Fluopicolide Human Health Risk Assessment D410653 

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

MEMORANDUM 

Date: May 8, 2013 

OFFICE OF 

CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

SUBJECT: Fluopicolide. Human Health Risk Assessment for the New Section 3 Tolerances 

on Rotational Corn. 

PC Code: 02741 2 

Decision No.: 471 299 

Petition No.: 2F8099 

Risk Assessment Type: Single Chemical 

Aggregate 

TXRNo.: NA 

MRID No.: 48809201 , 48842201 

DP Barcode: D41 0653 

Registration No.: 59639-140 

Regulatory Action: Section 3 Registration 

Case No.: N/A 

CAS No.: 239110-15-7 

40 CFR: §180.627 

FROM: Alaa Kamel, Ph.D., Chemist ~ ·~ 

Alexandra LaMay, Biologist c:/1 ~ .-.r-"..-/Y 

John Liccione, Ph.D., Toxicologist . 

Risk Assessment Branch V Nil V 0 / 

Health Effects Division (7509P) ) / fl---

THROUGH: Michael S. Metzger, Chi) A: p-0 y b 

Danette Drew, Senior ScieJis~ Risk Assessment Branch V N il 

Health Effects Division (7509P) 

TO: Tony Kish/Dominic Schuler, RM #22 

Fungicide Branch 

Registration Division (7505P) 

Page I of37 
Fluopicolide Human Health Risk Assessment D410653 

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 Occupational Assessment ................................................. 8 

2.3.3 Recommendations from Residential Assessment.. ................................................... 8 

3.0 Introduction ........................................................................................................................ 8 

3.1 Chemical Identity ........................................................................................................... 8 

3.2 Physical/Chemical Characteristics ............................................................................... 9 

3.3 Pesticide Use Pattern ............. ......................................................................................... 9 

3.4 Anticipated Exposure Pathways ............................................................. ...................... 9 

3.5 Consideration of Environmental Justice .................................................................... 10 

4.0 Hazard Characterization and Dose-Response Assessment .......................................... 10 

4.1 Toxicology Studies Available for Analysis ................................................................. 11 

4.2 Absorption, Distribution, Metabolism, & Elimination (ADME) ............ ......... ........ 11 

5.0 Dietary Exposure and Risk Assessment.. ....................................................................... 16 

5.1 Metabolite/Degradate Residue Profile ....................................................................... 16 

5.1.1 Summary of Plant and Animal Metabolism Studies ............................................. 16 

5.1.2 Summary of Environmental Degradation .............................................................. 16 

5.1.3 Comparison of Metabolic Pathways ....................................................................... 16 

5.1.4 Residues of Concern Summary and Rationale ...................................................... 16 

5.2 Food Residue Profile ...................................................... .............................................. 17 

5.3 Water Residue Profile .................................................................................................. 18 

5.4 Dietary Risk Assessment.. ........................ ...................... ......................... .... .... ............. 18 

6.0 Residential (Non-Occupational) Exposure/Risk Characterization ............ ................. 19 

6.1 Residential Handler Exposure .................................................................................... 19 

6.2 Post-Application Exposure ........................ ............................................... ................... 22 

6.5 Residential Bystander Post-application Inhalation Exposure ................................. 26 

6.6 Spray Drift ............................................................ ........................................................ 26 

7.0 Aggregate Exposure/Risk Characterization .................................................................. 27 

7.1 Acute Aggregate Risk. .................................................................................................. 27 

7.2 Short-Term Aggregate Risk ........................................................................................ 27 

7.3 Intermediate-Term Aggregate Risk .. ......................................................................... 27 

7.4 Chronic Aggregate Risk .............................................................................................. 28 

7.5 Cancer Aggregate Risk ................................................................................................ 28 

8.0 Cumulative Exposure/Risk Characterization ............................................................... 28 

9.0 Occupational Exposure/Risk Characterization ....... ..................................................... 28 

10.0 References ........................................................................................................... .............. 28 

Appendix A. Toxicology Profile and Executive Summaries .................................................. 29 

Page 2 of 37 
Fluopicolide Human Health Risk Assessment D410653

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A.1 Toxicology Data Requirements................................................................................... 29

A.2 Toxicity Profiles............................................................................................................ 30

A.3 Hazard Identification and Endpoint Selection .......................................................... 34

Appendix B. Review of Human Research................................................................................ 36

Appendix C. Residue Summary Table ................................................................37
Fluopicolide Human Health Risk Assessment D410653

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1.0 Executive Summary

The Health Effects Division (HED) of EPA's Office of Pesticide Programs has evaluated the 

toxicity and exposure databases for the active ingredient, fluopicolide, 2,6-dichloro-N-[3-chloro5-(trifluoromethyl)-2-pyridylmethyl]benzamide, and has conducted a human health risk 

assessment. The assessment was conducted to support proposed new tolerances on rotational

corn following application to primary crops. Fluopicolide shares a metabolite, 2,6-

dichlorobenzamide (BAM), with another active ingredient, dichlobenil. Residues of BAM are 

considered to be of regulatory concern, and separate toxicity data and endpoints for risk 

assessment have been selected for BAM. However, since the proposed change in use pattern

does not add significantly to the BAM dietary exposure, and residues of BAM due to 

fluopicolide applications are significantly lower than those from dichlobenil applications, the 

conclusions from the most recently conducted BAM human health risk assessment (D373401, D. 

