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

MEMORANDUM

Date: 		April 22, 2014

SUBJECT:	Fluopicolide and its Metabolite, 2,6-Dichlorobenzamide (BAM).  Human Health Risk Assessment to Support a Petition for an Increased Tolerance on Tuberous and Corm Subgroup 1C Vegetables.    
 
PC Code:  027412 (Fluopicolide) & 027402 (BAM)  
DP Barcode:  D415186
Decision No.:  481092
Registration No.:  59639-139
Petition No.:  3F8191
Regulatory Action:  Section 3 Registration
Risk Assessment Type:  Human Health
Case No.:  NA
TXR No.:  NA
CAS No.:  2008-54-4
MRID No.:  49177301 
40 CFR:  §180.627
		
FROM:	Peter Savoia, Chemist
		Risk Assessment Branch V/VII
		Health Effects Division (7509P)

THROUGH:	Michael S. Metzger, Branch Chief
		Matthew Lloyd, CIH; Industrial Hygienist
		Risk Assessment Branch V/VII
		Health Effects Division (7509P)

TO:		Tony Kish, Risk Manager
		Dominic Schuler, Risk Manager Reviewer
		Fungicide Branch
		Registration Division (7505P) 


The Valent U.S.A. Corporation has submitted petition PP#3F8191 which requests an increase in the tolerances on tuberous and corm subgroup 1C vegetables and potato processed waste established for the fungicide fluopicolide.  This action is being sought to prevent the possible seizure of commodities for over tolerance residues which were legally treated with an early season soil application that has since been restricted.  This document is HED's amended human health risk assessment incorporating the increased tolerances recommended for these commodities.  It contains updated sections of the most recent HED Human Health Risk Assessment of December 2013 completed for fluopicolide (D416744, A. Kamel, 12/18/2013).  In doing so, the following sections which include residue chemistry, dietary exposure, and aggregate risk assessment have been updated to reflect these amended tolerances.  Information contained in the December 2013 risk assessment remains unchanged unless specifically noted in this memorandum.  

1.0	Executive Summary	4
2.0	HED Recommendations	6
2.1	Data Deficiencies	6
2.2	Tolerance Considerations	6
2.2.1	Enforcement Analytical Method	6
2.2.2	Recommended Tolerances	7
2.2.3	Revisions to Petitioned-For Tolerances	7
2.2.4	International Harmonization	7
2.3	Label Recommendations	8
2.3.1	Recommendations from Residue Reviews	8
2.3.2	Recommendations from Residential Assessment	8
3.0	Introduction	9
3.1	Chemical Identity	9
3.2	Physical/Chemical Characteristics	10
3.3	Pesticide Use Pattern	10
3.4	Anticipated Exposure Pathways	11
3.5	Consideration of Environmental Justice	11
4.0	Hazard Characterization and Dose-Response Assessment	12
4.1	Toxicology Studies Available for Analysis	12
4.2	Absorption, Distribution, Metabolism, & Elimination (ADME)	12
4.2.1	Dermal Absorption	13
4.3	Toxicological Effects	13
4.4	Safety Factor for Infants and Children (FQPA Safety Factor)	14
4.4.1	Completeness of the Toxicology Database	14
4.4.2	Evidence of Neurotoxicity	14
4.4.3	Evidence of Sensitivity/Susceptibility in the Developing Young Animal	14
4.4.4	Residual Uncertainty in the Exposure Database	14
4.5	Toxicity Endpoint and Point of Departure Selections	15
4.5.1	Dose-Response Assessment	15
4.5.2	Recommendations for Combining Routes of Exposures for Risk Assessment	15
4.5.3	Cancer Classification and Risk Assessment Recommendation	16
4.5.4	Summary of points of Departure and Toxicity Endpoints	16
4.6	Endocrine Disruption	167
5.0	Dietary Exposure and Risk Assessment	18
5.1	Metabolite/Degradate Residue Profile	18
5.1.1	Summary of Plant and Animal Metabolism Studies	18
5.1.2	Summary of Environmental Degradation	198
5.1.3	Comparison of Metabolic Pathways	19
5.1.4	Residues of Concern Summary and Rationale	19
5.2	Food Residue Profile	19
5.3	Water Residue Profile	20
5.4	Dietary Risk Assessment	21
5.4.1	Description of Residue Data Used in Dietary Assessment	21
5.4.2	Percent Crop Treated Used in Dietary Assessment	21
5.4.3	Acute Dietary Risk Assessment	21
5.4.4	Chronic Dietary Risk Assessment	21
5.4.5	Cancer Dietary Risk Assessment	22
5.4.6	Summary Table	22
6.0	Residential (Non-Occupational) Exposure/Risk Characterization	22
6.1	Residential Handler Exposure	23
6.2	Post-Application Exposure	23
6.3	Residential Bystander Postapplication Inhalation Exposure	25
6.4	Spray Drift	25
7.0	Aggregate Exposure/Risk Characterization	26
7.1	Acute Aggregate Risk	26
7.2	Short-Term Aggregate Risk	26
7.3	Intermediate-Term Aggregate Risk	27
7.4	Chronic Aggregate Risk	27
8.0	Cumulative Exposure/Risk Characterization	27
9.0	Occupational Exposure/Risk Characterization	27
10.0	References	28
Appendix A.  Toxicology Profile and Executive Summaries	30
A.1	Toxicology Data Requirements	30
A.2	Toxicity Profiles	31
Appendix B.  Review of Human Research	37
Appendix C.  Physical/Chemical Properties	37
Appendix D.  Major Fluopicolide Residues	38

1.0	Executive Summary

The Health Effects Division (HED) has evaluated the toxicity and exposure databases to conduct a human health risk assessment for the fungicide active ingredient fluopicolide.  It was performed to support a petition to increase the tolerances on tuberous and corm subgroup 1C vegetables and potato processed waste.  Fluopicolide shares a metabolite, 2,6-dichlorobenzamide (BAM) with another active ingredient, dichlobenil; separate toxicity data and endpoints have been selected for BAM.  However, since increased tolerances on these commodities do not add significantly to the BAM dietary exposure, the conclusions from the most recently conducted BAM human health risk assessment remain unchanged.  The Agency will therefore rely on that assessment to support this use (D354111, D. Rate, 06/19/08).  This assessment addresses risks from the parent compound and its regulated metabolites, other than BAM.  

The principal registrant for fluopicolide is the Valent U.S.A. Corporation.  Fluopicolide is a fungicide that controls a wide range of diseases including downy mildews, late blight, and some Pythium species.  Valent is proposing the following changes to the §180.627 established tolerances:

§180.627(a) General. (1)
	Vegetable, tuberous and corm subgroup 1C............................0.02 ppm
	Vegetable, tuberous and corm subgroup 1C............................0.3 ppm
	Potato, processed potato waste............................................0.05 ppm
	Potato, processed potato waste............................................0.3 ppm

The toxicity database for fluopicolide is complete and demonstrates it has low acute toxicity by the oral, dermal and inhalation routes.  The subchronic and chronic toxicity studies showed that the primary effects of fluopicolide are in the liver.  Developmental toxicity in the rabbit occurred only at doses that caused severe maternal toxicity (including death).  In the rat, developmental effects were seen only at high dose levels in the presence of maternal toxicity. Toxicity endpoints and points of departure (PODs) are selected from the rabbit developmental and rat chronic/cancer studies for all routes (dietary, incidental oral, dermal and inhalation) and durations of exposure (with the exception of acute exposures; there is no endpoint attributable to a single dose).  The available data reveal that fluopicolide is not neurotoxic, carcinogenic, or mutagenic and does not appear to have immunotoxic potential. 

The Food Quality Protection Act (FQPA) safety factor was reduced to 1x because the toxicity database is complete, there is no evidence of quantitative susceptibility following in utero and/or postnatal exposure in the rabbit and rat developmental toxicity studies or in the 2-generation rat reproduction study, and the exposure assessments are unlikely to underestimate risk. There is low concern for the qualitative susceptibility observed in the rat developmental toxicity study because the offspring effects (reduced growth and skeletal defects) and late-term abortions are well characterized and accompanied by maternal toxicity.

There has been no new toxicity data received since the last human health risk assessment was carried out for fluopicolide in December 2013.  The available toxicity data are adequate to assess the hazard potential of this chemical since the database for fluopicolide is complete and there are no datagaps noted.  The relevant toxicity endpoints and uncertainty factors described in the prior risk assessment therefore remain appropriate for this evaluation.  This memorandum incorporates those portions of the December 2013 risk assessment which are pertinent to this evaluation (D416744, A. Kamel, 12/18/2013).

The residue chemistry database for both the parent compound and the BAM metabolite is complete and considered adequate to support all registered uses of fluopicolide.  No new residue chemistry data are required at this time.  Adequate metabolism (crops, livestock, and rotational crops), storage stability, and processing data are available.  Adequate methods are also available for the enforcement of all currently established tolerances.  In regard to amending the tolerances on tuberous and corm subgroup 1C vegetables and potato processed waste, Valent has provided adequate modeling calculations to estimate residue concentrations while field trials are being completed (MRID No. 49177301).  This action is being requested since there is a potential for fluopicolide limits to be exceeded because of an unintentional labeling error allowing for soil directed applications to be made on potatoes.  Upon submission of the completed field trial studies, the Agency will evaluate these data and determine if it is necessary to either increase or decrease these amended tolerances.  

There are no limits established on the use of fluopicolide by Codex or Mexico but there is a Canadian MRL of 0.02 ppm established on a number of tuberous and corm vegetables.  In regard to potato processed waste, Canada does not establish tolerances on livestock feedstuffs.  Consequently, upon amending the U.S. tolerance with this action, harmonization will not be possible with the Canadian MRL since Canada has not yet established directed soil applications on potatoes for use.  There are no other Codex, Canadian, or Mexican MRLs which have been established for the other uses which are the subject of this action. 

An acute dietary exposure and risk assessment was not conducted for fluopicolide because an endpoint attributable to a single dose was not identified from the available data.  Further, a cancer dietary exposure and risk assessment was not conducted because fluopicolide is not likely to be carcinogenic to humans.  A highly conservative chronic dietary exposure and risk assessment was conducted using tolerance levels and highest field trial residues, 100% crop treated assumptions for most commodities, default processing factors in the absence of empirical data, and modeled drinking water values.  Chronic dietary (food and water) estimated risks were well below HED's level of concern for the U.S. population and all population subgroups.  

There are no new residential uses associated with this action; however, fluopicolide is registered on residential turf and recreational sites, such as golf courses.  Exposure to fluopicolide from currently registered uses was assessed in 2013.  All short- and intermediate- term handler, post-application and aggregate residential risks had margins of exposure (MOEs) which were well above the level of concern of 100, and are not of concern.  

In accordance with the FQPA, an aggregate assessment was conducted which considered pesticide exposure and risk from the residential, food, and water pathways.  These exposures included adults applying fluopicolide in a residential setting (dermal and inhalation exposure), post-application exposure to adults and children (dermal exposure), and post-application oral exposure to children (by putting hands or objects in their mouth).  The estimated aggregate short-term risk estimates for all of the exposure scenarios were calculated and are not of concern.  

