### Fluopyram Human H ealth 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 Assess ment for Pr opo se d New Use as a Soil / In

Furrow Treatment for Co tto n and Peanut, and as a Seed Trea tment to Cotton and Soybean

, Plus a Proposal for Amended Inad vert en t Tolerances fo r the Crop Group 15 Cereal Grains and Crop Group 16 Forage

, Fodder

, and Straw of Cerea l

Grains.

DP Barcode: 0414231 P C Code : 080302

Dec i sion No.: 481199 Registrat i on No.: 264-RRAT ; 2 64-1078; 264 -108 4 ; 264- 1 085;264-1090;264- 1 091

Petition No .: 3F8190 Regulatory Actio n : Section 3 Registration

Risk Assessment Typ e: S in gle Che m ica l / Aggre gate
TXRNo.:NA Cas e No.: N A

CAS No.: 658066-35-4

40 CFR: 18 0.661 MRIDNo. : NA



### FROM: B arry O ' Keefe

, Senio r

# Biologist/Ri**·** s k

# ~~**es** r 

# Bl

Steve Funk

, Senior Chemist 

## >f**~** Whang Phang

, Senior Toxicologist · Ri sk Assessme n t B ranch III

## ~ . Health Effec t s Divi s ion (7509P) 

# Y 

# 0'4

THROUGH: Christine Olinger, Chief /}

## /~ /

Risk Assessment Branc h III**~/** 

### _ Health E f fects Division (7509P )

TO: Marcel Howar d

, Risk Management Team # 20 Fungicide Branch

R egistrat i o n D ivision (7505P)

The registrant

, Bay er C ropSci e nce
, is reque st in g new u ses offluopyram as a soiV in-furrow

treatme nt for cotton and peanut, and as a seed treatme nt to cotton and soybean. A l so, postemergent application to peanut by o ve rh ead c h emigation i s prop osed. Additionally, new rotational crop data have been su bm itted to support proposed amended inadvertent t o l erances for

the ce r eal grains (crop group 15) a nd the forage

, fodder

, and straw of cerea l g r ains (crop group 16).

Pa ge 

### 1 of 

### 5 1

### Fluopyram Human Health Risk Assessment DP No. D414231

The Registration Division (RD) of OPP has requested t h at the Heal t h Effects Division (HED)

evaluate the hazard and exposure data and conduct dietar y, aggregate

, occupational and

residentia l exposure assessments, as needed, to estimate the r isk to human health that will result

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

exposures.

The toxico l ogy reeva l uat ion was performed by Whang Phang, the drinking water assessment was conducted by Mohammed Ruhman (EPA Environmen tal Fate and Effects Division (EFED)), the

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

Steve Funk, and the occupationa l and residential exposure assessment and aggregate human

health risk assessments were conducted by Barry O'Keefe.

Page 2 of 

### 5 1

### Fluopyram Human Health Risk Assessment DP No. D414231

Page 3 of 51 1.0 Executive Summary

................................ ................................ ................................ ........... 5

2.0 HE D 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 Ph ysical/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

Page 4 of 51 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 Ta bles

................................ ................ 47 Appendix F. International Residue Limit Status Sheet

................................ .......................... 50

### Fluopyram Human Health Risk Assessment DP No. D414231

Page 5 of 51 1.0 Executive Summary

Fluopyram, ( N

- [2

- [3

- chloro

- 5

- (trifluoromethyl)

- 2

- pyridinyl]ethyl]

- 2

- (trifl uoromethyl)benzamide) is a broad

- spectrum syste mic fungicide of the pyridinyl

- ethyl

benzamide group. It acts by inhibiting succinate dehydrogenase in the cell respir ation of fungi. The mechanism of toxicity in mammals is not clearly defined

.

Use Profile The registrant, Bayer CropScience

, is requesting new uses of fluopy ram , as follows : 1) A s a n at

planting soil/in

- furrow treatment for cotton and p eanut 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 wea r 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 grou p 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 non

occupational exposures expected. However, t he proposed agricultural uses w ill result in short

and intermediate

- term dermal and inhalation occupational exposure s from handl er a nd post

application activities.