Rate, 3/19/08) remain unchanged and a revised quantitative BAM risk assessment will not be 

done to support the proposed tolerances. Aggregate risks from BAM exposure are not of 

concern. This assessment addresses risks from the parent compound fluopicolide and its 

metabolites PCA ( 3-chloro-5-trifluoromethylpyridine-2-carboxylic acid) and Px1 (3-

methylsulfinyl-5-trifluoromethylpyridine-2-carboxylic acid).

Fluopicolide is a fungicide that controls a wide range of diseases including downy mildews, late 

blight, and some Pythium species and is registered for use on a variety of agricultural crops and 

for use on turf (lawns, recreational areas, parks, golf courses and athletic fields) and ornamentals. 

Valent U.S.A. Corporation is petitioning to reduce the plant back interval (PBI) from 18 months 

to 30 days for rotated field corn on the label for V-10161 4 SC (EPA Reg. No. 59639-140) and to 

establish new inadvertent residue tolerances for fluopicolide on field corn forage, stover and

grain. 

The toxicity database for fluopicolide is complete. Fluopicolide 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). Fluopicolide is not neurotoxic, carcinogenic, or mutagenic. It does not appear to 

have immunotoxic potential. 

The Food Quality Protection Act (FQPA) safety factor was reduced to 1× 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.

The Agency has reviewed the residue chemistry database, as well as existing feeding studies 

with both parent compound and the BAM metabolite, and concluded that tolerances are not 

needed for livestock commodities. The new field trial data for rotation to corn was reviewed and 
Fluopicolide Human Health Risk Assessment D410653

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analyzed using the Organization of Economic Cooperation and Development (OECD) maximum

residue limit (MRL) calculation procedure. The results of the calculation indicated that the

proposed tolerances should be modified for the feed items corn, field forage and corn, field 

stover. The livestock dietary burden was unaffected by the new recommended tolerances on 

field corn forage, stover and grain.

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 was classified by 

HED as “not likely to be carcinogenic to humans”. A conservative chronic (food plus drinking 

water) dietary exposure and risk assessment was conducted using tolerance level residues, 100% 

crop treated assumptions, and empirical or default processing factors. Estimated drinking water 

concentrations (EDWCs) were derived from conservative modeling programs. 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 

these uses was previously assessed. An updated residential exposure assessment was completed 

for fluopicolide to reflect updates to HED’s 2012 Residential SOPs1along with policy changes 

for body weight assumptions. The residential risk estimates impact the aggregate assessment. 

All residential handler risk estimates are not of concern for fluopicolide. An updated residential 

post-application exposure assessment was also completed for fluopicolide for use on turf, golf 

courses, and ornamental plants/trees. All residential post-application risk estimates for 

fluopicolide were not of concern. Since the proposed change in use pattern does 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. 

In accordance with the FQPA, an aggregate assessment was conducted which considered 

pesticide exposure and risk from the residential, food, and water pathways. Residential exposures 

included adults applying fluopicolide in a residential setting (dermal and inhalation exposure), 

post-application exposure to adults and children (dermal exposure), and post-application oral 

exposure to children (by putting hands or objects in their mouth). The estimated aggregate shortterm risks for all of the exposure scenarios that were calculated were all below HED’s level of 

concern. 

There are no agricultural or occupational applications associated with this action (there are no 

direct applications to rotated field corn). Therefore, there is no potential occupational exposure 

associated with the proposed change in use pattern. Occupational exposure and risk assessments 

were previously conducted for existing fluopicolide uses. All handlers and post-application 

MOEs were not of risk concern. 

 

1 Available: http://www.epa.gov/pesticides/science/residential-exposure-sop.html
Fluopicolide Human Health Risk Assessment D410653

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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. 

For information on human studies see Appendix C. 

2.0 HED Recommendations

HED recommends allowing the rotation of field corn 30 days after use of fluopicolide on a 

primary crop, and for inadvertent residue tolerances of fluopicolide on field corn grain, stover 

and forage. Additional data are needed as outlined in Section 2.1 below. The specific tolerance 

recommendations are discussed in Section 2.2.

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. A “Turf Transferrable Residue” (TTR)

study is required for fluopicolide (parent only), since the dermal post-application “Margins of 

Exposure” (MOEs) for all life stages are less than 10 times the “Level of Concern” (LOC) based 

on default values for the fraction of application rate available for transfer after a turf application

(Guidance for Requiring/Waiving Turf Transferrable Residue (TTR) and Dislodgeable Foliar 

Residue (DFR) Studies. 6/7/2012, Exposure Science Advisory Council). 

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

D321209, 1/23/2007, A. Acierto, Residue Chemistry Chapter

An acceptable LC/MS/MS enforcement method, RM-43C-1 “Determination of Fluopicolide and 

BAM in Crops,” December 11, 2008) is available for the determination of fluopicolide and BAM 

in corn matrices. Samples are extracted twice with acetone:water (v:v, 3:1), and the combined 

extracts were concentrated to remove the acetone. The extract was mixed with a 5% sodium 

chloride solution, and the mixture was partitioned twice with methylene chloride. The 

methylene chloride phases were combined and concentrated to remove the methylene chloride. 

