UNITED ST ATES ENVIRONMENT AL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

OFFICE OF 

CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

MEMORANDUM 

DATE: 

SUBJECT: 

PC Code: 

Decision Nos.: 

Petition Nos.: 

22-July-2015 

Fludioxonil. Section 3 Registration for Use on Carrots, Stone Fruit, Group 12-12, 

and Rapeseed, Subgroup 20A. Human Health Risk Assessment. 

071503 DP Barcodes: 0426863 

491305 Registration Nos. 100-1242, 100-758 

4E8272 (Carrot) & Regulatory Action: NA 

4F8277 (Rapeseed) 

Risk Assessment Type: NA Case No.: NA 

TXR No.: 

MRID No.: 

FROM: 

THROUGH: 

TO: 

NA CAS No.: 131341-86-1 

None 40 CFR: §180.516 

William D. Wassell, Chemist ln/;J/ J}. 

Anwar Y. Dunbar, Ph.D., Pharmacologist 

James S. Miller, Environmental Scientist 

Risk Assessment Branch 1 (RAB 1) 

Health Effects Division (HED) (7509P~ J JI')) J.--~ 

Charles W. Smith III, Branch Chief ( #A fA!J 

George F. Kramer, Ph.D., Senior Che~~?J' ..,_,.. 

RABl/HED (7509P) ~ 

Barbara Madden/Laura Nollen, RM 05 

Registration Division (RD; 7505P) 

The HED of the Office of Pesticide Programs (OPP) is charged with estimating the risk to human 

health from exposure to pesticides. The RD of OPP has requested that HED evaluate hazard and 

exposure data and conduct dietary, occupational/residential, and aggregate exposure assessments, 

as needed, to estimate the risk to human health that will result from the registered and proposed 

uses of the fungicide fludioxonil (4-(2,2-difluoro-l ,3-benzodioxol-4-yl)-lH-pyrrole-3-

carbonitrile]. 

A summary of the findings and an assessment of human health risk resulting from the proposed 

and registered uses of fludioxonil are provided in this document. The risk assessment, residue 

chemistry data review, and dietary-exposure assessment were provided by William Wassell 

(RAB 1 ); the hazard characterization by Anwar Dunbar (RAB 1 ); the occupational/residential 

exposure assessment by James Miller (RABI); and the drinking water assessment by Cheryl 

Sutton, of the Environmental Fate and Effects Division (EFED). 

Page I of38 
Fludioxonil Human Health Risk Assessment DP# 426863 

Page 2 of 38 

Table of Contents 

1.0 Executive Summary ................................................................................................................ 3

2.0 HED Recommendations ......................................................................................................... 6

2.1 Data Deficiencies .......................................................................................................... 7

2.2 Tolerance Considerations .............................................................................................. 7

2.3 Label Recommendations ............................................................................................... 8

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

3.1 Identification of Active Ingredient ................................................................................ 8

3.2 Physical and Chemical Properties ................................................................................. 9

3.3 Pesticide Use Pattern/Directions ................................................................................... 9

3.4 Anticipated Exposure Pathways ................................................................................. 10

3.5 Consideration of Environmental Justice ..................................................................... 11

4.0 Hazard Characterization and Dose-Response Assessment ............................................... 11

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

4.2 Absorption, Distribution, Metabolism, & Elimination (ADME) ................................ 12

4.3 Toxicological Effects .................................................................................................. 12

4.4 FQPA Considerations ................................................................................................. 13

4.5 Dose-Response Assessment ........................................................................................ 13

4.6 Cumulative Risk......................................................................................................... 17

5.0 Exposure Assessment and Characterization ..................................................................... 17

5.1 Residues of Concern Summary and Rational ............................................................ 17

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

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

5.4 Dietary Risk Assessment ........................................................................................... 19

6.0 Residential (Non-Occupational Exposure/Risk) ............................................................... 20

6.1 Residential Handler Exposure and Risk .................................................................... 20

6.2 Residential Post-application Exposure and Risk ....................................................... 22

6.3 Residential Bystander Post-Application Inhalation Exposure ................................... 22

6.4 Spray Drift ................................................................................................................. 22

7.0 Aggregate Exposure/Risk Characterization ...................................................................... 23

7.1 Acute Aggregate Risk ................................................................................................ 23

7.2 Short-Term Aggregate Risk ....................................................................................... 23

7.3 Intermediate-Term and Chronic Aggregate Risk ....................................................... 24

8.0 Cumulative Risk ................................................................................................................... 24

9.0 Occupation Exposure .......................................................................................................... 24

9.1 Occupational Handle Exposure/Risk Estimates ......................................................... 24

9.2 Occupational Post-Application Exposure .................................................................. 27

Appendix A. Toxicity Profile Tables ........................................................................................ 29

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

Appendix B. Algorithms for Post-Harvest Treatments .......................................................... 33

Appendix C. Protection of Human Subjects of Research ...................................................... 38

Appendix D. International Residue Limit (IRL) Status Form .............................................. 38

 
Fludioxonil Human Health Risk Assessment DP# 426863 

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1.0 Executive Summary

Fludioxonil is a phenyl-pyrrole fungicide registered for use on a variety of field and vegetable 

crops, fruit trees, berries, herbs, and grasses. It can be applied as a seed treatment, an at-planting 

soil application, broadcast foliar application, and/or post-harvest application. A total of 26 enduse products (EPs) containing fludioxonil are currently registered to Syngenta Crop Protection 

for use on food/feed crops, with the majority of these EPs being registered for seed treatment 

uses. These EPs contain 0.13 to 50% fludioxonil as the active ingredient (ai) and are formulated 

as wettable-powders (WP), water-dispersible granules (WDG), flowable-concentrates (FlC), 

flowable suspension-concentrates (SC), and dusts. 

Permanent tolerances have been established for residues of fludioxonil per se in/on a variety of 

plant commodities, ranging from 0.01 ppm on numerous commodities to 500 ppm on citrus oil 

[40 CFR §180.516(a)(1)]. Specifically, tolerances for residues of fludioxonil are established 

in/on rapeseed, crambe, and lesquerella at 0.01 ppm, flax seed at 0.05 ppm, and stone fruit group 

12 at 5.0 ppm. Additionally, permanent tolerances have been established for residues of 

fludioxonil and its metabolites converted to 2,2-difluoro-l,3-benzodioxole-4-carboxylic acid 

in/on a livestock commodities ranging from 0.01 ppm to 0.05 ppm [40 CFR §180.516(a)(2)]. 

The proposed tolerances for residues of the fungicide fludioxonil are: 

Carrot ...................................................................................7.0 ppm 

Fruit, stone, group 12-12 ......................................................5.0 ppm 

Rapeseed, subgroup 20A, except Flax Seed .......................0.01 ppm 

The proposed use on carrot is for a post-harvest application. For stone fruit, the use and existing 

tolerance are being extended to other members of the redefined crop group 12-12. For rapeseed, 

the use and existing tolerance are being extended to other members of the rapeseed subgroup as 

fludioxonil is registered for use on rape seed which is the representative commodity of the 

subgroup 20A. 

Hazard Assessment: In all species tested, the effects in the fludioxonil database are indicative of 

toxicity to the liver, kidney, and hematopoietic system (dogs only). There were also decreased 

body weights and clinical signs throughout the database. Fludioxonil was non-toxic through the 

dermal route and there was no evidence of immunotoxicity when tested up to the limit dose. 

Fludioxonil was not mutagenic in the tests for gene mutations. There was no quantitative or 

qualitative evidence of increased susceptibility following in utero exposure to rats and rabbits or 

following pre-/postnatal exposure to rats. 

Food Quality Protection Act (FQPA) Safety Factor (SF) Decision: The fludioxonil risk 

assessment team recommends that the FQPA SF be reduced to 1X for all exposure scenarios 

based on the following considerations: 1) the toxicology database for fludioxonil is adequate for 

characterizing toxicity and quantification of risk for food and non-food uses; 2) there is minor 

evidence of neurotoxicity in fludioxonil hazard database (convulsions in mice) but it is protected 

for by the point of departure (POD) chosen for the chronic dietary exposure scenario; 3) there is 

no evidence of increased quantitative fetal susceptibility following in utero exposure in both rats 

and rabbits; and 4) there are no residual uncertainties in the exposure database. 

Dose-Response Assessment: There were no appropriate toxicological effects attributable to a 

single exposure (dose) observed in available oral toxicity studies, including maternal toxicity in 
Fludioxonil Human Health Risk Assessment DP# 426863 

Page 4 of 38 

the developmental toxicity studies. Therefore, a dose and endpoint were not identified for this 

risk assessment. The chronic reference dose (cRfD) of 0.33 mg/kg/day was based on the chronic 

study in dogs. At the lowest-observed adverse-effect level (LOAEL) of 297.8 mg/kg/day, there 

were decreased absolute body weights, increased platelets and fibrin in both sexes, cholesterol in 

males, and alkaline phosphatase release in both sexes. Enlarged livers in two females was 

observed along with biliary epithelial cell proliferation in one female. A quantitative dermal 

assessment is not required. Since there is no concern for increased quantitative 

sensitivity/susceptibility to offspring from fludioxonil exposure, the effects of concern in adults 

and offspring are adequately assessed in the dermal toxicity study where no adverse dermal or 

systemic effects were observed up to the limit dose (1000 mg/kg/day). The POD for the shortand intermediate-term incidental oral and inhalation endpoints is based upon the no-observed 

adverse-effect level (NOAEL) of 50 mg/kg/day in the subchronic dog study. At the LOAEL of 

250 mg/kg/day, there were decreased absolute body weights in both sexes, diarrhea, 

hematological alterations (increased platelets and fibrin, decreased red cells, hemoglobin, and 

packed cell volume), clinical chemistry alterations (increased alpha-1 and alpha-2 globulin in 

females), increased liver weights in both sexes, increased testes and ovary weights, and an 

increased severity (but not incidence) of bile duct proliferation. Fludioxonil was classified as a 

Group D carcinogen; therefore, there is no need for a quantitative cancer risk assessment. 

Dietary Risk Estimates (Food + Drinking Water)

A chronic aggregate (food + drinking water) exposure and risk assessment was conducted using 

the Dietary Exposure Evaluation Model - Food Consumption Intake Database (DEEM-FCID), 

(ver. 3.16), which uses food consumption data from the U.S. Department of Agriculture’s 

National Health and Nutrition Examination Survey, What We Eat in America, (USDA’s 

NHANES/WWEIA). This dietary survey was conducted from 2003 to 2008. The unrefined 

chronic analysis assumed DEEM (ver. 7.81) default processing factors, 100% crop treated (CT), 

and tolerance-level residues for all commodities. The chronic analysis also incorporated the 

drinking water estimates provided by EFED. The fludioxonil estimated drinking water 

concentrations (EDWCs) were Tier II estimates for surface water using the Pesticide Root Zone 

Model (v3.12.2, May 2005) and Exposure Analysis Modeling System (v 2.98.4.6, April 2005) 

(PRZM/EXAMS). The assessment is based on the maximum application rate of 2 pounds (lbs) 

ai/acre (A)/year for field-grown ornamentals. An EDWC of 0.0385 ppm was used in the chronic 

analysis. The resulting chronic food plus drinking water risk estimates are not of concern to 

HED (<100% of the chronic population-adjusted dose or cPAD) for all population subgroups of 

interest. 

Occupational/Residential Exposure Estimates

The formulated end-use product, Scholar® SC Fungicide, (EPA Reg. No. 100-1242; containing 

20.4 % fludioxonil) was evaluated in this assessment as a post-harvest fungicide for carrots. 

This product is formulated as a SC and is intended for use via dip/drench application for the 

control of white mold at a maximum application rate of 0.0024 lbs ai/gallon of solution. 

There is a potential for occupational exposure associated with handler (i.e., mixing and loading,) 

and post-application activities for the proposed uses on carrots. Based on application rates and 

label information, occupational exposure to fludioxonil is expected to occur for short- (1 to 30 

days) and intermediate-term (1 to 6 months) durations. Chronic occupational exposures are not 

expected and were not assessed. The occupational exposure scenarios assessed include postharvest dip/drench for the control of white mold/sclerotinia rot caused by Sclerotinia 

sclerotiorum. There are no new residential uses proposed for fludioxonil; however, fludioxonil 
Fludioxonil Human Health Risk Assessment DP# 426863 

Page 5 of 38 

is registered for use in residential areas, including parks, golf courses, athletic fields, residential 

lawns, ornamentals, and greenhouses. The residential uses were reassessed in a previous risk 

assessment (Memo, 01/19/14, L. Venkateshwara, D412253). The fludioxonil product labels 

direct mixers, loaders, applicators and other handlers to wear long-sleeved shirt and long pants, 

shoes plus socks, chemical-resistant gloves and protective eyewear such as goggles or face 

shield., but no respirator. 

After automated treatments of fludioxonil, dermal and inhalation exposure is anticipated for 

workers performing sorting, culling, and packing tasks. Since the workers experience exposure 

following the treatment, this is technically “post-application” exposure; however, unlike other 

post-application activities (e.g., harvesting, scouting, etc.), this treatment is not governed by the 

Worker Protection Standard (WPS) and potential re-entry intervals (REIs). Additionally, for 

workers in the warehouse or packaging facility not directly involved in the automated treatment 

process, there is potential for indirect inhalation exposure. Exposures for these various scenarios 

are assessed using data from MRID 43432901 (Maxey and Murphy, 1994). 

