UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

OFFICE OF

CHEMICAL SAFETY AND

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. 
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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
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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
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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 tolerances1:

§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 

 

1 Tolerances shown with a strikethrough are currently established tolerances that would be deleted:
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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 
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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, redissolved 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 
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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. 
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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. 
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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-trifluoromethylpyridine2-carboxylic acid 

P1X

AE 1344122

3-methylsulfinyl-5-

trifluoromethylpyridine-2-carboxylic 

acid

Cl

Cl

N

H

N

O

F Cl 3C

Cl

Cl

H2N

O

N

F Cl 3C

OH

O

N

F3C

OH

O

SOCH3
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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 10-7Pa 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.
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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)

NA1

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, nondietary 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 
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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 
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administration of fluopicolide. The major urinary and fecal metabolites were oxidative Ndealkylation cleavage products. 

4.2.1 Dermal Absorption

In a dermal penetration study, 

14C- 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/cm2skin) was applied to 12 cm2skin

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 
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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 
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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.
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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. 
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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 

Dermal ShortTermMaternal 

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 Shortand IntermediateTerm (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 
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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).
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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). 
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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

Chronic (non-cancer) 24.14 0.5

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.
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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 
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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 
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2012 Residential SOPs2along 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).

 

2 Available: http://www.epa.gov/pesticides/science/residential-exposure-sop.html
Fluopicolide Human Health Risk Assessment DP No. D415186

Page 24 of 38

Table 6.3. Residential Exposures for the Fluopicolide Aggregate Assessment.1

Lifestage

Residential Handler Residential Post-application 

Dose (mg/kg/day)2 MOE3 Dose (mg/kg/day)4 MOE5

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). 
Fluopicolide Human Health Risk Assessment DP No. D415186

Page 25 of 38

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 postapplication residential exposure of children. As this rate is equal to or higher than many of 
Fluopicolide Human Health Risk Assessment DP No. D415186

Page 26 of 38

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.

7.2 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/d

ay

LOC1

Max 

Allowable 

Exposure2

mg/kg/day

Average 

Food and 

Water 

Exposure 

mg/kg/day

Residential 

Exposure 

mg/kg/day3

Total 

Exposure 

mg/kg/day4

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 1× 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.
Fluopicolide Human Health Risk Assessment DP No. D415186

Page 27 of 38

7.3 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.

7.4 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.

7.5 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.

8.0 Cumulative Exposure/Risk Characterization

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

common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding 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/.

9.0 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. 
Fluopicolide Human Health Risk Assessment DP No. D415186

Page 28 of 38

10.0 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
Fluopicolide Human Health Risk Assessment DP No. D415186

Page 29 of 38

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
Fluopicolide Human Health Risk Assessment DP No. D415186

Page 30 of 38

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
Fluopicolide Human Health Risk Assessment DP No. D415186

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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 
Fluopicolide Human Health Risk Assessment DP No. D415186

Page 32 of 38

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

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 

46474122 (2001) 

Acceptable/guideline 

Maternal NOAEL = 20 mg/kg/day 

LOAEL = 60 mg/kg/day based on death, late-term
Fluopicolide Human Health Risk Assessment DP No. D415186

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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

(rabbit) F: 0, 5, 20, 60 mg/kg/day 

(GD 6-28) 

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) 
Fluopicolide Human Health Risk Assessment DP No. D415186

Page 34 of 38

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

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 

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. 
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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

mg/kg/day 

F: 0, 18.0, 125.2, 865.8 

mg/kg/day 

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-

dichlorobenzamide 

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)
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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.
Fluopicolide Human Health Risk Assessment DP No. D415186

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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
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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-trifluoromethylpyridine2-carboxylic acid 

P1X

AE 1344122

3-methylsulfinyl-5-

trifluoromethylpyridine-2-carboxylic 

acid

Cl

Cl

H2N

O

Cl

Cl

H2N

O

OH

N

F Cl 3C

OH

O

N

F3C

OH

O

SOCH3