The residue was dissolved in hexane and cleaned up on a silica gel cartridge, using hexane:ethyl 

acetate (80:20, v:v) to elute residues of fluopicolide and hexane:ethyl acetate (2:1, v:v) to elute 

residues of BAM. The eluates were combined, evaporated to dryness, and dissolved in 

methanol:water (3:2, v:v) for LC/MS/MS analysis. For some sample sets, the silica gel column 

cleanup step was modified as follows: residues were eluted from the silica gel cartridge using 

hexane:ethyl acetate (1:1, v:v); the eluate was evaporated to dryness and dissolved in 

acetonitrile; the acetonitrile was partitioned twice with hexane; and the acetonitrile phases were 

combined, evaporated to dryness, dissolved in methanol, and diluted with water for LC/MS/MS 

analysis. Results were reported in analyte equivalents.
Fluopicolide Human Health Risk Assessment D410653

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Adequate multiresidue method testing data for fluopicolide and its metabolites were previously 

submitted. Based on the results of the testing, the multiresidue methods are not appropriate for 

determining residues of fluopicolide or its metabolites (D321209, 1/23/2007, A. Acierto).

2.2.2 Recommended Tolerances

HED recommends that the tolerance expression for fluopicolide be amended under §180.627(d) 

to read as follows:

Tolerances are established for residues of the fungicide fluopicolide [2,6-dichloro-N-[[3-chloro5-(trifluoromethyl)-2-pyridinyl]methyl]benzamide], including its metabolites and degradates, in 

or on the commodities in the table below. Compliance with the tolerance levels specified below 

is to be determined by measuring only fluopicolide in or on the commodity. 

Tolerances (based on fluopicolide per se) are not needed for the processed commodities because 

residues of fluopicolide in grain at the 1× and the 5× exaggerated rate were below LOQ (<0.01 

ppm). The proposed and recommended tolerances for residues of fluopicolide are shown in 

Table 2.2.3.

Table 2.2.3. Tolerance Summary for Fluopicolide

Commodity Established/Proposed 

Tolerance (ppm)

Recommended 

Tolerance (ppm)

Comments

Correct Commodity Definition

Corn, field, forage 0.09 0.08

Corn, field, grain 0.01 0.01

Corn, field, stover 0.30 0.2

2.2.3 Revisions to Petitioned-For Tolerances

The recommended tolerance levels differ from the petition. Recommended tolerances were 

obtained using the Organization of Economic Cooperation and Development (OECD) calculation 

procedure. Residue data from the field trial locations (average of duplicate samples) for 

fluopicolide only were used in the OECD MRL calculation procedure. Censored data were 46%, 

100% and 27% for forage, grain and stover respectively. LOQ amounts (0.01 ppm) were entered 

if the detected amount was <LOQ. The petitioner also demonstrated that they used the OECD 

calculation procedure to calculate the proposed tolerances, however, the sum of fluopicolide + 

BAM and moisture content were included in their calculations. Since the tolerance expression 

includes monitoring of residues of fluopicolide only for rotational crops for both food and feed 

commodities, and that monitored samples will be analyzed without drying, it is not appropriate to 

consider residues of BAM and moisture content in tolerance calculations. The registrant should 

submit a revised Section F in which the proposed tolerances are the same as those recommended 

by the HED.

2.2.4 International Harmonization

A Codex tolerance for fluopicolide has been established at 0.2 ppm for the straw and fodder 

(dry) of cereal grains. The Codex and U.S. tolerance expressions are harmonized since they both 

include the parent compound, fluopicolide, only. There are no Canadian or Mexican MRLs for 

field corn commodities.
Fluopicolide Human Health Risk Assessment D410653

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2.3 Label Recommendations

2.3.1 Recommendations from Residue Reviews

None.

2.3.2 Recommendations from Occupational Assessment

Not applicable

2.3.3 Recommendations from Residential Assessment

None

3.0 Introduction

3.1 Chemical Identity

The chemical identity of fluopicolide and its metabolites BAM, PCA and P1x are shown in Table 

3.1.1.

TABLE 3.1.1. Test Compound Nomenclature.

Compound

Common name Fluopicolide

Company experimental name V-10161 (Valent); AE C638206 (Bayer)

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 product (EP) Presidio Fungicide (4 lb ai/gal suspension concentrate; EPA Reg. No. 59639-140) 

Compound

Common name BAM

Company experimental name AE C653711

Chemical name 2,6-dichlorobenzamide 

Compound

Common name PCA

Company experimental name AE C657188

Chemical name 3-chloro-5-trifluoromethylpyridine-2-carboxylic acid

Cl

Cl

N

H

N

O

F Cl 3C

Cl

Cl

H2N

O

N

F Cl 3C

OH

O
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TABLE 3.1.1. Test Compound Nomenclature.

Compound

Common name P1x

Company experimental name AE 1344122

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

3.2 Physical/Chemical Characteristics

The physical and chemical properties for fluopicolide are shown in Table 3.2.1

TABLE 3.2.1. Physicochemical Properties of the Technical Grade Test Compound Fluopicolide.

Parameter Value Reference1

Melting point/range 149 C MRID 46474015

pH 6.5 at 22.0 C MRID 46474013

Density 1.65 g/cm3at 30 oC MRID 46474016

Water solubility (20 C) 3.02 mg/L

2.86 mg/L at pH 4

2.80 mg/L at pH 7

2.80 mg/L at pH 9 

MRID 46474020

MRID 46474021

Solvent solubility (mg/L at 20 C) n-Hexane: 200

Ethanol: 19,200

Toluene: 20,500

Ethyl acetate: 37,700

Acetone: 74,700

Dichloromethane: 126,000

Dimethylsulfoxide: 183,000 

MRID 46474022

Vapor pressure at 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

3.3 Pesticide Use Pattern

The formulation is applied to the primary crop with a 30 day plant back interval on field corn. 

