Fluopyram Human Health Risk Assessment DP No. D385636

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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

OFFICE OF

CHEMICAL SAFETY AND

POLLUTION PREVENTION

MEMORANDUM

Date: November 23, 2011

SUBJECT: Fluopyram: Human Health Risk Assessment for Proposed Uses on Apples, 

Bananas (Import only), Cherries (Sweet and Tart), Dried Beans, Peanuts, Potatoes, Strawberries, 

Sugar Beets, Tree Nuts, Watermelon and Wine Grapes.

PC Code: 080302 DP Barcode: D385636

Decision No.: 402628 Registration No.: 264-RNTI

Petition No.: 8F7463 Regulatory Action: Section 3

Risk Assessment Type: Single Chemical/Aggregate Case No.: NA

TXR No.: NA CAS No.: 658066-35-4

MRID No.: NA 40 CFR: 180.xxx(pending)

FROM: Sheila Healy, Risk Assessor

Leung Cheng, Chemist

Barry O’Keefe, Biologist

Whang Phang, Toxicologist

Risk Assessment Branch III

Health Effects Division (7509P)

THROUGH: Paula Deschamp, Chief

Risk Assessment Branch III

Health Effects Division (7509P)

AND

Ray Kent, Designated Reviewer

Richard Loranger, Designated Reviewer

Risk Assessment Review Committee

TO: Shaja Joyner/Lisa Jones, Risk Management Team #20

Fungicide Branch

Registration Division (7505P)
Fluopyram Human Health Risk Assessment DP No. D385636

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1.0 Executive Summary........................................................................................................... 4

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

2.1 Data Deficiencies/Conditions of Registration .............................................................. 7

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

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

2.2.2 International Harmonization..................................................................................... 9

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

2.2.4 Revisions to Petitioned-For Tolerances.................................................................. 12

2.3 Label Recommendations.............................................................................................. 13

2.3.1 Recommendations from Residue Reviews.............................................................. 13

2.3.2 Recommendations from Occupational Exposure Assessment.............................. 13

3.0 Introduction...................................................................................................................... 13

3.1 Chemical Identity ......................................................................................................... 14

3.2 Physical/Chemical Characteristics ............................................................................. 14

3.3 Pesticide Use Pattern.................................................................................................... 14

3.4 Anticipated Exposure Pathways................................................................................. 16

3.5 Consideration of Environmental Justice.................................................................... 16

4.0 Hazard Characterization and Dose-Response Assessment.......................................... 17

4.1 Toxicology Studies Available for Analysis................................................................. 17

4.2 Absorption, Distribution, Metabolism, & Elimination (ADME)............................. 17

4.2.1 Dermal Absorption................................................................................................... 18

4.3 Toxicological Effects .................................................................................................... 18

4.4 Safety Factor for Infants and Children (FQPA Safety Factor) ............................... 19

4.4.1 Completeness of the Toxicology Database.............................................................. 19

4.4.2 Evidence of Neurotoxicity........................................................................................ 19

4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal........ 19

4.4.4 Residual Uncertainty in the Exposure Database ................................................... 19

4.5 Toxicity Endpoint and Point of Departure Selections.............................................. 20

4.5.1 Dose-Response Assessment...................................................................................... 20

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment..... 20

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

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

Assessment............................................................................................................................... 21

4.6 Endocrine Disruption................................................................................................... 23

5.1 Metabolite/Degradate Residue Profile ....................................................................... 23

5.1.1 Summary of Plant and Animal Metabolism Studies............................................. 24

5.1.2 Summary of Environmental Degradation.............................................................. 25

5.1.3 Comparison of Metabolic Pathways....................................................................... 25

5.1.4 Residues of Concern Summary and Rationale ...................................................... 26

5.2 Food Residue Profile .................................................................................................... 29

5.3 Water Residue Profile.................................................................................................. 31

5.4 Dietary Risk Assessment.............................................................................................. 31

5.4.1 Description of Residue Data Used in Dietary Assessment.................................... 31

5.4.2 Percent Crop Treated Used in Dietary Assessment .............................................. 32

5.4.3 Acute Dietary Risk Assessment............................................................................... 32

5.4.4 Chronic Dietary Risk Assessment........................................................................... 32
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5.4.5 Cancer Dietary Risk Assessment............................................................................. 33

5.4.6 Summary Table......................................................................................................... 33

6.0 Residential (Non-Occupational) Exposure/Risk Characterization ............................. 35

6.1 Residential Handler Exposure .................................................................................... 35

6.2 Residential Bystander Post-application Inhalation Exposure ................................. 35

6.3 Spray Drift.................................................................................................................... 35

7.0 Aggregate Exposure/Risk Characterization.................................................................. 35

7.1 Acute Aggregate Risk................................................................................................... 36

7.2 Short- and Intermediate-Term Aggregate Risk ........................................................ 36

7.3 Chronic Aggregate Risk .............................................................................................. 36

7.4 Cancer Aggregate Risk ................................................................................................ 36

8.0 Cumulative Exposure/Risk Characterization ............................................................... 36

9.0 Occupational Exposure/Risk Characterization ............................................................ 36

9.1 Short-/Intermediate- /Cancer Handler Risk.............................................................. 36

9.2 Short-/Intermediate-/Cancer Post-Application Risk ................................................ 37

9.2.2 Inhalation Post-application Risk............................................................................. 38

10.0 References......................................................................................................................... 39

Appendix A. Toxicology Profile and Executive Summaries .................................................. 40

A.1 Toxicology Data Requirements................................................................................... 40

A.2 Toxicity Profiles............................................................................................................ 41

A.3 Hazard Identification and Endpoint Selection.......................................................... 47

A.4 Executive Summaries................................................................................................... 50

Appendix B. Metabolism Summary Table ............................................................................... 81

Appendix C. Physical/Chemical Properties............................................................................. 94

Appendix D. Review of Human Research................................................................................ 95

Appendix E. Occupational Exposure/Risk Summary Tables................................................ 96

Appendix F. International Residue Limit Status Sheet........................................................ 104
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1.0 Executive Summary

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

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

The mechanism of toxicity in mammals is not clearly defined. Bayer CropSciences (BCS) 

submitted fluopyram as a Global Joint Review to USEPA, Canada (PMRA) and Germany (BVL)

in 2008. BCS initially proposed tolerances on practically all crop groups, hops, and globe 

artichoke. Independent hazard evaluations in the US and Canada both yielded the conclusion 

that fluopyram is a likely human carcinogen and the resulting lifetime cancer risks from the 

proposed array of crop uses were of concern. Consequently, BCS withdrew a majority of the 

primary crops initially proposed for this registration action and expanded the original rotatable 

crops of alfalfa and cotton to include canola, soybean, and cereals grains except rice.

Use Profile: The proposed uses of fluopyram addressed in this document are: apples, bananas 

(no US registration), cherries (sweet and tart), dried beans (selected), peanuts, potatoes, 

strawberries, sugar beets, tree nuts, watermelon, and wine grapes.

The proposed formulated end-use product is Fluopyram 500 SC Fungicide, a liquid formulation 

containing 41.5% ai (4.16 lb /gal) fluopyram. Applications of fluopyram may be applied to

agricultural crops using ground (chemigation, groundboom sprayers, airblast sprayers, low 

pressure hand wand sprayers, and backpack sprayers) or aerial equipment at maximum single 

rates ranging from 0.092 to 0.22 lb ai/A. Multiple applications may be made per season, up to a 

maximum of 0.45 lb ai/season. Applications may be made in greenhouses of 10 acres or larger 

for strawberries and watermelon. Preharvest intervals (PHIs) range from 0 to 14 days and the 

restricted entry interval (REI) is 12 hours. 

These actions will be the first registrations in the US. Registration is pending in the European 

Union and concurrent petitions are being reviewed in Canada. 

Human Health Risk Assessment

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

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

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

database. Liver tumors were observed in female rats and thyroid tumors, in male mice in chronic 

feeding studies. 

Fluopyram is classified as “Likely to be Carcinogenic to Humans” and a unit risk factor, Q1

*

, of 

1.55 x 10-2(mg/kg/day)-1 was used for the linear low dose extrapolation of cancer risk based on 

liver tumors in female rats. Fluopyram is not genotoxic or mutagenic. 

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

the acute neurotoxicity study in rats based on decreased motor and locomotor activity (NOAEL = 

50 mg/kg). Because this effect was reversible within 48 hours and attributed to generalized 

systemic toxicity, fluopyram is not considered a neurotoxicant. An acute endpoint attributable to 
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a single dose was not identified for females aged 13-49 years. The chronic 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). Inhalation endpoints, short- and intermediate-term, were selected 

from the multigeneration reproduction study based on liver effects in the parental generation;

inhalation and oral absorption equivalency is assumed (100%).

Fluopyram has low acute toxicity via the oral, dermal and inhalation routes of exposure. 

Fluopyram is not a skin or eye irritant or sensitizer under the conditions of the murine lymph 

node assay. 

Dietary Exposure (Food and Water)

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

The acute dietary food exposure assessment is conservative/unrefined, the chronic dietary

assessment is partially refined, and the cancer dietary assessment, highly refined. The 

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

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

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

and 100% crop treated values were utilized in the exposure estimates. Empirical or DEEMTM 

default processing factors were used. Combined dietary exposure from food and drinking water 

at the 95th percentile of exposure is estimated to be 0.021 mg/kg/day for the overall US 

population, equivalent to 4.2% of the aPAD. The population subgroup with the highest 

estimated acute dietary exposure to fluopyram is children 1-2 yrs old, with an estimated exposure 

at the 95th percentile of 0.042 mg/kg/day, equivalent to 8.4% of the aPAD. 

Chronic: A partially refined chronic dietary assessment was conducted. The assumptions of this 

dietary assessment included average field trial residues for all proposed crops and 100% crop 

treated (CT). Empirical or DEEMTM default processing factors were used. The surface water 

estimated drinking water concentration (EDWC) of 4.90 μg/L was incorporated directly into the 

dietary assessment. The results of the aggregate chronic dietary analysis for food and drinking 

water are below the Agency’s level of concern (<100% cPAD) for all population subgroups. 

Chronic dietary exposure was estimated at 0.00042 mg/kg/day for the US population (3.5% of 

the cPAD) and 0.0012 mg/kg/day (10% of the cPAD) for the most highly exposed population 

subgroup (children 1-2 yrs old). 

Cancer: The cancer dietary (food and drinking water) exposure estimate for the general US 

population is 2.9 x 10-6, with water contributing approximately 30% of the risk. The cancer 

dietary analysis included average residue levels, projected percent crop treated (PPCT) estimates 

based on the Market Leader and processing factors (empirical and default, commercial and 

household). Estimates were based on the maximum amount of acreage available for rotation 

following application to dry beans and potato. The DEEM analysis also assumed that all 

drinking water will contain fluopyram at the highest EDWC levels modeled by EFED for ground 

water or surface water. For these reasons it can be concluded that the cancer dietary analysis
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does not underestimate risk from chronic exposure to fluopyram.

Residential Exposure:

No residential uses for fluopyram have been proposed. 

Aggregate Risk:

Acute: Aggregate acute risk is equivalent to the acute dietary risk. There is potential acute 

exposure (~ 4.2% aPAD) via the diet (food and drinking water) as determined in Section 5.4.

Chronic: Aggregate chronic risk is equivalent to chronic dietary risk. There is potential chronic 

exposure (3.5% cPAD) via the diet (food and drinking water) as determined in Section 5.4. 

There are no proposed residential uses so short- or intermediate-term residential exposures are 

not likely to occur. Therefore neither short- nor intermediate-term aggregate risks were assessed. 

The aggregate cancer risk (food and drinking water) is 2.9 x 10-6(Table 5.4). The unit risk for 

fluopyram, Q1

*

, is 1.55x10-2(mg/kg/day) -1. The Q1

*

is based upon liver tumors in female rats 

and is expressed in human equivalents.

Occupational Exposure/Risk:

Agricultural Handlers: Occupational short-term (1 - 30 days) and intermediate-term (1 - 6 

months) dermal and inhalation exposures are expected for fluopyram handler activities 

associated with the proposed agricultural uses. 

A Margin of Exposure (MOE) greater than 100 for the inhalation and dermal routes of exposure

is deemed adequate to protect occupational fluopyram handlers. Non-cancer occupational risk 

estimates for dermal (with gloves) and inhalation short- and intermediate-term exposure 

durations all resulted in MOEs considerably greater than 100, and therefore, do not exceed 

HED’s level of concern (Table E1). MOEs for dermal (with gloves) exposure ranged from 

180,000 to 7,300 and MOEs for inhalation exposure ranged from 1,300,000 to 7,700. 

Handler cancer risks for private growers and commercial applicators were calculated for 

different exposure scenarios at different levels of personal protection. Handler cancer risk 

estimates for combined inhalation and dermal (with gloves) exposures for private growers ranged 

from 1.4 x 10-8to 5.6 x 10-7and for commercial workers ranged from 3.1 x 10-8to 8.8 x 10-7.

Agricultural Post-application: The occupational post-application non-cancer MOEs do not 

exceed HED’s level of concern (MOEs ≥100) with dermal MOEs ranging from 530 to 5,600 on 

the day of application (12 hours post-application).

Occupational post-application exposure scenarios for cancer risk estimates were assessed for 

individuals employed by multiple establishments (i.e., commercial or migratory farm workers) 

and were assumed to be exposed 30 days per year. The cancer risk estimates ranged from 5.1 x 
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10-7to 4.0 x 10-6. These estimates are considered conservative since the maximum application 

rate and shortest retreatment intervals were used to calculate the estimates.

Restricted Entry Interval: When postapplication risks are not a concern on day 0 (12 hours 

following application), the restricted entry interval (REI) is based on the acute toxicity of 

fluopyram technical material. Fluopyram is classified as Toxicity Category III by the acute oral 

and dermal routes of exposure, and Toxicity Category IV for acute inhalation, eye irritation 

potential, and skin irritation potential. Under the WPS for Agricultural Pesticides, active 

ingredients classified as acute toxicity categories III or IV for these routes are assigned a 12-hour 

REI. Therefore, the 12-hour REI that appears on the proposed label would be adequate. 

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 D) 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.

2.0 HED Recommendations

Pending submission of a revised Section B (see 2.3 Label Recommendations) and 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 other issues that 

would preclude granting conditional Section 3 registration for the requested uses of fluopyram, 

or establishing tolerances for residues of fluopyram. 

2.1 Data Deficiencies/Conditions of Registration

The following data are required as a condition of registration:

860.1900 Field Accumulation in Rotational Crops
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 The petitioner must submit extensive field rotational crop field trials conducted on canola, 

cereal grains (except rice), and soybean, and submit a repeat cotton trial due to crop failure.

In 2008, the Agency received data in support of the registrant’s proposed registrations and 

tolerances for a wide variety of primary crops in nearly all crop groups. These data included 

extensive rotational field trial data for alfalfa and cotton to support inadvertent tolerances and 

limited rotational field trial data for wheat, turnip, and mustard greens. Subsequent to the 2008 

petition, the registrant submitted a letter withdrawing their request for uses on numerous primary

crops. Thus, the Agency has concluded that extensive field rotational crop studies are required 

as a condition of registration to support the rotation to canola, cereal grains except rice, corn, and 

soybean following application of fluopyram to potato and dry beans. In addition, a repeat cotton 

trial is required as a condition of registration because of crop failure.

870.3465 90-Day Inhalation Toxicity

 The registrant must submit a subchronic inhalation study. 

Prior to 2010, the Agency frequently relied on oral toxicity studies to conduct inhalation risk 

assessments. In December 2009, the Agency sought expert advice and input from its Federal 

Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) on issues related to 

this route to route extrapolation approach in the absence of an inhalation toxicity study (i.e., the 

use of oral toxicity studies for inhalation risk assessment). Based on the SAP’s 

recommendations in the March 2, 2010 Final Report 

(http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html), the Agency has 

increased its focus on the uncertainties associated with route-to-route extrapolation and is 

presently requiring inhalation toxicity studies more frequently. The Agency has concluded that 

an inhalation toxicity study is required as a condition of registration to fully characterize the risk 

from inhalation exposure to fluopyram. 

The following data should be submitted with future uses:

875.2100 Foliar Dislodgeable Residue Dissipation

 Dislodgeable foliar residue (DFR), or turf transferable residue (TTR), studies may be 

required in the future if the use profile is expanded.

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

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

detection (GC/MSD) method, has been proposed for the enforcement of tolerances for fluopyram 

residues in/on crop commodities, and a high performance liquid chromatography method with 

tandem mass spectrometry detection (HPLC/MS/MS), Method 01079, has been proposed for the 
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enforcement of tolerances for residues of fluopyram and its metabolite, AE C656948-benzamide,

in livestock commodities. The validated limit of quantitation (LOQ) is 0.01 ppm for each 

analyte in each matrix. The proposed enforcement method for plant commodities (DFG Method 

S19) and livestock commodities (Method 01079) are deemed adequate as enforcement methods. 

Adequate HPLC/MS/MS methods were used for data collection for crop and livestock 

commodities. The FDA multiresidue methods of PAM Vol. I are suitable for the determination 

of fluopyram in non-fatty matrices (using Section 302), but are not suitable for detection of AE 

C656948-benzamide residues.

2.2.2 International Harmonization

Codex Maximum Residue Limits (CXLs) have been established for grape at 2 mg/kg and dried 

grapes (raisins) at 5 mg/kg, milk at 0.07 mg/kg, mammalian meat at 0.15 mg/kg, and edible offal 

mammalian (meat byproducts) at 0.7 mg/kg. For the purpose of international harmonization, 

HED is recommending establishment of US tolerances for wine grape at 2.0 ppm (raised from 

1.4 ppm), milk at 0.07 ppm (raised from 0.06 ppm), and hog meat byproducts at 0.70 ppm 

(raised from 0.45 ppm). An International Residue Limit Status sheet is attached (Appendix F).

The Codex MRL for grapes is based on field trials conducted in Europe, and is calculated by

rounding up of the statistically determined 1.3 mg/kg to 2 mg/kg. A US tolerance for dried 

grapes (raisins) is not needed as the tolerance request is for wine-type grapes only, which are not 

converted to raisins.

Harmonization of recommended US tolerances for meat and meat byproducts (other than hog) 

with Codex MRLs cannot be achieved. The Codex MRL for livestock is calculated on the basis 

of the diets listed in Annex 6 of the 2009 JMPR Report (OECD Feedstuffs Derived from Field 

Crops) and the use of a reasonable worst case diet/feed approach (RWCF) . The dietary burden 

was calculated using only grape pomace residue and 20% contribution to the Australian dairy

and beef cattle diets. The US tolerance was based on guidance “Revisions of Feedstuffs in Table 

1 of OPPTS Test Guideline 860.1000” and “Guidance on Constructing Maximum Reasonably

Balanced Diets (MRBD)”. Based on the US livestock diets (which does not include grape 

pomace) and the cattle feeding study, the meat byproduct (cattle, goat horse, sheep) tolerances 

need to be set at 1.1 ppm, a higher level than the 0.7 mg/kg Codex MRL for edible offal. 

Similarly, the US meat tolerances for these animals need to be set higher than the Codex MRL

(0.15 versus 0.1 ppm).

2.2.3 Recommended Tolerances

HED recommends that tolerances be established in/on the following commodities as indicated in 

Table 2.2.3.
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Table 2.2.3. Tolerance Summary for Fluopyram.

Commodity Proposed Tolerance 

(ppm)

Recommended/ 

Harmonized

Tolerance (ppm)

Comments; Correct Commodity 

Definition

(a)(1) It is recommended that tolerances be established for residues of the fungicide fluopyram (N-[2-[3-chloro-5-

(trifluoromethyl)-2-pyridinyl]ethyl]-2-(trifluoromethyl)benzamide), including its metabolites and degradates, in or 

on the commodities below. Compliance with the tolerance levels specified below is to be determined by 

measuring only fluopyram in or on the commodity.

Almond, hulls 8.0 8.0 Almond, hull

Apple 0.5 0.30

Apple, wet pomace 2.5 0.60

Banana (Import Tolerance) 1.0 1.0 Tolerance must include a 

footnote stating “No US 

registrations as of [date of FR 

notice].”

Beet, sugar, roots 0.10 0.04 Beet, sugar, root

Beet, sugar, tops 30 Remove Tolerance is not required.

Cherry 1.5 0.60

Grape, wine 2.0 2.0 Excludes grapes such as 

Thompson Seedless and Concord 

which may be used for purposes 

other than for wine. 

Nut, tree, group 14 and 

pistachio

0.05 0.05 Nut, tree, group 14

A separate tolerance is needed 

for pistachio; see below

Peanut 0.05 0.02

Pistachio 0.05 A separate tolerance is needed 

for pistachio.

Potato 0.05 0.02

Potato, processed potato waste 0.15 0.08

Strawberry 2.0 1.5

Watermelon 1.0 1.0

Vegetable, bean, dried, shelled 

(except soybean)

0.50 0.09 Bean, dry

(a)(2) It is recommended that tolerances be established for residues of the fungicide fluopyram (N-[2-[3-chloro-5-

(trifluoromethyl)-2-pyridinyl]ethyl]-2-(trifluoromethyl)benzamide), including its metabolites and degradates, in or 

on the commodities below. Compliance with the tolerance levels specified below is to be determined by 

measuring only the sum of fluopyram and its metabolite 2-(trifluoromethyl)benzamide, calculated as the 

stoichiometric equivalent of fluopyram, in or on the commodity.

Cattle, fat 0.10 0.11

Cattle, meat 0.10 0.15

Cattle, meat byproducts, except 

liver

0.10

1.1 Cattle, meat byproducts

Cattle, liver 1.2

Eggs 0.10 0.25 Egg

Goat, fat 0.10 0.11

Goat, meat 0.10 0.15
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Table 2.2.3. Tolerance Summary for Fluopyram.

Commodity Proposed Tolerance 

(ppm)

Recommended/ 

Harmonized

Tolerance (ppm)

Comments; Correct Commodity 

Definition

Goat, meat byproducts, except 

liver

0.10

1.1 Goat, meat byproducts

Goat, liver 1.2

Hog, fat 0.01 0.05

Hog, meat 0.01 0.05

Hog, meat byproducts, except 

liver

0.01

0.70 Hog, meat byproducts

Hog, liver 0.15

Horse, fat 0.10 0.11

Horse, meat 0.10 0.15

Horse, meat byproducts, except 

liver

0.10

1.1 Horse, meat byproducts

Horse, liver 1.2

Milk 1.2 0.07

Poultry, fat 0.05 0.20

Poultry, meat 0.03 0.15

Poultry, meat byproducts 0.20 0.60

Sheep, fat 0.10 0.11

Sheep, meat 0.10 0.15

Sheep, meat byproducts, 

except liver

0.10

1.1 Sheep, meat byproducts

Sheep, liver 1.2

(d) It is recommended that tolerances be established for indirect or inadvertent residues of fungicide fluopyram (N-

[2-[3-chloro-5-(trifluoromethyl)-2-pyridinyl]ethyl]-2-(trifluoromethyl)benzamide), including its metabolites and 

degradates, in or on the commodities below. Compliance with the tolerance levels specified below is to be 

determined by measuring only fluopyram in or on the commodity.

Alfalfa, forage 0.25 0.45

Alfalfa, hay 0.80 1.1

Canola 5.0 1.8

Corn, sweet, kernel plus cob 

with husk removed

0.10 Remove Tolerance is covered under 

Grain, cereal, group 15, except 

rice; see below

Cotton, gin byproducts 0.05 0.05

Cotton, undelinted seed 0.10 0.01

Grain, cereal, forage, fodder 

and straw, group 16, except 

rice; forage

8.0 4.0

Grain, cereal, forage, fodder 

and straw, group 16, except 

rice; hay, straw and stover

14 7.0

Grain, cereal, forage, fodder 

and straw, group 16, except 

rice; aspirated fractions

50 Remove Tolerance is not applicable.
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Table 2.2.3. Tolerance Summary for Fluopyram.

Commodity Proposed Tolerance 

(ppm)

Recommended/ 

Harmonized

Tolerance (ppm)

Comments; Correct Commodity 

Definition

Grain, cereal, group 15, except 

rice and sweet corn

3.0 1.5 Grain, cereal, group 15, except 

rice

Soybean, forage 8.0 4.0

Soybean, hay 30 15

Soybean, hulls 0.40 Remove Tolerance is not applicable.

Soybean, seed 0.30 0.10

2.2.4 Revisions to Petitioned-For Tolerances

Subsequent to the petition for establishment of tolerances and registration of uses on a wide 

variety of primary crops in nearly all crop groups, the petitioner submitted a letter withdrawing 

their request for certain crops. The petitioner also submitted a revised label specifying uses only 

on the following crops: apple; banana (no US registration); bean, dry; beet, sugar, root; cherry

(sweet and tart); grape,wine; nut tree crop group 14; peanut; pistachio, potatoes; strawberry; and 

watermelon. Therefore, HED is recommending revisions to the following proposed tolerances

because of use pattern revisions, use of primary crop residue data in place of field rotational crop 

data, harmonization with Codex MRLs and/or results from the NAFTA MRL calculator: 

 Apple wet pomace (0.60 ppm), peanut (0.02 ppm), processed potato waste (0.08 ppm), 

sugar beet root (0.04 ppm), and cotton undelinted seed (0.01 ppm). 

 Separate tolerances are recommended for the following commodities: apple (0.30 ppm),

cherry (0.06 ppm), dried beans (0.09 ppm), pistachio (0.05 ppm), potato (0.02 ppm) and 

strawberry (1.5 ppm).

 olerances for alfalfa and cotton commodities must be revised to be specified in terms of 

indirect or inadvertent residues of fluopyram. In addition, the recommended tolerances 

for alfalfa forage and hay are 0.45 ppm and 1.1 ppm, respectively. 

 Separate indirect or inadvertent residues of fluopyram are recommended for the 

following commodities: canola seed (1.8 ppm), grain, cereal, group 15 except rice (1.5 

ppm), grain, cereal, forage, fodder and straw, group 16, except rice; forage (4.0 ppm), 

grain, cereal, forage, fodder and straw, group 16, except rice; hay, straw and stover (7.0 

ppm), soybean, seed (0.10 ppm), soybean, forage (4.0 ppm), and soybean, hay (15 ppm). 

 For the purpose of harmonization with established Codex Maximum Residue Limits 

(CXLs), HED is recommending establishment of US tolerances for wine grape at 2.0 

ppm, milk at 0.07 ppm, and hog meat byproducts at 0.70 ppm. 

 Based on the maximum reasonable balanced dietary burdens, the following tolerances are 

recommended for the combined residues of fluopyram and AE C656948-benzamide in 

livestock commodities: For cattle, goat, horse, and sheep fat (0.11ppm), meat (0.15 
Fluopyram Human Health Risk Assessment DP No. D385636

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ppm), and meat byproducts (1.1 ppm); for hog fat and meat (0.05 ppm), for hog meat 

byproducts (0.70 ppm); for poultry fat (0.20 ppm), poultry meat (0.15 ppm), poultry meat 

byproducts (0.60 ppm); eggs (0.25 ppm) and milk (0.07 ppm).

 A tolerance need not be established for beet, sugar, tops as this commodity is no longer 

considered an animal feed item.

2.3 Label Recommendations

2.3.1 Recommendations from Residue Reviews

 The petitioner must submit proposed labels (with English translations if needed) for 

fluopyram uses on bananas in any countries from which the treated bananas may be 

imported into the US. The available data would support an application pattern of six 

applications of an SC formulation at 0.100 kg ai/ha/application (0.089 lb 

ai/A/application) with a 7-day retreatment interval (RTI) and a 0-day PHI. 

 The proposed label must be amended to specify minimum spray application volumes for 

wine grapes of 50 gallons per acre (GPA) for ground equipment. 

 For wine grapes, the proposed label should be amended to include a statement stating 

“Do not treat grapes such as Thompson Seedless and Concord which may be used for 

purposes other than for wine.” 

 The proposed labels must be amended to clarify that the unit for application rates is fluid

ounces per acre.

 Also, with the exception of the banana field trials and one grape field trial, no spray

adjuvants were used in any of the crop field trials. However, HED has recently reviewed 

bridging field trials conducted on strawberry, grape, cucumber, bulb onion, potato, 

lettuce, tomato, peach, apple and almond with and without addition of 0.125% v/v of a 

non-ionic surfactant (Induce®) and concluded that the addition of the NIS had no 

significant effect on the residue level concentration on these crops. Therefore, the 

product label must be amended to specify that non-ionic surfactants at a maximum of

0.125% v/v may be added to spray mixtures. 

 The label, under the rotational crop restrictions, must be amended to specify that canola, 

cereal grains (except rice) and soybean may be replanted 30 days following fluopyram 

application on dry beans and potato only, and that other crops not specified on the label 

may not be replanted following fluopyram-treated crops. 

2.3.2 Recommendations from Occupational Exposure Assessment

None

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

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

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

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

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

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

Group 7 fungicide. 

3.1 Chemical Identity

Table3.1. Fluopyram Nomenclature.

Chemical structure

Common name Fluopyram

Company experimental name AE C656948

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

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

(trifluoromethyl)benzamide

CAS registry number 658066-35-4

End-use product (EP) Fluopyram 500 SC Fungicide (4.16 lb/gal SC formulation; EPA File Symbol No. 

264-RNTI)

3.2 Physical/Chemical Characteristics

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

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

dermal absorption data estimate that less than 2% is absorbed via this route of exposure in 

humans and metabolism data in rats demonstrate rapid absorption with ~98% elimination with 

72 hours of administration. Fluopyram is persistent in soil (t 1⁄2 = 464 days) with very little 

(a)biotic degradation. Fluopyram, the major environmental residue and only compound modeled

for drinking water exposure, is mobile, soluble and stable in water.

3.3 Pesticide Use Pattern

CF3

N

H

O

N

Cl CF3
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Table 3.3. Summary of Directions for Use of Fluopyram

Applic. Timing;

Type; and 

Equipment

Formulation

[EPA File 

Symbol No.]

Applic. 

Rate 

(lb ai/A)

Max. No. 

Applic. 

per 

Season

Max. 

Seasonal 

Applic. Rate

(lb ai/A)

PHI

(days)

Use Directions and 

Limitations1

Apple

Postemergence;

Foliar spray;

Ground, or 

chemigation

4.16 lb/gal 

SC

[264-RNTI]

0.078-

0.222 NS 0.445 7

The proposed RTI is 7-14 

days.

Cherry 

Postemergence;

Foliar spray;

Ground, aerial, or 

chemigation

4.16 lb/gal 

SC

[264-RNTI]

0.092 NS 0.183 0

The proposed RTI is 5-7 

days. 

Dried shelled beans: bean (Lupinus spp., includes grain lupin, sweet lupin, white lupin, and white sweet lupin),

bean (Phaseolus spp., includes field bean, kidney bean, lima bean (dry), navy bean, pinto bean, tepary bean), bean 

(Vigna spp., includes adzuki bean, blackeyed pea, catjang, cowpea, Crowder pea, moth bean, mung bean, rice 

bean, southern pea, urd bean), other beans (broad bean (dry), chickpea, guar, lablab bean, lentil)

Postemergence;

Foliar spray;

Ground, aerial, or 

chemigation

4.16 lb/gal 

SC

[264-RNTI]

0.134 NS 0.268 14

The proposed RTI is 7-14 

days. Do not feed hay or 

threshings or allow

livestock to graze in treated 

areas.

Peanut

Postemergence;

Foliar spray;

Ground, aerial, or 

chemigation

4.16 lb/gal 

SC

[264-RNTI]

0.182-

0.222 NS 0.445 7

The proposed RTI is 14 

days. Do not feed hay or 

threshings or allow

livestock to graze in treated 

areas.

Potato 

Postemergence;

Foliar spray;

Ground, aerial, or 

chemigation

4.16 lb/gal 

SC

[264-RNTI]

0.130-

0.178 

(ground, 

chemigation)

0.092 

(aerial)

NS

0.356 

(ground, 

chemigation)

0.275

(aerial)

7

The proposed RTI is 5-7 

days. The grazing of 

livestock in treated areas 

within 7 days of 

application is prohibited.

Strawberry

Postemergence;

Drip/ 

chemigation, 

greenhouse spray

4.16 lb/gal 

SC

[264-RNTI]

0.222 NS 0.445

0 (drip 

application)

1 (greenhouse uses)

The proposed RTI is 5-7 

days. Applications may be 

made to strawberries 

grown in a greenhouse of 

10 acres or larger.

Sugar beet

Postemergence;

Foliar spray;

Ground, or 

chemigation

4.16 lb/gal 

SC

[264-RNTI]

0.111 NS 0.222 7

The proposed RTI is 5-7 

days. 
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Table 3.3. Summary of Directions for Use of Fluopyram

Applic. Timing;

Type; and 

Equipment

Formulation

[EPA File 

Symbol No.]

Applic. 

Rate 

(lb ai/A)

Max. No. 

Applic. 

per 

Season

Max. 

Seasonal 

Applic. Rate

(lb ai/A)

PHI

(days)

Use Directions and 

Limitations1

Tree nuts: almond, beech nut, Brazil nut, butternut, cashew, chestnut, chinquapin, filbert (hazelnut), hickory nut, 

macadamia nut (bush nut), pecan, pistachio, walnut [including black and English (Persian) walnuts]

Postemergence;

Foliar spray;

Ground, aerial, or 

chemigation

4.16 lb/gal 

SC

[264-RNTI]

0.104-

0.222 NS 0.445 14 The proposed RTI is 7-14 days.

Watermelon: watermelon (includes hybrids and/or varieties of Citrullus lanatus)

Postemergence;

Foliar spray;

Ground, or 

drip/chemigation

4.16 lb/gal 

SC

[264-RNTI]

0.078-

0.222 NS 0.445

0 (spray 

uses)

3 (greenhouse uses)

7 (drip 

applications)

The proposed RTI is 5-14 

days. Applications may be 

made to cucurbits grown in 

a greenhouse of 10 acres or 

larger.

