In an acute neurotoxicity study, transient decreased motor activity was seen only on the day of treatment, but no other findings demonstrating neurotoxicity were found.  In addition, no neurotoxicity was observed in the subchronic neurotoxicity study in the presence of other systemic adverse effects.  Fluopyram did not produce treatment-related effects on the immune system.

With oral dosing, fluopyram was rapidly absorbed from the gastro-intestinal (GI) tract of male and female rats; the percentage absorbed was approximately 93% of the administered dose.  The maximal plasma concentration was reached at 15 hours in males and 11 hours in females post dosing (5 mg/kg).  The absorbed fluopyram was quickly distributed within the central compartments of the body (e.g. blood, liver, and kidney) and showed a distinctive preference towards the liver and to a smaller extent to the kidneys.  The elimination results showed that 53-65% of administered radioactivity was eliminated via feces and 32-41% was eliminated via the urine.  Less than 0.07-0.09% of the administered dose was expired.  After 168 hours 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-glucuronic acid).  Bioaccumulation was not observed.

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

A parallel approach was used to estimate the dermal absorption factor in human skin by using a proportional relationship: rat in vivo/rat in vitro = human in vivo/human in vitro.  The dermal absorption values for human skin were calculated to be 0.2% for the neat formulation and 1.9% for the spray dilution.

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

The FQPA safety factor can be reduced to 1x because (1) the toxicology database is complete, (2) there is no evidence of neurotoxicity, (3) there is no evidence of increased susceptibility in the developing or young animals which were exposed during pre- or post-natal periods, and (4) there are no residual uncertainties in the exposure database.

4.2.1	Completeness of the Toxicology Database

The toxicology database for fluopyram is complete, and the available studies are adequate to characterize potential pre- and/or post-natal risks for infants and children, and includes acceptable developmental toxicity studies in the rat and rabbit, as well as acute and subchronic neurotoxicity studies.  HED waived the required subchronic inhalation study based on a weight of evidence approach (TXR 0056523, 01/20/2013.)

4.2.2	Evidence of Neurotoxicity

The fluopyram toxicology database did not demonstrate evidence of neurotoxicity.  Although transient decreases in motor and locomotor activities in the acute neurotoxicity study were seen on the day of treatment and limited use of hind-limbs and reduced motor activity was seen in the rat chronic/carcinogenicity study, there were no other associated neurobehavioral or histopathology changes found in other studies in the fluopyram toxicity database.  The effects seen in the chronic/carcinogenicity study were in the presence of increased mortality and morbidity such as general pallor and emaciated appearance.  Therefore, the reduced motor activity and limited use of hind-limbs seen in these two studies were judged to be the consequence of the systemic effects and not direct neurotoxicity.

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

The available developmental toxicity studies in rats and rabbits and the multi-generation reproduction in rats demonstrate no evidence of increased susceptibility in the developing or young animals which were exposed during pre- or post-natal periods.

4.2.4	Residual Uncertainty in the Exposure Database

There are no residual uncertainties in the exposure database.  The acute dietary exposure assessment was performed using conservative exposure inputs, including tolerance level residues for all crops, whereas the chronic dietary assessment included average field trial residue levels for all crops.  Both acute and chronic dietary assessments assumed 100% crop treated and incorporated empirical or default processing factors.  The dietary exposure assessment also assumed that all drinking water will contain fluopyram at the highest EDWC levels modeled by EFED for ground or surface water.  Therefore, it can be concluded that the dietary exposure analysis does not underestimate risk from acute and chronic dietary exposure to fluopyram.  While there is the potential for handler and post-application residential exposure, the best data and approaches currently available were used in the fluopyram residential assessment.  The Agency used the current conservative approaches for residential assessment, many of which include recent upgrades to the SOPs.  The Agency believes that the calculated risks represent conservative estimates of exposure because maximum application rates are used to define residue levels upon which the calculations are based.  Therefore, residential exposures are unlikely to be under estimated.

4.3	Toxicity Endpoint and Point of Departure Selections

4.3.1	Dose-Response Assessment

For fluopyram, HED has selected the most sensitive and protective endpoints from the database to establish points of departure for the risk assessment (Table <IP_ADDRESS>).  For acute oral exposure, an acute neurotoxicity study in rats has been used to select the dose (50 mg/kg) and endpoint for establishing the aRfD (0.5 mg/kg/day) for the general population.  The lowest observable adverse effect level (LOAEL) of 100 mg/kg is based on decreased motor and locomotor activity in females, an effect attributable to general toxicity.  For chronic dietary exposure, a combined chronic/carcinogenicity study in rats was used to select the dose (NOAEL=1.2 mg/kg/day) and endpoint for establishing the chronic reference dose (cRfD; 0.012 mg/kg/day).  The toxicity endpoint was based on follicular cell hypertrophy in the thyroid and increased liver weight with liver gross pathological and histopathological findings at 6.0 mg/kg/day.  The point of departure derived from this study is protective of the adverse thyroid effects observed in the mouse carcinogenicity study seen at 105 mg/kg/day.  A 2-generation reproduction study in rats was used to select the dose (NOAEL = 14.5 mg/kg/day) and endpoint for short-term incidental oral exposures.  The LOAEL of 82.8 mg/kg/day was based on clinical chemistry changes, increased kidney weight in parents, and decreased body weight with secondary decreases in spleen and thymus weights in the 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 (↑ prothrombin time and altered cholesterol levels) for short-and intermediate term dermal exposure.

4.3.2	Recommendation for Combining Routes of Exposures for Risk Assessment

Since the inhalation point of departure is based on an oral study, oral exposures can be combined with inhalation exposures.  Common toxicological effects were not observed at the LOAELs of studies selected for the assessment of short- and intermediate-term exposures by the dermal and inhalation routes; prothrombin time and altered cholesterol levels were the dermal endpoint whereas the inhalation endpoint was based on kidney, spleen and thymus effects accompanied by clinical chemistry and body weight changes.  Therefore, it is not appropriate to combine these routes of exposure for risk assessment.

4.3.3	Cancer Classification and Risk Assessment Recommendation

The CARC classified fluopyram as "Not Likely to be Carcinogenic to Humans" at doses that do not induce cellular proliferation in the liver or thyroid glands.  This classification was based on convincing evidence that non-genotoxic modes of action for liver tumors in rats and thyroid tumors in mice have been established and that the carcinogenic effects have been demonstrated as a result of a mode of action dependent on activation of the CAR/PXR receptors (CARC Report, May 8, 2014).

The CARC has determined that quantification of risk is not required.  There is sufficient data to ascertain the mode of action of fluopyram.  The chronic Reference Dose (RfD) is derived using the NOAEL of 1.2 mg/kg/day as the "point of departure" which is below the dose of 11 mg/kg/day that caused cell proliferation in the liver (i.e., a key event in tumor formation) and the subsequent liver tumors at a higher dose (89 mg/kg/day).  Additionally, there is no concern for mutagenicity.

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

Table <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 chemistry changes and increased kidney weight in parents, and decreased body weight and body weight gain with decreases in spleen and thymus weights 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).
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 chemistry changes and increased kidney weight in parents, and decreased body weight and body weight gain with decreases in spleen and thymus weights in offspring.
Cancer (oral, dermal, inhalation)
The CARC has classified fluopyram as "Not Likely to be Carcinogenic to Humans" at doses that do not induce cellular proliferation in the liver or thyroid glands and determined that quantification of cancer risk is not required.
Point of Departure (POD) = A data point or an estimated point that is derived from observed dose-response data and  used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures.  NOAEL = no observed adverse effect level.  LOAEL = lowest observed adverse effect level.  UF = uncertainty factor.  UFA = extrapolation from animal to human (interspecies).  UFH = potential variation in sensitivity among members of the human population (intraspecies).  FQPA SF = FQPA Safety Factor.  PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose.  MOE = margin of exposure.  LOC = level of concern.

Table <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).
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 chemistry changes and increased kidney weight in parents, and decreased body weight and body weight gain with decreases in spleen and thymus weights in offspring
Cancer (oral, dermal, inhalation)
The CARC has classified fluopyram as "Not Likely to be Carcinogenic to Humans" at doses that do not induce cellular proliferation in the liver or thyroid glands and has determined that quantification of cancer risk is not required.
Point of Departure (POD) = A data point or an estimated point that is derived from observed dose-response data and  used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures.  NOAEL = no observed adverse effect level.  LOAEL = lowest observed adverse effect level.  UF = uncertainty factor.  UFA = extrapolation from animal to human (interspecies).  UFH = potential variation in sensitivity among members of the human population (intraspecies).  MOE = margin of exposure.  LOC = level of concern.  N/A = not applicable.

5.0	Dietary Exposure and Risk Assessment

5.1	Residues of Concern Summary and Rationale

The nature of the residue in plants is adequately understood based on metabolism studies with grape, potato, bean, and red pepper (D387587, L. Cheng, 02/23/2011) and with wheat seed treatment (D420271, S. Funk, 05/20/2014).  The nature of the residue in rotational crops is adequately understood based on confined rotational crop studies with rotated Swiss chard, turnip, and wheat.  The metabolic pathway of fluopyram is similar in primary and rotational crops, and mainly involves hydroxylation of parent compound leading to AE C656948-7-hydroxy and AE C656948-8-hydroxy, conjugation of the hydroxylated parent compound, mainly with sugars, and cleavage of the molecule leading to AE C656948-benzamide, AE C656948-pyridyl-acetic acid (AE C656948-PAA), and AE C656948-pyridyl-carboxylic acid (AE C656948-PCA).  HED has determined that the residue of concern in plant commodities (primary and rotational crop) for tolerance enforcement is fluopyram, and for risk assessment is fluopyram in all crops except in legumes and oilseed crops where AE C656948-benzamide is also included.

The nature of the residue in livestock is adequately understood based on metabolism studies with goats and hens (D387587, L. Cheng, 02/23/2011).  Metabolism of fluopyram in livestock mainly involves hydroxylation of the parent compound to AE C656948-7-hydroxy and AE C656948-8-hydroxy, elimination of water from compounds hydroxylated in the ethylene bridge leading to AE C656948-Z/E-olefines, cleavage of the molecule leading to AE C656948-benzamide and AE C656948-PAA, and conjugation of the hydroxylated parent compound, mainly with glucuronic acid.  For tolerance enforcement, HED has determined that the residues of concern are fluopyram and AE C656948-benzamide.  For risk assessment, the residues of concern in ruminants are fluopyram and its metabolites AE C656948-benzamide, AE C656948-E-olefine, AE C656948-Z-olefine and AE C656948-7-hydroxy, and in hens are fluopyram and its metabolites AE C656948-benzamide, AE C656948-E-olefine, and AE C656948-Z-olefine.

A summary of metabolites and degradates to be included in the risk assessment and tolerance expressions is presented in Table 5.1.

Table 5.1.  Summary of Metabolites and Degradates to be included in the Risk Assessment and Tolerance Expressions.
                                    Matrix
                                Risk Assessment
                             Tolerance Expression
Plants
Primary Crop
Fluopyram
(Fluopyram + benzamide for legumes and oil seed crops)
Fluopyram

Rotational Crop
Fluopyram
(Fluopyram + benzamide for legumes and oil seed crops)
Fluopyram
Livestock
Ruminant
Fluopyram + benzamide + 7-OH-fluopyram + olefins (E, Z)
Fluopyram + benzamide

Poultry
Fluopyram + benzamide + olefins (E, Z)
Fluopyram + benzamide
Drinking Water
Fluopyram
Not Applicable

5.2	Food Residue Profile

The crop field trials are adequate for tolerance assessment and for risk assessment.  Residues were quantifiable in all cases except sweet corn.

