Fluopyram Human Health Risk Assessment DP No. 0414231 

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

MEMORANDUM 

DATE: September 22,2014 

OFFICE OF 

CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

SUBJECT: Fluopyram: Human Health Risk Assessment for Proposed New Use as a Soil/InFurrow Treatment for Cotton and Peanut, and as a Seed Treatment to Cotton and 

Soybean, Plus a Proposal for Amended Inadvertent Tolerances for the Crop 

Group 15 Cereal Grains and Crop Group 16 Forage, Fodder, and Straw of Cereal 

Grains. 

PC Code: 080302 DP Barcode: 0414231 

Decision No.: 481199 Registration No.: 264-RRAT; 264-1078; 264-1084; 

264-1085;264-1090;264-1091 

Petition No.: 3F8190 Regulatory Action: Section 3 Registration 

Risk Assessment Type: Single Chemical/ Aggregate 

TXRNo.:NA 

Case No.: NA 

CAS No.: 658066-35-4 

MRIDNo.: NA 40 CFR: 180.661 

FROM: Barry O'Keefe, Senior Biologist/Ri· sk ~~es r Bl 

Steve Funk, Senior Chemist >f ~ 

Whang Phang, Senior Toxicologist · 

Risk Assessment Branch III ~ . 

Health Effects Division (7509P) Y 

0'4 

THROUGH: Christine Olinger, Chief /} /~ / 

Risk Assessment Branch III ~/ _ 

Health Effects Division (7509P) 

TO: Marcel Howard, Risk Management Team #20 

Fungicide Branch 

Registration Division (7505P) 

The registrant, Bayer CropScience, is requesting new uses offluopyram as a soiVin-furrow 

treatment for cotton and peanut, and as a seed treatment to cotton and soybean. Also, postemergent application to peanut by overhead chemigation is proposed. Additionally, new 

rotational crop data have been submitted to support proposed amended inadvertent tolerances for 

the cereal grains (crop group 15) and the forage, fodder, and straw of cereal grains (crop group 

16). 

Page 1 of 51 
Fluopyram Human Health Risk Assessment DP No. D414231 

The Registration Division (RD) of OPP has requested that the Health Effects Division (HED) 

evaluate the hazard and exposure data and conduct dietary, aggregate, occupational and 

residential exposure assessments, as needed, to estimate the risk to human health that will result 

from the proposed uses offluopyram. This memorandum serves as HED's assessment ofthose 

exposures. 

The toxicology reevaluation was performed by Whang Phang, the drinking water assessment was 

conducted by Mohammed Ruhman (EPA Environmental Fate and Effects Division (EFED)), the 

review of the residue chemistry data and the dietary exposure assessment were conducted by 

Steve Funk, and the occupational and residential exposure assessment and aggregate human 

health risk assessments were conducted by Barry O'Keefe. 

Page 2 of 51 
Fluopyram Human Health Risk Assessment DP No. D414231

Page 3 of 51

1.0 Executive Summary ........................................................................................................... 5

2.0 HED Recommendations .................................................................................................... 7

2.1 Data Deficiencies ............................................................................................................ 8

2.2 Tolerance Considerations.............................................................................................. 8

2.2.1 Enforcement Analytical Method ............................................................................... 8

2.2.2 International Harmonization..................................................................................... 8

2.2.3 Recommended Tolerances......................................................................................... 9

2.2.4 Revisions to Petitioned-For Tolerances.................................................................. 10

2.3 Label Recommendations.............................................................................................. 11

3.0 Introduction...................................................................................................................... 11

3.1 Chemical Identity ......................................................................................................... 12

3.2 Physical/Chemical Characteristics ............................................................................. 12

3.3 Pesticide Use Pattern.................................................................................................... 12

3.4 Anticipated Exposure Pathways................................................................................. 14

3.5 Consideration of Environmental Justice.................................................................... 14

4.0 Hazard Characterization and Dose-Response Assessment.......................................... 15

4.1 Toxicological Effects .................................................................................................... 15

4.2 Safety Factor for Infants and Children (FQPA Safety Factor) ............................... 16

4.2.1 Completeness of the Toxicology Database.............................................................. 16

4.2.2 Evidence of Neurotoxicity ........................................................................................ 16

4.2.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal........ 16

4.2.4 Residual Uncertainty in the Exposure Database ................................................... 17

4.3 Toxicity Endpoint and Point of Departure Selections .............................................. 17

4.3.1 Dose-Response Assessment...................................................................................... 17

4.3.2 Recommendation for Combining Routes of Exposures for Risk Assessment..... 17

4.3.3 Cancer Classification and Risk Assessment Recommendation............................ 18

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

Assessment............................................................................................................................... 18

5.1 Residues of Concern Summary and Rationale .......................................................... 20

5.2 Food Residue Profile .................................................................................................... 21

5.3 Water Residue Profile.................................................................................................. 24

5.4 Dietary Risk Assessment.............................................................................................. 25

5.4.1 Description of Residue Data Used in Dietary Assessment.................................... 25

5.4.2 Percent Crop Treated Used in Dietary Assessment .............................................. 25

5.4.3 Acute Dietary Risk Assessment............................................................................... 25

5.4.4 Chronic Dietary Risk Assessment........................................................................... 25

5.4.5 Cancer Dietary Risk Assessment............................................................................. 26

5.4.6 Summary Table......................................................................................................... 26

6.0 Residential (Non-Occupational) Exposure/Risk Characterization ............................. 26

6.1 Residential Handler Exposure .................................................................................... 26

6.2 Residential Bystander Post-application Inhalation Exposure ................................. 26

6.3 Spray Drift.................................................................................................................... 27

7.0 Aggregate Exposure/Risk Characterization.................................................................. 27

8.0 Cumulative Exposure/Risk Characterization ............................................................... 27

9.0 Occupational Exposure/Risk Characterization ............................................................ 28

9.1 Short-/Intermediate-Term Handler Risk................................................................... 28
Fluopyram Human Health Risk Assessment DP No. D414231

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9.2 Short-/Intermediate-Term Post-Application Risk .................................................... 29

9.2.2 Inhalation Post-application Risk............................................................................. 30

10.0 References......................................................................................................................... 31

Appendix A. Toxicology Profile................................................................................................ 32

A.1 Toxicology Data Requirements................................................................................... 32

A.2 Toxicity Profiles............................................................................................................ 33

Appendix B. Physical/Chemical Properties............................................................................. 44

Appendix C. Review of Human Research................................................................................ 45

Appendix D. Summary of Residues from Rotational Crop Field Trials .............................. 46

Appendix E. Occupational Exposure/Risk Summary Tables................................................ 47

Appendix F. International Residue Limit Status Sheet.......................................................... 50
Fluopyram Human Health Risk Assessment DP No. D414231

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1.0 Executive Summary

Fluopyram, (N-[2-[3-chloro-5-(trifluoromethyl)-2-pyridinyl]ethyl]-2-

(trifluoromethyl)benzamide) is a broad-spectrum systemic fungicide of the pyridinyl-ethylbenzamide group. It acts by inhibiting succinate dehydrogenase in the cell respiration of fungi. 

The mechanism of toxicity in mammals is not clearly defined.

Use Profile

The registrant, Bayer CropScience, is requesting new uses of fluopyram, as follows: 1) As an atplanting soil/in-furrow treatment for cotton and peanut and as a post-emergent application to 

peanut by overhead chemigation on the Luna Privilege label (EPA Reg. No. 264-1078), a liquid 

formulation containing 41.5% ai (4.16 lb ai /gal); and 2) As a seed treatment to cotton and 

soybean on the new end-use product Fluopyram ST (EPA Reg. No. 264-RRAT), a liquid 

formulation containing 48.4% ai (5 lb ai/gal). 

The proposed Luna® Privilege label requires occupational handlers to wear the following 

personal protective equipment (PPE): long sleeved shirts, long pants, shoes, socks, and chemical 

resistant gloves. The proposed restricted entry interval (REI) is 12 hours. The proposed 

Fluopyram ST label requires occupational handlers to wear the following PPE: long-sleeved 

shirt, long pants, shoes plus socks, and waterproof gloves.

Additionally, new rotational crop data have been submitted to support a proposal for amended or 

lower inadvertent tolerances for the cereal grains (crop group 15) and the forage, fodder, and 

straw of cereal grains (crop group 16).

Exposure Profile

The proposed uses of fluopyram would result in new exposures from both food and drinking 

water. There are no existing or proposed residential uses, and therefore, there are no nonoccupational exposures expected. However, the proposed agricultural uses will result in shortand intermediate-term dermal and inhalation occupational exposures from handler and postapplication activities.

Hazard Characterization

The liver was the target organ across species and exposure duration. Treatment-related thyroid 

effects were also observed at dose levels causing adverse liver perturbations in rats and mice. 

Decreased body weight was a common clinical finding throughout the toxicology database. 

Liver tumors were observed in female rats and thyroid tumors were observed in male mice in 

chronic feeding studies. The Cancer Assessment Review Committee (CARC) classified 

fluopyram as “Not Likely to be Carcinogenic to Humans” at doses that do not induce cellular 

proliferation in the liver or thyroid glands. Fluopyram is not genotoxic or mutagenic.

HED recommends that the Food Quality Protection Act (FQPA) safety factor be reduced to 1x 

because there are no residual uncertainties with regard to pre- and postnatal susceptibility, the 

toxicology database is complete, and there is no evidence of neurotoxicity.
Fluopyram Human Health Risk Assessment DP No. D414231

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An acute dietary endpoint for the general population (including infants and children) was 

selected from the acute neurotoxicity study in rats based on decreased motor and locomotor 

activity (no observable adverse effect level (NOAEL) = 50 mg/kg). Because this effect was 

reversible within 48 hours and attributed to generalized systemic toxicity, fluopyram is not 

considered a neurotoxicant. The chronic dietary endpoint (NOAEL = 1.2 mg/kg/day) was based 

primarily on liver and thyroid effects in the chronic toxicity/carcinogenicity study in rats. Shortand intermediate-term dermal endpoints were chosen from a dermal toxicity study in rats in 

which liver effects were seen at the limit dose (NOAEL = 300 mg/kg/day). Short- and 

intermediate-term inhalation endpoints were selected from the multigeneration reproduction 

study in rats based on liver effects in the parental generation. Inhalation toxicity is assumed to 

be equivalent to oral toxicity.

Dietary Exposure (Food and Water)

The residue chemistry data and environmental fate data are adequate to assess human exposure. 

The acute and chronic dietary food exposure assessments are conservative and unrefined. The 

assessments are based on reliable data and will not underestimate exposure/risk.

Acute: The estimated acute dietary exposure to fluopyram from food and drinking water is 

below HED’s level of concern (<100%) for all population subgroups. Tolerance level residues, 

empirical or default processing factors, and 100% crop treated (CT) values were utilized in the 

exposure assessment. The acute estimated drinking water concentration (EDWC) was 

incorporated directly into the dietary assessment (87.5 μg/L) and was calculated by PRZM-GW 

modeling. Combined dietary exposure from food and drinking water at the 95th percentile of 

exposure utilized 1.8% of the acute population adjusted dose (aPAD) for the general US 

population, and 4.4% of the aPAD for children 1-2 years old, the population subgroup with the 

highest estimated acute dietary exposure to fluopyram. 

Chronic: The estimated chronic dietary exposure to fluopyram from food and drinking water is 

below HED’s level of concern (<100%) for all population subgroups. Average field trial 

residues, empirical or default processing factors, and 100% CT values were utilized in the 

exposure assessment. The chronic EDWC was incorporated directly into the dietary assessment 

(76.8 μg/L) and was calculated by PRZM-GW modeling. Chronic dietary exposure utilized 15% 

of the chronic population adjusted dose (cPAD) for the general US population, and 38% of the 

cPAD for the most highly exposed population subgroup (all infants (< 1 year old)). 

Residential Exposure

Based on the proposed labels, the products are not intended for use by homeowners, or by 

occupational handlers in residential settings. Additionally, there are no existing uses in 

residential settings. Therefore, non-occupational/residential risk assessments have not been 

completed.

Aggregate Risk

The aggregate acute and chronic risks are equivalent to the acute and chronic dietary risks and 

are not of concern.
Fluopyram Human Health Risk Assessment DP No. D414231

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Occupational Exposure/Risk

For the in-furrow uses on cotton and peanut, non-cancer risk estimates for dermal (baseline) and 

inhalation (no respirator) short- and intermediate-term occupational handler exposures all 

resulted in margins of exposure (MOEs) ≥100, and therefore, do not exceed HED’s level of 

concern (LOC), with MOEs ranging from 1,400 to 17,000 for dermal exposures and from 68,000 

to 300,000 for inhalation exposures. For the seed treatment uses on soybean and cotton seeds, 

non-cancer risk estimates for dermal and inhalation short- and intermediate-term occupational 

handler exposures all resulted in MOE ≥100, and therefore, do not exceed HED’s LOC, with 

MOEs ranging from 480 to 7,300 for dermal exposures and from 620 to 26,000 for inhalation 

exposures.

Short- and intermediate-term dermal post-application exposures and risks to occupational 

workers were estimated using standard values established by HED since no chemical-specific 

data were submitted. The occupational post-application non-cancer MOEs were not of concern 

(MOEs ≥100), with dermal MOEs ranging from 2,600 to 69,000.

Based on the Agency's current practices, a quantitative non-cancer occupational post-application 

inhalation exposure assessment was not performed for fluopyram at this time. 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 fluopyram.

Restricted Entry Interval (REI): The 12-hour REI that appears on the proposed labels would be 

adequate to protect for worker exposure.

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 studies (Appendix C) have been 

determined to require a review of their ethical conduct, and one of these studies is also subject to 

review by the Human Studies Review Board. All of the listed studies have received the 

appropriate review.

Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in this 

human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions 

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

http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf).

2.0 HED Recommendations

Pending submission of a revised Section B (see 2.3 Label Recommendations), a revised Section

F (see 2.2.3 Recommended Tolerances), and analytical reference standards (see requirements 

under Submittal of Analytical Reference Standards), there are no issues that would preclude 

granting Section 3 registration for the requested uses of fluopyram, or establishing tolerances for 

residues of fluopyram.
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2.1 Data Deficiencies

There are no data gaps that need to be fulfilled for the requested actions. However, an analytical 

reference standard for the AE C656948-benzamide metabolite must be submitted. The registrant 

is required to submit a reasonable amount of the analytical reference standard for the benzamide. 

The reference standard should be sent to the Analytical Chemistry Lab, which is located at Fort 

Meade, Maryland, to the attention of either Theresa Cole or Thuy Nguyen at the following 

address:

USEPA

National Pesticide Standards Repository/Analytical Chemistry Branch/OPP

701 Mapes Road

Fort George G. Meade, MD 20755-5350

(Note that the mail will be returned if the extended zip code is not used.)

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

The German multiresidue method DFG Method S 19, a gas chromatography with mass selective 

detection (GC/MSD) method, is the method for the enforcement of tolerances for fluopyram 

residues in/on crop commodities. The method was previously validated using samples of orange 

(fruit), oil seed rape (seeds), wheat (grain), lettuce (head) and dry peas (seeds). For fluopyram in 

these commodities, the limit of quantitation (LOQ) was 0.01 ppm, and the calculated limit of 

detection (LOD) was 0.003 ppm. The method was subjected to independent laboratory 

validation (ILV) using samples of cabbage (head), wheat (grain), orange (fruit) and oil seed rape 

(seed) fortified with fluopyram at 0.01 ppm and 0.10 ppm. The average recoveries were within 

acceptable limits (70-120%), and relative standard deviations (RSDs) were <20%.

A high performance liquid chromatography method with tandem mass spectrometry detection 

(HPLC/MS/MS), Method 01079, has been accepted for the enforcement of tolerances for 

residues of fluopyram and its metabolite, AE C656948-benzamide, in livestock commodities. 

The LOQ is 0.01 ppm and the calculated LOD is 0.003 ppm for each analyte in each matrix. The 

method was adequately validated using cattle milk, fat, muscle, liver, and kidney, and hen whole 

egg fortified with fluopyram and AE C656948-benzamide, each at 0.01 and 0.10 ppm. 

The method was subjected to ILV using samples of milk, eggs, beef muscle, and beef liver 

fortified with fluopyram and AE C656948-benzamide, each at 0.01 and 0.10 ppm (D387587, L. 