There are no new occupational uses associated with this action; therefore, the occupational exposure and risk assessments which showed no risks of concern previously conducted in 2013 to establish fluopicolide tolerances on rotational corn remain unchanged.     

Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and Low-Income Populations," http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf).

This assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide.  These studies have received the appropriate ethical review.

2.0	HED Recommendations

Pending the revision of Section F, there are no residue chemistry deficiencies that preclude establishing increased tolerances on tuberous and corm subgroup 1C vegetables and potato processed waste.  Additional data are needed as a condition of registration as outlined in section 2.1 below.  The specific tolerance recommendations are presented below in section 2.2 along with the required label modifications which are discussed in section 2.3.    

2.1	Data Deficiencies

The residue chemistry and toxicity data bases are complete and sufficient for characterizing the residues, dietary exposure, and hazard of fluopicolide.  However, the registrant is required to submit a revised Section F amending the proposed tolerance for potato processed waste to 1.0 ppm as specified in Table 2.2.3.  In accordance with 40CFR158, EPA is also requiring turf transferable residue (TTR) data as part of the 2013 risk assessment made to establish fluopicolide tolerances on rotational corn.

2.2	Tolerance Considerations

2.2.1	Enforcement Analytical Method

An acceptable LC/MS/MS enforcement method RM-43C-2 is available to enforce the tolerances established on tuberous and corm subgroup 1C vegetables as well as on other crop commodities.  Briefly, homogenized plant matrices are mixed with acetone/water, and the mixture is acidified.  An aqueous solution of L-cysteine hydrochloride is added, and the sample is extracted.  The extract is isolated by gravity filtration and diluted to volume with acetone and water.  An aliquot of the extract is concentrated to remove the acetone, and the concentrated extract is partitioned twice with methyl t-butyl ether (MTBE).  The MTBE phases are combined, and an aliquot is evaporated to dryness, re-dissolved in acetonitrile/water, and then filtered for LC/MS/MS analysis.  For Method RM-43C-2, the primary analytical column is packed with reversed-phase C18.  In addition, the method provides for an alternative column packed with a mixed phase of C18 plus a strong cation exchange packing material.  The LC/MS/MS method has a limit of quantitation (LOQ) for fluopicolide of 0.01 ppm.  

Adequate multi-residue method testing data for fluopicolide and its metabolites were previously submitted.  Based on the results of the testing, the multi-residue methods are not appropriate for determining residues of fluopicolide or its metabolites (D321209, A. Acierto, 01/23/2007).

2.2.2	Recommended Tolerances

Tolerances for residues of fluopicolide are currently expressed in terms of the parent compound only when defining its uses.  For this action, Valent is requesting to increase the tolerances on tuberous and corm subgroup 1C vegetables and potato processed waste.  Pending the revision of Section F, there are no residue chemistry deficiencies that preclude increasing the permanent tolerances on tuberous and corm subgroup 1C vegetables and potato processed waste for fluopicolide.  

Tolerances are established for residues of the fungicide fluopicolide [2,6-dichloro-N-[[3-chloro-5-(trifluoromethyl)-2-pyridinyl]methyl]benzamide], including its metabolites and degradates, in or on the commodities listed below.  Compliance with the tolerance levels specified below is to be determined by measuring only fluopicolide [2,6-dichloro-N-[[3-chloro-5-(trifluoromethyl)-2-pyridinyl]methyl]benzamide] in/on the commodities specified in Table 2.2.3:

Table 2.2.3.   Tolerance Summary for Fluopicolide.
                                   Commodity
                          Established Tolerance (ppm)
                           Proposed Tolerance (ppm)
                          Recommended Tolerance (ppm)
                                   Comments
                         Correct Commodity Definition
Potato, processed waste
                                     0.05
                                      0.3
                                      1.0
Potato, processed waste
Vegetable, tuberous and corm subgroup 1C
                                     0.02
                                      0.3
                                      0.3
Vegetable, tuberous and corm subgroup 1C

2.2.3	Revisions to Petitioned-For Tolerances

Based on the maximum residue levels estimated in the modeling calculations provided by the registrant, an amended tolerance of 0.3 ppm is appropriate for tuberous and corm subgroup 1C vegetables (current tolerance is 0.02 ppm).  In regard to potato processed waste, the registrant has proposed a tolerance of 0.3 ppm as well for this commodity.  Processing data previously provided for potato indicate that residues of fluopicolide concentrate in wet peels.  Based on the models provided by Valent, residues of fluopicolide found in/on potato tubers are estimated to be in the range of 0.2 to 0.25 ppm following directed soil application.  Using the highest estimated value of 0.25 ppm and the theoretical concentration factor of 4.0x, an amended tolerance of 1.0 ppm is recommended for potato processed waste.   

2.2.4	International Harmonization

The modeling calculations provided for fluopicolide are adequate to support increased tolerances on tuberous and corm subgroup 1C vegetables proposed with this action (D417354, P. Savoia, 04/22/2014).  There are no MRLs established on the fluopicolide uses by Codex or Mexico.  However, the establishment of an increased U.S. tolerance will exceed the Canadian MRL of 0.02 ppm on various tuberous and corm vegetables.  Harmonization with the Canadian MRL is not possible since Canada has not yet established directed soil applications on potatoes for use.  In regard to potato processed waste, Canada does not establish tolerances on livestock feedstuffs. 

2.3	Label Recommendations

2.3.1	Recommendations from Residue Reviews

Valent has previously submitted residue data to establish the foliar use of fluopicolide on tuberous and corm subgroup 1C vegetables.  These data were reviewed by the Agency and tolerances were set based on this proposed pattern of use.  However, use directions for early season soil application to potatoes were also listed on the registered labels but the tolerance assessment that was conducted did not include treatments made in this manner.  In response, the registrant submitted an amendment to temporarily restrict the soil application use on potatoes.  This action was followed by a petition request to increase these tolerances because there is a potential for fluopicolide limits to be exceeded.  The revised tolerances proposed by Valent are based upon modeling calculations while additional field trial data are completed.  The amendment of these tolerances will require that supporting residue studies must be submitted once completed and soil treatment uses will not appear on any registered labels.  The soil directed use will remain restricted until field trial data are submitted and these data are evaluated to determine if it is necessary to either increase or decrease the amended tolerances.  
          
2.3.2	Recommendations from Residential Assessment

There are no new residential uses associated with this action, and therefore no recommendations for the residential exposure assessment are necessary. Exposure to fluopicolide from the registered uses on residential turf and recreational sites, such as golf courses were assessed in the 2013 risk assessment. All short- and intermediate- term handler, post-application and aggregate residential risks had margins of exposure (MOEs) which were well above the level of concern of 100, and are not of concern.  














3.0	Introduction

3.1	Chemical Identity

Table 3.1.1		Fluopicolide Nomenclature.
Chemical structure
                                       
Empirical Formula
C14H8Cl3F3N2O
Common name
Fluopicolide
Company experimental name
AE C638206 
IUPAC name
2,6-dichloro-N-[3-chloro-5-(trifluoromethyl)-2-pyridylmethyl]benzamide 
CAS name
2,6-dichloro-N-[[3-chloro-5-(trifluoromethyl)-2-pyridinyl]methyl]benzamide 
CAS Registry Number
239110-15-7 
End-use products (EPs)
V-10161 4SC Fungicide (39.5% fluopicolide; EPA File Symbol No. 59639-RUN)
V-10161 Premix Fungicide (5.54% fluopicolide and 55.4% propamocarb; EPA File Symbol No. 59639 - RUE)
Chemical Class
Fungicide
Known Impurities of Concern
None


Table 3.1.2  Chemical Names and Structures of Regulated Fluopicolide Metabolites.
Common name/code
Chemical name
Chemical structure
BAM
AE C653711

2,6-dichlorobenzamide
                                       
PCA
AE C657188

3-chloro-5-trifluoromethylpyridine-2-carboxylic acid 
                                       
P1X
AE 1344122

3-methylsulfinyl-5-trifluoromethylpyridine-2-carboxylic acid
                                       



3.2	Physical/Chemical Characteristics

Fluopicolide is an active ingredient present in several registered fungicide products used to control plant pathogens such as downy mildews, late blight, and some Pythium species.  The appearance of pure analytical grade fluopicolide is that of a fine crystalline beige powder.  The pure analytical grade fluopicolide is noted to have a weak phenol-like odor while the technical grade product is noted to have no characteristic odor at all.  Fluopicolide is considered to be relatively stable at ambient temperatures.  It has an estimated vapor pressure of 8.03 x 10[-7] Pa making volatilization an unlikely route of dissipation.  Fluopicolide has partition coefficients of Log POW = 3.26 at pH 7.8 and 22 +- 1 C and Log POW = 2.9 at pH 4.0, 7.3 and 9.1 and 40 C indicating little potential for bioaccumulation.  When fluopicolide is released into the environment its residues can be found in soil and surface water.  Fluopicolide may be transported off-site to drinking water sources as entrained sediment or via spray drift during spray applications.  Fluopicolide is known to bind weakly to soils, however, there is evidence that adsorption to soil may increase over time as the product is used.  As a result, fluopicolide can be persistent in the environment because its residues can carry over into the following growing season.  A detailed summary of the physical/chemical characteristics of fluopicolide are presented in Appendix C for review.

3.3	Pesticide Use Pattern

A label change will not be associated with the establishment of an increased tolerance for tuberous and corm subgroup 1C vegetables.  As previously noted, following the registration of fluopicolide for foliar use on tuberous and corm subgroup 1C vegetables, use directions for early season soil application to potatoes were also listed on the registered labels.  For the application to soil, the use directions noted two directed soil treatments to be made at the maximum rate of 0.125 lb ai/A (140 g ai/ ha) following a 30-day re-treatment interval (RTI) as depicted below in Table 3.3.  However, the tolerance assessment that was made for the foliar use of fluopicolide on these crops did not include directed treatments made to soil.  As a result, the registrant was required to submit an amendment temporarily restricting the soil application use on potatoes while field trial data are acquired.  In the interim, the registrant has submitted the current petition which requests to increase these tolerances because there is a potential for fluopicolide limits to be exceeded on potatoes treated with soil directed applications.  Upon submission of the completed field trial studies, these data will be evaluated to determine if it is necessary to either increase or decrease the amended tolerances which will allow for the soil use label restriction to be removed. 








Table 3.3.  Summary of Directions Envisioned for the Directed Soil Application of Fluopicolide.
                       Applic. Timing, Type, and  Equip.
                          Formulation [EPA Reg. No.]
                            Applic. Rate (lb ai/A)
                          Max. No. Applic. per Season
                     Max. Seasonal Applic. Rate (lb ai/A)
                                  PHI (days)
                        Use Directions and Limitations
                   Tuberous and Corm Subgroup 1C Vegetables
                              Soil directed spray
                                   59639-139
                            Fluopicolide Technical
                          0.125 lb ai/A (140 g ai/ha)
                                       2
                          0.250 lb ai/A (280 g ai/ha)
                                     NA[1]
                              Pre-plant treatment
RTI: 30  days
For early season soil application for controlling pink rot in potatoes.
Follows one application at planting and the second at hilling.
[1] NA-Not Applicable

3.4	Anticipated Exposure Pathways

The Registration Division has requested an assessment of human health risk to support an increased tolerance for fluopicolide on tuberous and corm subgroup 1C vegetables.  Potatoes treated with soil directed applications may expose humans to greater levels of this pesticide active ingredient in food and drinking water since more of it may reach growing crops.  Fluopicolide is registered for use on agricultural crops as well as on turf (lawns, golf course, and recreational areas).  Exposure to fluopicolide may occur from ingestion of residues in/on foods and in drinking water, and via the dermal and inhalation routes for adults using fluopicolide products in residential settings.  In addition, both adults and children may be exposed dermally in post-application scenarios on turf; children may also be exposed orally in post-application scenarios for turf.  There is a potential for post-application dermal exposure for workers re-entering treated fields as well as occupational handler inhalation exposure during mixing/loading/applying for agricultural and commercial handlers.  