The previously reviewed cotton, peanut, and soybean processing study showed no concentration of fluopyram in oil and meal.  The canola and sunflower processing studies showed that fluopyram did not concentrate in meal or   refined oil.  The benzamide metabolite did not concentrate in meal or oil.

Fluopyram residues concentrate on apple wet pomace, corn bran, orange oil, potato wet peel, raisin, dried tomatoes, dried peaches, sugar beet (dried and refined sugar), wheat bran and wheat germ.

Existing storage stability study data are adequate to support the intervals of frozen storage of all raw agricultural and processed commodities from the proposed uses.  No corrections for degradation during storage are needed.

The livestock diets were revised using the recommended crop field trial data.  Exposures increased from 0.38 ppm for beef cattle, 1.2 ppm for dairy cattle, 0.083 ppm for poultry, and 0.082 ppm for swine to 3.58 ppm for beef cattle, 24.8 ppm for dairy cattle, 0.36 ppm for poultry, and 0.39 ppm for swine.

5.3	Water Residue Profile

The drinking water residues used in the dietary risk assessment were provided by the EFED (D427985M, A. Ruhman, 10/26/2015). The residue of concern in drinking water for this single chemical risk assessment is fluopyram, (Residues of Concern Knowledge-base Subcommittee [ROCKS], D367115, 07/16/2009).  The EFED estimated surface water and ground water residues for fluopyram using the surface water concentration calculator (SWCC) and PRZM-GW model, respectively.  The EDWCs includes all new uses and currently registered uses.  The drinking water models and their descriptions are available at the EPA internet site: http://www.epa.gov/oppefed1/models/water/.

For surface water EDWCs, the peak value is 50.6 ppb and the chronic (non-cancer) value is 17.3 ppb.

For ground water, the highest acute ground water EDWC is 97.6 ppb of parent fluopyram and the chronic value is 90.5 ppb of parent fluopyram.  Ground water EDWCs are used in the dietary assessment, since they were higher than those for surface water.  For the human health risk assessment, the highest relevant EDWCs are recommended.

Table 5.3.  Estimated Surface and Ground Water Concentrations for Fluopyram.
Scenario
Surface Water Conc., ppb
Ground Water Conc., ppb
Acute
                                     50.6
                                    97.6[a]
Chronic (non-cancer)
                                     17.3
                                    90.5[a]
Chronic (cancer)
                                     11.0
                                      NA

[a] Bold values were used in the dietary assessment.

5.4	Dietary Risk Assessment

5.4.1	Description of Residue Data Used in Dietary Assessment

The acute dietary analysis is an unrefined conservative assessment that included tolerance residue levels, the assumption of 100% crop treated, and processing factors (empirical and default).  The EDWC was incorporated directly into the acute dietary assessment (ground water EDWC of 97.6 ug/L) and was calculated by PRZM-GW modeling.

The chronic dietary analysis is a refined assessment that included average residue levels, % crop treated, and processing factors (empirical and default).  The EDWC from PRZM-GW modeling was incorporated directly into the chronic dietary assessment (ground water EDWC of 90.5 ug/L).

5.4.2	Percent Crop Treated Used in Dietary Assessment

The acute dietary exposure analysis assumed that 100% of the proposed crops were treated with fluopyram.

The Biological and Economic Analysis Division (BEAD) has provided updated percent crop treated data for new uses (PCTn) for fluopyram (DP# 427397, 09/22/2015), which includes both average and maximum PCT values.  In addition, the previous PCTn (2010 and 2011) were considered acceptable (DP# 370371 (2010); DP# 381225 (2011); DP# 387227 (2011).

The following average percent crop treated estimates were used in the chronic dietary risk assessment for the following crops that are currently registered/proposed for fluopyram:  potatoes 64%; sugar beets 48%; celery 60%; head lettuce 67%; leaf lettuce 62%; spinach 43% (BEAD recommends using USDA/NASS spinach PCT values as a proxy for Brassica leafy
vegetables and leafy vegetables); broccoli 24%; snap beans 44%; dry beans/peas 7%; soybeans 17%; fresh tomatoes 64%; processed tomatoes 57%; cantaloupes 22%; cucumbers 41%; pumpkins 45%; squash 47%; watermelons 54%; oranges 39%; apples 40%; pears 43%; peaches 56%; grape wine 79% (used for grape, wine and sherry); strawberries 75%; almonds 33%; corn field 9%; corn, sweet 50%; wheat 17% (from spring wheat at 17% and winter wheat at 6%); peanuts 67%; blueberries 54%; and blackberries 55%.

5.4.3	Acute Dietary Risk Assessment

Estimated acute dietary exposure to fluopyram from food and drinking water for all population subgroups is below 100% of the acute Population Adjusted Dose (aPAD).  Combined dietary exposure from food and drinking water at the 95[th] percentile of exposure is estimated to be 0.096117 mg/kg/day for the overall U.S. population, equivalent to19% of the aPAD.  The population subgroup with the highest estimated acute dietary exposure to fluopyram is children 1-2 years old, with an estimated exposure at the 95[th] percentile of 0.175170 mg/kg/day, equivalent to 35% of the aPAD.  HED is concerned when estimated dietary risk exceeds 100% of the aPAD (see Table 5.4.6).

5.4.4	Chronic Dietary Risk Assessment

Estimated chronic dietary exposure from food and drinking for all population subgroups is below 100% of the chronic Population Adjusted Dose (cPAD).  Combined dietary exposure from food and drinking water is estimated to be 0.003703 mg/kg/day for the general U.S. population, equivalent to 31% of the cPAD.  The population subgroup with the highest estimated chronic dietary exposure to fluopyram is children 1 to 2 years old, with an estimated exposure of 0.009733 mg/kg/day, equivalent to 81% of the cPAD.  HED is concerned when estimated dietary risk exceeds 100% of the cPAD (see Table 5.4.6).

5.4.5	Cancer Dietary Risk Assessment

The CARC classified fluopyram as "Not Likely to be Carcinogenic to Humans".  Therefore, a cancer dietary exposure analysis is not required.

5.4.6	Summary Table

Table 5.4.6.  Summary of Dietary (Food & Drinking Water) Exposure and Risk for Fluopyram
                              Population Subgroup
                                 Acute Dietary
                               (95th Percentile)
                                Chronic Dietary

                         Dietary Exposure (mg/kg/day)
                                    % aPAD
                               Dietary Exposure
                                  (mg/kg/day)
                                    % cPAD
General U.S. Population
                                   0.096117
                                      19
                                   0.003703
                                      31
All Infants (< 1 year old)
                                   0.137520
                                      28
                                   0.007331
                                      61
Children 1-2 years old
                                   0.175170
                                      35
                                   0.009733
                                      81
Children 3-5 years old
                                   0.160828
                                      32
                                   0.006787
                                      56
Children 6-12 years old
                                   0.092779
                                      19
                                   0.004079
                                      34
Youth 13-19 years old
                                   0.073266
                                      15
                                   0.002617
                                      22
Adults 20-49 years old
                                   0.088800
                                      18
                                   0.003324
                                      28
Adults 50+ years old
                                   0.091387
                                      18
                                   0.003315
                                      28
Females 13-49 years old
                                   0.092231
                                      18
                                   0.003256
                                      27
[1]The population subgroup with the highest estimated acute and chronic dietary (food + drinking water) exposure and risk is indicated by bold text.

 Residential (Non-Occupational) Exposure/Risk Characterization

Based on the proposed product labels, several products are intended for use by homeowners, or by occupational handlers in residential settings.  Therefore, non-occupational/residential risk assessments have been completed.

6.1	Residential Handler Exposure

The quantitative exposure/risk assessment developed for residential handlers is based on the residential handler scenarios of mixing, loading, and applying liquid formulations to gardens, ornamentals, fruit trees, and turf by manually pressurized handwand, hose-end sprayers, backpack, or sprinkler cans.  Short-term dermal and inhalation exposures were assessed for residential handlers.  All residential handler risk estimates are not of concern to HED (all MOEs >=100), with MOEs ranging from 8,900 to 190,000 for dermal exposures and 260,000 to 130,000 for inhalation exposures.  Summaries of the short-term risk estimates for residential handlers are included in Appendix D, Table D.1.

6.2	Residential Post-application Exposure

There is the potential for post-application exposure to fluopyram for individuals exposed as a result of being in an environment that has been previously treated with fluopyram.  The quantitative exposure/risk assessment for residential post-application exposures includes the following scenarios:

 Adults and children (1 to < 2 years old) dermal exposure to treated turf during high contact lawn activities,
 Children (1 to < 2 years old) incidental oral exposure as a result of contacting treated turf,
 Adults and youths (11 to <16 yr old) dermal exposure to treated turf during mowing and golfing activities,
 Children (6 to < 11 years old) dermal exposure to treated turf during golfing activities, and
 Adults and children (6 to < 11 years old) dermal exposure to treated gardens.

Exposures are expected to be short-term in duration.  Short-term dermal and incidental oral exposure and risk estimates have been assessed.  The exposure assessment for dermal exposure to treated gardens is protective of exposure to treated ornamental and fruit trees.

Turf Transferable Residue (TTR) data for Fluopyram
Because turf transferable residue data were not available for fluopyram, turf residues were estimated using default assumptions.  A TTR study is not required for fluopyram at this time.  Refer to Section 9.2.1 of this document for a detailed rationale.

Dislodgeable Foliar Residue (DFR) data for Fluopyram
Because dislodgeable foliar residue data were not available for fluopyram, foliar residues were estimated using default assumptions.  A DFR study is not required for fluopyram at this time.  Refer to Section 9.2.1 of this document for a detailed rationale.

Combining Exposure and Risk Estimates
HED combines risk values resulting from separate routes of exposure when it is likely they can occur simultaneously based on the use pattern and the behavior associated with the exposed population, and if the hazard associated with the points of departure is similar across routes.
Since dermal and incidental oral exposure routes do not share a common toxicological endpoint for fluopyram, risk estimates have not been combined for those routes.

Summaries of the short-term risk estimates for residential post-application exposures are included in Appendix D, Tables D.2 through D.4.

Tables D.2 and D.3 summarize the residential post-application exposure and risk estimates for exposures to treated lawns and turf.  The proposed liquid formulations do not lead to post-application risk estimates of concern.  Residential dermal post-application MOEs for all life stages range from 1,000 to 97,000.  Residential incidental oral post-application MOEs for children 1 to <2 years old range from 2,400 to 1,100,000.

Table D.4 summarizes the residential post-application exposure and risk estimates for exposures to treated gardens, ornamental trees and shrubs, and fruit trees.  The proposed liquid formulations do not lead to post-application risk estimates of concern (all MOEs >=100).  Residential dermal post-application MOEs for all life stages range from 2,100 to 33,000.

6.3	Residential Risk Estimates for Use in Aggregate Assessment

The most conservative residential handler or post-application risk estimates should be used in the aggregate risk assessment.  The residential exposures that are recommended for use in the aggregate assessment for fluopyram are as follows:

 The recommended residential exposure for use in the adult aggregate assessment reflects dermal post-application exposure to treated lawns from high contact activities.
 The recommended residential exposure for use in the children (11 to <16 years old) aggregate assessment reflects dermal post-application exposure from golfing.
 The recommended residential exposure for use in the children (6 to <11 years old) aggregate assessment reflected dermal post-application exposure to treated gardens.
 The recommended residential exposure for use in the children (1 to <2 years old) aggregate assessment reflects dermal post-application exposure to treated lawns from high contact activities.

The residential risk estimates from these exposures are presented in Table 6.3.1.

