Tolfenpyrad Human Health Risk Assessment DP No. 383820

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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

OFFICE OF

CHEMICAL SAFETY AND

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)
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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 ............................................................................... 6

2.2.2 International Harmonization..................................................................................... 6

2.2.3 Recommended Tolerances......................................................................................... 6

2.2.4 Revisions to Petitioned-For Tolerances.................................................................... 8

2.3 Label Recommendations................................................................................................ 8

2.3.1 Label Recommendations from Residue Reviews..................................................... 8

2.3.2 Label Recommendations from Occupational 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.............................................................. 17

4.4.2 Evidence of Neurotoxicity........................................................................................ 18

4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal........ 18

4.4.4 Residual Uncertainty in the Exposure Database ................................................... 18

4.5 Toxicity Endpoint and Point of Departure Selections.............................................. 18

4.5.1 Dose-Response Assessment...................................................................................... 18

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment..... 19

4.5.3 Cancer Classification and Risk Assessment Recommendation............................ 20

4.5.4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk 

Assessment............................................................................................................................... 20

5.0 Dietary Exposure and Risk Assessment......................................................................... 21

5.1 Metabolite/Degradate Residue Profile ....................................................................... 21

5.1.1 Summary of Plant and Animal Metabolism Studies............................................. 21

5.1.2 Summary of Environmental Degradation.............................................................. 22

5.1.3 Comparison of Metabolic Pathways....................................................................... 23

5.1.4 Residues of Concern Summary and Rationale ...................................................... 23

5.2 Food Residue Profile .................................................................................................... 24

5.3 Water Residue Profile.................................................................................................. 27

5.4 Dietary Risk Assessment.............................................................................................. 28

5.4.1 Description of Residue Data Used in Dietary Assessment.................................... 28

5.4.2 Percent Crop Treated Used in Dietary Assessment .............................................. 30

5.4.3 Acute Dietary Risk Assessment............................................................................... 30

5.4.4 Chronic Dietary Risk Assessment........................................................................... 31
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5.4.5 Cancer Dietary Risk Assessment............................................................................. 31

5.4.6 Summary Table......................................................................................................... 31

6.0 Residential (Non-Occupational) Exposure/Risk Characterization ............................. 32

6.1 Residential Bystander Post-Application Inhalation Exposure ................................ 32

6.2 Spray Drift.................................................................................................................... 32

8.0 Cumulative Exposure/Risk Characterization ............................................................... 33

9.0 Occupational Exposure/Risk Characterization ............................................................ 33

9.1 Short- and Intermediate-Term Handler Risk ........................................................... 34

9.2 Short- and Intermediate-Term Post-Application Risk............................................. 37

9.2.1 Dermal Post-Application Risk................................................................................. 37

9.2.2 Inhalation Post-Application Risk............................................................................ 37

10.0 References......................................................................................................................... 38

Appendix A. Toxicology Profile and Executive Summaries .................................................. 39

A.1 Toxicology Data Requirements................................................................................... 39

A.3 Triple-Pack Analysis for Tolfenpyrad ....................................................................... 47

A.4 Toxicological Doses and Endpoints for Use in Human Risk Assessments.............. 49

Appendix B. Metabolism Summary Table ............................................................................... 51

Appendix C. Physical/Chemical Properties............................................................................. 56

Appendix D. Review of Human Research................................................................................ 57

Appendix E. Bibliography of Submitted Studies.................................................................... 58
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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 
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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.
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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.
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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 

Proposed Recommended definition)

Tolerances for residues of tolfenpyrad

Almond hulls 5.0 6.0 Almond, hulls

Leaf lettuce 30 30 Vegetable, leafy, except Brassica, 

Head lettuce 5 group 4

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
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Table 2.2.3. Tolerance Summary for Tolfenpyrad.

Commodity Tolerance (ppm) Comments (correct commodity 

Proposed Recommended definition)

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
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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
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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]-1Hpyrazole-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).
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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.
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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

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 ft2per application 

(100 gal per 20,000 ft2typically 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.
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Table 3.3. Summary of Proposed Directions for Use of Tolfenpyrad.

Applic. 

Timing, Type, 

and Equip.

Formulation 

(EPA Reg. 

No.)†

Use Sites Max. Single 

Applic. Rate‡

Max. 