HED’s level of concern (LOC) for non-cancer risks (i.e., level of concern for Margins of 

Exposure or MOEs) is defined by the uncertainty factors. Both residential and occupational 

inhalation exposure scenarios utilized a 10x uncertainty factor for human to human extrapolation 

(UFH) and a 10x for animal to human extrapolation (UFA), for a total LOC of 100.

Residential Exposure/Risk: 

There are no new residential uses proposed for fludioxonil; however, fludioxonil is registered for 

use in residential areas, including parks, golf courses, athletic fields, residential lawns, 

ornamentals, and greenhouses. The residential uses were reassessed in a previous risk 

assessment (Memo, 01/19/14, L. Venkateshwara, D412253) to reflect updates to HED’s 2012 

Residential Standard Operating Procedures (SOPs), and the current PODs. A summary of 

residential exposure and risk estimates has been provided below for inclusion in the fludioxonil 

aggregate assessment. There are no short-term residential risk estimates of concern associated 

with the use of fludioxonil (i.e., MOEs ≥ 100). 

Occupational Handler Exposure/Risk: 

Occupational handlers are anticipated to have short- and intermediate-term dermal and inhalation 

exposures. However, since no short- or intermediate-term dermal PODs were selected, only 

inhalation exposures are assessed. There are no short- and intermediate-term occupational risk 

estimates of concern associated with the proposed new use of fludioxonil (i.e., MOEs ≥ 100). 

Occupational Post-application Exposure/Risk: 

Since no short- or intermediate-term dermal PODs were selected, post-application dermal 

exposures and risks were not quantitatively assessed for the proposed post-harvest uses on 

carrots. Post-application inhalation exposure is expected for post-harvest sorters and packers as 

well as post-harvest ambient air exposure. There are no post-application inhalation risk 

estimates of concern associated with the proposed new use of fludioxonil (i.e., MOEs ≥ 100). 

There are no short- and intermediate-term occupational risk estimates of concern associated with 

the proposed new use of fludioxonil. There are no data gaps in the exposure database. 

Aggregate-Risk Estimates
Fludioxonil Human Health Risk Assessment DP# 426863 

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Aggregate exposure risk assessments were done for the following scenarios: short-term (food + 

drinking water + residential) and chronic aggregate exposure (food + drinking water). An acute 

aggregate-risk assessment was not performed because no appropriate endpoint was available to 

determine the acute RfD for the general population or any population subgroup. The short-term 

assessment is considered protective of intermediate-term exposure. A long-term aggregate-risk 

assessment was not performed because there are no registered or proposed uses of fludioxonil 

that result in long-term residential exposures. An aggregate cancer risk assessment was not 

performed because fludioxonil is classified as a Group D carcinogen “not classifiable as to 

human carcinogenicity.” All short-term and chronic aggregate risks do not exceed HED’s LOC. 

Environmental-Justice Considerations

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.epa.gov/compliance/environmentaljustice/resources/policy/exec_order_12898.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 NHANES/WWEIA and are used in pesticide risk assessments for all 

registered food uses of a pesticide. These data are analyzed and categorized by subgroups based 

on age, season of the year, ethnic group, and region of the country. Additionally, OPP is able to 

assess dietary exposure to smaller, specialized subgroups and exposure assessments are 

performed when conditions or circumstances warrant. Whenever appropriate, non-dietary 

exposures based on home use of pesticide products and associated risks for adult applicators and 

for toddlers, youths, and adults entering or playing on treated areas post-application are 

evaluated. Further considerations are currently in development as OPP has committed resources 

and expertise to the development of specialized software and models that consider exposure to 

bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific 

subgroups. 

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 to determine their dermal and inhalation exposure. As 

indicated in Appendix C, these studies have been determined to require a review of their ethical 

conduct and have received that review. 

2.0 HED Recommendations 

There are no residue chemistry, toxicological, or occupational/residential exposure issues that 

would preclude establishment of a registration and the following permanent tolerance for the 

fungicide fludioxonil including its metabolites and degradates, in or on the commodities listed 

below. 

Carrot ...................................................................................7.0 ppm 

Fruit, stone, group 12-12 ......................................................5.0 ppm 

Rapeseed, subgroup 20A, except Flax Seed .......................0.01 ppm 
Fludioxonil Human Health Risk Assessment DP# 426863 

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The specific tolerance recommendations are discussed in Section 2.2.2. There are no 

recommended label modifications. 

2.1 Data Deficiencies 

None. 

2.2 Tolerance Considerations 

2.2.1 Enforcement Analytical Method 

Adequate high-performance liquid chromatography/ultraviolet (HPLC/UV) methods (Methods 

AG-597 and AG-597B) are available for enforcing tolerances for fludioxonil on plant 

commodities. The limits of quantification (LOQs) for these methods range from 0.008 to 0.05 

ppm depending on the plant commodity. Additionally, fludioxonil is recoverable by the 

multiresidue method QuEChERS (M. Anastassiades et al., JAOAC Int 86(2) 412-31) using 

high-performance liquid chromatography with tandem mass spectrometry detection (HPLCMS/MS) for analysis. A liquid chromatography and tandem mass-spectrometry detection (LCMS/MS) method (Analytical Method GRM025.03A) is suitable as an enforcement method for 

livestock commodities as defined in SOP No. ACB-019 (9/15/08). The livestock method is a 

common-moiety method in which fludioxonil and its metabolites of regulatory concern are 

converted to CGA192155 (2,2-difluoro-1,3-benzodioxole-4-carboxylic acid) for analysis. 

2.2.2 Recommended Tolerances 

Tolerances are currently established under 40 CFR §180.516 for residues of the fungicide 

fludioxonil, including its metabolites and degradates, in or on the commodities in the following 

table. Compliance with the tolerance levels specified in the following table is to be determined 

by measuring only fludioxonil. 

Table 2.2.2 Tolerance Summary for Fludioxonil.

Commodity Proposed 

Tolerance (ppm) 

Recommended 

Tolerance 

(ppm) 

Correct Commodity 

Definition/Comments 

To be established under 40 CFR §180.516 (a) General. (1) 

Carrots 7.0 

Fruit, stone, group 12-12 5.0 

Rapeseed subgroup 20A, except Flax Seed 0.01 

A revised Section F specifying the HED-recommended tolerances should be submitted. 

In conjunction with this proposal, the tolerance for residues in/on vegetable, root, except sugar 

beet, subgroup 1B should be changed to vegetable, root, except sugar beet and carrot, subgroup 

1B. The tolerances for residues in the individual commodities rapeseed, crambe, and lesquerella 

should be deleted as these commodities are included in the rapeseed subgroup 20A. 

2.2.3 Revisions to Petitioned-For Tolerances 

There are no revisions to the petitioned for tolerances. 
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2.2.4 International Harmonization 

An International Residue Limit (IRL) Status Form is appended to this document as Appendix D. 

The U.S. tolerance and Codex and Canadian maximum residue limits (MRLs) for fludioxonil 

in/on stone fruit are harmonized. The U.S. tolerance and Canadian MRL for residues in/on 

carrots are harmonized; however the Codex MRL is significantly lower. The U.S. tolerance and 

Canadian MRL for residues in carrots are based on a post-harvest use whereas the Codex MRL is 

based on a foliar use. The U.S. tolerance and Canadian MRL for fludioxonil in/on rapeseed are 

harmonized; however, the Codex MRL is not harmonized. Canadian MRLs for fludioxonil in/on 

flax seed, mustard seed, and poppy seed are not harmonized as these commodities are included 

in subgroup 20A. 

2.3 Label Recommendations

No revisions to the proposed label are required. 

2.3.1 Recommendations from Residue Reviews 

None. 

3.0 Introduction 

Fludioxonil is a phenyl-pyrrole fungicide registered for use on a variety of field and vegetable 

crops, fruit trees, berries, herbs, and grasses. It can be applied as a seed treatment, an at-planting 

soil application, broadcast foliar application, and/or post-harvest application. A total of 26 EPs 

containing fludioxonil are currently registered to Syngenta Crop Protection for use on food/feed 

crops, with the majority of these EPs being registered for seed treatment uses. These EPs contain 

0.13 to 50% fludioxonil as the ai and are formulated as WPs, WDGs, FlCs, SCs, and dusts. The 

chemical structure and nomenclature for fludioxonil are presented in Table 3.1. and the physical 

and chemical properties are presented in Table 3.2. 

3.1 Identification of Active Ingredient 

Table 3.1. Fludioxonil Nomenclature.

Compound 

Common name Fludioxonil 

Company experimental name CGA-173506 

IUPAC name 4-(2,2-difluoro-1,3-benzodioxol-4-yl) )-1H-pyrrole-3-carbonitrile 

CAS name 4-(2,2-difluoro-1,3-benzodioxol-4-yl)-1H-pyrrole-3-carbonitrile 

CAS registry number 131341-86-1 

End-use products (EPs) Scholar® SC Fungicide (EPA Reg. No. 100-1242) 

Maxim® 4FS Fungicide (EPA Reg. No. 100-758)
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3.2 Physical and Chemical Properties 

Table 3.2. Physicochemical Properties of Fludioxonil.

Parameter Value Reference 

Melting point 199.8°C DP# 325160, G. Kramer, 

pH 8-9 @ 25°C (1% aqueous dispersion) 11/16/2006 

Density 1.54 g/cm3 typical at 23°C 

Water solubility (25°C) 1.8 mg/L 

Solvent solubility (mg/L @ 25°C) Ethanol 44,000 

Acetone 190,000 

Toluene 2,700 

n-Octanol 20,000 

n-Hexane 7.8 

Vapor pressure (25°C) 2.9 x 10-9 mm Hg 

Dissociation constant, pKa pKa1 <0 

pKa2 ~ 14.1 

Octanol/water partition coefficient, Log(KOW) 4.12 @ 25°C 

UV/visible absorption spectrum 12,384 L/mol x cm @266 nm (neutral solution) 

12,327 L/mol x cm @ 265 nm (acidic solution) 

11,790 L/mol x cm @ 271 nm (basic solution) 

3.3 Pesticide Use Pattern/Directions

IR-4 is proposing the use of Scholar® SC Fungicide (EPA Reg. No. 100-1242) for the control of 

white mold on carrots. Applications are proposed as post-harvest in-line dip or drench 

applications at 16 fl oz (0.24 lbs ai) per 100 gallons. The application solution may be made 

using water, wax/emulsion, or aqueous dilution of wax/oil emulsion. The fruit should be dipped 

for approximately 30 seconds and allowed to drain. The following restriction is included: do not 

make more than one post-harvest application to carrots. 

The currently registered use for Scholar® SC on stone fruits (except cherries) is for in-line dip or 

drench application at 16 fl oz (0.24 lbs ai) per 100 gallons or in-line aqueous or fruit coating 

spray at 16 to 32 fl oz (0.24 to 0.48 lbs ai) per 200,000 lbs of fruit for the control of brown rot, 

gray mold, rhizopus rot, and gilbertella rot. The application may be made using water, 

wax/emulsion, or aqueous dilution of wax/oil emulsion. When performing the dip application, 

fruit should be dipped for approximately 30 seconds and allowed to drain. Use T-Jet, CDA, or 

similar application system for in-line aqueous or fruit coating applications. The following 

restrictions are included: do not make more than one post-harvest application to the fruit; for 

maximum efficacy, use low volume concentrate application systems for treatment of plums. 

The currently registered use for Scholar® SC on cherries is for in-line aqueous or flooder 

application at 16 to 32 fl oz (0.24 to 0.48 lbs ai) per 50,000 lbs of fruit. The application solution 

may be made using water, wax/emulsion, or aqueous dilution of wax/oil emulsion. Use flooders, 

T-Jet, or similar application systems. The following restrictions are included: do not make more 

than one post-harvest application to the fruit. 

The currently registered use for Maxim® 4FS (EPA Reg. No. 100-758) on rapeseed, flax, 

crambe, and lesquerella is for protection against seed-borne and soil-borne fungi which cause 

decay, damping-off, and seedling blight. Applications are made at 0.08 to 0.16 fl oz (0.0025 to 

0.0050 lbs ai) of formulated product per 100 pounds of seed. 

The proposed and registered use patterns are summarized in Table 3.3. 

 
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Table 3.3. Summary of Directions for Use of Fludioxonil. 

Applic. Timing, 

Type, and Equip.1 

Formulation 

[EPA Reg. 

No.] 

Applic. Rate 

Max. 

No. 

Applic. 

per 

Season 

Max. 

Seasonal 

Applic. Rate 

PHI 

(days)

Use Directions and 

Limitations 

Carrots 

Post-harvest dip or 

drench 

Suspension 

concentrate

[100-1242] 

16 fl oz per 100 gallons 

(0.24 lbs ai) 1 

16 fl oz per 

100 gallons 

(0.24 lbs ai) 

NA 

Carrots should be dipped for 

30 seconds and allowed to 

drain. Do not make more than 

one post-harvest application. 

Stone Fruit except Cherry 

Post-harvest dip, 

drench, in-line 

aqueous or fruit 

coating spray 

Suspension 

concentrate

[100-1242] 

16 to 32 fl oz per 100 

gallons (dip, drench) or 

per 200,000 lbs fruit 

(aqueous or fruit coating 

spray) 

(0.24 to 0.48 lbs ai) 

1 32 fl oz 

(0.48 lbs ai) NA 

When performing the dip 

application, fruit should be 

dipped for approximately 30 

seconds and allowed to drain. 

Use T-Jet, CDA, or similar 

application system for in-line 

aqueous or fruit coating 

applications. Do not make 

more than one post-harvest 

application to the fruit; for 

maximum efficacy, use low 

volume concentrate 

application systems for 

treatment of plums. 