H azard Characterization

The l iver was the target organ across specie s and exposure duration. Treatment

- related thyroid

effects were also observed at dose levels causing adverse liver perturbations in rats and mice. Decreased body weight w as a common clinical finding throughout the t oxicology 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

b ecause 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

Page 6 of 51 A n acute dietary endpoin t for the general populat ion (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 t his effect was

reversible within 48 hours and at tributed 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. Short

and 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

i ntermediate

- term i nhalation endpoints were selected from the multigeneration reproduction study in rats based on liver effects in the parental generation

. I nhalation toxicity is assumed to

be equivalent to o ral 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 assessment s are conservative and unrefined. The

assessments are based on reliable data and will not underestimate e xposure/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 e stimated drinking water concentration (EDWC) was incorporated directly into the dietary assessment ( 87.5 μg/L) and was calculated by PRZM

- GW modeling. Combined dietar y exposure from food and drinking water at the 95 th 

### percentile of

exposure utilized 1.8% of the acute population adjusted dose (aPAD) for the genera l US population, and 4.4% of the aPAD for children 1

- 2 years old, the population subgroup with the highest e stimated 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. A verage field trial

residues

, empirical or def ault processing factors, and 100% C T 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 pro posed 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 Ri sk

The a ggregate a cute and chronic risk s are equivalent to the acute and chronic dietary risk s and

are not of concern.

### Fluopyram Human Health Risk Assessment DP No. D414231

Page 7 of 51 Occupational Exposure/Risk

For the in

- furrow uses on cotton and peanut, n on

- cancer risk estimates for dermal ( baseline ) and

inhalation (no respirator) s hort

- and intermediate

- term occupational handler exposures all

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

concern (LOC) , with MOEs ranging from 1,4 00 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,

n on

- cancer risk estimates for dermal and inhalation s hort

- 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 n ew 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 lab els 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 Popula tions," 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 establish ing tolerances for residues of fluopyram.

### Fluopyram Human Health Risk Assessment DP No. D414231

Page 8 of 51 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 re ference 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 Pestici de 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

T he 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 sam ples 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 ( MRL s) established for soybean or

### Fluopyram Human Health Risk Assessment DP No. D414231

Page 9 of 51 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

whe re 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 l ess fluopyram in the livestock diets. The tolerances for the livestock commodities need to be lowered. Calculated values were adjusted slightly to a ffect 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 expr ession 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

Page 10 of 51 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 tria l 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 th at 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 ca nnot 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 p rimary 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 n ot support this assertion, possibly

### Fluopyram Human Health Risk Assessment DP No. D414231

Page 11 of 51 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 commo dity 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 re vised 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), Propulse TM 

### (264

- 1084), Luna ® 

### Tranquility (EP A 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 r eviewed 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) a nd 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 In troduction

Fluopyram (AE C656948) is a fungicide with a broad spectrum of activity against numerous fungal diseases, including Ascomycetes, leaf spots, molds, sc a b, 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 th e inhibition of the enzyme succinate dehydrogenase (complex II) within the fungal mitochondrial respiratory chain, thus blocking electron transport. Fluopyram is a Group 7 fungicide.

### Fluopyram Human Health Risk Assessment DP No. D414231

Page 12 of 51 3.1 Chemical Identity

Table 3.1. Fluopyram Nomenclature

. Chemical structure

Common name Fluopyram

Company experimental name AE C656948

IUPAC name N

- [2

- [3

- c hloro

- 5

- (trifluoromethyl)

- 2

- pyridyl]ethyl]

- α,α,α

- trifluoro

- o

- toluamide

CAS name N

- [2

- [3

- c hloro

- 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

- (T rifluoromethyl)

- benzamide



### 3.2 Physical/Chemical Characteristics

Fluopyram is not a highly lipophilic molecule (log K OW 

### = 3.3) and is not expected to pass the dermal barrier, pass through human milk

, or bioaccumulate in significant quantity. Emp i rical 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

admini stration. Fluopyram is persisten t in soil ( its half

- life is 4 64 days) w ith 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 summ ary 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) A s a n at

planting soil/in

- furrow treatment for cotton a nd p eanut 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)

.

