Document ID: EPA-HQ-OPP-2012-0909-0006
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2013-11-19T05:00Z

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)

Cell Cycle Kinetics Assay
47463707
The purpose of this study was to explain the polyploidy observed in a previously conducted Chinese hamster lung chromosome aberration study (MRID 47447824). In the absence of S9-activation, Tolfenpyrad caused cell cycle delay after exposure for as little as 3 hours and polyploidy after as little as 6 hours exposure.  The polyploidy observed in the previous chromosome aberration study was likely due to the inhibition of cell cycle progression.
870.6200a

Acute Neurotoxicity, Rat (gavage)
47447831
Levels tested: 0, 20, 40, 60 mg/kg/day in males and 0, 10, 20, or 40 mg/kg/day in females.
NOAEL (M/F) = 10 mg/kg/day
LOAEL (M/F) = 20 mg/kg/day, based on decreases in body weight, body weight gain and food consumption in females.
870.6200b

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

Developmental Neurotoxicity, Rat 
Not required
870.7485
Metabolism, Rat

47447837, 47447836, 47447834, 47447833, and 
47447835
The test compound was rapidly absorbed and excreted.  Total recoveries ranged from 91.3-99.6% of the administered dose (AD) across all groups and in both sexes.  Feces were the predominant route of excretion.  Across all single dose groups, 88.2-93.2% AD was excreted in the feces and 1.7-3.0% AD was eliminated in the urine.  Negligible amounts of radioactivity were recovered in the expired air and cage wash, both accounting for <=0.1% AD.  In the bile duct-cannulated rats at 48 h post-dosing, the majority of radioactivity was excreted in the bile (51.3-69.5% AD), with minor amounts eliminated in the feces (3.5-8.3% AD) and urine (0.7-3.0% AD), indicating that bile was the primary route of excretion for the absorbed test material.  Absorption (defined as radioactivity found in the bile, urine, cage wash, and carcass) was greater in males (72.8-77.8% AD) than in females (57.9-69.4% AD).  Females also had more radioactivity remaining in the gastrointestinal tract, and the amount remaining increased with dose. 
870.7600
Dermal Penetration, Rat
47447839
At 24 hours in the 1 g/L group, the dermal absorption (absorbed + absorbable dose) is 39.8%. 
Non guideline

New data
Comparative in vitro dermal absorption study using human and rat skin
48233401
At 24 hrs, the total absorbed dose (absorbed + absorbable dose) at the high dose was 1.12% in human skin and 26.78% in rats skin.  At the low dose, the total absorbed dose was 6.49% in human skin and 67.02% in rat skin. 
870.7800
Developmental Immunotoxicity, Rat (feeding)
47447840
Levels tested: 0, 0.75, 3 mg/kg/day 
Maternal NOAEL = 0.75 mg/kg/day
Maternal LOAEL = 3 mg/kg/day, based on decreased body weight (up to 10%), body weight gain (up to 36%), and food consumption in the P generation 

Offspring NOAEL = 0.75 mg/kg/day
Offspring LOAEL = 3 mg/kg/day, based on decreased survival, body weight, and body weight gains; increased incidence of blackish abdominal cavity and dark green abnormal intestinal content; and decreased thymus and spleen weights in the F1 and/or F2 generations 

Note: No treatment-related effects noted on the immune system. 
Non guideline
In vitro metabolism

47447838
Total recovery was 91.0-108.1% of the radioactivity added to the incubations, of which the parent compound accounted for 10.2-12.4%.  Only 1.4-1.9% of the radioactive residues were found in unidentified compounds; the remaining approximately 88% of the isolated metabolites were identified.  In addition to the parent, a total of 17 metabolites were identified.  The primary metabolite was OH-PT-CA (24.5-32.4%); other major metabolites included PT-CA (13.4-16.2%), CO-PT-CA (9.3-13.2%), OH-PT (7.6-8.4%), PT-OH (6.7-7.7%), and OH-PT-OH (3.8-5.3%).  The other metabolites were present at <5% of the total incubation dose.
The main metabolic pathways included the oxidations of the methyl moiety of T-CH3 and ω-1 carbon of CH3CH2-P.  The oxidation of these two carbons resulted in the formation of the hydroxylated metabolites PT-OH, OH-PT, and OH-PT-OH.  Further oxidation leads to the metabolites PT-CHO, PT-CA, OH-PT-CA, CO-PT, CO-PT-OH, and CO-PT-CA.  Other metabolic pathways include the bond cleavage of the amide and methylene moieties, the demethylation of N-CH3, or the formation of the vinyl group after hydroxylation of CH3CH2-P. 

A.3	Triple-Pack Analysis for TolfenpyradThe dermal absorption data and dermal toxicity data for tolfenpyrad were used to calculate a refined dermal equivalent dose (RDD) for short- and intermediate term dermal risk assessment.  To calculate a RDD, in vitro results using rat skin are corrected for any differences between in vitro and in vivo absorption rates (rats) and species differences seen between rats and humans.  This refinement in dermal absorption is important since absorption by human skin is usually lower than that by rat skin.  Accordingly, the combined use of data from the three studies and two testing systems offers greater precision in estimating human dermal absorption which strengthens the reliability of the dermal risk assessment.

Short-and Intermediate-Term Exposure-Dermal POD and Dermal Absorption Data

For dermal exposure scenarios, no hazard was identified. This is based on the lack of dermal toxicity at 200 mg/kg/day in a rat 21-day dermal toxicity study, and analyses of the newly submitted dermal absorption data.  Using the available dermal data for tolfenpyrad, a refined dermal equivalent dose (RDD) for human skin of 2065 mg/kg/day was calculated.  

      POD = dermal NOAEL = 200 mg/kg/day
      DAF (in vivo rat) = 39.8%
      In Vitro Human dermal absorption = 6.49%
      In Vitro Rat dermal absorption = 67.02% 
      
Refined Dermal Equivalent Dose(RDD)=DED x (animal in vitro/human in vitro)
POD=DED

RDD=200mg/kg/day x 67.02% / 6.49%= 2065 mg/kg/day
                                       
Long-Term Exposure-Oral POD and Dermal Absorption Data

Based on the use pattern of tolfenpyrad, long-term exposure is not anticipated.  

 Tolfenpyrad Triple Pack Data for Short and Intermediate Term Dermal exposure
                                  Parameters
                                  In Vivo Rat
                                 In Vitro Rat
                                In Vitro Human
                                   Comments

Study ID
                               MRID No. 47447839
                                TXR No. 0054937
                               MRID No.48233401
                                TXR No.0055527
                               MRID No.48233401
                                TXR No.0055527

Same formulation products were tested in all three studies. 

Low dose is identical in the in vitro rat and human studies

Identical exposure periods

Calculated a Refined Dermal Dose (RDD) to modify the dermal POD.