Table 6.3.1.  Recommendations for the Residential Exposures for the Fluopyram Aggregate Assessment.
                                   Lifestage
                              Dose (mg/kg/day)[4]
                                    MOE[5]
Adults [inhalation handler exposure from treating lawns by hose-end sprayer]
                                   0.000056
                                    260,000
Child (1 to <2 years old) [incidental oral hand-to-mouth post-application exposure to treated lawns]
                                    0.00615
                                     2,400

6.4	Residential Bystander Post-application Inhalation Exposure

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.regulations.gov/#!documentDetail;D=EPA-HQ-OPP-2009-0687-0037).  The agency has evaluated the SAP report and has developed a Volatilization Screening Tool and a subsequent Volatilization Screening Analysis (http://www.regulations.gov/#!docketDetail;D=EPA-HQ-OPP-2014-0219).  During Registration Review, the Agency will utilize this analysis to determine if data (i.e., flux studies, route-specific inhalation toxicological studies) or further analysis is required for fluopyram.

In addition to this screen, the Agency has developed a preliminary bystander volatilization inhalation exposure assessment for fluopyram utilizing the currently available inhalation toxicity and air monitoring data.

6.5	Non-Occupational Spray Drift Exposure and Risk Estimates

Spray drift is a potential source of exposure to those nearby pesticide applications.  This is particularly the case with aerial application, but, to a lesser extent, spray drift can also be a potential source of exposure from the ground application methods (e.g., groundboom and airblast) employed for fluopyram.  The agency has been working with the Spray Drift Task Force (a task force composed of various registrants which was developed as a result of a Data Call-In issued by EPA), EPA Regional Offices and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices (see the agency's Spray Drift website at http://www2.epa.gov/reducing-pesticide-drift for more information).  The agency has also developed a policy on how to appropriately consider spray drift as a potential source of exposure in risk assessments for pesticides.  The potential for spray drift will be quantitatively evaluated for each pesticide during the Registration Review process which ensures that all uses for that pesticide will be considered concurrently.  The approach is outlined in the revised (2012) Standard Operating Procedures For Residential Risk Assessment (SOPs) - Residential Exposure Assessment Standard Operating Procedures Addenda 1: Consideration of Spray Drift.  This document outlines the quantification of indirect non-occupational exposure to drift.

 Aggregate Exposure/Risk Characterization

In accordance with the FQPA, HED must consider and aggregate (add) pesticide exposures and risks from three major sources: food, drinking water, and residential exposures.  In an aggregate assessment, exposures from relevant sources are added together and compared to quantitative estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can be aggregated.  When aggregating exposures and risks from various sources, HED considers both the route and duration of exposure.  There is potential acute and chronic exposure via the diet (food and drinking water).  Additionally, there are proposed residential uses so short-term residential exposures are likely to occur; and therefore, short-term aggregate risks were assessed.

7.1	Acute Aggregate Risk

The aggregate acute risk estimates include exposure to residues of fluopyram in food and drinking water, and does not include dermal, inhalation, or incidental oral exposure.  As demonstrated under section 5.4.3, acute aggregate risks are not of concern.

 Short-Term Aggregate Risk

There is potential short-term exposure to fluopyram via dietary (which is considered background exposure) and residential (which is considered primary) exposure pathways.  For children 6 to <11 years old and youths 11 to <16 years old, these pathways lead to exposure via oral (background) as well as dermal (primary) routes.  For adults, these pathways lead to exposure via oral (background) as well as dermal and inhalation (primary) routes.  The most conservative scenarios were chosen for each.  For a description of the residential exposure scenarios considered in the aggregate assessment, see Section 6.3.

The short-term aggregate MOEs for small children and for adults are both 1,500, and are therefore not of concern to HED (see Table 7.2.1).

Table 7.2.1.  Short-Term Aggregate Risk Calculations
                                   Lifestage
                         Residential Exposure Scenario
                                NOAEL mg/kg/day
                                    LOC[1]
                                Max Exposure[2]
                        Residential Exposure mg/kg/day
                      Average Dietary Exposure mg/kg/day
                           Total Exposure mg/kg/day
                               Aggregate MOE[2]
                              Child 1 to <2 yr
   Incidental oral hand-to-mouth post-application exposure to treated lawns
                                     14.5
                                      100
                                     0.145
                                   0.000056
                                   0.009733
                                   0.009789
                                     1,500
                                     Adult
      Inhalation handler exposure from treating lawns by hose-end sprayer
                                     14.5
                                      100
                                     0.145
                                    0.00615
                                   0.003324
                                   0.009474
                                     1,500
[1] The Level of Concern MOE is 100.
[2] Maximum Exposure (mg/kg/day) = NOAEL/LOC MOE
[3] Aggregate MOE = [NOAEL / (Average Dietary Exposure + Residential Exposure)]

7.3	Chronic Aggregate Risk

Chronic exposure from the residential pathway is not anticipated based on the current fluopyram use pattern.  The chronic aggregate risk (food and drinking water) is below HED's LOC (i.e., <100% cPAD for the general U.S. population and all population subgroups).  See Section 5.4.4 for details.

 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/.

 Occupational Exposure/Risk Characterization

This document presents an assessment of the proposed uses of fluopyram on numerous agricultural field crops, turf grass, ornamentals, and Christmas trees, and seed treatment to peanuts.  Refer to Table 3.3.1 for a detailed description of the proposed uses.  Based on application rates and label information, only short- and intermediate-term exposures are expected for occupational handlers and post-application workers.  Long-term exposure is not expected for the proposed use patterns.

9.1	Short-/Intermediate-Term Handler Risk

Based on the anticipated use patterns and proposed labeling, types of equipment and techniques that can potentially be used, occupational handler exposure is expected from the proposed uses.  The quantitative dermal and inhalation exposure/risk assessment developed for occupational handlers is based on the following scenarios:

 Mixing/loading liquids for aerial and chemigation application,
 Mixing/loading liquids for groundboom application,
 Mixing/loading liquids for airblast application,
 Applying sprays via aerial equipment,
 Applying sprays via groundboom equipment,
 Applying sprays via airblast equipment,
 Flagging for aerial sprays,
 Mixing, loading, and applying liquids with manually pressurized handwand,
 Mixing, loading, and applying liquids with mechanically-pressurized handgun, and
 Mixing, loading, and applying liquids with a backpack.

The proposed labels require occupational handlers to wear the following attire and PPE: long sleeved shirts, long pants, shoes, socks, and chemical resistant gloves.  However, the FLU+TFS SC 32.5 and FLU+TFS SC 25 labels do not require the use of gloves.

For all exposure scenarios the risk estimates do not exceed HED's LOC (i.e., MOEs >=100) at baseline (i.e., long sleeved shirt, long pants, shoes plus socks, without gloves or a respirator).  The MOEs ranged from 410 to 1,500,000 for dermal exposure at baseline, 2,400 to 1,100,000 for dermal exposure with the addition of gloves, and 7,400 to 30,000,000 for inhalation exposure.  Refer to Appendix E, Table E.1, for the summary of occupational handler risk estimates.

The proposed seed treatment of peanuts is on the Luna[(R)] Privilege label (4.16 lb ai/gal) [EPA Reg. No. 264-1078], which requires water proof gloves for seed treatment activities and no gloves for baggers and bag sewers.

For seed treatment use on peanut seeds, the quantitative exposure/risk assessment developed for occupational handlers is based on the following scenarios: 1) Mixing/loading liquids for commercial seed treatment; 2) Bagging treated seed; 3) Sewing bags; 4) Multiple activities; and 5) Planting treated seed.  Risk estimates for dermal and inhalation short-term occupational handler exposures all resulted in MOEs >=100, and therefore, do not exceed HED's level of concern, with MOEs ranging from 1,400 to 9,200 for dermal exposures and from 1,700 to 17,000 for inhalation exposures.  Refer to Appendix E, Table E.2.

9.2	Short-/Intermediate-Term Post-Application Risk

HED uses the term post-application to describe exposures that occur when individuals are present in an environment that has been previously treated with a pesticide (also referred to as re-entry exposure).  Such exposures may occur when workers enter previously treated areas to perform job functions, including activities related to crop production, such as scouting for pests or harvesting.  Post-application exposure levels vary over time and depend on such things as the type of activity, the nature of the crop or target that was treated, the type of pesticide application, and the chemical's degradation properties.  In addition, the timing of pesticide applications, relative to harvest activities, can greatly reduce the potential for post-application exposure.

9.2.1	Dermal Post-application Risk

The post-application dermal exposure and risk estimates associated with agricultural crops, Christmas trees, and nursery ornamentals are summarized in Appendix E, Table E.4.  For each crop or crop group the post-application activities with the highest transfer coefficient and highest exposure contact are presented.  Short- and intermediate-term dermal post-application exposures and risks to occupational workers were estimated using standard values established by HED since no chemical-specific data were submitted.  The transfer coefficients (TC) used for all post-application activities were the TCs established by the Science Advisory Council for Exposure Policy Number 3.1 (http://www.epa.gov/pesticides/science/exposac_policy3.pdf).  This policy reflects adoption of all Agricultural Re-Entry Task Force (ARTF) data.  Use of the data in this policy requires compensation to the ARTF under FIFRA.  The transfer coefficients (TCs) used in this assessment were taken from the Agency's revised Agricultural Transfer Coefficient SOP.  Many of the TCs in this SOP are based on work of the ARTF.  The occupational post-application MOEs for all crops and crop groups and scenarios do not exceed HED's level of concern (MOEs >=100) on day 0 (i.e., 12 hours following application) with dermal MOEs ranging from 250 to 23,000.  All other scenarios involving lesser contact activities would have higher MOEs and are also not of concern.

For use on cotton, HED has also assessed the post-application dermal exposure and risk estimates for workers involved in harvesting cotton bolls.  Although most of cotton harvesting is done mechanically, there are still some activities, with the potential for exposure, that are associated with the harvesting of cotton.  The anticipated post-application activities and dermal transfer coefficients for these activities are presented in Appendix E, Table E.5.  The recommended transfer coefficients are derived from EPA's Science Advisory Council for Exposure (ExpoSAC) Policy 3 (http://www.epa.gov/pesticides/science/exposac-policy3-march2013.pdf).  No chemical specific data are available for the amount of residue available on the cotton bolls; i.e., dislodgeable boll residue (DBR) data.  Such data are available from a study with the active ingredient tribufos; i.e., MRID 42701601.  Note to RD:  These data may be proprietary, and subject to the data protection provisions of FIFRA, and therefore, may trigger a data compensation issue between registrants.  Since the proposed fluopyram labels include a 30 day pre-harvest interval, the best fit residue data used from MRID 42701601 was chosen from 30 days after harvest and then adjusted for the difference in application rates.  All of the cotton harvesting activities resulted in MOEs ranging from 3,100,000 to 17,000,000, which do not exceed the LOC, and are therefore not of concern; see Appendix F, Table F.6.

For use on turf, the exposure/risk assessment for the proposed uses results in a post-application occupational MOE of 9,000, which is above the dermal LOC (MOE >=100); and therefore is not of concern; see Appendix E, Table E.7.

Dislodgeable Foliar Residues:
There were no chemical-specific dislodgeable foliar residue data to assess post-application risks to workers while performing tasks related to crops treated with fluopyram.  For agricultural crops, occupational post-application exposures and risks were assessed using HED's default assumptions that 25% of the initial application is available for transfer on day 0 (i.e., 12 hours after application) and that the residue dissipates at a rate of 10% per day.