Cherry 

Post-harvest inline aqueous or 

flooder application 

Suspension 

concentrate

[100-1242] 

16 to 32 fl oz per 50,000 

lbs fruit 

(0.24 to 0.48 lbs ai) 

1 32 fl oz 

(0.48 lbs ai) NA 

Use flooders, T-Jet or similar 

application system. Do not 

make more than one postharvest application to the fruit. 

Rapeseed Subgroup 20A 

Seed treatment 

Water-based 

slurry 

[100-758] 

0.08 to 0.16 fl oz per 100 

lbs seed 

(0.0025 to 0.0050 lbs ai) 

1 

0.16 fl oz 

(0.0050 lbs 

ai) 

NA 

Seeds that are treated and 

bagged for later use must be 

labelled to say this seed has 

been treated with fludioxonil 

seed treatment. Do not use 

treated seed for feed, food, or 

oil purposes. 

The proposed or registered use directions for carrots, stone fruit, and rapeseed subgroup 20A are 

adequate to allow for evaluation of the uses. The available field trial data for fludioxonil on 

carrots support the proposed use directions. 

3.4 Anticipated Exposure Pathways 

The RD has requested an assessment of human health risk to support the registered and proposed 

new uses of fludioxonil on carrots, stone fruit, and rapeseed. Humans may be exposed to 

fludioxonil in food and drinking water since fludioxonil may be applied directly to growing 

crops. Occupational exposures to fludioxonil are expected for short- and intermediate-term 

durations when conducting handling and post-application activities. Furthermore, the currently 

registered residential uses are expected to result in short-term handler exposures for adults and 

short-term post-application exposures for adults and children. 
Fludioxonil Human Health Risk Assessment DP# 426863 

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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://epa.gov/compliance/ej/resources/policy/exec_order_12898.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 

NHANES/WWEIA (2003-2008) and are used in pesticide risk assessments for all registered food 

uses of a pesticide. These data are analyzed and categorized by subgroups based on age, season 

of the year, ethnic group, and region of the country. Additionally, OPP is able to assess dietary 

exposure to smaller, specialized subgroups and exposure assessments are performed when 

conditions or circumstances warrant. Whenever appropriate, non-dietary exposures based on 

home use of pesticide products and associated risks for adult applicators and for toddlers, youths, 

and adults entering or playing on treated areas postapplication 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 

Fludioxonil is a contact fungicide and is active through inhibition of protein kinases leading to 

reduced fungal growth and development. In mammals, kinases are ubiquitous enzymes and the 

effects in fludioxonil’s database are indicative of toxicity in multiple organ systems. 

4.1 Toxicology Studies Available for Analysis 

The hazard database for fludioxonil is adequate for FQPA evaluation and for dose-response 

evaluation. Fludioxonil was evaluated for toxicity through oral and dermal exposure in the 

following studies: 

(1) subchronic and chronic oral toxicity in rats, mice and dogs; 

(2) subchronic dermal toxicity in rats; 

(3) developmental toxicity in rats and rabbits; 

(4) reproductive and postnatal toxicity in rats; 

(5) carcinogenicity in mice and rats; 

(6) immunotoxicity in mice; 

(7) genotoxicity and mutagenicity studies toxicology studies; and 

(8) metabolism in rats. 

Appendix A includes a summary of the fludioxonil toxicological database. 

HED’s Hazard Assessment and Policy Committee (HASPOC) used a weight-of-evidence 

approach to require a 90-day inhalation study and to not require the neurotoxicity screening 

battery studies (Memo, D. Smegal, 02/29/2012, TXR# 0050679). After revisiting the 

requirement for an inhalation study based upon updated endpoints and a waiver request from the 
Fludioxonil Human Health Risk Assessment DP# 426863 

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registrant, the HASPOC determined that a subchronic inhalation study is not required at this time 

(TXR # 0053900). 

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

In the available data characterizing the ADME for fludioxonil, a pharmacokinetic study was not 

performed allowing for the determination of the peak plasma concentration levels (Cmax), or the 

time to peak plasma concentration levels (Tmax). Absorption from the gastrointestinal (GI) tract 

was estimated from the excretion data. Tissue distribution data showed that terminal residues 

were below the level of detection (LOD) for most tissues except the liver, kidneys, blood, and 

lungs. The major route of excretion was the feces, with approximately 80% of the administered 

radioactivity excreted by this route in both sexes at the low and high doses. The remaining 

radioactivity was excreted through the urine. Fludioxonil was well absorbed from the GI tract. 

In bile duct-cannulated rats, approximately 70% of an administered radioactive dose was 

excreted via this route, supporting the bile as the origin of the fecal radioactivity. There were no 

apparent sex- or dose-related differences in the routes of excretion for fludioxonil. Examination 

of urine for metabolites of fludioxonil showed at least 20 metabolites, each comprising a minor 

fraction of the administered dose (0.1 to 3.1%). There were no significant differences in urinary 

metabolites with sex or dose. 

4.2.1 Dermal Absorption 

There is no dermal penetration study available for fludioxonil; however, a dermal absorption 

factor is not needed since a quantitative dermal assessment was not required (see Section 4.5). 

4.3 Toxicological Effects 

In all species tested, the effects in the fludioxonil database are indicative of toxicity to the liver, 

kidney, and hematopoietic system (dogs only). There were also decreased body weights and 

clinical signs throughout the database. Fludioxonil was non-toxic through the dermal route and 

there was no evidence of immunotoxicity when tested up to and including the limit dose. 

Fludioxonil was not mutagenic in the tests for gene mutations. 

There was no quantitative or qualitative evidence of increased susceptibility following in utero

exposure to rats and rabbits or following pre-/postnatal exposure to rats. In a rat developmental 

toxicity study, fludioxonil caused an increase in fetal incidence and litter incidence of both 

dilated renal pelvis and ureter at the limit dose (1000 mg/kg/day). These effects are known to 

occur spontaneously in the rat, in addition to being transient and reversible which is consistent 

with the fludioxonil hazard database (not seen in offspring in the 2-generation reproductive 

study). Under current policy, the agency considers classification of these effects as treatmentrelated but conservative, and not indicative of an increased qualitative susceptibility. Maternal 

toxicity occurred at the same dose and manifested as body weight decrements. Fludioxonil was 

not developmentally toxic in rabbits. In the 2-generation reproduction study, parental and 

offspring effects occurred at the same dose and consisted of decreased body weights in parental 

and offspring animals, as well as increased clinical signs in parental animals. 

Fludioxonil is of low acute toxicity, since technical grade fludioxonil is in Toxicity Category III 

or IV for the full battery of acute tests and is not a dermal sensitizer. 
Fludioxonil Human Health Risk Assessment DP# 426863 

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4.4 FQPA Considerations 

The RAB1 risk assessment team determined that the FQPA SF can be reduced to 1X based on 

the following considerations described in greater detail in the sections below: 1) the toxicology 

database for fludioxonil is adequate for risk assessment; 2) there is no concern for increased preor postnatal quantitative or qualitative sensitivity in rats or rabbits; 3) there is low concern for 

neurotoxicity in the fludioxonil database; and 4) the exposure databases are sufficient and 

unlikely to underestimate exposure. 

4.4.1 Completeness of the Toxicology Database 

The existing toxicology database for fludioxonil is adequate for FQPA evaluation. 

Developmental toxicity studies in rats and rabbits and a two-generation reproduction study in 

rats, are available to evaluate in utero and pre-/postnatal exposure. 

4.4.2 Evidence of Neurotoxicity 

The only potential indicator of neurotoxicity for fludioxonil was convulsions in mice following 

handling in the mouse carcinogenicity study at the mid- and high-doses. The concern is low 

however since there was no supportive neuropathology, the effect was not seen at similar doses 

in a second mouse carcinogenicity study, there were no other signs of potential neurotoxicity 

observed in the database, and selected endpoints are protective of the effect seen in mice. 

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

There was no evidence of increased susceptibility following in utero exposure to rats and rabbits 

or following postnatal exposure to rats (see Section 4.3). 

4.4.4 Residual Uncertainty in the Exposure Database 

The dietary and residential exposure analyses are conservative and are not expected to 

underestimate exposure and risk. The dietary analysis assumed tolerance-level residues, DEEM 

(ver. 7.81) default processing factors, 100% crop-treated (CT), and modeled drinking water 

estimates. The residential exposure analysis is conservative since it is based on the default 

assumptions from the 2012 Residential SOPs. 

4.5 Dose-Response Assessment 

Since the last risk assessment for fludioxonil (Memo, G. Kramer, 05/12/2012, D389613), the 

scientific conclusions for the subchronic and chronic dog studies were updated to reflect current 

policy (TXR #0054048). These changes subsequently led to revision of the chronic dietary and 

inhalation endpoints described below. Furthermore, it was determined that an acute dietary 

assessment was no longer necessary for fludioxonil. This decision was based upon the following 

weight of evidence; 1) after re-evaluation of the hazard database, it was determined that there 

were no effects that could be attributed to single dose; and 2) the fetal effects in the 

developmental rat study occurred only at the limit dose (1000 mg/kg/day). 
Fludioxonil Human Health Risk Assessment DP# 426863 

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Acute dietary endpoint (all populations): 

There were no appropriate toxicological effects attributable to a single exposure (dose) observed 

in available oral toxicity studies, including maternal toxicity in the developmental toxicity 

studies. Therefore, a dose and endpoint were not identified for this risk assessment. 

Chronic dietary endpoint for the general population: 

The cRfD of 0.33 mg/kg/day was based on the chronic study in dogs. At the LOAEL of 297.8 

mg/kg/day, there were decreased absolute body weights, increased platelets and fibrin in both 

sexes, cholesterol in males, and alkaline phosphatase release in both sexes. Enlarged livers in 

two females were observed along with biliary epithelial cell proliferation in one female. A total 

UF of 100X (10X for interspecies extrapolation, 10X for intraspecies variability, and a 1X FQPA 

SF) was applied to the NOAEL of 33.1 mg/kg/day. Therefore, the cPAD is 0.33 mg/kg/day. 

This study is protective for the doses at which adverse effects were observed in other studies in 

the hazard database. This study is appropriate for the duration of exposure and is protective of 

all population subgroups. 

Dermal endpoint: 

A quantitative dermal assessment is not required. Since there is no concern for increased 

quantitative sensitivity/susceptibility to offspring from fludioxonil exposure, the effects of 

concern in adults and offspring are adequately assessed in the dermal toxicity study where no 

adverse dermal or systemic effects were observed up to the limit dose (1000 mg/kg/day). 

Short- and intermediate-term incidental oral and inhalation endpoints: 

The POD for the short- and intermediate-term incidental oral and inhalation endpoints is based 

upon the NOAEL of 50 mg/kg/day in the subchronic dog study. At the LOAEL of 250 

mg/kg/day, there were decreased absolute body weights in both sexes, diarrhea, hematological 

alterations (increased platelets and fibrin, decreased red cells, hemoglobin, and packed cell 

volume), clinical chemistry alterations (increased alpha-1 and alpha-2 globulin in females), 

increased liver weights in both sexes, increased testes and ovary weights, and an increased 

severity (but not incidence) of bile duct proliferation. This endpoint is protective of adverse 

effects seen in rats, mice, and dogs after subchronic repeated exposures to fludioxonil. A lower 

POD was observed in the developmental rabbit study (10 mg/kg/day), however the effects in that 

study are not considered adverse under current policy. A total UF of 100X (10X for interspecies 

extrapolation, 10X for intraspecies variability, and a 1X FQPA SF) was applied to the NOAEL 

of 50 mg/kg/day. Inhalation exposure is assumed to be equivalent to oral exposure. 

4.5.1 Recommendation for Combining Routes of Exposure for Risk Assessment 

When there are potential occupational and residential exposures to a pesticide, the risk 

assessment must address exposures from three major sources (oral, dermal, and inhalation) and 

determine whether the individual exposures can be combined if they have the same toxicological 

effects. Since the same study and effects were chosen for both routes, incidental oral and 

inhalation exposures can be combined. 

4.5.2 Cancer Classification and Risk Assessment Recommendations 

There was no evidence of carcinogenicity in male or female CD-1 mice and male SpragueDawley rats following dietary administration at doses that were adequate for assessing the 

carcinogenic potential of fludioxonil. In female Sprague-Dawley rats, there was a statistically 
Fludioxonil Human Health Risk Assessment DP# 426863 

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significant increase in tumor incidence only when hepatocellular adenomas and carcinomas were 

combined (not for individual tumor types). The pairwise increase for combined tumors was 

significant at p=0.03, which is not a strong indication of a positive effect. Further, statistical 

significance was only found when liver adenomas were combined with liver carcinomas. 

Finally, the increase in these tumors was within, but at the high-end, of the historical controls. 

Based on these findings and in accordance with the Agency's 1986 “Guidelines for Carcinogen 

Risk Assessment,” fludioxonil was classified as a Group D carcinogen; therefore, there is no 

need for a quantitative cancer risk assessment. The cancer classification of fludioxonil was not 

re-assessed since no new information on carcinogenicity of the compound was required. The 

classification is based on the guidance used when this assessment was completed (1996) and 

should continue to be considered scientifically sound. 

4.5.3 Summary of Points of Departure and Toxicity Endpoints Used in Human Health Risk 

Assessment 

Table 4.5.3.1. Summary of Toxicological Doses and Endpoints for Fludioxonil for Use in Dietary and NonOccupational Human-Health Risk Assessments. 