Test Material
                             EC Formulation (15%)
                             EC Formulation (15%)
                             EC Formulation (15%)

Exposure (hours)
                            0.5, 1, 2, 4, 10 and 24
                                      24
                                      24

Doses tested
Low
Mid
Hi
Low

High
Low
High

                                 0.91 ug/cm2

                                     8.41
                                    ug/cm2
                                       
                                     99.9
                                    ug/cm2
                                   1ug/cm2
                                 1500 ug/cm2
                                   1ug/cm2
                                 1500 ug/cm2

% Absorbed (+ absorbable) at 24  hrs
                                     39.8
                                     44.5
                                     22.09
                                     67.02
                                     26.78
                                     6.49
                                     1.12

Risk Values
POD = 21 day dermal study-dermal NOAEL of 200 mg/kg/day (LOAEL not determined) used to assess short-, intermediate, and long-term dermal exposure. Extra 3x was applied to long-term dermal exposure scenario to account for subchronic to chronic extrapolation. 

Dermal Equivalent Dose (DED)
For short-, and intermediate-term dermal exposures, DED =POD=200 mg/kg/day, since route specific study used.  For long-term dermal exposure, DED = 1.5 mg/kg/day (POD (0.6 mg/kg/day)-oral study DAF (39.8%)-in vivo rat) since an oral toxicity study with a NOAEL of 0.6 mg/kg/day was used.

Estimated Human In Vivo Dermal Absorption Factor
EC formulation (low dose)
DAF=in vivo rat absorption (39.8%) x in vitro human absorption (6.49%)   
                                                              in vitro rat absorption (67.02%)    

               Estimated In Vivo Human Dermal Absorption= 3.85%

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

A.4	Toxicological Doses and Endpoints for Use in Human Risk Assessments

A.4.1	Acute Reference Dose (aRfD)  -  All Populations

Study Selected:  Acute Neurotoxicity Study in Rats 
MRID No:  47447831	
Dose and Endpoint for Risk Assessment: NOAEL= 10 mg/kg/day, based on decreased body weight, body weight gain and food consumption observed at the LOAEL of 20 mg/kg/day.
Uncertainty Factor: 100x (10x interspecies extrapolation, 10x intraspecies variability)

Acute RfD =  = 0.1 mg/kg/day

Comments about Study/Endpoint/Uncertainty Factors: 
Although body weight changes are not usually the result of a single dose exposure, significant decreases in body weight (6-12%) and decreases in bodyweight gain (26%) were observed after a single dose exposure in a dietary study and are appropriate for acute dietary exposure.

No separate endpoint was identified for acute dietary exposure for females 13-49 years of age.  Resorptions seen in a range-finding developmental toxicity study in rabbits were considered for endpoint selection.  However, the resorptions were seen in the presence of significant maternal effects (emaciation, body weight changes, and mortality) and are considered secondary to maternal toxicity and not a result of a single exposure.  Therefore, the endpoint is not applicable to acute dietary risk assessment.   

A.4.2 Chronic Reference Dose (cRfD) 

Study Selected:  Combined Chronic Toxicity/Carcinogenicity Study in Rats
MRID No: 47463704	
Dose and Endpoint for Risk Assessment: NOAEL= 0.6 mg/kg/day, based on decreased body weight, body weight gain and food consumption of females, changes in the harderian glands (found in the eye) of males, histopathological changes in liver, kidney and lymph nodes in females, and histopathological changes in the kidney of males, observed at the LOAEL of 1.5 mg/kg/day.  
Uncertainty Factor: 100x (10x interspecies extrapolation, 10x intraspecies variability)

Chronic RfD =  = 0.006mg/kg/day

Comments about Study/Endpoint/Uncertainty Factors: 
The study is appropriate for chronic dietary exposure due to the route (oral) and long-term duration of dosing.  In addition, the dose selected is the lowest NOAEL in the toxicity database, and will therefore be protective of other observed toxic effects.  Chronic mouse and dog studies were also considered for chronic dietary exposure; however, the chronic rat study provided the most sensitive endpoint for chronic dietary risk assessment.  

A.4.3	Occupational Short- and Intermediate-Term Dermal Exposure 

For dermal exposure scenarios, no hazard was identified.  A 21-day dermal toxicity study in rats is available for tolfenpyrad.  No treatment-related effects were observed in the study at doses up to and including the highest dose tested of 200 mg/kg/day.   For short-and intermediate term dermal exposure, a refined dermal dose (RDD), for human skin, was calculated using the dermal toxicity study in rats and in vivo (rat) and in vitro (human and rat skin) dermal absorption data.  Using the data, a RDD of > 2000 mg/kg/day was calculated.  Since the RDD is significantly higher than the limit dose, short-, and intermediate-term dermal risk assessments were not performed.

A.4.4	Occupational Long-Term Dermal Exposure 

Based on the proposed use pattern for tolfenpyrad, long-term dermal exposure is not anticipated.

A.4.5	Occupational Short- and Intermediate-Term Inhalation Exposure 

Study Selected:  4 week inhalation toxicity study in rats
MRID No:  47447728	
Dose and Endpoint for Risk Assessment: NOAEL= 10 mg/m[3] (2.6 mg/kg/day
Uncertainty Factor: 100x (10x interspecies extrapolation, 10x intraspecies variability)

Comments about Study/Endpoint/Uncertainty Factors: 
No toxic effects were observed up to 10 mg/m3 (EPA calculated dose = 2.6 mg/kg/day) in the main study; however, mortality was observed in a range-finding study at 26 mg/m[3] (6.8 mg/kg/day).  No mortality was seen at the next lowest dose of 10.9 mg/m[3] in the range-finding study.  The developmental toxicity studies (rats and rabbits), the developmental immunotoxicity study in rats and the reproduction study in rats were all considered for short-and intermediate-term inhalation risk assessment.  However, the inhalation study was selected because it is a route specific study and considered more appropriate for inhalation risk assessment than the oral studies.  There is no evidence of increased quantitative susceptibility between the young and the adult (i.e., developmental/offspring toxicity occurred at the same dose level as adult toxicity) and the Agency concluded that selecting points of departure from route-specific studies that are protective for adults would also be protective for developmental/offspring effects.  Therefore, the inhalation study it is protective of potential offspring effects since it adequately measured systemic toxicity in adult animals.

A.4.6	Occupational Long-Term Inhalation Exposure 

Based on the proposed use pattern for tolfenpyrad, long-term inhalation exposure is not anticipated.