Wine Grapes: varieties only such as but not limited to these varieties: Chardonnay, Cabernet sauvignon, Syrah, 

Merlot, Pinot Noir, and Zinfandel

Postemergence;

Foliar spray;

Ground, or 

chemigation

4.16 lb/gal 

SC

[264-RNTI]

0.078-

0.222 NS 0.445 7

The proposed RTI is 12-21 

days.

3.4 Anticipated Exposure Pathways

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

proposed new use of fluopyram on apples, cherries (sweet and tart), dried beans, peanuts, 

potatoes, strawberries, sugar beets, tree nuts, watermelon and wine grapes. Humans may be 

exposed to fluopyram in food and drinking water, since fluopyram may be applied directly to 

growing crops and application may result in fluopyram reaching surface and ground water 

sources of drinking water. There are no residential uses of fluopyram, so exposure in residential 

or non-occupational settings is not likely. In an occupational setting, applicators may be exposed 

while handling the pesticide prior to application, as well as during application. There is a 

potential for post-application exposure for workers re-entering treated fields.

3.5 Consideration of Environmental Justice

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

human health risk assessment, in accordance with US 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 
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procedures. In line with OPP policy, HED estimates risks to population subgroups from 

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

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

Extensive data on food consumption patterns are compiled by the USDA under the Continuing 

Survey of Food Intake by Individuals (CSFII) and are used in pesticide risk assessments for all 

registered food uses of a pesticide. These data are analyzed and categorized by subgroups based 

on age, season of the year, ethnic group, and region of the country. Additionally, OPP is able to 

assess dietary exposure to smaller, specialized subgroups and exposure assessments are 

performed when conditions or circumstances warrant. Whenever appropriate, non-dietary

exposures based on home use of pesticide products and associated risks for adult applicators and 

for toddlers, youths, and adults entering or playing on treated areas post-application are 

evaluated. Further considerations are currently in development as OPP has committed resources 

and expertise to the development of specialized software and models that consider exposure to 

bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific 

subgroups.

4.0 Hazard Characterization and Dose-Response Assessment

4.1 Toxicology Studies Available for Analysis

The toxicology database for fluopyram is complete for risk assessment. There are acceptable 

studies available for toxicity endpoint selection; they include: 1) subchronic oral toxicity studies 

in rats, mice, and dogs; 2) chronic oral toxicity studies in rats and dogs, 3) carcinogenicity 

studies in rats and mice; 4) developmental studies in rats and rabbits, 5) a reproduction study in 

rats; 6) acute and subchronic neurotoxicity studies in rats; 7) subchronic dermal toxicity and 

dermal penetration studies in rats; and 8) immunotoxicity study in rats. There is also a complete 

mutagenicity study battery, metabolism studies in rats, and several mechanistic studies related to 

the mode of action for tumor formation. The submitted mechanistic studies are, however,

insufficient to support the proposed mode of action for tumor formation. Further MOA studies 

are ongoing. 

4.2 Absorption, Distribution, Metabolism, & Elimination (ADME)

With oral dosing, fluopyram was rapidly absorbed from the GI tract of male and female rats. 

Based on the results obtained in bile duct cannulated male rats, the percentage absorbed was 

approximately 93% of the administered dose. The maximal plasma concentration was reached at 

15 hours in males and 11 hours in females post dosing (5 mg/kg). Kinetics were influenced by 

the dose level as Tmax ≥ 35 hours in animals receiving 250 mg/kg.

The absorbed fluopyram was quickly distributed within the central compartments of the body

(e.g. blood, liver, and kidney) and showed a distinctive preference towards the liver and to a 

smaller extent to the kidneys. The major part of the dosed radioactivity (53-65%) was eliminated

via feces; 32-41% was eliminated via the urine. After 72 hours, the fecal excretion was nearly 

completed. In both sexes, the urinary excretion showed a slightly different behavior, as a clear 

plateau level was not reached during the sampling period of seven days and renal excretion was 

still ongoing on a low level. Less than 0.07-0.09% of the administered dose was expired. After 
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168 hrs post dosing 91-99% of the administered radioactivity was eliminated via urine and feces. 

Residue analysis showed that the highest radioactivity level was found in the liver (0.4 to 1.0% 

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

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

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

observed.

4.2.1 Dermal Absorption

In vivo dermal absorption studies of Fluopyram SC 500 neat formulation (500 mg fluopyram/ml) 

and the spray dilution (0.5 mg/ml) were conducted in rats. The results showed that the dermal 

penetration, as a percentage of the administered dose, was 4.5% for the neat formulation and 

12.8% for the spray dilution. Refinement of the dermal absorption factors for the neat 

formulation and spray dilution was achieved by conducting a study under similar conditions in 

vitro using rat skin and human skin. A parallelogram 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 refined dermal absorption values for human skin were 

calculated to be 0.2% for the neat formulation and 1.9% for the spray dilution.

4.3 Toxicological Effects

Decreased body weight and liver effects were the common and frequent findings in the 

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

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

hypertrophy, hepatocellular vacuolation, increased mitosis and hepatocellular necrosis. In 

female rats of the carcinogenicity study, increased liver tumors were also observed. Liver effects 

in rodents were seen at lower dose levels than those in the dogs. Thyroid effects were found at 

dose levels similar to those that produced liver effects in rats and mice; effects consisted of 

follicular cell hypertrophy, increased thyroid weight and hyperplasia at dose levels ≥100 

mg/kg/day. Changes in thyroid hormone levels (T3& T4) and increased TSH were also seen in

rats in a subchronic toxicity study where these parameters were measured. In male mice, there 

was an increased incidence of thyroid adenomas. In the genotoxicity battery, fluopyram was 

shown to have no genotoxic potential. The registrant is currently conducting mechanistic studies 

to demonstrate a mode of action for tumor formation.

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

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

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

treatment, but no other finding demonstrating neurotoxicity was found. In addition, no 

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

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

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

on these two metabolites were negative. 

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

4.4.1 Completeness of the Toxicology Database

As described in Section 4.1, the toxicology database for fluopyram is complete and includes the 

immunotoxicity study and neurotoxicity screening battery. The available studies are adequate to 

characterize potential pre- and/or post-natal risk for infants and children

4.4.2 Evidence of Neurotoxicity

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

transient decreases in motor and locomotor activities in the acute neurotoxicity study on the day

of treatment and limited use of hind-limbs and reduced motor activity in the rat 

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

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

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

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

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

consequence of the systemic effects and not direct neurotoxicity.

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

As mentioned in Section 4.3, the available developmental toxicity studies in rats and rabbits and 

the multi-generation reproduction in rats demonstrate no evidence of increased susceptibility in 

the developing or young animals which were exposed during pre- or post-natal periods.

4.4.4 Residual Uncertainty in the Exposure Database

There are no residual uncertainties in the exposure database. Although extended field rotational 

crop studies are required as a condition of registration, the rotational crop tolerances used in the 

dietary risk assessment are not expected to underestimate exposure because they are based on 

direct foliar treatment crop residue data as opposed to residues taken up by plants through roots 

from treated soil. The acute dietary exposure assessment was performed using tolerance level 

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

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

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

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

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

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

dietary exposure to fluopyram.
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4.5 Toxicity Endpoint and Point of Departure Selections

4.5.1 Dose-Response Assessment

The details for selecting toxicity endpoints and points of departure for various exposure 

scenarios are presented in the Appendix A.

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

to establish points of departure for the risk assessment. For example, for acute oral exposure, an 

acute neurotoxicity study in rats has been used to select the dose and endpoint for establishing 

the aRfD (0.5 mg/kg/day) for the general population. The LOAEL of 100 mg/kg is based on 

decreased motor and locomotor activity in females. The effect is attributable to general toxicity. 

For chronic dietary exposure, a combined chronic/carcinogenicity study in rats was used to select 

the dose (NOAEL=1.2 mg/kg/day) and endpoint for establishing the chronic reference dose 

(cRfD; 0.012 mg/kg/day). The toxicity endpoint was based on follicular cell hypertrophy in the 

thyroid and increased liver weight with liver gross pathological and histopathological findings at 

6.0 mg/kg/day. The point of departure derived from this study is protective of the adverse 

thyroid effects observed in the mouse carcinogenicity study seen at 105 mg/kg/day. A 2-

generation reproduction study in rats was used to select the dose (NOAEL = 14.5 mg/kg/day) 

and endpoint for short- and intermediate-term incidental oral exposure (though these endpoints 

are not necessary for this risk assessment since no residential uses are proposed). The LOAEL 

of 82.8 mg/kg/day was based on clinical pathology changes, increased liver weight, centrilobular 

hypertrophy in parents, and decreased body weight (-8.1%, p<0.05) and body weight gain (-8.6% 

p<0.05) with secondary decreases in spleen and thymus weights and secondary slight delay in 

preputial separation in offspring. This study was also chosen for short- and intermediate-term 

inhalation exposure scenarios, assuming inhalation and oral absorption equivalency (100%). A 

28-day dermal toxicity study was used to select the point of departure (NOAEL = 300 

mg/kg/day) and endpoint (liver toxicity) for short-and intermediate term dermal exposure.

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment

Per FQPA, 1996, when there are potential residential exposures to a pesticide, aggregate risk 

assessment must consider exposures from three major sources: oral, dermal, and inhalation 

exposures. There are no residential exposures expected with the currently proposed uses for 

fluopyram. 

Common toxicological effects were not observed at the LOAELs of studies selected for the 

assessment of short- and intermediate-term exposures by the dermal and inhalation routes; liver 

toxicity was the dermal endpoint whereas the inhalation endpoint was based on clinical spleen 

and thymus effects accompanied by clinical pathology and body weight changes. Therefore, it is 

not appropriate to combine these routes of exposure for risk assessment.

4.5.3 Cancer Classification and Risk Assessment Recommendation

In accordance with the EPA’s Final Guidelines for Carcinogen Risk Assessment (March, 2005), 

the Cancer Assessment Review Committee (CARC) classified fluopyram as “Likely to be 
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Carcinogenic to Humans” based on tumors in two species and two sexes: a treatment-related 

increase in thyroid follicular cell adenomas in high dose male mice and liver tumors in female 

rats at the high dose, with incidences exceeding that of the laboratory’s historical controls 

(CARC Report, Nov. 25, 2009). There is no mutagenic concern for fluopyram. The available 

mechanistic data are insufficient to support the proposed modes of action for the thyroid or liver 

tumors. 

The CARC recommended the use of a linear low dose extrapolation model applied to the animal 

data (Q1*) for quantitative estimation of human risk. The unit risk, Q1

*

(mg/kg/day)

-1

, of 

fluopyram based upon female rat liver combined adenoma and carcinoma tumor rates is 1.55 x 

10-2in human equivalents. 

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

Assessment

Table 4.5.4.1 Summary of Toxicological Doses and Endpoints for Fluopyram for Use in Dietary and NonOccupational Human Health Risk Assessments

Exposure/ 

Scenario

Point of 

Departure

Uncertainty/FQPA 

Safety Factors

RfD, PAD, 

Level of 

Concern for 

Risk 

Assessment

Study and Toxicological Effects

Acute Dietary 

(General 

Population, 

including 

Infants and 

Children)

NOAEL= 

50

mg/kg/day

UFA= 10X

UFH=10X

FQPA SF=1X

Acute RfD = 

0.50 

mg/kg/day

aPAD = 0.50 

mg/kg/day

Acute Neurotoxicity Study in Rats. 

The LOAEL of 100 mg/kg in females is 

based on decreased motor and locomotor 

activity in females. The LOAEL in males 

was 125 mg/kg/day. 

Acute Dietary

(Females 13-

49 years of 

age)

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

Chronic 

Dietary (All 

Populations)

NOAEL= 

1.2

mg/kg/day

UFA= 10X

UFH=10X

FQPA SF=1X

Chronic RfD 

= 0.012

mg/kg/day

cPAD = 0.012

mg/kg/day

Combined Chronic/Carcinogenicity in 

Rats

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

follicular cell hypertrophy in the thyroid, 

and increased liver weight with gross 

pathological and histopathological 

findings.

Incidental Oral 

Short-Term

(1-30 days)and 

IntermediateTerm (1-6 

months)

NOAEL= 

14.5

mg/kg/day

UFA= 10X

UFH=10X

FQPA SF=1X

Residential 

LOC for 

MOE = 100

Reproduction study in rats

The LOAEL of 82.8 mg/kg/day is based 

clinical pathology changes, decreased 

spleen and thymus weights, increased 

liver weight and centrilobular hypertrophy 

in parents, and decreased body weight and 

body weight gain with decreases in spleen 

and thymus weights and slight delay in 

preputial separation in offspring.
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Table 4.5.4.1 Summary of Toxicological Doses and Endpoints for Fluopyram for Use in Dietary and NonOccupational Human Health Risk Assessments

Exposure/ 

Scenario

Point of 

Departure

Uncertainty/FQPA 

Safety Factors

RfD, PAD, 

Level of 

Concern for 

Risk 

Assessment

Study and Toxicological Effects

Dermal ShortTerm (1-30 

days) and 

IntermediateTerm (1-6 

months)

NOAEL= 

300

mg/kg/day

UFA= 10X

UFH=10X

FQPA SF=1X

Residential 

LOC for 

MOE = 100

A 28-day dermal study in rats

The LOAEL of 1000 mg/kg/day is based 

on increased cholesterol (F), increased 

prothrombin time (M), and increased liver 

weights (M, F) associated with 

hepatocellular hypertrophy.

Inhalation 

Short- Term

(1-30 days)

and 

IntermediateTerm (1-6 

months)

NOAEL= 

14.5 

mg/kg/day

UFA= 10X

UFH=10X

FQPA SF=1X

Residential 

LOC for 

MOE = 100

Reproduction study in rats

The LOAEL of 82.8 mg/kg/day is based 

clinical pathology changes, decreased 

spleen and thymus weights, increased 

liver weight, and centrilobular 

hypertrophy in parents, and decreased 

body weight and body weight gain with 

decreases in spleen and thymus weights 

and slight delay in preputial separation in 

offspring.

Cancer (oral, 

dermal, 

inhalation)

Based on the liver tumor in female rats and thyroid tumor in male mice, the CARC classified 

fluopyram as a “Likely to be Carcinogenic to Human” and recommended the use of linear low

dose extrapolation model for risk assessment using a unit risk, Q1

*

=1.55x10-2(mg/kg/day)-1.

Point of Departure (POD) = A data point or an estimated point that is derived from observed dose-response data and 

used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human 

exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = 

uncertainty factor. UFA = extrapolation from animal to human (interspecies). UFH = potential variation in 

sensitivity among members of the human population (intraspecies). FQPA SF = FQPA Safety Factor. PAD = 

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

of concern. 

Table 4.5.4.2 Summary of Toxicological Doses and Endpoints for Fluopyram for Use in Occupational Human 

Health Risk Assessments

Exposure/ 

Scenario

Point of 

Departure

Uncertainty 

Factors

Level of Concern 

for Risk 

Assessment

Study and Toxicological Effects

Dermal ShortTerm (1-30 

days) and 

IntermediateTerm (1-6 

months)

NOAEL= 

300

mg/kg/day

UFA= 10X

UFH=10X

Occupational 

LOC for MOE = 

100

A 28-day dermal study in rats

The LOAEL of 1000 mg/kg/day is based 

on increased cholesterol (F), increased 

prothrombin time (M), and increased liver

weights (M, F) associated with 

hepatocellular hypertrophy.

Inhalation 

Short-Term (1-

30 days) and 

Intermediateterm (1-6 

months)

NOAEL= 

14.5 

mg/kg/day

UFA=10X

UFH=10X

Occupational

LOC for MOE = 

100

A 2-generation reproduction study in rats. 

The LOAEL of 82.8 mg/kg/day is based 

clinical pathology changes, increased liver 

weight, and centrilobular hypertrophy in 

parents, and decreased body weight and 

body weight gain with secondary decreases 

in spleen and thymus weights and 

secondary slight delay in preputial 

separation in offspring.
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Table 4.5.4.2 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

Cancer (oral, 

dermal, 

inhalation)

Based on the liver tumor in female rats and thyroid tumor in male mice, the CARC classified 

fluopyram as a “Likely to be Carcinogenic to Human” and recommended the use of linear low

dose extrapolation model for risk assessment using a unit risk, Q1

*

=1.55x10-2(mg/kg/day)-1

Point of Departure (POD) = A data point or an estimated point that is derived from observed dose-response data and 

used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human 

exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = 

uncertainty factor. UFA = extrapolation from animal to human (interspecies). UFH = potential variation in 

sensitivity among members of the human population (intraspecies). MOE = margin of exposure. LOC = level of 

concern. N/A = not applicable.

4.6 Endocrine Disruption

As required under FFDCA section 408(p), EPA has developed the Endocrine Disruptor 

Screening Program (EDSP) to determine whether certain substances (including pesticide active 

and other ingredients) may have an effect in humans or wildlife similar to an effect produced by 

a “naturally occurring estrogen, or other such endocrine effects as the Administrator may

designate.” The EDSP employs a two-tiered approach to making the statutorily required 

determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a 

chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal 

systems. Chemicals that go through Tier 1 screening and are found to have the potential to 

interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA 

will determine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 

testing is designed to identify any adverse endocrine related effects caused by the substance, and 

establish a dose-response relationship between the dose and the E, A, or T effect.

Between October 2009 and February 2010, EPA issued test orders/data call-ins for the first 

group of 67 chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. 

This list of chemicals was selected based on the potential for human exposure through pathways 

such as food and water, residential activity, and certain post-application agricultural scenarios. 

This list should not be construed as a list of known or likely endocrine disruptors.

Fluopyram is not among the group of 58 pesticide active ingredients on the initial list to be 

screened under the EDSP. Under FFDCA sec. 408(p) the Agency must screen all pesticide 

chemicals. Accordingly, EPA anticipates issuing future EDSP test orders/data call-ins for all 

pesticide active ingredients. 

For further information on the status of the EDSP, the policies and procedures, the list of 67 

chemicals, the test guidelines and the Tier 1 screening battery, please visit our website: 

http://www.epa.gov/endo/.

5.0 Dietary Exposure and Risk Assessment 

5.1 Metabolite/Degradate Residue Profile
Fluopyram Human Health Risk Assessment DP No. D385636

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5.1.1 Summary of Plant and Animal Metabolism Studies

PRIMARY CROPS: Adequate metabolism studies were conducted in grape, bean, potato and 

red pepper labeled in the phenyl ring or pyridine ring. Positions of the radiolabel are indicated 

below.

[phenyl-UL14C]AE C656948 [pyridyl-2,6-

14C]AE C656948

The results indicate that the parent is the major residue and that metabolism of fluopyram is 

similar within the submitted studies which represent three dissimilar crop groups. The 

metabolism of fluopyram in plants appears to proceed via hydroxylation of parent compound 

leading to AE C656948-7-hydroxy and AE C656948-8-hydroxy, conjugation of the hydroxylated 

parent compound mainly with sugars, and cleavage of the molecule leading to AE C656948-

benzamide, AE C656948-PAA, and AE C656948-PCA. Further conjugation of AE C656948-7-

hydroxy-glucose with malonic acid was observed in bean and red pepper; in addition, cleavage 

of the molecule yielded glycoside conjugates and AE C656948-hydroxyethyl conjugates in bean 

and red pepper.

ROTATIONAL CROPS: In confined rotational crop studies, parent fluopyram also accounted 

for the majority of residue. However, AE C656948-7-hydroxy (up to 39% TRR, plus its 

conjugate (up to 16% TRR)) was found in Swiss chard at all rotation intervals, and the 

methylsulfoxide metabolite was predominant in wheat grain at longer rotation intervals. The 

latter metabolite was detected up to 0.10 ppm in field rotational wheat trials and the AE 

C656948-7-hydroxy compound was found only in wheat straw at 0.10 ppm level. AE C656948-

Benzamide (up to 39% TRR) was also present in Swiss chard. 

POULTRY: The major component in all the edible matrices was the metabolite AE C656948-

benzamide, at 68.6% to 98.6% TRR. Other metabolites identified were AE C656948-Z-olefine 

(25.9% TRR in fat and ≤1.2% TRR in egg, muscle, and liver), AE C656948-E-olefine (≤2.3% 

TRR in fat and liver), and AE C656948-benzoic acid (0.3% TRR, in liver only). Parent 

compound was detected as a minor component only in eggs and fat at ≤2.5% TRR. 

Identification rates in the organs and tissues ranged from 93% to 99% TRR.

RUMINANTS: An adequate metabolism study was conducted on lactating goats with fluopyram

labeled on the phenyl or pyridine ring. When goats were orally dosed with [phenyl-UL14C]fluopyram, the major component detected in all the edible matrices was the metabolite AE 

C656948-benzamide (49.1% to 97.6% TRR). Other major compounds identified were AE 

C656948-Z-olefine and the parent compound, which were found at 13.1% and 18.2% TRR, 

respectively, in fat. AE C656948-Z-olefine was identified as a minor residue (<1% TRR) in 

milk and liver and was not found in muscle and kidney. The parent compound was identified as 

N

H

O

N

Cl CF3

CF3

*

N

H

O

N

Cl CF3

CF3

* *
Fluopyram Human Health Risk Assessment DP No. D385636

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a minor component in milk, liver, and kidney, at ≤1.7% TRR, and was not detected in muscle. 

When animals were dosed with [pyridyl-2,6-

14C]fluopyram, the parent compound was identified 

as a major component in milk, muscle, and fat (27.3-46.4% TRR) but was only found as a minor 

residue in liver (7.7% TRR) and was not found in kidney. The metabolite AE C656948-Zolefine was identified as a major metabolite in milk, muscle, and fat, at 12.9-33.7% TRR; it was 

found at 5.7% TRR in liver and was not found in kidney. The other isomer AE C656948-Eolefine was found at <5% TRR in milk, muscle, fat, and liver. AE C656948-7-hydroxy was also 

found to be a major component of milk, muscle, and fat, at 12.8-21.6% TRR, but a minor residue 

(≤6% TRR) in liver and kidney.

5.1.2 Summary of Environmental Degradation

Environmental fate studies indicate that the parent fluopyram is stable under environmental 

conditions. Reported half-lives range from 89 days in field and aqueous photolysis studies to 

>1000 days in aerobic/anaerobic water/sediment systems. Fluopyram is mobile in soil and can 

therefore, be expected to occur in surface water runoff and/or in ground water leachate. 

Four metabolites were identified in aerobic soil metabolism studies: AE C656948-7-hydroxy,

AE C656948-benzamide, AE C656948-pyridyl carboxylic acid (PCA), and lactame. None of the 

metabolites exceeded 10% of applied radioactivity nor were any of the metabolites considered 

more toxic than the parent.

AE C656948-7-hydroxy, AE C656948-benzamide, and AE C656948-PCA were also tracked in 

field dissipation studies. AE C656948-7-hydroxy, though structurally similar to the parent, was 

only found at 1-3% of the fluopyram levels. AE C656948-PCA (1.2-18%) and AE C656948-

benzamide (0.2-16.2%) were more abundant but showed rapid declines. Lactame, a proposed 

metabolite of parent fluopyram, was present at low levels in the soil system (1.2%) and as a 

major metabolite in the aqueous photolysis study (13%). Lactame is structurally dissimilar from 

parent fluopyram but would only be expected to form at significant levels in clear, shallow 

water. Based upon the low abundance of the metabolites in the soil studies and their rapid 

dissipation in the field studies, minimal exposure is expected through drinking water. 

Furthermore, none of the metabolites are considered more toxic than the parent. Therefore, these

metabolites are not considered of concern.

5.1.3 Comparison of Metabolic Pathways

In representative plants, the metabolism is limited and parent accounts for the majority of the 

residue. In legumes, however, metabolites AE C656948-benzamide or AE C656948-

pyridylacetic acid and pyridylcarboxylic acid also become major residues. The metabolic 

pathways begin with hydroxylation at the ethylene bridge, conjugation with sugars, and cleavage 

leading to the benzamide, pyridylacetic acid and pyridylcarboxylic acid. Fluopyram is the major 

residue in rotational crops.

In livestock the metabolism is more extensive. The metabolic profiles in poultry and ruminants 

are similar. In poultry (phenyl label), very little parent was present in eggs, muscle, liver or fat, 

and benzamide is the major residue in these matrices. A second major residue in poultry is the 
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Z-olefin. In lactating goats (phenyl label), parent was only present as a major residue in fat and 

the predominant residue is the benzamide in milk and tissues. In addition to Z-olefin, the 7-

hydroxy metabolite is a major residue in milk, muscle and fat.

In the rat, the metabolism is also very extensive leading to numerous excreted metabolites with 

very little parent detected. The metabolic pathway in the rat is very similar to those in plants and 

livestock, namely, hydroxylation in the ethylene bridge (and the phenyl ring), conjugation, and 

cleavage of the ethylene bridge to form benzamide, pyridylacetic acid and pyridylcarboxylic 

acid. Z- and E-Olefins are also present as metabolites. 

5.1.4 Residues of Concern Summary and Rationale

Primary and Rotational Crops

The metabolism in plants is relatively limited. In plant metabolism studies, unchanged parent 

accounted for >90% of the residues in grapes, beans (immature), and potatoes and 70% of the 

residue in red bell peppers. While several metabolites were quantified (most <1% TRR), only

AE C656948-benzamide exceeded 10% TRR in succulent and dry beans (52-64%).

Measurable quantities of parent and metabolites (AE C656948-pyridyl-acetic acid (PAA), 

AE C656948-pyridyl-carboxylic acid (PCA) and AE C656948-benzamide) were also found in 

succulent (at full maturity) and dry beans during European field trials. These metabolites were 

not measured in US field trials.

Of the major metabolites, AE C656948-benzamide, PAA and PCA result from hydrolysis of the 

ethylene bridge; AE C656948-benzamide is a phenyl cleavage product and PPA and PCA are 

pyridyl cleavage products. AE C656948-methyl-sulfoxide results from the substitution of the 

chlorine atom in PCA. None of the metabolites or their conjugates is expected to be more toxic 

than the parent fluopyram. Furthermore, inclusion of both phenyl and pyridyl metabolites as 

fluopyram equivalents for either risk assessment or tolerance expression, would overestimate 

total exposure to fluopyram. Parent fluopyram by itself is expected to be an adequate measure of 

misuse in primary crops. In addition, parent fluopyram can be measured by some of the FDA 

multiresidue methods (MRM) while the benzamide metabolite does not lend itself to MRM 

analysis. Therefore, HED recommends fluopyram only for tolerance expression. For risk 

assessment, HED recommends fluopyram only, except for legumes and oil seeds. For these 

commodities, HED recommends fluopyram + AE C656948-benzamide due to the high levels of 

the latter in the bean metabolism studies. 

Livestock Commodities

The metabolism in livestock is more extensive than was found in plant studies. The major 

residues identified at varying sampling intervals include parent, AE C656948-benzamide, 

AE C656948-7-hydroxy, and AE C656948 E- and Z-olefines. In the egg and poultry metabolism 

studies, AE C656948-benzamide (up to 99% TRR) accounted for the majority of residue in egg, 

muscle, fat, and liver. Parent fluopyram (18%) was found in eggs and AE C656948 -olefines

(14%) in the liver. Similarly in the goat, AE C656948-benzamide accounted for the majority of 

residue (up to 99% TRR) in milk, muscle, fat, liver, and kidney. Fluopyram (46%), 

AE C656948-7-hydroxy (22%), and AE C656948 –E-olefines (33%) were found at lower levels 

in milk, muscle, and fat. The phenyl metabolite, AE C656948-benzamide, was a major 
Fluopyram Human Health Risk Assessment DP No. D385636

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metabolite in both plant and livestock metabolism studies. However, the pyridyl metabolites, AE 

C656948-pyridyl-acetic acid (PAA) and AE C656948-pyridyl-carboxylic acid (PCA), were not

present in the livestock studies. While the fate of the pyridyl portion of the molecule is 

unknown, HED determined tolerance expression and risk assessment decisions could be made 

without fully elucidating the livestock metabolic pathway. Calculating the benzamide residues 

in terms of parent equivalents would likely account for the unknown pyridyl metabolites. 

Feeding studies confirmed the rapid transformation of parent fluopyram; AE C656948-

benzamide was the only major residue in edible poultry matrices while fluopyram, AE C656948-

benzamide and AE C656948 -olefines were measured in the milk and meat of dairy cattle. In the 

cattle study, the levels of benzamide metabolite were significantly higher than the parent in many 

samples.

Therefore, HED recommends fluopyram + AE C656948-benzamide for tolerance enforcement in 

ruminant and poultry commodities; fluopyram + AE C656948-benzamide + AE C656948-7-

hydroxy fluopyram + AE C656948 E- and Z-olefines for risk assessments in ruminant 

commodities; and fluopyram + AE C656948-benzamide + AE C656948 E- and Z-olefines for 

risk assessment in poultry.

The US, EU, and Canada are in agreement on parent fluopyram + AE C656948-benzamide for 

purposes of tolerance enforcement in livestock. The US, EU, and Canada are also in agreement 

regarding which compounds to include for risk assessment of poultry commodities. However, 

consistent with their decisions for plants, the EU has proposed the inclusion of the conjugated 

metabolites, AE C656948-7-OH-GA and AE C656948-8-OH-GA, for risk assessments in 

ruminants (see Table 5.1.4).
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Table 5.1.4. Summary of Metabolites and Degradates to be included in the Risk Assessment and Tolerance Expressions.

Matrix

US EU Canada

Risk Assessment Tolerance 

Expression Risk Assessment Tolerance Expression Risk Assessment Tolerance Expression

Plants Primary Crop Fluopyram

(Fluopyram + 

benzamide for 

legumes and oil seed 

crops)

Fluopyram Fluopyram + 

benzamide (M25) + 

7-OH-fluopyram 

(M08) + 7-OH-Glc 

(M11) + 7-OH-GlcMA(M12)

Fluopyram Fluopyram + 

(Fluopyram + 

benzamide for 

legumes and oil seed 

crops)

Fluopyram

Rotational Crop Fluopyram

(Fluopyram + 

benzamide for 

legumes and oil seed 

crops)

Fluopyram Fluopyram + 

benzamide (M25) + 

7-OH-fluopyram 

(M08) + 7-OH-Glc 

(M11) + 7-OH-GlcMA(M12)

Fluopyram Fluopyram

(Fluopyram + 

benzamide for 

legumes and oil seed 

crops)

Fluopyram

Livestock Ruminant Fluopyram + 

benzamide + 7-OHfluopyram + olefins 

(E, Z)

Fluopyram + 

benzamide

Fluopyram + 

benzamide + 7-OHfluopyram (M08)+ 

olefins (E, Z) + 7-

OH-GA(M09) + 7-

OH-GA (M20b)

Fluopyram + 

benzamide

Fluopyram + 

benzamide + 7-OHfluopyram + olefins 

(E, Z)

Fluopyram + 

benzamide

Poultry Fluopyram + 

benzamide + olefins 

(E, Z)

Fluopyram + 

benzamide

Fluopyram + 

benzamide + olefins 

(E, Z) 

Fluopyram + 

benzamide

Fluopyram + 

benzamide + olefins 

(E, Z)

Fluopyram + 

benzamide

Drinking Water Fluopyram Not Applicable Not Applicable Not Applicable Not Applicable Not Applicable
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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 apple, banana (import), cherry (sweet and tart), dry

beans, watermelon, wine grapes, peanut, potato, stone fruit, strawberry, sugar beet, and tree nuts 

(including pistachio). Crop field trial studies were conducted in North America and Europe. 

Residues are quantifiable in all crops. Residues tend to be surface residues and generally decline 

with increasing PHI. Processing studies indicate that residues concentrate substantially in wet 

apple pomace and potato wet peel and slightly in dried sugar beet pulp and refined sugar. 

Livestock feeding studies indicate low transfer of residues to meat, milk, poultry and eggs with 

the highest transfer in liver. Rotational crop data show uptake of finite residues in forage/leaf, 

hay and straw but very low residues in grain, seed and root.

 

Residue chemistry studies are supported by adequate storage stability data which demonstrate 

that fluopyram and its major metabolites are stable for at least 24 or 36 months in water- starch-, 

protein-, oil-, and acid-containing materials under frozen conditions. 

Table 5.2. Summary of Residues from the Crop Field Trials with Fluopyram

Crop Matrix Applic. Rate

(lb ai/A)

PHI 

(days)

Residues (ppm)

Mean

Std. 

Dev. HAFT 1 Min. Max.