Seasonal 

Applic. Rate

PHI 

(days)

Use Directions and Limitations

Leafy 

Vegetables 

(Crop Group 4), 

Cucurbit 

Vegetables 

(Crop Group 9), 

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 ft2per 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
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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 nonoccupational 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 128981, 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 

 

1

"Federal Actions to Address Environmental Justice in Minority Populations and Low-Income Populations"

(http://epa.gov/compliance/ej/resources/policy/exec_order_12898.pdf)
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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 [PY14C]- and [TO14C]-label positions in the single or multiple dose studies. However, in 

animals given multiple doses of pyrazole-labled (14C) 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
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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 treatmentrelated 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 
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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
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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.
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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/m3(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/m3(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. 
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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 NonOccupational 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.
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Table 4.5.4b Summary of Toxicological Doses and Endpoints for Tolfenpyrad for Use in Occupational Human 

Health Risk Assessments.

Exposure/

Scenario

Point of 

Departure

Uncertainty 

Factors

Level of 

Concern for

Risk 

Assessment Study and Toxicological Effects

Inhalation Short-Term And

Intermediate-Term

(Up to 6 months of Exposure)

NOAEL= 

2.6 

mg/kg/day

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-CA2and OH-PT-OH were identified in all primary crops; metabolites OHPT, 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.

 

2

See Appendix B for structures of the parent compound and metabolites.
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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 
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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-CA1(root crops only) Tolfenpyrad

Rotational Crop --

2

--

Livestock Ruminant Tolfenpyrad + PT-CA + OH-PT-CA3 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 
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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 
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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)

EP1PHI 

(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)
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Table 5.2.1. Summary of Residues from Field Trials Conducted with Tolfenpyrad.

Commodity Total App. 

Rate

(lb ai/A)

EP1PHI 

(days)

Residue Levels (ppm) 2

n Min. Max. HAFT 3 Median Mean Std. Dev.

Apple 0.397-0.404 SC 13-14 16 0.102 0.316 0.316 0.203 0.206 0.064

Pear 0.396-0.411 SC 14 6 0.068 0.355 0.355 0.177 0.197 0.104

Pear 0.397-0.412 EC 14 6 0.029 0.357 0.357 0.207 0.201 0.113

STONE FRUIT CROP GROUP 12 (proposed use = 0.56 lb ai/A total application rate; 14-day PHI)

Sweet Cherry 0.542-0.550 SC 14 6 0.267 0.896 0.896 0.524 0.551 0.238

Peach 0.489-0.568 SC 13-14 9 0.14 0.689 0.689 0.329 0.362 0.177

Plum 0.546-0.558 SC 14 6 0.124 0.929 0.929 0.323 0.402 0.311

GRAPE (proposed use = 0.41 lb ai/A total application rate; 7-day PHI)

Grape 0.395-0.409 SC 7 12 0.211 1.51 1.51 0.373 0.53 0.389

TREE NUTS CROP GROUP 14 (proposed use = 0.56 lb ai/A total application rate; 14-day PHI)

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 

Factor1

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
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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 

Factor1

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 μg/L, 

respectively. The maximum exposure estimate for ground water is 11 μg/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
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Table 5.3. Tolfenpyrad EDWCs in Surface Water and Ground Water for Use in Dietary Risk Assessment Based on 

the Use Pattern of Maximum Exposure, Nurseries and Christmas Trees. *

Use (maximum rate) Source† Cropped 

Area, %

1-in-10-year Conc., ppb

Peak 

(Acute) 

Mean 

(Chronic)

30-year Daily Average 

(Cancer)

Ornamental plants and Christmas 

trees (2.72 lbs a.i./A/year)

Ground 

water

N/A 11.0

* EDWCs were calculated based on total residues of concern (a summation of tolfenpyrad, PAM, PT-CA, PCA and 

PT(A)-4OH) and a percent cropped area of 87%.

†

Surface water estimates were derived using PRZM-EXAMS. Ground water estimates were derived using SCIGROW.

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-FCIDTM (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.
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Table 5.4.1. Summary of Crop Field Trial Residue Data Used in the Dietary Exposure and Risk Assessment for 

Tolfenpyrad.