Appendix B. Metabolism Summary Table

Summary of Metabolism of Tolfenpyrad in Target Crops, Livestock, and Rotational Crops.  Values shown are maxima from studies with tolyl- and pyrazole-labeled tolfenpyrad.  
Compound
Matrix
                                     % TRR
                                      ppm
Tolfenpyrad
Radish Root
54
0.235

Radish Top
85
9.311

Peach Fruit (56 DAT)
78.4
0.808

Peach Leaves (56 DAT)
32.6
21.1

Peach Stems (56 DAT)
70.9
11.1

Eggplant Fruit (28 DAT)
93.6
0.8

Eggplant Foliage (28 DAT)
93.6
206

Cabbage
55
4.74

Goat Milk
6.5
0.011

Goat Fat
17.3
0.062

Goat Muscle
10.1
0.014

Hen Eggs
2.4
0.004

Hen Fat
14.7
0.063

Hen Liver
0.2
0.004

Hen Muscle
1.8
0.002

Rat Feces
14.8% AD
--
PT-CA

Radish Root
21.5
0.113

Peach Leaves (56 DAT)
17
10.95

Peach Stems (56 DAT)
2.3
0.23

Goat Milk
54.1
0.092

Goat Fat
34.1
0.111

Goat Liver
58.7
14.8

Goat Kidney
62.6
4.33

Goat Muscle
67.8
0.088

Hen Eggs
64.4
0.105

Hen Fat
49.5
0.218

Hen Liver
90.4
1.54

Hen Muscle
84.8
0.095

Rot. Lettuce 120
13.3
0.002

Rot. Radish Tops 30
5.7
0.002

Rot. Radish Tops 120
16.7
0.002

Rot. Wheat Hay 30
5.3
0.001

Rat Urine
1.9% AD
--

Rat Bile (includes PT-CA glu)
22.3% AD
--

Rat Feces
36.2% AD
--
OH-PT-CA

Peach Leaves (56 DAT)
3.2
2.06

Cabbage
3
0.28

Goat Milk
16.9
0.029

Goat Liver
27.7
6.98

Goat Kidney
19.3
1.34

Goat Muscle
8.9
0.008

Hen Liver
5.2
0.094

Hen Muscle
2.7
0.003

Rat Bile
1.5% AD
--

Rat Feces
7.4% AD
--
Sul-OH-PT-CA

Rat Bile
3.3% AD
--

Rat Feces
9.2% AD
--
PT-CA glu
Peach Leaves (56 DAT)
7
3.6

Peach Stems (56 DAT)
6.3
0.8
PAM

Radish Root
9.9
0.043

Radish Top
2.1
0.149

Peach Leaves (56 DAT)
2.2
1.4

Peach Stems (56 DAT)
3.4
0.34

Rot. Lettuce 30
5.1
0.004

Rot. Lettuce 120
8.3
0.004

Rot. Lettuce 365
8.8
0.003

Rot. Radish Root 30
25.4
0.015

Rot. Radish Root 120
30
0.018

Rot. Radish Root 365
27.3
0.003

Rot. Radish Tops 30
12
0.015

Rot. Wheat Forage 30
1.1
0.006
OH-PAM

Radish Root
3.4
0.015

Peach Fruit (56 DAT)
3.9
0.03

Peach Leaves (56 DAT)
9
5.82

Hen Eggs
12.6
0.021

Hen Muscle
12.4
0.016

Rot. Lettuce 30
3.8
0.003

Rot. Lettuce 120
29.2
0.014

Rot. Lettuce 365
14.7
0.005

Rot. Radish Root 30
8.5
0.005

Rot. Radish Root 120
8.3
0.005

Rot. Radish Root 365
9.1
0.001

Rot. Radish Tops 30
14.4
0.018

Rot. Radish Tops 120
8.3
0.01

Rot. Radish Tops 365
6.5
0.003

Rot. Wheat Forage 30
5
0.027

Rot. Wheat Forage 120
8.4
0.022

Rot. Wheat Hay 30
6.8
0.045

Rot. Wheat Hay 120
5.5
0.041

Rot. Wheat Straw 30
11.5
0.142

Rot. Wheat Straw 120
8.2
0.064
OH-PAM conjugate
Radish Root
6.4
0.028

Rot. Lettuce 30
24.1
0.019

Rot. Lettuce 120
16.7
0.008

Rot. Lettuce 365
32.4
0.011

Rot. Radish Tops 30
20
0.025

Rot. Radish Tops 120
11.6
0.014

Rot. Radish Tops 365
15.2
0.007

Rot. Wheat Grain 30
7.1
0.004

Rot. Wheat Grain 120
19.6
0.009

Rot. Wheat Grain 365
12.5
0.001

Rot. Wheat Forage 30
29.7
0.16

Rot. Wheat Forage 120
19.5
0.051

Rot. Wheat Forage 365
77.1
0.148

Rot. Wheat Hay 30
38.4
0.255

Rot. Wheat Hay 120
31.6
0.233

Rot. Wheat Hay 365
16.4
0.043

Rot. Wheat Straw 30
32.1
0.397

Rot. Wheat Straw 120
25.4
0.199

Rot. Wheat Straw 365
19.7
0.059
PCA

Cabbage
2.2
0.21

Goat Milk
12.2
0.021

Goat Fat
28.6
0.078

Hen Eggs
14.4
0.024

Hen Fat
11.2
0.048

Rot. Wheat Hay 30
0.2
0.001

Rot. Wheat Hay 120
0.1
0.001

Rot. Wheat Straw 30
0.2
0.002

Rot. Wheat Straw 120
0.3
0.002
OH-PCA

Radish Root
1.8
0.008

Rot. Lettuce 30
20.3
0.016

Rot. Lettuce 120
27.1
0.013

Rot. Radish Root 30
1.7
0.001

Rot. Radish Tops 30
4
0.005

Rot. Radish Tops 120
2.5
0.003

Rot. Radish Tops 365
2.2
0.001

Rot. Wheat Grain 30
10.7
0.006

Rot. Wheat Grain 120
2.2
0.001

Rot. Wheat Forage 30
17.5
0.094

Rot. Wheat Forage 120
17.6
0.046

Rot. Wheat Forage 365
2.1
0.004

Rot. Wheat Hay 30
5.1
0.034

Rot. Wheat Hay 120
10.2
0.076

Rot. Wheat Hay 365
5.7
0.015

Rot. Wheat Straw 30
8.5
0.105

Rot. Wheat Straw 120
5.6
0.044

Rot. Wheat Straw 365
6.7
0.02
OH-PCA conjugate
Rot. Lettuce 30
26.6
0.021

Rot. Radish Root 30
27.1
0.016

Rot. Radish Tops 30
24
0.03

Rot. Wheat Grain 30
14.3
0.008

Rot. Wheat Grain 120
23.9
0.011

Rot. Wheat Grain 365
12.5
0.001

Rot. Wheat Forage 30
32.3
0.174

Rot. Wheat Forage 120
30.3
0.079

Rot. Wheat Hay 30
12.8
0.085

Rot. Wheat Hay 120
30.3
0.224

Rot. Wheat Hay 365
37.5
0.097

Rot. Wheat Straw 30
12.7
0.157

Rot. Wheat Straw 120
21.4
0.168

Rot. Wheat Straw 365
41.8
0.125
CA-T-NH2

Goat Milk
19.4
0.033

Goat Fat
5.3
0.019
OH-PT

Cabbage
7.99
0.76
OH-PT-OH
Peach Stems (56 DAT)
1.1
0.11

Cabbage
3.49
0.33
OH-PT-OH conjugate
Radish Top
3.8
0.355
OH-T-CA
Cabbage
3.9
0.33
OH-T-OH
Cabbage
3.7
0.31
OH-T-AM
Cabbage
1.9
0.16
CA-T-AM
Cabbage
2.4
0.2
CO-PT
Peach Stems (56 DAT)
1
0.1

Rat Bile
2.8% AD
--
CO-PT-OH
Cabbage
1.2
0.1
CA-T-CA

Peach Leaves (56 DAT)
11.1
5.7

Rot. Radish Root 30
6.3
0.001

Rot. Radish Tops 30
2.9
0.001
T-CA
Peach Leaves (56 DAT)
6.6
3.4
2OH-PAM
Peach Fruit (56 DAT)
4.5
0.035

Peach Leaves (56 DAT)
1.5
0.95
* Included compounds are >= 1% TRR (% AD in rat) in at least one matrix.  