POME FRUIT (proposed use = 0.445 lb ai/A total application rate, 0-day PHI; 7-day revised PHI)

Two Applications; Concentrate Spray

Apple 0.440-0.461 7 0.120 0.063 0.242 0.040 0.247

Two Applications; Dilute Spray

Apple 0.440-0.461 7 0.105 0.055 0.255 0.057 0.262

Four Applications; Concentrate Spray

Apple 0.477 – 0.479 7 0.084 0.021 0.101 0.061 0.107

DRIED BEANS (proposed use = 0.445 lb ai/A total application rate, 0-day PHI; revised use = 0.268 lb ai/A 

total application rate, 14-day PHI)

Dried bean seed 0.441 – 0.452 0

2

, 13-14 0.024 0.021 0.068 <0.01 0.076

GRAPE (proposed use = 0.445 lb ai/A total application rate, 7-day PHI; revised to wine grapes only)

Grape 0.439-0.458 6-7 0.401 0.229 0.948 0.096 0.950

PEANUT (proposed use = 0.445 lb ai/A total application rate, 7-day PHI)

Peanut 0.438 - 0.455 6-7 0.011 <0.01 0.017 <0.01 0.018

Peanut, hay 0.438 - 0.455 6-7 8.72 6.78 20.66 1.08 21.88

POTATO (proposed use = 0.445 lb ai/A total application rate, 7-day PHI; revised to 0.356 lb ai/A for 

ground applications and 0.275 lb ai/A for aerial applications)

Potato, tuber 0.437 - 0.454 6-7 0.01 0.002 0.017 <0.01 0.017

STRAWBERRY (proposed use = 0.445 lb ai/A total application rate, 0-day PHI for spray uses and drip 

application and 1-day PHI greenhouse uses; revised to delete field spray use)

Strawberry - drip 

irrigation field 0.442-0.468 0 0.026 0.028 0.10 <0.01 0.112

Strawberry - greenhouse 0.446 1 0.35 0.26 0.79 0.12 0.79
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Table 5.2. Summary of Residues from the Crop Field Trials with Fluopyram

Crop Matrix Applic. Rate

(lb ai/A)

PHI 

(days)

Residues (ppm)

Mean

Std. 

Dev. HAFT 1 Min. Max.

spray (European data)

SUGAR BEET (proposed use = 0.445 lb ai/A total application rate, 7-day PHI; revised to 0.222 lb ai/A)

Sugar beet, root 0.439 – 0.456 5-7 0.029 0.011 0.040 0.013 0.050

Sugar beet, tops 0.439 – 0.456 5-7 3.30 4.89 16.5 0.273 18.7

CUCURBIT VEGETABLES (proposed use = 0.445 lb ai/A total application rate, 0-day PHI spray uses, 3-

day PHI greenhouse uses, and 7-day PHI drip applications)

Foliar Spray Applications

Cucumber 0.432-0.454 0 0.094 0.045 0.144 0.037 0.189

Muskmelon 0.445-0.469 0 0.217 0.156 0.439 0.069 0.529

Summer squash 0.443-0.445 0 0.099 0.047 0.173 0.047 0.179

Drip Line Irrigation

Cucumber 0.446-0.456 7 0.022 0.017 0.057 <0.01 0.058

Muskmelon 0.446-0.455 5-7 0.015 0.008 0.027 <0.01 0.029

Summer squash 0.446 6-7 0.012 0.002 0.015 <0.01 0.017

Greenhouse Applications

Cucumber 

(European data) 0.535 2-4 0.15 0.09 0.29 0.04 0.29

Muskmelon 

(European data) 0.535 3

3

0.12 0.05 0.19 0.04 0.19

STONE FRUIT (proposed use = 0.445 lb ai/A total application rate, 0-day PHI; revised cherry use = 0.183 

lb ai/A, revised stone fruit use other than cherry = 0.367 lb ai/A)

Concentrate Spray

Cherry 0.447 – 0.460 0 0.425 0.223 0.639 0.066 0.641

Peach 0.436 – 0.456 0 0.29 0.105 0.44 0.126 0.457

Plum 0.429 – 0.445 0 0.082 0.085 0.257 0.022 0.286

Dilute Spray

Cherry 0.444 – 0.457 0 0.516 0.349 1.174 0.147 1.229

Peach 0.441 – 0.457 0 0.34 0.121 0.548 0.175 0.588

Plum 0.442 – 0.454 0 0.083 0.095 0.283 0.021 0.292

TREE NUT (proposed use = 0.445 lb ai/A total application rate, 14-day PHI)

Concentrate Spray

Almond 0.437-0.449 14 0.01 0.01 0.018 <0.01 0.019

Almond, hulls 0.437-0.449 14 3.18 1.09 4.25 1.93 4.45

Pecan 0.445-0.455 12-14 0.01 0.01 0.018 <0.01 0.021

Dilute Spray

Almond 0.439- 0.462 14 0.01 0.01 0.015 <0.01 0.016

Almond, hulls 0.439- 0.462 14 2.97 1.57 5.43 1.22 6.12

Pecan 0.448-.458 12-14 0.01 0.014 0.031 <0.01 0.045

BANANA - Latin America (no proposed use information was provided for banana)
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Table 5.2. Summary of Residues from the Crop Field Trials with Fluopyram

Crop Matrix Applic. Rate

(lb ai/A)

PHI 

(days)

Residues (ppm)

Mean

Std. 

Dev. HAFT 1 Min. Max.

Banana, whole fruit, 

bagged 0.587-0624 0 0.018 0.009 0.038 <0.01 0.040

Banana, whole fruit, 

unbagged 0.587-0624 0 0.164 0.140 0.510 0.018 0.526

1 HAFT = Highest Average Field Trial.

2At one trial (n=2), the bean plants were cut from the ground at a 0-day PHI and the seed was sampled 14 days later, after drying 

in the field. Sample residues from this trial were not the maximum residue or HAFT for the study

3

 The data include results from one trial with a PHI of 1 day (no sample collected at 3-day PHI) and one trial with a 

PHI of 7 days (residues were higher than those at the 3-day PHI).

5.3 Water Residue Profile

Estimated drinking water concentrations (EDWCs) for ground and surface water are presented in 

Table 5.3. Upper-bound ground water estimates were derived using the Tier I SCI-GROW 

model. Surface water concentrations were estimated using the Tier II PRZM/EXAMS model. 

The available data allowed for refinement of the estimates beyond our standard modeling 

approach by incorporating a 90th percentile foliar degradation rate of 0.131 day-1(half-life = 5.29 

days). The foliar decay rate was calculated from two plant residue field trial studiescin which 

residues were determined at various intervals following foliar application; no rain or irrigation 

occurring during the study period. All other inputs reflect high-end assumptions regarding 

application rates and percent cropped area (PCA = 0.87) in the watershed.

Table 5.3 Summary of Estimated Surface Water and Groundwater Concentrations 

for Fluopyram.

Scenario Surface Water Conc., ppb a Groundwater Conc., ppb b

Acute 12.97

Chronic (non-cancer) 4.90 0.319

Chronic (cancer) 3.487

a

From the Tier II PRZM-EXAMS - Index Reservoir model. Input parameters are based on FL cucumber and ME 

potato (chronic) scenarios using the maximum application rate, maximum number of applications and minimum 

intervals stated in the labels for fluopyram.

b

From the SCI-GROW model.

C GM090 (2007) conducted on leaf lettuce (Crop Group 4: leafy vegetables) in Sanger, CA. Bayer report number 

RAGMP085; GM230 (2007) conducted on mustard green leaves (Crop Subgroup 5B: leafy Brassica greens) in 

Sycamore, GA. Bayer Report Number: RAGMP063.

Shamim, M., 7/8/2011, D353319, D363812, D363820, D363821, D363822, D363824, and D369773

5.4 Dietary Risk Assessment

5.4.1 Description of Residue Data Used in Dietary Assessment
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For the acute dietary analysis: tolerance residue levels, 100% crop treated assumption and 

processing factors (empirical and default) were used. The EDWC was incorporated directly into 

the dietary assessment (1 in 10 yr annual peak of 13 μg/L) based on application rate of 

cucumber.

For the chronic dietary analysis: average residues, 100% CT and processing factors (empirical 

and default) were used. The EDWC was incorporated directly into the dietary assessment (1 in

10 yr annual mean of 4.9 μg/L) based on application rate of potato.

For the cancer dietary assessment: average residues, projected percent crop treated, and empirical 

processing factors were used. The EDWC was incorporated directly into the dietary assessment 

(1 in 30 yr annual mean of 3.5 μg/L) based on application rate of potato.

5.4.2 Percent Crop Treated Used in Dietary Assessment

The following average percent crop treated estimates (J. Alsadek and C. Chen, 05/23/2011, 

D387227) were used in the cancer dietary risk assessment for the following crops that are the 

subject of this petition for residues of fluopyram: almonds: 33%; apples: 40%; barley: 22%;

cherry: 49%; cotton: 7%; dry beans: 2.5%; grapes: 79%; oats: 23%; peanuts: 67%; potatoes: 

64%; rapeseed: 73%; rye: 63%; sorghum: 12%; soybeans: 1%; strawberries: 71%; sugar beets: 

48%; watermelon: 54%; and wheat: 1%. One hundred percent of the crops were assumed to 

have been treated for the acute and chronic dietary exposure assessments.

To calculate these projected percent crop treated values, BEAD used recent data from the 

National Agricultural Statistics Service (NASS) 2002-2006, and recent proprietary data (2006-

2010). The estimates for the primary crops are based on the market leader approach involving 

several registered fungicides, and the estimates for the rotational crops are based on 

acres of wheat, corn, sorghum, barley, oats, rye, millet, soybeans, canola, cotton, and alfalfa 

grown relative to the total acreage of dry beans and potato treated with fluopyram. 

5.4.3 Acute Dietary Risk Assessment

The acute dietary analysis included tolerance residue levels, 100% crop treated assumption and 

processing factors (empirical and default). Estimated drinking water concentration (EDWC) was 

incorporated directly into the dietary assessment (1 in 10 yr annual peak of 13μg/L) and was 

calculated based on a maximum application rate of 0.446 lb ai/A/season (cucumber).

Estimated acute dietary exposure to fluopyram from food and drinking water is below HED’s 

level of concern for all population subgroups (<100% (aPAD) acute Population Adjusted Dose). 

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

estimated to be 0.021 mg/kg/day for the overall US population, equivalent to 4.2% of the aPAD. 

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

children 1-2 years, with an estimated exposure at the 95th percentile of 0.042 mg/kg/day, 

equivalent to 8.4% of the aPAD (see Table 5.4.6).

5.4.4 Chronic Dietary Risk Assessment
Fluopyram Human Health Risk Assessment DP No. D385636

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The chronic dietary analysis used average residue levels, 100% crop treated assumption, and 

processing factors (empirical and default). EDWC was incorporated directly into the dietary

assessment (1 in 10 yr annual mean of 4.9 μg/L) and was calculated based on a maximum 

application rate of 0.356 lb ai/A/season (potato).

Chronic dietary exposure estimates for food and drinking water are well below HED’s level of 

concern (<100% (cPAD) chronic Population Adjusted Dose) for all population subgroups. The 

dietary exposure is estimated at 0.00042 mg/kg/day for the general US population (3.5% of the 

cPAD) and 0.0012 mg/kg/day (10% of the cPAD) for children 1-2 year olds, the population 

subgroup with the highest estimated chronic dietary exposure to fluopyram (see Table 5.4.6). 

5.4.5 Cancer Dietary Risk Assessment

The HED Cancer Peer Review Committee (CARC) classified fluopyram as “Likely to be 

Carcinogenic to Human” and recommended the use of linear low dose extrapolation model for 

risk assessment using a unit risk, Q1* = 1.55x10-2(mg/kg/day) -1. The cancer dietary analysis 

included average residue levels, projected percent crop treated (PPCT) estimates and processing 

factors (empirical and default). EDWC was incorporated directly into the dietary assessment (1

in 30 yr annual mean of 3.5 μg/L) and was calculated based on a maximum application rate of 

0.356 lb ai/A/season (potato). The cancer dietary (food and drinking water) risk estimate for the 

general US population is 2.9 x 10-6 (Table 5.4.6). Water, direct and indirect sources, contributes 

approximately 30% to the risk estimate, or 1.1 X 10-6. 

5.4.6 Summary Table

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

Population Subgroup

Acute Dietary

(95th Percentile) Chronic Dietary Cancer

Dietary 

Exposure 

(mg/kg/day)

% 

aPAD*

Dietary 

Exposure

(mg/kg/day)

% 

cPAD*

Dietary 

Exposure

(mg/kg/day)

Risk

General US Population 0.020741 4.2 0.000423 3.5 0.000188 2.9 x 10-6

All Infants (< 1 year old) 0.038195 7.6 0.000800 6.7

N/A N/A

Children 1-2 years old 0.042156 8.4 0.001239 10

Children 3-5 years old 0.035136 7.0 0.001017 8.5

Children 6-12 years old 0.024081 4.8 0.000574 4.8

Youth 13-19 years old 0.015398 3.1 0.000315 2.6

Adults 20-49 years old 0.013032 2.6 0.000320 2.7
Fluopyram Human Health Risk Assessment DP No. D385636

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

Population Subgroup

Acute Dietary

(95th Percentile) Chronic Dietary Cancer

Dietary 

Exposure 

(mg/kg/day)

% 

aPAD*

Dietary 

Exposure

(mg/kg/day)

% 

cPAD*

Dietary 

Exposure

(mg/kg/day)

Risk

Adults 50+ years old 0.011141 2.2 0.000353 2.9

Females 13-49 years old 0.012844 2.6 0.000326 2.7

*The population subgroup with the highest estimated acute and chronic dietary (food + drinking 

water) exposure and risk is indicated by bold text.

NA = not applicable
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6.0 Residential (Non-Occupational) Exposure/Risk Characterization

6.1 Residential Handler Exposure

Based on product label, the product is not intended for use by homeowners, or by occupational 

handlers in residential settings. Therefore, non-occupational/residential risk assessments have 

not been conducted.

6.2 Residential Bystander Post-application Inhalation Exposure

Based on the Agency's current practices, a quantitative post-application inhalation exposure 

assessment was not performed for fluopyram at this time primarily because of the low acute 

inhalation toxicity (Toxicity Category IV), low vapor pressure (1.2x10-6Pa at 20oC), and the low 

proposed use rate (0.22 lb ai/A). However, volatilization of pesticides may be a source of postapplication inhalation exposure to individuals nearby pesticide applications. The Agency sought 

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

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

and received the SAP’s final report on March 2, 2010 

(http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). The Agency is in the 

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

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

exposure into the Agency's risk assessments. If new policies or procedures are developed, the 

Agency may revisit the need for a quantitative post-application inhalation exposure assessment 

for fluopyram.

6.3 Spray Drift

Spray drift is always a potential source of exposure to residents nearby to spraying operations. 

This is particularly the case with aerial application, but to a lesser extent, could also be a 

potential source of exposure from the airblast and groundboom application methods additionally

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

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

the best spray drift management practices. The Agency is now requiring interim mitigation 

measures for aerial applications that must be placed on product labels/labeling. The Agency has 

completed its evaluation of the new database submitted by the Spray Drift Task Force, a 

membership of US pesticide registrants, and is developing a policy on how to appropriately 

apply the data and the AgDRIFT computer model to its risk assessments for pesticides applied 

by air, orchard airblast, and ground hydraulic methods. After the policy is in place, the Agency

may impose further refinements in spray drift management practices to reduce off-target drift 

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

7.0 Aggregate Exposure/Risk Characterization

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

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

assessment, exposures from relevant sources are added together and compared to quantitative 
Fluopyram Human Health Risk Assessment DP No. D385636

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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.

7.1 Acute Aggregate Risk

There is potential acute exposure via the diet (food and drinking water). Refer to Section 5.4.3.

7.2 Short- and Intermediate-Term Aggregate Risk

There are no proposed residential uses so short- or intermediate-term residential exposures are 

not likely to occur. Therefore neither short- nor intermediate-term aggregate risks were not 

assessed. 

7.3 Chronic Aggregate Risk

There is potential chronic exposure via the diet (food and drinking water). Refer to Section 

5.4.4.

7.4 Cancer Aggregate Risk

The aggregate cancer risk (food and drinking water) is 2.9 x 10-6(Table 5.4). The unit risk for 

fluopyram, Q1

*

, is 1.55x10-2(mg/kg/day) -1. The Q1

*

is based upon liver tumor in female rats 

and is expressed in human equivalents.

8.0 Cumulative Exposure/Risk Characterization

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a 

common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as 

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

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

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

substances. For information regarding EPA’s efforts to determine which chemicals have a 

common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the 

policy statements released by EPA’s Office of Pesticide Programs concerning common 

mechanism determinations and procedures for cumulating effects from substances found to have 

a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/.

9.0 Occupational Exposure/Risk Characterization

9.1 Short-/Intermediate- /Cancer Handler Risk

Fluopyram can be applied to agricultural crops using aerial, chemigation, groundboom, airblast, 

backpack, and low- and high-pressure sprayer application equipment. Broadcast foliar 

applications of fluopyram may be applied to agricultural crops at maximum single rates ranging 
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from 0.092 to 0.22 lb ai/A. Multiple applications may be made per season, up to a maximum of 

0.45 lb ai/season. Applications may be made in greenhouses of 10 acres or larger for 

strawberries, or watermelons. The proposed label requires handlers to wear chemical resistant 

gloves. Handler exposure is expected to be short- or intermediate-term in duration based on 

information provided on proposed labels

No chemical-specific handler exposure data were submitted in support of this Section 3

registration. To assess handler exposures for regulatory actions when chemical-specific 

monitoring data are not available, HED relies on the most scientifically-reliable surrogate data 

currently available from various sources such as the Pesticide Handler Exposure Database 

(PHED), the Agricultural Handler Exposure Task Force (AHETF), and the Outdoor Residential 

Exposure Task Force (ORETF). Some of this data, such as the industry task force data, is 

compensatory, subject to the data protection provisions of FIFRA. HED policy on use of 

surrogate data is described in more detail on the Agency's website 

(http://www.epa.gov/pesticides/science/handler-exposure-data.html). Scenario-specific 

surrogate exposure data, including their sources, are presented in the “Occupational Pesticide 

Handler Unit Exposure Surrogate Reference Table” 

(http://www.epa.gov/pesticides/science/handler-exposure-table.pdf). HED has developed a 

series of tables of standard unit exposure values for many occupational scenarios that can be 

utilized to ensure consistency in exposure.

Non-cancer occupational risk estimates for dermal (with gloves) and inhalation short- and 

intermediate-term exposure durations all resulted in MOEs considerably greater than 100, and 

therefore, do not exceed HED’s level of concern (Table E1). MOEs for dermal (with gloves)

exposure ranged from 180,000 to 7,300 and MOEs for inhalation exposure ranged from 

1,300,000 to 7,700.

Handler cancer risks for private growers and commercial applicators were calculated for 

different exposure scenarios at different levels of personal protection. Handler cancer risk 

estimates for combined inhalation and dermal (with gloves) exposures for private growers ranged 

from 1.4 x 10-8to 5.6 x 10-7 and for commercial workers ranged from 3.1 x 10-8to 8.8 x 10-7

(Tables E2 and E3, respectively).

9.2 Short-/Intermediate-/Cancer Post-Application Risk

9.2.1 Dermal Post-application Risk

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

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

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

the TCs established by the Science Advisory Council for Exposure Policy Number 3 

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

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

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

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

of the TCs in this SOP are based on work of the ARTF. The dislodgeable foliar residue (DFR) 
Fluopyram Human Health Risk Assessment DP No. D385636

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

the initial residue on treated foliage is 20% of the application rate and the residues degrade at a 

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

level of concern (MOEs ≥100) with dermal MOEs ranging from 5,600 to 530 (Table E4).

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

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

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

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

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

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

REI that appears on the proposed label is adequate.

Worker post-application cancer risk estimates were assessed for individuals employed by 

multiple establishments (i.e., commercial or migratory farm workers) and were assumed to be 

exposed 30 days per year. DFRs were estimated using the method described above in the noncancer post-application section (i.e., assuming 20% of the active ingredient is available initially

and a dissipation of 10% per day thereafter). HED used the average DFR residue (μg/cm2) over 

the minimum re-treatment interval for each crop or crop group to estimate cancer risk. The post 

application cancer risks estimates ranged from 5.1 x 10-7to 4.0 x 10-6(Table E5). These 

estimates are considered conservative, since the maximum application rate and shortest 

retreatment intervals were used to calculate the estimates. 

9.2.2 Inhalation Post-application Risk

Occupational post-application exposure can occur via the inhalation route. Based on the 

Agency's current practices, a quantitative post-application inhalation exposure assessment was 

not performed for fluopyram at this time primarily because of the low acute inhalation toxicity

(Toxicity Category IV), low vapor pressure (1.2x10-6Pa at 20oC), and the low proposed use rate 

(0.22 lb ai/A). However, there are multiple potential sources of post-application inhalation 

exposure to individuals performing post-application activities in previously treated fields. These 

potential sources include volatilization of pesticides and resuspension of dusts and/or particulates 

that contain pesticides. The Agency sought expert advice and input on issues related to 

volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act 

Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on 

March 2, 2010 (http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). The 

Agency is in the process of evaluating the SAP report as well as available post-application 

inhalation exposure data generated by the Agricultural Reentry Task Force and may, as 

appropriate, develop policies and procedures, to identify the need for and, subsequently, the way

to incorporate occupational post-application inhalation exposure into the Agency's risk 

assessments. If new policies or procedures are put into place, the Agency may revisit the need 

for a quantitative occupational post-application inhalation exposure assessment for fluopyram.

Proposed uses include applications in greenhouses. The WPS for Agricultural Pesticides 

contains requirements for protecting workers and bystanders from inhalation exposures during 

and after greenhouse applications through the use of ventilation requirements. For these reasons, 
Fluopyram Human Health Risk Assessment DP No. D385636

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post-application inhalation exposures and risks were not quantitatively assessed for the proposed 

greenhouse uses. 

10.0 References

O’ Keefe, B., 8/30/2011, D389135. Fluopyram: Occupational and Residential Exposure 

Assessment for Proposed Uses on Apples, Cherry (Sweet and Tart), Dried Beans, Peanut, Potato, 

Strawberry, Sugar Beets, Tree Nuts, Watermelon and Viniferous Variety Grapes. 

Cheng, L., 9/23/2011, D387587 and D389081. Fluopyram. Application for Section 3 

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

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

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

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

Summary of Analytical Chemistry and Residue Data.

Cheng, L., 9/29/2011, D389122. Fluopyram: Acute, Chronic, and Cancer Aggregate Dietary 

Exposure and Risk Assessments 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 (Except Rice) Crop Group 15, and Forage of Cereal Grains (Except Rice) 

Crop Group 16. 

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

Knowledgebase Subcommittee (ROCKS).

Shamim, M., 7/8/2011, D353319, D363812, D363820, D363821, D363822, D363824, and 

D369773. Estimated Drinking Water Concentrations of the new chemical Fluopyram from 

Apples, Beans (dry), Cherries, Cucurbits, Grapes (wine), Peanut, Potato, Stone Fruits, 

Strawberry, Sugar beet, and Tree Nuts for the Use in Human Health Risk Assessment. 

Kidwell, J., 12/23/2009. Fluopyram - ToxSAC Meeting on July 16, 2009: Addendum 1/13/2010

Kidwell, J., 11/25/2009, TXR0055261. Fluopyram: Report of the Cancer Assessment Review 

Committee.

Alsadek, J., 5/23/2011, D387227. Percent Crop Treated for New Uses of Fluopyram on 

Cantaloupe, Cucumber, Dry Beans, Peanuts, Potatoes, Pumpkin, Squash, Sugar Beet, and 

Watermelon. Analysis of the Bayer Crop Science Percent Crop Treated Estimates for Rotated 

Crops (Wheat, Corn, Sorghum, Barley, Oats, Rye, Millet, Soybeans, Canola, Cotton, and Alfalfa) 

from the Combined Acreage of Dry Beans and Potatoes.
Fluopyram Human Health Risk Assessment DP No. D385636

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Appendix A. Toxicology Profile and Executive Summaries

A.1 Toxicology Data Requirements

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

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

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

-

no

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
Fluopyram Human Health Risk Assessment DP No. D385636

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A.2 Toxicity Profiles

Table A.2.1 Acute Toxicity Profile - Fluopyram

Guideline 

No. Study Type MRID Results Toxicity Category

870.1100 Acute oral - rat 47372430 No mortalities observed at 2000 

mg/kg

III

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

870.1300 Acute inhalation - rat 47372435

47372434

LC50 at 4 hours > 5112 mg/m3

LC50 > 5.1 mg/L

IV

870.2400 Acute eye irritation - rabbit 47723701 Non-irritating IV

870.2500 Acute dermal irritation - rabbit 47372436 Non-irritating IV

870.2600 Skin sensitization - mouse 47372440 Non-sensitizing Not Applicable

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

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

Classification /Doses

Results

Non-guideline 28-day dietary rat 

study (exploratory)

47372516; (2004)

Acceptable

50, 400, 3200 ppm

(4., 31, & 254 mg/kg/day ♂

4.6, 36, & 263 mg/kg/day 

♀)

NOAEL = 31 mg/kg/day

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

prothrombin time (M),  cholesterol and triglycerides 

(M/F),  aspartate aminotransferase and alkaline 

phosphatase

 liver weight with hepatocellular hypertrophy (M/F)

 thyroid weight with follicular cell hypertrophy (M)

Non-guideline 28-day rat study 

(dietary) 

(preliminary)

AE C657188 (PCA), 

a soil metabolite of 

AE C638206

47372521; (2003)

Acceptable

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

ppm

(1.5; 15; 149; & 1,574 

mg/kg/day for ♂

1.6; 16; 162; & 1,581 

mg/kg/day for ♀)

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

effects were seen.

870.3100 90-day dietary rat 

study 

47372441; (2005)

Acceptable/guideline

0, 50, 200, 1000, 3200 ppm

♂: 3, 13, 61, & 204 

mg/kg/day 

♀: 4, 15, 70, & 230 

mg/kg/day 

NOAEL = 13 mg/kg/day

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

food consumption, hematology parameters affected. ↑ 

cholesterol conc & -glutamyltransferase activity. 

Slight ↑ in TSH, T3 & T4. 

Target organs were liver and thyroid gland (M/F) & 

kidney (M). ↑ 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. D385636

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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

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

Classification /Doses

Results

Non-guideline 28-day dietary 

study in the mouse 

(preliminary)

47372517; (2004)

Acceptable 

150; 1,000; 5,000 ppm

♂: 25, 162, & 747 mg/kg/day

♀: 31, 162, & 954 mg/kg/day

NOAEL = 25 mg/kg/day

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

(M), ↑ ALT (M), 

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

centrilobular hypertrophy, single cell and focal 

necrosis, hepatocellular eosinophilia and bile duct/oval 

cell hyperplasia (M/F). 

Adrenal gland: hypertrophy of zona fasciculata (F).

870.3100 90-day dietary 

study in the mouse

47372442; (2005)

Acceptable/guideline

30, 150, 1000 ppm

♂: 5, 27, & 188 mg/kg/day; 

♀: 7, 32, & 216 mg/kg/day

NOAEL = 27 mg/kg/day

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

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

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

adrenal gland weights, 87-92% (M)

Liver: centrilobular hypertrophy and

focal necrosis (M/F)

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

vacuolation (F).

Non-guideline 28-day oral 

toxicity study in 

dogs (gavage)

47372515; (2004)

Acceptable

30, 150, & 750 mg/kg/day

NOAEL = 150 mg/kg/day

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

count, hemoglobin, hematocrit (M), ↑ alkaline 

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

glutamyltransferase activity and triglyceride 

concentration (F).

↑ liver weights associated with hepatocellular 

hypertrophy (M/F).

870.3150 90-day dietary 

toxicity study in 

the dog

47372443; (2006)

Acceptable/guideline

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

ppm (at day 15, the high dose 

group dietary concentration 

was reduced due to lack of 

palatability)

♂: 29, 171, & 332 mg/kg/day 

♀: 33, 184, & 337 mg/kg/day

NOAEL = 29 mg/kg/day

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

characterized by ↑ alkaline phosphatase, -

glutamyltransferase activity, ALT & AST; ↓ albumin 

conc and bilirubin; ↑ liver weights associated with 

hepatocellular hypertrophy, intracytoplasmic 

eosinophilic droplets and single cell necrosis. Both 

sexes were affected.

870.3200 28-day dermal 

toxicity study in the 

rat

47372444; (2007)

Acceptable/guideline

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

NOAEL = 300 m/kg/day

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

and 

↑ liver weights associated with hepatocellular 

hypertrophy

870.3700 Developmental 

toxicity in the rat

47372445; (2008, Report)

(Study conducted in 2006)

Acceptable/guideline

Maternal NOAEL = 30 mg/kg/day

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

body weight gains and food consumption, higher liver 

weights and diffused centrilobular hepatocellular 

hypertrophy.

Developmental NOAEL= 150 mg/kg/day

Developmental LOAEL = 450 mg/kg/day based 

Decreased fetal body weight (5%), increased incidence 

of two minor variations at both the visceral and skeletal 

evaluation.
Fluopyram Human Health Risk Assessment DP No. D385636

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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

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

Classification /Doses

Results

870.3700 Developmental 

toxicity study in the 

rabbit

47372446; (2006)

Acceptable/guideline

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

(gavage, GD 6-28)

Maternal NOAEL = 25 mg/kg/day

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

body weight gain and food consumption.

Developmental NOAEL = 25 mg/kg/day

Developmental LOAEL = 75 mg/kg/day based on 

decreased fetal body weight (-11%).

Non-guideline Dose range-finding 

reproduction study 

in the rat

47372448; (2008) (Report)

(This study was conducted in 

2006)

Acceptable

30; 150; 750; & 1,500 ppm

♂: 2,10, 50, & 102 

mg/kg/day 

♀: 2, 12, 58, & 118 

mg/kg/day.

Parental NOAEL = 10 mg/kg/day 

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

liver and kidney weights

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

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

effect was seen in any of reproductive parameters 

examined.

870.3800 2-Generation 

reproduction study 

in the rat

47372447; (2008, Report)

(Study was conducted in 

2006)

Acceptable/guideline

40; 220; & 1, 200 ppm 

♂: 3, 15, 83 mg/kg/day 

(premating) 

♀: 3., 18, & 96 mg/kg/day 

(premating).

Parental NOAEL = 15 mg/kg/day

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

creatinine, total protein, and albumin. Increased kidney 

and liver weights. Increased incidence of liver 

hypertrophy.

Offspring NOAEL = 15 mg/kg/day

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

body weight and body weight gain with secondary 

decreases in spleen and thymus weights and secondary 

slight delay in preputial separation.

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

effect was seen in any of reproductive parameters 

examined.

870.4100 1-year toxicity study 

in dogs (dietary)

47372449; (2007)

Acceptable/guideline

100; 400; & 2,000 ppm

♂: 3, 13, & 68 mg/kg/day 

♀: 4, 14, & 66 mg/kg/day.

NOAEL = 13 mg/kg/day

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

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

Liver: centrilobular hypertrophy.

870.4200 Carcinogenicity 

study in the mouse

47372450; (2007)

Acceptable/guideline

30, 150, & 750 ppm

♂: 4, 21, & 105 mg/kg/day 

♀: 5, 27, & 129 mg/kg/day.

NOAEL = 4 mg/kg/day

LOAEL = 21 mg/kg/day based on treatment-related 

follicular cell hyperplasia in the thyroid gland, 

centrilobular to panlobular hypertrophy and 

hepatocellular single cell degeneration /necrosis in the 

liver. 

Thyroid gland follicular cell

adenomas in high dose males.
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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

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

Classification /Doses

Results

870.4300 Chronic 

/carcinogenicity 

study in the rat

47372501; (2008)

Acceptable/guideline

30, 150 & 750/375 ppm for

♂; 30, 150 and 1,500 ppm 

for ♀.

♂: 1.2, 6.0, & 29 mg/kg/day 

♀: 1.7, 8.6, & 89 mg/kg/day 

(Due to high mortality in 750 

ppm males, this 

concentration was reduced to 

375 ppm from week 85 

onward)

NOAEL = 1.2 mg/kg/day

LOAEL = 6.0 mg/kg/day based on treatment-related 

marked liver toxicity, nephropathy, and follicular cell 

hypertrophy in the thyroid gland.

Liver cell tumors (carcinoma and adenoma) in high 

dose females. 

870.5100 Ames test 47372502; (2006)

Acceptable/guideline

Doses: 16 to 5000 μg/plate

+/- metabolic activation

Negative

870.5100 Ames test 47372503; (2008)

Acceptable/guideline

Doses: 5 to 1581 μg/plate

 16 to 5000 μg/plate

+/- metabolic activation

Negative

870.5300 In-vitro

chromosome 

aberration (V79 

cells).

47372505; (2005)

Acceptable/guideline

Concentrations: 30, 60, 120, 

180, & 240 μg/ml.

Negative

870.5300 HPRT Test (V79 

cells).

47372504; (2006)

Acceptable/guideline

Concentrations: 4 to 256 

μg/ml

+/- metabolic activation.

Negative

870.5385 In-vivo micronucleus test in male 

mice

47372506; (2005)

Acceptable/guideline

Doses: 250, 500, & 1000 

mg/kg.

Negative

870.6200a Acute 

neurotoxicity 

screening battery

47372507; (2007)

Acceptable/guideline

Initial study

125; 500; and 2,000 

mg/kg/day

Follow-up study using only 

female rats 

25, 50 and 100 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.

NOAEL = 50 mg/kg/day

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

locomotor activity.
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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

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

Classification /Doses

Results

870.6200b Subchronic 

neurotoxicity 

screening battery

47372508; (2008, Report) 

(The study was conducted in 

2007)

Acceptable/guideline

100; 500; & 2,500 ppm 

♂: 7, 33, & 164 mg/kg/day 

♀: 8, 41, & 197 mg/kg/day

NOAEL = 33 mg/kg/day

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

which included increases in cholesterol and triglyceride 

levels, decrease in glucose level, decreases in 

hemoglobin and hematocrit, and deceases in body 

weight and food consumption.

No evidence of neurotoxicity in either neurobehavioral 

parameter or histopathology.