There are no direct uses of fluopicolide on corn.

3.4 Anticipated Exposure Pathways

Fluopicolide is registered for use on agricultural crops as well as on turf (lawns, golf course, 

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

N

F3C

OH

O

SOCH3
Fluopicolide Human Health Risk Assessment D410653

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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 reentering treated fields. 

Risk assessments have been previously prepared for the existing uses of fluopicolide (D384431 

D. Davis 12/9/10). This current risk assessment considers the proposed change in use pattern, as 

well as the different exposure pathways based on the existing uses of fluopicolide.

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 USDA under the Continuing 

Survey of Food Intake by Individuals (CSFII) and/or the CDC under the National Health and 

Nutrition Examination Survey/What We Eat in America (NHANES/WWEIA),are used in 

pesticide risk assessments for all registered food uses of a pesticide. These data are analyzed and 

categorized by subgroups based on age, season of the year, ethnic group, and region of the 

country. Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups 

and exposure assessments are performed when conditions or circumstances warrant. Whenever 

appropriate, non-dietary exposures based on home use of pesticide products and associated risks 

for adult applicators and for toddlers, youths, and adults entering or playing on treated areas 

post-application are evaluated. Further considerations are currently in development as OPP has 

committed resources and expertise to the development of specialized software and models that 

consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary 

patterns among specific subgroups.

4.0 Hazard Characterization and Dose-Response Assessment

Toxicological effects of fluopicolide were previously evaluated in the human health risk 

assessments conducted in 2007 and 2010 (D325091, N. Dodd, 11/21/07 and D384431, D. Davis, 

12/9/2010). A registration review scoping document was released in 2013 (D. Drew, D405060). 

Since that time 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 is not required at this time. 
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4.1 Toxicology Studies Available for Analysis

The toxicity database for fluopicolide is complete and sufficient for characterizing the hazard of 

fluopicolide. The registrant submitted an immunotoxicity study to fulfill the requirement of 40 

CFR §158 for pesticide registration. The Agency believes the existing data are sufficient for 

endpoint selection for exposure/risk assessment scenarios and for evaluation of the requirements 

under the FQPA. The toxicity endpoints and points of departure have not changed since the 

previous risk assessment (D384431, 2010). 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 (MRIDs 46474226, 46474239, 46474241, 46474242, and 

46474244) ), indicated that fluopicolide was 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 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 46474226) suggested a near-saturation of absorption at the high dose (100 

mg/kg bw). Based upon tissue burden data, neither fluopicolide nor its metabolites appear to 

undergo any significant tissue sequestration. With the exception of transiently higher levels in 

the liver, kidneys, and intestines during the elimination phase, radioactivity concentrations in any 

given tissue consistently represented considerably less than 1% of the administered dose within 

24 hours of administration of fluopicolide. The major urinary and fecal metabolites were 

oxidative N-dealkylation cleavage products. 

4.2.1 Dermal Absorption

In a dermal penetration study (MRID 46708638), 14C- Fluopicolide in a commercial concentrate, 

or aqueous dilution of a concentrate for the low dose, was applied to the skin of 5 male SpragueDawley rats/time point/dose. The dose (1.43 or 659 μg/cm2

skin) 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 ranged 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 
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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

The subchronic and chronic oral toxicity studies in rats and mice revealed liver toxicity in both 

species. Kidney and thyroid toxicity were observed in rats only. 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. An inhalation toxicity study is not available. The Hazard and Science Policy 

Council (HASPOC; TXR. 0056544) met on December 19, 2012 to discuss the need for this 

inhalation study. The HASPOC has determined that, based on a weight of evidence (WOE) 

approach, a 28-day inhalation toxicity study is not required at this time. This approach 

considered all of the available hazard and exposure information including (1) the 

physical/chemical properties of fluopicolide, including its potential to volatilize (8.03 x 10-7 Pa 

vapor pressure); (2) the low acute inhalation toxicity; (3) the primary target organs of 

fluopicolide are the liver and hematopoietic system following repeat oral exposure; (4) the use of 

an oral POD for fluopicolide results in screening level occupational/residential inhalation MOEs 

>40,000. 

Technical grade fluopicolide has low acute toxicity via oral, dermal and inhalation routes of 

exposure. Fluopicolide is not a dermal sensitizer, primary eye irritant, or primary skin irritant.

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

The Agency considers it appropriate to reduce the Food Quality Protection Act (FQPA) safety 

factor to 1× 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, 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 near the limit dose, and the exposure assessments are unlikely 

to underestimate risk.
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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

There are acute and subchronic neurotoxicity studies available. 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 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 near the limit dose.

4.4.4 Residual Uncertainty in the Exposure Database

The dietary exposure assessment is based on an exaggerated exposure scenario which assumes 

that all commodities being consumed retain either tolerance level-residues or highest field 

residues found. The residential exposure assessment assumes maximum label use rate as well as 

other conservative assumptions. Moreover, combining the residential incidental oral and dermal 

exposure scenarios is conservative. Therefore, there are no residual uncertainties in the exposure 

database and exposures to fluopicolide will not be underestimated. 