Commodity

Residue, ppm

Tolerance Mean Translated to

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 --
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Table 5.4.1. Summary of Crop Field Trial Residue Data Used in the Dietary Exposure and Risk Assessment for 

Tolfenpyrad.

Commodity

Residue, ppm

Tolerance Mean Translated to

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 95th 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 
Tolfenpyrad Human Health Risk Assessment DP No. 383820

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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 (95th 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
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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 nonagricultural 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 postapplication inhalation exposure to individuals nearby pesticide applications. The Agency sought 

expert advice and input on issues related to volatilization of pesticides from its Federal 

Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, 

and received the SAP’s final report on March 2, 2010.3 The Agency is in the process of 

evaluating the SAP report and may, as appropriate, develop policies and procedures to identify

the need for and, subsequently, the way to incorporate post-application inhalation exposure into 

the Agency's risk assessments. 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 practices4. 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.

 

3

See http://www.epa.gov/scipoly/sap/meetings/2009/120109meeting.html for the referenced SAP report.

4

See http://www.epa.gov/opp00001/factsheets/spraydrift.htm for more information on spray drift.
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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 enduse 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.
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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 
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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 mechanicallypressurized handgun sprayer for ornamental plants. All non-aerial application scenarios were 

assessed assuming a single layer of clothing and no respirator [i.e., baseline levels of personal 

protective equipment (PPE)]. For aerial applications, an engineering control (i.e., enclosed 

cockpit) was assumed and incorporated as part of the description of the scenario. All 

occupational handler scenarios for the proposed and existing uses resulted in risk estimates that 

are not of concern (i.e., MOEs are all greater than 100).

Table 9.1. Tolfenpyrad: Short- and Intermediate-Term Exposure and Risk Estimates for Occupational Handlers.†

Exposure 

Scenario Crops or Target

Max Single 

Application 

Rate a

Area or 

Amount 

Treated 

Inhalation Unit 

Exposure b

(mg/lb)

(Mitigation 

Level)

Inhalation

Dose c

(mg/kg/day) MOE d

Mixer/Loader

Aerial - Liquids

Citrus (Crop Group 10), grapes 

(raisin, table, wine), apple, 

crabapple, loquat, mayhaw, 

quince, pear, oriental pear 

0.28 lb ai/A 350 A

0.000219 

(Baseline)

(AHETF)

0.0002683 9,700

Leafy vegetables (Crop Group 

4), cucurbit vegetables (Crop 

Group 9), potatoes, brassica 

(cole) leafy vegetables (Crop 

Group 5), fruiting vegetables 

(Crop Group 8 plus okra)

0.21 lb ai/A 350 A 0.0002011 13,000

Stone fruit (Crop Group 12), 

tree nuts (Crop Group 14) 0.29 lb ai/A 350 A 0.0002778 9,400

Cotton 0.21 lb ai/A 1,200 A 0.0006897 3,800

Airblast - Liquids

Citrus (Crop Group 10), grapes 

(raisin, table, wine), apple, 

crabapple, loquat, mayhaw, 

quince, pear, oriental pear

0.28 lb ai/A 40 A 0.000219 

(Baseline)

(AHETF)

0.00003065 85,000

Stone fruit (Crop Group 12), 

tree nuts (Crop Group 14) 0.29 lb ai/A 40 A 0.00003175 82,000

Chemigation -

Liquids Potatoes; vegetable crops 0.21 lb ai/A 350 A

0.000219 

(Baseline)

(AHETF)

0.00020110 13,000

Ground -

Liquids

Leafy vegetables (Crop Group 

4), cucurbit vegetables (Crop 

Group 9), potatoes, brassica 

(cole) leafy vegetables (Crop 

Group 5), fruiting vegetables 

(Crop Group 8 plus okra)

0.21 lb ai/A 80 A

0.000219 

(Baseline)

(AHETF)

0.00004570 57,000

Cotton 0.21 lb ai/A 200 A 0.00011420 23,000

Applicator

Aerial – Liquids

Citrus (Crop Group 10), grapes 

(raisin, table, wine), apple, 

crabapple, loquat, mayhaw, 

quince, pear, oriental pear 

0.28 lb ai/A 350 A

0.000068 

(Engineering 

Control; 

Enclosed 

Cockpit) (PHED)

0.0000833 31,000
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Table 9.1. Tolfenpyrad: Short- and Intermediate-Term Exposure and Risk Estimates for Occupational Handlers.†