3.5	Consideration of Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and Low-Income Populations," (http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf.  As a part of every pesticide risk assessment, OPP considers a large variety of consumer subgroups according to well-established procedures.  In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup's food and water consumption, and activities in and around the home that involve pesticide use in a residential setting.  Extensive data on food consumption patterns are compiled by the U.S. Department of Agriculture's (USDA's) National Health and Nutrition Examination Survey/What We Eat in America, (NHANES/WWEIA), are used in pesticide risk assessments for all registered food uses of a pesticide.  These data are analyzed and categorized by subgroups based on age, season of the year, ethnic group, and region of the country.  Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant.  Whenever appropriate, non-dietary exposures based on home use of pesticide products and associated risks for adult applicators and for toddlers, youths, and adults entering or playing on treated areas post-application are evaluated.  Further considerations are currently in development as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.

4.0	Hazard Characterization and Dose-Response Assessment

Toxicological effects of fluopicolide were previously evaluated in the human health risk assessments conducted in 2010 and 2013 (D384431, D. Davis, 12/9/2010 and D416744, A. Kamel, 12/18/2013).   A registration review scoping document was released in 2013 (D405060, D. Drew, 02/10/2013).  Subsequently, an immunotoxicity study was submitted and reviewed.  The Hazard and Science Policy Council (HASPOC; TXR. 0056544) met on December 19, 2012 to discuss the need for a 28-day inhalation study.  The HASPOC has determined that, based on a weight of evidence (WOE) approach, a 28-day inhalation toxicity study can be waived.  

4.1	Toxicology Studies Available for Analysis

The toxicity database for fluopicolide is complete and sufficient for characterizing the hazard of fluopicolide.  The toxicity endpoints and points of departure have not changed since the previous risk assessment (D416744, A. Kamel, 12/18/2013).  The immunotoxicity study submitted did not impact the endpoints selected for risk assessment purposes for fluopicolide.  

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

The results of rat metabolism studies (MRID Nos. 46474226, 46474239, 46474241, 46474242, and 46474244) ), indicate that fluopicolide is readily absorbed and rapidly excreted within 72 hours following a single oral dose of 10 mg/kg.  Fecal elimination accounted for 68.8-72.4% of the administered radioactivity whereas urinary excretion accounted for only 18.8-21.4% of the administered radioactivity.  In the bile excretion study (MRID No. 46474244), 51.7% of the administered radioactive dose in both sexes was excreted by the cannulated bile duct indicating a significant portion of the radioactivity recovered in feces is derived from hepatic metabolism of fluopicolide.  

Time-course blood/plasma and tissue studies revealed rapid absorption and distribution of administered radioactivity to all organs and tissues followed by moderately rapid excretion with reduction to background levels in most tissues and organs within 72 hours.  Tissue concentrations peaked at 6-7 hours post-dosing and about 96% of the peak tissue concentrations were dissipated between 6-7 hours and 168 hours post-dose.  

Absorption and excretory patterns did not exhibit gender-related variability, but blood/plasma kinetic studies (MRID No. 46474226) suggested a near-saturation of absorption at the high dose (100 mg/kg bw).  Based upon tissue burden data, neither fluopicolide nor its metabolites appear to undergo any significant tissue sequestration.  With the exception of transiently higher levels in the liver, kidneys, and intestines during the elimination phase, radioactivity concentrations in any given tissue consistently represented considerably less than 1% of the administered dose within 24 hours of administration of fluopicolide.  The major urinary and fecal metabolites were oxidative N-dealkylation cleavage products.  

4.2.1	Dermal Absorption

In a dermal penetration study, [14]C- Fluopicolide in a commercial concentrate, or aqueous dilution of a concentrate for the low dose, was applied to the skin of 5 male Sprague-Dawley rats/time point/dose (MRID No. 46708638).  The dose (1.43 or 659 μg/cm[2] skin) was applied to 12 cm[2] skin and removed after 8 hours.  The animals were sacrificed at 8, 24, 72, or 144 hours after application.  Dermal absorption was found to range from 3-8% (high dose) to 22-37% (low dose).  The most conservative value for risk assessment is a dermal absorption of 37% observed at 24 hours after application.  In vitro dermal absorption data suggested that fluopicolide will penetrate human skin at a substantially lower rate (up to eight times less) than rat skin, providing confidence that a 37% dermal absorption factor is conservative for use in this risk assessment.

4.3	Toxicological Effects

Fluopicolide is a fungicide intended for the control of plant diseases caused by Oomycetes.  Fluopicolide controls a wide range of Oomycete (Phycomycete) diseases including downy mildews (Plasmopara, Pseudoperonospara, Peronospora, and Bremia), late blight (Phytophthora), and some Pythium species.  Fluopicolide appears to interfere with mitosis and cell division resulting in the rapid destabilization of fungal cell structures; this pesticidal mode of action has been characterized as novel and unique and unlike the known modes of action of other registered fungicides.  

The toxic effects of fluopicolide have been examined in subchronic and chronic oral toxicity studies made in rats and mice which revealed liver toxicity in both species.  Kidney and thyroid toxicity were observed in rats only.  The available data reveal that fluopicolide is not neurotoxic, carcinogenic, nor mutagenic.  Fluopicolide does not exhibit immunotoxic potential.

Developmental toxicity in the rabbit occurred only at doses that caused severe maternal toxicity (including death).  In the rat, developmental effects were seen only at high dose levels (700 mg/kg/day) in the presence of maternal toxicity.  Similarly, offspring effects (body weight, kidney) occurred only at levels causing toxicity in parents of the multi-generation reproductive toxicity study.  There is no evidence of increased quantitative susceptibility of rat or rabbit fetuses to in utero or post-natal exposure to fluopicolide.  

No toxic effects were observed in studies in which fluopicolide was administered by the dermal routes of exposure.  For the dermal point of departure, the oral developmental rabbit study was selected because  developmental effects were noted (qualitative susceptibility of the pups), which are not examined in dermal toxicity studies.  In addition, dermal absorption is high (i.e., 37% based on dermal penetration study).   An inhalation toxicity study is not available. The Hazard and Science Policy Council (HASPOC; TXR. 0056544) met on December 19, 2012 to discuss the need for this inhalation study.  The HASPOC has determined that, based on a weight of evidence (WOE) approach, a 28-day inhalation toxicity study is not required at this time.  This approach considered all of the available hazard and exposure information including (1) the physical/chemical properties of fluopicolide, including its potential to volatilize (8.03 x 10-7 Pa vapor pressure); (2) the low acute inhalation toxicity; (3) the primary target organs of fluopicolide are the liver and hematopoietic system following repeat oral exposure; (4) the use of an oral POD for fluopicolide results in screening level occupational/residential inhalation MOEs >40,000. 

Technical grade fluopicolide has low acute toxicity via oral, dermal and inhalation routes of exposure.  Fluopicolide is not a dermal sensitizer, primary eye irritant, or primary skin irritant.

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

The Agency considers it appropriate to reduce the Food Quality Protection Act (FQPA) safety factor to 1x because the toxicity database is complete.  It shows there is no evidence of quantitative susceptibility following in utero and/or postnatal exposure in the rabbit and rat developmental toxicity studies or in the 2-generation rat reproduction study.  These data also demonstrate there is low concern for the qualitative susceptibility observed in the rat developmental toxicity study because the offspring effects (reduced growth and skeletal defects) and late-term abortions are well characterized and accompanied by maternal toxicity (decreased maternal bodyweight), and the exposure assessments are unlikely to underestimate risk.

4.4.1	Completeness of the Toxicology Database

The database is complete and adequate to characterize potential pre- and/or post-natal risk for infants and children.  Developmental toxicity studies in rats and rabbits, and a rat reproduction study are available for FQPA assessment.

4.4.2	Evidence of Neurotoxicity

Neurotoxicity studies were conducted for fluopicolide.  No evidence of neurotoxicity was seen in the acute (CAN) or subchronic (SCN) oral rat neurotoxicity studies performed for fluopicolide.  The only neurotoxic effect was a transient lowering of body temperature in the ACN study, but this was observed at a high dose (2000 mg/kg) and not seen in the SCN study.

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

There is no evidence of quantitative susceptibility following in utero and/or postnatal exposure in the rabbit or rat developmental toxicity studies or in the 2-generation rat reproduction study.  Qualitative susceptibility observed in the rat developmental toxicity study included offspring effects (reduced growth and skeletal defects) and late-term abortions which were accompanied by maternal toxicity (i.e., mortality, abortion/premature delivery, decreased food consumption and bodyweight gain). .  

4.4.4	Residual Uncertainty in the Exposure Database

The dietary exposure assessment is based on an exaggerated exposure scenario which assumes that all commodities being consumed retain either tolerance level-residues or highest field residues found.  The residential exposure assessment assumes maximum label use rate as well as other conservative assumptions.  Moreover, combining the residential incidental oral and dermal exposure scenarios is conservative. Therefore, there are no residual uncertainties in the exposure database and exposures to fluopicolide will not be underestimated.   

Although EPA has required additional data on transferable residues from treated turf for fluopicolide, EPA is confident that it has not underestimated turf exposure due to the conservativeness of the default turf transfer value and conservative assumptions in the short-term turf assessment procedures (e.g., assuming residues do not degrade over the thirty day assessment period and assuming high-end activities on turf for every day of the assessment period).  The additional data on transferable turf residues have been required in case refinement of exposure assessments is needed in the future and to further EPA's general understanding of the availability of turf transferable pesticide residues.

4.5	Toxicity Endpoint and Point Departure Selections

4.5.1	Dose-Response Assessment

Details of the studies used for selecting toxicity endpoints and points of departure are presented in Appendix A of this assessment. 

An acute dietary assessment was not conducted because an endpoint attributable to a single dose has not been identified for fluopicolide.  For chronic dietary, incidental oral, dermal and inhalation exposures, the toxicity endpoints and doses for risk assessment were selected from the rabbit developmental and rat chronic/carcinogenicity studies which were considered co-critical for endpoint selection.  The toxicological profile for fluopicolide suggests that increased durations of exposure does not significantly increase the severity of observed effects.  

For the rabbit developmental study, the maternal LOAEL was 60 mg/kg/day based on death, abortions/premature deliveries (late-term), decreased food consumption, and decreased body weight gain.  The maternal NOAEL was 20 mg/kg/day.  In the combined chronic toxicity/carcinogenicity study in rats the LOAEL was 109 mg/kg/day based on decreased body weight gain and increased thyroid weight and increased incidence of thyroid lesions with a NOAEL of 31.5 mg/kg/day.  The NOAEL from the rabbit developmental study was used for the point of departure since it is protective of effects observed from similar dosing of the chronic/carcinogenicity rat study.  