Cheng, 09/23/2011).

2.2.2 International Harmonization

The tolerance expressions are harmonized among the US, Canada, and Codex for all plant 

commodities. The tolerance definitions are harmonized between the US and Canada for 

livestock commodities, but the Codex definition contains two additional metabolites (See 

Appendix E). There are no Codex maximum residue limits (MRLs) established for soybean or 
Fluopyram Human Health Risk Assessment DP No. D414231

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cottonseed or cereal grain commodities. The Codex MRL for peanut is 0.03 mg/kg, and the US 

tolerance cannot be lowered from 0.09 ppm as this might lead to apparent misuse situations 

where the label directions were followed. The existing US tolerance and Canadian MRL for 

cereal grains and soybean seed are harmonized, but the new lower US recommendations will 

cause disharmonization. The US cottonseed tolerance and Canadian cottonseed MRL are 

harmonized, and Canada has no MRL for peanut.

The lowering of the tolerances for the cereal grains (group 15), cereal grains forages, stovers, and 

straws (group 16), soybean forage, and soybean hay, all as rotational crops, resulted in 

considerably less fluopyram in the livestock diets. The tolerances for the livestock commodities 

need to be lowered. Calculated values were adjusted slightly to affect harmonization with 

Canada for all livestock commodity tolerances/MRLs. The Codex MRLs are generally higher 

(5X-60X), because they are based on a different residue definition, do not reflect the North 

American Free Trade Association (NAFTA) plant commodity use patterns, and do not consider 

the Maximum Reasonably Based Diet (See Appendix E).

2.2.3 Recommended Tolerances

HED has reviewed the available residue data and has determined the appropriate tolerance levels 

for residues of fluopyram to be established in/on the following commodities as indicated in Table 

2.2.3. The recommended tolerance expression is as stated in 40 CFR §180.661 (a), (b), and (d), 

and this expression agrees with the S. Knizner Memo of 05/27/2009.

Table 2.2.3. Tolerance Summary for Fluopyram.

Commodity

Established

Tolerance 

(ppm)

Proposed 

Tolerance

(ppm)

HED

Recommended 

Tolerance (ppm)

Comments

(correct commodity definition)

40 CFR §180.661(a)

Soybean, seed 0.10 0.04 0.04 Revoke existing tolerance 

under 40 CFR §180.661 (d)

Cotton, seed 0.01 0.01 0.01

Cotton, undelinted seed

Revoke existing tolerance 

under 40 CFR §180.661 (d)

Cotton, Gin by-products 0.05 0.80 0.70

Cotton, gin byproducts

Revoke existing tolerance 

under 40 CFR §180.661 (d)

Peanuts 0.02 0.09 0.09 Peanut

40 CFR §180.661(b)

Cattle, fat 0.11 0.10 0.05

Cattle, meat 0.15 0.10 0.05

Cattle, meat byproducts 1.1 0.70 0.40

Egg 0.25 0.15 0.06

Hog, fat 0.05 0.05 0.02

Hog, meat 0.05 0.10 0.02

Hog, meat byproducts 0.70 0.70 0.03

Milk 0.07 0.10 0.06

Poultry, fat 0.20 0.10 0.03

Poultry, meat 0.15 0.10 0.03

Poultry, meat byproducts 0.60 0.20 0.10
Fluopyram Human Health Risk Assessment DP No. D414231

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Table 2.2.3. Tolerance Summary for Fluopyram.

Commodity

Established

Tolerance 

(ppm)

Proposed 

Tolerance

(ppm)

HED

Recommended 

Tolerance (ppm)

Comments

(correct commodity definition)

Goat, fat 0.11 - 0.05

Goat, meat 0.15 - 0.05

Goat, meat byproducts 1.1 - 0.40

Horse, fat 0.11 - 0.05

Horse, meat 0.15 - 0.05

Horse, meat byproducts 1.1 - 0.40

Sheep, fat 0.11 - 0.05

Sheep, meat 0.15 - 0.05

Sheep, meat byproducts 1.1 - 0.40

40 CFR §180.661(d) Indirect or inadvertent residues

Grain, cereal, except rice 

Group 15 1.5 0.03 0.03 Grain, cereal, except rice, group 15

Grain, cereal, forage, 

Group 16 4.0 1.5 None Only one tolerance may be established for Group 16.

Grain, cereal, fodder, 

hay and straw 7.0 2.0 2.0 Grain, cereal, forage, fodder and straw, group 16

Soybean, forage 4.0 - 0.80

Soybean, hay 15 - 3.0

Soybean, seed 0.10 - Revoke Replaced by tolerance under 40

CFR §180.661 (a) 

Cotton, gin byproducts 0.05 - Revoke Replaced by tolerance under 40

CFR §180.661 (a) 

Cotton, undelinted seed 0.01 - Revoke Replaced by tolerance under 40

CFR §180.661 (a) 

2.2.4 Revisions to Petitioned-For Tolerances

The petitioned-for tolerances differ from the recommended tolerances for cotton gin byproducts 

and for cereal grain forage group 16. The proposed tolerance is 0.80 ppm for cotton gin 

byproducts, but the Organization for Economic Cooperation and Development (OECD) 

statistical calculation applied to the field trial residue data provides a recommended value of 0.70 

ppm. Two tolerances were proposed for the cereal grain forage, stover, and straw group 16, 1.5 

ppm for forage and 2.0 ppm for hay, fodder, and straw. Only one tolerance is possible for the 

group, and that is the higher value, 2.0 ppm.

Revised tolerances must be proposed for soybean forage (0.8 ppm) and soybean hay (3.0 ppm) as 

rotational crops. Feeding restrictions were proposed for the use of fluopyram on soybeans 

(primary crop). Such restrictions cannot apply to soybeans as a rotational crop, and new soybean 

data for soybean as a rotational crop were supplied to support the recommended tolerances. The 

previous values were based on an adjustment to soybean data from use of fluopyram on soybean 

as a primary crop.

Numerous poultry and cattle commodity tolerances were proposed, all being a reduction in the 

existing tolerances. The proposed values were intended to harmonize with the European Union 

and/or Codex. Inspection of the Codex MRL values does not support this assertion, possibly 
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resulting from an adjustment of Codex MRLs in 2012. The recommended tolerances were 

determined from recalculation of the livestock dietary burdens and adjusted upwards to 

harmonize with Canada. Also, while cattle commodity tolerance revisions were proposed, 

related tolerance changes for goats, horses, and sheep were not requested. Tolerance revisions 

are also needed for hog commodities. The recommended changes (Table 2.2.3) should be 

proposed by the registrant in a revised Section F.

2.3 Label Recommendations

For soybean seed treatment the proposed label (Fluopyram ST; EPA Reg. No. 264-RRAT) lists a 

0.45 lb ai/acre/season use from all uses. However, there is only one use and one application 

allowed at a rate 0.22 lb ai/acre/year. Therefore, the 0.45 lb ai/acre/season should be deleted.

Crops not listed as primary crops of the fluopyram labels (Fluopyram ST (EPA Reg. No. 264-

RRAT), Luna® Privilege (EPA Reg. No. 264-1078), PropulseTM (264-1084), Luna® Tranquility 

(EPA Reg. No. 264-1085), Luna® Sensation (EPA Reg. No. 264-1090), and Luna® Experience 

(EPA Reg. No. 264-1091)) or in the Rotational Crops Restrictions on the labels may not be 

rotated after use of fluopyram. The limited rotational crops studies previously reviewed 

indicated residues at an 8 month plantback interval. In the absence of a study with a longer 

plantback interval and/or extensive rotational crop field trials, crops not listed may not be 

rotated. The Luna Privilege label (EPA Reg. No. 264-1078) and the Fluopyram ST label (EPA 

Reg. No. 264-RRAT) should state that crop rotation is possible as follows. Cotton, dried beans, 

peanut, potato, sugar beet, strawberry, and watermelon may be rotated immediately. Replant to 

canola after 30 days, and replant to alfalfa after 14 days. Soybean and cereal grains (except rice) 

may be planted with a 7 month plantback interval. Apple, cherry, grapes, and tree nuts are 

currently listed for immediate plantback, but rotational crop restrictions do not apply to these

permanent crops. Different restrictions may apply to the mixed active ingredient formulations.

3.0 Introduction

Fluopyram (AE C656948) is a fungicide with a broad spectrum of activity against numerous 

fungal diseases, including Ascomycetes, leaf spots, molds, scab, Alternaria, Septoria, Monlinia, 

Botrytis, Sclerotinia, and powdery mildews in a wide range of crops and plants. Fluopyram 

represents a new class of chemistry (pyridylethylamide) and its biochemical mode of action has 

been shown to rely on the inhibition of the enzyme succinate dehydrogenase (complex II) within 

the fungal mitochondrial respiratory chain, thus blocking electron transport. Fluopyram is a 

Group 7 fungicide. 
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3.1 Chemical Identity

Table 3.1. Fluopyram Nomenclature.

Chemical structure

Common name Fluopyram

Company experimental name AE C656948

IUPAC name N-[2-[3-chloro-5-(trifluoromethyl)-2-pyridyl]ethyl]-α,α,α-trifluoro-o-toluamide

CAS name N-[2-[3-chloro-5-(trifluoromethyl)-2-pyridinyl]ethyl]-2-

(trifluoromethyl)benzamide

CAS registry number 658066-35-4

End-use product (EP) 264-RRAT Fluopyram ST (5 lb/gal)

264-1078 Luna® Privilege (4.16 lb/gal)

Chemical structure of AE 

C656948-benzamide

metabolite (included in the 

tolerance expression for 

livestock commodities)

2-(Trifluoromethyl)-benzamide

3.2 Physical/Chemical Characteristics

Fluopyram is not a highly lipophilic molecule (log KOW = 3.3) and is not expected to pass the 

dermal barrier, pass through human milk, or bioaccumulate in significant quantity. Empirical 

dermal absorption data estimate that less than 2% is absorbed dermally in humans and 

metabolism data in rats demonstrate rapid absorption with ~98% elimination with 72 hours of 

administration. Fluopyram is persistent in soil (its half-life is 464 days) with very little abiotic 

degradation. Fluopyram, the major environmental residue and only compound modeled for 

drinking water exposure, is mobile, soluble, and stable in water. A summary of the physical and 

chemical properties of fluopyram are presented in Appendix B.

3.3 Pesticide Use Pattern

The registrant, Bayer CropScience, is requesting new uses of fluopyram, as follows: 1) As an atplanting soil/in-furrow treatment for cotton and peanut and as a post-emergent application to 

peanut by overhead chemigation on the Luna Privilege label (EPA Reg. No. 264-1078), a liquid 

formulation containing 41.5% ai (4.16 lb ai /gal); and 2) As a seed treatment to cotton and 

soybean on the new end-use product Fluopyram ST (EPA Reg. No. 264-RRAT), a liquid 

formulation containing 48.4% ai (5 lb ai/gal). 

CF3

N

H

O

N

Cl CF3

CF3

NH2

O
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The proposed Luna® Privilege label requires occupational handlers to wear the following 

personal protective equipment (PPE): long sleeved shirts, long pants, shoes, socks, and chemical 

resistant gloves. The proposed restricted entry interval (REI) is 12 hours. The proposed 

Fluopyram ST label requires occupational handlers to wear the following PPE: long-sleeved 

shirt, long pants, shoes plus socks, and waterproof gloves.

Additionally, new rotational crop data have been submitted to support a proposal for amended or 

lower inadvertent tolerances for the cereal grains (crop group 15) and the forage, fodder, and 

straw of cereal grains (crop group 16).

The uses and application rates are described in Table 3.3.1.

Table 3.3.1. Summary of Proposed Directions for Use of Fluopyram.

Application 

Timing, Type, 

and Equip.

Formulation

[EPA Reg. 

No.]

Application 

Rate 

(lb ai/A)

Max. No. 

Applic. 

per 

Season

Max. 

Seasonal 

Applic. Rate

(lb ai/A)

PHI

(days)

Use Directions and 

Limitations

Cotton

Seed treatment 

with commercial 

slurry mixture 

equipment only

Fluopyram ST

(5 lb ai/gal)

[264-RRAT]

0.003472a

lb ai/lb seed

0.35 mg ai/seed

(1.97 fl oz

per 100,000

cotton seeds)

1

0.45 (from 

all uses) NA

Do not use treated 

seed for food, feed, 

or oil purposes.

In-furrow during 

planting.

Luna Privilege

(4.16 lb ai/gal) 

[264-1078]

0.22

(6.84 fl oz/A) 1 NS NA

Direct application 

into the furrow and 

cover with soil.

Soybean

Seed treatment 

with commercial 

slurry mixture 

equipment

Fluopyram ST

(5 lb ai/gal) 

[264-RRAT]

0.001983a

lb ai/lb seed

0.25 mg ai/seed

(1.97 fl oz

per 140,000

soybean seeds)

1

0.45 (from 

all uses) NA

Do not use treated 

seed for food, feed, 

or oil purposes.

Do not graze or feed 

soybean forage and 

hay to livestock.

Peanut

In-furrow during 

planting or by 

chemigation 

post-emergent.

Luna Privilege

(4.16 lb ai/gal) 

[264-1078]

0.22

(6.84 fl oz/A) 1

0.45 (from 

all uses) NA

Direct application 

into the furrow and 

cover with soil. Do 

not graze or feed 

peanut forage and 

hay to livestock.

a Based on seed counts (4,500 cotton seeds maximum/lb and 3,600 soybean seeds maximum/lb) from BEAD memo: 

“Acres Planted Per Day and Seeding Rates of Crops Grown in the United States.”.

Bayer CropScience also requested proposed rotational crop restrictions for the following 

fluopyram product labels: Fluopyram ST (EPA Reg. No. 264-RRAT), Luna® Privilege (EPA 

Reg. No. 264-1078), PropulseTM (264-1084), Luna® Tranquility (EPA Reg. No. 264-1085), 

Luna® Sensation (EPA Reg. No. 264-1090), and Luna® Experience (EPA Reg. No. 264-1091). 

A summary of the proposed rotational crop restriction plantback intervals (PBIs) is presented in 

the residue chemistry summary document for this action (Funk, S., 05/12/2014, D420271). The 
Fluopyram Human Health Risk Assessment DP No. D414231

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labels are adequate to allow evaluation of the residue data relative to the proposed new uses. The 

rotational crop PBIs specified are acceptable, but a statement must be added to each label to 

clarify that crops not listed as primary crops on the labels or in the Rotational Crops Restrictions 

on the labels may not be rotated after use of fluopyram. Previously reviewed limited rotational 

crop data showed that quantifiable residues are found on food/feed commodities at the longest 

PBI reported, about 280 days. The proposed labels should state that crop rotation is prohibited 

except for the following crops: cotton, dried beans, peanut, potato, soybean, sugar beet, 

strawberry, watermelon, alfalfa, canola, cereal grains. This prohibition should be placed under 

“Rotational Crop Restrictions.” The plantback intervals for the listed crops are immediate for 

cotton, dried, beans, peanut, potato, sugar beet, strawberry, and watermelon; 14 days for alfalfa;

30 days for canola, and 7 months for soybeans and cereal grains (except rice). These intervals 

apply only to fluopyram.

3.4 Anticipated Exposure Pathways

The Registration Division has requested an assessment of human health risk to support the 

proposed new use of fluopyram as a soil/in-furrow treatment for cotton and peanut, and as a seed 

treatment to cotton and soybean. Humans may be exposed to fluopyram in food and drinking 

water, since fluopyram may be applied directly to growing crops and application may result in 

fluopyram reaching surface and ground water sources of drinking water. There are no residential 

uses of fluopyram, so exposure in residential or non-occupational settings is not likely. In an 

occupational setting, applicators may be exposed while handling the pesticide prior to 

application, as well as during application. There is a potential for post-application exposure for 

workers re-entering treated fields.

3.5 Consideration of Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in this 

human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions 

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

(http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf. As a part of every pesticide risk 

assessment, OPP considers a large variety of consumer subgroups according to well-established 

procedures. In line with OPP policy, HED estimates risks to population subgroups from 

pesticide exposures that are based on patterns of that subgroup’s food and water consumption, 

and activities in and around the home that involve pesticide use in a residential setting. 