### Fluopyram Human Health Risk Assessment DP No. D414231

Page 13 of 51 The proposed Luna ® 

### Privilege label requires occupational handlers to wear the following personal protective equipment (PPE): long sleeved shirt s, 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 soc ks, 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 ] 0.003472 a

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 ] 0.001983 a

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 request ed proposed rotational crop restrictions for the following fluopyram product labels: Fluopyram ST (EPA Reg. No. 264

- RRAT ), Luna ® 

### Privilege (EPA Reg. No. 264

- 1078), Propulse TM 

### (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 doc ument for this action ( Funk, S., 05/12/2014, D420271). The

### Fluopyram Human Health Risk Assessment DP No. D414231

Page 14 of 51 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

cl arify th at c rops 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 foo d/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, ca nola, 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 p eanut, 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 applicati on 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 expo sed 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 resid ential 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 re gistered 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 cond itions 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 di etary

### Fluopyram Human Health Risk Assessment DP No. D414231

Page 15 of 51 patterns among specific subgroups.

4.0 Hazard Characterization and Dose

- Response Assessment

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

11/23/201 1 , 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 (thyr oid 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 Toxi cological Effects

L iver effects and d ecreased 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. L iver effect s were characterized by increased liver weight, hepatocellular hypertrophy, hepatocellular vacuolation, increased mitosis and hepatocellular necrosis

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

effects in rodent s 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 weigh t and hyperplasia

. C hanges in thyroid hormon e level s (T 3 

### & T 4 

### ) 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 t o have no genotoxic potential.

Fluopyram is not a developmental toxicant, nor did it adversely affect reproductive parameters. No evidence of qualitative or quantitative susceptibility w as observed in these studies

.

In an acute neurotoxicity study, transient decreased motor activity was seen only on the day of treatment, but no other finding s demonstrating neurotoxicity w ere found. In addition, no neurotoxicity was observed in the subchronic neurotoxicity study in the pre sence 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 ; t he percentage absor bed was approximately 93% of the administered dose. The

max imal plasma concentration was reached at 15 h ou rs in males and 11 h ou rs 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 small er extent to the kidney s. T he elimination results showed that 53

- 65% of administered radioactivity was eliminat ed 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 high est radioactivity level was found in the liver (0.4 to 1.0% of the

### Fluopyram Human Health Risk Assessment DP No. D414231

Page 16 of 51 administered radioactivity )

. Fluopyram was extensively metabolized and more than 29

metabolites were identified. T hree 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 methyl

sulfoxide, 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 F actor for Infants and Children (FQPA Safety Factor)

The FQPA safety factor can be reduced to 1x b ecause (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 uncertain ties in the exposure database.

4.2.1 Completeness o f the Toxicology Database

T he toxicology database for fluopyram is complete, and the available studies are adequate to characterize potential pre

- and/or post

- natal risk s for infants and childr en , 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 N eurotoxicity

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 limite d 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 c hronic/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

con sequence of the systemic effects and not direct neurotoxicity.

4.2.3 Evidence o f Sensitivity/Su sceptibility in the Developing o r Young Animal

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

- generation reproduction in rats d emonstrate no evidence of increased susceptibility in the developing or young animals which were exposed during pre

- or post

- natal periods.

### Fluopyram Human Health Risk Assessment DP No. D414231

Page 17 of 51 4.2.4 Residual Uncertainty in the Exposure Datab ase

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 fl uopyram 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 D eparture 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,

a n 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 th e 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 intermediate

term incidental oral exposure (though these endpoints are not nece ssary for this risk assessment since no residential uses are proposed) . The LOAEL of 82. 8 mg/kg/day was based on c linical pathology changes, increased liver weight

, centrilobular hypertrophy in parents, and decreased body weight (

- 8.1%, p<0.05) and body w eight 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 short

and intermediate term dermal exposure.