Exposure 

Scenario Crops or Target

Max Single 

Application 

Rate a

Area or 

Amount 

Treated 

Inhalation Unit 

Exposure b

(mg/lb)

(Mitigation 

Level)

Inhalation

Dose c

(mg/kg/day) MOE d

Leafy vegetables (Crop Group 

4), cucurbit vegetables (Crop 

Group 9), potatoes, brassica 

(cole) leafy vegetables (Crop 

Group 5), fruiting vegetables 

(Crop Group 8 plus okra)

0.21 lb ai/A 350 A

0.000068 

(Engineering 

Control) (PHED)

0.0000625 42,000

Stone fruit (Crop Group 12), 

tree nuts (Crop Group 14) 0.29 lb ai/A 350 A

0.000068 

(Engineering 

Control) (PHED)

0.0000863 30,000

Cotton 0.21 lb ai/A 1,200 A

0.000068 

(Engineering 

Control) (PHED)

0.0002137 12,000

Airblast - Liquids

Citrus (Crop Group 10), grapes 

(raisin, table, wine), apple, 

crabapple, loquat, mayhaw, 

quince, pear, oriental pear 

0.28 lb ai/A 40 A 0.00471 

(Baseline)

(AHETF)

0.0006594 3,900

Stone fruit (Crop Group 12), 

tree nuts (Crop Group 14) 0.29 lb ai/A 40 A 0.0006829 3,800

Open Cab 

Groundboom

Leafy vegetables (Crop Group 

4), cucurbit vegetables (Crop 

Group 9), potatoes, brassica 

(cole) leafy vegetables (Crop 

Group 5), fruiting vegetables 

(Crop Group 8 plus okra)

0.21 lb ai/A 80 A 0.00034 

(Baseline)

(AHETF)

0.0000709 37,000

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

Mechanicallypressurized 

Handgun Sprayer

Ornamentals 0.00313 lb 

ai/gal

1,000 

gal/day

0.120

(Baseline) 

(PHED)

0.004691 550

Backpack 

Sprayer Ornamentals 0.00313 lb ai/gal 40 gal/day

0.140

(Baseline) 

(AHETF)

0.000219 12,000

Manuallypressurized 

Handwand

Ornamentals 0.00313 lb 

ai/gal 40 gal/day

0.030

(Baseline) 

(PHED)

0.000049 53,000

†. Only the exposure and risk estimates using the max. single application rates 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 
Tolfenpyrad Human Health Risk Assessment DP No. 383820

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application rate (Higher Spray Volume) = 1.36 lb ai/A (at 10 gal/1000 ft2= 436 gal/A) 0.00313 lb ai/gal * 436 gal/A = 1.36 lb 

ai/A.

b. Occupational Pesticide Handler Unit Exposure Surrogate Reference Table (September 26, 2011).

c. Inhalation Dose (mg/kg/day) = Inhalation Unit Exposure (mg/lb ai) * 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 
Tolfenpyrad Human Health Risk Assessment DP No. 383820

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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.
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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. 
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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, 47463702 and Levels tested: 0, 15, 100, 300 pm or 0/0, 2.4/3.0, 
Tolfenpyrad Human Health Risk Assessment DP No. 383820

Page 41 of 65

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile for Tolfenpyrad

Type of 

Study/Guide 

line

Study Title MRID Results

Mouse 47447801 15.9/20.2, 46.2/57.9 mg/kg/day in males/females

NOAEL (M/F)-300 ppm or 46.2/57.9 mg/kg/day 

LOAEL (M/F)-not determined in main study; 600 

ppm (104/126 mg/kg/day) based on decreased body 

weights, body weight gains, clinical signs (rough 

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/m3or 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/m3

(analyzed aerosol concentrations achieved)
Tolfenpyrad Human Health Risk Assessment DP No. 383820

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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile for Tolfenpyrad

Type of 

Study/Guide 

line

Study Title MRID Results

870.3700a Developmental Toxicity, 

Rat (Gavage)

47447809 Levels tested: 0, 1, 3, 4.5 mg/kg/day; GD 6-15)

Maternal NOAEL =1 mg/kg/day

Maternal LOAEL = 3 mg/kg/day, based on 

decreased body weight gains and food consumption

Developmental NOAEL = 3 mg/kg/day

Developmental LOAEL = 4.5 mg/kg/day, based on 

increased incidences of 14th 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, 13th 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 
Tolfenpyrad Human Health Risk Assessment DP No. 383820

Page 43 of 65

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile for Tolfenpyrad

Type of 

Study/Guide 

line

Study Title MRID Results

on increased gestation duration

Offspring NOAEL = 15 ppm

Offspring LOAEL = 50 ppm, based on decreased 

body weights and body weight gains in both sexes.