Extensive data on food consumption patterns are compiled by the U.S. Department of 

Agriculture’s National Health and Nutrition Examination Survey, What We Eat in America, 

(NHANES/WWEIA) 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 and ethnic group. 

Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and 

exposure assessments are performed when conditions or circumstances warrant. Whenever 

appropriate, non-dietary exposures based on home use of pesticide products and associated risks 

for adult applicators and for toddlers, youths, and adults entering or playing on treated areas 

post-application are evaluated. Further considerations are currently in development as OPP has 

committed resources and expertise to the development of specialized software and models that 

consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary 
Fluopyram Human Health Risk Assessment DP No. D414231

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patterns among specific subgroups.

4.0 Hazard Characterization and Dose-Response Assessment

The last comprehensive risk assessment was completed in November, 2011 (Sheila Healy, 

11/23/2011, D385636). This assessment includes summaries of prior hazard characterization. 

However, the registrant submitted a series of new mechanistic studies to support the proposed 

mode of action (MOA) for tumor formation in female rats (liver tumor) and in male mice 

(thyroid tumor). The data from these studies were reviewed by the risk assessment team and 

analyzed by the Cancer Assessment Review Committee (CARC); the results are summarized in 

Section 4.3, Cancer Classification and Risk Assessment Recommendation.

4.1 Toxicological Effects

Liver effects and decreased body weight were the common and frequent findings in the 

subchronic and chronic oral toxicity studies in rats, mice, and dogs, and they appeared to be the 

most sensitive effects. Liver effects were characterized by increased liver weight, hepatocellular 

hypertrophy, hepatocellular vacuolation, increased mitosis and hepatocellular necrosis. 

Increased liver tumors were also observed in female rats in the carcinogenicity study. Liver 

effects in rodents were seen at lower dose levels (as low as 6 mg/kg) than those in the dogs. 

Thyroid effects were found at dose levels similar to those that produced liver effects in rats and 

mice; effects consisted of follicular cell hypertrophy, increased thyroid weight and hyperplasia. 

Changes in thyroid hormone levels (T3 & T4) and increased thyroid stimulating hormone (TSH)

were also seen in rats in a subchronic toxicity study. In male mice, there was an increased 

incidence of thyroid adenomas. In the genotoxicity battery, fluopyram was shown to have no 

genotoxic potential.

Fluopyram is not a developmental toxicant, nor did it adversely affect reproductive parameters. 

No evidence of qualitative or quantitative susceptibility was observed in these studies. 

In an acute neurotoxicity study, transient decreased motor activity was seen only on the day of 

treatment, but no other findings demonstrating neurotoxicity were found. In addition, no 

neurotoxicity was observed in the subchronic neurotoxicity study in the presence of other 

systemic adverse effects. Fluopyram did not produce treatment-related effects on the immune 

system.

With oral dosing, fluopyram was rapidly absorbed from the gastro-intestinal (GI) tract of male 

and female rats; the percentage absorbed was approximately 93% of the administered dose. The 

maximal plasma concentration was reached at 15 hours in males and 11 hours in females post 

dosing (5 mg/kg). The absorbed fluopyram was quickly distributed within the central 

compartments of the body (e.g. blood, liver, and kidney) and showed a distinctive preference 

towards the liver and to a smaller extent to the kidneys. The elimination results showed that 53-

65% of administered radioactivity was eliminated via feces and 32-41% was eliminated via the

urine. Less than 0.07-0.09% of the administered dose was expired. After 168 hrs post dosing 

91-99% of the administered radioactivity was eliminated via urine and feces. Residue analysis 

showed that the highest radioactivity level was found in the liver (0.4 to 1.0% of the 
Fluopyram Human Health Risk Assessment DP No. D414231

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administered radioactivity). Fluopyram was extensively metabolized and more than 29 

metabolites were identified. Three major groups of metabolites were formed in the liver

(fluopyram-7-OH-GA, 8-OH-GA and enol-glucuronic acid). Bioaccumulation was not observed.

Fluopyram plant metabolites, fluopyram-pyridyl-carboxylic acid and fluopyram methylsulfoxide, demonstrated less acute toxic potential than the parent compound. Mutagenicity tests

on these two metabolites were negative. 

A parallel approach was used to estimate the dermal absorption factor in human skin by using a 

proportional relationship: rat in vivo/rat in vitro = human in vivo/human in vitro. The dermal 

absorption values for human skin were calculated to be 0.2% for the neat formulation and 1.9% 

for the spray dilution.

4.2 Safety Factor for Infants and Children (FQPA Safety Factor)

The FQPA safety factor can be reduced to 1x because (1) the toxicology database is complete, 

(2) there is no evidence of neurotoxicity, (3) there is no evidence of increased susceptibility in 

the developing or young animals which were exposed during pre- or post-natal periods, and (4) 

there are no residual uncertainties in the exposure database.

4.2.1 Completeness of the Toxicology Database

The toxicology database for fluopyram is complete, and the available studies are adequate to 

characterize potential pre- and/or post-natal risks for infants and children, and includes 

acceptable developmental toxicity studies in the rat and rabbit, as well as acute and subchronic 

neurotoxicity studies. HED waived the required subchronic inhalation study based on a weight 

of evidence approach (TXR 0056523, 01/20/2013.)

4.2.2 Evidence of Neurotoxicity

The fluopyram toxicology database did not demonstrate evidence of neurotoxicity. Although 

transient decreases in motor and locomotor activities in the acute neurotoxicity study were seen 

on the day of treatment and limited use of hind-limbs and reduced motor activity was seen in the 

rat chronic/carcinogenicity study, there were no other associated neurobehavioral or 

histopathology changes found in other studies in the fluopyram toxicity database. The effects 

seen in the chronic/carcinogenicity study were in the presence of increased mortality and 

morbidity such as general pallor and emaciated appearance. Therefore, the reduced motor 

activity and limited use of hind-limbs seen in these two studies were judged to be the 

consequence of the systemic effects and not direct neurotoxicity.

4.2.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

The available developmental toxicity studies in rats and rabbits and the multi-generation 

reproduction in rats demonstrate no evidence of increased susceptibility in the developing or 

young animals which were exposed during pre- or post-natal periods.
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4.2.4 Residual Uncertainty in the Exposure Database

There are no residual uncertainties in the exposure database. The acute dietary exposure 

assessment was performed using conservative exposure inputs, including tolerance level residues 

for all crops, whereas the chronic dietary assessment included average field trial residue levels 

for all crops. Both acute and chronic dietary assessments assumed 100% crop treated and 

incorporated empirical or default processing factors. The dietary exposure assessment also 

assumed that all drinking water will contain fluopyram at the highest EDWC levels modeled by 

EFED for ground or surface water. Residential exposures are not expected. Therefore, it can be 

concluded that the dietary exposure analysis does not underestimate risk from acute and chronic 

dietary exposure to fluopyram.

4.3 Toxicity Endpoint and Point of Departure Selections

4.3.1 Dose-Response Assessment

For fluopyram, HED has selected the most sensitive and protective endpoints from the database 

to establish points of departure for the risk assessment (Table 4.5.4.1). For acute oral exposure, 

an acute neurotoxicity study in rats has been used to select the dose (50 mg/kg) and endpoint for 

establishing the aRfD (0.5 mg/kg/day) for the general population. The lowest observable 

adverse effect level (LOAEL) of 100 mg/kg is based on decreased motor and locomotor activity

in females, an effect attributable to general toxicity. For chronic dietary exposure, a combined 

chronic/carcinogenicity study in rats was used to select the dose (NOAEL=1.2 mg/kg/day) and 

endpoint for establishing the chronic reference dose (cRfD; 0.012 mg/kg/day). The toxicity 

endpoint was based on follicular cell hypertrophy in the thyroid and increased liver weight with 

liver gross pathological and histopathological findings at 6.0 mg/kg/day. The point of departure 

derived from this study is protective of the adverse thyroid effects observed in the mouse 

carcinogenicity study seen at 105 mg/kg/day. A 2-generation reproduction study in rats was 

used to select the dose (NOAEL = 14.5 mg/kg/day) and endpoint for short- and intermediateterm incidental oral exposure (though these endpoints are not necessary for this risk assessment 

since no residential uses are proposed). The LOAEL of 82.8 mg/kg/day was based on clinical 

pathology changes, increased liver weight, centrilobular hypertrophy in parents, and decreased 

body weight (-8.1%, p<0.05) and body weight gain (-8.6% p<0.05) with secondary decreases in 

spleen and thymus weights and secondary slight delay in preputial separation in offspring. This 

study was also chosen for short- and intermediate-term inhalation exposure scenarios, assuming 

inhalation and oral absorption equivalency (100%). A 28-day dermal toxicity study was used to 

select the point of departure (NOAEL = 300 mg/kg/day) and endpoint (liver toxicity) for shortand intermediate term dermal exposure.

4.3.2 Recommendation for Combining Routes of Exposures for Risk Assessment

Since the inhalation point of departure is based on an oral study, oral exposures can be combined 

with inhalation exposures. Common toxicological effects were not observed at the LOAELs of 

studies selected for the assessment of short- and intermediate-term exposures by the dermal and 

inhalation routes; liver toxicity was the dermal endpoint whereas the inhalation endpoint was 
Fluopyram Human Health Risk Assessment DP No. D414231

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based on clinical spleen and thymus effects accompanied by clinical pathology and body weight

changes. Therefore, it is not appropriate to combine these routes of exposure for risk assessment.

4.3.3 Cancer Classification and Risk Assessment Recommendation

The registrant, Bayer CropScience, submitted a new series of mechanistic studies. These studies 

have been reviewed and evaluated by the CARC. The CARC classified fluopyram as “Not 

Likely to be Carcinogenic to Humans” at doses that do not induce cellular proliferation in 

the liver or thyroid glands. This classification was based on convincing evidence that nongenotoxic modes of action for liver tumors in rats and thyroid tumors in mice have been 

established and that the carcinogenic effects have been demonstrated as a result of a mode of 

action dependent on activation of the CAR/PXR receptors (CARC Report, May 8, 2014).

The CARC has determined that quantification of risk is not required. There is sufficient data to 

ascertain the mode of action of fluopyram. The chronic Reference Dose (RfD) is derived using 

the NOAEL of 1.2 mg/kg/day as the “point of departure” which is below the dose of 11 

mg/kg/day that caused cell proliferation in the liver (i.e., a key event in tumor formation) and the 

subsequent liver tumors at a higher dose (89 mg/kg/day). Additionally, there is no concern for 

mutagenicity.

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

Assessment

Table 4.3.4.1. Summary of Toxicological Doses and Endpoints for Fluopyram 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= 

50

mg/kg/day

UFA= 10X

UFH=10X

FQPA SF=1X

Acute RfD = 

0.50

mg/kg/day

aPAD = 0.50

mg/kg/day

Acute Neurotoxicity Study in Rats. 

The LOAEL of 100 mg/kg in females is 

based on decreased motor and locomotor 

activity in females. The LOAEL in males 

was 125 mg/kg/day. 

Acute Dietary

(Females 13-

49 years of 

age)

An endpoint attributable to a single dose exposure has not been identified for this subpopulation.

Chronic 

Dietary (All 

Populations)

NOAEL= 

1.2

mg/kg/day

UFA= 10X

UFH=10X

FQPA SF=1X

Chronic RfD 

= 0.012

mg/kg/day

cPAD = 0.012

mg/kg/day

Combined Chronic/Carcinogenicity in 

Rats

The LOAEL of 6.0 mg/kg/day is based on 

follicular cell hypertrophy in the thyroid, 

and increased liver weight with gross 

pathological and histopathological 

findings.
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Table 4.3.4.1. Summary of Toxicological Doses and Endpoints for Fluopyram 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

Incidental Oral 

Short-Term 

(1-30 days)and 

IntermediateTerm (1-6 

months)

NOAEL= 

14.5

mg/kg/day

UFA= 10X

UFH=10X

FQPA SF=1X

Residential 

LOC for 

MOE = 100

Reproduction study in rats

The LOAEL of 82.8 mg/kg/day is based 

clinical pathology changes, decreased 

spleen and thymus weights, increased 

liver weight and centrilobular hypertrophy 

in parents, and decreased body weight and 

body weight gain with decreases in spleen 

and thymus weights and slight delay in 

preputial separation in offspring.

Dermal ShortTerm (1-30 

days) and 

IntermediateTerm (1-6 

months)

NOAEL= 

300

mg/kg/day

UFA= 10X

UFH=10X

FQPA SF=1X

Residential 

LOC for 

MOE = 100

A 28-day dermal study in rats

The LOAEL of 1000 mg/kg/day is based 

on increased cholesterol (F), increased 

prothrombin time (M), and increased liver 

weights (M, F) associated with 

hepatocellular hypertrophy.

Inhalation 

Short- Term 

(1-30 days)

and 

IntermediateTerm (1-6 

months)

NOAEL= 

14.5 

mg/kg/day

UFA= 10X

UFH=10X

FQPA SF=1X

Residential 

LOC for 

MOE = 100

Reproduction study in rats

The LOAEL of 82.8 mg/kg/day is based 

clinical pathology changes, decreased 

spleen and thymus weights, increased 

liver weight, and centrilobular 

hypertrophy in parents, and decreased 

body weight and body weight gain with 

decreases in spleen and thymus weights 

and slight delay in preputial separation in 

offspring.

Cancer (oral, 

dermal, 

inhalation)

The CARC has classified fluopyram as “Not Likely to be Carcinogenic to Humans” at doses that 

do not induce cellular proliferation in the liver or thyroid glands and determined that 

quantification of cancer risk is not required.

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). FQPA SF = FQPA Safety Factor. PAD = 

population adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level 

of concern. 

Table 4.3.4.2 Summary of Toxicological Doses and Endpoints for Fluopyram 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 ShortTerm (1-30 

days) and 

IntermediateTerm (1-6 

months)

NOAEL= 

300

mg/kg/day

UFA= 10X

UFH=10X

Occupational 

LOC for MOE = 

100

A 28-day dermal study in rats

The LOAEL of 1000 mg/kg/day is based 

on increased cholesterol (F), increased 

prothrombin time (M), and increased liver 

weights (M, F) associated with 

hepatocellular hypertrophy.
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Table 4.3.4.2 Summary of Toxicological Doses and Endpoints for Fluopyram 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 (1-

30 days) and 

Intermediateterm (1-6 

months)

NOAEL= 

14.5 

mg/kg/day

UFA=10X

UFH=10X

Occupational

LOC for MOE = 

100

A 2-generation reproduction study in rats. 

The LOAEL of 82.8 mg/kg/day is based 

clinical pathology changes, increased liver 

weight, and centrilobular hypertrophy in 

parents, and decreased body weight and 

body weight gain with secondary decreases 

in spleen and thymus weights and 

secondary slight delay in preputial 

separation in offspring.

Cancer (oral, 

dermal, 

inhalation)

The CARC has classified fluopyram as “Not Likely to be Carcinogenic to Humans” at doses that 

do not induce cellular proliferation in the liver or thyroid glands and has determined that 

quantification of cancer risk is not required.

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). MOE = margin of exposure. LOC = level of 

concern. N/A = not applicable.

5.0 Dietary Exposure and Risk Assessment 

5.1 Residues of Concern Summary and Rationale

The nature of the residue in plants is adequately understood based on metabolism studies with 

grape, potato, bean, and red pepper (D387587, L. Cheng, 02/23/2011) and with wheat seed 

treatment (D385636, S. Healy, 11/23/11). The nature of the residue in rotational crops is 

adequately understood based on confined rotational crop studies with rotated Swiss chard, turnip, 

and wheat. The metabolic pathway of fluopyram is similar in primary and rotational crops, and 

mainly involves hydroxylation of parent compound leading to AE C656948-7-hydroxy and AE 

C656948-8-hydroxy, conjugation of the hydroxylated parent compound, mainly with sugars, and 

cleavage of the molecule leading to AE C656948-benzamide, AE C656948-pyridyl-acetic acid 

(AE C656948-PAA), and AE C656948-pyridyl-carboxylic acid (AE C656948-PCA). HED has 

determined that the residue of concern in plant commodities (primary and rotational crop) for 

tolerance enforcement is fluopyram, and for risk assessment is fluopyram in all crops except in 

legumes and oilseed crops where AE C656948-benzamide is also included. 