4.5.2	Recommendations for Combining Routes of Exposure for Risk Assessment

When there are potential residential and occupational exposures to a pesticide, a risk assessment must address all major sources of exposure (oral, dermal, and inhalation).  In doing so, these exposures should be combined for risk assessment if they have the same toxicological effects.  For fluopicolide, the dermal, inhalation and incidental oral exposure routes share a common toxicological endpoint which enables risk estimates to be combined for these exposures.


4.5.3	Cancer Classification and Risk Assessment Recommendations

In accordance with the EPA's Final Guidelines for Carcinogen Risk Assessment (March, 2005), the CARC classified Fluopicolide as "Not Likely to be Carcinogenic to Humans".  This conclusion is based upon the evidence that a non-genotoxic, mitogenic mode of action for liver tumors was established in the mouse and that the carcinogenic effects were not likely at doses that do not cause perturbations of the liver.  Since all risk assessment points of departure were established at dose levels which protect for any liver toxicity, people will not be exposed above these levels, and regulating at these levels will protect for any potential carcinogenic effects.

There was no evidence of carcinogenicity in rats.


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

A summary of the toxicological endpoints and doses chosen for the relevant exposure scenarios for human risk assessment are found below in Table 4.5.4.        

Table 4.5.4. Summary of Toxicological Doses and Endpoints for Fluopicolide for Use in Dietary and 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 
                              (all populations) 
An endpoint attributable to a single dose was not identified from the available data. 
                      Chronic Dietary (all populations) 
                                   Maternal 
                              NOAEL=20 mg/kg/day 
                                   UFA=10x 
                                   UFH=10x 
                                 FQPA SF = 1X 
                                Chronic RfD = 
                                0.2 mg/kg/day 
                             cPAD = 0.2 mg/kg/day 
                   Developmental Toxicity Study in Rabbits 
LOAEL (maternal) = 60 mg/kg/day based on death, abortions/ premature deliveries, decreased food consumption and body weight gain. 
                                       
               Co-critical: Chronic/Oncogenicity Study in Rats 
                           NOAEL = 31.5 mg/kg/day. 
LOAEL = 109.4 mg/kg/day based on decreased body weight gain and increased thyroid weight and increased incidence of thyroid lesions. 
Incidental Oral Short-Terms 

                        Maternal NOAEL = 20 mg/kg/day 
                                   UFA=10x 
                                   UFH=10x 
                                 FQPA SF = 1X 
                           MOE = 100 (residential) 
                   Developmental Toxicity Study in Rabbits 
LOAEL (maternal) = 60 mg/kg/day based on death, abortions/ premature deliveries, decreased food consumption and body weight gain. 
                              Dermal Short- Term 
                        Maternal NOAEL = 20 mg/kg/day 
                                   UFA=10x 
                                   UFH=10x 
                                 FQPA SF = 1X 
                            37% dermal absorption 
                           MOE = 100 (residential) 
                   Developmental Toxicity Study in Rabbits 
LOAEL (maternal) = 60 mg/kg/day based on death, abortions/ premature deliveries, decreased food consumption and body weight gain. 
                                       
               Co-critical: Chronic/Oncogenicity Study in Rats 
NOAEL = 31.5 mg/kg/day. 
LOAEL = 109.4 mg/kg/day based on decreased body weight gain and increased thyroid weight and increased incidence of thyroid lesions. 
    Inhalation Short-  and Intermediate- Term (1-30 days, and 1-6 months) 
                        Maternal NOAEL = 20 mg/kg/day 
                                   UFA=10x 
                                   UFH=10x 
                                 FQPA SF = 1X 
         (inhalation and oral toxicity are assumed to be equivalent) 
                           MOE = 100 (residential) 
                   Developmental Toxicity Study in Rabbits 
LOAEL (maternal) = 60 mg/kg/day based on death, abortions/ premature deliveries, decreased food consumption and body weight gain. 

Co-critical: Chronic/Oncogenicity Study in Rats 
NOAEL = 31.5 mg/kg/day. 
LOAEL = 109.4 mg/kg/day based on decreased body weight gain and increased thyroid weight and increased incidence of thyroid lesions. 
                      Cancer (oral, dermal, inhalation) 
        Classification: "Not Likely to be Carcinogenic to Humans". 
 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. N/A = not applicable. 

4.6	Endocrine Disruption

As required under FFDCA section 408(p), EPA has developed the Endocrine Disruptor Screening Program (EDSP) to determine whether certain substances (including pesticide active and other ingredients) may have an effect in humans or wildlife similar to an effect produced by a "naturally occurring estrogen, or other such endocrine effects as the Administrator may designate."  The EDSP employs a two-tiered approach to making the statutorily required determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal systems.  Chemicals that go through Tier 1 screening and are found to have the potential to interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA will determine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 testing is designed to identify any adverse endocrine related effects caused by the substance, and establish a dose-response relationship between the dose and the E, A, or T effect.

Between October 2009 and February 2010, EPA issued test orders/data call-ins for the first group of 67 chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients.  This list of chemicals was selected based on the potential for human exposure through pathways such as food and water, residential activity, and certain post-application agricultural scenarios.  This list should not be construed as a list of known or likely endocrine disruptors.  Fluopicolide is not among the group of 58 pesticide active ingredients on the initial list to be screened under the EDSP.  Under FFDCA sec. 408(p) the Agency must screen all pesticide chemicals.  Accordingly, EPA anticipates issuing future EDSP test orders/data call-ins for all pesticide active ingredients. 

For further information on the status of the EDSP, the policies and procedures, the list of 67 chemicals, the test guidelines and the Tier 1 screening battery, please visit our website:  http://www.epa.gov/endo/.

5.0	Dietary Exposure and Risk Assessment 

5.1	Metabolite/Degradate Residue Profile

5.1.1	Summary of Plant and Animal Metabolism Studies

The qualitative nature of the residue for fluopicolide in primary crops is adequately understood based upon acceptable grape, lettuce, and potato metabolism studies.  HED has determined that the tolerance expression for all primary crops is fluopicolide (parent) only.  For risk assessment purposes, the residue of concern for tuberous and corm subgroup 1C vegetables includes the parent compound, fluopicolide, and its metabolites, 3-chloro-5-trifluoromethylpyridine-2-carboxylic acid (PCA) and BAM.  For all other primary crops, the residue of concern for risk assessment purposes includes the parent compound and the metabolite, BAM.  With regard to rotational crops, confined rotational crop study data demonstrate the potential for quantifiable residues of fluopicolide and its metabolites at a 12 month PBI.  The tolerance expression for rotational crops is fluopicolide (parent) only.  The residues of concern for the risk assessment for cereal grains as rotational crops are fluopicolide (parent), BAM, PCA, and P1X in grain for human food, and fluopicolide (parent) and BAM in forage/hay/straw and grain for livestock feed.  For livestock, the nature of the residue for fluopicolide is also adequately understood based upon acceptable ruminant and poultry metabolism studies.  The residue of concern for livestock commodities for tolerance setting purposes is fluopicolide (parent) only.  The residue of concern for risk assessment purposes in livestock commodities is fluopicolide and its BAM metabolite. 
 
5.1.2	Summary of Environmental Degradation

Based upon two aerobic soil metabolism studies that were provided, the Agency has determined that the residues of concern in drinking water are parent fluopicolide and the degradate BAM (D384431, D. S. Davis, 12/09/2010).  
5.1.3	Comparison of Metabolic Pathways

The metabolism of fluopicolide in rotational crops appeared to be more extensive than that observed in primary crops (grapes, lettuce, and potato).  Four rotational crop metabolites, 3-OH-BAM, P1X, AE C653598, and AE B102859, were not observed in the primary crop metabolism studies, but were found in the rotated crops. The metabolism of fluopicolide is qualitatively similar in primary plants.  In ruminants and poultry, the metabolism proceeds in a similar fashion as in plants.  In rats, fluopicolide was readily absorbed and rapidly excreted in the urine and feces.  The major metabolites identified in rat were the same as the plant metabolites BAM, 3-OH BAM, PCA and P1X indicating that the toxicity of the metabolites consumed by humans in foods were evaluated (see Appendix D).
  
5.1.4	Residues of Concern Summary and Rationale

The fluopicolide residues of concern for primary and rotational crops, livestock and drinking water are shown in Table 5.1.4.

Table 5.1.4.  Summary of Metabolites and Degradates to be included in the Risk Assessment and Tolerance Expression for Fluopicolide.
Matrix
Residues included in Risk Assessment
                   Residues included in Tolerance Expression
Plants

                                 Primary Crops

All primary crops except Tuberous and Corm Vegetables
Fluopicolide (parent) and BAM 
                                 Fluopicolide

Tuberous and Corm Vegetables
Fluopicolide (parent), PCA, and BAM


                               Rotational Crops

All rotational crops except cereal grains
Fluopicolide (parent) and BAM
                                 Fluopicolide

Cereal grains - grain for human food 
Fluopicolide (parent), PCA, P1X and BAM


Cereal grains - forage/hay/straw and grain for livestock feed
Fluopicolide (parent) and BAM 

Livestock
Fluopicolide (parent) and BAM 
                                 Fluopicolide
Drinking Water
Fluopicolide (parent) and BAM 
                                Not applicable

5.2	Food Residue Profile

For this petition, Valent is requesting to increase the fluopicolide tolerances established on tuberous and corm subgroup 1C vegetables.  The lower tolerances were initially set for a prior action which registered the foliar use of fluopicolide on these crops.  This tolerance assessment was supported by adequate field trial data acquired for potato and included an accompanying processing study. 
     
To support the current request to increase tolerances, Valent has provided adequate modeling calculations which estimate the concentration of fluopicolide that can occur in potato tubers through soil directed treatment (MRID No. 49177301).  

BAM dietary risks were not quantified as part of this assessment because the contribution of BAM from the use of fluopicolide is negligible compared to its contribution from the use of dichlobenil, another active ingredient sharing the same metabolite BAM.

The Agency previously concluded that the presence of residues of fluopicolide and BAM in milk, beef fat, kidney and liver is not likely.  The Agency also concluded that residues are not likely to be present in poultry commodities as a result of feeding feedstuffs containing residues of fluopicolide and BAM.  For the increased tolerance now recommended for processed potato waste, the livestock dietary burden was recalculated and determined to be unaffected.  Therefore, no modification to livestock tolerances is required, and dietary risk estimates for these commodities will be unchanged.

5.3	Water Residue Profile

Estimated Drinking Water Concentrations (EDWCs) for the residues of fluopicolide were recently determined to support the establishment of tolerances on tuberous and corm subgroup 1C vegetables for post-emergence foliar applications.  These analyses were provided by the Environmental Fate and Effects Division (EFED) in the memorandum "Tier II Drinking Water Exposure Assessment for Fluopicolide and its Major Degradate, 2,6-Dichlorbenzamide (BAM) for Use on Potatoes, Carrots, Sugar Beets and Brassica (Cole) Leafy Vegetables" (D370764, R. Miller, 07/20/2010).  