In accordance with 40 CFR §158, DFR data are required for all occupational (e.g., crop, nursery, greenhouse use sites) or residential (e.g., ornamental and vegetable gardens, pick your own farms, retail tree farms) uses that could result in post-application exposure to foliage.  In the absence of chemical-specific DFR data, EPA uses default values.  The 2012 Standard Operating Procedures for Residential Pesticide Exposure Assessment includes an analysis of a number of DFR studies, which resulted in the selection of a revised default values for the fraction of the application rate available for transfer after a foliar application (FAR).  These values are based on an analysis of 19 DFR studies.  Since that time, the Agricultural Re-entry Task Force has submitted information (MRID 49299201) that corrects an application rate error made in the original submission of "ARF039  -  Determination of Dermal and Inhalation Exposure to Reentry Workers During Chrysanthemum Pinching in a Greenhouse" (EPA MRID 45344501).  As a result, the range of FAR values was revised from 2% - 89% to 2% - 47%.  In the data, a large range of transferability is observed and this variability can potentially be attributable to many factors such as active ingredient; formulation; field conditions in the studies; weather conditions (e.g., humidity); or many other difficult to quantify factors.  Although witnessed across multiple chemicals, this range in FAR values is not expected when considering DFR data for a single chemical.  At this time, the ARTF submission did not alter the selection of 25% as the reasonable, high-end default value.  Because DFR data are not available for fluopyram, EPA is using the default value of 25%.  Although there may be a small degree of uncertainty in the use of the default DFR value for fluopyram (i.e., there is a small chance that the FAR value may exceed the applicable default value), it is likely that the health-protective aspects of EPA's occupational post-application assessment methodology will more than compensate for this potential uncertainty.  For example,  when assessing residential and occupational post-application exposure to gardens and ornamentals, EPA assumes the following:  exposures occur to zero-day (i.e., day of application ) residues every day of the assessed exposure duration (i.e., EPA assumes that no dissipation or degradation occurs, it doesn't rain, etc); individuals perform the same post-application activities performed in the transfer coefficient study day after day (e.g., weeding, harvesting, pruning, etc.); and individuals engage in these post-application activities for a high-end amount of time every day (represented by data reflecting time spent gardening based on survey data).

Given the conservatisms discussed above and the potential compounding nature of these conservatisms, EPA is able to rely upon the calculated exposure estimates with confidence that exposure is not being underestimated.

Since the highest estimated residential and occupational post-application exposures using default DFR values for fluopyram are minimal in comparison to the level of concern (i.e., the calculated MOE is greater than 2 times higher than the level of concern, residential MOE = 2,100 and occupational MOE = 250 compared to the LOC of 100); EPA is not imposing the 40 CFR §158 DFR data requirement at this time.  In this instance, it is unlikely that chemical-specific DFR data would be needed to further refine exposure assessments or would add appreciably to our overall understanding of the availability of dislodgeable foliar pesticide residues for fluopyram.

Turf Transferrable Residues
A turf transferrable residue study has not been submitted for fluopyram.  Therefore, HED's standard operating procedures and assumptions were used to determine an estimate of day zero fluopyram residues on treated turf.

In accordance with 40 CFR §158, TTR data are required for all occupational (e.g., sod farms, golf courses, parks, and recreational areas) or residential turf uses that could result in post-application exposure to turf.  In the absence of chemical-specific TTR data, EPA uses default values.  The 2012 Standard Operating Procedures for Residential Pesticide Exposure Assessment includes an analysis of all TTR data, available at the time, which resulted in the selection of revised liquid and granular default values for the fraction of the application rate available for transfer after a turf application (FAR).  These values are based on an analysis of 59 TTR studies performed with the Modified California Roller Method (36 studies using liquids, 11 studies using wettable powders/water dispersible granules, and 12 studies using granules).  The liquid results (N=131) indicate a range of FAR values from 0.0005% to 6.1% and the granular results (N=37) indicate a range of 0.00064% to 0.69%.  In both the liquid and granular data, a large range of transferability is observed and this variability can potentially be attributable to many factors such as active ingredient; formulation; field conditions in the studies; weather conditions (e.g., humidity); or many other difficult to quantify factors.  Although witnessed across multiple chemicals, this range in FAR values is not expected when considering TTR data for a single chemical.  HED selected 1% and 0.2% as high-end default values for liquid and granular products, respectively.  Because TTR data are not available for fluopyram, EPA is using the default value of 1%.  Although there may be a small degree of uncertainty in the use of the default TTR value for fluopyram (i.e., there is a small chance that the FAR value may exceed the applicable default value), it is likely that the health-protective aspects of EPA's residential and occupational post-application turf assessment methodology will more than compensate for this potential uncertainty (i.e., the methodology is likely to overestimate exposure by a factor greater than the factor than the highest measured FAR values exceed the defaults).  For example, when assessing residential post-application turf exposure, EPA assumes the following:  exposures occur to zero-day (i.e., day of application ) residues every day of the assessed exposure duration (i.e., EPA assumes that no dissipation or degradation occurs, it doesn't rain, the grass is not mowed, etc.); individuals perform the same post-application activities performed in the turf transfer coefficient study day after day (e.g., tumbling, playing on turf with toys, etc.); and individuals engage in these post-application activities for a high-end amount of time every day that is represented by data reflecting time children spend outdoors and not specifically engaged in activities on turf, when in actuality children do not spend all of their outdoor time on turf and high-end levels of activity will not occur every day.

Given the conservatisms discussed above and the potential compounding nature of these conservatisms, EPA is able to rely upon the calculated exposure estimates with confidence that exposure is not being underestimated.

Since the estimated residential turf post-application exposure from high contact activities on lawns and the occupational post-application activities on golf course turf using default TTR values for fluopyram are minimal in comparison to the level of concern (i.e., the calculated MOEs are greater than 10 times higher than the level of concern, residential MOE = 1,000 and occupational MOE = 9,000, compared to the LOC of 100); EPA is not imposing the 40 CFR §158 TTR data requirement at this time.  In this instance, it is unlikely that chemical-specific TTR data would be needed to further refine exposure assessments or would add appreciably to our general understanding of the availability of turf transferable pesticide residues.

Restricted Entry Interval:  Since post-application risks were not a concern on day 0 (12 hours following application), the REI is based on the acute toxicity of fluopyram technical material.  Fluopyram is classified as Toxicity Category III by the acute oral and dermal routes of exposure and Toxicity Category IV for acute inhalation, eye irritation potential and skin irritation potential.  Under the WPS for Agricultural Pesticides, active ingredients classified as acute toxicity categories III or IV for these routes are assigned a 12-hour REI.  Therefore, the 12-hour REI that appears on the proposed labels is adequate.

9.2.2	Inhalation Post-application Risk

There are multiple potential sources of post-application inhalation exposure to individuals performing post-application activities in previously treated fields.  These potential sources include volatilization of pesticides and resuspension of dusts and/or particulates that contain pesticides.  The agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP's final report on March 2, 2010 (http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html).  The agency has evaluated the SAP report and has developed a Volatilization Screening Tool and a subsequent Volatilization Screening Analysis (http://www.regulations.gov/#!docketDetail;D=EPA-HQ-OPP-2014-0219).  During Registration Review, the agency will utilize this analysis to determine if data (i.e., flux studies, route-specific inhalation toxicological studies) or further analysis is required for fluopyram].

In addition, the Agency is continuing to evaluate the available post-application inhalation exposure data generated by the Agricultural Reentry Task Force.  Given these two efforts, the Agency will continue to identify the need for and, subsequently, the way to incorporate occupational post-application inhalation exposure into the agency's risk assessments.

Although a quantitative occupational post-application inhalation exposure assessment was not performed, an inhalation exposure assessment was performed for occupational/commercial handlers.  Handler exposure resulting from application of pesticides outdoors is likely to result in higher exposure than post-application exposure.  Therefore, it is expected that these handler inhalation exposure estimates would be protective of most occupational post-application inhalation exposure scenarios."

10.0	References

O' Keefe, B., 12/18/2015, D426622.  Fluopyram:  Occupational and Residential Exposure Assessment for New Uses on artichoke (globe), Brassica (cole) leafy vegetables, Brassica (cole) leafy vegetables head and stem subgroup, bulb vegetables, canola, carrot, cereal grains (except rice), citrus, corn (including field, sweet, popcorn, and field corn grown for seed)cotton, cucurbit vegetables, fruiting vegetables, ginseng, grapes and small vines fruits (except fuzzy kiwifruit), herbs and spices (except black pepper), hops, leafy vegetables, legume vegetables (including soybean), peanut, pome fruits, potato and other root, tuberous and corm vegetables, small berries (caneberries and bushberries), stone fruit, strawberry and other low growing berries, sugar beet, sunflower subgroup, tree nuts; use as a seed treatment to peanuts; turf grass (golf courses, sod farms, sports fields, residential, industrial, municipal, commercial, and other turf grass areas), ornamentals (in residential and commercial settings), and Christmas trees.

Cheng, L., 09/23/2011, D387587 and D389081.  Fluopyram.  Application for Section 3 Registration for Use on Apple, Banana (Import only), Dried Beans, Cherry, Grape (Wine Production only), Peanut, Pistachio, Potato, Sugar Beet, Strawberry, Tree Nuts Crop Group 14, Watermelon, and Rotational Crops Alfalfa, Canola, Cotton, Cereal Grains Crop (Except Rice) Group 15, and Forage, Fodder, and Straw of Cereal Grains Crop (Except Rice) Group 16.  Summary of Analytical Chemistry and Residue Data.

Negussie, M., 11/10/2015, D426620.  Fluopyram.  Tolerances and Registration for Use on Crop Subgroup 1B, Subgroup 1C, Crop Group 2, Subgroup 3-07A, Subgroup 3-07B, Subgroup 4A, Subgroup 4B, Subgroup 5A, Subgroup 5B, Subgroup 6A, Subgroup 6B, Dry Bean, Subgroup 8-10A, Subgroup 8-10B, Subgroup 9A, Subgroup 9B, Subgroup 10-10, Group 11-10, Subgroup 12-12A, Subgroup 12-12B, Subgroup 12-12C, Subgroup 13-07A, Subgroup 13-07B, Subgroup 13-07F, Subgroup 13-07G, Crop Group 15 (except corn and rice), Crop Group 16, Subgroup 19A, Dill Seed, Subgroup 20A, Subgroup 20B,  Subgroup 20C, Artichoke (Globe), Hops, Soybean, and Sugarcane (Rotated).  Amended Tolerance Requests for the Registered Uses due to Crop Group/Subgroup Expansion Requests, Additional Use Patterns, and Tolerance Re-Assessments.  Summary of Analytical Chemistry and Residue Data.

Negussie, M., 11/10/2015, D426621. Fluopyram: Acute and Chronic Aggregate Dietary Exposure and Risk Assessments for Section 3 Registration for New Uses on Crop Subgroup 1B, Subgroup 1C, Crop Group 2, Subgroup 3-07A, Subgroup 3-07B, Subgroup 4A, Subgroup 4B, Subgroup 5A, Subgroup 5B, Subgroup 6A, Subgroup 6B, Dry Bean, Subgroup 8-10A, Subgroup 8-10B, Subgroup 9A, Subgroup 9B, Subgroup 10-10, Group 11-10, Subgroup 12-12A, Subgroup 12-12B, Subgroup 12-12C, Subgroup 13-07A, Subgroup 13-07B, Subgroup 13-07F, Subgroup 13-07G, Crop Group 15 (except corn and rice), Crop Group 16, Subgroup 19A, Dill Seed, Subgroup 20A, Subgroup 20B,  Subgroup 20C, Artichoke (Globe), Hops, Soybean, and Sugarcane (Rotated).  Amended Tolerance Requests for the Registered Uses due to Crop Group/Subgroup Expansion Requests, Additional Use Patterns, and Tolerance Re-Assessments.  Summary of Analytical Chemistry and Residue Data.