4.3.2 Recommendation for Combining Ro utes 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 w ere not observed at the LOAELs of

studies selected for the as sessment 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

Page 18 of 51 based on clinical spleen and thymus effects accompanied by clinical pathology and body weight changes. The refore, it is not appropriate to combine these routes of exposure for risk assessment.

4.3.3 Cancer Classification and Risk Assessment Recommendation

T he registrant , Bayer CropScience, submitted a new series of mechanistic studies. These s tudies have been reviewed and evaluated by the CARC. The CARC classifie d 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 base d on convincing evidence that non

genotoxic mode s of action for liver tumors in rats and thyroid tumors in mice ha ve been established and that the carcinogenic effects have been demonstrated as a result of a mode of action dependent on activation of the CA R / 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 con cern 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 Fluopy ram for Use in Dietary and Non

Occupational Human Health Risk Assessments

.

Exposure/

Scenario Point of

Departure Uncertainty/FQPA

Safety Factors RfD, PAD,

Level of

Concern for

Risk

Assessment Study and Toxicological Effects

Acute Dietary (General Population, including

Infants and Children) NOAEL=

50 mg/kg/day UF A = 10 X

UF H =10 X FQPA SF=1 X 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 UF A = 10 X

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

= 0.0 12 mg/kg/day

cPAD = 0.0 12 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.

### Fluopyram Human Health Risk Assessment DP No. D414231

Page 19 of 51 Table 4

. 3

. 4. 1

. Summary of Toxicological Doses and Endpoints for Fluopy ram for Use in Dietary and Non

Occupational Human Health Risk Assessments

.

Exposure/

Scenario Point of

Departure Uncertainty/FQPA

Safety Factors RfD, PAD,

Level of

Concern for

Risk

Assessment Study and Toxicological Effects

Incidental Oral

Short

- Term (1

- 30 days) and

Intermediate

Term (1

- 6 months) NOAEL=

14.5 mg/kg/day UF A = 10 X

UF H =10 X FQPA SF=1 X 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

preput ial separation in offspring.

Dermal Short

Term (1

- 30 days) and

Intermediate

Term (1

- 6 months) NOAEL=

300 mg/kg/day UF A = 10 X

UF H =10 X FQPA SF=1 X 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

Intermediate

Term (1

- 6 months) NOAEL=

1 4 .5 mg/kg/day UF A = 10 X

UF H =10 X FQPA SF=1 X 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 b ody 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. UF A = extrapolation from anima l to human (interspecies). UF H = 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 expos ure. 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 Short

Term (1

- 30 days) and

Intermediate

Term (1

- 6 months) NOAEL=

300 mg/kg/day UF A = 10 X

UF H =10 X 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

.

### Fluopyram Human Health Risk Assessment DP No. D414231

Page 20 of 51 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

Intermediate

term (1

- 6 months) NOAEL=

1 4 .5 mg/kg/day UF A =10 X

UF H =10 X Occupation al

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 secondar y 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. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). MOE = margin of exposure. LOC = level of concern. 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 (D38 5636, 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 rotation al 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 C 656948

- 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 as sessment 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

### Fluopyram Human Health Risk Assessment DP No. D414231

Page 21 of 51 fluopyram and its metabolites AE C656948

- benzamide, AE C656948

- E

- olefine, AE C656948

- Z

olefine and AE C656948

- 7

- hydroxy, and in hens are fluopyram and its metabolites AE C656 948

- benzamide, AE C656948

- E

- olefine, and AE C656948

- Z

- olefine.

A summary of m etabolites and d egradates to be included in the r isk a ssessment and t olerance

e xpressions 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 R isk 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 req uirements 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

- plant ing plus foliar treatment yielded quantifiable residues ( Highest

### Fluopyram Human Health Risk Assessment DP No. D414231

Page 22 of 51 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 res ults.

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 LAFT 3 HAFT 3 Median 3 Mean 3 SD 3

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.