Fluopicolide is not included as an analyte monitored in U.S. surface and groundwater under the USGS's National Water Quality Assessment (NAWQA) program.  Since there is not adequate monitoring data available, surface water concentrations were estimated using the Tier II model PRZM version 3.12/ EXAMS version 2.98.  Ground water concentrations were estimated using the Tier I SCI-GROW model.  The model and its description are available at the EPA internet site: http://www.epa.gov/oppefed1/models/water/.  

The recommended estimated drinking water concentrations (EDWCs) for fluopicolide are summarized below in Table 5.3.

Table 5.3.  Summary of Estimated Surface Water and Groundwater Concentrations for Fluopicolide based on the Tuberous and Corm Vegetable Foliar Use Pattern .

                                 Fluopicolide

                          Surface Water Conc., ppb 1
                           Groundwater Conc., ppb 2
Acute
                                     25.50
                                      0.5
Chronic (non-cancer)
                                     24.14
                                       
Chronic (cancer)
                                     22.36
                                       
[1] From the Tier II PRZM-EXAMS - Index Reservoir model.  Highest surface water EDWC assumed a maximum application rate of 0.125 lbs ai/A, a maximum number of 3 foliar applications and an RTI of 7 days.  For the premix label a maximum application rate of 0.09 lbs ai/A, a maximum of 4 applications and a 10 day RTI were evaluated but did not lead to the highest EDWC values.  The scenario that gave the maximum acute and chronic (non-cancer) EDWCs were aerial application to Florida Carrots.  The scenario that gave the maximum cancer EDWC was aerial application to potatoes.
 [2] From the SCI-GROW model assuming 3 applications of   0.125 lbs ai/A.
Note:  Since only a chronic dietary assessment was conducted, the value of 24.14 ppb is the value used to calculate exposure and risk.


5.4	Dietary Risk Assessment

5.4.1	Description of Residue Data Used in Dietary Assessment

For this dietary assessment, tolerance level residues were utilized for the established uses of fluopicolide except for rotational wheat commodities, and tuberous and corm vegetables.  Maximum residue values were used for these crops since metabolite concentrations are required to be included for risk assessment.  These residue values were carried forward from the previous dietary assessments made for fluopicolide (D381050, D. S. Davis, 08/19/2010 and D407936, A. Kamel, 04/08/2013).

For tuberous and corm commodities, an appropriate residue value for risk assessment includes the parent compound and PCA metabolite.  In order to estimate the level of fluopicolide that can occur from directed soil application, the registrant provided modeling calculations for tolerance setting purposes while field trials are completed.  This was represented by modeling the maximum application rate for directed soil treatment to estimate the percentage of fluopicolide residues which could be translocated to potato tubers.  To obtain a maximum residue value for risk assessment, a ratio was therefore determined for calculating a correlated level of the PCA metabolite.  This was done by evaluating all of the available studies relevant for determining the residues of fluopicolide in root and tuber crops (potato metabolism study, potato field trial studies, and confined rotational crop study).  Upon comparison, the 29 day plant-back interval for radish roots which tested the pyridinyl label examined in the confined rotational crop study gave the most conservative ratio (82% PCA relative to parent).  A maximum residue value of 0.54 ppm is therefore used for tuberous and corm vegetables which is determined by multiplying the modeled fluopicolide value recommended for tolerance (0.3 ppm) by a factor of 1.8X         

Empirical data were used to determine appropriate values for all relevant processed commodities which are carried forward from the previous dietary assessments made for fluopicolide (D381050, D. S. Davis, 08/19/2010 and D407936, A. Kamel, 04/08/2013).
  
5.4.2	Percent Crop Treated Used in Dietary Assessment

The dietary assessment performed in support of this action is considered to be a highly conservative analysis.  It includes tolerance level residues or maximum field trial residue levels for all crops, assumes 100% crop treated and uses empirical or default DEEM processing factors.  

5.4.3	Acute Dietary Risk Assessment

An acute dietary exposure and risk assessment was not conducted because an endpoint attributable to a single dose has not been identified for fluopicolide.

5.4.4	Chronic Dietary Risk Assessment

The chronic dietary exposure analysis and risk assessment made is a highly conservative analysis that uses tolerance level residues or maximum field trial residues and a 100% crop treated assumption (D417355, P. Savoia, 04/22/2014).  Dietary risk estimates were determined considering exposures from food and drinking water using EDWCs for all direct and indirect water sources provided by EFED.  The chronic risk estimates for fluopicolide are below the Agency's level of concern for the general U.S. population and all population subgroups (i.e., <100% of the chronic population adjusted dose).  The most highly exposed population subgroup is children ages 1-2 with an estimate for fluopicolide for food and water of 13% of the cPAD.

5.4.5	Cancer Dietary Risk Assessment

A cancer dietary exposure and risk assessment was not conducted since fluopicolide is not likely to be carcinogenic to humans.

5.4.6	Summary Table

 The established uses along with an increased tolerance on tuberous and corm subgroup 1C vegetables for fluopicolide will result in an estimated exposure to the U.S. Population which is equivalent to 7.7% of the cPAD.  The most highly exposed subgroup is children 1  -  2 years of age with an estimated exposure equivalent to 13% of the cPAD.  Results for all subpopulations are shown in the table below.  

 Table 5.4.6.  Summary of Dietary (Food and Drinking Water) Exposure and Risk for Fluopicolide
                              Population Subgroup
                                 Acute Dietary
                                Chronic Dietary
                                     Cancer
                                        
                          Dietary Exposure (mg/kg/day)
                                    % aPAD*
                                Dietary Exposure
                                  (mg/kg/day)
                                    % cPAD*
                                Dietary Exposure
                                  (mg/kg/day)
                                      Risk
 General U.S. Population
                                      N/A
 0.015484
 7.7
                                      N/A
                                      N/A
 All Infants (< 1 year old)
 
 0.010881
 5.4
                                        
                                        
 Children 1-2 years old
 
 0.025122
 13
 
 
 Children 3-5 years old
 
 0.023460
 12
 
 
 Children 6-12 years old
 
 0.014866
 7.4
 
 
 Youth 13-19 years old
 
 0.011526
 5.8
 
 
 Adults 20-49 years old
 
 0.015214
 7.6
 
 
 Adults 50-99 years old
 
 0.015629
 7.8
 
 
 Females 13-49 years old
 
 0.015484
 7.7
 
 
* %PADs are reported to 2 significant figures.  

6.0 Residential (Non-Occupational) Exposure/Risk Characterization

There are no proposed residential uses associated with this petition.  For this risk assessment there are existing residential uses that have been reassessed in this document to reflect updates to HED's 2012 Residential SOPs along with policy changes for body weight assumptions.  The revision of residential exposures will impact the human health aggregate risk assessment for fluopicolide.  There are products with uses on residential turf-grass and recreational sites.  The products may be applied to turf at rates up to 0.27 lb ai/A, for two applications at an interval of 14 days.  There are also uses on ornamental plants and trees with application rates up to 0.54 lb ai/A.  Since the increased tolerances recommended do not add significantly to the BAM dietary exposure, and there are no new residential uses, the conclusions from the most recently conducted BAM human health risk assessment remain unchanged and a revised quantitative BAM risk assessment is not required  -  aggregate risks for BAM are not of concern.

6.1	Post-Application Exposure

There is the potential for short-term post-application exposure for individuals exposed as a result of being in an environment that has been previously treated with fluopicolide.  These effects were previously evaluated in the human health risk assessments conducted in 2010 and 2013 (D384431, D. Davis, 12/9/2010 and D416744, A. Kamel, 12/18/2013).  All residential post-application risk estimates for fluopicolide were found to be "not of concern" (MOEs > LOCs) for all exposure scenarios and all lifestages.

6.2	Combined Exposure

Residential handler and post-application scenarios should generally not be combined.  Although there is potential for the same individual (i.e., adult) to apply a pesticide in and around the home and be exposed by reentering a treated area in the same day this is unlikely to occur day after day for 30 days.  Combining both of these exposure scenarios would also be inappropriate because of the unrealistically conservative nature of each individual assessment.

Because of the conservative nature of the individual turf and ornamental plants/trees assessments, these scenarios were not combined.  To depict the highest exposure and highest risk scenarios for the residential uses of fluopicolide, Table 6.3 reflects the residential risk estimates for use in the aggregate assessment.  These scenarios include;

   * The recommended residential exposure for use in the adult aggregate assessment reflects dermal post-application exposure to treated gardens.
   * 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 and hand-to-mouth exposures from post-application turf scenario (i.e., post-application exposure to treated turf).



Table 6.3.  Residential Exposures for the Fluopicolide Aggregate Assessment.[1]
                                   Lifestage
                              Residential Handler
                         Residential Post-application 
                                       
                              Dose (mg/kg/day)[2]
                                    MOE[3]
                              Dose (mg/kg/day)[4]
                                    MOE[5]
                                       
                                    Dermal
                                  Inhalation
                                     Total
                                    Dermal
                                  Inhalation
                                     Total
                                    Dermal
                                  Inhalation
                                     Oral
                                     Total
                                    Dermal
                                  Inhalation
                                     Oral
                                     Total
                                  Short-Term
Adult 
                                     0.01
                                    0.00003
                                     0.010
                                       -
                                       -
                                     1,900
                                     0.161
                                      N/A
                                      N/A
                                     0.161
                                      120
                                      N/A
                                      N/A
                                      120
Child (11 to < 16 years old)
                                      N/A
                                    0.0034
                                      N/A
                                      N/A
                                    0.0034
                                     5,800
                                      N/A
                                      N/A
                                     5,800
Child (6 to < 11 years old)
                                       
                                     0.095
                                      N/A
                                      N/A
                                     0.095
                                      210
                                      N/A
                                      N/A
                                      210
Child (1 to < 2 years old)
                                       
                                     0.074
                                      N/A
                                    0.0041
                                     0.078
                                      270
                                      N/A
                                     4,900
                                      260
1	Bolded risk estimates should contribute to the residential exposure portion of the aggregate assessment. 
2	Residential Handler Dose = the highest handler dose for each applicable lifestage of all scenarios assessed.  Total = dermal + inhalation.
3	Residential Handler MOE = the MOEs associated with the highest doses identified.  Total = 1 / (1/Dermal MOE) + (1/Inhalation MOE).
4	Residential Post-application Dose = the highest post-application dose for each applicable lifestage of all scenarios assessed.  Total = dermal + inhalation + incidental oral, where applicable.
5	Residential Post-application MOE = the MOEs associated with the highest doses identified.  Total = 1 / (1/Dermal MOE) + (1/Inhalation MOE) + (1/Incidental oral MOE).  





















6.3	Residential Bystander Post-Application Inhalation Exposure

Although there are no agricultural applications associated with this action, there are registered uses of fluopicolide on agricultural crops.  

Based on the Agency's current practices, a quantitative post-application inhalation exposure assessment was not performed for fluopicolide at this time primarily because of the low acute inhalation toxicity (Toxicity Category IV) and low vapor pressure (6 x 10[-9] mm Hg at 25° C).  However, volatilization of pesticides may be a source of post-application inhalation exposure to individuals nearby pesticide applications.  The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP's final report on March 2, 2010  Available at: http://www.epa.gov/scipoly/sap/meetings/2009/120109meeting.html.  The Agency is in the process of evaluating the SAP report and may, as appropriate, develop policies and procedures to identify the need for and, subsequently, the way to incorporate post-application inhalation exposure into the Agency's risk assessments.  If new policies or procedures are developed, the Agency may revisit the need for a quantitative post-application inhalation exposure assessment for fluopicolide.