Comparison of Radiolabeled Studies to Proposed Use Directions
Radiolabeled Study
Proposed Use; PHI (days) in parenthesis
Radish (48250449)
0.21 lb ai/A x 2 = 0.4 lb ai/A; PHI = 1 day
1X: grape (7), pome fruit (14), leafy veg. (1), potato (14), Brassica veg. (1), fruiting veg. (1), cotton (14)
0.7X: citrus (14), stone fruit (14), tree nuts (14)
0.47X: cucurbit veg. (1)
Peach (4825045-46)
0.67 lb ai/A[**]; PHI = 0, 14, 28, and 56 days

Eggplant (48250444)
0.67 lb ai/A[**]; PHI = 3, 7, 14, and 28 days

Cabbage (4825047-48)
0.67 lb ai/A[**]; PHI = 0, 7, 14, and 28 days

[**] Assuming 20% of the application adheres to the plant.  Actual application rate was 0.13 lb ai/A
1.6X: grape (7), pome fruit (14), leafy veg. (1), potato (14), Brassica veg. (1), fruiting veg. (1), cotton (14)
1.2X: citrus (14), stone fruit (14), tree nuts (14)
0.79X: cucurbit veg. (1)
Rot.Crops (48250476; Lettuce, radish, wheat)
~0.312 lb ai/A; PBI = 30, 120, 365 days
0.76X: grape (7), pome fruit (14), leafy veg. (1), potato (14), Brassica veg. (1), fruiting veg. (1), cotton (14)
0.58X: citrus (14), stone fruit (14), tree nuts (14)
0.37X: cucurbit veg. (1)
Livestock (48250450-51)
~ 12.5 ppm feeding level, all studies
DRAFT Dietary Burdens:
   Beef Cattle = 3.7 ppm
   Dairy Cattle = 2.2 ppm
   Poultry = 0.12 ppm
Rat (47447834, 36, 37)
Metabolism Study:  1 mg/kg, single dose; 20 mg/kg single dose; 1 mg/kg daily for 14 days
Not Applicable

Appendix C.  Physical/Chemical Properties

Table 3.2.  Physicochemical Properties of the Technical Grade Test Compound: Tolfenpyrad[1]
Parameter
Value
Reference
Molecular Weight
383.9
MRID 47447704
Melting point/range (PAI)[2]
85.5-88.5° C
MRID 47447705
pH
5.1
MRID 47447704
Density
1.25 g/cm[3]

Water solubility  (PAI)
0.061 mg/L 
MRID 47447705
Solvent solubility (temperature not specified) 
n-heptane	                 6.92 g/L
Xylene	                     218 g/L
1,2 dichloroethane	>250 g/L
Methanol	                 50.8 g/L
n-octanol	                 43.7 g/L
Acetone	                   250 g/L
Ethyl acetate 	250 g/L
MRID 47447704
Vapor pressure (PAI)
4 x 10[-5] Pa at 25 °C
(= 3.0 x 10[-8] mm Hg)
MRID 47447705

Dissociation constant, pKa
No dissociation constant in the environmental pH range

Partition coefficient, 
log10POW  (PAI)
4.3
MRID 47447705
Soil half-life
Aerobic = 15.1 days
Anaerobic = 216.6 days
Drinking Water Assessment (D383822)
[1] Refer to D354437.mem, 6/3/10
[2] PAI = Purified Active Ingredient

Appendix D.  Review of Human Research

This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical.  These data, which include studies from the Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1) and the Agricultural Handler Exposure Task Force (AHETF) database are subject to ethics review pursuant to 40 CFR 26, have received that review, and are compliant with applicable ethics requirements.  For certain studies that review may have included review by the Human Studies Review Board.  Descriptions of data sources as well as guidance on their use can be found at: http://www.epa.gov/pesticides/science/handler-exposure-data.html  and http://www.epa.gov/pesticides/science/post-app-exposure-data.html.