4.5 Toxicity Endpoint and Point of 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. The rabbit 

developmental study was therefore considered for all exposure scenarios, and was considered cocritical with the rat chronic/oncogenicity study for all scenarios except the incidental oral 

scenarios. 
Fluopicolide Human Health Risk Assessment D410653

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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/LOAEL 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 Recommendation for Combining Routes of Exposures for Risk Assessment

HED combines risk values resulting from separate routes of exposure when it is likely they can 

occur simultaneously based on the use pattern and the behavior associated with the exposed 

population, and if the hazard associated with the points of departure is similar across routes. 

Since dermal, inhalation and incidental oral exposure routes share a common toxicological 

endpoint for fluopicolide, risk estimates have been combined for those routes.

4.5.3 Cancer Classification and Risk Assessment Recommendation

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” based on 

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

Assessment 

Table 4.5.4.1. Summary of Toxicological Doses and Endpoints for 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 (1-30 days) 

and IntermediateTerms

(1 - 6 months) 

Maternal 

NOAEL = 

20 

mg/kg/day 

UFA=10x 

UFH=10x 

FQPA SF = 

1X 

MOE = 100 

(occupational) 

MOE = 100 

(residential) 

Developmental Toxicity Study in Rabbits 

LOAEL (maternal) = 60 mg/kg/day based on 

death, abortions/ premature deliveries, decreased 

food consumption and body weight gain. 

Dermal ShortIntermediate- and 

Long-Term (1-30 

days, 1-6 months, 

and >6 months) 

Maternal 

NOAEL = 

20 

mg/kg/day 

UFA=10x 

UFH=10x 

FQPA SF = 

1X 

37% dermal 

absorption 

MOE = 100 

(occupational) 

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 ShortIntermediate- and 

Long-term (1-30 

days, 1-6 months, 

and >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 

(occupational) 

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. 
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5.0 Dietary Exposure and Risk Assessment 

5.1 Metabolite/Degradate Residue Profile

5.1.1 Summary of Plant and Animal Metabolism Studies

Based on acceptable plant metabolism studies, the qualitative nature of the residue in primary 

plants is adequately understood. In rotational crops 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. In ruminant and poultry metabolism studies, the nature of the residue in livestock 

is adequately understood.

5.1.2 Summary of Environmental Degradation

The Agency has determined, based on two aerobic soil metabolism studies, that the residues of 

concern in drinking water are parent fluopicolide and the degradate BAM (Fluopicolide Risk 

Assessment Team, 4/12/07). 

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-OHBAM, 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 rat, 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.

5.1.4 Residues of Concern Summary and Rationale

A summary of the fluopicolide residues of concern is shown in Table 5.1.4.1
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Table 5.1.4.1. Summary of Fluopicolide Residues of Concern.

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

Adequate data were submitted for tolerance and risk assessments. The residue of concern for 

tolerance enforcement is fluopicolide per se. Concentration upon processing was not significant; 

therefore, the tolerance for field corn grain will cover residues in processed commodities. The 

residues of concern for risk assessment are fluopicolide, BAM, PCA and P1x. Field corn 

processed commodities may be used for human consumption. The dietary risk assessment for 

fluopicolide included residues of PCA and P1x. 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. Residues of fluopicolide, PCA and P1x in the raw agricultural 

commodities (corn grain) were all below the limit of detection (LOQ), Tolerances are not 

needed for the processed commodities because residues of fluopicolide in grain in all the crop 

field trials at the 1 × and 5× exaggerated rates were below LOQ (<0.01 ppm). The Agency 

previously concluded that the presence of residues of fluopicolide and BAM in milk, beef fat, 

kidney and liver are not likely. However, it is possible that quantifiable residues of BAM may 

be found in beef liver. In poultry, 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. The livestock dietary burden was unaffected by the new recommended 

tolerances on field corn forage, stover and grain.
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5.3 Water Residue Profile

“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” (R. Miller, D370764, 

6/20/10)

The Agency conducted a drinking water assessment (R. Miller, D370764, 6/20/10) using PRZM

version 3.12/ EXAMS version 2.98 models and estimated the concentration of fluopicolide in 

surface water to be 0.02414 ppm for chronic (non cancer) exposure. For the new use of 

fluopicolide on rotational corn, EFED has indicated that a new drinking water assessment 

(DWA) was not needed (Email communication with Michael Lowit, EFED 3/19/2013).

5.4 Dietary Risk Assessment

D407936, A. Kamel, 4/8/2013 “Fluopicolide. Chronic Aggregate Dietary (Food and Drinking Water) 

Exposure and Risk Assessment for the Section 3 Tolerances on Rotational Corn.” 

A chronic aggregate dietary (food and drinking water) exposure and risk assessment was

conducted for fluopicolide using the Dietary Exposure Evaluation Model software with the Food 

Commodity Intake Database (DEEM-FCID) Version 3.16. This software uses 2003-2008 food 

consumption data from the U.S. Department of Agriculture’s (USDA’s) National Health and 

Nutrition Examination Survey, What We Eat in America, (NHANES/WWEIA). The analysis 

was conducted to support Section 3 request for new tolerances for fluopicolide on rotational field 

corn. 

5.4.1 Chronic Dietary (Food and Drinking Water) Exposure Results and Characterization

Chronic dietary risk estimates for the U.S Population and all population subgroups are not of 

concern. The established and proposed uses of fluopicolide result in an estimated exposure to 

the U.S. Population equivalent to 7.6% of the chronic population adjusted dose (cPAD). The 

highest exposed subgroup is children 1 – 2 years of age with an estimated exposure equivalent to 

12% of the cPAD. This assessment is considered highly conservative as tolerance level residues, 

100% crop treated assumptions, and empirical or default processed fractions were used with the 

exception of tuberous and corm vegetables (subgroup 1C), and rotational wheat commodities, 

where the maximum residues from the field trial data were used.. Table 5.4.1.1 lists the chronic 

dietary exposure and risk estimates for fluopicolide.