The nature of the residue in livestock is adequately understood based on metabolism studies with 

goats and hens (D387587, L. Cheng, 02/23/2011). Metabolism of fluopyram in livestock mainly 

involves hydroxylation of the parent compound to AE C656948-7-hydroxy and AE C656948-8-

hydroxy, elimination of water from compounds hydroxylated in the ethylene bridge leading to 

AE C656948-Z/E-olefines, cleavage of the molecule leading to AE C656948-benzamide and AE 

C656948-PAA, and conjugation of the hydroxylated parent compound, mainly with glucuronic 

acid. For tolerance enforcement, HED has determined that the residues of concern are fluopyram 

and AE C656948-benzamide. For risk assessment, the residues of concern in ruminants are 
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fluopyram and its metabolites AE C656948-benzamide, AE C656948-E-olefine, AE C656948-Zolefine and AE C656948-7-hydroxy, and in hens are fluopyram and its metabolites AE C656948-

benzamide, AE C656948-E-olefine, and AE C656948-Z-olefine. 

A summary of metabolites and degradates to be included in the risk assessment and tolerance 

expressions is presented in Table 5.1.

Table 5.1. Summary of Metabolites and Degradates to be included in the Risk 

Assessment and Tolerance Expressions.

Matrix Risk Assessment Tolerance Expression

Plants

Primary 

Crop

Fluopyram

(Fluopyram + benzamide for legumes and oil seed crops) Fluopyram

Rotational 

Crop

Fluopyram

(Fluopyram + benzamide for legumes and oil seed crops) Fluopyram

Livestock

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

Z) Fluopyram + benzamide

Poultry Fluopyram + benzamide + olefins (E, Z) Fluopyram + benzamide

Drinking Water Fluopyram Not Applicable

5.2 Food Residue Profile

Adequate residue data are available to support dietary risk assessment as well as the proposed 

tolerances of the fungicide fluopyram in/on cotton, peanut, and soybean. Crop field trial studies 

were presented for cotton, peanut, and soybean. The soybean use is seed treatment, the cotton 

use is seed treatment and in-furrow at planting, and the peanut use is in-furrow at planting and 

foliar. In all cases the geographic distribution and number of trials meet the requirements of 

OCSPP 860.1500. In addition to determination of parent, the benzamide metabolite was 

determined in the soybean trials (oilseed) and peanut trials. Soybean hay and forage samples 

were not collected or analyzed. Finite residues were found on all commodities except cottonseed 

(seed treatment).

The trials reflect the proposed use patterns, although trials on crops with no proposed use 

patterns were also included. The number of trials and geographic distribution are adequate, and 

the intervals of frozen storage of samples from the trials are supported by adequate storage 

stability studies. The analytical data collection method was adequate and determined parent and 

benzamide.

For cottonseed, seed treatment and seed treatment plus in-furrow at-planting treatment yielded 

no residues (<0.01 ppm) on harvested cottonseed. Foliar application (no proposed use) yielded 

residues as high as 0.46 ppm. Benzamide was not found (<0.01 ppm) in any situation for 

cottonseed.

For peanut, in-furrow at-planting plus foliar treatment yielded quantifiable residues (Highest 
Fluopyram Human Health Risk Assessment DP No. D414231

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Average Field Trial (HAFT)) for both parent (0.06 ppm) and benzamide (0.01 ppm) on peanut 

nutmeats. This application pattern produced slightly higher residues (HAFT) than the proposed 

foliar only application. 

For the foliar application to peanuts (2 X 0.22 lb ai/acre, n = 3), extensive field trials had been 

reviewed previously and used to support the existing tolerance. Results of the current field trial 

studies agree with the previous results.

For soybean, seed plus foliar treatment (no proposed use) yielded residues about 3X greater than 

seed treatment only use. For the latter, no benzamide was found (<0.01 ppm).

Table 5.2.1. Summary of Residues from Field Trials with Fluopyram.

1

Crop 

Matrix Analyte

Applic. 

Rate

(lb 

ai/acre)

PHI 

(days) n

*

Residues (ppm)

Min.2 Max.2 LAFT3 HAFT3 Median3 Mean3 SD3

Cotton. Proposed Use = 0.062 lb ai/acre as seed treatment

Cottonseed,

undelinted

Fluopyram 0.060-

0.066

136-

206 11 <0.01 <0.01 <0.01 <0.01 <0.01 <0.01 -

Benzamide <0.01 <0.01 <0.01 <0.01 <0.01 <0.01 -

Cotton gin 

byproducts

Fluopyram 0.060-

0.066

136-

206 6

<0.01 0.469 <0.01 0.354 0.0122 0.0703 0.339

Benzamide <0.01 <0.01 <0.01 <0.01 <0.01 <0.01 -

Cotton. Proposed Use = 0.062 lb ai/acre as seed treatment + 0.22 lb ai/acre in-furrow at planting

Cottonseed,

undelinted

Fluopyram 0.29-

0.30

136-

206 11 <0.01 <0.01 <0.01 <0.01 <0.01 <0.01 -

Benzamide <0.01 <0.01 <0.01 <0.01 <0.01 <0.01 -

Cotton gin 

byproducts

Fluopyram 0.29-

0.30

136-

206 6

<0.01 0.0885 <0.01 0.0810 0.0149 0.0313 0.030

Benzamide <0.01 <0.01 <0.01 <0.01 <0.01 0.01 --

Peanut. Proposed Use = 0.22 lb ai/acre in-furrow at planting + 0.22 lb ai/acre foliar

Peanut Fluopyram

0.42-

0.52 6-10 12

<0.01 0.0632 <0.01 0.0617 0.01 0.0179 0.0172

Benzamide <0.01 0.0132 <0.01 0.0130 0.01 0.0103 0.0009

Peanut hay Fluopyram 1.578 24.808 1.697 23.250 9.873 11.206 7.139

Benzamide 0.0316 0.155 0.0414 0.148 0.0792 0.0886 0.0345

Peanut. Proposed Use = 2 X 0.22 lb ai/acre foliar

Peanut Fluopyram

0.42-

0.52 7 3

<0.01 <0.01

[0.018]4 <0.01 <0.01[0.017]

<0.01

[<0.01]

<0.01

[0.011] N/A

Benzamide <0.01 <0.01 <0.01 <0.01 <0.01 <0.01 N/A

Peanut hay Fluopyram 3.868 23.835

[21.88]4 4.052 18.100[20.66]

10.135

[6.19]

10.762

[8.72] 7.045

Benzamide 0.0652 0.237 0.0785 0.230 0.183 0.164 0.0775

Peanut. Proposed Use = 0.22 lb ai/acre in-furrow at planting + 0.22 lb ai/acre overhead foliar chemigation 

[No match to proposed PHI] 

Peanut Fluopyram

0.42-

0.52 28-30 3

<0.01 0.0168 <0.01 0.0155 0.0130 0.0128 0.0028

Benzamide <0.01 <0.01 <0.01 <0.01 0.01 0.01 N/A

Peanut hay Fluopyram 0.576 2.316 0.782 1.953 1.508 1.414 0.591

Benzamide <0.01 0.0246 <0.0104 0.0242 0.0231 0.0192 0.0077

Soybean. Proposed Use = 0.22 lb ai/acre (0.25 mg ai/seed) as seed treatment

Soybean, 

dry seed

Fluopyram 0.06-

0.14

110-

152 21 <0.01 0.0322 <0.01 0.0271 0.01 0.0137 0.0059

Benzamide <0.01 <0.01 <0.01 <0.01 0.01 0.01 N/A

Soybean. Use = 0.13 lb ai/acre (0.15 mg ai/seed) as seed treatment

Soybean, 

dry seed

Fluopyram 0.03-

0.09

82-

152 21 <0.01 0.0217 <0.01 0.0201 0.01 0.0111 0.0026

Benzamide <0.01 <0.01 <0.01 <0.01 0.01 0.01 N/A

1 Benzamide reported as parent equivalents. 
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2 Values based on total number of samples.

3 Values based on per-trial averages. LAFT = Lowest Average Field Trial, HAFT = Highest Average Field Trial, SD = Standard 

Deviation. For computation of the LAFT, HAFT, median, mean, and standard deviation, values < LOQ are assumed to be at the 

LOQ.

4 Results from previous field trials.

Processed Food and Feed

The processing data indicate that residues of fluopyram did not concentrate (processing factor 

<1x) in cotton meal, cotton hulls, and cotton refined oil. Residues of benzamide may concentrate 

slightly in cotton hulls (average processing factor >1.4x), but did not concentrate (processing 

factor <1x) in cotton meal and refined oil. 

The observed processing factors are less than the theoretical concentration factor of 3.8x for 

cotton hulls, 2.2x for cotton meal, 6.3x for cotton refined oil, 2.2x for peanut meal, and 2.8x for 

peanut oil (cited in Table 3 of the EPA Residue Chemistry Test Guideline OCSPP 860.1520).

A processing study for peanuts was reviewed previously and found acceptable (D387587, L. 

Cheng, 09/23/2011). The processing factors were 0.2 for each of meal and refined oil. 

Dietary Burden

Dietary burdens were previously calculated for livestock (D387587, L. Cheng, 09/23/2011): beef 

cattle, 1.90 ppm; dairy cattle, 3.39 ppm; poultry, 1.24 ppm; swine, 1.33 ppm. In estimating the 

livestock dietary burdens, residue values in alfalfa hay and meal were based on the extensive 

field rotational crop data, and almond hulls and sugar beet molasses were based on the foliar 

(primary) crop data. Since the proposed label permits limited crop rotation to canola, cereal 

grains, corn, and soybean with which there are feed items, and since extensive field rotational 

crop data were not available, the residue values used for canola meal, field/sweet corn 

forage/silage, sorghum, and wheat milled byproducts were based on half of the primary crop 

values (see ChemSAC minutes, 6/29/2011). Rotational crop studies are now available for cereal 

grains and soybeans. Additionally, there are feed items associated with the new uses on peanuts 

and soybeans. Therefore, the livestock dietary burdens have been recalculated. The secondary 

residue levels in livestock were estimated using point estimates of tissue:feed ratio (transfer 

factor).

The calculated dietary burdens based on the Maximum Reasonable Balanced Diet are suitable 

for tolerance-setting purposes. The feeding levels encompassed the calculated burdens, and the 

analytical method determined all components of the regulated residue. Expected residue levels 

and tolerances are indicated in Table 5.2.2. These values have been adjusted upward in some 

cases for purposes of harmonization with Canada.

Table 5.2.2. Estimation of Secondary Residues and Livestock Tolerances from Use of Fluopyram.

Commodity Expected Residue Total 

(ppm)

Tolerance

(ppm)

Milk 0.02 0.06

Muscle/Meat (cattle1) 0.03 0.05

Fat (cattle1) 0.02 0.05

Meat By-Products (cattle1) 0.22 (liver), 0.03 (kidney) 0.40
Fluopyram Human Health Risk Assessment DP No. D414231

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Table 5.2.2. Estimation of Secondary Residues and Livestock Tolerances from Use of Fluopyram.

Commodity Expected Residue Total 

(ppm)

Tolerance

(ppm)

Meat (hog) 0.02 0.02

Fat (hog) 0.02 0.02

Meat By-Product (hog) 0.02 0.03

Eggs 0.025 0.06

Muscle/Meat (poultry) 0.02 0.03

Fat (poultry) 0.02 0.03

Meat By-Products (poultry) 0.043 0.10

1Also applies to horse, sheep, and goat.

Field Rotational Crops

Bayer CropScience submitted the results of extended field rotational crop studies on field corn 

and sweet corn, wheat, and sorghum as representative commodities of cereal grain group 15 and 

cereal grain forage, fodder, and straw group 16. Bayer CropScience also submitted the results of 

an extended field rotational crop study on soybean forage, hay and seed.

The rotational crop trials with corn, wheat, and sorghum are adequate to evaluate the proposed 

PBI of 7 months for the cereal grains (except rice). The rotational crop studies conducted with 

soybean show that fluopyram residues on soybean seed from a 210 day PBI are 0.012 ppm 

(HAFT) and less than residues from seed treatment primary use (0.03 ppm HAFT). However, a 

rotational PBI of 7 months will be needed for soybeans from uses other than seed treatment of 

soybean to encompass the residues on forage and hay. While these may be restricted for the 

primary crop soybeans, such a restriction is not possible for soybeans as a rotational crop, and no 

data were provided for forage and hay from the primary crop use (seed treatment).

5.3 Water Residue Profile

The drinking water residues used in the dietary risk assessment were provided by the EFED 

(D414489, M. A. Ruhman, 04/16/2014). EFED estimated surface water and ground water 

residues for fluopyram using the Pesticide Root Zone Model- Exposure Analysis Modeling 

System (PRZM/EXAMS) model and the PRZM-GW model, respectively. PRZM-GW was run 

for new and currently registered uses. PRZM/EXAMS was run for the new crops of cotton, 

soybeans, and peanuts. The drinking water models and their descriptions are available at the 

EPA internet site: http://www.epa.gov/oppefed1/models/water/. 

For surface water EDWCs, the peak value of 19.42 μg/L for the new use on cotton is higher than 

the FL cucumber value of 12.97 ppb previously determined (D353319, 07/08/2011) and 

therefore it replaces the peak value assigned for fluopyram. The new chronic values are lower;

therefore, the value is unchanged at 4.90 ppb for chronic concentration (1-in-10 year mean).

For ground water, the highest acute ground water EDWC is 87.5 ppb of parent fluopyram and 

the chronic value is 76.8 ppb of parent fluopyram. These values are much higher than the 

SCIGROW derived acute/chronic value of 0.319 ppb previously determined. Ground water 

EDWCs are used in the dietary assessment, since they were higher than those for surface water. 
Fluopyram Human Health Risk Assessment DP No. D414231

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For the human health risk assessment, the highest relevant EDWCs are recommended. 

Table 5.3. Estimated Surface and Ground Water Concentrations for Fluopyram.

Scenario Surface Water Conc., ppb Ground Water Conc., ppb

Acute 19.4 87.5a

Chronic (non-cancer) 4.90 76.8a

Chronic (cancer) 3.487 NA

a Bold values were used in the dietary assessment.

5.4 Dietary Risk Assessment

5.4.1 Description of Residue Data Used in Dietary Assessment

The acute dietary analysis was unrefined conservative dietary assessment that included tolerance 

residue levels, the assumption of 100% crop treated, and processing factors (empirical and 

default). The EDWC was incorporated directly into the dietary assessment (ground water 

EDWC of 87.5 μg/L) and was calculated by PRZM-GW modeling.

The chronic dietary analysis was unrefined conservative dietary assessment that included 

average residue levels, the assumption of 100% crop treated, and processing factors (empirical 

and default). The EDWC from PRZM-GW modeling was incorporated directly into the dietary 

assessment (ground water EDWC of 76.8 μg/L).

5.4.2 Percent Crop Treated Used in Dietary Assessment

The acute and chronic dietary exposure analysis assumed that 100% of the proposed crops were 

treated with fluopyram.

5.4.3 Acute Dietary Risk Assessment

Estimated acute dietary exposure to fluopyram from food and drinking water for all population 

subgroups is below 100% of the acute Population Adjusted Dose (aPAD). Combined dietary 

exposure from food and drinking water at the 95th percentile of exposure is estimated to be 

0.0091mg/kg/day for the overall U.S. population, equivalent to 1.8% of the aPAD. The 

population subgroup with the highest estimated acute dietary exposure to fluopyram is children 

1-2 years old, with an estimated exposure at the 95th percentile of 0.022 mg/kg/day, equivalent to 

4.4% of the aPAD. HED is concerned when estimated dietary risk exceeds 100% of the aPAD

(see Table 5.4.6).

5.4.4 Chronic Dietary Risk Assessment

Estimated chronic dietary exposure from food and drinking for all population subgroups is below 

100% of the chronic Population Adjusted Dose (cPAD). Combined dietary exposure from food 

and drinking water is estimated to be 0.0018 mg/kg/day for the general U.S. population, 
Fluopyram Human Health Risk Assessment DP No. D414231

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equivalent to 15% of the cPAD. The population subgroup with the highest estimated chronic 

dietary exposure to fluopyram is all infants, with an estimated exposure of 0.0045 mg/kg/day, 

equivalent to 38% of the cPAD. HED is concerned when estimated dietary risk exceeds 100% of 

the cPAD (see Table 5.4.6). 

