UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
                            WASHINGTON, D.C.  20460
                                                                      OFFICE OF
                                                            CHEMICAL SAFETY AND
\* MERGEFORMAT
                                                           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)
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
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

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-ethyl-benzamide 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 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 DEEM(TM) default processing factors were used.  Combined dietary exposure from food and drinking water at the 95[th] 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 95[th] 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 DEEM(TM) default processing factors were used.  The surface water estimated drinking water concentration (EDWC) of 4.90 ug/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 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[-8] to 5.6 x 10[-][7] and for commercial workers ranged from 3.1 x 10[-][8] to 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 10[-][7] to 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

*	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 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.

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

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.
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 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(R)) 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

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

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 Limitations[1]
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, chemiga-tion)
                                0.092 (aerial)
                                      NS
                         0.356 (ground, chemiga-tion)
                                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 appli-cation)

                             1 (green-house 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.
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 (green-house uses)

                            7 (drip appli-cations)
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 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 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.

Fluopyram plant metabolites, fluopyram-pyridyl-carboxylic acid and fluopyram methyl-sulfoxide, demonstrated less acute toxic potential than the parent compound.  Mutagenicity tests on these two metabolites were negative.

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.

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 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[-2] in human equivalents.

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

Table <IP_ADDRESS>  Summary of Toxicological Doses and Endpoints for Fluopyram for Use in Dietary and Non-Occupational Human Health Risk Assessments
                              Exposure/ Scenario
                              Point of Departure
                        Uncertainty/FQPA Safety Factors
                RfD, PAD, Level of Concern for Risk Assessment
                        Study and Toxicological Effects
Acute Dietary (General Population, including Infants and Children)
NOAEL= 50 mg/kg/day
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 Intermediate-Term (1-6 months)
NOAEL= 14.5 mg/kg/day
UFA= 10X
UFH=10X
FQPA SF=1X

Residential LOC for MOE = 100
Reproduction study in rats
The LOAEL of 82.8 mg/kg/day is based clinical pathology changes, decreased spleen and thymus weights, increased liver weight and centrilobular hypertrophy in parents, and decreased body weight and body weight gain with decreases in spleen and thymus weights and slight delay in preputial separation in offspring.
Dermal Short-Term (1-30 days) and Intermediate-Term (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 Intermediate-Term (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 <IP_ADDRESS> Summary of Toxicological Doses and Endpoints for Fluopyram for Use in Occupational Human Health Risk Assessments
                              Exposure/ Scenario
                              Point of Departure
                              Uncertainty Factors
                     Level of Concern for Risk Assessment
                        Study and Toxicological Effects
Dermal Short-Term (1-30 days) and Intermediate-Term (1-6 months)
NOAEL= 300 mg/kg/day
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 Intermediate-term (1-6 months)
NOAEL= 14.5 mg/kg/day
UFA=10X
UFH=10X
Occupational LOC for MOE = 100
A 2-generation reproduction study in rats.  The LOAEL of 82.8 mg/kg/day is based clinical pathology changes, increased liver weight, and centrilobular hypertrophy in parents, and decreased body weight and body weight gain with secondary decreases in spleen and thymus weights and secondary slight delay in preputial separation in offspring.
Cancer (oral, dermal, inhalation)
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

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-UL-[14]C]AE C656948			[pyridyl-2,6-[14]C]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-UL-[14]C]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 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-[14]C]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-Z-olefine 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-E-olefine 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 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 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).

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-Glc-MA(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-Glc-MA(M12)
Fluopyram
Fluopyram
(Fluopyram + benzamide for legumes and oil seed crops)
Fluopyram
Livestock
Ruminant
Fluopyram + benzamide + 7-OH-fluopyram + olefins (E, Z)
Fluopyram + benzamide
Fluopyram + benzamide + 7-OH-fluopyram (M08)+ olefins (E, Z) + 7-OH-GA(M09) + 7-OH-GA (M20b)
Fluopyram + benzamide
Fluopyram + benzamide + 7-OH-fluopyram + 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

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 spray (European data)
                                     0.446
                                       1
                                     0.35
                                     0.26
                                     0.79
                                     0.12
                                     0.79
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)
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.
[2]At 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 90[th] 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 studies[c] in 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
                                     0.319
Chronic (non-cancer)
                                     4.90

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

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 ug/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 ug/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 ug/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 13ug/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 95[th] 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 95[th] 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

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 ug/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 ug/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
                              (95[th] 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

 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
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[-6] Pa at 20[o]C), and the low proposed use rate (0.22 lb ai/A).  However, volatilization of pesticides may be a source of post-application inhalation exposure to individuals nearby pesticide applications.  The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP's final report on March 2, 2010 (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 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.

80.2 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.

6.0 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/.

7.0 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 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[-8] to 5.6 x 10[-]7 and for commercial workers ranged from 3.1 x 10[-8] to 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) 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 non-cancer 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 (ug/cm[2]) 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[-][7] to 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[-6] Pa at 20[o]C), 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, 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.
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

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/m[3]

                              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.
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.
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.
870.4300