Ruhman, M. A., 10/26/2015: Refinement of the Estimated Drinking Water Concentrations of Fluopyram New Uses on Artichoke, Vegetables (Brassica, bulb, cucurbits, fruiting, leafy, legumes and root/tuberous/corm), Carrot, Cereal grains, Citrus, Cotton, Ginseng, Grapes, Small vines fruits, grasses (forage/feed/seed), Herbs, Hops, Soybean, Oil seed group, Ornamentals, Peanut, Pome fruits, Potato, Small berries, Stone fruit, Strawberry and other low-growing berries, Sugarbeet, Tree nuts and Turf for Use in Human Health Risk Assessment.

Ruhman, M. A., 04/01/2015: Estimated Drinking Water Concentrations of Fluopyram New Uses on Artichoke, Vegetables (Brassica, bulb, cucurbits, fruiting, leafy, legumes and root/tuberous/corm), Carrot, Cereal grains, Citrus, Cotton, Ginseng, Grapes, Small vines fruits, grasses (forage/feed/seed), Herbs, Hops, Soybean, Oil seed group, Ornamentals, Peanut, Pome fruits, Potato, Small berries, Stone fruit, Strawberry and other low-growing berries, Sugarbeet, Tree nuts and Turf for Use in Human Health Risk Assessment.

Scollon, E., 7/16/2009, D367115.  Fluopyram.  Report of the Residues of Concern Knowledgebase Subcommittee (ROCKS).

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

Rury, K., 01/30/2013, TXR 0056523.  Fluopyram: Summary of Hazard and Science Policy Council (HASPOC) Meeting of November 29, 2012:  Recommendations on the Waiver Request for the Subchronic Inhalation Study Data Requirement.

Appendix A.  Toxicology Profile

A.1	Toxicology Data Requirements
The requirements (40 CFR 158.500) for food use for fluopyram are in Table A.1. Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used.

Table A.1.  Toxicology Data Requirements.
                                     Study
                                   Technical

                                   Required
                                   Satisfied
870.1100    Acute Oral Toxicity
870.1200    Acute Dermal Toxicity
870.1300    Acute Inhalation Toxicity
870.2400    Primary Eye Irritation
870.2500    Primary Dermal Irritation
870.2600    Dermal Sensitization
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
870.3100    Oral Subchronic (rodent)
870.3150    Oral Subchronic (nonrodent)
870.3200    21-Day Dermal
870.3250    90-Day Dermal
870.3465    90-Day Inhalation
                                      yes
                                      yes
                                      yes
                                      no
                                      yes
                                      yes
                                      yes
                                      yes
                                       -
                                   Waived[a]
870.3700a  Developmental Toxicity (rodent)
870.3700b  Developmental Toxicity (nonrodent)
870.3800    Reproduction
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
870.4100a  Chronic Toxicity (rodent)
870.4100b  Chronic Toxicity (nonrodent)
870.4200a  Oncogenicity (rat)
870.4200b  Oncogenicity (mouse)
870.4300    Chronic/Oncogenicity
                                       -
                                      yes
                                       -
                                      yes
                                      yes
                                       -
                                      yes
                                       -
                                      yes
                                      yes
870.5100    Mutagenicity -- Gene Mutation - bacterial
870.5300    Mutagenicity -- Gene Mutation - mammalian
870.5xxx    Mutagenicity -- Structural Chromosomal Aberrations
870.5xxx    Mutagenicity -- Other Genotoxic Effects
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
870.6100a  Acute Delayed Neurotoxicity (hen)
870.6100b  90-Day Neurotoxicity (hen)
870.6200a  Acute Neurotoxicity Screening Battery (rat)
870.6200b  90-Day Neurotoxicity Screening Battery (rat)
870.6300    Develop. Neurotoxicity
                                      no
                                      no
                                      yes
                                      yes
                                      no
                                       -
                                       -
                                      yes
                                      yes
                                       -
870.7485    General Metabolism
870.7600    Dermal Penetration
870.7800    Immunotoxicity
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
[a] : (HASPOC, 1/30/2013; TXR 0056523) :

A.2	Toxicity Profiles

Table A.2.1	Acute Toxicity Profile for 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 for Fluopyram.
                                Guideline No.
                                  Study Type
                     MRID No. (year)/ Classification/Doses
                                    Results
Non-guideline

28-day dietary  rat study (exploratory)
47372516;  (2004)
Acceptable
50, 400, 3200  ppm
(4., 31,  & 254 mg/kg/day ♂
 4.6, 36,  &  263 mg/kg/day ♀)
NOAEL = 31 mg/kg/day
LOAEL = 254 mg/kg/day based on  platelet count and prothrombin time (M),  cholesterol and triglycerides (M/F),  aspartate aminotransferase and alkaline phosphatase
 liver weight with hepatocellular hypertrophy (M/F)
 thyroid weight with follicular cell hypertrophy (M)
Non-guideline

28-day rat study  (dietary) (preliminary)
AE C657188 (PCA), a soil metabolite of  AE C638206

47372521; (2003)
Acceptable
20; 200; 2,000, & 20,000 ppm

(1.5; 15; 149; & 1,574 mg/kg/day for ♂
1.6; 16; 162; & 1,581 mg/kg/day for ♀)
NOAEL=1574 mg/kg (HDT) no compound related effects were seen.

870.3100
90-day dietary rat study
47372441; (2005)
Acceptable/guideline
0, 50, 200, 1000, 3200 ppm

♂: 3, 13, 61, & 204 mg/kg/day
♀: 4, 15, 70, & 230 mg/kg/day
NOAEL = 13 mg/kg/day
LOAEL = 61 mg/kg/day based on ↓ body weight & food consumption, hematology parameters affected. ↑ cholesterol conc &  -glutamyltransferase activity. Slight ↑ in TSH, T3 & T4.
↑ liver, thyroid gland & kidney weights.
Liver: centrilobular hypertrophy & periportal to midzonal hepatocellular macrovacuolation. Thyroid gland: follicular cell hypertrophy.
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), ↑ prothrombin time (M).
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)

Acceptable
30; 150; 750; & 1,500 ppm

♂: 2,10, 50, & 102 mg/kg/day
♀: 2, 12, 58, & 118 mg/kg/day.
Parental NOAEL = 10 mg/kg/day
Parental LOAEL = 50 mg/kg/day based on increased liver and kidney weights

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

Reproductive NOAEL = 118 mg/kg/day (HDT) No effect was seen in any of reproductive parameters examined.
870.3800

2-Generation reproduction study in the rat
47372447; (2008, Report)

Acceptable/guideline
40; 220; & 1, 200 ppm

♂: 3, 15, 83 mg/kg/day (premating)
♀: 3, 18, & 96 mg/kg/day (premating).
Parental NOAEL = 15 mg/kg/day
Parental LOAEL = 83 mg/kg/day based on increased creatinine, total protein, and albumin, and increased kidney weight.

Offspring NOAEL = 15 mg/kg/day
Offspring LOAEL= 83 mg/kg/day based on decreased body weight (8%) with decreases in spleen and thymus weights.

Reproductive NOAEL = 96 mg/kg/day (HDT). No effect was seen in any of reproductive parameters examined.
870.4100

1-year toxicity study in dogs (dietary)
47372449; (2007)
Acceptable/guideline
100; 400; &  2,000 ppm

♂: 3, 13, & 68 mg/kg/day
♀: 4, 14, & 66 mg/kg/day.
NOAEL = 13 mg/kg/day
LOAEL = 66 mg/kg/day based on ↓ body weight & food consumption (M/F), ↑ alkaline phosphatase (M/F), Liver: centrilobular hypertrophy.
870.4200

Carcinogenicity study in the mouse
47372450;  (2007)
Acceptable/guideline
30, 150, & 750 ppm

♂: 4, 21, & 105 mg/kg/day
♀: 5, 27, & 129 mg/kg/day.
NOAEL = 4 mg/kg/day
LOAEL = 21 mg/kg/day based on follicular cell hyperplasia in the thyroid gland, centrilobular to panlobular hypertrophy and hepatocellular single cell degeneration /necrosis in the liver.

Thyroid gland follicular cell
adenomas in high dose males.
870.4300

Chronic /carcinogenicity study in the rat
47372501; (2008)
Acceptable/guideline
30, 150 & 750/375 ppm for ♂; 30, 150 and 1,500 ppm for ♀.

♂: 1.2, 6.0, & 29 mg/kg/day
♀: 1.7, 8.6, & 89 mg/kg/day

(Due to high mortality in 750 ppm males, this concentration was reduced to 375 ppm from week 85 onward)
NOAEL = 1.2 mg/kg/day
LOAEL = 6.0 mg/kg/day based on liver toxicity, nephropathy, and follicular cell hypertrophy in the thyroid gland.

Liver cell tumors (carcinoma and adenoma) in high dose females.
870.5100
Ames test
47372502; (2006)
Acceptable/guideline
Doses:  16 to 5000 μg/plate
+/- metabolic activation
Negative
870.5100
Ames test
47372503; (2008)
Acceptable/guideline
Doses: 5 to 1581 μg/plate
            16 to 5000 μg/plate
+/- metabolic activation
Negative
870.5300
In-vitro chromosome aberration (V79 cells).
47372505; (2005)
Acceptable/guideline
Concentrations: 30, 60, 120, 180, & 240 μg/ml.
Negative
870.5300
HPRT Test (V79 cells).
47372504; (2006)
Acceptable/guideline
Concentrations: 4 to 256 μg/ml
+/- metabolic activation.
Negative
870.5385
In-vivo micro-nucleus test in male mice
47372506; (2005)
Acceptable/guideline
Doses: 250, 500, & 1000 mg/kg.
Negative
870.6200a

Acute neurotoxicity screening battery
47372507; (2007)
Acceptable/guideline
Initial study
125; 500; and 2,000 mg/kg/day
NOAEL = 125 for males ; <125 for females
Based on ↓ motor and locomotor activity,  clinical signs and ↓ body temperature
LOAEL for male = 500 mg/kg/day based on ↓ motor and locomotor activity.

Follow-up study using only female rats
25, 50 and 100 mg/kg/day.
NOAEL = 50 mg/kg/day
LOAEL = 100 mg/kg/day based on ↓ motor and locomotor activity.
870.6200b
Subchronic neurotoxicity screening battery
47372508;  (2008, Report) (The study was conducted in 2007)
Acceptable/guideline
100; 500; & 2,500 ppm

♂: 7, 33, & 164 mg/kg/day
♀: 8, 41,  & 197 mg/kg/day
NOAEL = 33 mg/kg/day
LOAEL = 164 m/kg/day based on a host of effects which included increases in cholesterol and triglyceride levels, decrease in glucose level, decreases in hemoglobin and hematocrit, and deceases in body weight and food consumption.