5.4.5 Cancer Dietary Risk Assessment

The CARC classified fluopyram as “Not Likely to be Carcinogenic to Humans”. Therefore, a 

cancer dietary exposure analysis is not required.

5.4.6 Summary Table

Table 5.4.6. Summary of Dietary (Food & Drinking Water) Exposure and Risk for Fluopyram.

Population Subgroup

Acute Dietary

(95th Percentile) Chronic Dietary

Dietary Exposure 

(mg/kg/day) % aPAD* Dietary Exposure

(mg/kg/day)

% cPAD*

General US Population 0.009109 1.8 0.01851 15

All Infants (< 1 year old) 0.021149 4.2 0.004540 38

Children 1-2 years old 0.022081 4.4 0.003419 29

Children 3-5 years old 0.015110 3.0 0.002664 22

Children 6-12 years old 0.009693 1.9 0.001778 15

Youth 13-19 years old 0.006369 1.3 0.001350 11

Adults 20-49 years old 0.007177 1.4 0.001776 15

Adults 50+ years old 0.006934 1.4 0.001762 15

Females 13-49 years old 0.007385 1.5 0.001777 15

*The population subgroup with the highest estimated acute and chronic dietary (food + drinking water) exposure and risk is 

indicated by bold text.

6.0 Residential (Non-Occupational) Exposure/Risk Characterization

6.1 Residential Handler Exposure

Based on proposed and currently registered product labels, fluopyram is not intended for use by 

homeowners, or by occupational handlers in residential settings. Therefore, nonoccupational/residential risk assessments have not been conducted.

6.2 Residential Bystander Post-application Inhalation Exposure

Volatilization of pesticides may be a source of post-application inhalation exposure to 
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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 (http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). The 

agency has evaluated the SAP report and has developed a Volatilization Screening Tool and a 

subsequent Volatilization Screening Analysis 

(http://www.regulations.gov/#!docketDetail;D=EPA-HQ-OPP-2014-0219). During Registration 

Review, the agency will utilize this analysis to determine if data (i.e., flux studies, route-specific 

inhalation toxicological studies) or further analysis is required for fluopyram.

6.3 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 airblast and groundboom application methods additionally 

employed for fluopyram. The Agency has been working with the Spray Drift Task Force, EPA 

Regional Offices, and State Lead Agencies for pesticide regulation and other parties to develop 

the best spray drift management practices. 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 

and risks associated with aerial as well as other application types where appropriate.

7.0 Aggregate Exposure/Risk Characterization

In accordance with the FQPA, HED must consider and aggregate (add) pesticide exposures and 

risks from three major sources: food, drinking water, and residential exposures. In an aggregate 

assessment, exposures from relevant sources are added together and compared to 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. There is potential acute and chronic exposure via the diet (food and 

drinking water). Refer to Section 5.4. There are no proposed or existing residential uses so 

short- or intermediate-term residential exposures are not likely to occur. Therefore, neither 

short- nor intermediate-term aggregate risks were assessed. 

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 as 

to fluopyram and any other substances and fluopyram does not appear to produce a toxic 

metabolite produced by other substances. For the purposes of this tolerance action, therefore, 

EPA has not assumed that fluopyram has a common mechanism of toxicity with other 

substances. For information regarding EPA’s efforts to determine which chemicals have a 
Fluopyram Human Health Risk Assessment DP No. D414231

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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

9.1 Short-/Intermediate-Term Handler Risk

Fluopyram is proposed to be applied as an at-planting soil/in-furrow treatment for cotton and 

peanut, and as a seed treatment to cotton and soybean. The at-planting soil/in-furrow treatment 

for cotton and peanut is an amendment to the Luna® Privilege label (EPA Reg. No. 264-1078). 

Additionally, post-emergent application to peanut by overhead chemigation is proposed on the 

Luna® Privilege label. The proposed Luna® Privilege label requires occupational handlers to 

wear the following personal PPE: long sleeved shirts, long pants, shoes, socks, and chemical 

resistant gloves. The proposed REI is 12 hours.

The seed treatment to cotton and soybean is on the new end-use product Fluopyram ST (EPA 

Reg. No. 264-RRAT). The proposed Fluopyram ST label requires occupational handlers to wear 

the following PPE: long-sleeved shirt, long pants, shoes plus socks, and waterproof gloves.

Both in-furrow and seed treatment applications are restricted as single applications; however, 

handler exposure is expected to be short- or intermediate-term in duration.

For the in-furrow use on cotton and peanut, and the post-emergent chemigation use on peanuts

the quantitative dermal and inhalation exposure/risk assessment developed for occupational 

handlers is based on the following scenarios: 1) Mixing/loading liquids for chemigation, 2) 

Mixing/loading liquids for groundboom application, and 3) Applying sprays via groundboom 

equipment. The dermal and inhalation short- and intermediate-term occupational handler 

exposures all resulted in MOE ≥100, and therefore, do not exceed HED’s level of concern, with 

MOEs ranging from 1,400 to 17,000 for dermal exposure at baseline, 8,200 to 84,000 for dermal 

exposures with gloves, and from 68,000 to 300,000 for inhalation exposures. Refer to Appendix 

D, Table D.1.

For seed treatment use on cotton & soybean seeds, the quantitative exposure/risk assessment 

developed for occupational handlers is based on the following scenarios: 1) Mixing/loading 

liquids for commercial seed treatment; 2) Bagging treated seed; 3) Sewing bags; 4) Multiple 

activities; and 5) Planting treated seed. Risk estimates for dermal and inhalation short-term 

occupational handler exposures all resulted in MOE ≥100, and therefore, do not exceed HED’s 

level of concern, with MOEs ranging from 480 to 7,300 for dermal exposures and from 620 to 

26,000 for inhalation exposures. Refer to Appendix D, Table D.2. 
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9.2 Short-/Intermediate-Term Post-Application Risk

9.2.1 Dermal Post-application Risk

For the in-furrow use on cotton and peanut and the post-emergent chemigation use on peanuts

the quantitative dermal post-application exposure/risk assessment developed for workers is based 

on the scenarios of hand weeding and scouting for cotton and peanut, and the scenario of hand 

set irrigation for peanut.

Short- and intermediate-term dermal post-application exposures and risks to occupational 

workers were estimated using standard values established by HED since no chemical-specific 

data were submitted. The transfer coefficients (TC) used for all post-application activities were 

the TCs established by the Science Advisory Council for Exposure Policy Number 3.1

(http://www.epa.gov/pesticides/science/exposac_policy3.pdf). This policy reflects adoption of 

all Agricultural Re-Entry Task Force (ARTF) data. Use of the data in this policy requires 

compensation to the ARTF under FIFRA. The transfer coefficients (TCs) used in this 

assessment were taken from the Agency’s revised Agricultural Transfer Coefficient SOP. Many 

of the TCs in this SOP are based on work of the ARTF. The dislodgeable foliar residue (DFR) 

levels for agricultural crops were estimated using HED standard values where it is assumed that 

the initial residue on treated foliage is 25% of the application rate and the residues degrade at a 

rate of 10% per day. The occupational post-application non-cancer MOEs do not exceed HED’s 

level of concern (MOEs ≥100), with dermal MOEs ranging from 2,600 to 69,000. Refer to 

Appendix D, Table D.3.

Dislodgeable Foliar Residue (DFR): A DFR study is not required for fluopyram at this time. 

In accordance with 40 CFR158, DFR data are required for all occupational (e.g., crop, nursery, 

greenhouse use sites) or residential (e.g., ornamental and vegetable gardens, pick your own 

farms, retail tree farms) uses that could result in post-application exposure to foliage. In the

absence of chemical-specific DFR data, EPA uses default values. The 2012 Standard Operating 

Procedures for Residential Pesticide Exposure Assessment includes an analysis of a number of 

DFR studies, which resulted in the selection of a revised default values for the fraction of the 

application rate available for transfer after a foliar application (FAR). These values are based on 

an analysis of 19 DFR studies. Since that time, the Agricultural Re-entry Task Force has 

submitted information (MRID 49299201) that corrects an application rate error made in the 

original submission of “ARF039 – Determination of Dermal and Inhalation Exposure to Reentry 

Workers During Chrysanthemum Pinching in a Greenhouse” (EPA MRID 45344501). As a 

result, the range of FAR values was revised from 2% - 89% to 2% - 47%. In the data, a large 

range of transferability is observed and this variability can potentially be attributable to many 

factors such as active ingredient; formulation; field conditions in the studies; weather conditions 

(e.g., humidity); or many other difficult to quantify factors. Although witnessed across multiple 

chemicals, this range in FAR values is not expected when considering DFR data for a single 

chemical. At this time, the ARTF submission did not alter the selection of 25% as the 

reasonable, high-end default value. Because DFR data are not available for fluopyram, EPA is 

using the default value of 25%. Although there may be a small degree of uncertainty in the use 

of the default DFR value for fluopyram (i.e., there is a small chance that the FAR value may 
Fluopyram Human Health Risk Assessment DP No. D414231

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exceed the applicable default value), it is likely that the health-protective aspects of EPA’s 

occupational post-application assessment methodology will more than compensate for this 

potential uncertainty. For example, when assessing residential and occupational postapplication exposure to gardens and ornamentals, EPA assumes the following: exposures occur 

to zero-day (i.e., day of application ) residues every day of the assessed exposure duration (i.e., 

EPA assumes that no dissipation or degradation occurs, it doesn’t rain, etc); individuals perform 

the same post-application activities performed in the transfer coefficient study day after day (e.g., 

weeding, harvesting, pruning, etc.); and individuals engage in these post-application activities for 

a high-end amount of time every day (represented by data reflecting time spent gardening based 

on survey data).

Given the conservatisms discussed above and the potential compounding nature of these 

conservatisms, EPA is able to rely upon the calculated exposure estimates with confidence that 

exposure is not being underestimated. 

Since the highest estimated occupational post-application exposure using default DFR values for 

fluopyram is minimal in comparison to the level of concern (i.e., the calculated MOE is greater 

than 2 times higher than the level of concern, MOE = 2,600 compared to the LOC of 100); EPA 

is waiving the 40 CFR DFR data requirement. In this instance, it is unlikely that chemicalspecific DFR data would be needed to further refine exposure assessments or would add 

appreciably to our overall understanding of the availability of dislodgeable foliar pesticide 

residues for fluopyram. 

Restricted Entry Interval: Since postapplication risks were not a concern on day 0 (12 hours 

following application), the REI is based on the acute toxicity of fluopyram technical material. 

Fluopyram is classified as Toxicity Category III by the acute oral and dermal routes of exposure

and Toxicity Category IV for acute inhalation, eye irritation potential and skin irritation 

potential. Under the WPS for Agricultural Pesticides, active ingredients classified as acute 

toxicity categories III or IV for these routes are assigned a 12-hour REI. Therefore, the 12-hour 

REI that appears on the proposed labels is adequate.

9.2.2 Inhalation Post-application Risk

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 has 

evaluated the SAP report and has developed a Volatilization Screening Tool and a subsequent 

Volatilization Screening Analysis (http://www.regulations.gov/#!docketDetail;D=EPA-HQOPP-2014-0219). During Registration Review, the agency will utilize this analysis to determine 

if data (i.e., flux studies, route-specific inhalation toxicological studies) or further analysis is 

required for fluopyram].
Fluopyram Human Health Risk Assessment DP No. D414231

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In addition, the Agency is continuing to evaluate the available post-application inhalation 

exposure data generated by the Agricultural Reentry Task Force. Given these two efforts, the 

Agency will continue to identify the need for and, subsequently, the way to incorporate 

occupational post-application inhalation exposure into the agency's risk assessments.

Although a quantitative occupational postapplication inhalation exposure assessment was not 

performed, an inhalation exposure assessment was performed for occupational/commercial 

handlers. Handler exposure resulting from application of pesticides outdoors is likely to result in 

higher exposure than postapplication exposure. Therefore, it is expected that these handler 

inhalation exposure estimates would be protective of most occupational postapplication 

inhalation exposure scenarios.”

10.0 References

O’ Keefe, B., 05/30/2014, D419530. Fluopyram: Occupational and Residential Exposure 

Assessment for New Use as a Soil/In-Furrow Treatment for Cotton and Peanut, and as a Seed 

Treatment to Cotton and Soybean.

Cheng, L., 09/23/2011, D387587 and D389081. Fluopyram. Application for Section 3 

Registration for Use on Apple, Banana (Import only), Dried Beans, Cherry, Grape (Wine 

Production only), Peanut, Pistachio, Potato, Sugar Beet, Strawberry, Tree Nuts Crop Group 14, 

Watermelon, and Rotational Crops Alfalfa, Canola, Cotton, Cereal Grains Crop (Except Rice) 

Group 15, and Forage, Fodder, and Straw of Cereal Grains Crop (Except Rice) Group 16. 

Summary of Analytical Chemistry and Residue Data.

Funk, S., 05/12/2014, D420271. Fluopyram. Petition for the Establishment of Permanent 

Tolerances and Registration for Use on Peanut, Cotton, and Soybean. Amended Tolerance 

Requests for Soybeans and Cereal Grains as Rotational Crops. Summary of Analytical 

Chemistry and Residue Data.

Funk, S., 05/14/2014, D420272.drs. Fluopyram. Acute and Chronic Aggregate Dietary 

Exposure and Risk Assessments for Section 3 Registration for New or Amended Use on Peanut, 

Cotton, Soybean, Cereal Grains (except Rice).

Ruhman, M. A., 05/19/2014. Estimated Drinking Water Concentrations of Fluopyram New Uses 

on Cotton (in-furrow and seed treatment), Soybeans (seed treatment) and Peanuts (in-furrow 

and foliar applications) for the Use in Human Health Risk Assessment.

Scollon, E., 7/16/2009, D367115. Fluopyram. Report of the Residues of Concern 

Knowledgebase Subcommittee (ROCKS).

Rowland, J., 05/08/2014, TXR0056961. Fluopyram: Report of the Cancer Assessment Review 

Committee.
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Rury, K., 01/30/2013, TXR 0056523. Fluopyram: Summary of Hazard and Science Policy 

Council (HASPOC) Meeting of November 29, 2012: Recommendations on the Waiver Request 

for the Subchronic Inhalation Study Data Requirement.

Appendix A. Toxicology Profile

A.1 Toxicology Data Requirements

The requirements (40 CFR 158.500) for food use for fluopyram are in Table A.1. Use of the new 

guideline numbers does not imply that the new (1998) guideline protocols were used.

Table A.1. Toxicology Data Requirements.

Study

Technical

Required Satisfied

870.1100 Acute Oral Toxicity.......................................................

870.1200 Acute Dermal Toxicity ..................................................

870.1300 Acute Inhalation Toxicity..............................................

870.2400 Primary Eye Irritation....................................................

870.2500 Primary Dermal Irritation ..............................................

870.2600 Dermal Sensitization......................................................

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

870.3100 Oral Subchronic (rodent)...............................................

870.3150 Oral Subchronic (nonrodent) .........................................

870.3200 21-Day Dermal ..............................................................

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

870.3465 90-Day Inhalation..........................................................

yes

yes

yes

no

yes

yes

yes

yes

-

Waiveda

870.3700a Developmental Toxicity (rodent)...................................

870.3700b Developmental Toxicity (nonrodent).............................

870.3800 Reproduction .................................................................

yes

yes

yes

yes

yes

yes

870.4100a Chronic Toxicity (rodent) ..............................................

870.4100b Chronic Toxicity (nonrodent)........................................

870.4200a Oncogenicity (rat)..........................................................

870.4200b Oncogenicity (mouse)....................................................

870.4300 Chronic/Oncogenicity....................................................

-

yes

-

yes

yes

-

yes

-

yes

yes

870.5100 Mutagenicity—Gene Mutation - bacterial.....................

870.5300 Mutagenicity—Gene Mutation - mammalian................

870.5xxx Mutagenicity—Structural Chromosomal Aberrations...

870.5xxx Mutagenicity—Other Genotoxic Effects.......................

yes

yes

yes

yes

yes

yes

yes

yes

870.6100a Acute Delayed Neurotoxicity (hen)...............................

870.6100b 90-Day Neurotoxicity (hen)...........................................