Appendix E.  Bibliography of Submitted Studies

MRID
Citation
47447728
Kelly, D. (2008) Tolfenpyrad: Four-Week Inhalation Toxicity Study in Rats.  Project Number: DUPONT/22217, 16846, 782.  Unpublished study prepared by E.I. du Pont de Nemours & Co., Inc.  291 p.
47447731
Ikeya, M. (1999) Oral Acute Toxicity Study of OH-PT in Rats.  Project Number: T/10106, B/4162.  Unpublished study prepared by Bozo Research Center, Inc.  65 p.
47447733
Moore, G. (2008) Acute Dermal Toxicity Study in Rats - Limit Test: NAI-2302 (Tolfenpyrad) 15%EC.  Project Number: P322/RAT, 24304, 080212/3R.  Unpublished study prepared by Product Safety Laboratories.  14 p.
47447734
Wesson, C. (2006) Acute Inhalation Toxicity (Nose Only) Study in the Rat.  Project Number: 562/027, T/10007.  Unpublished study prepared by Safepharm Laboratories, Ltd.  48 p.
47447740
Shibata, R. (1997) A Dermal Sensitization Study of OMI-88 Technical in the Guinea Pig.  Project Number: T/10010, B/3513.  Unpublished study prepared by Bozo Research Center, Inc.  32 p.
47447741
Moore, G. (2008) Dermal Sensitization in Guinea Pigs (Buehler Method): NAI-2302 (Tolfenpyrad) 15% EC.  Project Number: 24305, P328, 080212/3R.  Unpublished study prepared by Product Safety Laboratories.  24 p.
47447742
Mutai, M. (1995) 4-Week Subacute Toxicity Study of AP81088 by Dietary Administration in Rats.  Project Number: T/10011.  Unpublished study prepared by Safety Laboratory, Pathology Group.  11 p.
47447743
Nishitomi, T. (1999) A 13-Week Subacute Oral Toxicity Study of OMI-88 Technical in Rats by Dietary Administration, Followed by a 4-Week Recovery Period.  Project Number: T/10012, 6L162.  Unpublished study prepared by Mitsubishi Chemical Safety Institute, Ltd.  246 p.
47447801
Trutter, J. (1999) 4-Week Dietary Range-Finding Study in Mice with OMI-88 Technical.  Project Number: T/10014, CHV/6287/102, 8270A.  Unpublished study prepared by Covance Laboratories, Inc.  211 p.
47447803
Nagashima, Y. (1997) A 13-Week Subacute Oral Toxicity Study of OMI-88 Technical in Beagle Dogs.  Project Number: T/10018, BOZO/B/3352.  Unpublished study prepared by Kannami Laboratory.  132 p.
47447804
Nagashima, Y. (2004) A 13-Week Oral Subacute Toxicity Study of OMI-88 Technical in Beagle Dogs (A Supplementary Study): Final Report.  Project Number: T/10019, BOZO/B/3644.  Unpublished study prepared by Kannami Laboratory - Bozo Research Center, Inc.  168 p.
47447805
Nagashima, Y. (1997) A 4-Week Oral Subacute Toxicity Study of OMI-88 Technical in Beagle Dogs (Dose Range Finding Study).  Project Number: T/10017, B/3351.  Unpublished study prepared by Bozo Research Center, Inc.  55 p.
47447806
Barnett, J. (2008) 21-Day Dermal Toxicity Study of Tolfenpyrad in Crl:CD(SD) Rats.  Project Number: XTH00005, 824690, W05899.  Unpublished study prepared by Charles River Laboratories.  361 p.
47447807
Maks, M. (2008) Waiver Request for 90-Day Dermal Rat Study: Tolfenpyral.  Project Number: TOL/TOX/01.  Unpublished study prepared by Nichino America, Inc.  5 p.
47447808
Maks, M. (2008) Waiver Request for 90-Day Rat Inhalation Study: Tolfenpyral.  Project Number: TOL/TOX/02.  Unpublished study prepared by Nichino America, Inc.  4 p.
47447809
Hoshino, N. (1999) A Teratogenicity Study of OMI-88 Technical in Rats.  Project Number: T/10024, B031577, 6L611.  Unpublished study prepared by Mitsubishi Chemical Safety Institute, Ltd.  156 p.
47447810
Matsuura, I. (1996) A Preliminary Teratogenicity Study of AP81088 in Rabbits.  Project Number: T/10029, B031577, 5L485HEO.  Unpublished study prepared by Mitsubishi Chemical Safety Institute, Ltd.  140 p.
47447811
Fujii, O. (1997) A Teratogenicity Study of OMI-88 Technical in Rabbits.  Project Number: T10030, 6L612.  Unpublished study prepared by Mitsubishi Chemical Safety Institute, Ltd.  126 p.
47447812
Hoshino, N. (1999) Additional Fetus Examination to "A Teratogenicity Study of OMI-88 Technical in Rats".  Project Number: 9L550, T/10028.  Unpublished study prepared by Mitsubishi Chemical Safety Institute, Ltd.  91 p.
47447813
Hoshino, N. (2008) Addendum to the Study Entitled "Effects of OMI-88 (Tolfenpyrad) on a Teratogenicity Study in Rats" for Agrichemical Application to the U.S. EPA.  Project Number: B071133, 6L611.  Unpublished study prepared by Mitsubishi Chemical Safety Institute, Ltd.  17 p.
47447814
Hoshino, N. (2008) Addendum to the Study Entitled "Effects of OMI-88 (Tolfenpyrad) on a Teratogenicity Study in Rabbits" for Agrichemical Application to the U.S. EPA.  Project Number: B071134, 6L612.  Unpublished study prepared by Mitsubishi Chemical Safety Institute, Ltd.  16 p.
47447815
Maks, M. (2008) Addendum 2 to "Effects of OMI-88 (Tolfenpyrad) on a Teratogenicity Study on Rats".  Project Number: 6L611.  Unpublished study prepared by Nichino America, Inc.  6 p.
47447816
Matsuura, I. (1996) A Preliminary Reproduction Study of AP81088 in Rats.  Project Number: T/10021, 5L484KEO, 5L484.  Unpublished study prepared by Mitsubishi Chemical Safety Institute, Ltd.  249 p.
47447817
Nishitomi, T. (1999) A Two-Generation Reproduction Toxicity Study of OMI-88 Technical in Rats.  Project Number: T/10022, 7L027.  Unpublished study prepared by Mitsubishi Chemical Safety Institute, Ltd.  1123 p.
47447818
Nagashima, Y. (1999) A 52-Week Oral Chronic Toxicity Study  of OMI-88 Technical in Beagle Dogs.  Project Number: T/10020, B/3949.  Unpublished study prepared by Bozo Research Center, Inc.  183 p.
47447822
Ozaki, M. (1999) A Reverse Mutation Test of OH-PT Using Bacteria.  Project Number: T/10109, M/1016.  Unpublished study prepared by Bozo Research Center, Inc.  28 p.
47447824
Riley, S. (1997) OMI-88 Technical: Induction of Chromosome Aberrations in Cultured Chinese Hamster Lung (CHL) Cells: Final Report.  Project Number: 1509/2/1052, T/10034.  Unpublished study prepared by Covance Laboratories, Ltd.  63 p.
47447826
Ozaki, M. (2001) A Chromosomal Aberration Test of OH-PT Using CHL Cells.  Project Number: T/10111, M/1090.  Unpublished study prepared by Bozo Research Center, Inc.  45 p.
47447827
Saigo, K. (2000) A Micronucleus Test of OH-PT in Rats.  Project Number: SBL/92/14, T/10110.  Unpublished study prepared by Shin Nippon Biomedical Laboratories, Ltd.  28 p.
47447829
Maks, M. (2008) Waiver Request for Delayed Neurotoxicity (Acute)-Hen Study.  Project Number: TOL/TOX/04.  Unpublished study prepared by Nichino America, Inc.  4 p.