870.7485 ADME study in rats 47372509; (2008)

Acceptable/guideline

5 & 250 mg/kg (single dose 

by gavage )(14 C on phenyl 

ring)

5 mg/kg (radiolabeled

fluopyram) after 14 days pretreatment

With oral dosing, fluopyram was rapidly absorbed 

(93.2 % of administered radioactivity) from the GI tract 

of male and female rats. The max. plasma 

concentration was reached at 15 hrs in males and 11 

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

post dosing 91-99 % of the administered radioactivity 

was eliminated via urine and feces. The ratio of renal 

and fecal elimination was comparable (45% via urine 

and 47% via feces). The organ which contained the 

highest radioactivity was the liver (0.4 to 1.0 % of the 

administered radioactivity.) Considerable enterohepatic 

circulation was demonstrated by the results. Fluopyram 

was extensively metabolized and 29 metabolites were 

identified. It was proposed that three main metabolite

groups were formed in the liver (fluopyram-7-OH-GA, 

8-OH-GA and enol-GA) (GA=glucuronic acid).

870.7485 ADME in the rat 47372511; (2008)

Acceptable/guideline

Single oral dose, 5 mg/kg 

(gavage) (14C in positions 2 

& 6 of the pyridyl ring)

With oral dosing, fluopyram was absorbed rapidly and 

efficiently eliminated from the body (>98% of the 

administered radioactivity was eliminated) after 72 hrs 

post dosing. No significant residues remained in the 

body. Considerable enterohepatic circulation occurred. 

Three main metabolite groups were formed in the liver 

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

(GA=glucuronic acid).

870.7485 Distribution of total 

radioactivity in male 

& female rats

47372513; (2008)

Acceptable/non-guideline

Single dose 14C in the phenyl 

ring of fluopyram at 3 

mg/kg.

Distribution occurred in almost all organs with liver 

reaching the maximal concentration first, and most of 

the tissue reaching the peak concentration at 

approximately 24 hr post-dosing. By 136 hr post dosing 

little of the radioactivity was present in most organs 

except nasal mucosa. 

870.7485 Distribution of 14C 

labeled fluopyram.

47372512; (2008)

Acceptable/non-guideline

3 mg/kg for ♂ & 4.5 mg/kg 

for ♀ (Single oral dose; 14C 

on pyridyl ring of 

fluopyram.)

Fluopyram was readily absorbed from the GI tract and 

distributed among almost all organs. The data indicated 

that peak value was reached at approximately 1 hr after 

dosing in most organs with liver having the higher 

concentration than other organs. From peak values, a 

continuous but slow decline of radioactivity 

concentrations was observed for all organs.

870.7485 Metabolism in 

organs and tissues in 

rats

47372509; (2008)

Acceptable/non-guideline 5 

mg/kg (Single oral dose; 14C 

in the 2 & 6 position of the 

pyridyl ring of fluopyram).

AE C656948 was extensively metabolized, and more 

than 20 metabolites were identified. The report 

concluded that the major metabolic transformation was 

oxidation and took place mainly at the ethylene bridge 

of the molecule. The major metabolites were AE 

C656948-7-hydroxy and AE C656948-pyridyl-acetic 

acid.
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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

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

Classification /Doses

Results

870.7600 In-vitro dermal 

absorption study 

with human and rat 

skin

47372514 (2007)

Acceptable

500 mg AE C656948 & 0.5 

mg AE C656948 (spray 

dilution)

Dermatomed skin membranes from human and rat were 

examined. The report stated that over a period of 24 

hrs the potentially absorbable [14C] –AE C656948 was 

1.8% and 12.4 % for human and rat skin, respectively. 

This results in approximately 6x difference between 

dermatomed human and rat skin. Rat skin being more 

permeable.

In-vivo dermal 

absorption

47567201 (2008)

Acceptable/guideline

0, 60 μg (spray dilution) and 

60 mg (neat)

The maximal dermal absorption rates for neat 

formulation and spray dilution were 4.5% and 12.8% of 

the applied dose, respectively.

870.7800 28-Day 

immunotoxicity 

study in rats

48239930; (2010)

Acceptable/guideline

0, 200, 600, 1800 ppm

0, 17.2, 53.6, 156.3 

mg/kg/day.

Immunotoxicity NOAEL for anti-SRBC IgM response 

= 156.3 mg/kg/day (HDT).

Non-guideline 7-Day mechanistic 

study in female rats 

(dietary 

administration)

47372520; (2008)

Acceptable/non-guideline

3,000 ppm (193 mg/kg/day).

Feeding fluopyram at 193 mg/kg/day in the diet to 

female rats did not affect body weight, clinical signs or

food or water consumption. 

Mean absolute and relative liver weights were 

increased (40 to 43%) relative to the controls. This 

increase was associated with enlarged and dark livers 

in 13/15 females. 

At histological examination, minimal to slight 

centrilobular to panlobular hepatocellular hypertrophy 

was found in all treated animals. 

There was a 4x increase in mean BrdU labeling index 

in both the perilobular and centrilobular areas of the 

hepatic lobule in treated animals relative to the 

controls.

A slight increase in total P-450 content and in mean 

EROD activity, a moderate increase in mean PROD 

and BROD activities and a marked increase in mean 

UDPGT activity (all statistically different from the 

control group (p≤0.01)) were seen. The report 

concluded that AE C656948 has the ability to induce 

moderately phenobarbital-inducible hepatic enzymes 

(total cytochrome P-450, BROD and PROD and 

UDPGT) as well as liver hypertrophy and cell 

proliferation in the liver.
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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

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

Classification /Doses

Results

Non-guideline 7-Day mechanistic 

study with 

Phenobarbital

Reduction in activity in all treated animals & slight 

reduction in body weight gain. Mean absolute and 

relative liver weights were increased (≈ 22%) relative 

to the controls. Dark liver was found in 5/14 females 

and enlarged liver in 3/14 females. Minimal to slight 

centrilobular to panlobular hepatocellular hypertrophy 

was found in all treated animals. A 2x increase in mean 

BrdU labeling index in the perilobular and centrilobular 

areas in the treated animals. A moderate increase in 

total P-450 content and in mean PROD, BROD and 

UDPGT activities (all statistically different from the 

control group p≤0.01). The report states that 

phenobarbital has the ability to induce hepatic enzymes 

like total cytochrome P-450, PROD, BROD and 

UDPGT activities as well as liver hypertrophy and cell 

proliferation in the liver. 

Non-guideline 14-Day dietary 

administration to the 

mice (hepato-toxicity 

and thyroid hormone 

investigations)

47372519; (2008

Acceptable/non-guideline

2,000 ppm

308 and 314 mg/kg for 3 or 

14 days, respectively.

After 3 days of exposure, mean T3 level was not 

changed, whereas mean T4 level was decreased (-30%) 

while mean TSH level was increased (+18%) relative 

to the controls. Mean absolute and relative liver 

weights were increased by approximately 60%. 

Enlarged liver was found in all the treated animals. 

Diffuse centrilobular to panlobular hepatocellular 

hypertrophy and an increased number of mitoses were 

observed in all examined treated animals. In addition, 

hepatocellular single cell necrosis was observed in 1/5 

treated animals. No significant microscopic change 

was observed in the thyroid gland.

Total cytochrome P-450 content was markedly 

increased (+116%) by the treatment. EROD activities 

were marginally increased (+235%), whereas PROD 

and BROD activities were markedly increased 

(respectively +2890% and +8717%) relative to 

controls. No significant changes were observed in 

UDPGT. 

Non-guideline Phenobarbital 14-

day mechanistic 

study in the mouse 

(gavage)(hepatotoxicity and thyroid 

hormone 

investigations)

47372522; (2008)

Acceptable/non-guideline

80 mg/kg for 3 or 14 days 

by gavage.

The report stated that phenobarbital administration at a 

dose level of 80 mg/kg body weight/day in the mouse 

for 3 and 14 days induced significant liver changes 

including increases in hepatic total cytochrome P-450, 

PROD and BROD activities. Phenobarbital also 

induced a modification of the normal thyroid hormone 

balance (in particular by a decrease in T4 and/or T3 

after 3 and/or 14 days of exposure together with a 

concomitant increase in TSH level after 14 days.)

Non-guideline In-vitro studies on 

the potential 

interactions with 

thyroid peroxidasecatalyzed reactions

47372518; (2008)

Acceptable/non-guideline

300 μM

Fluopyram at 300 μM did not affect thyroid peroxidase

(TPO)-catalyzed guaiacol oxidation and TPO-catalyzed

iodine formation. Therefore, the data show that 

fluopyram does not affect thyroid hormone synthesis at 

the level of TPO.

A.3 Hazard Identification and Endpoint Selection

A.3.1 Acute Reference Dose (aRfD) - Females age 13-49
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Study Selected: None

MRID No: N/A

Dose and Endpoint for Risk Assessment: None 

Uncertainty Factor: Not applicable

Comments about Study/Endpoint/Uncertainty Factors: An endpoint attributable to a single 

dose was not identified.

A.3.2 Acute Reference Dose (aRfD) - General Population

Study Selected: Acute Neurotoxicity Studies in Rats 

MRID No: 47372507

Dose and Endpoint for Risk Assessment: NOAEL= 50 mg/kg/day 

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

Acute RfD = 

100 ( )

50 / /

UF

mg kg day = 0.50 mg/kg/day

Comments about Study/Endpoint/Uncertainty Factors: 

An acute neurotoxicity study in rats was used to select the dose and endpoint for establishing the 

general population aRfD of 0.5 mg/kg/day. The LOAEL of 100 mg/kg is based on decreased 

motor and locomotor activity in females. The LOAEL in males was 125 mg/kg/day. This acute 

endpoint is appropriate for the route and duration of exposure as well as for the population of 

concern.

A.3.3 Chronic Reference Dose (cRfD) `

Study Selected: Combined Chronic Toxicity/Carcinogenicity Study in Rats

MRID No: 47372501

Dose and Endpoint for Risk Assessment: NOAEL= 1.20 mg/kg/day

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

Chronic RfD = 

100 ( )

1.20 / /

UF

mg kg day = 0.012 mg/kg/day

Comments about Study/Endpoint/Uncertainty Factors:

A combined chronic/carcinogenicity study in rats was used to select the dose and endpoint for 

establishing the cRfD of 0.012 mg/kg/day. The LOAEL of 6.0 mg/kg/day is based on 

nephropathy, follicular cell hypertrophy in the thyroid, and increased liver weight with gross 

pathological and histopathological findings. The selection of the point of departure and toxicity

endpoint from this study endpoint is appropriate for the duration and population of concern. In 

addition it will be protective of thyroid effects (thyroid hyperplasia and thyroid follicular cell 

tumors) seen in mice at 750 ppm (105 mg/kg/day). 
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A.3.4 Incidental Oral Exposure (Short- and Intermediate-Term)

Study Selected: 2-Generation Reproduction-Rat

MRID No: 47342447

Dose and Endpoint for Risk Assessment: NOAEL= 14.5 mg/kg/day

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

Comments about Study/Endpoint/Uncertainty Factors:

A 2-generation reproduction study in rats was used to select the dose and endpoint for short- and 

intermediate-term incidental oral exposure. The LOAEL of 82.8 mg/kg/day is based on clinical 

pathology changes, increased liver weight, protein droplet nephropathy (M) and centrilobular 

hypertrophy in parents, and decreased body weight (-8.1%, p<0.05) and body weight gain (-8.6% 

p<0.05) with secondary decreases in spleen and thymus weights and secondary slight delay in 

preputial separation in offspring. This endpoint is appropriate for the population of concern 

(children) since this body weight/body weight gain effect occurred post-natally and is not an in 

utero effect.

A.3.5 Dermal Exposure (Short-, Intermediate- and Long-Term)

Dermal absorption studies of Fluopyram SC 500 neat formulation (500 mg fluopyram/ml) or the 

spray dilution (0.5 mg/ml) were conducted in rats in vivo. The conservative estimates of the 

percentage of the administered dose absorbed were 4.5% for the neat formulation and 

12.8% for the spray dilution. Refinement of the dermal absorption factors for the neat 

formulation and spray dilution was achieved by conducting in vitro studies under similar 

conditions (e.g. same material, same times, similar treatment of the skin including tape stripping) 

using rat skin and human skin. With the results from both in vivo and in vitro studies, a 

parallelogram (also called a "Triple Pack") approach was used to calculate 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 refined dermal absorption values for human skin were 0.2% for 

the neat formulation and 1.9% for the spray dilution.

Short- and Intermediate-Term Dermal Exposure 

Study Selected: 28-day Dermal -- Rat

MRID No: 47567201

Dose and Endpoint for Risk Assessment: Dermal NOAEL= 300 mg/kg/day

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

Comments about Study/Endpoint/Uncertainty Factors:

A 28-day dermal study was selected for the dose and endpoint for short and intermediate term 

dermal exposure. The LOAEL of 1000 mg/kg/day (oral equivalent = 45 mg/kg/day) is based on 

increased cholesterol (females), increased prothrombin time (males) and increased liver weights 

(males & females) associated with hepatocellular hypertrophy. The 28-day dermal toxicity study

in rats is the appropriate route of exposure and measures all endpoints of concern. An oral study 

was not chosen for a dermal endpoint since no increased sensitivity was seen in the 
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developmental rat or rabbit studies or in the 2-generation reproduction study in rats. The dermal 

endpoint is protective of effects from any in utero exposure. In addition, this 28-day dermal 

toxicity study is appropriate for both the short- and intermediate-term exposures. Since dermal 

absorption is so low (<1% in humans for the concentrate), it is unlikely that the internal dose 

would lead to a progression of toxicity.

A.3.6 Inhalation Exposure (Short-, Intermediate- and Long-Term) 

Short- and Intermediate-Term Inhalation Exposure 

See Incidental Oral exposure ( A3.4). The assumed inhalation absorption factor is 100%. 

Long-Term Inhalation Exposure 

Long-term Inhalation exposure is not anticipated.

A.4 Executive Summaries

A.4.1 Subchronic Toxicity

870.3100 90-Day Oral Toxicity – Rat

In a subchronic oral toxicity study (MRID 47372441), fluopyram (99.0% a.i., Lot/Batch PFI 

0304) was administered in the diet to ten Wistar (Rj:WI [IOPS HAN]) rats/sex/dose group at 

dose levels of 0, 50, 200, 1000, or 3200 ppm (equivalent to 0/0, 3.06/3.63, 12.5/14.6, 60.5/70.1, 

and 204/230 mg/kg/day in males/females) for at least 90 days. Additionally, groups of ten 

rats/sex/dose group were administered the test substance in the diet at dose levels of 0 or 3200 

ppm for at least 90 days and then maintained on basal diet for a minimum of 28 days to examine 

the reversibility of any treatment-related effects. In addition to the customary parameters, 

animals of the main treatment group were assessed for neurotoxicity on Study Weeks 11 and 12 

by observers who were “blind” to the dose groups of the animals. Motor activity, sensor 

reactivity, and grip strength were recorded. Additionally, during Weeks 3 and 13 of the 

treatment period, and Week 5 of the recovery period, blood samples were collected and T3, T4, 

and TSH levels were measured.

There were no effects of treatment observed on clinical signs, motor activity, sensor reactivity, 

grip strength, or ophthalmoscopic examinations.

There were no treatment-related deaths. One 1000 ppm male was euthanized on Day 37 having 

had a distended abdomen between Days 22 and 37 and general pallor between Days 27 and 37. 

This animal was noted to have a pale appearance and an enlarged, irregular, and red mottled liver 

at necropsy; a cause of death was not reported. One 50 ppm male was killed on Day 57 having 

been noted to have labored and noisy respiration, a wasted appearance, piloerection, and ocular 

discharge from both eyes on the day of termination, together with a body weight loss of 8.2 

g/day and reduced food consumption during the week prior to sacrifice. The condition of this
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animal was attributed to accidental trauma, as soiled fur around both eyes and a fracture of the 

nasal cavity were discovered at necropsy. All other animals survived to scheduled termination.

At 3200 ppm, the liver toxicity findings observed at 1000 ppm were increased in severity and 

magnitude and more frequently noted in both sexes. In addition to the findings in the liver noted 

above, triglycerides were increased in the females and higher mean prothrombin times were 

noted in the males. In the thyroid, absolute and relative weights were increased in both sexes, 

with minimal to slight diffuse follicular cell hypertrophy noted in the majority (8/10) of the 

males; minimal diffuse follicular cell hypertrophy was noted in one female. TSH was increased 

in both sexes at Week 3, and in the males at Week 13. T3 was increased in the females at Week 

3, and in the males at Week 13. T4 was increased in the females at Week 3. Additionally at this 

dose, body weights were slightly decreased throughout the study, resulting in a decrease in 

overall body weight gains in both sexes. Food consumption was slightly decreased from Day 29-

90 in the females.

Treatment-related liver toxicity was observed at 1000 ppm. Absolute and relative (to body) liver 

weights were increased by 20-27% in both sexes. Total cholesterol was increased by 45-48% in 

both sexes, and gamma glutamyltransferase was increased by 480% in the females. At necropsy, 

obviously large liver was observed in 6/9 males and 7/10 females, dark liver was noted in 2/9 

males, and prominent liver lobulation was observed in 4/9 males. Minimal to slight diffuse 

centrilobular hepatocellular hypertrophy was noted in 9/9 males and 7/10 females, and minimal 

focal/multifocal periportal to midzonal hepatocellular macrovacuolation was observed in 6/10 

females. Additionally at 1000 ppm, minimal to slight diffuse follicular cell hypertrophy was 

noted in 4/9 males and 2/10 females, and TSH and T4 were increased by 54% and 43%, 

respectively, in the males.

At 200 ppm, certain effects (such as increased total cholesterol, increased gamma 

glutamyltransferase in females only, enlarged liver, minimal diffuse centrilobular hepatocellular 

hypertrophy and minimal focal/multifocal periportal to midzonal hepatocellular 

macrovacuolation) were found in a small number of test animals. The severity and magnitude of 

effect were minimal relative to the effects seen in 1000 ppm group. These minor findings were 

considered to represent an adaptive response of the liver to exposure to the test compound and 

were not considered adverse.

Kidney toxicity was noted in the males at 1000 ppm and above. Absolute and relative kidney

weights were increased by 25-34%. Obviously large kidney and pale kidney were noted in the 

majority of the 1000 ppm and above males at necropsy, and in 1-3 males at 50 and 200 ppm. 

The increased weights were associated with microscopic changes of hyaline droplet nephropathy 

(hyaline droplets in the proximal tubule, focal/multifocal basophilic tubules, granular casts in the

medulla, and focal/multifocal hyaline casts) observed in all dose groups, increasing in severity 

and frequency with increasing dose. Cellular casts in the urine were also noted at all dose levels 

in the males. This nephropathy was considered to be due to accumulation of 2u-globulin, a 

common toxicological finding in young male rats following exposure to toxicants. Therefore, 

these findings were not considered relevant to human health considerations.
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During the recovery period, there was a tendency towards reversibility in the majority of the 

animals treated with 3200 ppm of the test compound. The findings in the male kidney tended to 

be the most persistent.

The LOAEL is 1000 ppm (equivalent to 60.5/70.1 mg/kg/day in males/females), based on 

liver toxicity as described above and diffuse follicular cell hypertrophy in both sexes, and 

increased TSH and T4 in the males. The NOAEL is 200 ppm (equivalent to 12.5/14.6 

mg/kg/day in males/females).

This study is considered acceptable/guideline and satisfies the requirements (OPPTS 870.3100; 

OECD 408) for a subchronic toxicity study in rodents.

870.3100 90-Day Oral Toxicity – Mouse

In a subchronic oral toxicity study (MRID 47372442), fluopyram (99.0% a.i., Lot/Batch PFI 

0304) was administered in the diet to ten C57BL/6J mice/sex/dose group at dose levels of 0, 30, 

150, or 1000 ppm (equivalent to 0/0, 5.4/6.8, 26.6/32.0, and 188/216 mg/kg/day in 

males/females) for at least 90 days.

There were no effects of treatment observed on clinical signs, body weights, body weight gains, 

or food consumption.

There were no treatment-related deaths. One 30 ppm male was found dead on Day 30 after a 

body weight loss of 6.9 g between Days 15-29 and reduced food consumption between Days 9-

29. Clinical signs included reduced motor activity on Days 22-23 together with wasted 

appearance and hunched posture during Days 22-29. Spontaneous hydrocephalus was observed 

at necropsy and confirmed microscopically. This was considered to be the cause of death for this 

animal. One control male was killed for humane reasons on Day 69 after an accidental trauma. 

All other mice survived to scheduled termination.

Treatment-related liver toxicity was observed at 1000 ppm. Alanine aminotransferase was 

increased by 109-205% in both sexes, and alkaline phosphatase and aspartate aminotransferase 

were increased by 21% and 46%, respectively, in males. Absolute and relative (to body) liver 

weights were increased by 36-45% in both sexes, corresponding to enlarged liver in 8/10 males 

and 9/10 females. Dark liver was noted in 5/10 males and 10/10 females. Microscopically, 

centrilobular hepatocellular hypertrophy was observed in 10/10 males (moderate severity) and 

10/10 females (minimal to moderate severity). Focal necrosis was noted in 3/10 males (minimal 

severity) and 6/10 females (minimal to slight severity).

Additionally at 1000 ppm, absolute and relative adrenal gland weights were increased by 87-92% 

in the males. Microscopically in the adrenal glands, there was a lower incidence of cortical 

ceroid pigment in the males, and a greater incidence of minimal to slight cortical vacuolation in 

the females.

At 150 ppm, absolute and relative liver weights were increased by 14-28% in both sexes. 

Centrilobular hepatocellular hypertrophy was observed in 10/10 males (minimal to slight 
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severity) and 5/10 females (minimal severity). These minor findings were considered to 

represent an adaptive response of the liver to exposure to the test compound and were not 

considered adverse.

The LOAEL is 1000 ppm (equivalent to 188/216 mg/kg/day in males/females), based on 

liver toxicity as described above in both sexes, increased adrenal gland weights and lower 

incidence of adrenal gland cortical ceroid pigment in males, and a greater incidence of 

cortical vacuolation of the adrenal gland in females. The NOAEL is 150 ppm (equivalent to

26.6/32.0 mg/kg/day in males/females).

This study is considered acceptable/guideline and satisfies the requirements (OPPTS 870.3100; 

OECD 408) for a subchronic toxicity study in rodents.

870.3150 90-Day Oral Toxicity – Dog

In a subchronic oral toxicity study (MRID 47372443), fluopyram (94.6% a.i., Batch 08528/0002) 

was administered in the diet to four beagle dogs/sex/dose group at dose levels of 0, 800, 5000, or 

20,000 ppm (equivalent to 0/0, 28.5/32.9, 171/184, and 332/337 mg/kg/day in males/females) for 

at least 90 days. The highest dietary concentration was reduced to 10,000 ppm on Day 15 due to 

body weight losses and decreased food consumption during the first two weeks, which were 

attributed to a lack of palatability of the test substance in the diet.

There were no effects of treatment observed on mortality, during the ophthalmoscopic 

examinations, or on urinalysis. All dogs survived to scheduled euthanasia.

Treatment-related liver toxicity was observed at 5000 ppm. Absolute and relative (to body) liver 

weights were increased by 59-69% in the males and by 35-49% in the females. The following 

changes in clinical chemistry parameters were observed in both sexes at Weeks 8 and 13: (i) 

alkaline phosphatase was increased by 169-300%; (ii) gamma glutamyltransferase was increased 

by 50-200%; (iii) albumin was decreased by 17-22%; and (iv) albumin/globulin ratio was 

decreased by 21-34%. The changes generally increased in magnitude with time. At necropsy, 

enlarged liver was noted in 1/4 males and females. The following microscopic findings were 

noted in the liver (all compared to 0 controls): (i) minimal to slight diffuse hepatocellular 

hypertrophy in 4/4 males and females; (ii) multifocal intracytoplasmic eosinophilic droplets in 

3/4 males (minimal to slight severity) and 4/4 females (minimal to moderate severity); and (iii) 

focal/multifocal hepatocellular single cell necrosis in 2/4 males (minimal severity).

Additionally at 5000 ppm, overall (Weeks 1-13) food consumption was decreased by 7% in 

males and by 22% in females. This decrease was also attributed to a lack of palatability of the 

dietary formulations. Thymic involution (decreased size of cortex) was increased in severity 

(minimal to slight) in all males and females compared to controls (minimal); however, this 

finding was considered to be secondary to the decreased food consumption.

At 20,000/10,000 ppm, the findings observed at 5000 ppm were increased in severity and 

magnitude and more frequently noted in both sexes. In addition to the findings in the liver noted 

above, increases in aspartate aminotransferase (incr. 54-75%) and alanine aminotransferase (incr. 
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259-594%) were noted in the males at Weeks 8 and 13. Additional findings of toxicity included 

a wasted appearance noted for one male and two females. This observation was noted in 

correlation with body weight loss and corresponding marked reduction in food consumption in 

both sexes during Weeks 1 and 2. These findings were attributed to a lack of palatability of the 

test diets at this concentration. Overall (Weeks 1-13) body weight losses of 0.8 kg in males and 

1.1 kg in females were noted (compared to gains of 1.0 kg in controls), corresponding to 

decreases in overall food consumption of 25% and 46% in males and females, respectively. 

Platelet counts were increased by 30-56% in both sexes during Weeks 8 and 13.

Also at 20,000/10,000 ppm, absolute and relative thymus weights were decreased by 61-71% in 

the females, and 4/4 females were in anestrus compared to 1/4 controls. These findings were 

considered to be secondary to the reductions in body weight gains and food consumption.

At 800 ppm, absolute and relative liver weights were increased by 25-39% in both sexes. This 

finding was considered to represent an adaptive response of the liver to exposure to the test 

compound, and was not considered adverse.

The LOAEL is 5000 ppm (equivalent to 171/184 mg/kg/day in males/females), based on 

liver toxicity as described above in both sexes. The NOAEL is 800 ppm (equivalent to 

28.5/32.9 mg/kg/day in males/females).

This study is considered acceptable/guideline and satisfies the requirements (OPPTS 870.3150; 

OECD 409) for a subchronic toxicity study in dogs.

870.3200 21/28-Day Dermal Toxicity – Rat

In a 28-day dermal toxicity study (MRID 47372444), fluopyram (94.7% a.i., Batch 08528/0002) 

was applied to the shaved (intact) dorsal and lateral skin of ten Wistar rats/sex/dose group at dose 

levels of 0, 100, 300, and 1000 mg/kg/day for a minimum of six hours/day, five consecutive 

days/week, for four weeks.

There were no effects of treatment observed on mortality, clinical signs, body weights, food 

consumption, or gross pathology.

At 1000 mg/kg/day, treatment-related effects were observed on the liver. Relative (to body) liver 

weights were increased in the males, and absolute and relative liver weights were increased in 

the females. Microscopically, increased incidence of centrilobular and mid-zonal hypertrophy

were observed in the liver of males and females. Additionally, prothrombin time was increased 

in the males, and total cholesterol was increased in the females.

The LOAEL for systemic toxicity is 1000 mg/kg/day, based on liver toxicity as described 

above. The NOAEL is 300 mg/kg/day.

There were no local effects observed on the skin at any dose level.

The LOAEL for dermal toxicity was not observed. The NOAEL is 1000 mg/kg/day.
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This study is considered acceptable/guideline and satisfies the requirements (OPPTS 870.3200; 

OECD 410) for a 28-day dermal toxicity study in rats.

A.4.2 Prenatal Developmental Toxicity

870.3700a Prenatal Developmental Toxicity Study – Rat

In a developmental toxicity study (MRID 47372445), AE C656948 (Fluopyram, 94.6% a.i.; 

Lot/Batch # 08528/0002) in 0.5% aqueous methylcellulose 400 was administered via daily oral 

gavage in a dose volume of 10 mL/kg to 23 time-mated Sprague-Dawley rats/dose group at 

doses of 0, 30, 150, or 450 mg/kg/day from gestation days (GD) 6-20. On GD 21, all dams were 

euthanized; each dam’s uterus was removed via cesarean section and its contents examined. 

Fetuses were examined for external, visceral, and skeletal malformations and variations. 

No compound-related effects were observed on mortality, clinical signs of toxicity, or pregnancy

rate.

At 450 mg/kg/day, maternal body weight gain was decreased (p<0.01) by 16% during GD 6-21, 

and food consumption was decreased by 13-15% at all intervals from GD 6-14. Liver weights 

were increased (p<0.01) by 40% compared to controls and enlarged liver was also noted grossly 

in 4/23 females at this dose (vs. 0/23 controls). Microscopic findings were limited to slight to 

marked diffuse centrilobular hepatocellular hypertrophy in all treated females at this dose (vs. 

0/23 controls).

At 150 mg/kg/day, maternal body weight gain was decreased by 6% during GD 6-21, and food 

consumption was decreased by 10-18% at all intervals from GD 6-14. Liver weights were 

increased (p<0.01) by 15% compared to controls. Microscopic findings were limited to minimal 

to moderate diffuse centrilobular hepatocellular hypertrophy in 20/23 females at this dose (vs. 

0/23 controls).

At 30 mg/kg/day, food consumption was decreased (p<0.01) by 10% on GD 6-8; however, 

overall (GD 6-21) body weight gains were similar to controls.

The maternal LOAEL is 150 mg/kg/day based on decreased body weight gains and food 

consumption, and liver effects (increased liver weights and incidence of diffuse 

centrilobular hepatocellular hypertrophy). The maternal NOAEL is 30 mg/kg/day.

There were no treatment-related effects on abortions, premature deliveries, complete litter 

resorptions, or dead fetuses and no effects of treatment on the numbers of litters, live fetuses, 

early resorptions, or late resorptions. There were no treatment-related external, visceral, or 

skeletal malformations, and no external variations. 

At 450 mg/kg/day, mean fetal body weight was decreased (p<0.05) by 5% for both the combined 

and separate sexes. The incidence of the visceral variations “thymic remnant present 
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(unilateral/bilateral)” and “ureter (unilateral/bilateral); convoluted and /or dilated” was higher at 

the fetal and/or litter level than in the control group, and was outside the historical control range 

for both parameters. Additionally, there was a higher incidence of the skeletal variations “at 

least one thoracic centrum split/split cartilage” and “at least one thoracic centrum: dumbbell 

and/or bipartite/normal cartilage”, compared with the control group. The incidence was outside 

the historical control range at both the fetal and litter level for both findings.

The developmental LOAEL was 450 mg/kg/day based on decreased fetal body weights, and 

increased incidence of visceral and skeletal variations. The developmental NOAEL is 150 

mg/kg/day.

This study is classified acceptable/guideline and satisfies the guideline requirement for a 

developmental toxicity study (OPPTS 870.3700; OECD 414) in rats.

870.3700b Prenatal Developmental Toxicity Study – Rabbit

In a developmental toxicity study (MRID 47372446), 

AE C656948 (Fluopyram, 94.6% a.i.; Lot/Batch # 08528/0002) in 0.5% aqueous methylcellulose 

400 was administered via daily oral gavage in a dose volume of 4 mL/kg to 23 time-mated New

Zealand White rabbits/dose group at doses of 0, 10, 25, or 75 mg/kg/day from gestation days 

(GD) 6-28. On GD 29, all surviving females were euthanized; each doe’s uterus was removed 

via cesarean section and its contents examined. Fetuses were examined for external, visceral, 

and skeletal malformations and variations.

No compound-related effects were observed on mortality, clinical signs of toxicity, pregnancy

rate, macroscopic findings, or liver parameters (weight or pathology).

On GD 21 one female at 75 mg/kg/day died and one control female was sacrificed due to 

accidental trauma on GD 15. Both deaths were attributable to a gavage error. The macroscopic 

observation showed hemorrhaging in the lung of both females together with hemorrhaging and 

foam in the trachea of one female and a trachea filled with fluid for the other female. In 

addition, one female was killed for humane reasons on GD 23 at 25 mg/kg/day, following a 

slight loss in body weight and a reduction in food consumption between GD 20 and 22. Clinical 

signs in this female consisted of a limited use of the right hindlimb on GD 22 and 23. The 

macroscopic observation showed a severe fracture of the right hindlimb, in association with 

massive subcutaneous hemorrhaging and a distal epiphysal femoral disjunction. The condition 

of this animal was considered to be due to accidental trauma. 

At 75 mg/kg/day, mean body weight gain was decreased (p<0.01) between GD 14-18 (0.02 kg 

vs. 0.09 kg for controls) and between GD 18-22 (0.02 kg vs. 0.07 kg for controls). Thereafter, 

mean body weight gain was similar to the controls, resulting in an overall (GD 6-29) decreased 

(not significant )body weight gain of 35% (0.20 kg treated vs. 0.31 kg controls). Maternal 

corrected body weight change was decreased (not statistically significant) by 47% (-0.25 kg 

treated vs. -0.17 kg controls). Mean maternal food consumption was also reduced (p<0.01) by 

22-34% at all intervals between GD 14-26.
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The maternal LOAEL was 75 mg/kg/day based on decreased body weight gains (absolute 

and corrected) and food consumption. The maternal NOAEL is 25 mg/kg/day.

There were no treatment-related effects on abortions, premature deliveries, complete litter 

resorptions, or dead fetuses and no effects of treatment on the numbers of litters, live fetuses, 

early resorptions, or late resorptions. There were no treatment-related external, visceral, or 

skeletal variations or malformations.

At 75 mg/kg/day, mean fetal body weight was decreased (p<0.05) by 11% for both the combined 

and separate sexes.

The developmental LOAEL was 75 mg/kg/day based on decreased fetal body weights. The 

developmental NOAEL is 25 mg/kg/day.

This study is classified acceptable/guideline and satisfies the guideline requirement for a 

developmental toxicity study (OPPTS 870.3700b; OECD 414) in rabbits.