Although a quantitative residential post-application inhalation exposure assessment was not performed, an inhalation exposure assessment was performed for handlers.  This exposure scenario is representative of a worst case inhalation exposure and should be considered protective of post-application inhalation exposure scenarios for fluopicolide.

6.4 	Spray Drift

Although there are no agricultural applications associated with this action, there are registered uses of fluopicolide on agricultural crops.  

Spray drift is always a potential source of exposure to residents nearby to spraying operations.  This is particularly the case with aerial application, but, to a lesser extent, could also be a potential source of exposure from the ground application method employed for fluopicolide.  The Agency has been working with the Spray Drift Task Force, EPA Regional Offices and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices (see the Agency's Spray Drift website for more information (Available: 
http://www.epa.gov/opp00001/factsheets/spraydrift.htm.  Agency has completed its evaluation of the new database submitted by the Spray Drift Task Force, a membership of U.S. pesticide registrants, and is developing a policy on how to appropriately apply the data and the AgDRIFT computer model to its risk assessments for pesticides applied by air, orchard airblast and ground hydraulic methods.  After the policy is in place, the Agency may impose further refinements in spray drift management practices to reduce off-target drift with specific products with significant risk estimates associated with drift.

It is noted that the 0.27 lb ai/acre application rate for turf was modeled to estimate post-application residential exposure of children.  As this rate is equal to or higher than many of agricultural application rates, this scenario is protective of any exposure of children via spray drift from agricultural fluopicolide applications.

7.0 Aggregate Exposure/Risk Characterization

In compliance with FQPA, HED must aggregate (add) pesticide exposures and risks from three major sources: food, drinking water, and residential exposures.  To perform this aggregate assessment, exposures from all 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.  Fluopicolide is registered for use in residential settings as well as for use on food; therefore, an aggregate risk was conducted which combined average food residues with non-occupational estimates of exposure.

7.1	Acute Aggregate Risk

An acute aggregate assessment was not conducted because an endpoint attributable to a single dose was not identified from the available data for fluopicolide.

68.2 Short- and Intermediate-Term Aggregate Risk

Short-term aggregate assessments include exposures that will occur from one to thirty days and include the most protective short-term residential exposure scenarios along with chronic food and water exposures.  The exposure scenario used for adults and children was post-application exposure to treated gardens.  Table 7.2.1 presents the most appropriate scenario for aggregate food and water as well as short-term residential risk calculations.  The short-term aggregate risk estimates were not of concern for adults or children.

Table 7.2.1  Short-Term Aggregate Risk Calculations
                                  Population
                              Short-Term Scenario
                                       
                                NOAEL mg/kg/day
                                    LOC[1]
                      Max Allowable Exposure[2] mg/kg/day
                   Average Food and Water Exposure mg/kg/day
                       Residential Exposure mg/kg/day[3]
                          Total Exposure mg/kg/day[4]
                Aggregate MOE (food, water, and residential)[5]
Adult Male
                                      20
                                      100
                                      0.2
 0.015629
                                     0.161
                                   0.176629
                                      110
Adult Female
                                       
                                       
                                       
 0.015484
                                     0.161
                                   0.176484
                                      110
Child (6-<11yr)[6]
                                       
                                       
                                       
 0.014866
                                     0.095
                                   0.109866
                                      180
[1] For LOC calculation a 10x standard inter-species, 10x  intra- species and 1x FPQA uncertainty factors are included. 
[2] Maximum Allowable Exposure (mg/kg/day) = NOAEL/LOC
3 Residential Exposure = [Oral exposure + Dermal exposure + Inhalation Exposure].  Values from Table 6.3
[4] Total Exposure = Avg Food & Water Exposure + Residential Exposure)
[5] Aggregate MOE = [NOAEL / (Avg Food & Water Exposure + Residential Exposure)]
6 This age group represents the most rerpresentative of a high-end exposure residential scenario among children.  The average food and water exposure daily dose was selected for the corresponding age group (6-12 yr.) from Table 5.4.1.1.


71.2 Intermediate-Term Aggregate Risk

Intermediate-term exposures to fluopicolide are not likely because of the intermittent nature of applications by homeowners and the exposure pattern to golfing.  

71.3 Chronic Aggregate Risk

Chronic or long-term aggregate assessments include exposures that will exceed six (6) months.    Since there are no chronic non-occupational (residential) exposures, the chronic aggregate assessment only includes food and drinking water exposures.  Refer to section 5.4.1 for a detailed discussion of the chronic dietary assessment.

71.4 Cancer Aggregate Risk

HED has considered fluopicolide to be classified as "not likely to be carcinogenic to humans"; no quantification of cancer risks is required.

6.0 Cumulative Exposure/Risk Characterization

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding for  fluopicolide or any other substance.  Although fluopicolide shares a common metabolite, BAM, with dichlobenil, quantification of risks for residues of BAM resulting from fluopicolide was not done as part of this assessment since they contribute an insignificant amount to the total BAM exposure.  Furthermore, aggregate risks to BAM are not of concern.  For the purposes of this tolerance action, EPA has not assumed that fluopicolide has a common mechanism of toxicity with other substances.  For information regarding EPA's efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA's Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on EPA's website at:  http://www.epa.gov/pesticides/cumulative/.

7.0 Occupational Exposure/Risk Characterization

There are no new agricultural or occupational applications associated with this action which requests to increase the tolerances on tuberous and corm subgroup 1C vegetables.  Therefore, there is no potential occupational exposure associated with the proposed change in use pattern. 









8.0 References

DP No.:	D416744	
Subject:	Fluopicolide.  Revised Human Health Risk Assessment for the New Section 3 Tolerances on Rotational Corn.   	
From:	A. Kamel, A. LaMay, and J. Liccione
To:	T. Kish and D. Schuler
Date:	02/18/2013
MRIDs:	None

DP No.:	D354111	
Subject:	2,6-Dichlorobenzamide (BAM).  2,6-Dichlorobenzamide (BAM) as a Metabolite/Degradate of Fluopicolide and Dichlobenil.  Human Health Risk Assessment for Proposed Uses of Rhubarb, Dichlobenil on Caneberries (Subgroup 13-07A), and Bushberries (Subgroup 13-07B).  	
From:	D. Rate
To:	S. Stanton
Date:	06/19/2008
MRIDs:	None

MRID No.:	49177301 Allen, R. (2013) Fluopicolide: Proposal for a Revised Tolerance on Potato.  Laboratory Project ID VP-38438.  Unpublished study prepared by Valent Technical Center.  19 p.

DP No.:	D321209	
Subject:	Fluopicolide.  PP#5E6903; Petition for Tolerances on Imported Grapes and Raisins.  Summary of Analytical Chemistry and Residue Data.  
From:	A. Acierto
To:	J. Whitehurst and T. Kish
Date:	01/23/2007
MRIDs:	46474025-46474045, 46474101-46474106, 46708525, and 46708542

DP No.:	D417354
Subject:	Fluopicolide.  Section 3 Registration of an Amended Tolerance on Tuberous and Corm Subgroup 1C Vegetables and Potato Processed Waste for Fluopicolide. 
From:	P. Savoia
To:	D. Schuler and T. Kish
Dated:	04/22/2014
MRID No.:	49177301







DP No.:	D384431	
Subject:	Fluopicolide and its Metabolite, 2,6-Dichlorobenzamide (BAM).  Amended Human Health Risk Assessment to Support New Section 3 Uses on Brassica Leafy Greens Subgroup 5B, Potatoes, Sugar Beets, Carrots and to Allow Rotation to Wheat.  	
From:	D. S. Davis and A. LaMay
To:	J. Whitehurst and T. Kish
Date:	12/09/2010
MRIDs:	None

DP No.:	D405060	
Subject:	Fluopicolide Human Health Risk Assessment Scoping Document in Support of Registration Review.	
From:	D. Drew, A. LaMay, and J. Liccione
To:	R. Wasem
Date:	02/10/2013
MRIDs:	None

TXR No.:	0056544	
Subject:	Fluopicolide: Summary of Hazard and Science Policy Council (HASPOC) Meetings of December 19, 2012: Recommendations on the Requirement of a Subchronic Inhalation Study.  	
From:	K. Rury
To:	D. Drew, J. Liccione, and M. Metzger
Date:	12/19/2012
MRIDs:	None

DP No.:	D370764
Subject:	Tier II Drinking Water Exposure Assessment for Fluopicolide and its Major Degradate, 2,6-Dichlorbenzamide (BAM) for Uses on Potatoes, Carrots, Sugar Beets, and Brassica (Cole) Leafy Vegetables.  
From:	R. Miller
To:	T. Kish and J. Whitehurst 
Dated:	07/20/2010
MRID No.:	None

DP No.:	D417355
Subject:	Fluopicolide.  Chronic Aggregate Dietary Exposure Assessment of Food and Drinking Water to Support a Petition for an Increased Tolerance on Tuberous and Corm Subgroup 1C Vegetables.  
From:	P. Savoia
To:	D. Schuler and T. Kish
Dated:	04/22/2014
MRID No.:	None


Appendix A.  Toxicology Profile and Executive Summaries

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
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
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
                                      yes
                                      yes
                                      yes
                                      yes
870.5100    Mutagenicity -- Gene Mutation - bacterial	
870.5300    Mutagenicity -- Gene Mutation - mammalian	
870.5xxx    Mutagenicity -- Structural Chromosomal Aberrations	
870.5xxx    Mutagenicity -- Other Genotoxic Effects	
                                      yes
                                       
                                      yes
                                       
                                      yes
                                      yes
                                      yes
                                       
                                      yes
                                       
                                      yes
                                      yes
870.6100a  Acute Delayed Neurotoxicity (hen)	
870.6100b  90-Day Neurotoxicity (hen)	
870.6200a  Acute Neurotoxicity Screening Battery (rat)	
870.6200b  90-Day Neurotoxicity Screening Battery (rat)	
870.6300    Develop. Neurotoxicity	
                                      no
                                      no
                                      yes
                                       
                                      yes
                                      no
                                       -
                                       -
                                      yes
                                       
                                      yes
                                       -
870.7485    General Metabolism	
870.7600    Dermal Penetration	
870.7800    Immunotoxicity	
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes

A.2	Toxicity Profiles

Table A.2.1	Acute Toxicity Profile - Test Substance 
Guideline No.
Study Type
MRID(s)
                                    Results
                               Toxicity Category
                                   870.1100 
                        Acute oral [rat] Fluopicolide 
                         Technical 98.3% (AE C638206) 
                        Formulation SC 40 (AE C638206) 
                        Formulation SC61 (AE B066752) 
                                   46708601 
                                   46709903 
                                   46709803 
                            LD50>= 2000 mg/kg (f) 
                          LD50 >= 2000 mg/kg (m/f) 
                          LD50 >= 2000 mg/kg (m/f) 
                                     III 
                                     III 
                                     III 
                                   870.1200 
                              Acute dermal [rat] 
                         Technical 97.7% (AE C638206) 
                        Formulation SC40 (AE C638206) 
                        Formulation SC61 (AE B066752) 
                                   46708605 
                                   46709904 
                                   46709804 
                             LD50 >= 5000 mg/kg 
                             LD50 >= 4000 mg/kg 
                              LD50 >=4000 mg/kg 
                                      IV 
                                     III 
                                     III 
                                   870.1300 
                            Acute inhalation [rat] 
                            Technical (AE C638206) 
                        Formulation SC40 (AE C638206) 
                        Formulation SC61 (AE B066752) 
                                   46708606 
                                   46709905 
                                   46709805 
                              LC50 >= 5.16 mg/L 
                             LC50 >= 1.789 mg/L 
                             LC50 >= 3.195 mg/L 
                                      IV 
                                     III 
                                      IV 
                                   870.2400 
                        Acute eye irritation [rabbit] 
                         Technical 97.7% (AE C638206) 
                        Formulation SC40 (AE C638206) 
                        Formulation SC61 (AE B066752) 
                                   46708607 
                              46709906 46709806 
                        slight conjuctival irritation 
                   chemosis/corneal opacity in both studies 
                                      IV 
                                     III 
                                     III 
                                   870.2500 
                       Acute dermal irritation [rabbit] 
                         Technical 97.7% (AE C638206) 
                        Formulation SC40 (AE C638206) 
                        Formulation SC61 (AE B066752) 
                                   46708650 
                                   46709907 
                                   46709807 
                              None (PDII = 0.00) 
                             slight (PDII = 0.08) 
                             slight (PDII = 0.25) 
                                      IV 
                                      IV 
                                      IV 


Table A.2.2	Subchronic, Chronic and Other Toxicity Profile
                                Guideline No. 
                                  Study Type
                    MRID No. (year)/ Classification /Doses
                                    Results
                                   870.3050 
                       28-day dietary toxicity (mouse) 
46708609 (2000) 
                             Acceptable/Guideline 
         M/F: 0/0, 0.95/1.19, 10.4/12.9, 100/129, 980/1242 mg/kg/day 
                 NOAEL = 980/1242 mg/kg/day; the limit dose). 
                         The LOAEL was not observed. 
                                   870.3050 
                        28-day dietary toxicity (rat) 
                               46708610 (2000) 
                             Acceptable/Guideline 
        M/F: 0/0, 1.8/1.8, 17.4/17.9, 174/184, and 1720/1820 mg/kg/day 
                NOAEL = 17.4/17.9 mg/kg/day in males/females). 
The LOAEL = 174/184 mg/kg/day (M/F) based on decreased body weight gain and food conversion in females and nephrotoxicity in males. 
                                   870.3050 
                        28-day dietary toxicity (rat) 
                     AE 1344122 (Fluopicolide metabolite) 
                               46708611 (2003) 
                             Acceptable/Guideline 
      M/F: 0/0, 1.5/1.7, 14.9/16.8, 151.6/167.1, 1495.3/1615.5 mg/kg/day 
                        NOAEL = 151.6/167.1 mg/kg/day. 
LOAEL = 1495.3/1615.5 mg/kg/day based on decreased body weights and body weight gains in both sexes, and nephrotoxicity in females. 
                                   870.3050 
                        28-day dietary toxicity (rat) 
                    AE C657378 (a Fluopicolide metabolite) 
                               46708612 (2003) 
                             Acceptable/Guideline 
    M/F: 0/0, 1.6/2.1, 16.2/20.4, 159.2/230.6, and 1775.0/1930.8 mg/kg/day 
                        NOAEL = 159.2/230.6 mg/kg/day. 
LOAEL = 1775.0/1930.8 mg/kg/day based on decreases in body weight and body weight gain (males); increased absolute (females) and relative liver weight (both sexes) and relative kidney weight (males); increased cholesterol (both sexes); and histopathological effects in the liver (females), the kidneys (males), and thyroid (both sexes). 
                                   870.3050 
                          28-day oral toxicity (dog) 
                               46708613 (2000) 
                           Acceptable/Non-guideline 
                          0, 10, 100, 1000 mg/kg/day 
                     NOAEL = 1000 mg/kg/day (limit dose). 
                           LOAEL was not observed. 
                                   870.3100 
                          90-Day oral toxicity (rat) 
                               46474112 (2000) 
                             Acceptable/guideline 
                         M: 0, 7.4, 109, 1668 mg/kg/d 
                        F: 0, 8.4, 119, 1673 mg/kg/day 
          NOAEL = 109 mg/kg/day for males; 8.4 mg/kg/day for females 
LOAEL = 1668 mg/kg/day for males and 119 mg/kg/day for females based on hypertrophy of the zona glomerulosa in the adrenal gland (M/F), decreased cellularity of the bone marrow (M/F), and trabecular hyperostosis of the bone joint (M) 
                                   870.3100 
                         90-Day oral toxicity (mouse) 
                               46474114 (2000) 
                             Acceptable/guideline 
                    M/F: 0, 5.5, 53, 545 or 1092 mg/kg/day 
                         NOAEL = 1092 mg/kg/day (M/F) 
                            LOAEL = not identified 
                                   870.3100 
                         90-Day oral toxicity (mouse) 
                               46474116 (2001) 
                             Acceptable/guideline 
                      M: 0, 10.4, 37.8, 161, 770 mg/kg/d 
                     F: 0, 12.6, 52.8, 207, 965 mg/kg/day 
          NOAEL = 770 mg/kg/day for males; 207 mg/kg/day for females 
LOAEL = not identified for males; 965 mg/kg/day for females based on increased incidence of liver oval cell proliferation 
                                   870.3150 
                          90-Day oral toxicity (dog) 
                               46474118 (2000) 
                             Acceptable/guideline 
                      M&F: 0, 5, 70, 1000 mg/kg/day 
                         NOAEL = 1000 mg/kg/day (M/F) 
                         LOAEL = not identified (M/F) 
                                   870.3200 
                     21/28-Day dermal toxicity (species) 
                               46708614 (2003) 
                             Acceptable Guideline 
                       0, 100, 250, 500, 1000 mg/kg/day 
                            NOAEL = 1000 mg/kg/day 
                          LOAEL > 1000 mg/kg/day 
                    No local or systemic toxicity observed 
                                  870.3700a 
                       Prenatal developmental in (rat) 
                                 Pilot study 
                               46708615 (2000) 
                           Acceptable/non-guideline 
                       F: 500, 1000 mg/kg/day (GD 7-20) 
NOAEL/LOAEL not determined. Only four animals/group. Purpose of study was to determine high-dose level for 46474120. 
                                  870.3700a 
                       Prenatal developmental in (rat) 
                               46474120 (2001) 
                             Acceptable/guideline 
                     F: 0, 5, 60, 700 mg/kg/day (GD 7-20) 
                        Maternal NOAEL = 60 mg/kg/day 
          LOAEL = 700 mg/kg/day based on decreased body weight gain 
                      Developmental NOAEL = 60 mg/kg/day 
 LOAEL = 700 mg/kg/day based on delayed fetal growth and delayed ossification 
                                  870.3700b 
                      Prenatal developmental in (rabbit) 
                                 Pilot study 
                               46708616 (2000) 
                           Acceptable/non-guideline 
                F: 25, 50, 100, 250, 500, or 1000 mg/kg bw/day 
                                  (GD 6-28) 
                        Maternal NOAEL = 25 mg/kg/day 
LOAEL = 50 mg/kg/day based on reduced defecation and abortion in a single dose 
                     Developmental NOAEL = 1000 mg/kg/day 
                             LOAEL = not observed 
                                  870.3700b 
                      Prenatal developmental in (rabbit) 
                               46474122 (2001) 
                             Acceptable/guideline 
                     F: 0, 5, 20, 60 mg/kg/day (GD 6-28) 
                        Maternal NOAEL = 20 mg/kg/day 
LOAEL = 60 mg/kg/day based on death, late-term abortion/premature delivery, decreased food consumption and weight gain 
                      Developmental NOAEL = 20 mg/kg/day 
LOAEL = 60 mg/kg/day based on abortion/premature delivery, decreased fetal body weight and crown-rump length 
                                   870.3800 
                      Reproduction and fertility effects 
                                    (rat) 
                               46474124 (2003) 
                       46474125 (additional data, 2004) 
                        46474126 (range-finding, 2002) 
                             Acceptable/guideline 
                        M: 0, 7.4, 36.4, 144.6 mg/kg/d 
                       F: 0, 8.1, 41.0, 159.7 mg/kg/day 
             Parental/Systemic NOAEL = 36.4/41.0 mg/kg/day (M/F) 
LOAEL = 144.6/159.7 mg/kg/day (M/F) based on kidney toxicity in males and females and decreased weight gain in females. 
              Reproductive NOAEL = _144.6/159.7 mg/kg/day (M/F) 
                           LOAEL = not identified. 
                 Offspring NOAEL = 36.4/41.0 mg/kg/day (M/F) 
LOAEL = 144.6/159.7 mg/kg/day (M/F) based on decreased body weight and weight gain. 
                                  870.4100b 
                            Chronic toxicity (dog) 
                               44674128 (2002) 
                             Acceptable/guideline 
                     M&F: 0, 70, 300, 1000 mg/kg/day 
                NOAEL = 300 mg/kg/day (M); _1000 mg/kg/day (F) 
LOAEL = 1000 mg/kg/day based on decreased body weight gain (M); not identified (F) 
                                  870.4200b 
                               Carcinogenicity 
                                   (mouse) 
                               46474130 (2003) 
                             Acceptable/guideline 
                        M: 0, 7.9, 64.5, 551.0 mg/kg/d 
                      F: 0, 11.5, 91.9, 772.3 mg/kg/day 
                      NOAEL = 64.5/91.9 mg/kg/day (M/F) 
LOAEL = 551.0/772.3 mg/kg/day (M/F) based on decreased body weight and weight gain and liver lesions. 
                        no evidence of carcinogenicity 
                                   870.4300 
                           Chronic/ Carcinogenicity 
                                    (rat) 
                               46474139 (2003) 
                             Acceptable/guideline 
                    M: 0, 2.1, 8.4, 31.5, 109.4 mg/kg/day 
                    F: 0, 2.8, 10.8, 41.0, 142.2 mg/kg/day 
                      NOAEL = 31.5/41.0 mg/kg/day (M/F) 
LOAEL = 109.4/142.2 mg/kg/day based on decreased body weight gain (M/F) and thyroid toxicity (M). 
                        no evidence of carcinogenicity 
                                   870.5100 
                                Gene Mutation 
                           (Salmonella typhimurium) 
                               46474146 (2001) 
                            Unacceptable/guideline 
                             1.6- 5000 μg/plate 
                               46474202 (2001) 
                             Acceptable/guideline 
                             1.6- 5000 μg/plate 
                               46474148 (2001) 
                             Acceptable/guideline 
                             1.6- 5000 μg/plate 
                               46474144 (2001) 
                             Acceptable/guideline 
                             1.6- 5000 μg/plate 
                               46474142 (2004) 
                             Acceptable/guideline 
            AE638206 (batch mixture of PP/241067/1 and PP/241024) 
                              5 - 5000 μg/plate 
  negative (non-mutagenic) Upgradeable if purity for test material is given. 
                           negative (non-mutagenic) 
                           negative (non-mutagenic) 
                           negative (non-mutagenic 
                             positive (mutagenic) 
                                   870.5300 
                                Gene mutation 
                         (Chinese hamster lung cells) 
                               46474204 (2000) 
                             Acceptable/guideline 
            AE638206 (batch mixture of PP/241067/1 and PP/241024) 
                               1.2- 3820 μg/mL 
                           negative (non-mutagenic) 
                                   870.5375 
                                 Cytogenetics 
                               46474208 (2001) 
                             Acceptable/guideline 
                              1.22 to 625 μg/mL 
                               46474206 (2004) 
                             Acceptable/guideline 
            AE638206 (batch mixture of PP/241067/1 and PP/241024) 
                              3.2 to 100 μg/mL 
                     negative for chromosome aberrations 
                     positive for aberrations without S9 
                                   870.5395 
                                 Micronucleus 
                                   (mouse) 
                               46474214 (2003) 
                             Acceptable/guideline 
                          150, 300 or 600 mg/kg/day 
                               46474210 (2005) 
                             Acceptable/guideline 
            AE638206 (batch mixture of PP/241067/1 and PP/241024) 
                          200, 600 or 2000 mg/kg/day 
                               46474212 (2005) 
   Acceptable guideline AE C638206 (Batch No. OP 2050046 at 2000 mg/kg/day 
                      negative at doses up to 600 mg/kg 
                      negative at doses up to 2000 mg/kg 
                        negative at dose of 2000 mg/kg 
                                   870.5550 
                          Unscheduled DNA Synthesis 
                              (rat hepatocytes) 
                               42169839 (1989) 
                             Acceptable/guideline 
    negative at concentration up to 300 μg/mL in cultured rat hepatocytes 
                  (no OPPTS no./ FIFRA test guideline 84-2) 
                              Other Genotoxicity 
                 Unscheduled DNA synthesis (rat hepatocytes) 
                               46474216 (2000) 
                             Acceptable/guideline 
            AE638206 (batch mixture of PP/241067/1 and PP/241024) 
                              600 or 2000 mg/kg 
 negative at concentrations up to 2000 mg/kg in hepatocytes from treated rats 
                                  870.6200a 
                    Acute neurotoxicity screening battery 
                                    (rat) 
                               46474218 (2002) 
                        46474219 (range-finding, 2002) 
                             Acceptable/guideline 
                         M/F: 0, 10, 100, 2000 mg/kg 
                           NOAEL = 100 mg/kg (M/F) 
   LOAEL = 2000 mg/kg (M/F) based on transiently lowered body temperature. 
                                  870.6200b 
                  Subchronic neurotoxicity screening battery 
                               46474221 (2002) 
                      46474222 (positive control, 2002) 
                             Acceptable/guideline 
                      M: 0, 15.0, 106.6, 780.6 mg/kg/day 
                      F: 0, 18.0, 125.2, 865.8 mg/kg/day 
                      NOAEL = 106.6/18.0 mg/kg/day (M/F) 
LOAEL = 780.6/125.2 mg/kg/day based on decreased body weight gain, food consumption, and food efficiency. 
                                   870.6300 
                         Developmental neurotoxicity 
                                     None 
                                   870.7485 
                       Metabolism and pharmacokinetics 
                                    (rat) 
                         46474242 (2004)-main studies 
                               46474241 (2001) 
                               46474244 (2003) 
                               46474226 (2003) 
                               46474239 (2003) 
rapid absorption, metabolism and excretion; main metabolites were oxidative N-dealkylation cleavage products. Primary route of excretion is fecal and urinary with little accumulation in the tissues. 
                                   870.7485 
                       Metabolism and pharmacokinetics 
                                    (rat) 
                               46708632 (2002) 
                           Acceptable Non-guideline 
Most of the metabolites observed were derivatives of AE C638206 fitting well with the prior known metabolites, implying cysteine or N-acetyl-cysteine introduction on the phenyl ring from gluthione conjugation, hydroxylation, or other conjugations. 
                                   870.7485 
                       Metabolism and pharmacokinetics 
                                    (rat) 
                               AE C657188 (PCA) 
                               46708636 (2002) 
                             Acceptable Guideline 
AE C657188 (PCA) showed high (87%) absorption but low (14  -  21%) metabolism. Excretion is mainly through the urine, with a minor portion in the feces. 
                                   870.7485 
                       Metabolism and pharmacokinetics 
                                    (rat) 
                      AE C653711 (2,6-dichloro-benzamide 
                               46708633 (2003) 
                               46708634 (2003) 
                               46708635 (2003) 
                             Acceptable Guideline 
Absorption: 50-79%. Metabolized extensively to 18 identified compounds. The majority of the radioactivity was associated with a mercapturic acid conjugate of hydroxyl-chlorobenzamide (15-5-26.2%), present in the urine Excretion mainly through urine and feces. 
                                   870.7600 
                              Dermal penetration 
                                    (rat) 
                               46708638 (2003) 
                             Acceptable Guideline 
                            1.43, 659 ug/cm2 skin 
                                In vivo study 
                         Dermal Penetration rate: 37% 
                                   870.7600 
                              Dermal penetration 
                                (comparative) 
                               46708637 (2003) 
                           Acceptable Non-guideline 
                             1.9, 744 ug/cm2 skin 
                                In vitro study 
    Rat skin dermal penetration rate is 7.8 times greater than human skin. 