47447830
Kilpatrick, H. (2003) OMI-88 Technical Neurotoxicity Study by Dietary Administration to CD Rats for 13 Weeks.  Project Number: MUB/146/024442, T/10036.  Unpublished study prepared by Huntingdon Life Sciences, Ltd.  356 p.
47447831
Barnett, J. (2008) Tolfenpyrad: Oral (Gavage) Acute Neurotoxicity Study in Crl: CD(SD) Rats.  Project Number: XTH00001.  Unpublished study prepared by Charles River Laboratories.  745 p.
47447832
Maks, M. (2008) Waiver Request for Developmental Neurotoxicity Study.  Project Number: TOL/TOX/03.  Unpublished study prepared by Nihon Nohyaku Co., Ltd.  5 p.
47447833
Okada, M. (1997) Fate of OMI-88 in Rats-Preliminary Study.  Project Number: T/10039, 6L190.  Unpublished study prepared by Mitsubishi Chemical Safety Institute, Ltd.  44 p.
47447834
Nishitomi, T. (1999) Fate of OMI-88 in Rats-Metabolism Study After a Single Oral Administration.  Project Number: T/10042, 7L366.  Unpublished study prepared by Mitsubishi Chemical Safety Institute, Ltd.  88 p.
47447835
Kitazawa, K. (1998) Fate of OMI-88 in Rats: Structural Identification of its Metabolites.  Project Number: T/10043, 7L367.  Unpublished study prepared by Mitsubishi Chemical Safety Institute, Ltd.  86 p.
47447836
Okada, M. (1999) Fate of OMI-88 in Rats - Absorption, Distribution, and Excretion by Repeated Oral Administration.  Project Number: 8L127, T/10065.  Unpublished study prepared by Mitsubishi Chemical Safety Institute, Ltd.  112 p.
47447837
Miyagawa, M. (1998) Pharmacokinetic Study of OMI-88 in Rats - Absorption, Distribution and Excretion after a Single Oral Administration - (Study No.: 7L365).  Project Number: 7L365, T/10041.  Unpublished study prepared by Mitsubishi Chemical Safety Institute, Ltd.  141 p.
47447838
Fujii, O. (1997) Metabolism Study of OMI-88 in Rat Liver S-9.  Project Number: T/10040, 6L165.  Unpublished study prepared by Mitsubishi Chemical Safety Institute, Ltd.  55 p.
47447839
Fasano, W. (2007) Tolfenpyrad 15% EC: In vivo Dermal Penetration in the Rat.  Project Number: 1643, 16846, DUPONT/21646.  Unpublished study prepared by E.I. du Pont de Nemours & Co., Inc.  159 p.
47447840
Atai, H. (1999) Next Generation Immunotoxicity Study of OMI-88 Technical in Rats.  Project Number: T/10037, 8L894.  Unpublished study prepared by Mitsubishi Chemical Safety Institute, Ltd.  619 p.
47457501
Glaza, S. (1997) Acute Oral Toxicity Study of OMI-88 Technical in Rats: Final Report.  Project Number: COVANCE/6649/108T/10.  Unpublished study prepared by Covance Laboratories, Inc.  69 p.
47457502
Omori, M. (2000) An Acute Oral Toxicity Study of OMI-88% Emulsion in Rats.  Project Number: SBL13/61, T/10045.  Unpublished study prepared by Shin Nippon Biomedical Laboratories, ltd.  98 p.
47457503
Glaza, S. (1997) Acute Dermal Toxicity Study of OMI-88 Technical in Rats.  Project Number: CHW/6649/103, T/10006.  Unpublished study prepared by Corning Hazleton Inc.  49 p.
47457504
Omori, M. (2000) An Acute Inhalation Toxicity Study of OMI-88 15% Emulsion in Rats.  Project Number: SBL13/60, T/10048.  Unpublished study prepared by Shin Nippon Biomedical Laboratories, ltd.  84 p.
47457505
Glaza, S. (1996) Primary Eye Irritation Study of OMI-88 Technical in Rabbits: Final Report.  Project Number: CHW/6649/105, T/10009.  Unpublished study prepared by Corning Hazleton Inc.  38 p.
47457506
Sato, M. (2000) A Primary Eye Irritation Study of OMI-88 15% Emulsion in Rabbits.  Project Number: SBL13/65, T/10050.  Unpublished study prepared by Shin Nippon Biomedical Laboratories, ltd.  29 p.
47457507
Glaza, S. (1996) Primary Dermal Irritation Study of OMI-88 Technical in Rabbits: Final Report.  Project Number: CHW/6649/104, T/10008.  Unpublished study prepared by Corning Hazleton Inc.  30 p.
47457508
Sato, M. (2000) A Primary Dermal Irritation Study of OMI-88 15% Emulsion in Rabbits.  Project Number: SBL13/66, T/10049.  Unpublished study prepared by Shin Nippon Biomedical Laboratories, ltd.  21 p.
47463702
Trutter, J. (1999) 13- Week Dietary Toxicity Study in Mice with OMI-88 Technical: Final Report.  Project Number: 6287/104, T/10015.  Unpublished study prepared by Covance Laboratories, Inc.  346 p.
47463703
Ivett, J. (1999) 78- Week Dietary Oncogenicity Study in Mice with OMI-88 Technical: Final Report.  Project Number: 6287/110, T/10016.  Unpublished study prepared by Covance Laboratories, Inc.  1562 p.
47463704
Chida, T. (1999) A Chronic Toxicity/ Carcinogenicity Study of OMI-88 Technical in Rats by Dietary Administration.  Project Number: T/10013, 6L792, B031577.  Unpublished study prepared by Kashima Chemical Company, Ltd.  1315 p.
47463705
Ballantyne (1997) OMI-88 Technical: Reverse Mutation in Five Histidine-Requiring Strains of Salmonella typhimurium and One Tryptophan-Requiring Strain of Escherichia coli: Final Report.  Project Number: 1509/1/1052, T/10031.  Unpublished study prepared by Covance Laboratories, Ltd.  74 p.
47463706
Cifone, M. (2007) L5178Y TK +/- Mouse Lymphoma Forward Mutation Assay with a Confirmatory Assay: Final Report.  Project Number: 7883/100, 28781/0/431OECD.  Unpublished study prepared by Covance Laboratories, Inc.  84 p.
47463707
Murli, H. (2007) Cell Cycle Kinetics in Chinese Hamster Lung (CHL)Cells: Final Report.  Project Number: 7883/102, 28781/0/443.  Unpublished study prepared by Covance Laboratories, Inc.  53 p.
47463708
Xu, Yong (2007) In vivo Mouse Bone Marrow Micronucleus Assay: Final Report.  Project Number: 7883/101, 28781/0/455OECD.  Unpublished study prepared by Covance Laboratories, Inc.  67 p.
47904801
Arce, G. (2009) Nichino America, Inc. Rebuttal to the Tolfenpyrad Briefing Document (August 8, 2009) and the Draft DER: Developmental Immunotoxicity Study in Rats and the Draft DER: Multigeneration Reproduction Study in Rats.  Project Number: TOL/TOX/05.  Unpublished study prepared by Nichino America, Inc.  37 p.
47904802
Maks, M. (2009) Supplement 1 to: A Teratogenicity Study of OMI-88 Technical in Rats (Study Number 6L611 (MRID No. 47447815) and Next Generation Immunotoxicity Study of OMI-88 Technical Rats (Study Number 8L894) (MRID No. 47447840).  Project Number: T/10037, T/10024.  Unpublished study prepared by Nichino America, Inc.  20 p.
48233401