870.4100 Chronic Toxicity-1 Year, 

Dog (feeding)

47442818 Levels tested: 0, 1, 5, 10 (reduced from 20) 

mg/kg/day 

NOAEL (M/F) 5 mg/kg/day

LOAEL (M/F) 10 mg/kg/day, based on mortality, 

vomiting, decreased body weights, body weight 

gains, food consumption,, increased serum alanine 

aminotransferase in the males, and microscopic liver 

findings in males and females

870.4200a 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) 47463706 Negative. There was no evidence of induced mutant 

colonies over background in the presence or absence 

of S9-activation.
Tolfenpyrad Human Health Risk Assessment DP No. 383820

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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile for Tolfenpyrad

Type of 

Study/Guide 

line

Study Title MRID Results

In Vitro Gene Mutation 

assay in mouse lymphoma

cells

870.5375 Technical (OMI-88)

In vitro Mammalian 

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 μg/mL) during 

Trial 1 (24 hr, -S9). The biological significance of 

polyploidy in vitro is not completely understood at 

the present time. Therefore, this finding was not 

considered to be an adverse treatment-related effect. 

The positive controls induced the appropriate 

response in the presence and absence of S9 in both 

trials. 

870.5375 Metabolite (OH-PT)

In vitro Mammalian 

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 47447831 Levels tested: 0, 20, 40, 60 mg/kg/day in males and 
Tolfenpyrad Human Health Risk Assessment DP No. 383820

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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile for Tolfenpyrad

Type of 

Study/Guide 

line

Study Title MRID Results

(gavage) 0, 10, 20, or 40 mg/kg/day in females.

NOAEL (M/F) = 10 mg/kg/day

LOAEL (M/F) = 20 mg/kg/day, based on decreases 

in body weight, body 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 
Tolfenpyrad Human Health Risk Assessment DP No. 383820

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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile for Tolfenpyrad

Type of 

Study/Guide 

line

Study Title MRID Results

gains; increased incidence of blackish abdominal 

cavity and dark green abnormal intestinal content; 

and decreased thymus and spleen weights in the F1 

and/or F2 generations 

Note: No treatment-related effects 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-PTCA (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 OHPT-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.
Tolfenpyrad Human Health Risk Assessment DP No. 383820

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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 shortand 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 

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 

μg/c

m

2

8.41

μg/c

m

2

99.9

μg/c

m

2

1μg/cm21500 

μg/cm2

1μg/cm21500 

μg/cm2

% Absorbed (+ 

absorbable) at 

24 hrs

39.8 44.5 22.09 67.02 26.78 6.49 1.12
Tolfenpyrad Human Health Risk Assessment DP No. 383820

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

determined) used to assess short-, intermediate, and long-term dermal exposure. 

Extra 3x was applied to long-term dermal exposure scenario to account for 

subchronic to chronic extrapolation. 

exposure 

periods

Calculated a 

Refined 

Dermal Dose 

(RDD) to 

modify the 

dermal POD.

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 

IntermediateTerm 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
Tolfenpyrad Human Health Risk Assessment DP No. 383820

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

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

Study Selected: Acute Neurotoxicity Study in Rats 

MRID No: 47447831

Dose and Endpoint for Risk Assessment: NOAEL= 10 mg/kg/day, based on decreased body

weight, body weight gain and food consumption observed at the LOAEL of 20 mg/kg/day.

Uncertainty Factor: 100x (10x interspecies extrapolation, 10x intraspecies variability)

Acute RfD = 

100 ( )

10 / /

UF

mg kg day

= 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 = 

100 ( )

0 .6 / /

UF

mg kg day = 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 
Tolfenpyrad Human Health Risk Assessment DP No. 383820

Page 50 of 65

were also considered for chronic dietary exposure; however, the chronic rat study provided the 

most sensitive endpoint for chronic dietary risk assessment. 