870.6200a Acute Neurotoxicity Screening Battery (rat) .................

870.6200b 90-Day Neurotoxicity Screening Battery (rat)...............

870.6300 Develop. Neurotoxicity .................................................

no

no

yes

yes

no

-

-

yes

yes

-

870.7485 General Metabolism ......................................................

870.7600 Dermal Penetration ........................................................

870.7800 Immunotoxicity .............................................................

yes

yes

yes

yes

yes

yes

a

: (HASPOC, 1/30/2013; TXR 0056523) : 
Fluopyram Human Health Risk Assessment DP No. D414231

Page 33 of 51

A.2 Toxicity Profiles

Table A.2.1 Acute Toxicity Profile - Fluopyram

Guideline 

No. Study Type MRID Results Toxicity Category

870.1100 Acute oral - rat 47372430 No mortalities observed at 2000 

mg/kg

III

870.1200 Acute dermal -rat 47372432 LD50 > 2000 mg/kg III

870.1300 Acute inhalation - rat 47372435

47372434

LC50 at 4 hours > 5112 mg/m3

LC50 > 5.1 mg/L

IV

870.2400 Acute eye irritation - rabbit 47723701 Non-irritating IV

870.2500 Acute dermal irritation - rabbit 47372436 Non-irritating IV

870.2600 Skin sensitization - mouse 47372440 Non-sensitizing Not Applicable

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

Guideline No. Study Type MRID No. (year)/ 

Classification/Doses

Results

Non-guideline 28-day dietary rat 

study (exploratory)

47372516; (2004)

Acceptable

50, 400, 3200 ppm

(4., 31, & 254 mg/kg/day ♂

4.6, 36, & 263 mg/kg/day 

♀)

NOAEL = 31 mg/kg/day

LOAEL = 254 mg/kg/day based on  platelet count and 

prothrombin time (M),  cholesterol and triglycerides 

(M/F),  aspartate aminotransferase and alkaline 

phosphatase

 liver weight with hepatocellular hypertrophy (M/F)

 thyroid weight with follicular cell hypertrophy (M)

Non-guideline 28-day rat study 

(dietary) 

(preliminary)

AE C657188 (PCA), 

a soil metabolite of 

AE C638206

47372521; (2003)

Acceptable

20; 200; 2,000, & 20,000 

ppm

(1.5; 15; 149; & 1,574 

mg/kg/day for ♂

1.6; 16; 162; & 1,581 

mg/kg/day for ♀)

NOAEL=1574 mg/kg (HDT) no compound related 

effects were seen.

870.3100 90-day dietary rat 

study 

47372441; (2005)

Acceptable/guideline

0, 50, 200, 1000, 3200 ppm

♂: 3, 13, 61, & 204 

mg/kg/day 

♀: 4, 15, 70, & 230 

mg/kg/day 

NOAEL = 13 mg/kg/day

LOAEL = 61 mg/kg/day based on ↓ body weight & 

food consumption, hematology parameters affected. ↑ 

cholesterol conc & -glutamyltransferase activity. 

Slight ↑ in TSH, T3 & T4. 

↑ liver, thyroid gland & kidney weights.

Liver: centrilobular hypertrophy & periportal to 

midzonal hepatocellular macrovacuolation. Thyroid 

gland: follicular cell hypertrophy. 
Fluopyram Human Health Risk Assessment DP No. D414231

Page 34 of 51

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

Guideline No. Study Type MRID No. (year)/ 

Classification/Doses

Results

Non-guideline 28-day dietary study 

in the mouse 

(preliminary)

47372517; (2004)

Acceptable 

150; 1,000; 5,000 ppm

♂: 25, 162, & 747 mg/kg/day

♀: 31, 162, & 954 mg/kg/day

NOAEL = 25 mg/kg/day

LOAEL = 162 mg/kg/day based on ↓ body weight gain 

(M), ↑ ALT (M), 

↑ liver weights, 27-49% (M/F) associated with: 

centrilobular hypertrophy, single cell and focal 

necrosis, hepatocellular eosinophilia and bile duct/oval 

cell hyperplasia (M/F). 

Adrenal gland: hypertrophy of zona fasciculata (F).

870.3100 90-day dietary study 

in the mouse

47372442; (2005)

Acceptable/guideline

30, 150, 1000 ppm

♂: 5, 27, & 188 mg/kg/day; 

♀: 7, 32, & 216 mg/kg/day

NOAEL = 27 mg/kg/day

LOAEL = 188 mg/kg/day based on ↑ ALT & ↓ 

albumin conc. (M/F), ↓ cholesterol conc & ↑ alkaline 

phosphatase (M), ↑ liver weights, 34-45% (M/F), ↑ 

adrenal gland weights, 87-92% (M)

Liver: centrilobular hypertrophy and

focal necrosis (M/F)

Adrenal gland: ↓ ceroid pigment (M), ↑ cortical 

vacuolation (F).

Non-guideline 28-day oral toxicity

study in dogs 

(gavage)

47372515; (2004)

Acceptable

30, 150, & 750 mg/kg/day

NOAEL = 150 mg/kg/day

LOAEL = 750 mg/kg/day based on ↓ erythrocyte 

count, hemoglobin, hematocrit (M), ↑ alkaline 

phosphatase (M/F), ↓ albumin conc. (M/F), ↑ -

glutamyltransferase activity and triglyceride 

concentration (F).

↑ liver weights associated with hepatocellular 

hypertrophy (M/F).

870.3150 90-day dietary 

toxicity study in the 

dog

47372443; (2006)

Acceptable/guideline

800; 5,000, & 20,000/10,000 

ppm (at day 15, the high dose 

group dietary concentration 

was reduced due to lack of 

palatability)

♂: 29, 171, & 332 mg/kg/day

♀: 33, 184, & 337 mg/kg/day

NOAEL = 29 mg/kg/day

LOAEL = 171 mg/kg/day based on liver effects 

characterized by ↑ alkaline phosphatase, -

glutamyltransferase activity, ALT & AST; ↓ albumin 

conc and bilirubin; ↑ liver weights associated with 

hepatocellular hypertrophy, intracytoplasmic 

eosinophilic droplets and single cell necrosis. Both 

sexes were affected.

870.3200 28-day dermal 

toxicity study in the 

rat

47372444; (2007)

Acceptable/guideline

100; 300; & 1,000 mg/kg/day

NOAEL = 300 m/kg/day

LOAEL = 1,000 mg/kg/day based on ↑ cholesterol (F), 

and 

↑ liver weights associated with hepatocellular 

hypertrophy

870.3700 Developmental 

toxicity in the rat

47372445; (2008, Report)

(Study conducted in 2006)

Acceptable/guideline

Maternal NOAEL = 30 mg/kg/day

Maternal LOAEL = 150 mg/kg/day based on decreased 

body weight gains and food consumption, higher liver 

weights and diffused centrilobular hepatocellular 

hypertrophy.

Developmental NOAEL= 150 mg/kg/day

Developmental LOAEL = 450 mg/kg/day based 

Decreased fetal body weight (5%), increased incidence 

of two minor variations at both the visceral and skeletal 

evaluation.
Fluopyram Human Health Risk Assessment DP No. D414231

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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

Guideline No. Study Type MRID No. (year)/ 

Classification/Doses

Results

870.3700 Developmental 

toxicity study in the 

rabbit

47372446; (2006)

Acceptable/guideline

10, 25, & 75 mg/kg bw/day 

(gavage, GD 6-28)

Maternal NOAEL = 25 mg/kg/day

Maternal LOAEL = 75 mg/kg/day based on reduced 

body weight gain and food consumption.

Developmental NOAEL = 25 mg/kg/day

Developmental LOAEL = 75 mg/kg/day based on 

decreased fetal body weight (-11%).

Non-guideline Dose range-finding 

reproduction study 

in the rat

47372448; (2008) (Report)

Acceptable

30; 150; 750; & 1,500 ppm

♂: 2,10, 50, & 102 

mg/kg/day 

♀: 2, 12, 58, & 118 

mg/kg/day.

Parental NOAEL = 10 mg/kg/day 

Parental LOAEL = 50 mg/kg/day based on increased 

liver and kidney weights

Offspring NOAEL = 118 mg/kg/day (HDT)

Reproductive NOAEL = 118 mg/kg/day (HDT) No 

effect was seen in any of reproductive parameters 

examined.

870.3800 2-Generation 

reproduction study 

in the rat

47372447; (2008, Report)

Acceptable/guideline

40; 220; & 1, 200 ppm 

♂: 3, 15, 83 mg/kg/day 

(premating) 

♀: 3, 18, & 96 mg/kg/day 

(premating).

Parental NOAEL = 15 mg/kg/day

Parental LOAEL = 83 mg/kg/day based on increased 

creatinine, total protein, and albumin. Increased kidney 

and liver weights. Increased incidence of liver 

hypertrophy.

Offspring NOAEL = 15 mg/kg/day

Offspring LOAEL= 83 mg/kg/day based on decreased 

body weight (8%) with decreases in spleen and thymus 

weights and slight delay in preputial separation.

Reproductive NOAEL = 96 mg/kg/day (HDT). No 

effect was seen in any of reproductive parameters 

examined.

870.4100 1-year toxicity study 

in dogs (dietary)

47372449; (2007)

Acceptable/guideline

100; 400; & 2,000 ppm

♂: 3, 13, & 68 mg/kg/day 

♀: 4, 14, & 66 mg/kg/day.

NOAEL = 13 mg/kg/day

LOAEL = 66 mg/kg/day based on ↓ body weight & 

food consumption (M/F), ↑ alkaline phosphatase (M/F), 

Liver: centrilobular hypertrophy.

870.4200 Carcinogenicity 

study in the mouse

47372450; (2007)

Acceptable/guideline

30, 150, & 750 ppm

♂: 4, 21, & 105 mg/kg/day 

♀: 5, 27, & 129 mg/kg/day.

NOAEL = 4 mg/kg/day

LOAEL = 21 mg/kg/day based on follicular cell 

hyperplasia in the thyroid gland, centrilobular to 

panlobular hypertrophy and hepatocellular single cell 

degeneration /necrosis in the liver. 

Thyroid gland follicular cell

adenomas in high dose males.
Fluopyram Human Health Risk Assessment DP No. D414231

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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

Guideline No. Study Type MRID No. (year)/ 

Classification/Doses

Results

870.4300 Chronic 

/carcinogenicity 

study in the rat

47372501; (2008)

Acceptable/guideline

30, 150 & 750/375 ppm for

♂; 30, 150 and 1,500 ppm 

for ♀.

♂: 1.2, 6.0, & 29 mg/kg/day 

♀: 1.7, 8.6, & 89 mg/kg/day 

(Due to high mortality in 750 

ppm males, this 

concentration was reduced to 

375 ppm from week 85 

onward)

NOAEL = 1.2 mg/kg/day

LOAEL = 6.0 mg/kg/day based on liver toxicity, 

nephropathy, and follicular cell hypertrophy in the 

thyroid gland.

Liver cell tumors (carcinoma and adenoma) in high 

dose females. 

870.5100 Ames test 47372502; (2006)

Acceptable/guideline

Doses: 16 to 5000 μg/plate

+/- metabolic activation

Negative

870.5100 Ames test 47372503; (2008)

Acceptable/guideline

Doses: 5 to 1581 μg/plate

 16 to 5000 μg/plate

+/- metabolic activation

Negative

870.5300 In-vitro

chromosome 

aberration (V79 

cells).

47372505; (2005)

Acceptable/guideline

Concentrations: 30, 60, 120, 

180, & 240 μg/ml.

Negative

870.5300 HPRT Test (V79 

cells).

47372504; (2006)

Acceptable/guideline

Concentrations: 4 to 256 

μg/ml

+/- metabolic activation.

Negative

870.5385 In-vivo micronucleus test in male 

mice

47372506; (2005)

Acceptable/guideline

Doses: 250, 500, & 1000 

mg/kg.

Negative

870.6200a Acute neurotoxicity 

screening battery

47372507; (2007)

Acceptable/guideline

Initial study

125; 500; and 2,000 

mg/kg/day

NOAEL = 125 for males ; <125 for females

Based on ↓ motor and locomotor activity, clinical 

signs and ↓ body temperature

LOAEL for male = 500 mg/kg/day based on ↓ motor 

and locomotor activity.

Follow-up study using only 

female rats 

25, 50 and 100 mg/kg/day.

NOAEL = 50 mg/kg/day

LOAEL = 100 mg/kg/day based on ↓ motor and 

locomotor activity.
Fluopyram Human Health Risk Assessment DP No. D414231

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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

Guideline No. Study Type MRID No. (year)/ 

Classification/Doses

Results

870.6200b Subchronic 

neurotoxicity 

screening battery

47372508; (2008, Report) 

(The study was conducted in 

2007)

Acceptable/guideline

100; 500; & 2,500 ppm 

♂: 7, 33, & 164 mg/kg/day 

♀: 8, 41, & 197 mg/kg/day

NOAEL = 33 mg/kg/day

LOAEL = 164 m/kg/day based on a host of effects 

which included increases in cholesterol and triglyceride 

levels, decrease in glucose level, decreases in 

hemoglobin and hematocrit, and deceases in body 

weight and food consumption.

No evidence of neurotoxicity in either neurobehavioral 

parameter or histopathology.

870.7485 ADME study in rats 47372509; (2008)

Acceptable/guideline

5 & 250 mg/kg (single dose 

by gavage )(14 C on phenyl 

ring)

5 mg/kg (radiolabeled

fluopyram) after 14 days pretreatment

With oral dosing, fluopyram was rapidly absorbed 

(93.2 % of administered radioactivity) from the GI tract 

of male and female rats. The max. plasma 

concentration was reached at 15 hrs in males and 11 

hrs in females post dosing with 5 mg/kg. After 168 hrs 

post dosing 91-99 % of the administered radioactivity 

was eliminated via urine(32-41% of the administered 

dose) and feces (53-65% of the administered dose). The 

ratio of renal and fecal elimination was comparable 

(45% via urine and 47% via feces). The organ which 

contained the highest radioactivity was the liver (0.4 to 

1.0 % of the administered radioactivity.) Considerable 

enterohepatic circulation was demonstrated by the 

results. Fluopyram was extensively metabolized and 29 

metabolites were identified. It was proposed that three 

main metabolite groups were formed in the liver 

(fluopyram-7-OH-GA, 8-OH-GA and enol-GA) 

(GA=glucuronic acid).

870.7485 ADME in the rat 47372511; (2008)

Acceptable/guideline

Single oral dose, 5 mg/kg 

(gavage) (14C in positions 2 

& 6 of the pyridyl ring)

With oral dosing, fluopyram was absorbed rapidly and 

efficiently eliminated from the body (>98% of the 

administered radioactivity was eliminated) after 72 hrs 

post dosing. No significant residues remained in the 

body. Considerable enterohepatic circulation occurred. 

Three main metabolite groups were formed in the liver 

(fluopyram-7-OH-GA, 8-OH-GA and enol-GA) 

(GA=glucuronic acid).

870.7485 Distribution of total 

radioactivity in male 

& female rats

47372513; (2008)

Acceptable/non-guideline

Single dose 14C in the phenyl 

ring of fluopyram at 3 

mg/kg.

Distribution occurred in almost all organs with liver 

reaching the maximal concentration first, and most of 

the tissue reaching the peak concentration at 

approximately 24 hr post-dosing. By 136 hr post dosing 

little of the radioactivity was present in most organs 

except nasal mucosa. 

870.7485 Distribution of 14C 

labeled fluopyram.

47372512; (2008)

Acceptable/non-guideline

3 mg/kg for ♂ & 4.5 mg/kg 

for ♀ (Single oral dose; 14C 

on pyridyl ring of 

fluopyram.)

Fluopyram was readily absorbed from the GI tract and 

distributed among almost all organs. Peak level was 

reached at approximately 1 hr after dosing in most 

organs with liver having the higher concentration than 

other organs. From peak levels, a continuous but slow 

decline of radioactivity concentrations was observed 

for all organs.

870.7485 Metabolism in 

organs and tissues in 

rats

47372509; (2008)

Acceptable/non-guideline 5 

mg/kg (Single oral dose; 14C 

in the 2 & 6 position of the 

pyridyl ring of fluopyram).