No evidence of neurotoxicity in either neurobehavioral parameter or histopathology.
870.7485
ADME study in rats
47372509; (2008)
Acceptable/guideline
5 & 250 mg/kg (single dose  by gavage )([14] C on phenyl ring)

5 mg/kg (radiolabeled fluopyram) after 14 days pre-treatment
With oral dosing, fluopyram was rapidly absorbed (93.2 % of administered radioactivity) from the GI tract of male and female rats. The max. plasma concentration was reached at 15 hrs in males and  11 hrs in females post dosing with 5 mg/kg. After 168 hrs post dosing 91-99 % of the administered radioactivity was eliminated via urine(32-41% of the administered dose) and feces (53-65% of the administered dose). The ratio of renal and fecal elimination was comparable (45% via urine and 47% via feces). The organ which contained the highest radioactivity was the liver (0.4 to 1.0 % of the administered radioactivity.) Considerable enterohepatic circulation was demonstrated by the results. Fluopyram was extensively metabolized and 29 metabolites were identified. It was proposed that three main metabolite groups were formed in the liver (fluopyram-7-OH-GA, 8-OH-GA and enol-GA) (GA=glucuronic acid).
870.7485
ADME in the rat
47372511; (2008)
Acceptable/guideline
Single oral dose, 5 mg/kg (gavage) ([14]C in positions 2 & 6 of  the pyridyl ring)
With oral dosing, fluopyram was absorbed rapidly and efficiently eliminated from the body (>98% of the administered radioactivity was eliminated) after 72 hrs post dosing. No significant residues remained in the body. Considerable enterohepatic circulation occurred. Three main metabolite groups were formed in the liver (fluopyram-7-OH-GA, 8-OH-GA and enol-GA) (GA=glucuronic acid).
870.7485
Distribution of total radioactivity in male & female rats
47372513;  (2008)
Acceptable/non-guideline
Single dose [14]C in the phenyl ring of fluopyram at 3 mg/kg.
Distribution occurred in almost all organs with liver reaching the maximal concentration first, and most of the tissue reaching the peak concentration at approximately 24 hr post-dosing. By 136 hr post dosing little of the radioactivity was present in most organs except nasal mucosa.
870.7485
Distribution of [14]C labeled fluopyram.
47372512;  (2008)
Acceptable/non-guideline
3 mg/kg for ♂ & 4.5 mg/kg for ♀ (Single oral dose; [14]C on pyridyl ring of fluopyram.)
Fluopyram was readily absorbed from the GI tract and distributed among almost all organs. Peak level was reached at approximately 1 hr after dosing in most organs with liver having the higher concentration than other organs. From peak levels, a continuous but slow decline of radioactivity concentrations was observed for all organs.
870.7485
Metabolism in organs and tissues in rats
47372509;  (2008)
Acceptable/non-guideline 5 mg/kg (Single oral dose; [14]C in the 2 & 6 position of the pyridyl ring of fluopyram).
AE C656948 was extensively metabolized, and more than 20 metabolites were identified. The major metabolic transformation was oxidation and took place mainly at the ethylene bridge of the molecule. The major metabolites were AE C656948-7-hydroxy and AE C656948-pyridyl-acetic acid.
870.7600
In-vitro dermal absorption study with human and rat skin
47372514 (2007)
Acceptable
500 mg AE C656948 & 0.5 mg AE C656948 (spray dilution)
Dermatomed skin membranes from human and rat were examined. The report stated that over a period of 24 hrs the potentially absorbable [[14]C]  - AE C656948 was 1.8% and 12.4 % for human and rat skin, respectively. This results in approximately 6x difference between dermatomed human and rat skin. Rat skin being more permeable.

In-vivo dermal absorption
47567201 (2008)
Acceptable/guideline

0, 60 ug (spray dilution) and 60 mg (neat)
The maximal dermal absorption rates for neat formulation and spray dilution were 4.5% and 12.8% of the applied dose, respectively.
870.7800
28-Day immunotoxicity study in rats
48239930; (2010)
Acceptable/guideline
0, 200, 600, 1800 ppm
0, 17.2, 53.6, 156.3 mg/kg/day.
Immunotoxicity NOAEL for anti-SRBC IgM response = 156.3 mg/kg/day (HDT).
                              Mechanistic Studies
Non-guideline
7-Day mechanistic study in female rats (dietary administration)
47372520;  (2008)
Acceptable/non-guideline
3,000 ppm (193 mg/kg/day).
Feeding fluopyram at 193 mg/kg/day in the diet to female rats did not affect body weight, clinical signs or food or water consumption.
Mean absolute and relative liver weights were increased (40 to 43%) relative to the controls. This increase was associated with enlarged and dark livers in 13/15 females.
At histological examination, minimal to slight centrilobular to panlobular hepatocellular hypertrophy was found in all treated animals.
There was a 4x increase in mean BrdU labeling index in both the perilobular and centrilobular areas of the hepatic lobule in treated animals relative to the controls.
A slight increase  in total P-450 content and in mean EROD activity, a moderate increase in mean PROD and BROD activities and a marked increase in mean UDPGT activity (all statistically different from the control group (p<=0.01)) were seen.  The report concluded that AE C656948 has the ability to induce moderately phenobarbital-inducible hepatic enzymes (total cytochrome P-450, BROD and PROD and UDPGT) as well as liver hypertrophy and cell proliferation in the liver.
Non-guideline
7-Day mechanistic study with Phenobarbital

Reduction in activity in all treated animals & slight reduction in body weight gain.  Mean absolute and relative liver weights were increased (≈ 22%) relative to the controls. Dark liver was found in 5/14 females and enlarged liver in 3/14 females.  Minimal to slight centrilobular to panlobular hepatocellular hypertrophy was found in all treated animals. A 2x increase in mean BrdU labeling index in the perilobular and centrilobular areas in the treated animals. A moderate increase in total P-450 content and in mean PROD, BROD and UDPGT activities (all statistically different from the control group p<=0.01). The report states that phenobarbital has the ability to induce hepatic enzymes like total cytochrome P-450, PROD, BROD and UDPGT activities as well as liver hypertrophy and cell proliferation in the liver.
Non-guideline
14-Day dietary administration  to the mice (hepatotoxicity and thyroid hormone investigations)
47372519; (2008
Acceptable/non-guideline
2,000 ppm
308 and 314 mg/kg for 3 or 14 days, respectively.
After 3 days of exposure, mean T3 level was not changed, whereas mean T4 level was decreased (-30%) while mean TSH level was increased (+18%) relative to the controls.  Mean absolute and relative liver weights were increased by approximately 60%. Enlarged liver was found in all the treated animals. Diffuse centrilobular to panlobular hepatocellular hypertrophy and an increased number of mitoses were observed in all examined treated animals. In addition, hepatocellular single cell necrosis was observed in 1/5 treated animals.  No significant microscopic change was observed in the thyroid gland.
Total cytochrome P-450 content was markedly increased (+116%) by the treatment. EROD activities were marginally increased (+235%), whereas PROD and BROD activities were markedly increased (respectively +2890% and +8717%) relative to controls. No significant changes were observed in UDPGT.
Non-guideline
Phenobarbital  14-day mechanistic study in the mouse  (gavage)(hepato-toxicity and thyroid hormone investigations)
47372522;  (2008)
Acceptable/non-guideline
80 mg/kg for 3 or 14 days by gavage.
The report stated that phenobarbital administration at a dose level of 80 mg/kg body weight/day in the mouse for 3 and 14 days induced significant liver changes including increases in hepatic total cytochrome P-450, PROD and BROD activities. Phenobarbital also induced a modification of the normal thyroid hormone balance (in particular by a decrease in T4 and/or T3 after 3 and/or 14 days of exposure together with a concomitant increase in TSH level after 14 days.)
Non-guideline
In-vitro studies on the potential interactions with thyroid peroxidase-catalyzed reactions
47372518;  (2008)
Acceptable/non-guideline
300 μM
Fluopyram at 300 μM did not affect thyroid peroxidase (TPO)-catalyzed guaiacol oxidation and TPO-catalyzed iodine formation. Therefore, the data show that fluopyram does not affect thyroid hormone synthesis at the level of TPO.
Non-guideline
Mechanistic 3-Day toxicity study in the mouse by gavage (thyroid hormone investigations)
49005901 (2012)
Acceptable/non-guideline
0, 100 or 300 mg/kg bw/day for 3 days.
There were no compound related effects on mortality or clinical signs. Plasma T4 levels were significantly decreased in treated animals at all time-points with no obvious time-related trends, Plasma TSH levels were comparable to controls.

Non-guideline
Mechanistic Investigations in the Liver of Female Rats Following Dietary Administration for 28 days
49005902 (2012)
Acceptable/non-guideline
0, 30, 75, 150, 600 or 1500 ppm (0, 2.2, 5.6, 11.3, 44.5, or 111.4 mg/kg bw/day) for 28 days. A one month recovery period in control and high dose animals assessed reversibility of effects. Phenobarbital was used as a positive control at 80 mg/kg bw/day.

Absolute and relative liver weights were increased at >= 44.5 mg/kg bw/day fluopyram and in the phenobarbital-treated group. Following the recovery phase, liver weights were nearly identical among control, high dose fluopyram- and phenobarbital-treated rats. Visibly enlarged livers were seen starting at 5.6 mg/kg bw/day with red foci and prominent lobulation being recorded at higher dose levels. Hepatocellular hypertrophy was observed starting at 44.5 mg/kg bw/day.

After 28 days of treatment, mean liver cell proliferation was increased in the fluopyram treated groups starting at 5.6 mg/kg bw/day and in the phenobarbital group. Enzyme activity was increased in fluopyram- and phenobarbital-treated rats. These activity levels showed partial reversibility following recovery.

Gene transcript expression was increased for both fluopyram- and phenobarbital-treated rats, though there were notable differences in expression between compounds. Partial reversibility was evident after a month without treatment.

Non-guideline
28-Day Toxicity Study for Proliferation Assessment in the male Mouse
49005904 (2012)
Acceptable/non-guideline
0 or 750 ppm (0 or 127 mg/kg bw/day) for 28 days
Phenobarbital (gavage) as positive control

Enlarged and dark livers were present in treated mice. Phenobarbital-treated mice also exhibited dark thyroids without microscopic correlates.

The BrdU labeling index was increased in the fluopyram group, but not the phenobarbital group.

Non-guideline
28-Day Toxicity Study for Thyroid Cell Proliferation in the Mouse
49005905 (2013)
Acceptable/non-guideline
0, 30, 75, 150, 600, 750 or 1500 ppm (0, 5, 13, 25, 99, 124 or 247 mg/kg bw/day) for 28 days.
(28-day recovery groups consisted of control and high dose animals)
There were no compound related effects on mortality, clinical signs, body weight, food or water consumption, organ weights, or gross and histologic pathology. The proliferation index in the thyroid was increased starting at 25 mg/kg bw/day.
Non-guideline
28-Day Dietary Study to Determine Potential Role of the Nuclear Pregnane X Receptor (PXR) and Constitutive Androstane Receptor (CAR) on the Thyroid Changes Following the Administration of Fluopyram to Male Mice (C57BL/6J and PXR KO/CAR KO).
49005906 (2013)
Acceptable/non-guideline
0, 750 or 1500 ppm (125 or 256 mg/kg bw/day for wild type and 130 or 247 mg/kg bw/day for knockout) for 28 days.

There were no effects on mortality, clinical signs, body weight or food or water consumption. Liver weights were increased in all fluopyram-treated mice. Enlarged livers were observed in the wild type groups, but not in controls or knockout groups. In treated wild type mice, there was an increase in hepatocellular hypertrophy. There were no similar treatment-related effects in the knockout mice.

Thyroid cell proliferation was increased in wild type mice, while the knockout mice had a slight decrease in proliferation index that was likely incidental.

Total cytochrome P-450 content was increased in treated wild type mice, but not in treated knockout mice. PROD activity was greatly increased in treated wild type mice and slightly increased in treated knockout mice. BQ activity was increased in wild type mice while the knockout mice showed slight decreases. Thyroxine glucuronosyl transferase (T4-GT) and bilirubin glucuronidation (BIL-GT) activities were increased in treated wild type mice, but showed no change in treated knockout mice except for a slight decrease in T4-GT activity at 247 mg/kg bw/day.

There was a significant increase of Tsh beta transcript in the pituitary gland of treated wild type mice and a slight decrease in the same measure for high dose knockout mice.

Non-guideline
Enzyme and DNA-Synthesis Induction in Cultured Human Hepatocytes, Main Study
49005907 (2013)
Acceptable/non-guideline
0, 1, 3, 10, 30, 100 or 300 uM fluopyram or at 10, 100 or 1000 uM phenobarbital for 96 hours.
Epidermal growth factor, at 25 ng/mL, was used as a positive control

ATP concentration in the fluopyram groups indicated that cytotoxicity begins around 100 uM fluopyram. Phenobarbital did not affect ATP levels.