Acute dietary exposure and cancer risk assessments were not conducted because an endpoint 

attributable to a single dose has not been identified for fluopicolide and that it is not a possible 

carcinogen.
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Table 5.4.1.1. 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 N/A

0.015176 7.6

N/A N/A

All Infants (<1 year old) 0.010336 5.2

Children 1-2 years old 0.024340 12

Children 3-5 years old 0.022836 11

Children 6-12 years old 0.014425 7.2

Youth 13-19 years old 0.011252 5.6

Adults 20-49 years old 0.014965 7.5

Adults 50-99 years old 0.015368 7.7

Females 13-49 years old 0.015252 7.6

*The subpopulation with the highest risk estimate is bolded.

N/A = not available

6.0 Residential (Non-Occupational) Exposure/Risk Characterization

There are no proposed residential uses associated with this petition; however, there are existing 

residential uses that have been reassessed in this document to reflect updates to HED’s 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 turfgrass 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 

proposed change in use pattern does 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 Residential Handler Exposure

HED believes that there are distinct tasks related to applications and that exposures can vary 

depending on the specifics of each task. Residential handlers are addressed somewhat differently 

by HED as homeowners who are assumed to complete all elements of an application without use 

of any protective equipment. It is possible for residential handlers to apply these products; 

therefore, residential handlers may receive short-term dermal and inhalation exposure to 

fluopicolide when applying the product. The quantitative exposure/risk assessment developed for 

residential handlers is based on application of liquid formulation to turf/lawns and gardens/trees 

using handheld equipment. A series of assumptions and exposure factors served as the basis for 

completing the residential handler risk assessments. Residential handler exposure is expected to 

 

2 Available: http://www.epa.gov/pesticides/science/residential-exposure-sop.html
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be short-term in duration. Intermediate-term exposures are not likely because of the intermittent 

nature of applications by homeowners. Dermal and inhalation risk estimates were combined in 

this assessment, since the toxicological effects for these exposure routes were identical (the same 

studies / endpoints / PODs were used to quantify risks).

All residential handler non-cancer risk estimates are not of concern (i.e., MOEs are > 100). 

Combined dermal and inhalation MOEs for residential handlers range from 1,900 (handler 

applying liquid to lawns and trees with backpack sprayer) to 45,000 (handlers applying liquid to 

lawns with sprinkler can). The results of combined short-term residential handler exposure and 

risk estimates for fluopicolide are shown in Table 6.1.1
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Table 6.1.1. Residential Handler Non-cancer (Short-Term) Exposure and Risk Estimates for Fluopicolide.

Exposure Scenario Level of 

Concern

Dermal Unit 

Exposure 

(mg/lb ai)

Inhalation Unit 

Exposure 

(mg/lb ai)

Maximum 

Application 

Rate1

Area Treated 

or Amount 

Handled Daily2

Dermal Inhalation Total

Dose 

(mg/kg/day)3 MOE4 Dose (mg/kg/day)5 MOE6 MOE7

Mixer/Loader/Applicator

Gardens/Trees, Liquid, Manuallypressurized handwand

100

63 0.018

0.0025 lb 

ai/gallon 5 gallons 0.0042 4,700 0.0000033 6,100,000 4,700

Lawns/Turf, Liquid, Manuallypressurized handwand0.003 lb 

ai/gallon 5 gallons 0.0051 3900 0.0000039 5,100,000 3,900

Gardens/Trees, Liquid, Manuallypressurized handwand0.0000125 lb 

ai/ft2 1200 ft2

0.0051 3,900 0.0000039 5,100,000 3,900

Gardens/Trees, Liquid, Hose-end 

Sprayer/Sprinkler Can

58 0.0014

0.0000125 lb 

ai/ft2 1200 ft2

0.0047 4,300 0.0000003 66,000,000 4,300

Gardens/Trees, Liquid, Hose-end 

Sprayer

0.0025 lb 

ai/gallon 11 gallons 0.0086 2,300 0.00000056 36,000,000 2,300

Gardens/Trees, Liquid, Sprinkler 

Can

0.0025 lb 

ai/gallon 5 gallons 0.0039 5,100 0.00000025 79,000,000 5,100

Lawns/Turf, Liquid, Hose-end 

Sprayer

13.4 0.022

0.27 lb 

ai/acre 0.5 acres 0.0097 2,100 0.000043 460,000 2,100

Lawns/Turf, Liquid, Sprinkler 

Can

0.0000062 lb 

ai/ft2 1000 ft2

0.00045 45,000 0.000002 10,000,000 45,000

Gardens/Trees, Liquid, Backpack

130 0.14

0.0000125 lb 

ai/ft2 1200 ft2

0.01 1,900 0.00003 660,000 1,900

Gardens/Trees, Liquid, Backpack 0.0025 lb 

ai/gallon 5 gallons 0.0087 2,300 0.000025 790,000 2,300

Lawns/Turf, Liquid, Backpack 0.003 lb 

ai/gallon 5 gallons 0.01 1,900 0.00003 660,000 1,900

1 Based on registered labels. Application rate for turf is 0.27 lb ai/acre, or 0.0000062 lb ai/ft2. The label states that a volume of 2 gallons treats 1000 sq. ft, which is equivalent to 

87 gallons per acre. Therefore, the turf rate is 0.003 lb ai/gallon. Application rate for ornamental plants is 0.54 lb ai/acre, which is equivalent to 0.0000125 lb ai/ft2. The label 

states that 100 gallons treats 20,000 sq ft, which is equivalent to 218 gallons per acre. Therefore, the ornamental plant rate is 0.0025 lb ai/gallon.