Exposure/ 

Scenario POD Uncertainty/ FQPA SFs 

RfD, PAD, 

LOC for 

Risk 

Assessment 

Study and Toxicological Effects

Acute Dietary 

(General 

Population, 

including 

Infants and 

Children) 

There were no appropriate toxicological effects attributable to a single exposure (dose) observed 

in available oral toxicity studies, including maternal toxicity in the developmental toxicity 

studies. Therefore, a dose and endpoint were not identified for this risk assessment. 

Chronic 

Dietary (All 

Populations) 

NOAEL = 

33.1 

mg/kg/day 

UFA = 10X 

UFH = 10X 

FQPA SF = 1X 

Chronic RfD 

= 0.33 

mg/kg/day 

cPAD = 0.33 

mg/kg/day 

Chronic toxicity in dogsLOAEL = 297.8 mg/kg/day based upon 

decreased absolute body weights, 

increased platelets and fibrin in both 

sexes, cholesterol in males, and increased 

alkaline phosphatase release in both 

sexes. Enlarged livers in two females 

were observed along with biliary 

epithelial cell proliferation in one female. 

Incidental 

Oral Short- (1-

30 days) and 

IntermediateTerm (1-6 

months) 

NOAEL = 50 

mg/kg/day 

UFA = 10X 

UFH = 10X 

FQPA SF = 1X 

Residential 

LOC for 

MOE = 100 

Subchronic toxicity in dogsLOAEL = 250 mg/kg/day based upon 

decreased absolute body weights in both 

sexes, diarrhea, hematological alterations 

(increased platelets and fibrin, decreased 

red cells, hemoglobin, and packed cell 

volume), clinical chemistry alterations 

(increased alpha-1 and alpha-2 globulin 

in females), increased liver weights in 

both sexes, increased testes and ovary 

weights, and an increased severity (but 

not incidence) of bile duct proliferation. 

Dermal Short- 

(1-30 days) 

and 

IntermediateTerm (1-6 

months) 

No hazard identified and therefore quantification is not required. There are no developmental 

concerns via the dermal route and no systemic toxicity was seen following dermal exposure. 
Fludioxonil Human Health Risk Assessment DP# 426863 

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Table 4.5.3.1. Summary of Toxicological Doses and Endpoints for Fludioxonil for Use in Dietary and NonOccupational Human-Health Risk Assessments. 

Exposure/ 

Scenario POD Uncertainty/ FQPA SFs 

RfD, PAD, 

LOC for 

Risk 

Assessment 

Study and Toxicological Effects

Inhalation 

Short- (1-30 

days) and 

IntermediateTerm (1-6 

months) 

Oral NOAEL 

= 50 

mg/kg/day 

Inhalation 

assumed 

equivalent to 

oral. 

UFA = 10X 

UFH = 10X 

FQPA SF = 1X 

Residential 

LOC for 

MOE = 100 

Subchronic toxicity in dogsLOAEL = 250 mg/kg/day based upon 

decreased absolute body weights in both 

sexes, diarrhea, hematological alterations 

(increased platelets and fibrin, decreased 

red cells, hemoglobin, and packed cell 

volume), clinical chemistry alterations 

(increased alpha-1 and alpha-2 globulin 

in females), increased liver weights in 

both sexes, increased testes and ovary 

weights, and an increased severity (but 

not incidence) of bile duct proliferation. 

Cancer (oral, 

dermal, 

inhalation) 

Classification: Group D chemical - not classifiable as to human carcinogenicity. 

Point of departure (POD) = A data point or an estimated point that is derived from observed dose-response data 

and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant 

human exposures. NOAEL = no-observed adverse-effect level. LOAEL = lowest-observed adverse-effect level. 

UF = uncertainty factor. UFA = extrapolation from animal to human (interspecies). UFH = potential variation in 

sensitivity among members of the human population (intraspecies). FQPA SF = FQPA Safety Factor. PAD = 

population-adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = 

level of concern. 

Table 4.5.3.1. Summary of Toxicological Doses and Endpoints for Fludioxonil for Use in Occupational 

Human-Health Risk Assessments. 

Exposure/ 

Scenario POD UFs LOC for Risk Assessment Study and Toxicological Effects 

Dermal Short- 

(1-30 days) 

and 

IntermediateTerm (1-6 

months) 

No hazard identified and therefore quantification is not required. There are no developmental 

concerns via the dermal route and no systemic toxicity was seen following dermal exposure. 

Inhalation 

Short- (1-30 

days) and 

IntermediateTerm (1-6 

months) 

Oral NOAEL 

= 50 

mg/kg/day 

(inhalation 

absorption = 

100%)a

UFA =10X 

UFH = 10X 

Occupational 

LOC for MOE = 

100 

Subchronic toxicity in dogsLOAEL = 250 mg/kg/day based upon 

decreased absolute body weights in both 

sexes, diarrhea, hematological alterations 

(increased platelets and fibrin, decreased 

red cells, hemoglobin, and packed cell 

volume), clinical chemistry alterations 

(increased alpha-1 and alpha-2 globulin in 

females), increased liver weights in both 

sexes, increased testes and ovary weights, 

and an increased severity (but not 

incidence) of bile duct proliferation. 

Cancer (oral, 

dermal, 

inhalation) 

Classification: Group D chemical - not classifiable as to human carcinogenicity. 

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 
Fludioxonil Human Health Risk Assessment DP# 426863 

Page 17 of 38 

sensitivity among members of the human population (intraspecies). MOE = margin of exposure. LOC = level of 

concern. 

a

 Inhalation absorption default value of 100% is used with oral toxicity endpoint for route-to-route extrapolation. 

4.6 Cumulative Risk

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

common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding for 

fludioxonil and any other substances; and fludioxonil does not appear to produce a toxic 

metabolite produced by other substances. For the purposes of this action, therefore, EPA has 

assumed that fludioxonil does not have 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/. 

5.0 Exposure Assessment and Characterization 

Summary of Analytical Chemistry and Residue Data, pending, W. Wassell, D421064 

Chronic Dietary Exposure and Risk Assessment, pending, W. Wassell, D426862 

MARC Decision Memo, 01/18/2000, W. Donovan, D262022 

5.1 Residues of Concern Summary and Rational 

The nature of fludioxonil in plants is understood based on adequate metabolism studies utilizing 

foliar applications to peaches, grapes, onions, head lettuce, and seed treatment applications to 

rice, wheat, cotton, and soybeans. Based on the results of these studies, HED has determined 

that the residues of concern in plants is fludioxonil. 

Adequate poultry and ruminant metabolism studies are available. The metabolism of fludioxonil 

in ruminants involves hydroxylation of the pyrrole ring followed by formation of glucuronide or 

sulfate conjugates. In poultry, fludioxonil is metabolized by oxidation, ring hydroxylation, 

degradation of the pyrrole moiety, and formation of glucuronide or sulfate conjugates. Based on 

the results of these studies, HED has concluded that the residues of concern in ruminants, for 

purposes of tolerance expression and risk assessment, are fludioxonil and Metabolite B-1 [4-

(2',2'-difluoro-1',3'-benzdioxol-4'-yl)-1H-pyrrole-3-carbonitrile, 2-O-glucuronide]. The residues 

of concern in poultry, for purposes of tolerance expression and risk assessment, are fludioxonil, 

CGA-344623 [2-cyano-3-(2,2-difluoro-1,3-benzdioxol-4-yl)succinamic acid], and Metabolite I-1 

[4-(2',2'-difluoro-1',3'-benzdioxol-4'-yl)-pyrrole-3-carbonitrile, 1-O-sulfate ester]. 

In the rotational crop metabolism studies, fludioxonil and metabolite CGA-192155 were found at 

levels exceeding 0.01 ppm on some commodities. However, the HED MARC determined that 

this metabolite is not of sufficient toxicological concern to identify it as a residue of concern. 

Hence, fludioxonil per se was determined to be the residue of concern in rotational crops. 

5.2 Food Residue Profile 

Fludioxonil is a fungicide proposed for use on carrots. The registered use on stone fruit group 12 

is being expanded to the redefined group 12-12. The registered use on rapeseed is being 
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expanded to the rapeseed subgroup 20A. Fludioxonil may be applied as a seed treatment, foliar 

application during crop growth or as a post-harvest treatment. 

When used as a seed treatment, fludioxonil aids the suppression of certain fungal diseases in soil, 

crown, and foliar. When used as a foliar application, fludioxonil is used to control certain foliar, 

stem, and root diseases. When used post-harvest, it is a protective fungicide used to aid in the 

control of post-harvest diseases during storage prior to sale. 

Permanent tolerances have been established for residues of fludioxonil per se in/on a variety of 

plant commodities, ranging from 0.01 ppm on numerous commodities to 500 ppm on citrus oil 

[40 CFR §180.516(a)(1)]. Additionally, permanent tolerances have been established for residues 

of fludioxonil and its metabolites converted to 2,2-difluoro-l,3-benzodioxole-4-carboxylic acid 

in/on a livestock commodities ranging from 0.01 ppm to 0.05 ppm [40 CFR §180.516(a)(2)]. 

The HED-recommended tolerances for residues of the fungicide fludioxonil are: 

Carrot ...................................................................................7.0 ppm 

Fruit, stone, group 12-12 ......................................................5.0 ppm 

Rapeseed, subgroup 20A ....................................................0.01 ppm 

Adequate crop field trial data are available for fludioxonil on carrot. Based on the results of 

these trials, the appropriate tolerance for residues of fludioxonil in/on carrot is 7.0 ppm. 

Tolerances for residues in stone fruit group 12 and rapeseed are already established. A revised 

Section F is required. 

In conjunction with this proposal, the tolerance for residues in/on vegetable, root, except sugar 

beet, subgroup 1B should be changed to vegetable. root, except sugar beet and carrot, subgroup 

1B. Additionally, tolerances for residues of fludioxonil in/on rapeseed, crambe, lesquerella, and 

flax seed should be deleted as the tolerance for residues on rapeseed subgroup 20A covers these 

commodities. 

5.3 Water Residue Profile 

Memo, 9/17/2014, C. Sutton, D421066 

Estimated drinking water concentrations (EDWCs) were generated using EFED’s standard suite 

of models (DP#389616, C. Sutton, 10/27/2011). The Pesticide Root Zone Model (PRZM, 

v3.12.2, May 2005) and Exposure Analysis Modeling System (EXAMS, v2.98.4.6, April 2005) 

are simulation models used to generate EDWCs of fludioxonil residues that may occur in surface 

water used as drinking water. The PRZM model simulates pesticide movement and 

transformation on and across the agricultural field resulting from crop applications. Percentcropped areas (PCA) that account for the maximum area within a watershed that may be planted 

with the modeled crop are applied to concentrations predicted by PRZM/EXAMS. The models 

and their descriptions are available at the EPA internet site: 

http://www.epa.gov/oppefed1/models/water/. 

Screening Concentration in Ground Water (SCI-GROW v2.3, July 2003) is a regression model 

used as a screening tool to estimate pesticide concentrations found in groundwater used as 

drinking water. The output of SCI-GROW represents the concentrations of fludioxonil that 

might be expected in shallow unconfined aquifers under sandy soils, which is representative of 
Fludioxonil Human Health Risk Assessment DP# 426863 

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the groundwater most vulnerable to pesticide contamination and likely to serve as a drinking 

water source. 

Because the maximum proposed application rates among all of the uses considered for this 

assessment is less than the rates previously assessed by EFED for ornamentals, the EDWCs 

based on use on ornamentals are recommended for use in the human-health dietary assessment. 

However, based on information provided in Syngenta’s 9/9/2011 submission “Fludioxonil 

Registration Review Public Comments Response to Initial 60-Day Comment Period, Case 

Number: 7017, Docket Number: EPA-HQ-OPP-2010-1067,” EFED concurs that the use of the 

container-grown ornamentals application rate is not appropriate for estimating EDWCs. As 

noted by the registrant, the strong adsorption of the pesticide to the potting media used for 

container-grown ornamentals, as well as the use of containers, results in attenuation of pesticide 

movement from the containers to the underlying soil in the field, thereby reducing potential 

runoff of the pesticide. Thus, EFED now recommends that the values from the Tier I DWA of 

6/22/2009 (D364264) be used in HED’s human health dietary assessment. The values in the Tier 

I DWA are based on the use of fludioxonil on field-grown ornamentals at one application of 2 lb 

ai/A/yr. The resulting acute and chronic EDWCs in surface water were 83.8 ppb (1-in-10-year 

acute estimate) and 38.5 ppb (1-in-10-year chronic estimate), respectively. The EDWC for 

groundwater (for both acute and chronic analysis) is 0.2 ppb. Since the surface water 

concentrations were the highest; the chronic dietary runs were conducted assuming water 

residues of 0.0385 ppm, respectively, for all water sources (direct and indirect). 

Table 5.3. Tier II Estimated Drinking Water Concentrations (EDWCs) Resulting From Applications 

of Fludioxonil on Ornamentals (Total Rate of 4 lb ai/A/yr). 

Drinking water source 

(model) Use 1-in-10-year acute (μg/L)

1-in-10-year chronic 

(μg/L)

Surface water 

(PRZM/EXAMS) 

Container-grown 

ornamental 83.8 38.5 

Groundwater (SCI-GROW) Container-grown 

ornamental 0.2 0.2 

An EDWC of 0.0385 ppm was used in the chronic analysis. 

5.4 Dietary Risk Assessment 

Memo, pending, W. Wassell, Dxxxxxx 

There is no study with a single dose and endpoint appropriate for the acute scenario and there is 

no evidence of carcinogenic potential. Therefore, these risk assessments were not performed for 

fludioxonil. 