Citation:  Jones, A. (2010) Tolfenpyrad: Comparative in vitro Dermal Absorption Study Using Human and Rat Skin.  Project Number: LMS00014, T/10160.  Unpublished study prepared by Huntingdon Life Sciences, Ltd.  68 p.
48233402
Maks, M. (2010) Additional Data to Support 90-Day Dermal Rat Requirement for Greenhouse Use Pattern for Tolfenpyrad 15EC Insecticide.  Project Number: TOL/TOX/13.  Unpublished study prepared by Nichino America, Inc. 8 p.
48250444
Kunihiko, O. (1998) Metabolism Study of OMI-88 on Eggplants.  Project Number: R/10005, 6L191.  Unpublished study prepared by Mitsubishi Chemical Safety Institute, Ltd.  202 p.
48250445
Ogawa, K. (1998) Metabolism Study of OMI-88 [TO-(Carbon 14)] on Peach Plants.  Project Number: R/10003, 7L336.  Unpublished study prepared by Mitsubishi Chemical Safety Institute, Ltd.  61 p.
48250446
Ogawa, K. (1999) Metabolism Study of OMI-88 [PY-Carbon 14] on Peach Plants.  Project Number: R/10004, 8L123.  Unpublished study prepared by Mitsubishi Chemical Safety Institute, Ltd.  52 p.
48250447
Ogawa, K. (1998) Metabolism Study of OMI-88 [TO-Carbon 14] on Cabbage.  Project Number: R/10001, 7L170.  Unpublished study prepared by Mitsubishi Chemical Safety Institute, Ltd.  55 p.
48250448
Ogawa, K. (1999) Metabolism Study of OMI-88 [PY-Carbon 14] on Cabbage.  Project Number: R/10002, 8L122.  Unpublished study prepared by Mitsubishi Chemical Safety Institute, Ltd.  43 p.
48250449
Quistad, G.; Kovatchev, A. (2008) A Metabolism Study with [Pyrazole (Carbon 14)] and [Tolyl Ring-U-(Carbon 14)]Tolfenpyrad in Radish.  Project Number: 1740W.  Unpublished study prepared by PTRL West, Inc., and Excel Research Services, Inc. 176 p.
48250450
Quistad, G.; Kovatchev, A. (2007) The Metabolism of (Carbon 14)Tolfenpyrad (2 Radiolabels) in the Lactating Goat.  Project Number: R/10160, 1556W.  Unpublished study prepared by PTRL West, Inc. and Genesis Midwest Laboratories.  245 p.
48250451
Quistad, G.; Kovatchev, A. (2007) The Metabolism of (Carbon 14)Tolfenpyrad (2 Radiolabels) in Laying Hens.  Project Number: R/10161, 1557W.  Unpublished study prepared by PTRL West, Inc., and Genesis Midwest Laboratories.  243 p.
48250452
Boatwright, M. (2007) Independent Laboratory Validation of Morse Laboratories, Inc. Analytical Method "Determination of Tolfenpyrad and its OH-PT Metabolite in Crops (Raw Agricultural and Processed Commodities)".  Project Number: 070269.  Unpublished study prepared by Golden Pacific Laboratories, LLC.  81 p.
48250453
Reed, R. (2007) Validation of the Residue Analytical Method: "Determination of Tolfenpyrad and its OH-PT Metabolite in Crops (Raw Agricultural Commodities)".  Project Number: MLI/07/1, ML07/1350/NAI, A/10037.  Unpublished study prepared by Morse Laboratories, Inc.  237 p.
48250454
Brookey, F. (2009) Validation of the Analytical Method: "Determination of Tolfenpyrad (Including its PT-CA and PCA Metabolites) in Soil".  Project Number: A/10040, MLI/07/03, ML07/1375/NAI.  Unpublished study prepared by Morse Laboratories, Inc.  166 p.
48250455
Class, T.; Gocer, M. (2010) Independent Laboratory Validation of an Analytical Method for the Determination of Tolfenpyrad and It's Metabolites PT-CA, OH-PT-CA and PCA in Foodstuffs of Animal Origin, Using LC/MS/MS.  Project Number: P/1750/G, A/10042.  Unpublished study prepared by PTRL Europe Gmbh.  79 p.
48250456
Arndt, T. (2009) Independent Laboratory Validation of the Analytical Method for Tolfenpyrad and its Metabolites PT-CA and PCA in Soil.  Project Number: A/10041, 1934W.  Unpublished study prepared by PTRL West, Inc.  91 p.
48250457
Brooks, M. (2010) Waiver Request for Multi-Residue Method for Tolfenpyrad and Crop Uses.  Project Number: TOL/RES/01.  Unpublished study prepared by Nichino America, Inc.  5 p.
48250458
Arndt, T. (2010) Magnitude of Tolfenpyrad Residues in Bovine Tissues and Milk from a 28-Day Feeding Study.  Project Number: 1841/W, 1841/W/1, 213/013/10.  Unpublished study prepared by PTRL West, Inc., and Genesis Midwest Laboratories.  923 p.
48250459
Chisolm, K. (2010) Tolfenpyrad: Request for Waiver of: Magnitude of the Residue in Poultry Meat and Egg Commodities.  Project Number: TOL/RES/02.  Unpublished study prepared by Nichino America, Inc.  6 p.
48250460
Carringer, S. (2009) Magnitude of the Residue of Tolfenpyrad and its Metabolite in or on Grape Raw Agricultural and Processed Commodities Following Two Foliar Applications of NAI-2303 15SC: Final Report.  Project Number: TCI/08/195/01, TCI/08/195, TCI/08/195/02.  Unpublished study prepared by Morse Laboratories, Inc., University of Idaho, Cooperative Extension and Reality Research.  275 p.
48250461
Wyatt, D. (2008) Magnitude of the Residue of Tolfenpyrad and its Metabolite in or on Apple Raw Agricultural and Processed Commodities Followinng Two Applications of NAI-2303 15SC: Final Report.  Project Number: TCI/07/166.  Unpublished study prepared by University of Idaho, Cooperative Extension, Morse Laboratories, Inc. and Reality Research.  367 p.
48250462
Carringer, S. (2008) Magnitude of the Residue of Tolfenpyrad and its Metabolite in or on Potato Raw Agricultural and Processed Commodities Following Two Foliar Applications of NAI-2302 15EC.  Project Number: TCI/07/163, TCI/07/163/01, TCI/07/163/02.  Unpublished study prepared by University of Idaho, Cooperative Extension, Morse Laboratories, Inc. and Reality Research.  342 p.
48250463
Carringer, S. (2008) Magnitude of the Residue of Tolfenpyrad and its Metabolite in or on Fruiting Vegetable Raw Agricultural and Processed Commodities Following Two Foliar Applications of NAI-2302 15EC or NAI-2303 15SC: Final Report.  Project Number: TCI/07/164, TCI/07/164/01, TCI/07/164/02.  Unpublished study prepared by Morse Laboratories, Inc., National Food Laboratory, and Crop Management Strategies, Inc.  462 p.
48250464
Stewart, E. (2008) Tolfenpyrad Residues on Leafy Vegetables (Leaf Lettuce, Head Lettuce, Celery and Spinach) from trials Conducted in the United States in 2007: Final Report.  Project Number: SARS/07/03, SARS/07/04, SARS/07/05.  Unpublished study prepared by Stewart Agricultural Research Services, Inc.  328 p.
48250465
Stewart, E. (2008) Tolfenpyrad Residues on Brassica (Cole) Leafy Vegetables (Cauliflower, Cabbage and Mustard Greens) from Trials Conducted in the United States in 2007.  Project Number: SARS/07/07, SARS/07/08, SARS/07/09.  Unpublished study prepared by Stewart Agricultural Research Services, Inc.  273 p.