A.3	Hazard Identification and Endpoint Selection
A.3.1	Acute Reference Dose (aRfD) - Females age 13-49
Study Selected: None.
Comments:   No appropriate endpoint attributable to a single exposure (dose) was identified from the database.  

A.3.2	Chronic Reference Dose (cRfD) 

Study Selected:  Developmental Toxicity Study in Rabbits MRID No:  46474122
Dose and Endpoint for Risk Assessment:   NOAEL = 20 mg/kg/day based on death, abortions/premature deliveries, decreased food consumption and body weight gain at 60 mg/kg/day.  
Uncertainty Factor:  100x (10x interspecies extrapolation, 10x intraspecies variability, 1x FQPA)
Comments on Study/Endpoint/Uncertainty Factors:  This study is considered to be the most appropriate for chronic dietary dose and endpoint selection with support of the chronic/oncogenicity study in rats (co-critical study).   In the latter study, the NOAEL was 31.5 mg/kg/day based on decreased body weight gain and increased thyroid weight and increased incidence of thyroid lesions at 109.4 mg/kg/day.  

A.3.4	Incidental Oral Exposure (Short- and Intermediate-Term)

Study Selected:  Developmental Toxicity Study in Rabbits MRID No:  46474122
Dose and Endpoint for Risk Assessment:   NOAEL = 20 mg/kg/day based on death, abortions/premature deliveries, decreased food consumption and body weight gain at 60 mg/kg/day.  
Uncertainty Factor:  100x (10x interspecies extrapolation, 10x intraspecies variability, 1x FQPA)

Comments on Study/Endpoint/Uncertainty Factors:  The endpoint of concern in this study is 
appropriate for the population (infant and children) and duration of concern.  

A.3.5	Dermal Exposure (Short-, Intermediate- and Long-Term) 

Study Selected:  Developmental Toxicity Study in Rabbits MRID No:  46474122
Dose and Endpoint for Risk Assessment:   NOAEL = 20 mg/kg/day based on death, abortions/premature deliveries, decreased food consumption and body weight gain at 60 mg/kg/day.  
Uncertainty Factor:  100x (10x interspecies extrapolation, 10x intraspecies variability, 1x FQPA)

Comments on Study/Endpoint/Uncertainty Factors:  The developmental study is selected since developmental endpoints are not examined in dermal toxicity studies.   It is also protective of effects observed in the chronic toxicity studies, i.e.,  decreased body weight gain and increased thyroid weight and increased incidence of thyroid lesions.

A.3.6	Inhalation Exposure (Short-, Intermediate- and Long-Term) 

Study Selected:  Developmental Toxicity Study in Rabbits MRID No:  46474122
Dose and Endpoint for Risk Assessment:   NOAEL = 20 mg/kg/day based on death, abortions/premature deliveries, decreased food consumption and body weight gain at 60 mg/kg/day.  
Uncertainty Factor:  100x (10x interspecies extrapolation, 10x intraspecies variability, 1x FQPA)


Comments on Study/Endpoint/Uncertainty Factors:  The developmental toxicity study is 
protective of any potential developmental effects.  It is also protective of effects observed in the chronic toxicity studies, i.e., decreased body weight gain and increased thyroid weight and increased incidence of thyroid lesions.



Appendix B.  Review of Human Research

This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical.  These data, which include studies from Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1); the Agricultural Handler Exposure Task Force (AHETF) database; the ARTF database; and the Outdoor Residential Exposure Task Force (ORETF) database, are (1) subject to ethics review pursuant to 40 CFR 26, (2) have received that review, and (3) are compliant with applicable ethics requirements.  For certain studies, the ethics review may have included review by the Human Studies Review Board.  Descriptions of data sources, as well as guidance on their use, can be found at the Agency website

Appendix C.  Physical/Chemical Properties

                  Physicochemical Properties of Fluopicolide.
Parameter
Value
Reference
Molecular Weight
383.59
                                       *
Melting point/range 
149 C 
MRID 46474015
pH 
6.5 at 22.0 C (1% suspension) 
MRID 46474013
Density 
1.65 g/cm3 (30 °C)
MRID 46474016
Water solubility (20 C) 
2.86 mg/L at pH 4
2.80 mg/L at pH 7
2.80 mg/L at pH 9 
MRID 46474021
Solvent solubility (g/L at 20 C) 
n-Hexane:	0.20
Ethanol:	19.2
Toluene:	20.5
Ethyl acetate:	37.7
Acetone:	74.7
Dichloromethane:	126
Dimethyl sulfoxide:	183 
MRID 46474022
Vapor pressure (25 C) 
8.03 x 10-7 Pa 
MRID 46474023
Dissociation constant (pKa) 
No evidence of ionization in the pH range of 1.9 to 9.8 
MRID 46474017
Octanol/water partition coefficient Log(KOW) 
Log POW = 3.26 at pH 7.8 and 22 +- 1 C 
MRID 46474018

Log POW = 2.9 at pH 4.0, 7.3 and 9.1 and 40 C 
MRID 46474019
UV/visible absorption spectrum 
Absorption maxima wavelengths (nm): 
	In methanol:	203 and 271
	In methanol/HCl:	202 and 270
	In methanol/NaOH:	219 and 271 
MRID 46474014
*The molecular weight was calculated from the Periodic Table.


Appendix D.  Major Fluopicolide Metabolites

       Chemical Names and Structures of Major Fluopicolide Metabolites.
Common name/code
Chemical name
Chemical structure
BAM
AE C653711

2,6-dichlorobenzamide
                                       
3-OH-BAM or BAM-OH
AE C657378
2,6-dichloro-3-hydroxybenzamide
                                       
PCA
AE C657188

3-chloro-5-trifluoromethylpyridine-2-carboxylic acid 
                                       
P1X
AE 1344122

3-methylsulfinyl-5-trifluoromethylpyridine-2-carboxylic acid
                                       