An unrefined fludioxonil chronic exposure and risk assessment was conducted using DEEMFCID (ver. 3.16) which incorporates food consumption data from USDA’s NHANES/WWEIA 

(2003-2008). The chronic analysis assumed DEEM (ver. 7.81) default processing factors, 100% 

CT, tolerance-level residues for all commodities, and modeled drinking water estimates. The 

resulting chronic risk estimates are not of concern to HED. The most highly exposed population 

subgroup was children 1-2 years old utilizing 71% of the cPAD. See Table 5.4.1 for a summary 

of the results of the dietary assessment. 

 
Fludioxonil Human Health Risk Assessment DP# 426863 

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Table 5.4.1. Summary of Dietary (Food and Drinking Water) Exposure Risk for Fludioxonil.1

Population Subgroup cPAD (mg/kg/day)

Chronic Dietary

Dietary 

Exposure 

(mg/kg/day)

% cPAD

General U.S. Population 

0.33

0.060754 18 

All Infants (<1 year old) 0.096650 29 

Children 1-2 years old* 0.232759 71 

Children 3-5 years old 0.171557 52 

Children 6-12 years old 0.083311 25 

Youth 13-19 years old 0.049740 15 

Adults 20-49 years old 0.045760 14 

Adults 50+ years old 0.045352 14 

Females 13-49 years old 0.046659 14 

* The population subgroup with the greatest risk estimate is bolded. 

6.0 Residential (Non-Occupational Exposure/Risk)

There are no proposed residential uses at this time; however, there are existing residential uses 

that have been reassessed in previous documents to reflect updates to HED’s 2012 Residential 

SOPs1 along with policy changes for body weight assumptions. The revision of residential 

exposures will impact the human health aggregate risk assessment for fludioxonil. 

6.1 Residential Handler Exposure and Risk

Short-term inhalation risk estimates to residential handlers did not exceed HED’s LOC for all 

scenarios (i.e., MOEs ≥ 100). Post-application incidental oral risk estimates also did not exceed 

HED’s LOC for any of the scenarios assessed (i.e., MOEs ≥ 100). 

For the full scope of residential uses for fludioxonil see (Memo, L. Venkateshwara, 05/28/14 

D417127; Memo, L. Venkateshwara, 01/09/14, D412253, and Memo, J. Miller, 08/15/14, 

D416160). A summary is listed below in table 6.1. 

 

 

1 Available: http://www.epa.gov/pesticides/science/residential-exposure-sop.html
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Table 6.1. Short-term Residential Handler Exposure and Risk Estimates for Fludioxonil. 

Exposure Scenario Application 

Rate1

Area 

Treated 

Daily2

Baseline Unit 

Exposures2,3

(mg/lb ai) 

Baseline 

Dose4

(mg/kg/day) 

Baseline MOE5

Inhalation Inhalation Inhalation 

Mixer/Loader/Applicator 

Mixing/Loading/Applying 

Wettable Powder in 

Water-soluble Packaging 

with Manually-pressurized 

Handwand to Turf6

0.0000156 

lb ai/ ft2 1000 ft2 0.018 3.5E-06 14,000,000 

Mixing/Loading/Applying 

Wettable Powder in 

Water-soluble Packaging 

with Backpack Sprayer to 

Turf6

0.0000156 

lb ai/ ft2 1000 ft2 0.018 3.5E-06 14,000,000 

Mixing/Loading/Applying 

Wettable Powder in 

Water-soluble Packaging 

with Hose- end sprayer to 

Turf 

0.68 lb ai/A 0.5 

acres 0.034 1.4E-04 350,000 

Mixing/Loading/Applying 

Wettable Powder in 

Water-soluble Packaging 

with Sprinkler Can to Turf 

0.0000156 

lb ai/ ft2 1000 ft2

 0.034 6.6E-06 7,500,000 

Mixing/Loading/Applying 

Wettable Powder in 

Water-soluble Packaging 

with Manually-pressurized 

Handwand to Gardens 

and Trees 

0.00094 lb 

ai/ft2 1200 ft2 0.018 0.00025 200,000 

Mixing/Loading/Applying 

Wettable Powder in 

Water-soluble Packaging 

with Backpack Sprayer to 

Gardens and Trees 

0.00094 lb 

ai/ft2 1200 ft2

 0.018 0.00025 200,000 

Mixing/Loading/Applying 

Wettable Powder in 

Water-soluble Packaging 

with Hose- end sprayer to 

Gardens and Trees 

0.00094 lb 

ai/ft2 1200 ft2

 0.034 0.00048 100,000 

Mixing/Loading/Applying 

Wettable Powder in 

Water-soluble Packaging 

with Sprinkler Can to 

Gardens and Trees 

0.00094 lb 

ai/ft2 1200 ft2

 0.034 0.00048 100,000 

1. Application rates based on label for fludioxonil (Medallion® Fungicide, EPA Reg. No. 100-769). 2. Based on HED’s SOP for Residential Pesticide Exposure Assessment; Lawns/Turf (Feb. 2012). 3. Baseline inhalation: no respirator. 

4. Dose (mg/kg/day) = daily unit exposure (mg/lbs ai) x application rate (lbs ai/area treated or amount handled) x area treated or 

amount handled * absorption factor (inhalation = 100%)/body weight (80 kg). 5. MOE = NOAEL (50 mg/kg/day)/daily dose (mg/kg/day). Level of concern = 100. 

6. The recommended amount handled for these equipment scenarios is in units of gallons/day in the HED Residential SOP 

(February 2012); however, the label does not provide an application rate in units of lbs ai/gallon. Therefore, 1000 ft2

 was 

assumed for the area treated, representing a worst-case broadcast spray. 
Fludioxonil Human Health Risk Assessment DP# 426863 

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6.2 Residential Post-application Exposure and Risk 

There is the potential for post-application exposure for individuals exposed as a result of being in 

an environment that has been previously treated with fludioxonil. The lifestages selected for each 

post-application scenario are based on an analysis provided as an Appendix in the 2012 

Residential SOPs2

. While not the only life stage potentially exposed for these post-application 

scenarios, the life stage that is included in the quantitative assessment is health protective for the 

exposures and risk estimates for any other potentially exposed life stage. The quantitative 

exposure/risk assessment for residential post-application exposures are summarized in Table 6.2. 

Table 6.2 Short -Term Residential Post-application Exposure and Risk Estimates for Fludioxonil. 

Lifestage Post-application Exposure Scenario Dose (mg/kg/day) Short-term MOEs4

Child 1 to 2 years 

old 

Turf - 

sprays 

Hand to Mouth1 0.0101 4,800 

Object to Mouth2 0.00031 160,000 

Incidental Soil Ingestion 2.2E-05 2,200,000 1. Hand-to-Mouth = [hand residue loading (mg/cm2

)*(fraction hand surface area mouthed/event (0.127/event)*typical surface 

area of one hand (150 cm2))*(exposure time (1.5 hrs/day)*number of replenishment intervals/hr (4 intervals/hr)*(1-(1-saliva 

extraction factor (0.5)^(number of hand-to-mouth contact events per hour (13.9 events/hr); Hand Residue Loading = (fraction 

of ai on hands compared to total surface residue from dermal TC study (0.06)*dermal exposure (mg))/typical surface area of 

one hand (150 cm2). 2. Object-to-mouth = ((object residue (μg/cm2)*CF1 (1.0E-3 mg/μg)*object surface area mouthed/event (10 

cm2/event))*(exposure time (1.5 hrs/day)*number of replenishment intervals/hr (4))*(1-((1-extraction by saliva 

(0.48))^(number of object-to-mouth events/hr (8.8 events/hr)/ number of replenishment intervals/hr))))/body weight (11 kg). 3. Soil ingestion = (soil residue (7.0746975 μg/g) *ingestion rate (50 mg/kg/day) *cf(0.000001))/body weight (11 kg). 4. MOE = NOAEL/daily dose (mg ai/kg/day); oral NOAEL = 50 mg/kg/day. 

Table 6.2 reflects the residential risk estimates that are recommended for use in the aggregate 

assessment for fludioxonil. 

6.3 Residential Bystander Post-Application Inhalation Exposure 

Volatilization of pesticides may be a source of post-application inhalation exposure to 

individuals nearby pesticide applications. The Agency sought expert advice and input on issues 

related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act 

(FIFRA) Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report 

on March 2, 2010 (http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). The 

Agency has evaluated the SAP report and has developed a Volatilization Screening Tool and a 

subsequent Volatilization Screening Analysis 

(http://www.regulations.gov/#!docketDetail;D=EPA-HQ-OPP-2014-0219). 

During Registration Review, the agency will utilize this analysis to determine if data (i.e., flux 

studies, route-specific inhalation toxicological studies) or further analysis is required for 

fludioxonil. 

6.4 Spray Drift 

Spray drift is a potential source of exposure to those nearby pesticide applications. This is 

particularly the case with aerial application, but, to a lesser extent, spray drift can also be a 

potential source of exposure from the ground application methods (e.g., groundboom and 

airblast) employed for prohexadione calcium. The Agency has been working with the Spray 

Drift Task Force (a task force composed of various registrants which was developed as a result 

of a Data Call-In issued by EPA), EPA Regional Offices, and State Lead Agencies for pesticide 

 

2

 Available: http://www.epa.gov/pesticides/science/residential-exposure-sop.html
Fludioxonil Human Health Risk Assessment DP# 426863 

Page 23 of 38 

regulation and other parties to develop the best spray drift management practices (see the 

agency’s Spray Drift website for more information). 3 The Agency has also developed a policy 

on how to appropriately consider spray drift as a potential source of exposure in risk assessments 

for pesticides. The potential for spray drift will be quantitatively evaluated for each pesticide 

during the Registration Review process which ensures that all uses for that pesticide will be 

considered concurrently. The approach is outlined in the revised (2012) Standard Operating 

Procedures For Residential Risk Assessment (SOPs) - Residential Exposure Assessment 

Standard Operating Procedures Addenda 1: Consideration of Spray Drift. This document

outlines the quantification of indirect non-occupational exposure to drift. 

7.0 Aggregate Exposure/Risk Characterization

In accordance with the FQPA, HED must consider and aggregate pesticide exposures and risks 

from dietary (food and drinking water) and residential (dermal, inhalation, and incidental oral) 

sources. When aggregating exposures and risks from these sources, HED considers the route and 

duration of exposure as well as the toxicological effects for each route. Based on this and the 

proposed/registered uses, aggregate short-term and chronic assessments were conducted. 

7.1 Acute Aggregate Risk

An acute aggregate risk assessment was not performed because no appropriate endpoint was 

available to determine the aRfD for the general population or any population subgroup. 

7.2 Short-Term Aggregate Risk 

Table 7.2.1 reflects the residential risk estimates that are recommended for use in the aggregate 

assessment for fludioxonil. 

 The recommended residential exposure for use in the adult aggregate assessment reflects 

inhalation exposure from mixing/loading/applying a wettable powder in water-soluble 

packaging with hose end sprayer/sprinkler can to gardens and trees. 

 The recommended residential exposure for children 1 to 2 years old aggregate assessment 

reflects incidental oral exposures (hand-to-mouth) from post-application exposure to 

outdoor treated turf. 

Table 7.2.1 Recommendations for the Residential Exposures for the Fludioxonil Aggregate Assessment. 

Lifestage Exposure 

Scenario 

Dose (mg/kg/day)1 MOE2

Dermal Inhalation Oral Total Dermal Inhalation Oral Total 

Adult 

Handler: 

Treating Turf 

and 

Gardens/Trees 

N/A 0.00062 N/A 0.00062 N/A 81,000 N/A 81,000

Child (1 to 

2 years 

old) 

Hand to mouth 

(HTM) from 

treated turf 

N/A N/A 0.0101 0.0101 N/A N/A 4,800 4,800

1

 Dose = the highest dose for each applicable lifestage of all residential scenarios assessed. Total = dermal + inhalation + incidental oral (where 

applicable). 2

 MOE = the MOEs associated with the highest residential doses. Total = 1 ÷ (1/Dermal MOE) + (1/Inhalation MOE) + (1/Incidental Oral MOE), 

where applicable. 

 

3

 Available: http://www.epa.gov/opp00001/factsheets/spraydrift.htm 
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Short-term aggregate risk is calculated in Table 7.2.2 below. All short-term aggregate exposure 

estimates resulted in MOEs greater than 100, and were not of concern 

Table 7.2.2 Short-Term Aggregate Risk Calculations.

Population 

Short-Term Scenario 

NOAEL 

mg/kg/day 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 

Adults 50+ years 

old 50 100 0.50 0.045352 0.00062 0.45515 110 

Children 1 to 2 

years old 50 100 0.50 0.232759 0.0101 0.242859 210 

1

 The LOC includes the standard inter- and intra-species UFs (UFA and UFH, respectively) totaling 100. 2

 Maximum allowable exposure (mg/kg/day) = NOAEL/LOC. 

3 Residential exposure from Table 7.2.1. 

4

 Total exposure = average food & drinking water exposure + residential exposure). 5

 Aggregate MOE = [NOAEL ÷ (average food & drinking water exposure + residential exposure)]. 

7.3 Intermediate-Term and Chronic Aggregate Risk 

Intermediate- and long-term aggregate risk assessments were not performed because there are no 

registered or proposed uses of fludioxonil that result in intermediate- or long-term residential 

exposures. The chronic aggregate exposure assessment consists of exposure from food and 

water only. The chronic dietary exposure estimates were ≤71% the cPAD and, therefore, do not 

exceed HED’s LOC (see Section 4.5). 