A.4.3 Reproductive Toxicity

870.3800 Reproduction and Fertility Effects – Rat

In a two-generation reproduction toxicity study (MRID 47372447), AE C656948 (Fluopyram, 

94.7% a.i.; Lot/Batch # 08528/0002) was administered continuously in the diet at dose levels of 

0, 40, 220, or 1200 ppm (equivalent to 0/0, 2.65/3.15, 14.5/17.2, and 82.8/96.0 mg/kg/day in 

males/females, respectively) for two consecutive generations. The P generation animals 

(30/sex/dose group) were fed the test diets for 10 weeks prior to mating to produce the F1 litters. 

F1 offspring selected to be parents of the next generation (30/sex/dose group) were fed the same 

test diet concentrations as their parents. F1 parents were fed the test diets for 10 weeks prior to 

mating to produce the F2 generation. The F2 offspring were terminated after weaning.

There were no effects of treatment on mortality, clinical signs of toxicity, or food consumption in 

either sex in either generation during pre-mating. Furthermore, no treatment-related effects on 

body weight gain or food consumption were observed during gestation or lactation in either 

generation. No treatment-related gross necropsy findings were observed in either sex in either 

generation.

During pre-mating (Weeks 1-10), body weight gains were decreased by 20 and 10% in the 1200 

ppm females of the P and F1 generations, respectively. Additionally in the P generation females, 

decreases in body weight were observed at 1200 ppm during Days 0-13 of gestation (decr 5-6%) 

and on Day 0 of lactation (decr 5%).

At 1200 ppm, treatment-related clinical chemistry findings were limited to increased creatinine, 

total protein, and albumin in the P-generation males, increased urea nitrogen and total protein in 

F1 males, and increased cholesterol in the F1 females. Additionally at this dose, hematology

changes included decreased hemoglobin and hematocrit in the P-generation females, decreased 
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hemoglobin in F1 females, and increased white blood cell and monocyte counts in the F1 

females.

In both the P- and F1 generations, test substance-related increases were noted at 1200 ppm in 

absolute and relative kidney (right and left) weights in the males, and absolute and relative liver 

weights in both sexes. Additionally in the F1 females, absolute and relative spleen weights were 

decreased at 1200 ppm and relative spleen weight was also decreased in 220 ppm. It was stated 

that the decreases in spleen weights (absolute and/or relative) in the F1 females were not 

associated with corresponding micropathology findings. However, as white blood cell 

parameters were changed in F1 animals and spleen weights were later found to be affected in F1 

and F2 pups as well, this finding may be treatment related and further studies may be required to 

clarify reasons for this observation.

In the P-generation, test substance-related micropathology findings noted at 1200 ppm included 

increased incidence of protein droplet nephropathy and lymphocytic infiltration in the kidneys of 

the males, and increased incidence of centrilobular hypertrophy in the livers of both sexes. It 

was stated that these findings were in accordance with findings of other studies over a similar 

duration.

The LOAEL for parental toxicity is 1200 ppm (equivalent to 82.8/96.0 mg/kg/day in 

males/females, respectively) based on: decreases in body weight gain during pre-mating in 

the P- and F1 generation females; decreased body weights during gestation and lactation in 

P generation females; clinical chemistry effects (increased creatinine, total protein, albumin 

and urea nitrogen in males and increased cholesterol in F1 females); hematology effects 

(decreased hemoglobin and hematocrit in the P-generation females, decreased hemoglobin 

in F1 females, and increased white blood cell and monocyte counts in the F1 females); 

increased kidney weight associated with an increased incidence of protein droplet 

nephropathy and lymphocytic infiltration in P- and F1 generation males; and increased 

liver weights associated with an increased incidence of centrilobular hypertrophy in both 

sexes. The NOAEL is 220 ppm (equivalent to 14.5/17.2 mg/kg/day in males/females, 

respectively).

There were no treatment-related effects on: viability, clinical signs, birth or live birth indices; 

lactation index, or pup sex ratio for either generation. Vaginal patency was similar to controls in 

the F1 females, and anogenital distance on PND 0 was unaffected by treatment in the F2 pups. 

There were no treatment-related macroscopic or microscopic findings in the F1 or F2 pups.

At 1200 ppm, F1 pup body weights (combined male and female) were decreased (not significant 

[NS]) by 5% on PND 14 and 21, resulting in a 5% decreased in overall (PND 0-21) body weight 

gain. F2 pup body weights were decreased (NS, except p<=0.05 on PND 21) by 6-8% on PND 

4-21. Overall body weight gain throughout lactation was also decreased by 9% in these animals.

At 1200 ppm, test substance-related decreases in organ weights in F2 generation pups were 

limited to decreased absolute and relative spleen and thymus weights in males, females, and 

combined pups.
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A slight delay in preputial separation in the 1200 ppm F1 males was observed (42.5 days) 

compared to controls. It was stated that although statistically significant, the number of days to 

criteria was within the range of historical controls (40.7-44.0 days). Therefore, this finding was 

considered secondary to the reduced body weight observed in the males during lactation.

The LOAEL for offspring toxicity is 1200 ppm (equivalent to 82.8/96.0 mg/kg/day in 

males/females, respectively) based on decreased pup body weights and overall body weight 

gains in the F1 and F2 generations, and decreased spleen and thymus weights in both sexes 

in the F2 generation. The NOAEL is 220 ppm (equivalent to 14.5/17.2 mg/kg/day in 

males/females, respectively).

There were no effects of treatment in either generation on: estrous cycle number or length, 

sperm parameters (motility, counts, or morphology), mating, fertility or gestation indices, days to 

insemination, gestation length, or the median number of implants. Ovarian follicle counts in the 

F1 females were similar to controls.

The LOAEL for reproductive toxicity was not observed. The NOAEL is 1200 ppm 

(equivalent to 82.8/96.0 mg/kg/day in males/females, respectively).

This study is classified as acceptable/guideline and satisfies the guideline requirements (OPPTS 

870.3800; OECD 416) for a two-generation reproduction study in the rat.

A.4.4 Chronic Toxicity

870.4100a (870.4300) Chronic Toxicity – Rat

In a combined chronic toxicity / carcinogenicity study (MRID 47372501), AE C656948 (94.5% 

a.i., Batch 08528/0002) was administered in the diet to 60 Wistar (Rj: WI [IOPS HAN]) 

rats/sex/dose group at dose levels of 0, 30, 150, 750 (males only), or 1500 (females only) ppm 

(equivalent to 0/0, 1.20/1.68, 6.0/8.6, 29 (males), and 89 (females) mg/kg day in males/females) 

for up to 24 months. In the 750 ppm males, the dose level was reduced to 375 ppm from Week 

85 onward due to increased mortality. In addition, an interim sacrifice was performed at Week 

52 on groups of 10 rats/sex/dose that were treated as above.

At 1500 ppm (females only), increased incidence of hair loss and wasted appearance was noted. 

Mean body weights were significantly reduced in both sexes. 

At 750/375 ppm (males only), there was a statistically significant increase in mortality at Week 

52 and after 24 months, although no clear cause for these premature deaths could be established.

Mean body weight was significantly reduced in both sexes at various time during the study..

Liver toxicity became apparent by an increase in organ weight at 150 ppm and above in male rats 

and at 1500 ppm in females that was sometimes accompanied. Clinical chemistry findings 

suggesting hepatotoxicity were minor in nature and were observed at 750/375 and 1500 ppm. 

They comprised occasionally higher mean triglyceride concentrations and slightly lower mean 

glucose concentrations in the females. Activity of alkaline phosphatase was reduced in both 
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sexes throughout the study but achieved statistical significance only occasionally. Histological 

changes included a higher incidence of altered hepatocytes (eosinophilic foci) and hepatocellular 

brown pigments, focal or multifocal hepatocellular vacuolation, increased number of mitoses, 

centrilobular to panlobular hypertrophy and hepatocellular single cell necrosis, with females 

being much more affected. At 150 ppm, however, histopathological finding (hypertrophy) was 

confined to male rats corresponding to the increased organ weight noted at this dose.

In the kidney, marked degenerative changes such as chronic progressive nephropathy or 

focal/multifocal (medullar or cortical) tubular dilatation, together with an increased incidence of 

tubular golden/brown pigments (mainly in females) and collecting ducts hyperplasia, were 

observed at the high dose. In addition, a higher incidence of hyaline droplets and of renal cysts

was noted in male rats. At the mid dose level of 150 ppm, male rats still displayed a higher 

frequency of tubular hypertrophy or dilatation. During the first year of treatment, but not 

thereafter, urinalysis revealed higher incidences of abnormal color of urine (orange to red) in 

females and a higher incidence and severity of cellular casts in males. This latter finding was 

also confirmed in male rats receiving the intermediate dose.

Effects of AE C656948 on the thyroid gland were demonstrated by increased organ weights at 

the highest dose level in both sexes that were associated with histopathological changes 

(follicular cell hyperplasia and/or hypertrophy and colloid alteration/depletion). At 150 ppm, 

colloid alteration was noted in the females, and follicular cell hypertrophy was observed in the 

males. Both findings were reduced in frequency and severity compared to the high dose groups.

The eyes were affected by long-term treatment was seen in treated animals at 150 ppm or above. 

Ophthalmologic examination revealed abnormal color of the retinal fundus in females after 12 

months. At the 24-month examination, this condition was observed in females and males, 

together with small retinal vessels. In addition, hyper-reflectivity in the retina was noted in 

females and corneal opacity, edema of the cornea and nuclear opacity in males. These effects 

were more severe at the top dose level and less pronounced but still present after 2 years in the 

male and female groups receiving 150 ppm. Histologically, bilateral retinal atrophy was noted at 

the highest dose level, together with a higher incidence of lens degeneration. 

A tendency towards lower erythrocyte parameters (hemoglobin concentration, mean corpuscular 

volume, hematocrit and/or mean corpuscular hemoglobin) was observed in the 1500 ppm 

females throughout the study confirming evidence from short-term studies that the red blood 

cells might be an additional target. The same tendency was observed in 750/375 ppm males at 

most time points; however, statistical significance was not achieved. The assumption of an 

effect on the blood was further substantiated by a more frequent occurrence of extramedullary

hematopoiesis in the livers of high dose females.

The LOAEL is 150 ppm (6.0mg/kg/day) based on nephropathy, follicular cell hypertrophy 

in the thyroid, eye effect, and liver effect characterized by increased liver weight, gross and 

histopathological findings. The NOAEL is 30 ppm (1.2 mg/kg/day). 

At the doses tested, there was a treatment-related increase in tumor incidence compared to 

controls. At the end of the 2-year carcinogenicity phase, the incidence of liver cell tumors 
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(carcinoma and adenoma) was significantly increased in females receiving 1500 ppm. The 

combined incidence of female rats with benign and malign liver tumors was 11 (including 3 

animals with carcinoma) as compared to 2 in each of the control, low and mid dose groups. No 

such increment was seen in male rats but the very different actual compound intakes do not allow 

for a meaningful comparison. Dosing was considered adequate based on the findings of liver, 

kidney, thyroid, and ocular toxicity as described above.

This study is considered acceptable/guideline and satisfies the requirements (OPPTS 870.4300; 

OECD 453) for a combined chronic toxicity / carcinogenicity study in rats.

870.4100b Chronic Toxicity – Dog

In a chronic oral toxicity study (MRID 47372449), fluopyram (94.6% a.i., Batch 08528/0002) 

was administered in the diet to four beagle dogs/sex/dose group at dose levels of 0, 100, 400, or 

2000 ppm (equivalent to 0/0, 3.0/3.8, 13.2/14.4, and 67.6/66.1 mg/kg/day in males/females) for 

at least 1 year.

There were no effects of treatment observed on mortality, clinical signs, ophthalmoscopic 

examinations, hematology, urinalysis, or gross pathology.

At 2000 ppm, body weight losses were observed in both sexes during Week 1 (-0.2 kg and 

-0.1 kg in males and females, respectively, compared to gains of +0.1 kg, and 0.0 kg in control 

males and females). These body weight losses corresponded to decreased food consumption 

(decr. 30% and 24% in males and females, respectively) during Week 1. The decrease in food 

consumption persisted in females until the end of the study. Additionally at 2000 ppm, alkaline 

phosphatase was increased by 58-187% in males and females at Weeks 3, 6, and 12, and minimal 

diffuse centrilobular hepatocellular hypertrophy was observed microscopically in 3/4 males. 

No treatment-related effects were seen in 400 and 100 ppm groups. 

The LOAEL was 2000 ppm (equivalent to 67.1/66.1 mg/kg/day in males/females) based 

decrease in food consumption and corresponding slight decrease in body weight, increases 

in alkaline phosphatase and centrilobular hepatocellular hypertrophy. NOAEL was 400 

ppm (13.2/14.4 mg/kg/day in males/females). 

This study is considered acceptable/guideline and satisfies the requirements (OPPTS 

870.4100b; OECD 452) for a subchronic toxicity study in dogs.

A.4.5 Carcinogenicity

870.4200a Carcinogenicity Study – rat

See A.4.4 for Combined Chronic Toxicity/Carcinogenicity Study in Rats (870.4300).

870.4200b Carcinogenicity (feeding) – Mouse
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In a carcinogenicity study (MRID 47372450), AE C656948 (≥94.5% a.i., Batch 08528/0002) 

was administered in the diet to 50 C57BL/6J mice/sex/dose group at dose levels of 0, 30, 150, or 

750 ppm (equivalent to 0/0, 4.2/5.3, 20.9/26.8, and 105/129 mg/kg day in males/females) for up 

to 78 weeks. In addition, an interim sacrifice was performed at Week 52 on groups of 10 

mice/sex/dose that were treated as above.

There were no unscheduled deaths or clinical signs occurring during the study that could be 

attributed to treatment. The survival rate was not different among the control and dose groups. 

Body weight gain was decreased only in the 150 ppm and above males and only during the 

second trimester of the study (weeks 26 to 54). Afterwards, some compensatory growth was 

observed resulting in a mean final body weight that was similar to the control group value.

Mean absolute and relative liver weights were markedly increased in the 150 ppm and above 

males and females at interim sacrifice as well as at study termination. The increment exhibited a 

clear dose response. At these dose levels, gross necropsy findings such as dark and enlarged 

livers were corroborated by an increase in non-neoplastic histopathological lesions such as 

centrilobular to panlobular hypertrophy, hepatocellular cholestasis, single cell 

degeneration/necrosis or eosinophilic foci. A few of these non-neoplastic effects on the liver 

were observed only in males pointing to a higher vulnerability of this sex with regard to 

hepatotoxicity.

Toxic effects on the thyroid were noted at 750 ppm in both males and females and in the 150 

ppm males. The main non-neoplastic finding, follicular cell hyperplasia, was apparent in male 

mice at the interim sacrifice.

Mean absolute and relative kidney weights were decreased at the 750 ppm dose level in both 

sexes. In addition, a higher incidence and/or severity of bilateral cortical basophilic tubules, 

hyaline casts(s) and interstitial mononuclear cell infiltrates, glomerular congestion/

hemorrhage(s), and more pronounced amyloid deposition (mainly in the glomerular interstitium) 

was noted at this dose but only in females.

At 30 ppm, mean absolute and relative liver weight was higher in the males than in the control

group, but by less than 10 % although the difference was statistically significant. More 

important, this organ weight increase was not accompanied by liver cell hypertrophy. The only 

histopathological finding in the liver at this dose level was diffuse centrilobular vacuolation. 

Therefore, these minor findings were not considered adverse.

The LOAEL is 150 ppm (equivalent to 20.9/26.8 mg/kg/day in males/females), based on 

liver and thyroid toxicity as described above. The NOAEL is 30 ppm (equivalent to 4.2/5.3 

mg/kg/day in males/females).

At the doses tested, there was a treatment-related increase in tumor incidence compared to 

controls. A higher incidence (p<=0.05) of follicular cell adenoma was observed in the 750 ppm 

males (7/50) as compared to the controls (1/50). Dosing was considered adequate based on the 

findings of liver and thyroid toxicity as described above.
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This study is considered acceptable/guideline and satisfies the requirements (OPPTS 

870.4200b; OECD 451)for a combined chronic toxicity / carcinogenicity study in rats.

A.4.6 Mutagenicity

Gene Mutation

Guideline 870.5100, In vitro Bacterial 

Gene Mutation (Salmonella 

typhimurium/ E. coli)/ mammalian 

activation gene mutation assay.

MRID 47372503

Acceptable/Guideline

In a reverse gene mutation assay in bacteria, Salmonella typhimurium strains 

TA98, TA100, TA102, TA1535, and TA1537 were exposed to AE C656948

in dimethylsulfoxide (DMSO) at concentrations of 0, 16, 50, 158, 500, 1581, 

or 5000 μg/plate (initial trial) and 0, 5, 16, 50, 158, 500, or 1581 μg/plate 

both in the presence and absence of S9-activation. Standard strain-specific 

mutagens served as positive controls. AE C656948 was tested up to cytotoxic 

concentrations. There were no marked increases in the mean number of 

revertants/plate in any strain in either trial in the presence or absence of S9. 

The positive controls induced the appropriate response in all strains in the 

presence and absence of S9-activation. There was no evidence of induced 

mutant colonies over background

Guideline 870.5300, V79 Cells 

/Mammalian Activation Gene Forward 

Mutation Assay at the HGPRT Locus.

MRID 47372504

Acceptable/Guideline

In a mammalian cell gene mutation assay at the HGPRT locus, V79 lung 

fibroblast cells cultured in vitro were exposed to AE C656948 in DMSO at 

concentrations of 0, 4, 8, 16, 32, 64, 128, or 256 μg/mL (+/-S9) for 5 hours. 

The positive controls were ethyl methanesulfonate (-S9) and 

dimethylbenzanthracene (+S9). AE C656948 was tested up to the limit of 

solubility. No marked increase in mutant frequency was observed in the 

presence or absence of S9-activation. The positive controls induced the 

appropriate response (+/-S9). There was no evidence of induced mutant 

colonies over background in the presence or absence of S9-activation.

Cytogenetics

Guideline 870.5375, In Vitro

Chromosomal Aberration Assay in 

Chinese Hamster V79 Cells.

MRID 47372505

Acceptable/Guideline

In a mammalian cell cytogenetics assay, Chinese hamster V79 cell cultures 

were exposed to AE C656948 in DMSO at concentrations of 0, 30, 60, 120, 

180, or 240 μg/mL for 4 hours (with a 14- or 26-hour recovery period) in the 

presence of S9 and 18 hours of continuous exposure in the absence of S9. 

Cells were harvested at 18 or 30 hours after initiation of dosing (+S9) and 18 

hours after initiation of dosing (-S9). The positive controls were mitomycin 

C (-S9) and cyclophosphamide (+S9). AE C656948 was tested up to the limit 

of solubility and cytotoxicity. No biologically relevant or statistically

significant increases in the number of metaphases with aberrations were 

observed at any concentration at any harvest time in the presence or absence 

of S9. The positive controls induced the appropriate response in the presence 

and absence of S9. There was no evidence of chromosome aberrations 

induced over background in the presence or absence of S9-activation.
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Guideline 870.5395, Micronucleus 

Assay in Mice.

MRID 47372506

Acceptable/Guideline

In a bone marrow micronucleus assay, young adult male NMRI mice were 

treated with AE C656948 in 0.5% aqueous Cremophor at doses of 0, 250, 

500, or 1000 mg/kg, i.p. Bone marrow cells were harvested at 24 hours after 

final dosing. Cyclophosphamide served as the positive control. All animals 

survived to scheduled sacrifice. Clinical signs including apathy, semianesthetized state, roughened fur, weight loss, sternal recumbency, spasm, 

body stretching, and difficulty in breathing were observed at all dose levels 

until sacrifice. There was an increase in the number of normochromatic 

erythrocytes in all fluopyram treated groups compare to controls although the 

difference was only statistically significant at 1000 mg/kg. This 

demonstrated a relevant and sufficient systemic exposure of the animals to the 

test substance. The MPCE (micronucleated polychromatic erythrocytes)

frequency was comparable between vehicle controls and all treated groups. 

The positive control induced the appropriate response. There was no 

significant increase in the frequency of micronucleated polychromatic 

erythrocytes in bone marrow.

A.4.7 Neurotoxicity

870.6200 Acute Neurotoxicity Screening Battery

In an acute neurotoxicity study (MRID 47372507), groups of 12 non-fasted young adult Wistar 

rats/sex/dose were given a single oral gavage dose (10 mL/kg) of Fluopyram (94.7% a.i.; 

Lot/Batch # 08528/0002) in aqueous 2% (v/v) Cremophor EL at dose levels of 0, 125, 500, or 

2000 mg/kg (limit dose) and were observed for 14 days. Neurobehavioral assessment (functional 

observational battery [FOB] and motor activity testing) was performed in all rats at one week 

prior to dosing and on Days 0 (approximately 1 hour post-dosing), 7, and 14. At study

termination, all animals were necropsied, and 6 rats/sex/dose were euthanized and perfused in 

situ for neuropathological examination. The brain and peripheral nervous system tissues 

collected from the perfused animals in the control and 2000 mg/kg groups were subjected to 

histopathological evaluation. Because motor and locomotor activity were impaired in females 

even at the lowest dose level of 125 mg/kg, a follow-up study was initiated in order to establish a 

clear NOAEL. For this purpose, 12 females/group were treated in the same manner as in the 

initial study at dose levels of 0, 25, 50, or 100 mg/kg. In-life observations were limited to FOB 

and motor activity measurements at one week prior to dosing and on Day 0 (approximately 1 

hour post-dosing). The animals were sacrificed at 2 or 3 days post-dosing and were discarded 

without further examinations. Positive control data were not provided.

There were no compound-related effects on mortality, body weight, brain weight (absolute and 

relative), and gross or neuropathology observed at any dose.

In the initial study, compound-related clinical signs were limited to urine stain in 4/12 males at 

2000 mg/kg. In the FOB on Day 0, mean body temperature was decreased in the 500 and 2000 

mg/kg females (37.4°C and 36.9°C, respectively vs. 37.9°C for controls). At 500 and 2000 

mg/kg, total session motor and locomotor activity were decreased by 51-72% and 49-77%, 

respectively, in both sexes on Day 0. Additionally in the 125 mg/kg females, total session motor 

and locomotor activity were decreased by 26-31% on Day 0. 
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In the follow-up study, total session motor and locomotor activity were decreased by 38% each 

in the 100 mg/kg females on Day 0.

The LOAEL is 100 mg/kg, based on decreased motor and locomotor activity in the females. 

The NOAEL is 50 mg/kg.

The initial study is considered to be acceptable whereas the follow-up study in females is only

supplementary. However, because a full study in both sexes is available, the information 

obtained from both experiments, when taken together, is considered complete and sufficient to 

address this annex point. This study is classified as acceptable/guideline and satisfies the 

guideline requirement (OPPTS 870.6200a; OECD 424) for an acute neurotoxicity study in the 

rat.

870.6200 Subchronic Neurotoxicity Screening Battery

In a subchronic neurotoxicity study (MRID 47372508), groups of 12 young adult Wistar 

rats/sex/dose were exposed to Fluopyram (94.7% a.i.; Lot/Batch # 08528/0002) in the diet at 

nominal concentrations of 0, 100, 500, or 2500 ppm (equivalent to 0/0, 6.69/8.05, 33.2/41.2, and 

164.2/197.1 mg/kg/day, M/F) for 13 weeks. Neurobehavioral assessment (functional 

observational battery [FOB] and motor activity testing) was performed in all rats at one week 

prior to dosing and during Weeks 2, 4, 8, and 13. At study termination, all rats were necropsied, 

and 6 rats/sex/dose were euthanized and perfused in situ for neuropathological examination. The 

brain and peripheral nervous system tissues collected from the perfused animals in the control 

and 2500 ppm groups were subjected to histopathological evaluation. Positive control data were 

not provided; however, it was stated that previous studies conducted at this laboratory had 

demonstrated the sensitivity of the test system and the methods used, as well as the adequacy of 

training of technical personnel. 

There were no compound-related effects on mortality, clinical signs of toxicity, ophthalmoscopic 

examinations, FOB parameters, motor or locomotor activity, brain weight (absolute and relative), 

and gross or neuropathology observed at any dose.

At 2500 ppm, body weights were decreased by 4-7% in males and 5-12% in females from Day

21 throughout the remainder of the study. Overall (Days 0-91) body weight gains were 

decreased by 10% in males and 26% in females. Additionally at this dose, food consumption 

was decreased by 15% in the males on Day 21 and by 13-24% in the females from Day 21 

throughout the remainder of the study. Compound-related increases in clinical chemistry

parameters included: (i) cholesterol (incr 44-69%) in both sexes; (ii) triglycerides (incr 90%) in 

females; (iii) protein (incr 9%) in females; (iv) globulin (incr 16%) in females; and (v) albumin 

(incr 10%) in males. Additionally, glucose levels were decreased by 6-15% in both sexes at this 

dose. The findings in clinical chemistry were likely due to changes in liver function induced by

Fluopyram, as well known from other studies with this compound at comparable dose levels. In 

the 2500 ppm females, compound-related decreases in hematology parameters included: (i) 

hemoglobin (decr 10%); (ii) mean corpuscular hemoglobin (MCH, decr 14%); (iii) mean 

corpuscular volume (MCV, decr 13%); and (iv) hematocrit (decr 9%). Additionally, hemoglobin 

distribution width (HDW) was increased by 28% in females at this dose. 
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At 500 ppm, decreased food consumption (decr 7-12%) was observed in females on Days 21-42, 

63-70, and 91. However, these decreases did not result in significant decreases in body weights 

or body weight gain in this group.

No evidence of neurotoxicity was observed in either sex at any dose.

The LOAEL is 2500 ppm (164.2/197.1 mg/kg/day, M/F), based on decreases in body weight, 

body weight gain, and food consumption, and differences in clinical chemistry and 

hematology parameters. The NOAEL is 500 ppm (equivalent to 33.2/41.2 mg/kg/day, M/F).

This study is classified as acceptable/guideline and satisfies the guideline requirement (OPPTS 

870.6200b; OECD 424) for a subchronic neurotoxicity study in the rat.

A.4.8 Metabolism

870.7485 Metabolism – Rat

In a metabolism study (MRID 47372509), [phenyl-UL14C]-AE C656948 (Batch/Lot No. not 

provided; radiochemical purity >98%) in aqueous 0.5% Tragacanth was administered by oral 

gavage to groups of Wistar [Hsd/Cpb: WU] rats for the following experiments: (i) a single 5 

mg/kg dose administered to five bile duct cannulated males; (ii) a single 5 mg/kg dose 

administered to four rats/sex; (iii) a single 250 mg/kg dose administered to four rats/sex; and (iv) 

5 mg/kg doses of non-radiolabeled test material administered daily for 14 days to four males, 

followed by one dose of radiolabeled test material at 5 mg/kg. All animals were killed 168 hours 

after the final dose was administered except the bile duct-cannulated animals, which were 

terminated at 48 hours post-dosing. Metabolite profiles were determined for pooled urine, feces, 

and bile (where applicable) samples collected from all of the experimental groups.

[Phenyl-UL14C] -AE C656948 was rapidly absorbed from the gastrointestinal tract in all test 

groups. Absorption commenced immediately after oral dosing as shown by the plasma curves 

and the values calculated for the absorption half-lives (0.1 – 0.5 h). Based on the results 

obtained in bile duct cannulated male rats, the absorption rate accounted for more than 93%. The 

test material was widely distributed in the body with highest organ/tissue concentrations found in 

liver, kidney, erythrocytes and adrenals. In the experiments in non-cannulated rats, the majority 

of the administered dose had been excreted 168 h post dosing with fecal excretion accounting for 

47%-64% and urinary excretion accounting for 35%-45% of the administered dose. 

Nonetheless, total residues in body (GIT excluded) were still found in the range between 2 and 

6%. The high values in the excretory organs liver and kidney suggest that excretion was still 

ongoing. Despite these observations, the experiment with repeated administration did not 

provide indications of a relevant potential for bioaccumulation since excretion and residues 

patterns were not altered. Considerable enterohepatic circulation was proven by high biliary

(78.5% within 48 hours in males) and low renal excretion in the bile fistulation test.

The test compound was extensively metabolized, with a high number of metabolites occurring of 

which 9 to 22 could be structurally identified and quantified in the different groups and matrices. 
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The ethyl linking group of the molecule was the preferred site for metabolism. The metabolic 

transformations detected were hydroxylation of the ethyl linking group of the parent compound 

forming AE C656948-7-hydroxy and 8-hydroxy metabolites. Further oxidation of AE C656948-

7-hydroxy and 8-hydroxy metabolites resulted in AE C656948-enol which was further 

conjugated with glucuronic acid. Hydroxylation of the phenyl ring led to AE C656948-phenol 

and AE C656948-7-OH-phenol. All of the hydroxylated metabolites were conjugated mainly 

with glucuronic acid and, to a lower extent, with sulfate. The cleavage of the molecule yielded 

AE C656948-benzamide that was one of the most abundant metabolites. This molecule was 

further metabolized via oxidation, hydroxylation and conjugation to AE C656948-benzoic acid 

and various AE C656948-benzamide- and AE C656948-hydroxybenzamide-conjugates. The 

phenyl ring moiety was also conjugated with glutathione followed by further degradation to 

AE C656948-7-OH-methyl-sulfone, AE C656948-BA-methyl-sulfoxide, and AE C656948-BAmethyl-sulfone.

This study is classified acceptable/guideline and satisfies the requirements [OPPTS 870.7485, 

OECD 417] for a metabolism study in rats.

In a metabolism study (MRID 47372511), [pyridyl-2,6-

14C]-AE C656948 (Batch/Lot No. not 

provided; radiochemical purity >99%) in aqueous 0.5% Tragacanth was administered by oral 

gavage to groups of Wistar [Hsd/Cpb: WU] rats for the following two experiments: a single 5 

mg/kg dose administered to six bile duct cannulated males; and a single 5 mg/kg dose 

administered to four rats/sex. All animals were killed 168 hours after the final dose was 

administered except the bile duct-cannulated animals, which were terminated at 48 hours postdosing. Metabolite profiles were determined for pooled urine, feces, and bile (where applicable) 

samples collected from all of the experimental groups.

[Pyridyl-2,6-

14C]-AE C656948 was rapidly absorbed from the gastrointestinal tract in all test 

groups. The absorption commenced immediately after oral dosing as shown by the plasma 

curves and the values calculated for the absorption half-lives (0.3 – 0.4 h). Based on the results 

obtained in bile duct cannulated male rats, the absorption rate accounted for 97.7 % of the 

recovered radioactivity and, thus, the administered dose may be considered to be virtually

completely absorbed and systemically bioavailable.

The test material was widely distributed in the body with highest organ/tissue concentrations 

found in liver and erythrocytes.

Excretion was almost completed 72 h after administration. At this time, males and females had 

excreted more than 98 % of the administered dose via urine and feces with some minor sexrelated differences. In bile duct-cannulated male rats, the major part of radioactivity (86.8 %) 

was eliminated via bile proving, together with the low renal excretion in the bile fistulation 

experiment, the significant enterohepatic circulation of this compound. At 168 h after oral 

administration, residues in most of the organs and tissues of male and females rats were very low 

(<0.1 % of the dose) and, thus, retention or accumulation of AE C656948 or its metabolites are

not expected.
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Metabolism was extensive with up to 25 metabolites in the different groups and matrices that 

could be identified and quantified. The ethyl linking group of the molecule was the preferred 

site for metabolism. The metabolic transformations detected were hydroxylation of the ethyl 

linking group of the parent compound forming AE C656948-7-hydroxy and -8-hydroxy 

metabolites. Further oxidation of AE C656948-7-hydroxy and 8-hydroxy metabolites resulted in 

AE C656948-enol, which was conjugated with glucuronic acid. Hydroxylation of the phenyl

ring of AE C656948 led to AE C656948-phenol and AE C656948-7-OH-phenol. All of the 

hydroxylated metabolites were conjugated mainly with glucuronic acid and, to a lesser extent,

with sulfate. Hydrolytic cleavage and subsequent oxidation mainly led to AE C656948-pyridylacetic acid (PAA), AE C656948-ethyl-diol, and -pyridyl-carboxylic acid (PCA).

This study is classified acceptable/guideline and satisfies the requirements [OPPTS 870.7485, 

OECD 417] for a metabolism study in rats.

870.7600 Dermal Absorption – Rat

In an in vitro dermal absorption study (MRID 47372514) where dermatomed rat and human skin 

membranes maintained in flow through diffusion cells at approximately 32°C. The dermatomed 

skin membranes were exposed to [14C]-AC C56948 at two concentrations: one was a neat 

formulation (500 mg AE C656 948/ml formulation) and the other was the spray dilution (0.5 mg 

AE C656948/ml formulation). The two formulations were applied at a rate of 10 μL/cm2to the 

mounted skin samples. Receptor fluid samples were collected at hourly interval for the duration 

of the study (24 hours). Eight hours post-application, epidermal membranes were washed. At the 

end of the study, the skin samples were swabbed and tape-stripped to remove residual test 

material from the skin surface.

The results demonstrated the recovery to be 100.7% to 103.1% of the applied concentration for 

both high and low concentrations. For the neat formulation, majority of the radioactivity was 

found in the skin swab (100.9% & 100.1% of the applied concentration in human skin and rat 

skin, respectively) and tap-stripes (0.707% and 0.728% of the applied concentrations for human 

and rats skin, respectively). The percentages of the test material found in the receptor fluid from 

0-24 hours were 0.004% and 0.077% of the applied concentrations for human and rat skin, 

respectively. For the spray dilution, The mean percentages of the applied concentrations 

considered to be potentially absorbable (directly absorbed plus remaining at the application site) 

were 0.101% and 2.097% for human and rat skin, respectively. The results of the neat formation 

experiment yielded a factor of difference of 21 between human and rat skin.