There was no effect on DNA synthesis with either fluopyram or phenobarbital. The positive control substance generated a large increase in DNA synthesis.

There was no dose-related increase in PROD activity with fluopyram treatment, though all dose levels up to cytotoxic levels showed an approximate 2-fold increase over controls. The same general effect was seen with phenobarbital. There was a dose-dependent increase in BROD activity following fluopyram treatment. Phenobarbital treatment also produced an increase at the high dose. There was a slight increase in BQ activity at low dose levels of fluopyram. Phenobarbital caused a dose-related increase at the mid and high dose level.

Non-guideline
Enzyme and DNA-Synthesis Induction in Cultured Rat Hepatocytes, Main Study
49005908 (2013)
Acceptable/non-guideline
0, 1, 3, 10, 30, 100 or 300 uM fluopyram or at 10, 100 or 1000 uM phenobarbital for 96 hours. The test vehicle was DMSO. Epidermal growth factor, at 25 ng/mL, was used as a positive control.

ATP concentration in the fluopyram groups was comparable to controls until cytotoxic levels. Phenobarbital did not appear to have an effect on ATP levels.

DNA synthesis was increased with fluopyram and phenobarbital. Cytotoxicity at 100 and 300 uM fluopyram impacted the results. The positive control substance generated a large increase in DNA synthesis.

There was an increase in PROD, BROD and BQ activity following fluopyram and phenobarbital treatment until cytotoxic levels.

Non-guideline
Mechanistic 3-Day Toxicity Study in the Mouse by Oral Gavage (Thyroid Hormone Investigations)
49005909 (2011)
Acceptable/non-guideline
0, 100 or 300 mg/kg bw/day for 3 days. Phenobarbital was used as a positive control at 80 mg/kg bw/day.
There were no compound related effects on mortality, clinical signs, body weight or gross pathology. There were small decreases in body weight gains in all treated groups, though this effect lacked a dose-response relationship in the fluopyram groups.

Plasma T4 levels were significantly decreased in all fluopyram- and phenobarbital-treated mice, but plasma TSH levels were comparable to controls. There was an increase in Tsh beta transcript in the pituitary in all treated groups.
Non-guideline
Mechanistic 28-Day Toxicity Study in the Mouse by Dietary Administration (Hepatotoxicity and Thyroid Hormone Investigations)
49005911 (2012) (28-day dietary study)
49005903 (2013) (PROD and BQ assessment)
Acceptable/non-guideline
0, 30, 75, 150, 600 or 750 ppm (0, 5, 13, 25, 102 or 128 mg/kg bw/day) for 28 days. Phenobarbital was used as a positive control at 80 mg/kg bw/day.
There were no treatment-related clinical signs or mortalities in the fluopyram groups. The phenobarbital group showed reduced motor activity during the dosing phase and there were three deaths between days 2 and 7. There were no treatment-related clinical signs in any group during the recovery phase. There was no effect on body weight related to fluopyram treatment. Decreased body weight and body weight gain were noted in phenobarbital-treated mice during treatment followed by increased body weight gains compared to controls during the recovery phase. There was no effect on food consumption in the fluopyram-treated groups. The phenobarbital group had a small reduction in food consumption during the first week of dosing.

Plasma T4 levels were decreased in fluopyram- and phenobarbital-treated animals while plasma TSH levels were comparable amongst all groups. Following the recovery phase, plasma hormone levels were comparable across groups.

Absolute and relative liver weights were increased in both fluopyram-treated mice starting at 25 mg/kg bw/day and the phenobarbital-treated mice following the dosing phase. After the recovery phase, all groups had comparable liver weights.

UDPGT enzymatic activity towards bilirubin was increased in all treated animals and reached statistical significance at 102 and 128 mg/kg bw/day of fluopyram. Similar results were noted for UDPGT activity towards thyroxine, though the dose-response relationship was not strong at the high dose. Following the recovery phase, the UDPGT activities were roughly comparable to controls. PROD and BQ activities were increased in fluopyram- and phenobarbital-treated mice at 28 days. The activities of both PROD and BQ were statistically comparable to controls following the recovery period.

There was an increase of Tsh beta transcript in the pituitary gland of fluopyram- and phenobarbital-treated animals following the dosing phase. After the recovery phase, the fluopyram-treated mice had slightly elevated relative tsh b, but the phenobarbital-treated mice were similar to controls.

Appendix B.  Physical/Chemical Properties

Table B1.  Physicochemical Properties of Fluopyram.
Parameter
Value
Reference
Melting point
118 ºC
MRID 47372240
pH
6.6 (1% aqueous solution; pure substance)
MRID 47372236
Density
1.53
MRID 47372242
Water solubility (20 °C)
Distilled water (pH 6.7) = 16 mg/L
pH 4 = 15 mg/L
pH 7 = 16 mg/L
pH 9 = 15 mg/L
MRID 47372247
Solvent solubility (g/L at 20 °C)
heptane	0.66
toluene	62.2
dichloromethane	>250
methanol	>250
acetone	>250
ethyl acetate	>250
dimethyl sulfoxide	>250
MRID 47372248
Vapor pressure
1.2 x 10-6 Pa at 20 ºC
3.1 x 10-6 Pa at 25 ºC
2.9 x 10-4 Pa at 50 ºC
MRID 47372249
Dissociation constant (pKa)
0.5 (23 ºC)
MRID 47372243
Octanol/water partition coefficient Log(KOW)
3.3
MRID 47372245
UV/visible absorption spectrum
Peak max at 270 nm
MRID 47372237

Appendix C.  Review of Human Research

The PHED Task Force, 1995.  The Pesticide Handlers Exposure Database, Version 1.1.  Electronic Database.  Task Force Members: Health Canada, U.S. EPA, and the National Agricultural Chemicals Associations, released February 1995.

The Agricultural Handler Exposure Task Force (AHETF), 2011. The Occupational Handler Unit Exposure Surrogate Reference Table.  U.S. EPA.  Released June 21, 2011.

Data from the Outdoor Residential Exposure Task Force (ORETF).

HED Residential Standard Operating Procedures (2012).

Appendix D.  Residential Handler and Post-application Exposure and Risk Estimates

Table D.1.  Residential Handler Short-term Exposure and Risk Estimates for Fluopyram.
                                   Use Site
                                  Equipment/
                              Application Method
                              Application Rate[1]
                    Area Treated or Amount HandledDaily[2]
                                Exposure Route
                           Unit Exposure (mg/lb ai)
                           Daily Dose[3] (mg/kg/day)
                                    MOE[4]
                                Gardens / Trees
                         Manually-Pressurized Handwand
                               0.00223 lb ai/gal
                                     5 gal
                                    Dermal
                                      63
                                    0.0088
                                    34,000

                                  Inhalation
                                     0.018
                                   0.0000025
                                   5,800,000
                                Gardens / Trees
                         Manually-Pressurized Handwand
                            0.000005119 lb ai/ft[2]
                                  1200 ft[2]
                                    Dermal
                                      63
                                    0.0048
                                    62,000

                                  Inhalation
                                     0.018
                                   0.0000014
                                  10,000,000
                                Gardens / Trees
                               Hose-End Sprayer
                               0.00223 lb ai/gal
                                    11 gal
                                    Dermal
                                      58
                                     0.018
                                    17,000

                                  Inhalation
                                    0.0014
                                  0.00000043
                                  34,000,000
                                Gardens / Trees
                               Hose-End Sprayer
                            0.000005119 lb ai/ft[2]
                                  1200 ft[2]
                                    Dermal
                                      58
                                    0.0045
                                    67,000

                                  Inhalation
                                    0.0014
                                  0.00000011
                                  130,000,000
                                Gardens / Trees
                                   Backpack
                               0.00223 lb ai/gal
                                     5 gal
                                    Dermal
                                      130
                                     0.018
                                    17,000

                                  Inhalation
                                     0.14
                                   0.000020
                                    740,000
                                Gardens / Trees
                                   Backpack
                            0.000005119 lb ai/ft[2]
                                  1200 ft[2]
                                    Dermal
                                      130
                                     0.010
                                    30,000

                                  Inhalation
                                     0.14
                                   0.000011
                                   1,300,000
                                Gardens / Trees
                                 Sprinkler Can
                               0.00223 lb ai/gal
                                     5 gal
                                    Dermal
                                      58
                                    0.0081
                                    37,000

                                  Inhalation
                                    0.0014
                                  0.00000020
                                  74,000,000
                                Gardens / Trees
                                 Sprinkler Can
                            0.000005119 lb ai/ft[2]
                                  1200 ft[2]
                                    Dermal
                                      58
                                    0.0045
                                    67,000

                                  Inhalation
                                    0.0014
                                  0.00000011
                                  130,000,000
                                 Lawns / Turf
                         Manually-Pressurized Handwand
                               0.00404 lb ai/gal
                                     5 gal
                                    Dermal
                                      63
                                     0.016
                                    19,000

                                  Inhalation
                                     0.018
                                   0.0000045
                                   3,200,000
                                 Lawns / Turf
                               Hose-End Sprayer
                                 0.404 lb ai/A
                                     0.5 A
                                    Dermal
                                     13.4
                                     0.034
                                     8,900

                                  Inhalation
                                     0.022
                                   0.000056
                                    260,000
                                 Lawns / Turf
                                   Backpack
                               0.00404 lb ai/gal
                                     5 gal
                                    Dermal
                                      130
                                     0.033
                                     9,100

                                  Inhalation
                                     0.14
                                   0.000035
                                    410,000
                                 Lawns / Turf
                                 Sprinkler Can
                           0.000009285 lb ai / ft[2]
                                  1000 ft[2]
                                    Dermal
                                     13.4
                                    0.0016
                                    190,000

                                  Inhalation
                                     0.022
                                   0.0000026
                                   5,700,000
[1] Maximum Single Application Rate.
[2] Units Treated taken from Science Advisory Council for Exposure, Standard Operating Procedure 9.1, Standard Values for Daily Acres Treated in Agriculture, Rev. 25 SEP 2001.
[3] Daily Dose = Unit Exposure x Application Rate x Units Treated  Body Weight (80 kg).
[4] Margin Of Exposure (MOE) = NOAEL (mg/kg/day)  Daily Dose (mg/kg/day); where the NOAEL = 300 mg/kg/day for dermal exposure & 14.5 mg/kg/day for inhalation exposure.

Table D.2.  Residential Post-Application Dermal Short-Term Exposure and Risk Estimates from Turf.
                                   Scenario
                          Application Rate (lb ai/A)
                              TTR[1] (ug/cm[2])
                              Exposure Time (hr)
                                  Population
                                      TC
                                  (cm[2]/hr)
                           Daily Dose[2] (mg/kg/day)
                                    MOE[3]
                               Golf Course Turf
                                     0.446
                                    0.0496
                                       4
                                    Adults
                                     5,300
                                    0.0131
                                    23,000

                          Youths 11 to <16 yr old
                                     4,400
                                    0.0153
                                    20,000

                          Children 6 to <11 yr old
                                     2,900
                                    0.0180
                                    17,000
                            High Contact Activities
                                     0.404
                                    0.0449
                                      1.5
                                    Adults
                                    180,000
                                     0.152
                                     2,000

                          Children 1 to <2 yr old
                                    49,000
                                     0.300
                                     1,000
                                  Mowing Turf
                                     0.404
                                    0.0449
                                       1
                                    Adults
                                     5,500
                                    0.00309
                                    97,000

                          Youths 11 to <16 yr old
                                     4,500
                                    0.00355
                                    85,000
[1] TTR derived as follows: 0.446 lb ai/A x 4.54E+8 ug/lb x 2.47E-8 A/cm[2]x 0.01 (fraction of transferable ai) = 0.0496 ug/cm[2] or 0.404 lb ai/A x 4.54E+8 ug/lb x 2.47E-8 A/cm[2]x 0.01 (fraction of transferable ai) = 0.0449 ug/cm[2].
[2] Daily Dose = [TTR (ug/cm[2]) x (0.001 mg/ug) x Dermal Transfer Coefficient x Exposure Time] / [Body weight (80 kg for adults, 57 kg for youths 11 to <16 yr, 32 kg for children 6 to <11 yr, and 11 kg for children 1 to <2 yr old)].
[3] MOE = NOAEL/Daily Dose.  Short-Term NOAEL = 300 mg/kg/day.