8.0 Cumulative Risk 

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

common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding for 

prohexadione calcium and any other substances; and prohexadione calcium does not appear to 

produce a toxic metabolite produced by other substances. For the purposes of this tolerance 

action, therefore, EPA has assumed that prohexadione calcium does not have 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 Occupation Exposure 

The proposed uses are for agricultural crops; therefore, there is potential for occupational handler 

and post-application exposure. Application methods, maximum application rates, and use sites 

are summarized in Table 3.3. Occupational handler and post-application exposure is expected 

and based on the use pattern and information provided on the labels, is expected to be short- or 

intermediate-term based on the use pattern and information provided on the labels. 

9.1 Occupational Handler Exposure/Risk Estimates
Fludioxonil Human Health Risk Assessment DP# 426863 

Page 25 of 38 

HED uses the term handlers to describe those individuals who are involved in the pesticide 

application process. HED believes that there are distinct job functions or tasks related to 

applications and exposures can vary depending on the specifics of each task. Job requirements 

(amount of chemical used in each application), the kinds of equipment used, the target being 

treated, and the level of protection used by a handler can cause exposure levels to differ in a 

manner specific to each application event. 

Based on the anticipated use patterns and current labeling, types of equipment and techniques 

that can potentially be used, occupational handler exposure is expected from the proposed uses. 

The quantitative exposure/risk assessment developed for occupational handlers is based on the 

following scenarios: 

 Mixing and loading liquid formulation for application using an automated dip/drench 

application system. 

Occupational Handler Exposure Data and Assumptions: A series of assumptions and exposure 

factors served as the basis for completing the occupational handler risk assessments. Each 

assumption and factor is detailed below on an individual basis.

Application Rate: The current action involves a post-harvest application of Scholar SC® (EPA 

Reg. No. 100-1242) to carrots for the control of white mold at a proposed application rate of 

0.0024 lbs ai/gal of solution. 

 Label specific application rate: 16 fl oz formulated product/100 gal solution with 1.92 lbs 

ai/gal solution. 

 Conversion: (16 fl oz/100 gal solution) x (1 gal/128 fl oz) = 0.125 gal 

0.125 gal x 1.92 lbs ai/gal solution = 0.0024 lbs ai/gal solution. 

Unit Exposures: It is the policy of HED to use the best available data to assess handler exposure. 

Sources of generic handler data, used as surrogate data in the absence of chemical-specific data, 

include Pesticide Handlers Exposure Database (PHED), ver. 1.1, the Agricultural Handler 

Exposure Task Force (AHETF) database, the Outdoor Residential Exposure Task Force 

(ORETF) database, or other registrant-submitted occupational exposure studies. Some of these 

data are proprietary (e.g., AHETF data), and subject to the data protection provisions of FIFRA. 

The standard values recommended for use in predicting handler exposure that are used in this 

assessment, known as unit exposures, are outlined in the Occupational Pesticide Handler Unit 

Exposure Surrogate Reference Table4

, which, along with additional information on HED policy 

on use of surrogate data, including descriptions of the various sources, can be found at the 

Agency website5

. For this assessment, HED’s draft Post Harvest Treatment SOP (03/23/2012) 

was used with inhalation unit of exposures of 0.083 and 0.219 μg/lbs ai for automated; closed 

system and liquid applications, respectively. 

Area Treated or Amount Handled: Since the label application rate is given as a percent solution 

and does not provide information on the amount of commodity to be treated, a default estimate 

of 25,000 gallons was used per HED’s draft Post Harvest Treatment SOP. This is based on a 

study which indicated that 20,000 – 35,000 gallon vats were used for treatment of approximately 

 

4 Available: http://www.epa.gov/opp00001/science/handler-exposure-table.pdf 5 Available: http://www.epa.gov/pesticides/science/handler-exposure-data.html
Fludioxonil Human Health Risk Assessment DP# 426863 

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15,000 lbs of pears (300 boxes/day, 50 lbs/box). Use of this estimate assumes a worker is 

producing a fresh batch of pesticide per treatment. In most cases, one batch can be used for 

several treatments, so it is unlikely that this amount of volume is handled on a regular basis. 

Exposure Duration: HED classifies exposures from 1 to 30 days as short-term and exposures 

from 30 days to six months as intermediate-term. Exposure duration is determined by many 

things, including the exposed population, the use site, the pest pressure triggering the use of the 

pesticide, and the cultural practices surrounding that use site. For most agricultural uses, it is 

reasonable to believe that occupational handlers will not apply the same chemical every day for 

more than a one-month time frame; however, there may be a large agribusiness and/or 

commercial applicators who may apply a product over a period of weeks (e.g., completing 

multiple applications for multiple clients within a region). 

For fludioxonil, based on the proposed use, short- and intermediate-term exposures are expected 

for the following reasons: (1) type of application method, and (2) maximum number of 

applications per year. 

Mitigation/Personal Protective Equipment: Estimates of inhalation exposure were calculated for 

various levels of personal protective equipment (PPE). Results are presented for “baseline,” 

defined as a single layer of clothing consisting of a long-sleeved shirt, long pants, shoes plus 

socks, no protective gloves, and no respirator. The fludioxonil product labels direct mixers, 

loaders, applicators, and other handlers to wear long-sleeved shirts and long pants, shoes plus 

socks, chemical-resistant gloves and protective eyewear such as goggles or face shield. 

Occupational Handler Non-Cancer Exposure and Risk Estimate Equations: The algorithms 

used to estimate non-cancer exposure and dose for occupational handlers can be found in 

Appendix B. 

Summary of Occupational Handler Non-Cancer Exposure and Risk Estimates: For label 

specified occupational exposure scenarios, the lowest short- and intermediate-term occupational 

handler inhalation exposure and risk estimate is 300,000 for mixers/loaders of a liquid using an 

automated dip/drench system for carrots. This exposure scenario is summarized in table 9.1. 

Table 6.1.1. Occupational Handler Non-Cancer Exposure and Risk Estimates for Fludioxonil. 

Exposure 

Scenario Crop 

Level 

of 

Concern 

Inhalation Unit 

Exposure 

(μg/lb ai)1 Maximum 

Application 

Rate2

Area Treated or 

Amount Handled 

Daily3

Inhalation 

Mitigation 

Level 

Dose 

(mg/kg/day)4

MOE5 

Baseline

Mixer/Loader 

Dip/Drench 

Automated 

System 

Liquid

Carrots 100 0.219 

(no respirator) 

0.0024 lbs ai/gal

(16 fl oz/100 

gal) 

25,000 gal soln. N/A 300,000 

1. Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table”. Level of mitigation: Engineering Control (PostHarvest draft SOP 3/23/2012). 

2. Based on the proposed label (Reg. No. 100-1242). 

3. Exposure Science Advisory Council Policy: Post Harvest draft SOP (3/23/2012). 

4. Inhalation dose = inhalation unit exposure (μg/lbs ai) × conversion factor (0.001 mg/μg) × application rate (lbs ai/gal) × amount handled 

(gal/day) ÷ body weight (80 kg). 

5. Inhalation MOE = inhalation NOAEL (50 mg/kg/day) ÷ inhalation dose (mg/kg/day). 
Fludioxonil Human Health Risk Assessment DP# 426863 

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9.2 Occupational Post-Application Exposure

HED uses the term post-application to describe exposures that occur when individuals are 

present in an environment that has been previously treated with a pesticide (also referred to as reentry exposure). Such exposures may occur when workers enter previously treated areas to 

perform job functions, including activities related to crop production such as scouting for pests 

or harvesting. In the case of a post-harvest treatment, post application activities include sorting 

and packing the treated commodity. Post-application exposure levels vary over time and depend 

on such things as the type of activity, the nature of the crop or target that was treated, the type of 

pesticide application, and the chemical’s degradation properties. 

Occupational Post-Application Inhalation Exposure Data and Assumptions: A series of 

assumptions and exposure factors served as the basis for completing the occupational postapplication risk assessments. Each assumption and factor is detailed below on an individual 

basis. 

Exposure Duration: Fludioxonil is a post-harvest application via dip/drench application 

equipment. Post application activities include packers, sorters, and ambient air exposure 

scenarios. Based on the proposed use, short-, and intermediate-term exposures are expected for 

the following reasons: (1) type of application method, and (2) maximum number of applications 

per year. 

Application Rate: For application rates, see the use profile table in section 3.4 for details. 

Exposure Time: The average occupational workday is assumed to be 8 hours. 

Occupational Post-Application Non-Cancer Dermal Exposure and Risk Estimate Equations: 

The algorithms used to estimate non-cancer exposure and dose for occupational post-application 

workers can be found in Appendix B. 

Occupational Post-application Non-Cancer Inhalation Risk Estimates: Post application 

exposure scenarios include post-harvest packers and sorters. Post application exposures to sorters 

and packers (MOE = 20,000), as well as ambient air exposure (MOE = 430,000) are not of 

concern to HED (i.e., MOE > 100). See table 6.2.1 for details. 

Table 9.2. Occupational Post-application Non-Cancer Exposure and Risk Estimates for 

Fludioxonil.

Crop/Site Activities 

Inhalation 

Unit Exposures 

(μg/% ai) 

Baseline 

Inhalation Dose 

(mg/kg/day)2 

Baseline 

MOE3

Short-term/Intermediate-term 

Carrots 

Dip/Drench 

Sorters 6,720 0.0025 200,000 Packers 6,760 

Ambient Air 

Exposure 307 0.0001 430,000 

1

 Application rate: 16 fl oz/100 gal x 20.4 % ai x gal/128 fl. oz. = 0.024 gal ai/100gal. 2

 Daily inhalation dose = [UE (unit exposure μg/ % ai) × AR (% ai in solution) x AF (100%)  body weight (kg). 3

 MOE = POD (mg/kg/day)/daily inhalation dose. 

Restricted Entry Interval: The REI specified on the proposed label is based on the acute toxicity 
Fludioxonil Human Health Risk Assessment DP# 426863 

Page 28 of 38 

of fludioxonil. Fludioxonil is classified as Toxicity Category III via the dermal route and 

Toxicity Category IV for skin irritation potential, and acute inhalation. It is not a skin sensitizer. 

However, since the workers experience exposure following the treatment, this is technically 

“post-application” exposure; however, unlike other post-application activities (e.g., harvesting, 

scouting, etc.), this treatment is not governed by the WPS and potential REIs. 

cc: W. Wassell, (RAB1), A. Dunbar (RAB1), J. Miller (RAB1) 

RDI: Branch (xx/xx/2015) 
Fludioxonil Human Health Risk Assessment DP# 426863 

Page 29 of 38 

Appendix A. Toxicity Profile Tables 

A.1. Toxicology Data Requirements 

The requirements (40 CFR 158.340) for a food use and non-food use for fludioxonil are in Table 1. Use of the new 

guideline numbers does not imply that the new (1998) guideline protocols were used. 

Study Technical

Required Satisfied

870.1100 Acute Oral Toxicity ....................................................... 

870.1200 Acute Dermal Toxicity .................................................. 

870.1300 Acute Inhalation Toxicity .............................................. 

870.2400 Primary Eye Irritation .................................................... 

870.2500 Primary Dermal Irritation .............................................. 

870.2600 Dermal Sensitization ..................................................... 

Yes 

Yes 

Yes 

Yes 

Yes 

Yes 

Yes 

Yes 

Yes 

Yes 

Yes 

Yes 

870.3100 Oral Subchronic (rodent) ............................................... 

870.3150 Oral Subchronic (nonrodent) ......................................... 

870.3200 21-Day Dermal .............................................................. 

870.3465 90-Day Inhalation .......................................................... 

Yes 

Yes 

Yes 

No1

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) ........................................ 

870.4200b Oncogenicity (mouse) ................................................... 

870.4300 Chronic/Oncogenicity (rat) ............................................ 

No 

Yes 

Yes 

Yes 

- 

Yes 

Yes 

Yes 

870.5100 Mutagenicity—Gene Mutation - bacterial ..................... 

870.5300 Mutagenicity—Gene Mutation - mammalian ................ 

870.5375 Mutagenicity—Structural Chromosomal Aberrations ... 

870.5385 Mutagenicity— Bone marrow Chrom. Ab .................... 

870.5395 Mutagenicity- In vivo Mouse micronucleus assay...... 

870.5395 Mutagenicity-In vivo Rat micronucleus assay............ 

870.5450 Mutagenicity-Dominant lethal assay in mice............ 

870.5550 Mutagenicity-In vitro unscheduled DNA synthesis...... 

Yes 

Yes 

Yes 

Yes 

Yes 

Yes 

Yes 

Yes 

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 

No2 

No2 

No 

- 

- 

- 

- 

- 

870.7485 General Metabolism ...................................................... 

870.7600 Dermal Penetration ........................................................ 

870.7800 Immunotoxicity ............................................................. 

Yes 

No 

Yes 

Yes 

- 

Yes 1

 Study is not required at this time based upon weight of evidence decisions by the HASPOC. Decisions are 

discussed in detail in TXR#s 0053900. 

2

 HASPOC concluded that the neurotoxicity studies are not required at this time (TXR #0056079). 

A2. Acute Toxicity Profile 

Table A2. Acute Toxicity of Technical Grade Fludioxonil. 