2 Based on HED’s 2012 Residential SOPs (http://www.epa.gov/pesticides/science/residential-exposure-sop.html).

3 Dermal Dose = Dermal Unit Exposure (mg/lb ai) × Application Rate (lb ai/acre or gal) × Area Treated or Amount Handled (A/day or gallons/day) × Dermal Absorption Factor 

(%) ÷ Body Weight (kg).

4 Dermal MOE = Dermal NOAEL (mg/kg/day) ÷ Dermal Dose (mg/kg/day).

5 Inhalation Dose = Inhalation Unit Exposure (mg/lb ai) × Application Rate (lb ai/acre or gal) × Area Treated or Amount Handled (A/day or gallons/day) ÷ Body Weight (kg).

6 Inhalation MOE = Inhalation NOAEL (mg/kg/day) ÷ Inhalation Dose (mg/kg/day).

7 Total MOE = NOAEL (mg/kg/day) ÷ (Dermal Dose + Inhalation Dose)
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6.2 Post-Application Exposure

There is the potential for short-term post-application exposure to fluopicolide for individuals 

exposed as a result of being in an environment that has been previously treated with fluopicolide. 

There is also a potential for exposure to BAM during post-application activities on fluopicolidetreated turf and plants; however, foliar residues and therefore exposures to BAM are expected to 

be insignificant and were therefore not included in this risk assessment. The quantitative 

exposure/risk assessment for residential post-application exposures includes the following 

scenarios: 

Adults and children (1 to < 2 years old) dermal exposure to treated turf during high 

contact lawn activities.

Children (1 to < 2 years old) incidental oral exposure to treated turf.

Adult and children (11 to < 16 years old) dermal exposure to treated turf during mowing 

and golfing activities.

Children (6 to < 11 years old) dermal exposure to treated turf during golfing activities.

Adult and children (6 to < 11 years old) dermal exposure to treated gardens.

The exposure assessment for dermal exposure to treated gardens is protective of exposure to 

treated ornamental trees. The lifestages selected for each post-application scenario are based on 

an analysis provided as an Appendix in the 2012 Residential SOPs. These lifestages are not the 

only lifestages that could be potentially exposed for these post-application scenarios; however, 

the assessment of these lifestages is health protective for the exposures and risk estimates for any 

other potentially exposed lifestages.

A series of assumptions and exposure factors served as the basis for completing the residential 

post-application risk assessment. Each assumption and factor is detailed in the 2012 Residential 

SOPs. Because turf transferable residue (TTR) data were not available fluopicolide, turf residues 

were estimated using default assumptions. A dislodgeable foliar residue (DFR) study for 

fluopicolide use on leaf lettuce was submitted (MRID 46708641) and reviewed by the Agency 

for use in assessing post-application activities. The target application rate for each application 

was 0.119 lb ai/A; 3 applications were completed at an approximate re-treatment interval of 5 

days. The total target application was 0.3575 lb ai/A. A linear regression analysis was conducted 

using the natural logarithm of the individual DFR values. The maximum predicted day 0 residue 

from the DFR study is 0.36 μg/cm2. For risk assessment purposes, this residue value is scaled 

from the study application rate of 0.12 lb ai/acre to the maximum registered application rate on 

ornamental trees of 0.54 lb ae/acre; the residue value for risk assessment is 1.62 μg/cm2 on day 0.

HED combines risk values resulting from separate routes of exposure when it is likely they can 

occur simultaneously based on the use pattern and the behavior associated with the exposed 

population, and if the hazard associated with the points of departure is similar across routes. 

Since dermal and incidental oral exposure routes share a common toxicological endpoint for 

fluopicolide, risk estimates have been combined for those routes. The incidental oral scenarios 

(i.e., hand-to-mouth and object-to-mouth) should be considered inter-related and it is likely that 

they occur interspersed amongst each other across time. Combining all of these scenarios with 

the dermal exposure scenario would be overly-conservative because of the conservative nature of 
Fluopicolide Human Health Risk Assessment D410653

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each individual assessment. Therefore, for fluopicolide, the post-application exposure scenarios 

that were combined for children 1 < 2 years old are the dermal and hand-to-mouth scenarios. 

This combination is a protective estimate of children’s exposure to pesticides used on turf. All 

residential post-application risk estimates for fluopicolide were found to be “not of concern” 

(MOEs > LOCs) for all exposure scenarios and all lifestages. Table 6.2.1 summarizes the 

residential post application exposure and risk estimates for fluopicolide.

Table 6.2.1. Residential Post-application Non-cancer (Short-Term) Exposure and Risk Estimates for Fluopicolide.