For the spray dilution, the majority of the applied radioactivity was again found in the skin swab 

(97.6% and 86.2% of the applied concentrations in human and rat skin swabs, respectively), and 

tap-stripes contained 1.12% and 2.33% of the applied concentrations in human and rat skin, 

respectively. The percentages of the test material found in the receptor fluid from 0-24 hours 

were 1.23% and 8.56% of the applied concentrations for human and rat skin, respectively. The 

mean percentages of the applied concentrations considered to be potentially absorbable (directly 

absorbed plus remaining at the application site) were 1.77% and 12.43% for human skin and rat 

skin, respectively. The results of spray dilution experiment showed that there was a factor of 

difference of 7 between human and skin. 
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This study is considered acceptable and provides information regarding in vitro dermal 

absorption of fluopyram.

In a dermal absorption study, 8 groups of four male Wistar Rj:WI (IUPS HAN) rats (7 to 9 

weeks old, body weights ranging from 240 to 377 g) were exposed for eight hours either to a 

neat formulation containing 500 mg [14C]-fluopyram/mL or to a 1:1000 spray dilution (0.5 

mg/mL) (radiolabeled at the phenyl ring). Twenty-four hours prior to dosing, an area of dorsal 

skin was shaved. Approximately 120 μL of each dose formulation in total (divided into two 

portions) was applied to the shaved area of ca 2 x 6 cm2resulting in a final amount of nearly 60 

mg fluopyram/animal (56.4 – 59.4 mg) in the high dose and of nearly 60 μg fluopyram/animal in 

the low dose experiment. The topical concentrations per cm2 skin ranged from 4.7 to 4.95 

mg/cm2for the concentrate and from 5.08 to 5.28 μg/cm2for the dilution. Rounding of the 

applied concentrations to 5 or 0.005 mg/cm2, respectively, seems appropriate. When dose 

application was complete, the treated skin was semi-occluded with a perforated plastic cover that 

prevented loss of test substance but allowed air circulation.

At termination of the eight-hour exposure period, the cover was removed and the skin swabbed 

with 1 % Tween 80 in phosphate buffered saline (PBS) until no more radioactivity was 

detectable on the swabs. Subsequently, animals of the first high and low dose groups were 

sacrificed whereas the other three groups per dose level were terminated at 24, 72, or 168 hours 

after dosing. Urine and faeces were collected separately at 0 - 8, 8 – 24, and, thereafter, at 24-

hour intervals until sacrifice. At termination, cardiac blood was taken and tape stripping was 

performed to remove the Stratum corneum. Up to 15 or 20 tape strips were taken until a “shiny” 

appearance of the epidermis became evident. The excreta (including cage wash), cardiac blood, 

carcass, samples of untreated skin, fur from the dose site, application site skin and samples of the 

skin directly surrounding the treated sites, individual tape strips, cover dressings, and swabs were 

analyzed for radioactivity by liquid scintillation counting. 

The results showed no clinical signs in the treated rats. The mean total recovery in all four 

groups was slightly above 100 % with mean values ranging from 100.5 to 103.2 % for the neat 

formulation. Most of the radioactivity was detected in skin swabs immediately after dosing

suggesting poor absorption. The distribution of radioactivity in the different compartments is 

summarized in Table 1 for neat formulation. Estimation of dermal absorption is based on the 

amount that is considered potentially absorbable for the individual groups. For neat formulation, 

a maximum potential dermal absorption was 4.5 % after 24 hours post dosing. 

After single topical application of [14C]-fluopyram in the 1:1000 spray dilution(0.5 mg/mL), total 

recoveries in the different groups were slightly less than in the high dose experiment but, with 

mean values ranging from 89.7 to 98.8 %. Again, the major portion of radioactivity was found in 

skin swabs immediately after treatment but the total percentage of dermal absorption was higher. 

The highest mean value for the potentially absorbable amount was at 8 hrs (at the end of the 

treatment period: 8 hours); the dermal absorption rate was 12.8 %.
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In summary, under the conditions of this study, the maximal dermal absorption rates for neat 

formulation and spray dilution are 4.5% and 12.8% of the applied dose, respectively.

This study is considered acceptable/guideline and satisfies the requirements for in vivo dermal 

absorption study in rats (Guideline 870.7600). 

A.4.9 Immunotoxicity

870.7800 Immunotoxicity

In an immunotoxicity study (MRID 48239930) Fluopyram (94.7% a.i., batch number: MixBatch: 08528/0002) was administered to female Wistar Rj:WI (IOPS HAN) rats (10/dose) 

through diet at dose levels of 0, 200, 600, or 1800 ppm (0, 17.2, 53.6, or 156.3 mg/kg/day, 

respectively) for 28 days. The positive control group consisting of 10 female Wistar Rj:WI

(IOPS HAN) rats were administered 3.5 mg/kg/day cyclophosphamide daily via gavage for 28 

days. On Day 26, all test animals received a 0.5 mL intravenous injection of sheep red blood 

cells (SRBCs) at a concentration of 5x108cells/mL. On Day 30, blood samples (0.5 mL) were 

taken from all groups by puncture of the retro-orbital venous plexus. The level of anti-SRBC 

IgM in response to SRBC antigen administration was determined with an Enzyme-Linked 

Immunosorbent Assay (ELISA). Other parameters evaluated were: clinical condition, mortality, 

body weight, body weight gain, food consumption, spleen weight, and thymus weight.

In the treated animals there were no treatment-related effects on clinical signs of toxicity, body

weight, body weight gain, food consumption, gross pathology, and spleen or thymus weights. 

The anti-SRBC IgM ELISA results showed that there were no statistical differences in quantity 

of anti-SRBC IgM in any treatment group when compared with the vehicle controls. A high 

inter-individual variability was noted in all the treatment groups as well as in the control group. 

Evaluation of individual animal data did not show any trend or distribution that would 

demonstrate significant suppression of anti-SRBC antibody response.

The Natural Killer (NK) cells activity assay was not performed in this study. The toxicology

database for fluopyram does not show any evidence of treatment-related effects on the immune 

system. The overall weight of evidence suggests that this chemical does not directly target the 

immune system. Under HED guidance, NK cells activity assay is not required at this time.

The immunotoxicity NOAEL for anti-SRBC IgM response is 1800 ppm (156.3 mg/kg/day) 

and the LOAEL was not established.

This immunotoxicity study is classified acceptable / guideline and satisfies the guideline 

requirement for an immunotoxicity study (OPPTS 870.7800) in rats.

A.4.9 Special/Other Studies 

Non-Guideline: Mode of Action
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In a non-guideline, mechanistic study (MRID 47372523), phenobarbital (99.6% a.i., Lot/Batch 

06100228) in 0.5% aqueous methylcellulose 400 was administered by oral gavage to groups of 

15 female Wistar (Rj: WI [IOPS HAN]) rats/dose group at dose levels of 0 or 80 mg/kg day for 

seven days. An 80 mg/100 mL aqueous solution of bromodeoxyuridine (BrdU) was provided as 

drinking water during the treatment period to allow evaluation of liver cell proliferation. The 

rats were observed regularly for changes in mortality, clinical signs of toxicity, body weight, and 

food and water consumption. On the day of necropsy, the rats were exsanguinated and 

necropsied. Brain and liver were weighed, and duodenum and two central sections of the left 

and medial lobes of the liver were removed and fixed in neutral buffered 10% formalin. BrdU 

incorporation was determined by immunohistochemical staining, and labeling indices were 

calculated for the centrilobular and periportal zones. The remaining portions of the liver from 10 

females from each group were taken, and microsomal preparations were made and analyzed for 

total cytochrome P-450 content and activities of ethoxyresorufin-O-deethylase (EROD), 

benzoxyresorufin-O-dealkylase (BROD), pentoxyresorufin-O-deethylase (PROD), and UDPglucuronosyltransferase (UDPGT). The purpose of this study was to confirm the ability of 

phenobarbital to induce enhanced activity of hepatic enzymes and to cause hepatocellular 

hypertrophy and proliferation when administered at 80 mg/kg/day for seven days.

There were no treatment-related deaths. One treated female was found dead on Day 5; however, 

a cause of death was not determined. All treated rats displayed reduced motor activity. Treated 

rats had no mean body weight gain during treatment, while control rats gained 7 g. Food and 

water consumption were similar to controls.

In the treated females, absolute and relative (to body) liver weights were increased by 19-22%. 

The weight increase was associated with enlarged (3/14) and dark (5/14) livers observed at 

necropsy, and diffuse centrilobular to panlobular hepatocellular hypertrophy observed 

microscopically in all treated females. BrdU labeling indices were approximately 2-fold higher 

in treated females compared to controls, and the centrilobular labeling index was higher than the 

periportal labeling index. Total cytochrome P-450 content was increased by 57%, EROD 

activity was increased by 24%, UDPGT activity was increased by 93%, PROD activity was 

increased by 439%, and BROD activity was increased by 1823%.

These data demonstrated the ability of phenobarbital to induce enhanced activity of hepatic 

enzymes and to cause hepatocellular hypertrophy and proliferation when administered at 80 

mg/kg/day for seven days.

This study is considered acceptable/non-guideline and provides information regarding the 

effects of oral gavage administration of the test compound on rat liver.

In a non-guideline, mechanistic study (MRID 47372519), AE C656948 (94.7% a.i., Lot/Batch 

08528/0002) was administered in the diet to groups of 15 male C57BL/6J mice/dose group at 

dose levels of 0 or 2000 ppm (equivalent to 0 and 311 mg/kg day) for either three or fourteen 

days. The rats were observed regularly for changes in mortality, clinical signs of toxicity, body

weight, and food consumption. On the days of necropsy (Days 4 or 15), blood samples were 

taken from all animals for determination of TSH, T3, and T4 hormone levels. The mice were 
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then exsanguinated and necropsied. Brain and liver were weighed, and pieces of the left and 

medial lobes of the liver from five mice/group were removed and fixed in neutral buffered 10% 

formalin. The remaining portions of the liver from these mice and the whole livers from the 

other ten males from each group were pooled (two whole livers pooled with one remaining 

portion) to generate five liver samples. Microsomal preparations were made from these five 

pooled samples and analyzed for total cytochrome P-450 content and activities of 

ethoxyresorufin-O-deethylase (EROD), benzoxyresorufin-O-dealkylase (BROD), 

pentoxyresorufin-O-deethylase (PROD), and UDP-glucuronosyltransferase (UDPGT).

No mortalities were observed, and there were no clinical signs of toxicity. Body weights and 

body weight gains were unaffected by treatment. There was a slight decrease in food 

consumption noted in the 3-day treatment group (decr. 12.5%) and in the 14-day treatment group 

after 1 week of exposure (decr. 5.1%). T4 levels were decreased by 30% after 3 days and by 27% 

after 14 days of treatment; TSH levels were increased by 18% after 3 days and by 7% after 14 

days of treatment. These results were consistent with the known feedback regulation mechanism 

of thyroid hormone homeostasis. No relevant changes in gross or microscopic pathology were 

observed in the thyroid gland.

Absolute and relative (to body) liver weights were increased by 59-61% at Days 4 and 15. The 

weight increases were associated with enlarged and/or dark livers observed at necropsy, and 

centrilobular to panlobular hepatocellular hypertrophy observed microscopically in all treated 

males (5/5 mice at Days 4 and 15). Additionally, an increased number of mitoses was observed 

in 5/5 males on Day 4, and single cell necrosis was noted in 4/5 males on Day 15. Total 

cytochrome P-450 content was increased by 71-116%, EROD activity was increased by 165-

235%, PROD activity was increased by 2163-2890%, and BROD activity was increased by 

8717-9061% on Days 4 and 15. In contrast, UDPGT activity was unaffected by treatment.

AE C656948 demonstrated the ability to induce total cytochrome P-450, PROD, BROD, and 

EROD activities in mouse liver after 3 and/or 14 days of dietary exposure at the high dose level 

of 2000 ppm. Hepatotoxicity became further apparent by liver weight increases and concomitant 

histological lesions. Rapid onset of these changes was noted in the 3-day experimental group. 

Furthermore, exposure to the test compound resulted in disturbance of thyroid hormone balance 

in male mice by causing a decrease in T4 levels with a concomitant increase in TSH. However, 

there were no microscopic findings of thyroid toxicity, perhaps due to the relatively short 

exposure period.

This study is considered acceptable/non-guideline and provides information regarding the 

effects of dietary administration of the test compound on mouse liver and thyroid.

In a non-guideline, mechanistic study (MRID 47372520), AE C656948 (94.7% a.i., Batch 

08528/0002) was administered in the diet to groups of 15 female Wistar (Rj: WI [IOPS HAN]) 

rats/dose group at dose levels of 0 or 3000 ppm (equivalent to 0 and 193 mg/kg day) for seven 

days. An 80 mg/100 mL aqueous solution of bromodeoxyuridine (BrdU) was provided as 

drinking water during the treatment period to allow evaluation of liver cell proliferation. The 

rats were observed regularly for changes in mortality, clinical signs of toxicity, body weight, and 
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food and water consumption. On the day of necropsy, the rats were exsanguinated and 

necropsied. Brain and liver were weighed, and duodenum and two central sections of the left 

and medial lobes of the liver were removed and fixed in neutral buffered 10% formalin. BrdU 

incorporation was determined by immunohistochemical staining, and labeling indices were 

calculated for the centrilobular and periportal zones. The remaining portions of the liver from 10 

females from each group were taken, and microsomal preparations were made and analyzed for 

total cytochrome P-450 content and activities of ethoxyresorufin-O-deethylase (EROD), 

benzoxyresorufin-O-dealkylase (BROD), pentoxyresorufin-O-deethylase (PROD), and UDPglucuronosyltransferase (UDPGT). The purpose of this study was to investigate the effects of 

the test compound on the liver, particularly hepatocellular hypertrophy and proliferation and 

induction of hepatic xenobiotic metabolizing enzymes.

There were no deaths or clinical signs observed in either group during treatment. Body weight 

and food and water consumption were similar to controls.

In the 3000 ppm females, absolute and relative (to body) liver weights were increased by 40-

43%. The weight increase was associated with enlarged livers in nearly all treated females at 

necropsy, and diffuse centrilobular to panlobular hepatocellular hypertrophy was seen 

microscopically in all treated females. BrdU labeling indices were approximately 4-fold higher 

in treated females compared to controls. Total cytochrome P-450 content was increased by 35%, 

EROD activity was increased by 115%, PROD activity was increased by 329%, UDPGT activity 

was increased by 378%, and BROD activity was increased by 1066%.

These data demonstrated that the test compound, when administered at 3000 ppm for seven days, 

induced xenobiotic metabolizing enzymes in female rat liver, and caused hepatocellular 

hypertrophy and proliferation.

This study is considered acceptable/non-guideline and provides information regarding the 

effects of dietary administration of the test compound on rat liver.

In a non-guideline, mechanistic study (MRID 47372522), phenobarbital (99.6% a.i., Lot/Batch 

06100228) in 0.5% aqueous methylcellulose 400 was administered by daily oral gavage to 

groups of 15 male C57BL/6J mice/dose group at dose levels of 0 or 80 mg/kg day for either three 

or fourteen days. The rats were observed regularly for changes in mortality, clinical signs of 

toxicity, body weight, and food consumption. On the days of necropsy (Days 4 or 15), blood 

samples were taken from all animals for determination of TSH, T3, and T4 hormone levels. The 

mice were then exsanguinated and necropsied. Brain and liver were weighed, and pieces of the 

left and medial lobes of the liver from five mice/group were removed and fixed in neutral 

buffered 10% formalin. The remaining portions of the liver from these mice and the whole livers 

from the other ten males from each group were pooled (two whole livers pooled with one 

remaining portion) to generate five liver samples. Microsomal preparations were made from 

these five pooled samples and analyzed for total cytochrome P-450 content and activities of 

ethoxyresorufin-O-deethylase (EROD), benzoxyresorufin-O-dealkylase (BROD), 

pentoxyresorufin-O-deethylase (PROD), and UDP-glucuronosyltransferase (UDPGT).
Fluopyram Human Health Risk Assessment DP No. D385636

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No mortalities were observed, and there were no clinical signs of toxicity. In the 3-day exposure 

group, an overall mean body weight loss of 0.6 g was observed compared to a 0.3 g gain in the 

controls. Similarly in the 14-day exposure group, a mean body weight loss of 0.3 g was noted on 

Day 7 compared to a 0.4 g gain in the controls. A slight decrease in food consumption was noted 

in the 14-day treatment group at the beginning of treatment.

T4 levels were decreased by 27% after 3 days and by 19% after 14 days of treatment; TSH levels 

were increased by 9% after 14 days of treatment. No relevant changes in gross or microscopic 

pathology were observed in the thyroid gland.

Absolute and relative (to body) liver weights were increased by 5-23% at Days 4 and 15. The 

weight increases were associated with enlarged and/or dark livers observed at necropsy, and 

centrilobular to panlobular hepatocellular hypertrophy observed microscopically (4/5 mice at 

Day 4; 5/5 mice at Day 15). Additionally, an increased number of mitoses was observed in 3/5 

males on Day 4. Total cytochrome P-450 content was increased by 36-146%, EROD activity

was increased by 297-375%, PROD activity was increased by 1345-1381%, and BROD activity

was increased by 2844-4930% on Days 4 and 15. In contrast, UDPGT activity was unaffected 

by treatment.

In summary, the results of this study demonstrated that phenobarbital administration (by gavage) 

at 80 mg/kg produced liver toxicity in male C57BL/6J mice by induction of hepatic xenobiotic 

metabolizing enzymes and causing gross and microscopic pathological changes in the liver. 

Furthermore, it had the potential to modify thyroid hormone balance by causing a decrease in T4 

and a concomitant increase in TSH levels.

This study is considered acceptable/non-guideline and provides information regarding the 

effects of oral gavage administration of phenobarbital on mouse liver and thyroid.

Non-Guideline: ADME

In a non-guideline study (MRID 47372510), [pyridyl-2,6-

14C]-AE C656948 (Batch/Lot No. not 

provided; radiochemical purity >99%) in aqueous 0.5% Tragacanth was administered by oral 

gavage to three groups of four Wistar [Hsd/Cpb: WU] rats/sex at a nominal doses of 5 mg/kg. 

Groups were terminated at 1, 4, or 24 hours post-dosing, and urine, feces, and plasma were 

collected. Radioactivity was measured in urine, plasma, carcass, kidneys, liver, gastrointestinal 

tract (with feces), skin, and perirenal fat. Metabolic profiles were determined for plasma, urine 

pools, and extracts of liver, kidney, and fat for each time point.

The overall recovery accounted for 97.2-98.8% of the administered dose in males and 97.8-

99.7% of the administered dose in females. The majority of radioactivity was detected in the 

gastrointestinal tract (with feces) in the males at all time points; in females, the majority of 

radioactivity was detected in the body without the gastrointestinal tract at 1 hour post-dosing, 

then in the gastrointestinal tract (with feces) at 4 and 24 hours post-dosing.

The highest TRR (total radioactive residues) were detected in the organs and tissues as well as in 

the combined GIT plus feces at one hour after administration. The distribution of the 

radioactivity within the central compartments of the body (e.g. blood, liver, and kidney) was fast 
Fluopyram Human Health Risk Assessment DP No. D385636

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and showed a distinctive preference towards the liver as the main organ responsible for 

metabolism and to a smaller extent to the kidney. Residues decreased significantly towards 

study termination. In comparison to the male rats, the TRR values of organs and tissues from 

female rats were higher at nearly all points in time.

[Pyridyl-2,6-

14C]-AE C656948 was extensively metabolized and more than 20 metabolites were 

identified. Molecular cleavage occurred at least in a range of 23-34% of the administered dose 

in both sexes represented by numerous label-specific metabolites. In the various samples, some 

sex differences were observed with regard to the ratio of pyridyl label-specific and common 

metabolites which contained the intact molecular structure. The metabolic transformation of the 

parent compound was generally more pronounced in male rats. This was obvious from 

somewhat higher findings of unchanged parent compound in tissues of female rats compared to

male rats. The metabolism of [pyridyl-2,6-

14C]-AE C656948 in male and female rats was 

principally oxidative and took place mainly at the ethylene bridge of the molecule. The 

metabolic transformations detected were hydroxylation of the ethyl linking group of the parent 

compound forming AE C656948-7-hydroxy and -8-hydroxy metabolites and one dihydroxylated metabolite. Hydroxylation of the phenyl ring of AE C656948 led to AE C656948-

phenol and -7-OH-phenol. Hydrolytic cleavage led to AE C656948-pyridyl-hydroxyethyl and -

pyridyl-carboxylic acid (PCA). Subsequent oxidation of AE C656948-pyridyl-hydroxyethyl led 

to mainly AE C656948-pyridyl-acetic acid (PAA) and to a lesser extent to AE C656948-ethyldiol, and -hydroxy-PAA. Elimination of water from compounds hydroxylated in the ethylene 

bridge afforded the AE C656948-Z-olefine and E-olefine (E- and Z-olefine can isomerise into 

each other). As the double bond of the olefine may be a target for epoxidation and a dihydroxymetabolite which could result from hydrolysis of an epoxide by epoxide hydroxylase was 

observed, the olefine was considered to be of potential toxicological relevance. Several 

hydroxylated metabolites were conjugated with glucuronic acid and, to a lesser extent, with 

sulfate.

This study is classified acceptable/non-guideline and provides information regarding the 

distribution, excretion, and metabolism of the test compound following oral dosing in rats.

In a non-guideline study (MRID 47372513), [phenyl-UL14C]-AE C656948 (Batch/Lot No. not 

provided; radiochemical purity >98%) in aqueous 0.5% Tragacanth was administered by oral 

gavage to eight Wistar [Hsd/Cpb: WU] rats/sex at a nominal dose of 3 mg/kg. Urine and feces 

were collected at regular intervals up to 168 hours post-dosing. Carbon dioxide and other 

volatiles from expired air were trapped and sampled at 24 and 48 hours post-dosing. The 

distribution of total radioactivity in organs and tissues was determined at regular intervals by

means of quantitative whole-body autoradiography. Groups of one male and one female each 

were killed at 1, 4, 8, 24, 48, 72, 120, and 168 hours post-dosing. The animals were fixed in a 

stretched position and immediately frozen at approximately -70°C. The frozen carcass was then 

embedded in a slurry of carboxymethylcellulose (7-8%), and the slurry was deep frozen. 

Sections were then cut from the block using a microtome; the sections were attached to adhesive 

tape and freeze-dried overnight. Four sections from each animal showing the relevant organs 

and tissues were exposed using imaging plates, and the exposed plates were scanned. A control 
Fluopyram Human Health Risk Assessment DP No. D385636

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animal of each sex was similarly dosed, and prepared as above four hours post-dosing to correct 

for possible chemographic effects.

The distribution and elimination of radioactivity in males and females was very similar. In both 

sexes, [phenyl-UL14C]- AE C656948 was readily absorbed from the gastrointestinal tract and 

distributed to almost all organs and tissues. The major part of the dosed radioactivity (53-65%)

was excreted with feces; 32-41% was excreted via the urine. After 72 hours, the fecal excretion 

was nearly completed. In the males, only a very minor part of the dose was excreted between 72 

and 168 hours after dosing. In both sexes, the urinary excretion showed a slightly different 

behavior, as a clear plateau level was not reached during the sampling period of seven days and 

renal excretion was still ongoing on a low level. Less than 0.07-0.09% of the administered dose 

was expired, demonstrating the stability of the 14C-phenyl labeling position. For nearly all 

organs and tissues, the highest concentration equivalents (CEQmax) were reached during the first 

day after administration. In females, the CEQmax for the nasal mucosa and glandula preputialis 

peaked after 48 hours. For most organs of the central compartment (e.g. liver, kidney) as well as

peripheral tissues such as fat, muscle, some glands (e.g. adrenal, thyroid, Harderian) and nasal 

mucosa, the CEQmax was higher than in blood at the times of tmax and t168 h suggesting a rapid 

clearance from blood and distribution to organs and tissues of the animals. In the females, the 

higher values for the organs at t168 h indicate a still ongoing degradation (liver) and excretion 

(kidney) and a delayed depletion of test compound related radioactivity from the other organs. 

The equivalent concentrations in blood and all organs and tissues declined up to the end of the 

study (168 h post-dosing). In males, the highest value was detected in the nasal mucosa (52.1% 

of the maximum equivalent concentration). In females, the highest values were detected in the 

glandula preputialis (24% of the maximum equivalent concentration) and in the nasal mucosa 

(55%). In both sexes, the lowest was in the pineal body. 

This study is classified acceptable/non-guideline and provides information regarding the 

distribution and excretion of the test compound following oral dosing in rats.

Non-Guideline: Range-Finding, Oral Toxicity

In a range-finding oral toxicity study (MRID 47372515), fluopyram (99.0% a.i., Lot/Batch PFI 

0304) in aqueous 0.4% methylcellulose 400 was administered by daily oral gavage (5 mL/kg) to 

two beagle dogs/sex/dose group at dose levels of 0, 30, 150, or 750 mg/kg/day for at least 28 

days. Mortality, clinical signs of toxicity, body weights, and food consumption were recorded at 

regular intervals. Ophthalmoscopic examinations, hematology and clinical chemistry

measurements, and urinalysis were performed prior to administration of the test compound and 

approximately at the end of treatment. On Days 29 and 30, all animals were euthanized and 

subjected to a gross necropsy. Histopathological examinations were also performed 

(organs/tissues not specified).

There were no effects of treatment on mortality, clinical signs, body weights, body weight gains, 

food consumption, ophthalmoscopic examinations, or urinalysis.

At 750 mg/kg/day, diffuse centrilobular to panlobular hepatocellular hypertrophy was observed 

in 2/2 males (minimal to slight severity) and 2/2 females (slight severity), and focal/multifocal 
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eosinophilic inclusion bodies were noted in 1/2 males (minimal severity) and 2/2 females 

(minimal to slight severity). Additionally at this dose, it was stated that the two males 

demonstrated decreased erythrocyte counts, hemoglobin, and hematocrit, and a high alkaline 

phosphatase activity was observed in one male and one female. The female also exhibited high 

gamma-glutamyltransferase activity and increased triglycerides. It was further stated that 

absolute and relative (to body) liver weights were clearly increased in both sexes at 750 

mg/kg/day. As no data regarding the magnitude of these changes were presented, the reviewers 

cannot be certain as to the severity and adverse nature of these findings.

At 150 mg/kg/day and below, the only finding reported was a slight increase in liver weights in 

both sexes at 150 mg/kg/day and in males at 30 mg/kg/day. This finding was considered to be an 

adaptive response of the liver to exposure to the test compound.

The LOAEL is 750 mg/kg/day, based on liver toxicity as described above in both sexes, and 

hematology findings in males. The NOAEL is 150 mg/kg/day.

This study is classified acceptable/non-guideline and provides sufficient data to aid in dose 

level selection for the definitive subchronic oral toxicity study in dogs.

In a range-finding oral toxicity study (MRID 47372516), fluopyram (98.6% a.i., Lot/Batch FLH 

999) was administered in the diet to five Wistar (Rj:WI [IOPS HAN]) rats/sex/dose group at 

dose levels of 0, 50, 400, or 3200 ppm (equivalent to 0/0, 4.0/4.6, 31.0/36.1, and 254/263 

mg/kg/day in males/females) for 28 days. Mortality, clinical signs of toxicity, body weights, and 

food consumption were recorded at regular intervals. On Day 29, blood samples were collected 

for measurement of hematology and clinical chemistry parameters, and all animals were then 

subjected to a gross necropsy. Histopathological examinations were performed on the adrenal 

gland, brain, liver, kidney, lung, ovary, pituitary, spleen, testis, and thyroid (with parathyroid). 

Additionally, microsomal preparations were made from the livers of all rats and analyzed for 

total cytochrome P-450 content and activities of ethoxyresorufin-O-deethylase (EROD), 

benzoxyresorufin-O-dealkylase (BROD), and pentoxyresorufin-O-deethylase (PROD).

All animals survived to scheduled termination. There were no effects of treatment on clinical 

signs.

Treatment-related systemic effects were observed at 3200 ppm. Body weight gains were 

decreased by 12-28% in males (Weeks 1 and 3) and by 16-29% in females (Weeks 1, 3, and 4). 

Additionally in the females, overall body weight gains were decreased by 14%, and food 

consumption was reduced by 4-10% throughout the study.

Liver toxicity was noted at 3200 ppm. Absolute and relative (to body) liver weights were each 

increased by 54% in males, and by 65% and 73%, respectively, in females. These weight 

increases were associated with enlarged and dark livers at necropsy, and minimal to moderate 

centrilobular hepatocellular hypertrophy in most animals in both sexes. Total cytochrome P-450 

levels were increased by 37% and 41% in males and females, respectively, with increases in 

BROD (1831% in males, 3002% in females) and PROD (941% males, 1526% in females). 

Males exhibited a 30% increase in platelet count and increased prothrombin time (18.0 s treated 
Fluopyram Human Health Risk Assessment DP No. D385636

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vs. 13.4 s controls), and total cholesterol and triglycerides were increased in males (82% and 

148%, respectively) and females (84% and 152%, respectively).

Also at 3200 ppm, absolute and relative thyroid weights were increased by 43% and 41%, 

respectively, in males, with hypertrophy of the follicular cells noted in 3/5 males.

At 400 ppm, absolute and relative liver weights were increased by 12% and 7%, respectively, in 

males, and by 16% and 15%, respectively, in females. These changes were not statistically

significant. Goss examination showed enlarged and dark livers, and histological evaluation 

revealed centrilobular hepatocellular hypertrophy. However, the magnitude, incidence, and 

severity were lower than those observed at 3200 ppm. Total cytochrome P-450 levels were 

increased by 20% and 15% in males and females, respectively, with increases in BROD (698% 

in males, 842% in females) and PROD (350% in males, 360% in females). The liver effects at 

400 ppm were considered as an adaptive response of the liver to the exposure of the test 

compound and were not adverse.

Increased absolute and relative kidney weights were observed in the 400 ppm and above males 

(19-20% absolute weight; 15-18% relative weight). These increased weights were associated 

with microscopic changes of hyaline droplet nephropathy (basophilic tubules, hyaline droplets in 

the proximal tubule, and granular casts in the medulla). This nephropathy was considered to be 

due to accumulation of 2μ-globulin, a common toxicological finding in young male rats 

following exposure to toxicants. Therefore, this finding was not considered relevant to human 

health considerations.

The LOAEL is 3200 ppm (equivalent to 254/263 mg/kg/day in males/females), based on 

decreased body weight gains and liver toxicity as described above in both sexes, increased 

thyroid weights and hypertrophy of the follicular cells in males, and decreased overall body 

weight gains and food consumption in females. The NOAEL is 400 ppm (equivalent to 

31.0/36.1 mg/kg/day in males/females).

This study is classified acceptable/non-guideline. Although it satisfies the majority of the 

requirements for a repeated dose 28-day oral toxicity study in rodents (OPPTS 870.3050; OECD 

407), it was stated that as a range-finding study, it was not intended to meet guideline 

requirements.

In a range-finding oral toxicity study (MRID 47372517), fluopyram (99.4% a.i., Lot/Batch FLH 

1046) was administered in the diet to five C57BL/6J mice/sex/dose group at dose levels of 0, 

150, 1000, or 5000 ppm (equivalent to 0/0, 24.7/31.1, 162/197, and 747/954 mg/kg/day in 

males/females) for 28 days. Mortality, clinical signs of toxicity, body weights, and food 

consumption were recorded at regular intervals. On Day 29, blood samples were collected for 

measurement of clinical chemistry parameters, and all animals were then subjected to a gross 

necropsy. Histopathological examinations were performed on the adrenal gland, liver, kidney, 

lung, ovary, spleen, testis, and thyroid (with parathyroid).
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At 5000 ppm, the maximum tolerated dose was exceeded. All males and 3/5 females were 

euthanized between Days 17 and 27. These animals were observed with reduced motor activity, 

hunched posture, piloerection, wasted appearance, and/or coldness to the touch in both sexes, 

with labored respiration in 3/5 males and distended abdomen in 2/3 females, noted mainly on the 

day of euthanasia or for a few days prior. A loss of body weight and reduced food intake 

accompanied these signs. At necropsy, a pale pancreas was observed in all males and in 2/3 

females. Rounded borders were observed in the liver in 3/5 males and 1/3 females. Dark liver 

was observed in 4/5 males and all females; enlarged liver was observed in 1/5 males and 2/3 

females. Thymus size was clearly reduced in 4/5 males and 1/3 females and distended abdomen 

was noted in 3/5 males. Red liquid was noted in the thoracic cavity in all males. Treatmentrelated effects were seen in the adrenal glands, liver, lungs, spleen, thymus, and thyroid gland. 

Hypertrophy, vacuolation, and degeneration/necrosis of the zona fasciculata were seen in the 

adrenal glands in all animals, together with perivascular and intra-alveolar hemorrhage and 

degeneration/inflammation of pulmonary veins in the lungs and erythroid extramedullary

hematopoiesis in the spleen. Focal hemorrhage was seen in the thyroid gland in 3/5 males, and 

decreased cellularity of the cortex and focal hemorrhage were seen in the thymus in all animals 

where examination was possible. In the liver, hypertrophy of hepatocytes (mainly centrilobular), 

hepatocellular eosinophilia, bile duct/oval cell hyperplasia, focal necrosis and single 

hepatocellular necrosis were seen in all animals, and centrilobular degeneration/necrosis in 1/5 

males. It was considered that premature sacrifice in all males and 1/3 females was associated 

with intrathoracic hemorrhage, as the majority of the decedents had areas of hemorrhage in the 

thoracic cavity, thyroid gland, lungs, and thymus.