### Fluopyram Human Health Risk Assessment DP No. D414231

Page 23 of 51 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 pro cessing 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 OCSP P 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 l ivestock (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 c rop 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 est imated 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 a re 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. Esti mation of Secondary Residues and Livestock Tolerances from Use of Fluopyram

.

Commodity Expected Residue Total (ppm) Tolerance (ppm)

Milk 0.02 0.06

Muscle/Meat (cattle 1 ) 0.03 0.05

Fat (cattle 1 ) 0.02 0.05

Meat By

- Products (cattle 1 ) 0.22 (liver), 0.03 (kidney) 0.40

### Fluopyram Human Health Risk Assessment DP No. D414231

Page 24 of 51 Table 5. 2 .2. Esti mation 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

1 Also 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 month s for the cereal grains (except rice). The rotational cro p 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 soybean s 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 e s timated surface water and ground w ater 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 cott on, 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. Th ese 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

Page 25 of 51 For the human health risk assessment, the highest relevant EDWCs are recommended.

Table 5.3

. Estimated Surface and Ground W at er Concentrations for Fluopyram

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

Acute 19 .4 87.5 a

Chronic (non

- cancer) 4.90 76.8 a

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

T he 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.

T he chronic dietary analysis was unrefined conservative dietary assessment that included average residue level s, 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 95 th 

### 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 95 th 

### 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 drin king 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

Page 26 of 51 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 & Drinki ng Water ) Exposure and Risk for Fluopyram

.

Population Subgroup Acute Dietary
( 

### 95 th 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 2 9

Children 3

- 5 years old 0.015110 3.0 0.002664 22

Children 6

- 12 years old 0.009693 1.9 0.001778 1 5

Youth 13

- 19 years old 0.006369 1. 3 0.001350 11

Adults 20

- 49 years old 0.007177 1.4 0.001776 1 5

Adults 50+ years old 0.006934 1. 4 0.001762 1 5

Females 13

- 49 years old 0.007385 1. 5 0.001777 1 5

* 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 label s
, fluopyram is not intended for use by homeowners, or by occupational handlers in residential settings. Therefore, non

occupational/residential r isk assessments have not been conducted

.

6.2 Residential Bystander Post

- application Inhalation Exposure

Volatilization of pesticides may be a source of post

- application inhalati on exposure to

### Fluopyram Human Health Risk Assessment DP No. D414231

Page 27 of 51 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 Screeni ng 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 analysi s 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 t he 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 hydr aulic 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 Exposur e/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, neith er 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 me chanism of toxici ty finding as to fluopyram and any othe r 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 co mmon 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

Page 28 of 51 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 Chara cterization

9.1 Short

- /Intermediate

- Term Handler Risk

Fluopyram is proposed to be applied as a n at

- planting soil/in

- furrow treatment for cotton and

p eanut, and as a seed treatment to cotton and soybean

. The at

- planting soil/in

- furrow treatment

for cotto n 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 occupationa l 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. 2 64

- 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 i n

- f

urrow u se on c otton and p eanut, and the p ost

- e mergent c hemigation use on p eanuts

t he 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) Applyi ng sprays via groundboom equipment. The dermal and inhalation s hort

- 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 expo sure 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 s eed t reatment u se on c otton & s oybean s eeds , t he 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. R isk estimates for dermal and inhalatio n s hort

- 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.

### Fluopyram Human Health Risk Assessment DP No. D414231

Page 29 of 51 9.2 Short

- /Intermediate

- Term Post

- Application Risk

9.2.1 Dermal Post

- application Risk

For the i n

- f

urrow u se on c otton and p eanut and the p ost

- e mergent c hemigation use on p eanuts

t he quantitative dermal post

- application exposure/risk assessment developed for workers is based

on the s cenarios 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 exposure s 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 AR TF 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 f or agricultural crops were estimated using HED standard values where it is assumed that the initial residue on treated foliage is 2 5 % of the application rate and the residues degrade at a rate of 10% per day. The occupational post