Guideline 

No. Study Type MRID No. Results Toxicity Category 

870.1100 Acute Oral 43124105 LD50 > 5000 mg/kg IV 

870.1200 Acute Dermal 43124106 LD50 > 2000 mg/kg III 

870.1300 Acute Inhalation 43080019 LC50 = 2.636 mg/L IV 

870.2400 Primary Eye Irritation 43124107 slight irritant III 

870.2500 Primary Skin Irritation 43124108 non-irritating IV 

870.2600 Dermal Sensitization 43080024 not a sensitizer - 
Fludioxonil Human Health Risk Assessment DP# 426863 

Page 30 of 38 

Note: It is recognized that some studies in the fludioxonil database have conservative NOAEL/LOAEL values that 

are based on effects that are not considered adverse according to current HED policy (e.g., body weight gain). 

These updates, however, would result in higher NOAEL/LOAEL values and would not impact the selected 

endpoints. Consequently, given the current risk picture for fludioxonil, the Agency did not find it necessary to 

update these studies at this time. 

A.2.2. Toxicity Profile of Fludioxonil 

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

Guideline 

No. Study Type MRID No. (year)/ Classification /Doses Results

870.3100 90-Day oral 

toxicity (rat) 

43080026 (1990) 

Acceptable/guideline 

0, 10, 100, 1000, 7000, 

20,000 ppm 

M: 0.8, 6.6, 64, 428, 

1283 mg/kg/day 

F: 1.0, 7.1, 70, 462, 1288 

mg/kg/day 

NOAEL = 64 mg/kg/day (M) and 70 

mg/kg/day (F). 

LOAEL = 428 mg/kg/day (M) and 462 

mg/kg/day (F) based on decreased weight gain 

(both sexes), chronic nephropathy (M), and 

centrilobular hepatocyte hypertrophy (F). 

870.3100 90-Day oral 

toxicity (mouse) 

43080027 (1990) 

Acceptable/guideline 

0, 10, 100, 1000, 3000, 

7000 ppm 

M: 1.3, 13.9, 144, 445, 

1052 mg/kg/day 

F: 1.9, 16.8, 178, 559, 

1307 mg/kg/day 

NOAEL = 445 mg/kg day (M) and 559 

mg/kg/day (F). 

LOAEL = 1052 mg/kg/day (M) and 1307 

mg/kg/day (F) based on decreased body 

weight gain (F), increased alkaline 

phosphatase (M), increased relative liver 

weight, increased incidence of nephropathy 

and centrilobular hypertrophy (both sexes). 

870.3150 90-Day oral 

toxicity (dog) 

43080029 (1990) 

Acceptable/guideline 

0, 200, 2000, 

15,000/10,000 ppm 

M & F: 5, 50, 375/250 

mg/kg/day 

NOAEL = 50 mg/kg/day (both sexes). 

LOAEL = 250 mg/kg/day based upon 

decreased absolute body weights in both sexes, 

diarrhea, hematological alterations (increased 

platelets and fibrin, decreased red cells, 

hemoglobin, and packed cell volume), clinical 

chemistry alterations (increased alpha-1 and 

alpha-2 globulin in females), increased liver 

weights in both sexes, increased testes and 

ovary weights, and an increased severity (but 

not incidence) of bile duct proliferation. 

870.3200 28-Day dermal 

toxicity (rat) 

43080030 (1990) 

Acceptable/guideline 

M & F: 0, 40, 200, or 

1000 mg/kg/day 

NOAEL 1000 mg/kg/day for both sexes. 

LOAEL was not established. 

870.3700a Prenatal 

developmental in 

(rat) 

43080034 (1988) 

Acceptable/guideline 

F: 0, 10, 100, or 1000 

mg/kg/day 

Maternal NOAEL = 100 mg/kg/day. 

LOAEL = 1000 mg/kg/day based on reduction 

in corrected weight gain. 

Developmental NOAEL = 100 mg/kg/day. 

LOAEL = 1000 mg/kg/day based on increase 

in the fetal incidence and litter incidence of 

dilated renal pelvis and dilated ureter. 

870.3700b Prenatal 

developmental in 

(rabbit) 

43080035 (1989) 

Acceptable/guideline 

F: 0, 10, 100, or 300 

mg/kg/day 

Maternal NOAEL = 10 mg/kg/day. 

LOAEL = 100 mg /kg/day based on decreased 

body weight gain and decreased food 

efficiency. 

Developmental NOAEL 300 mg/kg/day. 
Fludioxonil Human Health Risk Assessment DP# 426863 

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

Guideline 

No. Study Type MRID No. (year)/ Classification /Doses Results

870.3800 Reproduction and 

fertility effects 

(rat) 

43080036 (1992) 

Acceptable/guideline 

0, 30, 300, or 3,000 ppm 

F0F1 M: 2.19, 22.13, 

221.61 mg/kg/day 

F0F1 F: 2.45, 24.24, 

249.67 mg/kg/day 

Parental/Systemic NOAEL = 22.13 mg/kg/day 

(M) and 24.24 mg/kg/day (F). 

LOAEL = 221.61 mg/kg/day (M) and 249.67 

mg/kg/day (F) based on increased clinical 

signs, decreased body weights, decreased 

weight gain, and decreased food consumption 

in both sexes. 

Reproductive/Offspring NOAEL = 22.13 

mg/kg/day (M) and 24.24 mg/kg/day (F). 

LOAEL = 221.61 mg/kg/day (M) and 249.67 

mg/kg/day (F) based on reduced pup weights 

during lactation. 

870.4100b Chronic toxicity 

(dog) 

43080031 (1992) 

Acceptable/guideline 

0, 100, 1000, or 8,000 

ppm 

M: 0, 3.1, 33.1, or 297.8 

mg/kg/day 

F: 0, 3.3, 35.5, or 330.7 

mg/kg/day 

NOAEL = 33.1/35.5 mg/kg/day (M/F). 

LOAEL = 297.8/330.7 mg/kg/day (M/F) based 

upon decreased absolute body weights, 

increased platelets and fibrin in both sexes, 

cholesterol in males, and alkaline phosphatase 

release in both sexes. Enlarged livers in two 

females was observed along with biliary 

epithelial cell proliferation in one female. 

870.4200 Carcinogenicity 

(mouse) 

43080032 (1993) 

0, 10, 100, 1,000 or 

3,000 ppm 

M: 1.1, 11.3, 112, or 360 

mg/kg/day 

F: 1.4, 13.5, 133, or 417 

mg/kg/day 

NOAEL = 11.3 mg/kg/day (M) and 133 

mg/kg/day (F). 

LOAEL = 112 mg/kg/day (M) and 417 

mg/kg/day (F) based on the increased incidence 

of mice convulsing when handled (M), 

increased absolute liver weight, and grossly 

enlarged livers (F).

Evidence of malignant lymphomas in 

females. 

870.4200 Carcinogenicity 

(mouse) 

43080033 (1993) 

Acceptable/guideline 

0, 3, 30, 5000, or 7,000 

ppm 

M: 0.33, 3.3, 590, or 851 

mg/kg/day 

F: 0.41, 4.1, 715, or 

1,008 mg/kg/day 

NOAEL = 590 mg/kg/day (M) and 715 

mg/kg/day (F). 

LOAEL = 851 mg/kg/day (M) and 1008 

mg/kg/day (F) based on reduced survival (F), 

decreased body weights (M), bile duct 

hyperplasia (M), and severe nephropathy (both 

sexes). 

No evidence of carcinogenicity. 

870.4300 Chronic/ 

Carcinogenicity 

(rat) 

43080037 (1993) 

Acceptable/guideline 

0,10, 30, 100, 1,000, or 

3,000 ppm 

M: 0.37, 1.1, 3.7, 37, or 

113 mg/kg/day 

F: 0.44, 1.3, 4.4, 44, or 

141 mg/kg/day 

NOAEL = 37 mg/kg/day (M) and 44 

mg/kg/day (F). 

LOAEL = 113 mg/kg/day (M) and 141 

mg/kg/day (F) based on decreased mean body 

weight gain, slight anemia (F), and increased 

incidence and severity of liver lesions 

(degeneration) in both sexes.

Evidence of hepatocellular tumors in female 

rats.

870.5100 Gene mutation in 

bacteria 

43080038 (1989) 

Acceptable/guideline 

Strains TA 98, 100, 1535, 1537 of S. 

typhimurium, and strain WP2uvrA of E. coli

were negative for mutagenic activity when 

tested from 20 to 5000 μg/plate in absence and 

presence of metabolic activation. 

870.5300 Gene mutation in 

mammalian cells 

in culture 

43152501 (1989) 

Acceptable/guideline 

Chinese hamster V79 ovary cells were tested 

from 0.50 to 60 μg/mL. Negative up to limit 

of solubility and cytotoxicity. 
Fludioxonil Human Health Risk Assessment DP# 426863 

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

Guideline 

No. Study Type MRID No. (year)/ Classification /Doses Results

870.5375 in vitro 

Chromosome 

aberration 

43080040 (1989) 

Acceptable/guideline 

Chinese hamster ovary cells were tested with 

and without metabolic activation from 1.37 to 

700 μg/mL. Positive for non-disjunction of 

chromosomes both in the presence and 

absence of activation. 

870.5385 870.5385 

Bone marrow 

chromosome 

aberrations assay 

43080042 (1993) 

Acceptable/guideline 

Chinese hamsters were orally dosed at levels 

from 1250 to 5000 mg/kg. There was no 

significant increase in the frequency of 

chromosome aberrations in bone marrow at 

any dose tested. 

870.5395 In vivo Mouse 

micronucleus 

assay 

43080041 (1990) 

Acceptable/guideline 

Both sexes of NMRI mice were dosed up to 

5000 mg/kg/day. There were no significant 

increases in the number or percentage of 

micronucleated polychromatic erythrocytes. 

870.5395 In vivo Rat 

hepatocyte 

micronucleus 

assay 

43080043 (1991) 

Acceptable/guideline 

Male rats were orally dosed 1250, 2500, and 

5000 mg/kg and hepatocytes were harvested. 

Micronucleated hepatocytes were found in 

Phase II at the low and mid dose levels but not 

at the high dose level and not in Phase I. 

Positive for mutagenicity in hepatocytes 

exposed in vivo. 

870.5450 in vitro

unscheduled 

DNA synthesis 

assay

43080039 (1989) 

Acceptable/guideline 

There was no evidence of unscheduled DNA 

synthesis in rat hepatocytes at doses from 4.1 

to 5000 μg/mL. 

870.5550 

 

Dominant lethal 

assay in mice

43080044 (1992) 

Acceptable/guideline 

Male mice singly dosed at 0, 1250, 2500, or 

5000 mg/kg/day and mated for 8 consecutive 

weeks had no evidence of a dominant lethal 

mutation. 

870.7485 Metabolism and 

pharmacokinetics 

(rat) 

43560504, 43560505, 

43429513 (1990) 

Acceptable/ 

Guideline 

14C-Fludioxonil given by gavage and bile-duct 

cannulation to groups of male and female rats. 

Absorption was estimated to be between 67-

91%. Terminal tissue distribution showed that 

terminal residues were below the limit of 

detection for most tissues except the liver, 

kidneys, blood, and lungs, which showed low 

levels. The major route of excretion was the 

feces, with approximately 80% of the 

administered radioactivity excreted by this 

route in male and female rats at both the low 

and high dose. The remaining radioactivity 

was excreted through urine. In bile ductcannulated rats, approximately 70% of an 

administered radioactive dose was excreted 

via this route, supporting the bile as the origin 

of the fecal radioactivity. There were no 

apparent sex- or dose-related differences in the 

routes of excretion for fludioxonil. 

Examination of urine for metabolites of 

fludioxonil showed at least 20 metabolites, 

each comprising a minor fraction of the 

administered dose (0.1-3.1%). 
Fludioxonil Human Health Risk Assessment DP# 426863 

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

Guideline 

No. Study Type MRID No. (year)/ Classification /Doses Results

870.7800 Immunotoxicity 

(mouse) 

48478502 (2011) 

Acceptable/guideline 

0, 1000, 2000, 5000 ppm 

(equivalent to 0, 253.8, 

454, 1230 mg/kg/day 

[F]) 

Systemic NOAEL = 1230 mg/kg/day. 

Systemic LOAEL = not established. 

Immunotoxicity NOAEL = 1230 mg/kg/day. 

Immunotoxicity LOAEL = not established. 

Appendix B. Algorithms for Post-Harvest Treatments 

Occupational Handler: Dip/Drench Application 

Mixing/Loading Exposure 

Workers will mix and load pesticide formulations for both automated post-harvest commodity 

treatments and sprays for loaded trucks. However, for sprays to loaded trucks, the same worker 

is likely to mix/load and apply treatments with powered handguns; that scenario is not further 

discussed as it does not apply to the current petitions. In the case of automated treatments, 

workers will mix/load the pesticide formulation into large bins or vats to produce a dilute 

solution. For this scenario, the standard HED assessment methodology for handling pesticides is 

appropriate: 

Dose (mg) = [UE (mg/lbs ai) * AaiH (lbs ai) * AF] ÷ BW (kg) 

Where: 

UE = unit exposure (expressed as amount of exposure per amount of ai handled). 

 

Default estimates for formulation-specific mixing/loading dermal and inhalation unit 

exposures are provided in HED’s Occupational Pesticide Handler Unit Exposure 

Surrogate Reference Table6

 found on EPA’s webpage detailing occupational handler 

exposure assessment7

. Values are formulation-specific, including closed-system 

mixing/loading which is a potential scenario due to the large volumes being handled for 

dipping vats/bins. 

 

AaiH = amount of ai handled. 

The amount of ai handled is calculated using the application rate and, depending on the 

units given for the application rate, assumptions for amount of commodity to be treated 

or amount of solution volume to mix. 

