2.4/3.0, 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 coats, hunched posture, ataxia, hypoactivity), and moribundity/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 mouse 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-week  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-week 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 movement, 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 submitted 870.3465 4-Week Inhalation Toxicity, Rat 47447728 and 48250484 (range-finding) Levels tested: 0, 0.50, 2.0, 10 mg/m3 or 0, 0.0005, 0.002, and 0.01 mg/L NOAEL = 10 mg/m3 (EPA calculated 2.6 mg/kg/day) LOAEL = not determined Decreased body weight and mortality (2/6) observed at 26 mg/m3 (EPA calculated 6.8 mg/kg/day) in range-finding study. No mortality seen at the next lowest dose of 10.9 mg/m3 Range-finding levels tested 5, 10, 25,100 mg/m3 (targeted); 3.6, 10.9, 26.0, and 79.3 mg/m[3] (analyzed aerosol concentrations achieved)  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 was 9 mg/kg/day in the preliminary study (MRID 47447810) based on a single mortality, emaciation, 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 study 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, increased 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 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 870.4200a 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 on 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 mesenteric 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)

In Vitro Gene Mutation assay in mouse lymphoma cells  47463706 Negative. There was no evidence of induced mutant colonies over background in the presence or absence of S9-activation.

870.5375 Technical (OMI-88)

In vitro Mammalian Cytogenetics (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 treated 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 ug/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 Cytogenetics (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-activation. 870.5395 Technical (OMI-88)

In Vivo Mammalian Cytogenetics - Erythrocyte Micronucleus Assay  47447827 Negative.  There 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 Cytogenetics - Erythrocyte Micronucleus Assay  47463708 Negative.  There was no significant increase in the frequency of micronucleated polychromatic erythrocytes in bone marrow after any treatment time.  Non-guideline Technical (OMI-88)