- application non

- cancer M OEs 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 val ues for the fraction of the application rate available for transfer after a foliar application (F AR 

### ). 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 F AR 

### 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; weat her conditions (e.g., humidity); or many other difficult to quantify factors. Although witnessed across multiple chemicals, this range in F AR 

### values is not expected when considering DFR data for a single chemical. At this time, the ARTF submission did no t 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 f luopyram (i.e., there is a small chance that the F AR 

### value may

### Fluopyram Human Health Risk Assessment DP No. D414231

Page 30 of 51 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 post

application 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 d uration (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 the se 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 i n 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 chemica l

specific 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 postapplicati on 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 T oxicity C ategory III by the acute oral and dermal route s of exposure and Toxicity Category IV for acute inhalation, eye irritation potential and skin irrita tion 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 label s 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

- HQ

O PP

- 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

Page 31 of 51 In addition, the Agency is continu ing 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 pos t

- 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

handle rs. 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 occupation al postapplication inhalation exposure scenarios.”

10.0 References

O’ Keefe, B., 05 / 30 / 201 4
, D 419530

. 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., 0 9 / 23 /2011, D387587 and D 389081. 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 Resid ue 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 o f 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 R ice)

.

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 /20 14 , TXR 0056961

. Fluopyram : Report of the Cancer Assessment Review

Committee

.

### Fluopyram Human Health Risk Assessment DP No. D414231

Page 32 of 51 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.

A ppendix A

. Toxicology Profile

A.1 Tox icology 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

- Waived a

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 Profile s

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 LD 50 > 2000 mg/kg III

870.1300 Acute inhalation

- rat 47372435

47372434 LC 50 at 4 hours > 5112 mg/m 3

LC 50 > 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/ova l 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 gl and: ↓ ceroid pigment (M), ↑ cortical vacuolation (F).

Non

- guideline 28

- day oral tox icity

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

tox icity 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 droplet s 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 fe tal body weight (5%), increased incidence

of two minor variations at both the visceral and skeletal

evaluation.

### Fluopyram Human Health Risk Assessment DP No. D414231

Page 35 of 51 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 r educed body weight gain and food consumption.

Developmental NOAEL = 25 mg/kg/day Developmental LOAEL = 75 mg/kg/day based on

d ecreased 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 b ased 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. Increase d kidney and liver weights. Increased incidence of liver hypertrophy.

Offspring NOAEL = 15 mg/kg/day Offspring LOAEL= 83 mg/kg/day based on d ecreased 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 b a sed on follicular cell hyperplasia in the thyroid gland, centrilobular to panlobular hypertrophy and hepatocellular single cell degeneratio n /necrosis in the liver.

Thyroid gland follicular cell adenomas in high dose males.

### Fluopyram Human Health Risk Assessment DP No. D414231

Page 36 of 51 Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

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

Classification/Doses Results

870.4300 Chronic

/carcino genicity 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 micro

nucleus 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

Page 37 of 51 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 (radiola beled fluopyram) after 14 days pre

treatment 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. A fter 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 fec es). 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 i dentified. It was proposed that three

main metabolit e 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) ( 14 C in position s 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 14 C 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 14 C

labeled fluopyram. 47372512; (2008)

Acceptable/non

- guideline
3 mg/kg for ♂ & 4.5 mg/kg for ♀ (Single oral dose; 14 C on pyridyl ring of

f l uopyram. ) Fluopyram was readily absorbed from the GI tract and distributed among almost all organs. P eak level was reached at approximately 1 hr after dosing in most organs with liver having the higher concentration than other organs. From peak level s, 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; 14 C

in the 2 & 6 p osition 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 a t 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

Page 38 of 51 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 [ 14 C]

– 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 we re 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 t o 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 i n 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 act ivities 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 cytochro me 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

Page 39 of 51 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 hepato cellular 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 l iver.