Table D.3.  Residential Post-Application Incidental Oral Exposure and Risk Estimates to 1 to <2 Year Olds from Turf.
                                   Scenario
                               Application Rate
                                   (lb ai/A)
                            Daily Dose (mg/kg/day)
                                      MOE
                                 Hand-to-Mouth
                                     0.404
                                    0.00615
                                     2,400
                                Object-to-Mouth
                                     0.404
                                   0.000187
                                    78,000
                                Soil Ingestion
                                     0.404
                                   0.000014
                                   1,100,000
[1] TTR derived as follows: 0.404 lb ai/A x 4.54E+8 ug/lb x 2.47E-8 A/cm[2]x 0.01 (fraction of transferable ai) = 0.0449 ug/cm[2].
[2] Based on HED's 2012 Residential SOPs: Lawns/Turf (http://www.epa.gov/pesticides/science/residential-exposure-sop.html).
[3] MOE = NOAEL/Daily Dose.  Short-Term NOAEL = 14.5 mg/kg/day.

Table D.4.  Residential Post-Application Dermal Short-Term Exposure and Risk Estimates from Gardens, Ornamentals and Fruit Trees.
                                   Scenario
                          Application Rate (lb ai/A)
                              DFR[1] (ug/cm[2])
                              Exposure Time (hr)
                                  Population
                                      TC
                                  (cm[2]/hr)
                           Daily Dose[2] (mg/kg/day)
                                    MOE[3]
                                    Gardens
                                     0.223
                                     0.625
                                      2.2
                                    Adults
                                     8,400
                                     0.143
                                     2,100

                                      1.1
                          Children 6 to <11 yr old
                                     4,600
                                    0.0980
                                     3,100
                                     Trees
                                     0.223
                                     0.625
                                      1.0
                                    Adults
                                     1,700
                                    0.0132
                                    23,000

                                      0.5
                          Children 6 to <11 yr old
                                      930
                                    0.0090
                                    33,000
[1] DFR derived as follows: 0.223 lb ai/A x 4.54E+8 ug/lb x 2.47E-8 A/cm[2]x 0.25 (fraction of transferable ai) = 0.625 ug/cm[2].
[2] Daily Dose = [DFR (ug/cm[2]) x (0.001 mg/ug) x Dermal Transfer Coefficient x Exposure Time] / [Body weight (80 kg for adults and 32 kg for children 6 to <11 yr)].
[3] MOE = NOAEL/Daily Dose.  Short-Term NOAEL = 300 mg/kg/day.

Appendix E.  Occupational Handler and Post-application Exposure/Risk Summary Tables

Table E.1. Occupational Short- and Intermediate-Term Dermal and Inhalation Exposures and Risk Estimates For Fluopyram
                               Exposure Scenario
                                Crop or Target
                         Maximum Application Rate[a]
                                   (lb ai/A)
                        Area Treated Daily[b] (A/day)
                               Unit Exposure[d]
                         Daily Exposure[e] (mg/kg/day)
                                    MOE[f]

Baseline Dermal[c] (mg/lb ai)
PPE-G Dermal[c] (mg/lb ai)
Baseline Inhalation[c] (ug/lb ai)
Baseline Dermal
PPE-G Dermal
Baseline Inhalation
Baseline Dermal
PPE-G Dermal
Baseline Inhalation
                                 Mixer/Loader
  Mixing/Loading Liquid Concentrates for Aerial and Chemigation Applications
Artichoke (globe); Brassica (cole) Leafy Vegetables; Bulb Vegetables; Carrot; Citrus; Cucurbit Vegetables; Fruiting Vegetables; Ginseng; Grapes and Small Vine Fruits (except Fuzzy Kiwifruit); Herbs and Spices (except Black Pepper); Hops; Leafy Vegetables; Pome Fruit; Other Root, Tuberous and Corm Vegetables; Small Berries (Caneberries and Bushberries); Stone Fruit; Strawberry and Other Low-Growing Berries
                                     0.222
                                      350
                                     0.22
                                    0.0376
                                     0.219
                                     0.214
                                    0.0365
                                    2.13E-4
                                     1,400
                                     8,200
                                    68,000

               Brassica Leafy Vegetables Head and Stem Subgroup
                                     0.125
                                      350

                                     0.120
                                    0.0206
                                    1.20E-4
                                     2,500
                                    15,000
                                    120,000

Canola Subgroup; Cereal grains; Forage, Fodder, or Straw from Cereal Grains; Cotton; Legume Vegetables (including Soybean); Potato; Sugar Beet; Sunflower subgroup
                                     0.222
                                     1200

                                     0.733
                                     0.125
                                    7.29E-4
                                      410
                                     2,400
                                    20,000

           Nursery (ornamentals, vegetables, trees, container stock)
                                     0.131
                                      60

                                    0.0216
                                    0.00370
                                    2.15E-5
                                    14,000
                                    81,000
                                    670,000

                                      Sod
                                     0.446
                                      350

                                     0.429
                                    0.0734
                                    4.28E-4
                                      700
                                     4,100
                                    34,000
        Mixing/Loading Liquids Concentrates for Groundboom Applications
Artichoke (globe); Brassica (cole) Leafy Vegetables; Bulb Vegetables; Carrot; Citrus; Cucurbit Vegetables; Fruiting Vegetables; Ginseng; Grapes and Small Vine Fruits (except Fuzzy Kiwifruit); Herbs and Spices (except Black Pepper); Hops; Leafy Vegetables; Pome Fruit; Other Root, Tuberous and Corm Vegetables; Small Berries (Caneberries and Bushberries); Stone Fruit; Strawberry and Other Low-Growing Berries
                                     0.222
                                      80
                                     0.22
                                    0.0376
                                     0.219
                                    0.0489
                                    0.00835
                                    4.86E-5
                                     6,00
                                    36,000
                                    300,000

               Brassica Leafy Vegetables Head and Stem Subgroup
                                     0.125
                                      80

                                    0.0275
                                    0.00470
                                    2.74E-5
                                    11,000
                                    64,000
                                    530,000

Canola Subgroup; Cereal grains; Forage, Fodder, or Straw from Cereal Grains; Cotton; Legume Vegetables (including Soybean); Potato; Sugar Beet; Sunflower subgroup
                                     0.222
                                      200

                                     0.122
                                    0.0209
                                    1.22E-4
                                     2,500
                                    14,000
                                    120,000

                            Field Grown Ornamentals
                                     0.131
                                      40

                                    0.0144
                                    0.00246
                                    1.44E-5
                                    21,000
                                    120,000
                                    1.0E+6

           Nursery (ornamentals, vegetables, trees, container stock)
                                     0.131
                                      60

                                    0.0216
                                    0.0037
                                    2.15E-5
                                    14,000
                                    81,000
                                    670,000

                                      Sod
                                     0.446
                                      80

                                    0.0981
                                    0.0168
                                    9.76E-5
                                     3,100
                                    18,000
                                    150,000

                                     Turf
                                     0.446
                                      40

                                    0.0490
                                    0.00839
                                    4.89E-5
                                     6,100
                                    36,000
                                    300,000
         Mixing/Loading Liquids Concentrates for Airblast Applications
           Nursery (ornamentals, vegetables, trees, container stock)
                                     0.131
                                      20
                                     0.22
                                    0.0376
                                     0.219
                                    0.00720
                                    0.00123
                                    7.18E-6
                                    42,000
                                    240,000
                                    2.0E+6

Grapes and Small Vine Fruits (except Fuzzy Kiwifruit); Pome Fruit; Stone Fruit;
                                     0.222
                                      40

                                    0.0244
                                    0.00418
                                    2.43E-5
                                    12,000
                                    72,000
                                    600,000
                                  Applicator
                     Applying Sprays via Aerial Equipment
Artichoke (globe); Brassica (cole) Leafy Vegetables; Bulb Vegetables; Carrot; Citrus; Cucurbit Vegetables; Fruiting Vegetables; Ginseng; Grapes and Small Vine Fruits (except Fuzzy Kiwifruit); Herbs and Spices (except Black Pepper); Hops; Leafy Vegetables; Pome Fruit; Other Root, Tuberous and Corm Vegetables; Small Berries (Caneberries and Bushberries); Stone Fruit; Strawberry and Other Low-Growing Berries
                                     0.222
                                      350
                                  0.00208[g]
                                    No Data
                                   0.0049[g]
                                    0.00203
                                    No Data
                                    4.76E-6
                                    150,000
                                    No Data
                                    3.0E+6

               Brassica Leafy Vegetables Head and Stem Subgroup
                                     0.125
                                      350

                                    0.00114
                                    No Data
                                    2.68E-6
                                    260,000
                                    No Data
                                    5.4E+6

Canola Subgroup; Cereal grains; Forage, Fodder, or Straw from Cereal Grains; Cotton; Legume Vegetables (including Soybean); Potato; Sugar Beet; Sunflower subgroup
                                     0.22
                                     1200

                                    0.00693
                                    No Data
                                    1.64E-5
                                    43,000
                                    No Data
                                    880,000

           Nursery (ornamentals, vegetables, trees, container stock)
                                     0.131
                                      60

                                   0.000204
                                    No Data
                                    4.81E-7
                                    1.5E+6
                                    No Data
                                    3.0E+7

                                      Sod
                                     0.446
                                      350

                                    0.00406
                                    No Data
                                    9.56E-6
                                    74,000
                                    No Data
                                    1.5E+6
                   Applying Sprays via Groundboom Equipment
Artichoke (globe); Brassica (cole) Leafy Vegetables; Bulb Vegetables; Carrot; Citrus; Cucurbit Vegetables; Fruiting Vegetables; Ginseng; Grapes and Small Vine Fruits (except Fuzzy Kiwifruit); Herbs and Spices (except Black Pepper); Hops; Leafy Vegetables; Pome Fruit; Other Root, Tuberous and Corm Vegetables; Small Berries (Caneberries and Bushberries); Stone Fruit; Strawberry and Other Low-Growing Berries
                                     0.222
                                      80
                                    0.0786
                                    0.0161
                                     0.34
                                    0.0175
                                    0.00358
                                    7.55E-5
                                    17,000
                                    84,000
                                    190,000

               Brassica Leafy Vegetables Head and Stem Subgroup
                                     0.125
                                      80

                                    0.00983
                                    0.00201
                                    4.25E-5
                                    31,000
                                    150,000
                                    340,000

Canola Subgroup; Cereal grains; Forage, Fodder, or Straw from Cereal Grains; Cotton; Legume Vegetables (including Soybean); Potato; Sugar Beet; Sunflower subgroup
                                     0.222
                                      200

                                    0.0436
                                    0.00894
                                    1.89E-4
                                     6,900
                                    34,000
                                    77,000

                            Field Grown Ornamentals
                                     0.131
                                      40

                                    0.00515
                                    0.00106
                                    2.23E-5
                                    58,000
                                    280,000
                                    650,000

           Nursery (ornamentals, vegetables, trees, container stock)
                                     0.131
                                      60

                                    0.00773
                                    0.00159
                                    3.34E-5
                                    39,000
                                    190,000
                                    430,000

                                      Sod
                                     0.446
                                      80