48250466
Greenland, R. (2009) Tolfenpyrad Residues on Tree Nuts (Almond and Pecan) from Trials Conducted in the United States in 2008: Final Report.  Project Number: SARS/08/01, SARS/08/02, R/10178.  Unpublished study prepared by Stewart Agricultural Research Services, Inc.  227 p.
48250467
Greenland, R. (2009) Tolfenpyrad Residues on Stone Fruit (Cherry, Peach, Plum and the Processed Commodity, Prune) from Trials Conducted in the United States in 2008: Final Report.  Project Number: SARS/08/13, SARS/08/14, SARS/08/15.  Unpublished study prepared by Stewart Agricultural Research Services, Inc.  306 p.
48250468
Wyatt, D. (2008) Magnitude of the Residue of Tolfenpyrad and its Metabolite in or on Citrus Raw Agricultural and Processed Commodities Following Two Foliar Applications of NAI-2303 15SC or NAI-2302 15EC: Final Report.  Project Number: TCI/07/184, TCI/07/184/01, TCI/07/184/02.  Unpublished study prepared by Morse Laboratories, Inc., University of Idaho, Cooperative Extension and Florida Pesticide Research, Inc.  552 p.
48250469
Wyatt, D. (2008) Magnitude of the Residue of Tolfenpyrad and its Metabolite in or on Cotton Raw Agricultural and Processed Commodities Following Two Foliar Applications of NAI-2302 15EC: Final Report.  Project Number: TCI/07/165, TCI/07/165/01, TCI/07/165/02.  Unpublished study prepared by Morse Laboratories, Inc., GLP Technologies and Southeast Ag Research, Inc.  334 p.
48250470
Greenland, R. (2009) Tolfenpyrad Residues on Cucurbits (Cucumber, Cantaloupe and Summer Squash) from Trials Conducted in the United States in 2008: Final Report.  Project Number: SARS/08/10, SARS/08/11, SARS/08/12.  Unpublished study prepared by Stewart Agricultural Research Services, Inc.  247 p.
48250471
Carringer, S. (2009) Magnitude of the Residue of Tolfenpyrad and its Metabolite in or on Pear Raw Agricultural Commodities Following Two Foliar Applications of NAI-2303 15SC or NAI-2302 15EC: Final Report.  Project Number: TCI/08/196, TCI/08/196/01, TCI/08/196/02.  Unpublished study prepared by Morse Laboratories, Inc., Reality Research and Research for Hire.  234 p.
48250472
Komatsu, K.; Yabusaki, T. (1998) Residue of OMI-88: Residue of OMI-88 on/in Green Tea.  Project Number: R/10027.  Unpublished study prepared by Japan Food Research Laboratories.  23 p.
48250473
Hagio, S. (1998) Residue of OMI-88 on/in Green Tea.  Project Number: R/10028.  Unpublished study prepared by Mitsubishi Chemical Safety Institute, Ltd.  20 p.
48250474
Yabusaki, T. (2005) Residue of Tolfenpyrad: Residue of Tolfenpyrad (Hachi-Hachi) on/in Green Tea.  Project Number: R/10097.  Unpublished study prepared by Japan Food Research Laboratories.  21 p.
48250475
Otsubo, S. (2005) Residue of Tolfenpyrad: Residue of Tolfenpyrad (Hachi-Hachi) on/in Green Tea.  Project Number: R/10098.  Unpublished study prepared by Japan Ecotech Company, Ltd.  18 p.
48250476
Quistad, G.; Kovatchev, A.; Hiler, R. (2008) A Confined Rotational Crop Study with [Pyrazole-(Carbon 14)] and [Tolyl Ring-U-(Carbon 14)] Tolfenpyrad Using Radish, Lettuce, and Wheat.  Project Number: 1550W, R/10171.  Unpublished study prepared by PTRL West, Inc., and Research for Hire.  409 p.
48250477
Carringer, S. (2010) Field Accumulation of Tolfenpyrad and its OH-PAM, OH-PCA, and PAM Metabolites in Rotational Crops: Final Report.  Project Number: TCI/09/235, TCI/09/235/01, TCI/09/235/02.  Unpublished study prepared by PTRL West, Inc., Agvise Laboratories, Inc. and South Texas Ag Research, Inc.  859 p.
48250478
Durando, J. (2010) NAI-2303 15%SC (Tolfenpyrad 15SC): Acute Oral Toxicity Up and Down Procedure in Rats.  Project Number: 28303, P320/UDP, 090929/2D.  Unpublished study prepared by Eurofins/Product Safety Laboratories.  16 p.
48250479
Durando, J. (2010) NAI-2303 15%SC (Tolfenpyrad 15SC): Acute Dermal Toxicity Study in Rats - Limit Test.  Project Number: T/10154, 28304, P322/RAT.  Unpublished study prepared by Eurofins/Product Safety Laboratories.  15 p.
48250480
Durando, J. (2010) NAI-2303 15%SC (Tolfenpyrad 15SC): Acute Inhalation Toxicity Study in Rats.  Project Number: T/10155, 28305, P330.  Unpublished study prepared by Eurofins/Product Safety Laboratories.  35 p.
48250481
Durando, J. (2010) NAI-2303 15%SC (Tolfenpyrad 15SC): Primary Eye Irritation Study in Rabbits.  Project Number: T/10157, 28306, P324.  Unpublished study prepared by Eurofins/Product Safety Laboratories.  16 p.
48250482
Durando, J. (2010) NAI-2303 15%SC (Tolfenpyrad 15SC): Primary Skin Irritation Study in Rabbits.  Project Number: T/10156, 28307, P326.  Unpublished study prepared by Eurofins/Product Safety Laboratories.  16 p.
48250483
Durando, J. (2010) NAI-2303 15%SC (Tolfenpyrad 15SC): Dermal Sensitization Study in Guinea Pigs (Buehler Method).  Project Number: T/10158, 28308, P328.  Unpublished study prepared by Eurofins/Product Safety Laboratories.  25 p.
48250484
Arcee, G. (2010) Tolfenpyrad: Range-Finding Inhalation Toxicity Study in Rats: Supplement 1 to Tolfenpyrad: Four-Week Inhalation Toxicity Study in Rats.  Project Number: DUPONT/22217R, T/10159, 16846.  Unpublished study prepared by Dupont Haskell Laboratory.  73 p.
48250485
Buxton, P. (2010) Method Validation to Support Analysis of Tolfenpyrad in Corn Oil Dose Formulations for Nihon Nohyaku Co., Ltd..  Project Number: XTH00010AX/07/384, A/10043.  Unpublished study prepared by Charles River Laboratories.  36 p.
48250488
Wyatt, D. (2009) Dissipation of Dislodgeable Foliar Residues of Tolfenpyrad Following Two Applications to Apple Trees: Final Report.  Project Number: TCI/08/188, TCI/08/188/01, TCI/08/188/02.  Unpublished study prepared by Carringers, Inc., Morse Laboratories, Inc. and Reality Research.  216 p.
48250489
Wyatt, D. (2009) Dissipation of Dislodgeable Foliar Residues of Tolfenpyrad Following Two Applications to Cantaloupes: Final Report.  Project Number: TCI/08/190, R/10182, TCI/08/190/01.  Unpublished study prepared by Morse Laboratories, Inc., Carringers, Inc. and Southeast Ag Research, Inc.  214 p.
48250490
Wyatt, D. (2009) Dissipation of Dislodgeable Foliar Residues of Tolfenpyrad Following Two Applications to Grapes: Final Report.  Project Number: R/10181, TCI/08/189, TCI/08/189/01.  Unpublished study prepared by Morse Laboratories, Inc., Reality Research and Agsearch.  212 p.