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 wer e 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) (hepato

toxicity 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 incre ases 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 in crease in TSH level after 14 days. )

Non

- guideline In

- vitro studies on

the potential

interactions with thyroid peroxid a se

catalyzed reactions 47372518; (2008)

Acceptable /non

- guideline 300 μM Fluopyram at 300 μM did not affect thyroid per oxidase ( TP O)

- 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

- poin ts with no

obvious time

- related trends, Plasma TSH levels were comparable to controls.

### Fluopyram Human Health Risk Assessment DP No. D414231

Page 40 of 51 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 a nd 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 phenobarbital

treated 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 prolifer ation 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 recove ry.

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

- guideli ne 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 fluopyra m

- 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 m ice.

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 k nockout 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 DNA

Synthesis 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 cytotoxici ty 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 activit y 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.

### Fluopyram Human Health Risk Assessment DP No. D414231

Page 42 of 51 Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

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

Classification/Doses Results

Non

- guideline Enzyme and DNA

Synthesis 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. Epide rmal 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 flu opyram 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 relat ionship 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

.

### Fluopyram Human Health Risk Assessment DP No. D414231

Page 43 of 51 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

mortal ities 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 m g/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 a nd 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 pituit ary 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.

### Fluopyram Human Health Risk Assessment DP No. D414231

Page 44 of 51 Appendix B

. Physical/Chemical Properties

Table B 1. 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 (pK
a ) 0.5 (23 oC) MRID 47372243

Octanol/water partition coefficient Log(K OW ) 3.3 MRID 47372245

UV/visible absorption spectrum Peak max at 270 nm MRID 47372237

### Fluopyram Human Health Risk Assessment DP No. D414231

Page 45 of 51 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 AH ETF . EPA has reviewed all the studies supporting these multi

- pesticide generic exposure databases, and h as 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.

### Fluopyram Human Health Risk Assessment DP No. D414231

Page 46 of 51 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 T otal A application R ate. 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.

### Fluopyram Human Health Risk Assessment DP No. D414231

Page 47 of 51 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

Rate a (lb ai/A ) Area

Treated Daily b (A/day) Unit Exposure d Daily Exposure e (mg/kg/day) MOE f

Baseline

Dermal c (mg/lb ai) PPE

- G

Dermal c (mg/lb ai) Baseline

Inhalation c (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.

### Fluopyram Human Health Risk Assessment DP No. D414231

Page 48 of 51 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

Rate b

lb ai/lb

seed Amount of

Seed Treated

or Planted Per Day d lb seed/day Dermal

Unit Exposure c mg/lb Inhalation

Unit Exposure c mg/lb Dermal

Dose e mg/kg/day Inhalation

Dose f mg/kg/day Dermal

MOE f

LOC = 100 Inhalation

MOE h

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 pe r day from HED Exposure Science Advisory Council Interim Policy 15.1 and the BEAD memo “Acres Planted Per Day and Seeding Rat es 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 (m g/kg/day). Level of concern = 100.

### Fluopyram Human Health Risk Assessment DP No. D414231

Page 49 of 51 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 application a (μg/cm 2 ) Work Activity &

Maximum Transfer

Coefficient b
(cm 2 /hr) Daily Dose c

(mg/kg/day) MOE d

(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/cm 2 ) = application rate (lb ai/A) x (1

- daily dissipation rate) t x 4.54E+8 μg/lb x 24.7E

- 9 A/cm 2 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)

### Fluopyram Human Health Risk Assessment DP No. D414231

Page 50 of 51 Appendix F

. International Residue Limit Status Sheet



## Fluopyram (080302 )

Summary of US and International Tolerances and Maximum Residue Limits Residue Definition :
US Canada Mexico 2 

### Codex 3

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)

benzam ide, all expressed as fluopyram

.



### Commodity 1 

### Tolerance (ppm) /Maximum Residue Limit (mg/kg)

US Canada Mexico 2 

### Codex 3

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

### Fluopyram Human Health Risk Assessment DP No. D414231

Page 51 of 51 Summary of US and International Tolerances and Maximum Residue Limits Residue Definition :
US Canada Mexico 2 

### Codex 3
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. MR Ls indicated as proposed have not been finalized by the CCPR and the CAC.