The application rate is typically specified on the pesticide product label. In the case of 

commodity treatments, particularly those used in automated processes where the fruits 

and vegetables are treated on conveyer belts from large vats of diluted pesticide, this rate 

may appear on the label as a concentration of ai in the application solution (ppm or as a 

 

6 http://www.epa.gov/pesticides/science/handler-exposure-table.pdf 7 http://www.epa.gov/pesticides/science/handler-exposure-data.html 
Fludioxonil Human Health Risk Assessment DP# 426863 

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percent solution). Rates may also appear as mass of product per mass of commodity 

(e.g., gallons product/ton of commodity). Regardless, rates should be converted in the 

equation to account for units in terms of amount of ai handled. 

 If the application rate is given based on the amount of commodity (e.g., 

per ton of fruit) to be treated, the default estimate is 144,000 lbs, 

calculated as the product of 90 lbs commodity per box, 200 boxes per 

hour, and 8 hours per day.8 This is considered to be a conservative, highend capacity estimate. 

 If the estimate is given as a concentration of ai in application solution and 

does not provide information on the amount of commodity to be treated, 

use a default estimate of 25,000 gallons. This is based on MRID 

43432901 referenced above which used 20,000 – 35,000 gallon vats for 

treatment of approximately 15,000 lbs of pears (300 boxes/day, 50 

lbs/box). Use of this estimate assumes a worker is producing a fresh batch 

of pesticide per treatment. In most cases, one batch can be used for 

several treatments, so it is unlikely that this amount is handled on a regular 

basis. 

 

BW = body weight. 

For adults (males and females combined) a default body weight of 80 kg is 

recommended. A default body weight of 69 kg is recommended for females (13 to 49 

years), should it be required based on a chemical’s toxicity. Both reflect current HED 

policy (HED Hot Sheet #31). 

AF = absorption factor (route-specific). 

If no information is available, 100% absorption of external exposure is typically assumed 

when an oral toxicity study is used to estimate dermal and inhalation risk. Route-specific 

toxicity dosing studies, on the other hand, account for rate of absorption. 

Post-application Exposure during Automated Post-Harvest Treatments 

During automated treatments, dermal and inhalation exposure is anticipated for workers 

performing sorting, culling, and packing tasks. Since the workers experience exposure following 

the treatment, this is technically “post-application” exposure; however, unlike other postapplication activities (e.g., harvesting, scouting, etc.), this treatment is not governed by the WPS 

and potential REIs. Additionally, for workers in the warehouse or packaging facility not directly 

involved in the automated treatment process, there is potential for indirect inhalation exposure. 

Exposures for these various scenarios are assessed using data from MRID 43432901 (Maxey and 

Murphy, 1994). 

Given the potential effects of these different variables, it is a reasonable approach to group 

sorters and packers for the purposes of exposure assessment. (Though presenting inhalation 

exposures separately for each task results in no meaningful difference, this is done to be 

 8 For additional reference, see: http://tru-juice.com/tw/about-process.htm and http://edis.ifas.ufl.edu/ae184 
Fludioxonil Human Health Risk Assessment DP# 426863 

Page 35 of 38 

consistent with the separation of dermal exposures by task). No additional sub-setting of the data 

by crop or facility will be conducted. A summary of these results is provided in the Table B.1 

below. 

For exposure assessment, the recommended use of the data based on the analyses discussed 

above is presented in Table B.2 below. As is standard practice for routine short-/intermediate-/ 

or long-term assessments, the arithmetic mean is presented since it is the recommended default 

estimate. 

Table B.2. Post-Harvest Sorters/Packers: Recommended Unit Exposures (μg/percent ai; arithmetic 

mean)a

Exposure Route PPEb Sorters Packers 

Dermal 

Tshirt/NG 21600 15300 

SL/NG 15500 10000 

SL/G 10500 9500 

Inhalation 

NR 6720 6760 

PF5 1340 1350 

PF10 672 675 a

 Means estimated as described in Table B.1. 

b SL = single layer (long pants, long sleeve-shirt, shoes/socks), calculated from exposure monitoring assuming 

50% protection to forearms by a long-sleeve shirt; NG = no chemical-resistant gloves; G = chemical-resistant 

gloves, calculated assuming a protection factor of 90%; NR = no respirator; PF5 = NR value * 0.2 (i.e., protection 

factor 5); PF10 = NR value * .10 (i.e., protection factor 10).

The assessment methodology using these data is as follows: 

 

Dose (μg) = [UE (μg/% ai) * AR (percent ai in solution) * AF] ÷ BW (kg) 

Table B.1. Summary Analysis of Sorter/Packer Exposure Data from MRID 43432901 

Statistic 

Dermal (μg/percent ai)6 Inhalation (μg/percent ai)7

Sorters 

(n=30) 

Packers 

(n=30) 

Sorters 

(n=30) 

Packers 

(n=31) 

Range 415 – 67900 229 – 26500 9.05 – 7310 8.71 – 4550 

GM1 8300 4020 823 374 

GSD1 3.99 5.13 7.76 11.1 

AM1 Empirical2 16800 9760 2500 1810 

Parametric3 21600 15300 6720 6760 

95th

Percentile 

Empirical4 47800 22900 6690 4130 

Parametric5 80700 59100 23900 19600 1

 GM = geometric mean; GSD = geometric standard deviation; AM = arithmetic mean. Statistics are estimated 

assuming a lognormal distribution and independent measurements. Statistics can also be estimated using a variance 

component model accounting for correlation between measurements conducted within the same field study (i.e., 

measurements collected within the same facility). 

2

 Simple average. 

3

 AM = GM*exp{0.5*((lnGSD)^2)}. 

4

 Based on the rank ordering. 

5 95th = GM * GSD^1.645. 6 Calculated as sum of inner dosimeter, outer arm dosimeter, and hand rinse measurements, normalized to percent ai 

in solution. Exposure monitoring is reflective of individuals wearing short-sleeve shirts without chemical-resistant 

gloves. The lower body was not measured. See Table B.2 for estimates that consider additional clothing or PPE. 7 Calculated as product of air concentration, breathing rate, and monitoring time (mg/m3

 * m3/minute * minutes), 

normalized to percent ai in solution. Exposure monitoring reflects workers without respirators (NR = no respirator). 

See Table B.2 for estimates that consider protection by respirators. 
Fludioxonil Human Health Risk Assessment DP# 426863 

Page 36 of 38 

Where: 

UE = unit exposure (expressed as amount of exposure per concentration of ai in solution). 

 

Table B.2. presents the recommended default estimates for dermal and inhalation unit 

exposures for various PPE levels. 

 

AR = application rate. 

The application rate is typically specified on the pesticide product label. To ensure 

proper units conversion, it should be expressed in terms of percent ai in solution which 

may require conversion for labels that express rates in terms of mass ai per volume 

solution. 

AF = absorption factor (route-specific). 

If no information is available, 100% absorption of external exposure is typically assumed 

when an oral toxicity study is used to estimate dermal and inhalation risk. Route-specific 

toxicity dosing studies, on the other hand, account for absorption. 

BW = body weight. 

For adults (males and females combined) a default body weight of 80 kg is 

recommended. A default body weight of 69 kg is recommended for females (13 to 49 

years), should it be required based on a chemical’s toxicity. Both reflect current HED 

policy (HED Hot Sheet #31). 

Indirect Inhalation Exposure 

Ambient/area air monitoring was also conducted in Maxey and Murphy (1994), documenting 

that the automated treatment process can indirectly lead to inhalation exposure to other workers 

not directly involved in the process. All samples were conducted in facilities that treated citrus 

fruit, so these results apply generically for all treatments. A summary is provided in Table B.3 

below. 

Table B.3. Summary Results for Ambient Air Samples. 

Statistic Inhalation Exposure (μg/% ai)6

(n=22) 

Range 2.71 – 1570 

GM1 96.7 

GSD1 4.57 

AM1 Empirical2 235 

Parametric3 307 

95th Percentile Empirical4 702 

Parametric5 1180 1

 GM = geometric mean; GSD = geometric standard deviation; AM = arithmetic mean. Statistics are estimated 

assuming a lognormal distribution and independent measurements. Statistics can also be estimated using a 

variance component model accounting for correlation between measurements conducted within the same field 

study (i.e., measurements collected within the same facility). 

2

 Simple average. 

3

 AM = GM*exp{0.5*((lnGSD)^2)}. 

4

 Based on the rank ordering. 

5 95th = GM * GSD^1.645. 
Fludioxonil Human Health Risk Assessment DP# 426863 

Page 37 of 38 

6 Calculated as product of air concentration, breathing rate, and monitoring time (mg/m3

 * m3/minute * minutes), 

normalized to % ai in solution. Exposure monitoring reflects workers without respirators (NR = no respirator). 

See Table B.4 for estimates that consider protection by respirators. 

In terms of exposure assessment categories, the recommended use of the data based on the 

analyses discussed above is presented in Table B.4 below. As is standard practice for routine 

short-/intermediate-/or long-term assessments, the arithmetic mean is presented since it is the 

recommended default estimate. Additionally, since the results do not allow differentiation by 

crop or any other treatment characteristic, these estimates should be generically applied to all 

post-harvest commodity treatments. 

Table B.4. Post-Harvest Ambient Air: Recommended Inhalation Unit Exposures 

(μg/percent ai; arithmetic mean)a

NR 307 

PF5 61.4 

PF10 30.7 a

 Means estimated as described in Table B.3. 

b NR = no respirator; PF5 = NR value * 0.2 (i.e., protection factor 5); PF10 = NR value * 0.10 (i.e., protection 

factor 10).

Similar to sorters and packers, the methodology using the ambient exposure data to assess 

indirect inhalation exposure is as follows: 

Dose (μg) = [UE (μg/percent ai) * AR (% ai in solution) * AF] ÷ BW (kg) 

Where: 

UE = unit exposure (expressed as amount of exposure per % active ingredient in solution). 

 

Table B.4. presents the recommended default estimates for inhalation unit exposures for 

various PPE levels. 

 

AR = application rate. 

The application rate is typically specified on the pesticide product label. To ensure 

proper units conversion, it should be expressed in terms of percent ai in solution which 

may require conversion for labels that express rates in terms of mass of ai per volume 

solution. 

AF = absorption factor (route-specific). 

If no information is available, 100% absorption of external exposure is typically assumed 

when an oral toxicity study is used to estimate dermal and inhalation risk. Route-specific 

toxicity dosing studies, on the other hand, account for absorption. 

BW = body weight. 

For adults (males and females combined) a default body weight of 80 kg is 

recommended. A default body weight of 69 kg is recommended for females (age 13 to 

49 years), should it be required based on a chemical’s toxicity. Both reflect current HED 

policy (HED Hot Sheet #31). 
Fludioxonil Human Health Risk Assessment DP# 426863 

Page 38 of 38 

Appendix C. Protection of Human Subjects of Research 

Many such studies, involving exposure to many different pesticides, comprise generic pesticide 

exposure databases such as Pesticide Handlers Exposure Database (PHED), Outdoor Residential 

Exposure Task Force (ORETF), Agricultural Handlers Exposure Task Force (AHETF), and the 

Agricultural Reentry Task Force (ARTF) databases. EPA has reviewed all the studies in these 

multi-pesticide generic exposure databases, and based on available evidence has found them to 

have been neither fundamentally unethical nor significantly deficient relative to standards of 

ethical research conduct prevailing when they were conducted. There is no regulatory barrier to 

continued reliance on these studies, and all applicable requirements of EPA’s Rule for the 

Protection of Human Subjects of Research (40 CFR §26) have been satisfied. 

Appendix D. International Residue Limit (IRL) Status Form 

Fludioxonil (071503; 10/30/2014) 

Summary of US and International Tolerances and Maximum Residue Limits 

Residue Definition: 

US Canada Mexico2 Codex3

40 CFR §180.490: 

Plant: 4-(2,2-difluoro-1,3-

benzodioxol-4-yl) 1H-pyrrole-3-

carbonitrile 

Livestock: N/A 

4-(2,2-difluoro-1,3-

benzodioxol-4-yl) 1Hpyrrole-3-carbonitrile 

 Plants: Fludioxonil 

Livestock: fludioxonil and its 

benzopyrrole metabolites, 

determined as 2,2-difluoro-1,3-

benzodioxole-4-caboxylic acid and 

expressed as fludioxonil. The 

residue is fat soluble. 

Commodity1 Tolerance (ppm) /Maximum Residue Limit (mg/kg) 

US Canada Mexico2 Codex 

Carrots 7.0 7 carrot roots 0.7 

Fruit, stone 

group 12-12 

5.0 

5.0 apricots, fresh prune 

plums, nectarines, 

peaches, plumcots, 

plums, prune plums, 

sweet cherries, tart 

cherries 

 5 Po 

Rapeseed 

subgroup 20A 

0.01 

0.05 flax seed 

0.02 mustard seed, 

poppy seed 

0.01 rapeseed (canola) 

 0.02 rape seed (*) 

 

 

Completed: M. Negussie; 11/03/14 

1

 Includes only commodities of interest for this action. Tolerance values should be the HED recommendations and 

not those proposed by the applicant. 

2 Mexico adopts US tolerances and/or Codex MRLs for its export purposes. 

3 * = absent at the limit of quantitation; Po = postharvest treatment, such as treatment of stored grains. PoP = 

processed postharvest treated commodity, such as processing of treated stored wheat. (fat) = to be measured on the 

fat portion of the sample. MRLs indicated as proposed have not been finalized by the CCPR and the CAC.