In the two surviving females dosed at 5000 ppm, distended abdomen was noted between Days 8 

and 10 in one animal. Body weights, body weight gains, and food consumption were similar to 

controls. Total cholesterol was increased by 118%, total protein was increased by 16%, and 

alanine aminotransferase was increased by 384%. Absolute and relative (to body) liver weights 

were increased by 132-144%. Enlarged liver was observed in both females; dark liver was noted 

in 1/2 females. Hypertrophy of the zona fasciculata was seen in the adrenal glands in both 

females. The following microscopic findings were noted in the liver of both females: moderate 

hypertrophy of centrilobular hepatocytes, slight focal necrosis, minimal hepatocellular 

eosinophilia, and minimal bile duct/oval cell hyperplasia. Additionally, minimal single cell 

hepatocellular necrosis was observed in 1/2 females.

At 1000 ppm and below, there were no effects of treatment on mortality, clinical signs, body

weights, body weight gains, or food consumption.

Liver toxicity was noted at 1000 ppm. Alanine aminotransferase was increased by 259% in 

males. Absolute and relative liver weights were increased by 41-46% in males, and by 27-38% 

in females. Enlarged liver was observed in all males and 4/5 females; dark liver was noted in 3/5 

males and 2/5 females. The following microscopic findings were noted: hypertrophy of 

centrilobular hepatocytes in 5/5 males (moderate severity) and 5/5 females (minimal to slight 

severity); minimal single cell hepatocellular necrosis in 5/5 males; minimal focal necrosis in 3/5 

males and 2/5 females; and minimal bile duct/oval cell hyperplasia in 1/5 females.
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Additionally at 1000 ppm, hypertrophy of the zona fasciculata was seen in the adrenal glands of 

3/5 females.

The following findings were observed at 150 ppm. Absolute and relative liver weights were 

increased by 18-21% in males and 16-17% in females, and hypertrophy of centrilobular 

hepatocytes was noted in 5/5 males (minimal to slight severity) and 2/5 females (minimal 

severity). These minor findings were considered to represent an adaptive change of the liver to 

exposure to the test compound, and were not considered adverse.

The LOAEL is 1000 ppm (equivalent to 162/197 mg/kg/day in males/females), based on 

liver toxicity as described above in both sexes, and microscopic findings in the adrenal 

glands in females. The NOAEL is 150 ppm (equivalent to 24.7/31.1 mg/kg/day in 

males/females).

This study is classified acceptable/non-guideline. Although it satisfies the majority of the 

requirements for a repeated dose 28-day oral toxicity study in rodents (OPPTS 870.3050; OECD 

407), it was stated that as a range-finding study, it was not intended to meet guideline 

requirements.
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Appendix B. Metabolism Summary Table

Table B.1 Tabular Summary of Fluopyram and Metabolites.

Chemical Name (other 

names in parentheses) and 

Structure

Matrix Percent TRR (PPM)1

Matrices - Major Residue 

(>10% TRR)

Matrices - Minor Residue 

(<10% TRR)

N-[2-[3-chloro-5-

(trifluoromethyl)-2-

pyridinyl]ethyl]-2-

(trifluoromethyl)-

benzamide

(fluopyram; AE C656948)

Grape Fruit: 97.6 (1.82) [PH]

95.8 (1.63) [PY]

Leaves: 91.8 (44.11) [PH]

91.3 (39.00) [PY]

Potato Tuber: 68.8 (0.006) [PH]

23.2 (0.003) [PY]

Leaves: 98.0 (46.69) [PH]

98.1 (21.26) [PY]

Bean Green bean:

93.9 (1.31) [PH]

99.3 (3.86) [PY]

Foliage: 

93.8 (34.39) [PH]

92.3 (35.53) [PY]

Succulent bean:

11.4 (<0.01) [PH]

Succulent bean:

4.8 (<0.01) [PY]

Dry bean: 12.6 (0.02) [PH] Dry bean: 5.7 (0.02) [PY]

Straw: 90.2 (14.94) [PH]

87.1 (16.56) [PY]

Pepper, bell Fruit: 48.9 (0.019) [PH]

16.2 (0.010) [PY]

32.8 (0.049) [PY; 

4x]

Foliage: 64.0 (2.27) [PH]

70.1 (1.64) [PY]

Rotational Crops

-Swiss Chard 32.7-56.0 (0.055-0.302) [PH]

37.3-56.7 (0.081-0.323) [PY]

-Turnip Root 77.7-83.5 (0.010-0.054)

 [PH; 30- and 139-day]

86.1-94.6 (0.010-0.031) [PY]

-Turnip Tops 54.3-68.4 (0.060-0.605) [PH]

59.9-70.6 (0.061-0.399) [PY]

-Wheat Forage 59.2-74.9 (0.075-0.588) [PH]

70.2-77.9 (0.113-0.442) [PY]

-Wheat Hay 57.5-76.9 (0.748-1.370) [PH]

66.9-78.9 (0.473-1.421) [PY]

-Wheat Straw 50.1-74.1 (0.516-4.557) [PH]

58.3-73.9 (0.945-4.926) [PY]

-Wheat Grain 28.4-61.9 (0.007-0.104) [PH]

20.4-33.4 (0.012-0.137) [PY]

N

H

O

N

Cl CF3

CF3
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Table B.1 Tabular Summary of Fluopyram and Metabolites.

Chemical Name (other 

names in parentheses) and 

Structure

Matrix Percent TRR (PPM)1

Matrices - Major Residue 

(>10% TRR)

Matrices - Minor Residue 

(<10% TRR)

fluopyram (continued) Poultry (hen) Egg (days 1-6):

14.7 (0.023) [PY]

Egg (days 1-6):

0.7 (0.024) [PH]

Egg (days 7-14):

1.4 (0.026) [PH]

6.0 (0.017) [PY]

Fat: 12.2 (0.061) [PY] Fat: 2.5 (0.042) [PH]

Muscle: 1.0 (0.001) [PY]

Ruminant (goat) Milk: 42.5 (0.023) [PY] Milk: 0.7-1.7 (0.002-

0.004) [PH]

Fat: 18.2 (0.073) [PH]

46.4 (0.173) [PY]

Liver: 0.6 (0.047) [PH]

7.7 (0.110) [PY]

Muscle: 27.3 (0.011) [PY] Kidney: 0.4 (0.009) [PH]

N-{2-[3-chloro-1-oxido-5-

(trifluoromethyl) pyridin2-yl]ethyl}-2-

(trifluoromethyl)-

benzamide

(AE C656948-N-oxide; 

M01)

Pepper, bell Foliage: 2.9 (0.07) [PY]

N-{(E)-2-[3-chloro-5-

(trifluoromethyl)pyridin-2-

yl]ethenyl}-2-

(trifluoromethyl)-

benzamide

(AE C656948-E-olefine;

BCS-AA10627; M02)

Poultry (hen) Egg (days 1-6):

1.0 (0.001) [PY]

Egg (days 7-14):

1.0 (0.003) [PY]

Muscle: 3.9 (0.002) [PY]

Fat: 12.4 (0.062) [PY] Fat: 2.3 (0.037) [PH]

Liver: 11.8 (0.063) [PY] Liver: 0.3 (0.028) [PH]

Ruminant (goat) Milk: 2.0 (0.001) [PY]

Muscle: 1.9 (0.001) [PY]

Fat: 8.6 (0.034) [PH]

2.2 (0.008) [PY]

Liver: 0.3 (0.021) [PH]

4.1 (0.058) [PY]

N

H

O

N

+

Cl CF3

CF3

O

N

H

O

N

Cl CF3

CF3
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Table B.1 Tabular Summary of Fluopyram and Metabolites.

Chemical Name (other 

names in parentheses) and 

Structure

Matrix Percent TRR (PPM)1

Matrices - Major Residue 

(>10% TRR)

Matrices - Minor Residue 

(<10% TRR)

N-{(Z)-2-[3-chloro-5-

(trifluoromethyl)pyridin-2-

yl]ethenyl}-2-

(trifluoromethyl)-

benzamide

(AE C656948-Z-olefine; 

BCS-AA10650; M03)

Poultry (hen)

Egg (days 7-14):

15.4 (0.044) [PY]

Egg (days 1-6):

0.5 (0.010) [PH] 

4.1 (0.006) [PY]

Egg (days 7-14):

1.2 (0.044) [PH]

Muscle: 33.0 (0.016) [PY] Muscle: 0.5 (0.015) [PH]

Fat: 25.9 (0.425) [PH]

70.5 (0.350) [PY]

Liver: 0.2 (0.016) [PH]

1.9 (0.010) [PY]

Ruminant (goat) Milk: 12.9 (0.007) [PY] Milk: 0.7 (0.002) [PH]

Muscle: 21.6 (0.009) [PY] Liver: 0.2 (0.015) [PH]

5.7 (0.081) [PY]

Fat: 13.1 (0.052) [PH]

33.7 (0.125) [PY]

AE C656948-phenol-glc 

(M06)

Rotational Crops

-Turnip tops 10.1-16.2 (0.010-0.092) [PH]

12.0-18.4 (0.014-0.068) [PY]

AE C656948-phenol-GA 

(M07)

Ruminant (goat) Liver: 0.8 (0.068) [PH]

2.0 (0.029) [PY]

Kidney: 1.2 (0.027) [PH]

3.2 (0.013) [PY]

N

H

O

N

Cl

CF3

CF3

N

O

N

Cl CF3

CF3

OH

OH

HO

O

HO

O

N

H

O

N

Cl CF3

CF3

O

HO OH

HO

O

HO

O
Fluopyram Human Health Risk Assessment DP No. D385636

Page 84 of 105

Table B.1 Tabular Summary of Fluopyram and Metabolites.

Chemical Name (other 

names in parentheses) and 

Structure

Matrix Percent TRR (PPM)1

Matrices - Major Residue 

(>10% TRR)

Matrices - Minor Residue 

(<10% TRR)

N-{2-[3-chloro-5-

(trifluoromethyl)pyridin-2-

yl]-2-hydroxyethyl}-2-

(trifluoromethyl) 

benzamide

(AE C656948-7-hydroxy; 

BCS-AA10065; M08)

Grape Fruit: 0.3 (<0.01) [PH/PY]

Leaves: 0.7 (0.35) [PH]

1.0 (0.43) [PY]

Potato Tuber: 1.2 (<0.001) [PH]

1.1 (<0.001) [PY]

Leaves: 0.8 (0.36) [PH]

0.6 (0.12) [PY]

Bean Foliage:

0.7 (0.26) [PH]

1.6 (0.60) [PY]

Succulent bean:

4.0 (<0.01) [PH/PY]

Dry bean: 2.5 (<0.01) [PH]

4.0 (0.01) [PY]

Straw: 0.7 (0.12) [PH]

1.1 (0.20) [PY]

Pepper, bell Fruit: 9.0 (0.003) [PH]

3.7 (0.006) [PY; 4x]

Foliage: 6.8 (0.24) [PH]

5.1 (0.12) [PY]

Rotational Crops

-Swiss chard 20.9-35.4 (0.057-0.134) [PH]

28.0-38.6 (0.081-0.160) [PY]

-Turnip roots 3.6-4.1 (0.001-0.002)

 [PH; 30- and 139-day]

3.1-6.1 (≤0.001) [PY]

-Turnip tops 3.3-8.2 (0.007-0.029) [PH]

3.5-8.3 (0.005-0.020) [PY]

-Wheat forage 2.4-6.3 (0.002-0.030) [PH]

2.1-5.6 (0.003-0.018) [PY]

-Wheat hay 12.6 (0.193) [PH; 280-day] 4.3-5.2 (0.059-0.077)

 [PH; 30- and 139-day]

3.8-8.6 (0.057-0.068) [PY]

-Wheat straw 12.3 (0.127) [PH; 280-day]

10.1 (0.164) [PY; 280-day]

5.6-6.0 (0.208-0.346)

 [PH; 30- and 139-day]

6.1-7.4 (0.156-0.494) 

 [PY; 30- and 139-day]

-Wheat grain 1.3-3.4 (0.001-0.005) [PH]

0.8-2.3 (0.001-0.008) [PY]

Poultry (hen) Egg (days 1-6):

3.9 (0.006) [PY]

Egg (days 7-14):

0.9 (0.002) [PY]

Liver: 0.8 (0.004) [PY]

OH

N

H

O

N

Cl CF3

CF3
Fluopyram Human Health Risk Assessment DP No. D385636

Page 85 of 105

Table B.1 Tabular Summary of Fluopyram and Metabolites.

Chemical Name (other 

names in parentheses) and 

Structure

Matrix Percent TRR (PPM)1

Matrices - Major Residue 

(>10% TRR)

Matrices - Minor Residue 

(<10% TRR)

AE C656948-7-hydroxy, 

continued

Ruminant (goat) Milk: 16.2 (0.009) [PY] Milk: 0.8-1.8 (0.002-

0.004) [PH]

Muscle: 21.6 (0.009) [PY] Muscle: 0.3 (0.002) [PH]

Fat: 12.8 (0.048) [PY] Fat: 7.7 (0.031) [PH]

Liver: 0.9 (0.073) [PH]

6.1 (0.086) [PY]

Kidney: 0.6 (0.014) [PH]

1.0 (0.004) [PY]

1-[3-chloro-5-

(trifluoromethyl)pyridin-2-

yl]-2-{[2-

(trifluoromethyl)-

benzoyl]amino}ethyl betaD-glucopyranosiduronic 

acid

(AE C656948-7-OH-GA; 

M09)

Ruminant (goat) Milk: 0.6 (0.002) [PH]

4.8 (0.003) [PY]

Muscle: 11.7 (0.005) [PY] Muscle: 0.3 (0.002) [PH]

Liver: 26.3 (0.375) [PY] Liver: 4.3 (0.363) [PH]

Kidney: 51.4 (0.208) [PY] Kidney: 9.4 (0.216) [PH]

1-[3-chloro-5-

(trifluoromethyl)pyridin-2-

yl]-2-({[2-

(trifluoromethyl)phenyl]-

carbonyl}amino)ethyl 

hydrogen sulfate

(AE C656948-7-OH-SA;

M10)

Rotational Crops

-Swiss chard 12.1-15.6 (0.020-0.059)

 [PH; 139- and 280-day]

13.5-16.8 (0.029-0.058)

 [PY; 139- and 280-day]

7.0 (0.038) [PH; 30-day]

7.9 (0.045) [PY; 30-day]

-Turnip tops 0.7-1.0 (0.001-0.006)

 [PH; 30- and 139-day]

0.4-0.7 (<0.001-0.004) [PY]

O OH

OH

OH

O

OH

N

H

O

N

Cl CF3

CF3

O

O

N

H

O

N

Cl CF3

CF3

O S O

OH
Fluopyram Human Health Risk Assessment DP No. D385636

Page 86 of 105

Table B.1 Tabular Summary of Fluopyram and Metabolites.

Chemical Name (other 

names in parentheses) and 

Structure

Matrix Percent TRR (PPM)1

Matrices - Major Residue 

(>10% TRR)

Matrices - Minor Residue 

(<10% TRR)

N-[2-[3-chloro-5-

(trifluoromethyl)pyridin-2-

yl]-2-(beta-Dglucopyranosyloxy)ethyl]-

2-(trifluoromethyl) 

benzamide

(AE C656948-7-hydroxyglc; M11)

Grape Leaves: 0.7 (0.35) [PH]

0.8 (0.34) [PY]

Bean Foliage:

0.4 (0.15) [PH]

0.6 (0.25) [PY]

Succulent bean:

1.7 (<0.01) [PH]

1.4 (<0.01) [PY]

Dry bean: 1.3 (<0.01) [PY]

Straw: 0.4 (0.07) [PH]

0.7 (0.14) [PY]

Pepper, bell Fruit: 3.9 (0.001) [PH]

Foliage: 8.9 (0.31) [PH]

9.2 (0.22) [PY]

Rotational Crops

-Swiss chard 1.0-1.8 (0.002-0.007) [PH]

0.9-1.8 (0.003-0.006) [PY]

-Turnip tops 0.4-0.9 (0.001-0.004)

 [PH; 30- and 139-day]

0.3-1.6 (0.001-0.002) [PY]

-Wheat forage 2.0-3.4 (0.002-0.016) [PH]

1.0-3.0 (0.002-0.005) [PY]

-Wheat hay 1.4-3.4 (0.023-0.052) [PH]

0.9-3.0 (0.016-0.024) [PY]

-Wheat straw 2.8-6.9 (0.071-0.169) [PH]

2.3-3.7 (0.059-0.203) [PY]

-Wheat grain 1.2 (0.002) [PH; 30-day]

O OH

OH

OH

O

OH

N

H

O

N

Cl CF3

CF3
Fluopyram Human Health Risk Assessment DP No. D385636

Page 87 of 105

Table B.1 Tabular Summary of Fluopyram and Metabolites.

Chemical Name (other 

names in parentheses) and 

Structure

Matrix Percent TRR (PPM)1

Matrices - Major Residue 

(>10% TRR)

Matrices - Minor Residue 

(<10% TRR)

1-[3-chloro-5-

(trifluoromethyl)pyridin-2-

yl]-2-{[2-

(trifluoromethyl)-

benzoyl]amino}ethyl 6-O-

(carboxyacetyl)-beta-Dglucopyranoside

(AE C656948-7-hydroxyglc-MA; M12)

Bean Foliage:

2.2 (0.82) [PH]

3.2 (1.22) [PY]

Succulent bean:

2.2 (<0.01) [PH]

Straw: 4.1 (0.68) [PH]

4.7 (0.90) [PY]

Pepper, bell Foliage: 0.7 (0.02) [PH]

Rotational Crops

-Swiss chard 0.3 (0.001) [PH; 30-day]

-Turnip tops 2.0-2.9 (0.002-0.019) [PH]

2.5-4.0 (0.004-0.014) [PY]

-Wheat forage 3.2-9.7 (0.003-0.049) [PH]

3.3-8.6 (0.005-0.036) [PY]

-Wheat hay 11.1 (0.170) [PH; 280-day]

10.7 (0.075) [PY; 280-day]

6.1-6.8 (0.077-0.107)

 [PH; 30- and 139-day]

5.4-8.4 (0.081-0.097)

 [PY; 30- and 139-day]

-Wheat straw

11.8 (0.190) [PY; 280-day]

5.5-9.2 (0.095-0.340) [PH]

6.0-6.7 (0.153-0.448)

 [PY; 30- and 139-day]

-Wheat grain 1.7 (0.003) [PH; 30-day]

O

OH

OH

OH

O

N

H

O

N

Cl CF3

CF3

O

O

HO

O
Fluopyram Human Health Risk Assessment DP No. D385636

Page 88 of 105

Table B.1 Tabular Summary of Fluopyram and Metabolites.

Chemical Name (other 

names in parentheses) and 

Structure

Matrix Percent TRR (PPM)1

Matrices - Major Residue 

(>10% TRR)

Matrices - Minor Residue 

(<10% TRR)

N-{2-[3-chloro-5-

(trifluoromethyl)pyridin-2-

yl]-1-hydroxyethyl}-2-

(trifluoromethyl) 

benzamide

(AE C656948-8-hydroxy; 

M18)

Grape Leaves: 0.6 (0.28) [PH]

0.8 (0.34) [PY]

Bean Foliage:

0.3 (0.11) [PH]

0.5 (0.21) [PY]

Succulent bean:

6.0 (<0.01) [PH]

2.7 (<0.01) [PY]

Dry bean: 2.1 (<0.01) [PH]

1.6 (<0.01) [PY]

Straw: 0.6 (0.09) [PH]

0.9 (0.17) [PY]

Pepper, bell Foliage: 0.5 (0.02) [PH]

Rotational Crops

-Swiss chard 0.7-1.4 (0.002-0.004) [PH]

0.9-1.3 (0.003-0.005) [PY]

-Turnip roots 0.9-2.3 (≤0.001)

 [PH; 30- and 139-day]

1.5 (0.001) [PY; 30-day]

-Turnip tops 0.3-0.4 (<0.001-0.003) [PH]

0.3-0.5 (<0.001-0.002) [PY]

-Wheat forage 0.3-0.5 (<0.001-0.004) [PH]

0.7 (0.004) [PY; 139-day]

-Wheat hay 0.6-1.1 (0.009-0.016) [PH]

0.4-0.7 (0.006-0.007)

 [PY; 30- and 139-day]

-Wheat straw 1.3-1.4 (0.014-0.087) [PH]

1.2-1.7 (0.028-0.087) [PY]

-Wheat grain 0.9 (0.001) [PH; 30-day]

1-[3-chloro-5-

(trifluoromethyl)pyridin-2-

yl]-1-{[2-

(trifluoromethyl)-

benzoyl]amino}ethyl 6-O-

(carboxyacetyl)-beta-Dglucopyranoside

(AE C656948-8-hydroxyglc-MA; M19)

Rotational Crops

-Wheat forage 1.0-2.2 (0.001-0.009) [PH]

1.2-1.7 (0.003-0.007)

 [PY; 139- and 280-day]

-Wheat hay 0.8-1.4 (0.014-0.021) [PH]

0.6-1.7 (0.010-0.014) [PY]

-Wheat straw 0.7-1.2 (0.043-0.046)

 [PH; 30- and 139-day]

0.4-1.2 (0.019-0.028) [PY]

N

H

O

N

Cl CF3

CF3 OH

O

HO

HO

OH

O

O

O

OH

O

N

H

O

N

Cl CF3

CF3
Fluopyram Human Health Risk Assessment DP No. D385636

Page 89 of 105

Table B.1 Tabular Summary of Fluopyram and Metabolites.

Chemical Name (other 

names in parentheses) and 

Structure

Matrix Percent TRR (PPM)1

Matrices - Major Residue 

(>10% TRR)

Matrices - Minor Residue 

(<10% TRR)

2-[3-chloro-5-

(trifluoromethyl)pyridin-2-

yl]-1-{[2-

(trifluoromethyl)-

benzoyl]amino}ethyl betaD-glucopyranosiduronic 

acid

(AE C656948-8-OH-GA; 

M20)

Ruminant (goat) Milk: 1.1 (0.001) [PY]

Muscle: 2.5 (0.001) [PY]

Liver: 2.1 (0.174) [PH]

9.5 (0.136) [PY]

Kidney: 17.7 (0.071) [PY] Kidney: 3.6 (0.082) [PH]

AE C656948-di-OH-GA 

(M21)

Ruminant (goat) Kidney: 0.7 (0.015) [PH]

1.7 (0.007) [PY]

Liver: 1.0 (0.014) [PY]

AE C656948-hydroxyglyc-gluc (M22)Bean Dry bean: 10.4 (0.01) [PH] Dry bean: 5.6 (0.02) [PY]

Succulent bean:

6.7 (<0.01) [PH]

4.5 (<0.01) [PY]

Straw: 0.2 (0.03) [PY]

HO

HO

OH

O

OH

O

O

N

H

O

N

Cl CF3

CF3

OH

OH

N

H

O

N

Cl CF3

CF3

OH

OH

OH

O

OH

O

O

- H2O

N

H

O

N

Cl CF3

CF3

glyc = glycoside

gluc = glucuronic acid

glyc - gluc
Fluopyram Human Health Risk Assessment DP No. D385636

Page 90 of 105

Table B.1 Tabular Summary of Fluopyram and Metabolites.

Chemical Name (other 

names in parentheses) and 

Structure

Matrix Percent TRR (PPM)1

Matrices - Major Residue 

(>10% TRR)

Matrices - Minor Residue 

(<10% TRR)

2-(trifluoromethyl)-

benzamide

(AE C656948-benzamide; 

AE F148815; BCSAA10014; M25)

Grape Fruit: 0.7 (0.01) [PH]

Potato Tuber: 7.1 (0.001) [PH]

Leaves: 0.5 (0.23) [PH]

Bean Succulent bean:

51.6 (0.04) [PH]

Foliage:

0.5 (0.17) [PH]

Dry bean: 64.0 (0.08) [PH] Straw: 0.6 (0.10) [PH]

Pepper, bell Fruit: 16.1 (0.006) [PH] 

Foliage: 10.1 (0.36) [PH]

Rotational Crops

-Swiss chard 10.3-11.1 (0.017-0.060)

 [PH; 30- and 280-day]

7.4 (0.028) [PH; 139-day]

-Turnip roots 4.0-5.8 (0.001-0.003)

 [PH; 30- and 139-day]

-Turnip tops 11.7 (0.012) [PH; 280-day] 5.6-9.7 (0.006-0.086)

 [PH; 30- and 139-day]

-Wheat forage 3.5-8.0 (0.006-0.028) [PH]

-Wheat hay 3.7-6.2 (0.041-0.095) [PH]

-Wheat straw 2.8-6.6 (0.068-0.169) [PH]

-Wheat grain 3.3-5.9 (0.001-0.007) [PH]

Poultry (hen) Egg (days 1-6):

95.8 (1.735) [PH]

Egg (days 7-14):

96.3 (3.447) [PH]

Muscle: 98.6 (3.233) [PH]

Fat: 68.6 (1.126) [PH]

Liver: 92.3 (8.737) [PH]

Ruminant (goat) Milk: 88.4-89.2 (0.202-

0.246) [PH]

Muscle: 97.6 (0.719) [PH]

Fat: 49.1 (0.196) [PH]

Liver: 82.8 (6.941) [PH]

Kidney: 77.1 (1.769) [PH]

AE C656948-benzamideSA (M31)Ruminant (goat) Milk: 4.3 (0.010-0.012) 

[PH]

Muscle: 0.7 (0.005) [PH]

Liver: 1.6 (0.133) [PH]

Kidney: 2.5 (0.058) [PH]

NH2

CF3 O

NH2

CF3 O

O

S

O

HO O
Fluopyram Human Health Risk Assessment DP No. D385636

Page 91 of 105

Table B.1 Tabular Summary of Fluopyram and Metabolites.

Chemical Name (other 

names in parentheses) and 

Structure

Matrix Percent TRR (PPM)1

Matrices - Major Residue 

(>10% TRR)

Matrices - Minor Residue 

(<10% TRR)

2-(trifluoromethyl)-

benzoic acid

(AE C656948-benzoic 

acid; M33)

Rotational Crops

-Turnip Root 3.7 (0.002) [PH; 30-day]

-Turnip Tops 0.6 (0.005) [PH; 30-day]

-Wheat Forage 0.4-1.7 (0.002-0.003)

 [PH; 30- and 139- days]

-Wheat Hay 0.3-0.6 (0.004-0.011)

 [PH; 30- and 139- days]

-Wheat Grain 13.0-13.6 (0.003-0.007)

 [PH; 139- and 280-day]

6.9 (0.012) [PH; 30-day]

Poultry (hen) Liver: 0.3 (0.024) [PH]

2-[3-chloro-5-

(trifluoromethyl)pyridin-2-

yl]ethyl beta-Dglucopyranoside

(AE C656948-

hydroxyethyl-glc; M35)

Bean Foliage:

0.2 (0.06) [PY]

Succulent bean:

1.9 (<0.01) [PY]

Dry bean: 3.1 (0.01) [PY]

2-[3-chloro-5-

(trifluoromethyl)pyridin-2-

yl]ethyl 6-O-beta-Dglucopyranosyl-beta-Dglucopyranoside

(AE C656948-

hydroxyethyl-di-glc; M36)

Pepper, bell Foliage: 7.0 (0.16) [PY]

OH

CF3 O

OH

OH

HO

O

HO

O N

Cl CF3

O

OH

HO

HO

O

OH

O

HO OH

HO

O

N

Cl CF3
Fluopyram Human Health Risk Assessment DP No. D385636

Page 92 of 105

Table B.1 Tabular Summary of Fluopyram and Metabolites.

Chemical Name (other 

names in parentheses) and 

Structure

Matrix Percent TRR (PPM)1

Matrices - Major Residue 

(>10% TRR)

Matrices - Minor Residue 

(<10% TRR)

2-[3-chloro-5-

(trifluoromethyl)pyridin-2-

yl]ethyl beta-Dglucopyranosiduronic acid

(AE C656948-

hydroxyethyl-GA; M37)

Ruminant (goat) Kidney: 4.3 (0.017) [PY]

[3-chloro-5-

(trifluoromethyl)pyridin-2-

yl]acetic acid

(AE C656948-pyridylacetic acid (PAA); M40)

Bean Succulent bean:

29.5 (0.05) [PY]

Dry bean: 22.6 (0.07) [PY] Straw: 0.2 (0.04) [PY]

Pepper, bell Fruit: 9.8 (0.015) [PY; 4x]

Poultry (hen) Egg (days 1-6):

6.4 (0.010) [PY]

Egg (days 7-14):

3.7 (0.011) [PY]

Liver: 1.3 (0.007) [PY]

Ruminant (goat) Kidney: 8.6 (0.035) [PY]

AE C656948-PAAglycoside (M42)Pepper, bell Fruit: 38.0 (0.023) [PY]

32.2 (0.048) [PY; 

4x]

3-chloro-5-

(trifluoromethyl)pyridine2-carboxylic acid

(AE C656948-pyridylcarboxylic acid (PCA); 

M43)

Grape Fruit: 0.9 (0.02) [PY]

Leaves: 0.8 (0.33) [PY]

Potato Tubers: 49.8 (0.006) [PY] Leaves: 0.5 (0.11) [PY]

Bean Succulent bean:

31.0 (0.05) [PY]

Foliage:

0.5 (0.19) [PY]

Dry bean: 32.5 (0.10) [PY] Straw: 0.6 (0.11) [PY]

Pepper, bell Fruit: 43.5 (0.026) [PY]

 19.5 (0.029) [PY; 4x]

Rotational Crops

-Swiss chard 0.2-1.8 (<0.001-0.010) [PY]

-Turnip roots 6.0 (0.002) [PY; 30-day]

-Turnip tops 1.1-4.3 (0.001-0.024) [PY]

-Wheat forage 16.5 (0.026) [PY; 30-day] 0.9-1.0 (0.002-0.006)

 [PY; 139- and 280-day]

-Wheat hay 0.5-4.9 (0.004-0.088) [PY]

-Wheat straw 0.9 (0.060) [PY; 30-day]

-Wheat grain 16.4-55.9 (0.011-0.230) [PY]

O

OH

HO

HO

O

HO

N

Cl

O

CF3

N

Cl CF3

HO

O

N

Cl CF3

O

O

glyc

HO

N

Cl CF3

O
Fluopyram Human Health Risk Assessment DP No. D385636

Page 93 of 105

Table B.1 Tabular Summary of Fluopyram and Metabolites.

Chemical Name (other 

names in parentheses) and 

Structure

Matrix Percent TRR (PPM)1

Matrices - Major Residue 

(>10% TRR)

Matrices - Minor Residue 

(<10% TRR)

3-(methylsulfinyl)-5-

(trifluoromethyl) pyridine2-carboxylic acid

(AE C656948-methylsulfoxide; M45)

Rotational Crops

-Swiss chard 0.4-0.5 (0.001-0.003) [PY]

-Wheat forage 2.0-2.2 (0.003-0.012)

 [PY; 139- and 280-day]

-Wheat hay 3.5-4.7 (0.025-0.046)

 [PY; 139- and 280-day]

-Wheat straw 1.2 (0.019-0.031)

[PY; 139- and 280-day]

-Wheat grain 20.3-49.0 (0.008-0.035)

[PY; 139- and 280-day]

1.2 (0.005) [PY; 30-day]

1

 Fluopyram was radiolabeled in the phenyl ring [PH] or on the pyridyl ring [PY].

Grape; 47372524-47372525; three applications at total rate of 0.446 lb ai/A (500 g ai/ha); 1x label rate; 

postemergence (BBCH 17-19, 71, and 81); 18-day PHI (fruit) and 19-day PHI (leaves).

Potato; 47372528-47372529; three applications at total rate of 0.446 lb ai/A (500 g ai/ha); postemergence (BBCH 

16, 55, and 71); 51-day PHI.

Bean; 47372526-47372527; two applications at total rate of 0.446 lb ai/A (500 g ai/ha); postemergence (BBCH 51 

and 75); 4-day PHI for green bean and foliage (BBCH 75), and 29-day PHI for mature succulent bean, dried 

bean, and straw.

Pepper, bell; 47372530-47372531; 5 mg ai/plant and 20 mg ai/plant, drip irrigation to plants grown on stone wool; 

x rate compared to label rate for tomato could not be determined; postemergence BBCH 15-17; fruit harvested 

at 55 to 96 days posttreatment and combined for analysis; 97-day PHI for remaining plant material; results for 

fruit treated at exaggerated rate reported only for PY-label.

Rotational Crops (turnip, Swiss chard & wheat); 47372631-32; 0.46-0.48 lb ai/A (514-534 g ai/ha); ~1x label rate; 

applied to bare soil; 30-, 139- and 280-day PBIs; metabolite levels across all PBIs are reported unless 

otherwise noted.

Hen; 47372532-33; 25.96-26.42 ppm; 14 days dosing; 24-hour PSI. 

Goat; 47372534-35; 44.62-46.26 ppm; 5 days dosing; 24-hour PSI. For milk, results represent morning and 

evening samples for PH study, and evening samples only for PY study.

CF3

N

S

O

HO

O

H3C
Fluopyram Human Health Risk Assessment DP No. D385636

Page 94 of 105

Appendix C. Physical/Chemical Properties

Table C1. Physicochemical Properties of Fluopyram.