Lifestage

Post-application Exposure 

Scenario Application 

Rate1

Dose 

(mg/kg/day)2 MOEs3

Combined Routes

(X indicates included 

in Combined MOE)

Combined MOEs

Use Site Route of Exposure

Adult

Turf Dermal – High 

Contact 

0.27 lb 

ai/acre for 

turf, 0.54 lb 

ai/acre for 

garden/trees

0.043 460

N/A N/A

Garden Dermal 0.161 120

Turf

Dermal - Mowing 0.00089 23,000

Dermal- Golfing 0.0034 5,900

11 to < 16 year 

old

Dermal- Mowing 0.00088 23,000

Dermal- Golfing 0.0034 5,800

6 to < 11 year 

old

Dermal- Golfing 0.0040 5,000

Garden Dermal 0.095 210

1 to < 2 year 

old Turf

Dermal 0.074 270 X

260 Hand-to-Mouth 0.0041 4,900 X

Object-to-Mouth 0.00012 160,000

Incidental Soil N/A N/A

Ingestion 9.1E-06 2,200,000

1 Based on registered label.

2 Dose (mg/kg/day) equations can be found in Appendix A.

3 MOE = POD (mg/kg/day) ÷ Dose (mg/kg/day).

4 Combined MOE = 1 ÷ (1/dermal MOE) + (1/inhalation MOE) + (1/incidental oral MOE), where applicable.

6.3 Combined Residential Risk Estimates (Multiple Exposure Scenarios)

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.

6.4 Residential Risk Estimates for Use in Aggregate Assessment

Table 6.4.1 reflects the residential risk estimates for use in the aggregate assessment for 

fluopicolide, which represent the highest exposure and highest risk scenarios for the fluopicolide 

residential uses.
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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).
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Table 6.4.1. 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 D410653

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6.5 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.

6.6 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). The 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 

agricultural application rates, this scenario is protective of any exposure of children via spray 

drift from agricultural fluopicolide applications.
Fluopicolide Human Health Risk Assessment D410653

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7.0 Aggregate Exposure/Risk Characterization

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

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

assessment, exposures from relevant sources are added together and compared to quantitative 

estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can be aggregated. When 

aggregating exposures and risks from various sources, HED considers both the route and 

duration of exposure. 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-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 conservative 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

0.015368 0.161 0.176368 110

Adult Female 0.015252 0.161 0.176252 110

Child (6-<11yr)6

0.014425 0.095 0.109425 183

1

For LOC calculation a 10× standard inter-species, 10× 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 6.4.1

4 Total Exposure = Avg Food & Water Exposure + Residential Exposure)

5

(Avg Food & Water Exposure + Residential Exposure)]

6 This age group represents the most conservative 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.

7.3 Intermediate-Term Aggregate Risk

Intermediate-term exposures are not likely because of the intermittent nature of applications by 

homeowners. 
Fluopicolide Human Health Risk Assessment D410653

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7.4 Chronic Aggregate Risk

Chronic or long-term aggregate assessments include exposures that will exceed six months. 

Since there are no chronic non-occupational (residential) exposures, the chornic aggregate 

assessment includes food and drinking water only. 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 as 

to fluopicolide and any other substances. 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 agricultural or occupational applications associated with this action. Therefore, 

there is no potential occupational exposure associated with the proposed change in use pattern. 

10.0 References

Residue Chemistry Summary (A. Kamel, 4/17/2013, D410652)

Dietary Exposure Assessment (A. Kamel, 4/8/2013, D407936)

Occupational/Residential Exposure Assessment (A. LaMay, 4/2/2013, D040413)

Human Health Risk Assessment (D. Davis, 12/09/2010, D384431) and references therein.
Fluopicolide Human Health Risk Assessment D410653

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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 D410653

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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 D410653

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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 D410653

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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 D410653

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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.5300 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. 
Fluopicolide Human Health Risk Assessment D410653

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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.
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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 website3

 

3

http://www.epa.gov/pesticides/science/handler-exposure-data.html and

http://www.epa.gov/opp00001/science/residential-exposure-sop.html
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Appendix C. Residue Summary Table

Appendix E. Summary of Residue Data in Rotational Crops Following Primary Treatment with 

Fluopicolide.

Commodity Total Applic. 

Rate

(lb ai/A) 

[g ai/ha]

PBI 

(days)

Residue Levels1

(ppm fluopicolide equivalents)

n Sample 

Min.

Sample 

Max.

LAFT2 HAFT2 Median Mean Std. 

Dev.

Fluopicolide

Forage 0.366-0.387 

[410-433]

28-41 19 <0.010 0.071 <0.010 0.069 0.010 0.017 0.014

Grain 20 <0.010 <0.010 <0.010 <0.010 0.010 0.010 N/A

Stover 21 <0.010 0.174 <0.010 0.158 0.016 0.028 0.034

Forage 0.749-0.771 

[840-864]

29-33 3 0.018 0.048 0.021 0.044 0.026 0.030 0.012

Grain 3 <0.010 <0.010 <0.010 <0.010 0.010 0.010 N/A

Stover 3 0.058 0.124 0.062 0.113 0.074 0.083 0.026

Forage 1.917 [2149] 31 1 0.236 0.299 0.268 0.268 0.268 0.268 N/A

Grain 1 <0.010 <0.010 <0.010 <0.010 0.010 0.010 N/A

Stover 1 0.322 0.419 0.371 0.371 0.371 0.371 N/A

1

 Except for sample min/max, values reflect per trial averages; n = no. of field trials. For calculation of median, mean, and 

standard deviation, the LOQ in fluopicolide equivalents (0.010 ppm for fluopicolide, 0.020 ppm for BAM, 0.034 ppm for PCA, 

and 0.030 ppm for P1x) was used for any results reported as <LOQ in. N/A = Not applicable.

2

 LAFT = lowest average field trial; HAFT = highest average field trial.