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

For dermal exposure scenarios, no hazard was identified. A 21-day dermal toxicity study in rats 

is available for 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/m3(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/m3(6.8 

mg/kg/day). No mortality was seen at the next lowest dose of 10.9 mg/m3in 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 intermediateterm 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.
Tolfenpyrad Human Health Risk Assessment DP No. 383820

Page 51 of 65

O

Cl

H3C

OH

N

N

CH3

NH

O

O

OH

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
Tolfenpyrad Human Health Risk Assessment DP No. 383820

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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

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
Tolfenpyrad Human Health Risk Assessment DP No. 383820

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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

Rot. Radish Tops 365 15.2 0.007

Rot. Wheat Grain 30 7.1 0.004

Rot. Wheat Grain 120 19.6 0.009

Rot. Wheat Grain 365 12.5 0.001

Rot. Wheat Forage 30 29.7 0.16

Rot. Wheat Forage 120 19.5 0.051

Rot. Wheat Forage 365 77.1 0.148

Rot. Wheat Hay 30 38.4 0.255

Rot. Wheat Hay 120 31.6 0.233

Rot. Wheat Hay 365 16.4 0.043

Rot. Wheat Straw 30 32.1 0.397

Rot. Wheat Straw 120 25.4 0.199

Rot. Wheat Straw 365 19.7 0.059

PCA Cabbage 2.2 0.21

Goat Milk 12.2 0.021

Goat Fat 28.6 0.078

Hen Eggs 14.4 0.024

Hen Fat 11.2 0.048

Rot. Wheat Hay 30 0.2 0.001

Rot. Wheat Hay 120 0.1 0.001

Rot. Wheat Straw 30 0.2 0.002

Rot. Wheat Straw 120 0.3 0.002

OH-PCA Radish Root 1.8 0.008

Rot. Lettuce 30 20.3 0.016

Rot. Lettuce 120 27.1 0.013

Rot. Radish Root 30 1.7 0.001

Rot. Radish Tops 30 4 0.005

Rot. Radish Tops 120 2.5 0.003

Rot. Radish Tops 365 2.2 0.001

Rot. Wheat Grain 30 10.7 0.006

Rot. Wheat Grain 120 2.2 0.001

Rot. Wheat Forage 30 17.5 0.094

Rot. Wheat Forage 120 17.6 0.046

Rot. Wheat Forage 365 2.1 0.004

Rot. Wheat Hay 30 5.1 0.034

Rot. Wheat Hay 120 10.2 0.076

Rot. Wheat Hay 365 5.7 0.015

Rot. Wheat Straw 30 8.5 0.105

Rot. Wheat Straw 120 5.6 0.044

Rot. Wheat Straw 365 6.7 0.02

OH-PCA conjugate Rot. Lettuce 30 26.6 0.021

Rot. Radish Root 30 27.1 0.016

Rot. Radish Tops 30 24 0.03

Rot. Wheat Grain 30 14.3 0.008

Rot. Wheat Grain 120 23.9 0.011

O

HO Cl

CH3

N

N

H3C
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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

Rot. Wheat Grain 365 12.5 0.001

Rot. Wheat Forage 30 32.3 0.174

Rot. Wheat Forage 120 30.3 0.079

Rot. Wheat Hay 30 12.8 0.085

Rot. Wheat Hay 120 30.3 0.224

Rot. Wheat Hay 365 37.5 0.097

Rot. Wheat Straw 30 12.7 0.157

Rot. Wheat Straw 120 21.4 0.168

Rot. Wheat Straw 365 41.8 0.125

CA-T-NH2 Goat Milk 19.4 0.033

Goat Fat 5.3 0.019

OH-PT Cabbage 7.99 0.76

OH-PT-OH Peach Stems (56 DAT) 1.1 0.11

Cabbage 3.49 0.33

OH-PT-OH conjugate Radish Top 3.8 0.355

OH-T-CA Cabbage 3.9 0.33

OH-T-OH Cabbage 3.7 0.31

OH-T-AM Cabbage 1.9 0.16

CA-T-AM Cabbage 2.4 0.2

CO-PT Peach Stems (56 DAT) 1 0.1

Rat Bile 2.8% AD --

CO-PT-OH Cabbage 1.2 0.1

CA-T-CA Peach Leaves (56 DAT) 11.1 5.7

Rot. Radish Root 30 6.3 0.001

Rot. Radish Tops 30 2.9 0.001

T-CA Peach Leaves (56 DAT) 6.6 3.4

2OH-PAM Peach Fruit (56 DAT) 4.5 0.035

Peach Leaves (56 DAT) 1.5 0.95

* Included compounds are ≥ 1% TRR (% AD in rat) in at least one matrix. 