Parameter Value Reference

Melting point 118 oC MRID 47372240

pH 6.6 (1% aqueous solution; pure substance) MRID 47372236

Density 1.53 MRID 47372242

Water solubility (20 °C) Distilled water (pH 6.7) = 16 mg/L

pH 4 = 15 mg/L

pH 7 = 16 mg/L

pH 9 = 15 mg/L

MRID 47372247

Solvent solubility (g/L at 20 °C) heptane 0.66

toluene 62.2

dichloromethane >250

methanol >250

acetone >250

ethyl acetate >250

dimethyl sulfoxide >250

MRID 47372248

Vapor pressure 1.2 x 10-6 Pa at 20 oC

3.1 x 10-6 Pa at 25 oC

2.9 x 10-4 Pa at 50 oC

MRID 47372249

Dissociation constant (pKa) 0.5 (23 oC) MRID 47372243

Octanol/water partition coefficient 

Log(KOW)

3.3 MRID 47372245

UV/visible absorption spectrum Peak max at 270 nm MRID 47372237
Fluopyram Human Health Risk Assessment DP No. D385636

Page 95 of 105

Appendix D. Review of Human Research

This risk assessment relies in part on data from studies in which adult human subjects were 

intentionally exposed to a pesticide 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, ORETF and AHETF. EPA has reviewed all the 

studies supporting these multi-pesticide generic exposure databases, and has found no clear and 

convincing evidence that the conduct of any of them was either fundamentally unethical or 

significantly deficient relative to the ethical standards prevailing at the time the research was 

conducted. All applicable requirements of EPA’s Rule for the Protection of Human Subjects of 

Research (40 CFR Part 26) have been satisfied, and there is no regulatory barrier to continued 

reliance on these studies.
Fluopyram Human Health Risk Assessment DP No. D385636

Page 96 of 105

Appendix E. Occupational Exposure/Risk Summary Tables

Table E1. Non-Cancer Occupational Short- and Intermediate-Term Dermal and Inhalation Exposures and Risk Estimates For Fluopyram

Exposure Scenario Crop or Target

Application

Ratea

(lb ai/A)

Area 

Treated 

Dailyb

(A/day) 

Unit Exposured Daily Exposuree(mg/kg/day) MOEf

Baseline 

Dermalc

(mg/lb ai)

PPE-G 

Dermalc

(mg/lb ai)

Baseline 

Inhalationc

(μg/lb ai)

Baseline 

Dermal

PPE-G 

Dermal

Baseline 

Inhalation

Baseline 

Dermal

PPE-G 

Dermal

Baseline 

Inhalation

Mixer/Loader

Mixing/Loading Liquid 

Concentrates for Aerial 

Applications

Peanut, Strawberry, Tree 

Nuts 0.22

350 0.22 0.0376 0.219

0.242 0.0414 0.000241 1,200 7,300 60,000

Dried Beans 0.13 0.143 0.0244 0.000142 2,100 12,000 100,000

Cherry, Potato 0.092 0.101 0.0173 0.000101 3,000 17,000 140,000

Mixing/Loading Liquid 

Concentrates for 

Chemigation Applications

Apples, Peanut, 

Strawberry, Tree Nuts, 

Watermelon (field and 

greenhouse), Viniferous 

variety Grapes

0.22

350 0.22 0.0376 0.219

0.242 0.0414 0.000241 1,200 7,300 60,000

Potato 0.18 0.198 0.338 0.000197 1,500 8,900 74,000

Dried Beans 0.13 0.143 0.0244 0.000142 2,100 12,000 100,000

Sugar Beet 0.11 0.121 0.0207 0.000120 2,500 15,000 120,000

Cherry 0.092 0.101 0.0173 0.000101 3,000 17,000 140,000

Mixing/Loading Liquids 

Concentrates for 

Groundboom Applications

Apples, Peanut, 

Strawberry, Tree Nuts, 

Watermelon (field and 

greenhouse), Viniferous 

variety Grapes

0.22

80 0.22 0.0376 0.219

0.0553 0.00945 0.0000551 5,400 32,000 260,000

Potato 0.18 0.0452 0.00773 0.0000451 6,600 39,000 320,000

Dried Beans 0.13 0.0327 0.00559 0.0000325 9,200 54,000 450,000

Sugar Beet 0.11 0.0277 0.00473 0.0000275 11,000 63,000 530,000

Cherry 0.092 0.0231 0.00395 0.0000230 13,000 76,000 630,000

Mixing/Loading Liquids 

Concentrates for Airblast 

Applications

Apples, Tree Nuts, 

Viniferous variety Grapes 0.22 40 0.22 0.0376 0.219 0.0277 0.00473 0.0000275 11,000 63,000 530,000

Cherry 0.092 0.0116 0.00198 0.0000115 26,000 150,000 1,300,000

Applicator

Applying Sprays via Aerial 

Equipment

Peanut, Strawberry, Tree 

Nuts 0.22

350 0.005 No Data 0.068

0.00550 No Data 0.0000748 55,000 No Data 190,000

Dried Beans 0.13 0.00325 No Data 0.0000442 92,000 No Data 190,000

Cherry, Potato 0.092 0.00230 No Data 0.0000313 130,000 No Data 190,000

Applying Sprays via 

Groundboom Equipment

Apples, Peanut, 

Strawberry, Tree Nuts, 

Watermelon (field and 

greenhouse), Viniferous 

variety Grapes

0.22

80 0.0786 0.0161 0.34

0.0198 0.00405 0.0000855 15,000 74,000 170,000

Potato 0.18 0.0162 0.00331 0.0000699 19,000 91,000 210,000

Dried Beans 0.13 0.0117 0.00239 0.0000505 26,000 130,000 290,000

Sugar Beet 0.11 0.00988 0.00202 0.0000427 30,000 150,000 340,000

Cherry 0.092 0.00826 0.00169 0.0000357 36,000 180,000 410,000
Fluopyram Human Health Risk Assessment DP No. D385636

Page 97 of 105

Table E1. Non-Cancer Occupational Short- and Intermediate-Term Dermal and Inhalation Exposures and Risk Estimates For Fluopyram

Exposure Scenario Crop or Target

Application

Ratea

(lb ai/A)

Area 

Treated 

Dailyb

(A/day) 

Unit Exposured Daily Exposuree(mg/kg/day) MOEf

Baseline 

Dermalc

(mg/lb ai)

PPE-G 

Dermalc

(mg/lb ai)

Baseline 

Inhalationc

(μg/lb ai)

Baseline 

Dermal

PPE-G 

Dermal

Baseline 

Inhalation

Baseline 

Dermal

PPE-G 

Dermal

Baseline 

Inhalation

Applying Sprays via 

Airblast Equipment

Apples, Tree Nuts, 

Viniferous variety Grapes 0.22 40 0.36 0.24 4.5 0.0453 0.0302 0.000566 6,600 9,900 26,000

Cherry 0.092 0.0189 0.0126 0.000237 16,00 24,000 61,000

Flagger

Flagging for Aerial Sprays 

Applications

Peanut, Strawberry, Tree 

Nuts 0.22

350 0.011 NA 0.35

0.0121 NA 0.000385 25,000 NA 38,000

Dried Beans 0.13 0.00715 NA 0.000228 42,000 NA 64,000

Cherry, Potato 0.092 0.00506 NA 0.000161 59,000 NA 90,000

Mixer/Loader/Applicator

Mixing/Loading/Applying 

Liquid Concentrates with 

Low Pressure Hand wand

Greenhouse Only: 

Strawberries & 

Watermelon

0.22 5 100 0.43 30 1.57 0.00676 0.000471 190 44,000 31,000

Mixing/Loading/Applying 

Liquid Concentrates with 

High Pressure Hand wand

Greenhouse Only: 

Strawberries & 

Watermelon

0.22 5 3.5 2.5 0.12 0.0550 0.0393 0.00189 5,500 7,600 7,700

Mixing/Loading/Applying 

Liquid Concentrates with a 

Backpack

Greenhouse Only: 

Strawberries & 

Watermelon

0.22 5 2.51 2.5 30 0.0394 0.0393 0.000471 7,600 7,600 31,000

a. Application Rates are based on proposed uses from the fluopyram labels (Fluopyram 500 SC).

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.

Engineering control unit exposure for applying sprays via aerial equipment = enclosed cockpit. 

d. Unit Exposures are based on PHED Version 1.1. 

e. Daily Exposure (mg/kg/day) = Application Rate (lb ai/A) * Unit Exposure (mg/lb ai) * Area Treated or Amount Applied (acre/day) / 70 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. D385636

Page 98 of 105

Table E2. Occupational Handler Estimated Cancer Risks for Private Growers.

Exposure Scenario Crop or Target

Application

Ratea

(lb ai/A)

Area 

Treated 

Dailyb

(acres/day) 

Unit Exposured Average Daily Dosee(mg/kg/day) LADD f(mg/kg/day) Cancer Riskg

Baseline 

Dermalc

(mg/lb ai)

PPE-G 

Dermalc

(mg/lb ai)

Baseline 

Inhalationc

(μg/lb ai)

Baseline 

Dermal

PPE-G 

Dermal

Baseline 

Inhalation

Baseline 

Dermal

PPE-G 

Dermal

Baseline 

Inhalation

Baseline 

Dermal + 

Inhalation

PPE-G 

Dermal + 

Inhalation

Mixer/Loader

Mixing/Loading 

Liquid Concentrates 

for Aerial 

Applications

Peanut, Strawberry, 

Tree Nuts 0.22

350 0.22 0.0376 0.219

4.60E-3 7.87E-4 2.41E-4 6.30E-5 1.08E-5 3.30E-6 1.1E-6 2.2E-7

Dried Beans 0.13 2.72E-3 4.64E-4 1.42E-4 3.72E-5 6.35E-6 1.95E-6 6.1E-7 1.3E-7

Cherry, Potato 0.092 1.92E-3 3.29E-4 1.01E-4 2.63E-5 4.50E-6 1.38E-6 4.3E-7 9.1E-8

Mixing/Loading 

Liquid Concentrates 

for Chemigation 

Applications

Apples, Peanut, 

Strawberry, Tree 

Nuts, Watermelon

(field and 

greenhouse),

Viniferous variety 

Grapes

0.22

350 0.22 0.0376 0.219

4.60E-3 7.87E-4 2.41E-4 6.30E-5 1.08E-5 3.30E-6 1.1E-6 2.2E-7

Potato 0.18 3.76E-3 6.42E-4 1.97E-4 5.15E-5 8.80E-6 2.70E-6 8.4E-7 1.8E-7

Dried Beans 0.13 2.72E-3 4.64E-4 1.42E-4 3.72E-5 6.35E-6 1.95E-6 6.1E-7 1.3E-7

Sugar Beet 0.11 2.30E-3 3.93E-4 1.20E-4 3.15E-5 5.39E-6 1.64E-6 5.1E-7 1.1E-7

Cherry 0.092 1.92E-3 3.29E-4 1.01E-4 2.63E-5 4.50E-6 1.38E-6 4.3E-7 9.1E-8

Mixing/Loading 

Liquids 

Concentrates for 

Groundboom 

Applications

Apples, Peanut, 

Strawberry, Tree 

Nuts, Watermelon

(field and 

greenhouse),

Viniferous variety 

Grapes

0.22

80 0.22 0.0376 0.219

1.05E-3 1.80E-4 5.51E-5 1.44E-5 2.46E-6 7.55E-7 2.3E-7 5.0E-8

Potato 0.18 8.59E-4 1.47E-4 4.51E-5 1.18E-5 2.01E-6 6.18E-7 1.9E-7 4.1E-8

Dried Beans 0.13 6.21E-4 1.06E-4 3.25E-5 8.51E-6 1.45E-6 4.45E-7 1.4E-7 2.9E-8

Sugar Beet 0.11 5.26E-4 8.99E-5 2.75E-5 7.21E-6 1.23E-6 3.77E-7 1.2E-7 2.5E-8

Cherry 0.092 4.39E-4 7.51E-5 2.30E-5 6.01E-6 1.03E-6 3.15E-7 9.8E-8 2.1E-8

Mixing/Loading 

Liquids 

Concentrates for 

Airblast 

Applications

Apples, Tree Nuts, 

Viniferous variety 

Grapes

0.22

40 0.22 0.0376 0.219

5.26E-4 8.99E-5 2.75E-5 7.21E-6 1.23E-6 3.77E-7 1.2E-7 2.5E-8

Cherry 0.092 2.20E-4 3.76E-5 1.15E-5 3.02E-6 5.15E-7 1.58E-7 4.9E-8 1.0E-8

Applicator

Applying Sprays via 

Aerial Equipment

Peanut, Strawberry, 

Tree Nuts 0.22

350

0.005 

(Eng. 

Control)

No Data

0.068 

(Eng. 

Control)

1.04E-4

(Eng. 

Control)

No Data

0.0000748

(Eng. 

Control)

1.43E-6

No 

Data 1.02E-6 3.8E-8 No Data

Dried Beans 0.13 6.18E-5 No Data 0.0000442 8.46E-7

No 

Data 5.75E-7 2.2E-8 No Data

Cherry, Potato 0.092 4.37E-5 No Data 0.0000313 5.99E-7

No 

Data 4.29E-7 1.6E-8 No Data

Applying Sprays via 

Groundboom 

Apples, Peanut, 

Strawberry, Tree 0.22 80 0.0786 0.0161 0.34 3.76E-4 7.70E-5 0.0000855 5.15E-6 1.05E-6 1.17E-6 9.8E-8 3.4E-8
Fluopyram Human Health Risk Assessment DP No. D385636

Page 99 of 105

Table E2. Occupational Handler Estimated Cancer Risks for Private Growers.

Exposure Scenario Crop or Target

Application

Ratea

(lb ai/A)

Area 

Treated 

Dailyb

(acres/day) 

Unit Exposured Average Daily Dosee(mg/kg/day) LADD f(mg/kg/day) Cancer Riskg

Baseline 

Dermalc

(mg/lb ai)

PPE-G 

Dermalc

(mg/lb ai)

Baseline 

Inhalationc

(μg/lb ai)

Baseline 

Dermal

PPE-G 

Dermal

Baseline 

Inhalation

Baseline 

Dermal

PPE-G 

Dermal

Baseline 

Inhalation

Baseline 

Dermal + 

Inhalation

PPE-G 

Dermal + 

Inhalation

Equipment Nuts, Watermelon

(field and 

greenhouse),

Viniferous variety 

Grapes

Potato 0.18 3.08E-4 6.29E-5 6.99E-5 4.22E-6 8.62E-7 9.58E-7 8.0E-8 2.8E-8

Dried Beans 0.13 2.22E-4 4.54E-5 5.05E-5 3.04E-6 6.22E-7 6.92E-7 5.8E-8 2.0E-8

Sugar Beet 0.11 1.88E-4 3.84E-5 4.27E-5 2.57E-6 5.26E-7 5.85E-7 4.9E-8 1.7E-8

Cherry 0.092 1.57E-4 3.21E-5 3.57E-5 2.15E-6 4.40E-7 4.89E-7 4.1E-8 1.4E-8

Applying Sprays via 

Airblast Equipment

Apples, Tree Nuts, 

Viniferous variety 

Grapes

0.22 40 0.36 0.24 4.5 8.61E-4 5.74E-4 5.66E-4 1.18E-5 7.86E-6 7.75E-6 3.0E-7 2.4E-7

Cherry 0.092 3.59E-4 2.39E-4 2.37E-4 4.92E-6 3.28E-6 3.25E-6 1.3E-7 1.0E-7

Flagger

Flagging for Aerial 

Sprays Applications

Peanut, Strawberry, 

Tree Nuts 0.22

350 0.011 NA 0.35

2.30E-4 NA 3.85E-4 3.15E-6 NA 5.27E-6 1.3E-7 NA

Dried Beans 0.13 1.36E-4 NA 2.28E-4 1.86E-6 NA 3.12E-6 7.7E-8 NA

Cherry, Potato 0.092 9.61E-5 NA 1.61E-4 1.32E-6 NA 2.21E-6 5.5E-8 NA

Mixer/Loader/Applicator

Mixing/Loading/ 

Applying Liquid 

Concentrates with 

Low Pressure Hand 

wand

Greenhouse Only: 

Strawberries & 

Watermelon

0.22 5 100 0.43 30 2.98E-2 1.28E-4 4.71E-4 4.09E-4 1.76E-6 6.45E-6 6.4E-6 1.3E-7

Mixing/Loading/ 

Applying Liquid 

Concentrates with 

High Pressure Hand 

wand

Greenhouse Only:

Strawberries & 

Watermelon

0.22 5 3.5 2.5 120 1.05E-3 7.47E-4 1.89E-3 1.43E-5 1.02E-5 2.59E-5 6.2E-7 5.6E-7

Mixing/Loading/ 

Applying Liquid 

Concentrates with a 

Backpack

Greenhouse Only: 

Strawberries & 

Watermelon

0.22 5 2.51 2.5 30 7.49E-4 7.47E-4 4.71E-4 1.03E-5 1.02E-5 6.45E-6 2.6E-7 2.6E-7

a. Application Rates are based on proposed uses from the fluopyram labels (Fluopyram 500 SC).

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. Engineering control unit exposure for 

applying sprays via aerial equipment = enclosed cockpit. 

d. Unit Exposures are based on PHED Version 1.1, or AHETF data. 

e. Average Daily Dose (ADD) (mg/kg/day) = Application Rate (lb ai/A) * Unit Exposure (mg/lb ai) * Area Treated or Amount Applied (acre/day) * Absorption Factor (1.9% dermal, 100% inhalation)/ 

70 kg.

f. Lifetime Average Daily Dose (LADD) = ADD (mg/kg/day) x (10 days per year treated by Private Growers / 365 days per year) x (35 years working duration / 70 years per lifetime).

g. Cancer Risk = Q1* (1.55E-2 (mg/kg/day)-1) x LADD mg/kg/day).
Fluopyram Human Health Risk Assessment DP No. D385636

Page 100 of 105

Table E3. Occupational Handler Estimated Cancer Risks for Commercial Applicators.

Exposure Scenario Crop or Target

Application 

Ratea

(lb ai/A)

Area 

Treated 

Dailyb

(acres/day) 

Unit Exposured Average Daily Dosee(mg/kg/day) LADD f(mg/kg/day) Cancer Riskg

Baseline 

Dermalc

(mg/lb ai)

PPE-G 

Dermalc

(mg/lb ai)

Baseline 

Inhalationc

(μg/lb ai)

Baseline 

Dermal

PPE-G 

Dermal

Baseline 

Inhalation

Baseline 

Dermal

PPE-G 

Dermal

Baseline 

Inhalation

Baseline 

Dermal + 

Inhalation

PPE-G 

Dermal + 

Inhalation

Mixer/Loader

Mixing/Loading 

Liquid Concentrates 

for Aerial 

Applications

Peanut, Strawberry, 

Tree Nuts 0.22

350 0.22 0.0376 0.219

4.60E-3 7.87E-4 2.41E-4 1.89E-4 3.23E-5 9.90E-6 3.1E-6 6.5E-7

Dried Beans 0.13 2.72E-3 4.64E-4 1.42E-4 1.12E-4 1.91E-5 5.84E-6 1.8E-6 3.9E-7

Cherry, Potato 0.092 1.92E-3 3.29E-4 1.01E-4 7.89E-5 1.35E-5 4.15E-6 1.3E-6 2.7E-7

Mixing/Loading 

Liquid Concentrates 

for Chemigation 

Applications

Apples, Peanut, 

Strawberry, Tree 

Nuts, Watermelon

(field and 

greenhouse), 

Viniferous variety 

Grapes,

0.22

350 0.22 0.0376 0.219

4.60E-3 7.87E-4 2.41E-4 1.89E-4 3.23E-5 9.90E-6 3.1E-6 6.5E-7

Potato 0.18 3.76E-3 6.42E-4 1.97E-4 1.55E-4 2.64E-5 8.10E-6 2.5E-6 5.3E-7

Dried Beans 0.13 2.72E-3 4.64E-4 1.42E-4 1.12E-4 1.91E-5 5.84E-6 1.8E-6 3.9E-7

Sugar Beet 0.11 2.30E-3 3.93E-4 1.20E-4 9.45E-5 1.62E-5 4.93E-6 1.5E-6 3.3E-7

Cherry 0.092 1.92E-3 3.29E-4 1.01E-4 7.89E-5 1.35E-5 4.15E-6 1.3E-6 2.7E-7

Mixing/Loading 

Liquids 

Concentrates for 

Groundboom 

Applications

Apples, Peanut, 

Strawberry, Tree 

Nuts, Watermelon

(field and 

greenhouse), 

Viniferous variety 

Grapes,

0.22

80 0.22 0.0376 0.219

1.05E-3 1.8E-4 5.51E-5 4.32E-5 7.38E-6 2.26E-6 7.1E-7 1.5E-7

Potato 0.18 8.59E-4 1.47E-4 4.51E-5 3.53E-5 6.04E-6 1.85E-6 5.8E-7 1.2E-7

Dried Beans 0.13 6.21E-4 1.06E-4 3.25E-5 2.55E-5 4.36E-6 1.34E-6 4.2E-7 8.8E-8

Sugar Beet 0.11 5.26E-4 8.99E-5 2.75E-5 2.16E-5 3.69E-6 1.13E-6 3.5E-7 7.5E-8

Cherry, Stone Fruit 0.092 4.39E-4 7.51E-5 2.30E-5 1.80E-5 3.08E-6 9.45E-7 2.9E-7 6.2E-8

Mixing/Loading 

Liquids 

Concentrates for 

Airblast 

Applications

Apples, Tree Nuts, 

Viniferous variety 

Grapes

0.22

40 0.22 0.0376 0.219

5.26E-4 8.99E-5 2.75E-5 2.16E-5 3.69E-6 1.13E-6 3.5E-7 7.5E-8

Cherry 0.092 2.20E-4 3.76E-5 1.15E-5 9.06E-6 1.55E-6 4.73E-7 1.5E-7 3.1E-8

Applicator

Applying Sprays via 

Aerial Equipment

Peanut, Strawberry, 

Tree Nuts 0.22

350

0.005 

(Eng. 

Control)

No Data

0.068 

(Eng. 

Control)

1.05E-4

(Eng. 

Control)

No Data

7.48E-5

(Eng. 

Control)

4.29E-6

No 

Data 3.07E-6 1.1E-7 No Data

Dried Beans 0.13 6.18E-5 No Data 4.42E-5 2.54E-6

No 

Data 1.82E-6 6.8E-8 No Data

Cherry, Potato 0.092 4.37E-5 No Data 3.13E-5 1.80E-6

No 

Data 1.29E-6 4.8E-8 No Data

Applying Sprays via 

Groundboom 

Equipment

Apples, Peanut, 

Strawberry, Tree 

Nuts, Watermelon

0.22 80 0.0786 0.0161 0.34 3.76E-4 7.70E-5 8.55E-5 1.55E-5 3.16E-6 3.51E-6 2.9E-7 1.0E-7
Fluopyram Human Health Risk Assessment DP No. D385636

Page 101 of 105

Table E3. Occupational Handler Estimated Cancer Risks for Commercial Applicators.

Exposure Scenario Crop or Target

Application 

Ratea

(lb ai/A)

Area 

Treated 

Dailyb

(acres/day) 

Unit Exposured Average Daily Dosee(mg/kg/day) LADD f(mg/kg/day) Cancer Riskg

Baseline 

Dermalc

(mg/lb ai)

PPE-G 

Dermalc

(mg/lb ai)

Baseline 

Inhalationc

(μg/lb ai)

Baseline 

Dermal

PPE-G 

Dermal

Baseline 

Inhalation

Baseline 

Dermal

PPE-G 

Dermal

Baseline 

Inhalation

Baseline 

Dermal + 

Inhalation

PPE-G 

Dermal + 

Inhalation

(field and 

greenhouse), 

Viniferous variety 

Grapes,

Potato 0.18 3.08E-4 6.29E-5 6.99E-5 1.26E-5 2.58E-6 2.87E-6 2.4E-7 8.5E-8

Dried Beans 0.13 2.22E-4 4.54E-5 5.05E-5 9.14E-6 1.87E-6 2.08E-6 1.7E-7 6.1E-8

Sugar Beet 0.11 1.88E-4 3.84E-5 4.27E-5 7.71E-6 1.58E-6 1.75E-6 1.5E-7 5.2E-8

Cherry 0.092 1.57E-4 3.21E-5 3.57E-5 6.45E-6 1.32E-6 1.47E-6 1.2E-7 4.3E-8

Applying Sprays via 

Airblast Equipment

Apples, Tree Nuts, 

Viniferous variety 

Grapes

0.22 40 0.36 0.24 4.5 8.61E-4 5.74E-4 5.66E-4 3.54E-5 2.36E-5 2.33E-5 9.1E-7 7.3E-7

Cherry 0.092 40 0.36 0.24 4.5 3.59E-4 2.39E-4 2.37E-4 1.48E-5 9.84E-6 9.74E-6 3.8E-7 3.0E-7

Flagger

Flagging for Aerial 

Sprays Applications

Peanut, Strawberry, 

Tree Nuts 0.22

350 0.011 NA 0.35

2.30E-4 NA 3.85E-4 9.45E-6 NA 1.58E-5 3.9E-7 NA

Dried Beans 0.13 1.36E-4 NA 2.28E-4 5.58E-6 NA 9.34E-6 2.3E-7 NA

Cherry, Potato 0.092 9.61E-5 NA 1.61E-4 3.95E-6 NA 6.62E-6 1.6E-7 NA

Mixer/Loader/Applicator

Mixing/Loading/ 

Applying Liquid 

Concentrates with 

Low Pressure Hand 

wand

Greenhouse Only: 

Strawberries & 

Watermelon

0.22 5 100 0.43 30 2.98E-2 1.28E-4 4.71E-4 1.23E-3 5.28E-6 1.94E-5 1.9E-5 3.8E-7

Mixing/Loading/ 

Applying Liquid 

Concentrates with 

High Pressure Hand 

wand

Greenhouse Only: 

Strawberries & 

Watermelon

0.22 5 3.5 2.5 120 1.05E-3 7.47E-4 1.89E-3 4.29E-5 3.07 2.59E-5 1.1E-6 8.8E-7

Mixing/Loading/ 

Applying Liquid 

Concentrates with a 

Backpack

Greenhouse Only: 

Strawberries & 

Watermelon

0.22 5 2.51 2.5 30 7.49E-4 7.47E-4 4.71E-4 3.08E-5 3.07E-5 1.94E-5 7.8E-7 7.8E-7

a. Application Rates are based on proposed uses from the fluopyram labels (Fluopyram 500 SC).

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. Engineering control unit exposure for 

applying sprays via aerial equipment = enclosed cockpit. 

d. Unit Exposures are based on PHED Version 1.1, or AHETF data.

e. Average Daily Dose (ADD) (mg/kg/day) = Application Rate (lb ai/A) * Unit Exposure (mg/lb ai) * Area Treated or Amount Applied (acre/day) * Absorption Factor (1.9% dermal, 100% inhalation)/ 

70 kg.

f. Lifetime Average Daily Dose (LADD) = ADD (mg/kg/day) x (30 days per year treated by Commercial Growers / 365 days per year) x (35 years working duration / 70 years per lifetime).

g. Cancer Risk = Q1* (1.55E-2 (mg/kg/day)-1) x Dermal LADD mg/kg/day).
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Table E.4. Summary of Occupational Non-Cancer Postapplication Risks (Short- and 

Intermediate-Term) with HED Default Assumptions.

Crop 

Grouping

Application 

rate

(lb ai/acre)

Default DFR 

on 0 days (12 

hrs) after 

applicationa

(μg/cm2)

Work Activity & 

Maximum Transfer 

Coefficientb(cm2/hr)

Daily Dosec

(mg/kg/day)

MOEd

(LOC = 100)

Apples 0.22 0.493 3,600 - Thinning 0.203 1,500

Cherry 0.092 0.206 3,600 - Thinning 0.0848 3,500

Dried Beans 0.13 0.292 1,900 - Irrigation 0.0634 4,700

Peanuts 0.22 0.493 1,900 - Irrigation 0.107 2,800

Potatoes 0.18 0.404 1,900 - Irrigation 0.0877 3,400

Strawberries 0.22 0.493 1,100 – Hand Harvest 0.0620 4,800

Sugar Beets 0.11 0.247 1,900 - Irrigation 0.0536 5,600

Tree Nuts 0.22 0.493 3,600 - Thinning 0.203 1,500

Watermelon 0.22 0.493 1,900 - Irrigation 0.107 2,800

Viniferous variety

Grapes 0.22 0.493 10,100 - Harvest (hand), Training, Tying, Leaf Pulling 0.569 530

a. Default DFR (μg/cm2) = application rate (lb ai/A) x (1- daily dissipation rate) tx 4.54E+8 μg/lb x 24.7E-9 A/cm2x 

20% 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 (70 kg)

d. MOE = NOAEL (300 mg/kg/day) / Daily Dose (mg/kg/day)
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Table E5. Summary of Occupational Postapplication Cancer Risks with HED Default Assumptions.

Crop Grouping

Average DFR 

after applicationa

(μg/cm2)

Work Activity & 

Maximum Transfer Coefficientb

(cm2/hr)

Dermal Average 

Daily Dosec

(mg/kg/day)

Dermal LADDd

(mg/kg/day)

Cancer Riske

Apples 0.351 3,600 - Thinning 2.74E-3 1.13E-4 1.7E-6

Cherry 0.161 3,600 - Thinning 1.26E-3 5.18E-5 8.0E-7

Dried Beans 0.208 1,900 - Irrigation 8.59E-4 3.53E-5 5.5E-7

Peanuts 0.261 1,900 - Irrigation 1.08E-3 4.44E-5 6.9E-7

Potatoes 0.315 1,900 - Irrigation 1.30E-3 5.34E-5 8.3E-7

Strawberries 0.385 1,100 - Hand Harvest 9.20E-4 3.78E-5 5.9E-7

Sugar Beets 0.193 1,900 - Irrigation 7.96E-4 3.27E-5 5.1E-7

Tree Nuts 0.351 3,600 - Thinning 2.74E-3 1.13E-4 1.7E-6

Watermelon 0.385 1,900 - Irrigation 1.59E-3 6.53E-5 1.0E-6

Viniferous variety Grapes 0.283 10,100 - Harvest (hand), Training, Tying, Leaf 

Pulling 6.21E-3 2.55E-4 4.0E-6

a. Average DFR residue averaged over the shortest number of re-treatment days for each crop or crop group (μg/cm2).

b. Crops were assessed using the highest transfer coefficient (TC) available.

c. Dermal Average Daily Dose (ADD) = Average DFR x TC x (1 mg/1000 μg) x ET (8 hr/day) x Dermal Absorption Factor (1.9%)/ body weight (70 kg).

d. Dermal Lifetime Average Daily Dose (LADD) = Dermal ADD (mg/kg/day) x (30 days per year treated / 365 days per year) x (35 years working duration / 70 years per 

lifetime).

e. Cancer Risk = Q1* (1.55E-2 (mg/kg/day)-1) x Dermal LADD mg/kg/day).
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Appendix F. International Residue Limit Status Sheet

Summary of US and International Tolerances and Maximum Residue Limits 

Residue Definition:

US Canada Mexico2 Codex3

40 CFR 180.XXX:

Plants: fluopyram (N-[2-[3-chloro-5-

(trifluoromethyl)-2-pyridinyl]ethyl]-2-

(trifluoromethyl)benzamide).

Livestock: sum of fluopyram (N-[2-[3-

chloro-5-(trifluoromethyl)-2-pyridinyl]ethyl]-

2-(trifluoromethyl)benzamide) and its 

benzamide metabolite [2-(trifluoromethyl)-

benzamide], calculated as the stoichiometric 

equivalent of fluopyram

Identical 

to US

Plants: fluopyram.

Animal commodities: Sum of fluopyram 

and 2-(trifluoromethyl)benzamide, 

expressed as fluopyram.

Commodity1 Tolerance (ppm) /Maximum Residue Limit (mg/kg)

US Canada Mexico2 Codex3

Almond hull 8.0

Apple 0.30

Apple wet pomace 0.60

Banana (import) 1.0

Bean, dry 0.09

Cherry 0.60

Nut, tree, group 14 0.05

Peanut 0.02

Pistachio 0.05

Potato 0.02

Potato processed waste 0.08

Strawberry 1.5

Sugar beet 0.04

Watermelon 1.0

Wine Grapes 2.0 5 Dried grapes (=currants, raisins and 

sultanas) ; 2 Grapes (proposed)

Alfalfa forage 0.45

Alfalfa hay 1.1

Canola 1.8

Cotton gin byproducts 0.05

Cotton undelinted seed 0.01

Grain, cereal, group 15, except rice 1.5

Grain, cereal, forage, fodder and 

straw, group 15, except rice; forage 4.0

Grain, cereal, forage, fodder and 

straw, group 15, except rice; hay, 

straw and stover

7.0

Soybean forage 4.0

Soybean hay 15

Soybean seed 0.10
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Summary of US and International Tolerances and Maximum Residue Limits 

Residue Definition:

US Canada Mexico2 Codex3

Cattle, fat 0.11

Cattle, meat 0.15 0.1 Meat (from mammals other than 

marine mammals)

Cattle, meat byproducts 1.1 0.7 Edible offal (mammalian)

Cattle, liver

Eggs 0.25

Goat, fat 0.11

Goat, meat 0.15

Goat, meat byproducts 1.1

Hog, fat 0.05

Hog, meat 0.05

Hog, meat byproducts 0.70

Horse, fat 0.11

Horse, meat 0.15

Horse, meat byproducts 1.1

Milk 0.07 Milks 0.07

Poultry, fat 0.20

Poultry, meat 0.15

Poultry, meat byproducts 0.60

Sheep, fat 0.11

Sheep, meat 0.15

Sheep, meat byproducts 1.1

1

Includes only commodities of interest for this action. Tolerance values should be the HED recommendations and 

not those proposed by the applicant.

2 Mexico adopts US tolerances and/or Codex MRLs for its export purposes.

3 * = absent at the limit of quantitation; Po = postharvest treatment, such as treatment of stored grains. PoP = 

processed postharvest treated commodity, such as processing of treated stored wheat. (fat) = to be measured on the 

fat portion of the sample. MRLs indicated as proposed have not been finalized by the CCPR and the CAC.