AE C656948 was extensively metabolized, and more 

than 20 metabolites were identified. The major 

metabolic transformation was oxidation and took place 

mainly at the ethylene bridge of the molecule. The 

major metabolites were AE C656948-7-hydroxy and 

AE C656948-pyridyl-acetic acid.
Fluopyram Human Health Risk Assessment DP No. D414231

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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

Guideline No. Study Type MRID No. (year)/ 

Classification/Doses

Results

870.7600 In-vitro dermal 

absorption study 

with human and rat 

skin

47372514 (2007)

Acceptable

500 mg AE C656948 & 0.5 

mg AE C656948 (spray 

dilution)

Dermatomed skin membranes from human and rat were 

examined. The report stated that over a period of 24 hrs 

the potentially absorbable [14C] –AE C656948 was 

1.8% and 12.4 % for human and rat skin, respectively. 

This results in approximately 6x difference between 

dermatomed human and rat skin. Rat skin being more 

permeable.

In-vivo dermal 

absorption

47567201 (2008)

Acceptable/guideline

0, 60 μg (spray dilution) and 

60 mg (neat)

The maximal dermal absorption rates for neat 

formulation and spray dilution were 4.5% and 12.8% of 

the applied dose, respectively.

870.7800 28-Day 

immunotoxicity 

study in rats

48239930; (2010)

Acceptable/guideline

0, 200, 600, 1800 ppm

0, 17.2, 53.6, 156.3 

mg/kg/day.

Immunotoxicity NOAEL for anti-SRBC IgM response 

= 156.3 mg/kg/day (HDT).

Mechanistic Studies

Non-guideline 7-Day mechanistic 

study in female rats 

(dietary 

administration)

47372520; (2008)

Acceptable/non-guideline

3,000 ppm (193 mg/kg/day).

Feeding fluopyram at 193 mg/kg/day in the diet to 

female rats did not affect body weight, clinical signs or

food or water consumption. 

Mean absolute and relative liver weights were 

increased (40 to 43%) relative to the controls. This 

increase was associated with enlarged and dark livers 

in 13/15 females. 

At histological examination, minimal to slight 

centrilobular to panlobular hepatocellular hypertrophy 

was found in all treated animals. 

There was a 4x increase in mean BrdU labeling index 

in both the perilobular and centrilobular areas of the 

hepatic lobule in treated animals relative to the 

controls.

A slight increase in total P-450 content and in mean 

EROD activity, a moderate increase in mean PROD 

and BROD activities and a marked increase in mean 

UDPGT activity (all statistically different from the 

control group (p≤0.01)) were seen. The report 

concluded that AE C656948 has the ability to induce 

moderately phenobarbital-inducible hepatic enzymes 

(total cytochrome P-450, BROD and PROD and 

UDPGT) as well as liver hypertrophy and cell 

proliferation in the liver.
Fluopyram Human Health Risk Assessment DP No. D414231

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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

Guideline No. Study Type MRID No. (year)/ 

Classification/Doses

Results

Non-guideline 7-Day mechanistic 

study with 

Phenobarbital

Reduction in activity in all treated animals & slight 

reduction in body weight gain. Mean absolute and 

relative liver weights were increased (≈ 22%) relative 

to the controls. Dark liver was found in 5/14 females 

and enlarged liver in 3/14 females. Minimal to slight 

centrilobular to panlobular hepatocellular hypertrophy 

was found in all treated animals. A 2x increase in mean 

BrdU labeling index in the perilobular and centrilobular 

areas in the treated animals. A moderate increase in 

total P-450 content and in mean PROD, BROD and 

UDPGT activities (all statistically different from the 

control group p≤0.01). The report states that 

phenobarbital has the ability to induce hepatic enzymes 

like total cytochrome P-450, PROD, BROD and 

UDPGT activities as well as liver hypertrophy and cell 

proliferation in the liver. 

Non-guideline 14-Day dietary 

administration to the 

mice (hepato-toxicity 

and thyroid hormone 

investigations)

47372519; (2008

Acceptable/non-guideline

2,000 ppm

308 and 314 mg/kg for 3 or 

14 days, respectively.

After 3 days of exposure, mean T3 level was not 

changed, whereas mean T4 level was decreased (-30%) 

while mean TSH level was increased (+18%) relative 

to the controls. Mean absolute and relative liver 

weights were increased by approximately 60%. 

Enlarged liver was found in all the treated animals. 

Diffuse centrilobular to panlobular hepatocellular 

hypertrophy and an increased number of mitoses were 

observed in all examined treated animals. In addition, 

hepatocellular single cell necrosis was observed in 1/5 

treated animals. No significant microscopic change 

was observed in the thyroid gland.

Total cytochrome P-450 content was markedly 

increased (+116%) by the treatment. EROD activities 

were marginally increased (+235%), whereas PROD 

and BROD activities were markedly increased 

(respectively +2890% and +8717%) relative to 

controls. No significant changes were observed in 

UDPGT. 

Non-guideline Phenobarbital 14-

day mechanistic 

study in the mouse 

(gavage)(hepatotoxicity and thyroid 

hormone 

investigations)

47372522; (2008)

Acceptable/non-guideline

80 mg/kg for 3 or 14 days by 

gavage.

The report stated that phenobarbital administration at a 

dose level of 80 mg/kg body weight/day in the mouse 

for 3 and 14 days induced significant liver changes 

including increases in hepatic total cytochrome P-450, 

PROD and BROD activities. Phenobarbital also 

induced a modification of the normal thyroid hormone 

balance (in particular by a decrease in T4 and/or T3 

after 3 and/or 14 days of exposure together with a 

concomitant increase in TSH level after 14 days.)

Non-guideline In-vitro studies on 

the potential 

interactions with 

thyroid peroxidasecatalyzed reactions

47372518; (2008)

Acceptable/non-guideline

300 μM

Fluopyram at 300 μM did not affect thyroid peroxidase

(TPO)-catalyzed guaiacol oxidation and TPO-catalyzed

iodine formation. Therefore, the data show that 

fluopyram does not affect thyroid hormone synthesis at 

the level of TPO.

Non-guideline Mechanistic 3-Day 

toxicity study in the 

mouse by gavage 

(thyroid hormone 

investigations)

49005901 (2012)

Acceptable/non-guideline

0, 100 or 300 mg/kg bw/day 

for 3 days.

There were no compound related effects on mortality 

or clinical signs. Plasma T4 levels were significantly 

decreased in treated animals at all time-points with no 

obvious time-related trends, Plasma TSH levels were 

comparable to controls.
Fluopyram Human Health Risk Assessment DP No. D414231

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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

Guideline No. Study Type MRID No. (year)/ 

Classification/Doses

Results

Non-guideline Mechanistic 

Investigations in the 

Liver of Female 

Rats Following 

Dietary 

Administration for 

28 days

49005902 (2012)

Acceptable/non-guideline

0, 30, 75, 150, 600 or 1500 

ppm (0, 2.2, 5.6, 11.3, 44.5, 

or 111.4 mg/kg bw/day) for 

28 days. A one month 

recovery period in control 

and high dose animals 

assessed reversibility of 

effects. Phenobarbital was 

used as a positive control at 

80 mg/kg bw/day.

Absolute and relative liver weights were increased at ≥ 

44.5 mg/kg bw/day fluopyram and in the 

phenobarbital-treated group. Following the recovery 

phase, liver weights were nearly identical among 

control, high dose fluopyram- and phenobarbitaltreated rats. Visibly enlarged livers were seen starting 

at 5.6 mg/kg bw/day with red foci and prominent 

lobulation being recorded at higher dose levels. 

Hepatocellular hypertrophy was observed starting at 

44.5 mg/kg bw/day.

After 28 days of treatment, mean liver cell proliferation 

was increased in the fluopyram treated groups starting 

at 5.6 mg/kg bw/day and in the phenobarbital group. 

Enzyme activity was increased in fluopyram- and 

phenobarbital-treated rats. These activity levels showed 

partial reversibility following recovery.

Gene transcript expression was increased for both 

fluopyram- and phenobarbital-treated rats, though there 

were notable differences in expression between 

compounds. Partial reversibility was evident after a 

month without treatment.

Non-guideline 28-Day Toxicity 

Study for 

Proliferation 

Assessment in the 

male Mouse

49005904 (2012)

Acceptable/non-guideline

0 or 750 ppm (0 or 127 

mg/kg bw/day) for 28 days

Phenobarbital (gavage) as 

positive control

Enlarged and dark livers were present in treated mice. 

Phenobarbital-treated mice also exhibited dark thyroids 

without microscopic correlates.

The BrdU labeling index was increased in the 

fluopyram group, but not the phenobarbital group.

Non-guideline 28-Day Toxicity 

Study for Thyroid 

Cell Proliferation in 

the Mouse

49005905 (2013)

Acceptable/non-guideline

0, 30, 75, 150, 600, 750 or 

1500 ppm (0, 5, 13, 25, 99, 

124 or 247 mg/kg bw/day) 

for 28 days.

(28-day recovery groups 

consisted of control and high 

dose animals) 

There were no compound related effects on mortality, 

clinical signs, body weight, food or water consumption, 

organ weights, or gross and histologic pathology. The 

proliferation index in the thyroid was increased starting 

at 25 mg/kg bw/day.
Fluopyram Human Health Risk Assessment DP No. D414231

Page 41 of 51

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

Guideline No. Study Type MRID No. (year)/ 

Classification/Doses

Results

Non-guideline 28-Day Dietary 

Study to Determine 

Potential Role of the 

Nuclear Pregnane X 

Receptor (Pxr) and 

Constitutive 

Androstane 

Receptor (Car) on 

the Thyroid 

Changes Following 

the Administration 

of Fluopyram to 

Male Mice 

(C57BL/6J and Pxr 

KO/Car KO).

49005906 (2013)

Acceptable/non-guideline

0, 750 or 1500 ppm (125 or 

256 mg/kg bw/day for wild 

type and 130 or 247 mg/kg 

bw/day for knockout) for 28 

days.

There were no effects on mortality, clinical signs, body 

weight or food or water consumption. Liver weights 

were increased in all fluopyram-treated mice. Enlarged 

livers were observed in the wild type groups, but not in 

controls or knockout groups. In treated wild type mice, 

there was an increase in hepatocellular hypertrophy. 

There were no similar treatment-related effects in the 

knockout mice.

Thyroid cell proliferation was increased in wild type 

mice, while the knockout mice had a slight decrease in 

proliferation index that was likely incidental.

Total cytochrome P-450 content was increased in 

treated wild type mice, but not in treated knockout 

mice. PROD activity was greatly increased in treated 

wild type mice and slightly increased in treated 

knockout mice. BQ activity was increased in wild type 

mice while the knockout mice showed slight decreases. 

Thyroxine glucuronosyl transferase (T4-GT) and 

bilirubin glucuronidation (BIL-GT) activities were 

increased in treated wild type mice, but showed no 

change in treated knockout mice except for a slight 

decrease in T4-GT activity at 247 mg/kg bw/day.

There was a significant increase of Tsh beta transcript 

in the pituitary gland of treated wild type mice and a 

slight decrease in the same measure for high dose 

knockout mice.

Non-guideline Enzyme and DNASynthesis Induction 

in Cultured Human 

Hepatocytes, Main 

Study

49005907 (2013)

Acceptable/non-guideline

0, 1, 3, 10, 30, 100 or 300 

μM fluopyram or at 10, 100 

or 1000 μM phenobarbital 

for 96 hours.

Epidermal growth factor, at 

25 ng/mL, was used as a 

positive control

ATP concentration in the fluopyram groups indicated 

that cytotoxicity begins around 100 μM fluopyram. 

Phenobarbital did not affect ATP levels.

There was no effect on DNA synthesis with either 

fluopyram or phenobarbital. The positive control 

substance generated a large increase in DNA synthesis.

There was no dose-related increase in PROD activity 

with fluopyram treatment, though all dose levels up to 

cytotoxic levels showed an approximate 2-fold increase 

over controls. The same general effect was seen with 

phenobarbital. There was a dose-dependent increase in 

BROD activity following fluopyram treatment. 

Phenobarbital treatment also produced an increase at 

the high dose. There was a slight increase in BQ 

activity at low dose levels of fluopyram. Phenobarbital 

caused a dose-related increase at the mid and high dose 

level.
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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

Guideline No. Study Type MRID No. (year)/ 

Classification/Doses

Results

Non-guideline Enzyme and DNASynthesis Induction 

in Cultured Rat 

Hepatocytes, Main 

Study

49005908 (2013)

Acceptable/non-guideline

0, 1, 3, 10, 30, 100 or 300 

μM fluopyram or at 10, 100 

or 1000 μM phenobarbital 

for 96 hours. The test vehicle 

was DMSO. Epidermal 

growth factor, at 25 ng/mL, 

was used as a positive contro

ATP concentration in the fluopyram groups was 

comparable to controls until cytotoxic levels. 

Phenobarbital did not appear to have an effect on ATP 

levels.

DNA synthesis was increased with fluopyram and 

phenobarbital. Cytotoxicity at 100 and 300 μM 

fluopyram impacted the results. The positive control 

substance generated a large increase in DNA synthesis.

There was an increase in PROD, BROD and BQ 

activity following fluopyram and phenobarbital 

treatment until cytotoxic levels.

Non-guideline Mechanistic 3-Day 

Toxicity Study in 

the Mouse by Oral 

Gavage (Thyroid 

Hormone 

Investigations)

49005909 (2011)

Acceptable/non-guideline

0, 100 or 300 mg/kg bw/day 

for 3 days. Phenobarbital was 

used as a positive control at 

80 mg/kg bw/day.

There were no compound related effects on mortality, 

clinical signs, body weight or gross pathology. There 

were small decreases in body weight gains in all treated 

groups, though this effect lacked a dose-response 

relationship in the fluopyram groups.

Plasma T4 levels were significantly decreased in all 

fluopyram- and phenobarbital-treated mice, but plasma 

TSH levels were comparable to controls. There was an 

increase in Tsh beta transcript in the pituitary in all 

treated groups.
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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

Guideline No. Study Type MRID No. (year)/ 

Classification/Doses

Results

Non-guideline Mechanistic 28-Day 

Toxicity Study in 

the Mouse by 

Dietary 

Administration 

(Hepatotoxicity and 

Thyroid Hormone 

Investigations)

49005911 (2012) (28-day 

dietary study)

49005903 (2013) (PROD and 

BQ assessment)

Acceptable/non-guideline

0, 30, 75, 150, 600 or 750 

ppm (0, 5, 13, 25, 102 or 128 

mg/kg bw/day) for 28 days. 

Phenobarbital was used as a 

positive control at 80 mg/kg 

bw/day.

There were no treatment-related clinical signs or 

mortalities in the fluopyram groups. The phenobarbital 

group showed reduced motor activity during the dosing 

phase and there were three deaths between days 2 and 

7. There were no treatment-related clinical signs in any 

group during the recovery phase. There was no effect 

on body weight related to fluopyram treatment. 

Decreased body weight and body weight gain were 

noted in phenobarbital-treated mice during treatment 

followed by increased body weight gains compared to 

controls during the recovery phase. There was no effect 

on food consumption in the fluopyram-treated groups. 

The phenobarbital group had a small reduction in food 

consumption during the first week of dosing.

Plasma T4 levels were decreased in fluopyram- and 

phenobarbital-treated animals while plasma TSH levels 

were comparable amongst all groups. Following the 

recovery phase, plasma hormone levels were 

comparable across groups.

Absolute and relative liver weights were increased in 

both fluopyram-treated mice starting at 25 mg/kg 

bw/day and the phenobarbital-treated mice following 

the dosing phase. After the recovery phase, all groups 

had comparable liver weights.

UDPGT enzymatic activity towards bilirubin was 

increased in all treated animals and reached statistical 

significance at 102 and 128 mg/kg bw/day of 

fluopyram. Similar results were noted for UDPGT 

activity towards thyroxine, though the dose-response 

relationship was not strong at the high dose. Following 

the recovery phase, the UDPGT activities were roughly 

comparable to controls. PROD and BQ activities were 

increased in fluopyram- and phenobarbital-treated mice 

at 28 days. The activities of both PROD and BQ were 

statistically comparable to controls following the 

recovery period.