Comparison of Radiolabeled Studies to Proposed Use Directions

Radiolabeled Study Proposed Use; PHI (days) in parenthesis

Radish (48250449)

0.21 lb ai/A × 2 = 0.4 lb ai/A; PHI = 1 day

1X: grape (7), pome fruit (14), leafy veg. (1), potato

(14), Brassica veg. (1), fruiting veg. (1), cotton (14)

0.7X: citrus (14), stone fruit (14), tree nuts (14)

0.47X: cucurbit veg. (1)

O

OH

O

NH2
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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
Tolfenpyrad Human Health Risk Assessment DP No. 383820

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Appendix C. Physical/Chemical Properties

Table 3.2. Physicochemical Properties of the Technical Grade Test Compound: Tolfenpyrad1

Parameter Value Reference

Molecular Weight 383.9 MRID 47447704

Melting point/range (PAI)285.5-88.5° C MRID 47447705

pH 5.1 MRID 47447704

Density 1.25 g/cm3

Water solubility (PAI) 0.061 mg/L MRID 47447705

Solvent solubility 

(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 10-5Pa 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
Tolfenpyrad Human Health Risk Assessment DP No. 383820

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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.
Tolfenpyrad Human Health Risk Assessment DP No. 383820

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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.
Tolfenpyrad Human Health Risk Assessment DP No. 383820

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MRID Citation

47447810 Matsuura, I. (1996) A Preliminary Teratogenicity Study of AP81088 in Rabbits. Project 

Number: T/10029, B031577, 5L485HEO. Unpublished study prepared by Mitsubishi 

Chemical Safety Institute, Ltd. 140 p.

47447811 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.
Tolfenpyrad Human Health Risk Assessment DP No. 383820

Page 60 of 65

MRID Citation

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

6L190. Unpublished study prepared by Mitsubishi Chemical Safety Institute, Ltd. 44 p.

47447834 Nishitomi, T. (1999) Fate of OMI-88 in Rats-Metabolism Study After a Single Oral 

Administration. Project Number: T/10042, 7L366. Unpublished study prepared by 

Mitsubishi Chemical Safety Institute, Ltd. 88 p.

47447835 Kitazawa, K. (1998) Fate of OMI-88 in Rats: Structural 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.
Tolfenpyrad Human Health Risk Assessment DP No. 383820

Page 61 of 65

MRID Citation

47463702 Trutter, J. (1999) 13- Week Dietary Toxicity Study in Mice with OMI-88 Technical: Final 

Report. Project Number: 6287/104, T/10015. Unpublished study prepared by Covance 

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.
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MRID Citation

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

Number: R/10002, 8L122. Unpublished study prepared by Mitsubishi Chemical Safety 

Institute, Ltd. 43 p.

48250449 Quistad, G.; Kovatchev, A. (2008) A Metabolism Study with [Pyrazole (Carbon 14)] and 

[Tolyl Ring-U-(Carbon 14)]Tolfenpyrad in Radish. Project Number: 1740W. Unpublished 

study prepared by PTRL West, Inc., and Excel Research Services, Inc. 176 p.

48250450 Quistad, G.; Kovatchev, A. (2007) The Metabolism of (Carbon 14)Tolfenpyrad (2 

Radiolabels) in the Lactating Goat. Project Number: R/10160, 1556W. Unpublished study 

prepared by PTRL West, Inc. and Genesis Midwest Laboratories. 245 p.

48250451 Quistad, G.; Kovatchev, A. (2007) The Metabolism of (Carbon 14)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.
Tolfenpyrad Human Health Risk Assessment DP No. 383820

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MRID Citation

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 NAI2303 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.
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MRID Citation

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.
Tolfenpyrad Human Health Risk Assessment DP No. 383820

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MRID Citation

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.