There was an increase of Tsh beta transcript in the 

pituitary gland of fluopyram- and phenobarbital-treated 

animals following the dosing phase. After the recovery 

phase, the fluopyram-treated mice had slightly elevated 

relative tsh b, but the phenobarbital-treated mice were 

similar to controls.
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Appendix B. Physical/Chemical Properties

Table B1. Physicochemical Properties of Fluopyram.

Parameter Value Reference

Melting point 118 oC MRID 47372240

pH 6.6 (1% aqueous solution; pure substance) MRID 47372236

Density 1.53 MRID 47372242

Water solubility (20 °C) Distilled water (pH 6.7) = 16 mg/L

pH 4 = 15 mg/L

pH 7 = 16 mg/L

pH 9 = 15 mg/L

MRID 47372247

Solvent solubility (g/L at 20 °C) heptane 0.66

toluene 62.2

dichloromethane >250

methanol >250

acetone >250

ethyl acetate >250

dimethyl sulfoxide >250

MRID 47372248

Vapor pressure 1.2 x 10-6 Pa at 20 oC

3.1 x 10-6 Pa at 25 oC

2.9 x 10-4 Pa at 50 oC

MRID 47372249

Dissociation constant (pKa) 0.5 (23 oC) MRID 47372243

Octanol/water partition coefficient 

Log(KOW)

3.3 MRID 47372245

UV/visible absorption spectrum Peak max at 270 nm MRID 47372237
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Appendix C. Review of Human Research

This risk assessment relies in part on data from studies in which adult human subjects were 

intentionally exposed to a pesticide to determine their dermal and inhalation exposure. Many 

such studies, involving exposure to many different pesticides, comprise generic pesticide 

exposure databases such as PHED, ARTF, and AHETF. EPA has reviewed all the studies 

supporting these multi-pesticide generic exposure databases, and has found no clear and 

convincing evidence that the conduct of any of them was either fundamentally unethical or 

significantly deficient relative to the ethical standards prevailing at the time the research was 

conducted. All applicable requirements of EPA’s Rule for the Protection of Human Subjects of 

Research (40 CFR Part 26) have been satisfied, and there is no regulatory barrier to continued 

reliance on these studies.
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Appendix D. Summary of Residues from Rotational Crop Field Trials

Table D.1. Summary of Residues from Rotational Crop Field Trials with Fluopyram. Proposed Use of 0.45 

lb ai/acre TotalAapplication Rate.

Crop 

Matrix Analyte Applic. Rate(lb ai/acre)

PHI+ 

(days) n

* Residues (ppm)

Min.† Max.† LAFT* HAFT* Median* Mean* SD*

Plant-Back Interval =203 - 228 Days

Field corn, 

forage

fluopyram 0.439-0.462

(0.492-0.518)

26-137

15

<0.01 0.165 <0.01 0.165 0.0144 0.0317 0.0409

Field corn, 

grain 57-200 <0.01 <0.01 <0.01 <0.01 0.01 0.01 N/A

Field corn, 

stover 57-200 14 <0.01 0.165 <0.01 0.165 0.0144 0.0317 0.0409

Plant-Back Interval = 202 - 210Days

Sweet 

corn, 

forage

fluopyram 0.441-0.462

(0.494-0.518)

66-122

9

<0.01 0.161 <0.01 0.153 0.0313 0.0563 0.0515

Sweet 

corn, 

K+CWHR

66-122

<0.01 <0.01 <0.01 <0.01 0.01 0.01 N/A

Sweet 

corn, 

stover

99-144

0.0185 0.361 0.0206 0.331 0.0816 0.104 0.100

Plant-Back Interval =185-228 Days

Wheat, 

forage

fluopyram 0.441-0.462 

(0.494-0.518)

29-137 14 <0.01 0.895 0.0121 0.834 0.166 0.271 0.267

Wheat, 

hay 66-170 13 0.0112 1.471 0.0116 1.371 0.190 0.324 0.365

Wheat, 

grain 89-190 14 <0.01 0.0270 <0.01 0.0201 0.01 0.0117 0.0030

Wheat, 

straw 89-190 14 <0.01 0.817 0.0148 0.746 0.169 0.231 0.216

Plant-Back Interval =203-215 Days

Sorghum, 

forage

fluopyram 0.442-0.462 

(0.495-0.518)

77-142

12

<0.01 0.147 <0.01 0.143 0.0474 0.0575 0.0417

Sorghum, 

grain 105-189 <0.01 0.0161 <0.01 0.0158 0.01 0.0106 0.0017

Sorghum, 

stover 105-189 <0.01 0.252 <0.01 0.236 0.0539 0.0892 0.0821

Plant-Back Interval =203-238 Days

Soybean, 

forage

fluopyram

0.441-0.459

(0.495-0.515)

49-98

19

<0.01 0.581 <0.01 0.567 0.037 0.116 0.167

Soybean, 

hay 49-98 <0.01 1.875 <0.01 1.735 0.108 0.300 0.473

Soybean, 

seed 132-181 <0.01 0.0129 <0.01 0.0119 <0.01 0.0102 0.0005

Soybean, 

forage 2-

(Trifluoromethyl

)

benzamide

49-98 <0.01 0.0356 <0.01 0.0352 <0.01 0.0129 0.0073

Soybean, 

hay 49-98 <0.01 0.107 <0.01 0.102 <0.01 0.0207 0.0233

Soybean, 

seed 132-181 <0.01 <0.01 <0.01 <0.01 <0.01 <0.01 N/A

+ Interval from planting to harvest.

† Values based on total number of samples.

* Values based on per-trial averages. LAFT = Lowest Average Field Trial, HAFT = Highest Average Field Trial, SD = Standard 

Deviation. For computation of the LAFT, HAFT, median, mean, and standard deviation, values < LOQ are assumed to be at the 

LOQ.
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Appendix E. Occupational Exposure/Risk Summary Tables

Table E.1. Non-Cancer Occupational Short- and Intermediate-Term Dermal and Inhalation Exposures and Risk Estimates For Fluopyram

Exposure Scenario Crop or 

Target

Application

Ratea

(lb ai/A)

Area 

Treated 

Dailyb

(A/day) 

Unit Exposured Daily Exposuree(mg/kg/day) MOEf

Baseline 

Dermalc

(mg/lb ai)

PPE-G 

Dermalc

(mg/lb ai)

Baseline 

Inhalationc

(μg/lb ai)

Baseline 

Dermal

PPE-G 

Dermal

Baseline 

Inhalation

Baseline 

Dermal

PPE-G 

Dermal

Baseline 

Inhalation

Mixer/Loader

Mixing/Loading Liquid 

Concentrates for 

Chemigation Applications

Peanut 0.22 350 0.22 0.0376 0.219 0.214 0.0366 0.000213 1,400 8,200 68,000

Mixing/Loading Liquids 

Concentrates for 

Groundboom Applications

Peanut 0.22 80 0.22 0.0376 0.219 0.0489 0.00836 0.0000486 6,100 36,000 300,000

Cotton 0.22 200 0.22 0.0376 0.219 0.122 0.0209 0.000122 2,500 14,000 120,000

Applicator

Applying Sprays via 

Groundboom Equipment

Peanut 0.22 80 0.0786 0.0161 0.34 0.0175 0.00358 0.0000756 17,000 84,000 190,000

Cotton 0.22 200 0.0786 0.0161 0.34 0.0436 0.00895 0.000189 6,900 34,000 77,000

a. Application Rates are based on proposed uses from the fluopyram label (Luna® Privilege).

b. Science Advisory Council Policy No. 9.1.

c. Baseline Dermal: Long-sleeve shirt, long pants, and no gloves. PPE-G Dermal: Baseline plus chemical-resistant gloves. Baseline Inhalation: no respirator.

d. Unit Exposures are based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (May 2013). 

e. Daily Exposure (mg/kg/day) = Application Rate (lb ai/A) * Unit Exposure (mg/lb ai) * Area Treated or Amount Applied (acre/day) / 80 kg.

f. MOE = NOAEL (mg/kg/day) / Daily Exposure (mg/kg/day); where dermal NOAEL = 300 mg/kg/day and inhalation NOAEL = 14.5 mg/kg/day.
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Table E.2. Summary of Short- and Intermediate-Term Handler Exposures and Risk Estimates for Fluopyram 

Seed Treatment of Cotton and Peanut Seed.a

Crop

Maximum 

Application 

Rateb

lb ai/lb 

seed

Amount of 

Seed Treated 

or Planted 

Per Dayd

lb seed/day

Dermal

Unit 

Exposurec

mg/lb

Inhalation

Unit 

Exposurec

mg/lb

Dermal 

Dosee

mg/kg/day

Inhalation 

Dosef

mg/kg/day

Dermal 

MOEf

LOC = 100

Inhalation 

MOEh

LOC = 100

Loader/Applicator

Soybean 0.001983 281,250

0.023 0.00034

0.1603 0.002370 1,900 6,100

Cotton 0.003472 339,500 0.3389 0.005010 890 2,900

Sewer

Soybean 0.001983 281,250

0.0062 0.00023

0.04322 0.001603 6,900 9,000

Cotton 0.003472 339,500 0.09135 0.003389 3,300 4,300

Bagger

Soybean 0.001983 281,250

0.0091 0.00016

0.06344 0.001115 4,700 13,000

Cotton 0.003472 339,500 0.1341 0.002357 2,200 6,200

Multiple Activities

Soybean 0.001983 281,250

0.042 0.0016

0.2928 0.01115 1,000 1,300

Cotton 0.003472 339,500 0.6188 0.02357 480 620

Planters

Soybean 0.001983 26,600

0.25 0.0034

0.1648 0.002242 1,800 6,500

Cotton 0.003472 3776 0.04099 0.0005574 7,300 26,000

a Seed treatment rate calculations are based on the following assumptions:

Soybean: 3,600 seeds per lb; 133 lb of seed planted per acre, 200 acres planted per day.

Cotton: 4,500 seeds per lb; 18.9 lb of seed planted per acre, 200 acres planted per day.

b Application Rate based on proposed label for fluopyram (Fluopyram ST, EPA Reg. No. 264-RRAT).

c Unit Exposures from HED Exposure Science Advisory Council Policy 14: Standard Operating Procedures for Seed Treatment (baseline inhalation = no respirator; dermal unit exposure 

includes PPE with gloves for loading/applicator, multiple activities and planter scenarios).

d HED default for lb seed treated/planted per day from HED Exposure Science Advisory Council Interim Policy 15.1 and the BEAD memo “Acres Planted Per Day and Seeding Rates of 

Crops Grown in the United States” (J. Becker, March 2011).

e Daily Dermal Dose (mg/kg/day) = daily dermal unit exposure (mg/lb ai) × application rate (lb ai/lb seed) × amount planted (lb seed/day) ÷ body weight (80 kg adult).

f Daily Inhalation Dose (mg/kg/day) = daily inhalation unit exposure (mg/lb ai) × application rate (lb ai/lb seed) × amount planted (lb seed/day) ÷ body weight (80 kg adult).

g Dermal MOE = NOAEL (300 mg/kg/day for short- and intermediate-term exposure) ÷ Dermal Dose (mg/kg/day). Level of concern = 100.

h Inhalation MOE = NOAEL (14.5 mg/kg/day for short- and intermediate-term exposure) ÷ Inhalation Dose (mg/kg/day). Level of concern = 100.
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Table E.3. Summary of Occupational Non-Cancer Post-application Risks (Short- and Intermediate-Term) with 

HED Default Assumptions.

Crops

Application 

rate

(lb ai/acre)

Default DFR on 0 

days (12 hr) after 

applicationa

(μg/cm2)

Work Activity & 

Maximum Transfer 

Coefficientb

(cm2/hr)

Daily Dosec

(mg/kg/day)

MOEd

(LOC = 100)

Peanut 0.22 0.617

1,900 Irrigation (Hand Set) 0.1172 2,600

210 Scouting 0.01295 23,000

70 Weeding (Hand) 0.004317 69,000

Cotton 0.22 0.617 210 Scouting 0.01295 23,000

70 Weeding (Hand) 0.004317 69,000

a. Default DFR (μg/cm2) = application rate (lb ai/A) x (1- daily dissipation rate) t x 4.54E+8 μg/lb x 24.7E-9 A/cm2 x 25% DFR after initial 

treatment.

b. Crops were assessed using the highest transfer coefficient (TC) available.

c. Daily Dose = DFR x TC x (1 mg/1000 μg) x ET (8 hr/day) / body weight (80 kg)

d. MOE = NOAEL (300 mg/kg/day) / Daily Dose (mg/kg/day)
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Appendix F. International Residue Limit Status Sheet

Fluopyram (080302)

Summary of US and International Tolerances and Maximum Residue Limits 

Residue Definition:

US Canada Mexico2 Codex3

40 CFR 180.XXX:

Plants: fluopyram (N-[2-[3-chloro-5-

(trifluoromethyl)-2-pyridinyl]ethyl]-2-

(trifluoromethyl)benzamide).

Livestock: sum of fluopyram (N-[2-[3-

chloro-5-(trifluoromethyl)-2-pyridinyl]ethyl]-

2-(trifluoromethyl)benzamide) and its 

benzamide metabolite [2-(trifluoromethyl)-

benzamide], calculated as the stoichiometric 

equivalent of fluopyram

Identical to 

US

Plants: fluopyram.

Animal commodities: Sum of 

fluopyram, 2-

(trifluoromethyl)benzamide, and the 

combined 

residues N-{(E)-2-[3-chloro-5-

(trifluoromethyl)pyridin-2-yl]ethenyl}-

2-trifluoromethyl) benzamide and N-

{(Z)-2-[3-chloro-5-

(trifluoromethyl)pyridin-2-

yl]ethenyl}-2-trifluoromethyl) 

benzamide, all expressed as fluopyram.

Commodity1 Tolerance (ppm) /Maximum Residue Limit (mg/kg)

US Canada Mexico2 Codex3

Soybean, seed 0.04 0.1 -

Cotton, undelinted seed 0.01 0.01 -

Cotton, Gin by-products 0.70 - -

Grain, cereal, except rice Group 15

0.03

1.5 (barley, 

buckwheat, 

field corn, 

sweet corn, 

pearl 

millet, 

proso 

millet, oat, 

popcorn, 

rye, 

sorghum 

teosinte, 

triticale, 

wheat, 

wild rice)

-

Grain, cereal, forage, fodder, hay, 

and straw Group 16 2.0 -

-

Peanut 0.09 - 0.03

Cattle, fat 0.05 0.05 -

Cattle, meat 0.05 0.05 3 Meat (from mammals other than 

marine mammals)

Cattle, meat byproducts 0.40 0.4 Kidney 3

Liver 3

Goat, fat 0.05 0.05 -

Goat, meat 0.05 0.05 0.5 Meat (from mammals other than 

marine mammals)

Goat, meat byproducts 0.40 0.4 Kidney 0.5

Liver 3
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Summary of US and International Tolerances and Maximum Residue Limits 

Residue Definition:

US Canada Mexico2 Codex3

Hog, fat 0.02 0.02 -

Hog, meat 0.02 0.02 0.5 Meat (from mammals other than 

marine mammals)

Hog, meat byproducts 0.03 0.03 Kidney 0.5

Liver 3

Horse, fat 0.05 0.05 -

Horse, meat 0.05 0.05 0.5 Meat (from mammals other than 

marine mammals)

Horse, meat byproducts 0.40 0.4 Kidney 0.5

Liver 3

Sheep, fat 0.05 0.05 -

Sheep, meat 0.05 0.05 0.5 Meat (from mammals other than 

marine mammals)

Sheep, meat byproducts 0.40 0.4 Kidney 0.5

Liver 3

Milk 0.06 0.06 0.3

Poultry, fat 0.03 0.03 -

Poultry, meat 0.03 0.03 0.2

Poultry, meat byproducts 0.10 0.1 0.7

Eggs 0.06 0.06 0.3

1

Includes only commodities of interest for this action. Tolerance values should be the HED recommendations and 

not those proposed by the applicant.

2 Mexico adopts US tolerances and/or Codex MRLs for its export purposes.

3 * = absent at the limit of quantitation; Po = postharvest treatment, such as treatment of stored grains. PoP = 

processed postharvest treated commodity, such as processing of treated stored wheat. (fat) = to be measured on the 

fat portion of the sample. MRLs indicated as proposed have not been finalized by the CCPR and the CAC.