UNITED ST ATES ENVIRONMENT AL PROTECTION AGENCY WASHINGTON, D

. C. 20460

OFFICE OF CHEMICAL SAFETY AND POLLUT I ON 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

e xposure assessment by James Miller (RABI) ; and the drinking water assessment by Cheryl Sutton

, of the Environmental Fate and E ffects Division (EFED).

Page I of38Fludioxonil 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......................................................................................................... 1 7 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-applica tion Exposure and Risk ....................................................... 22 6.3 Residential Bystander Post-A pplication 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 Re sidue Limit (IRL) Status Form .............................................. 38Fludioxonil Human Health Risk Assessment DP# 426863

Page 3 of 38 

### 1.0 Executive Summary

Fludioxonil is a phenyl-pyrrole fung icide registered for use on a variety of field and vegetable crops, fruit trees, berries, herbs, a nd 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 curr ently 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 ingred ient (ai) and are formulated as wettable-powders (WP), water-d ispersible granules (WDG), flowable-concentrates (FlC), flowable suspension-concentrates (SC), and dusts.

Permanent tolerances have been es tablished for residues of fludioxonil per se in/on a variety of plant commodities, ranging from 0.01 ppm on nu merous commodities to 500 ppm on citrus oil [40 CFR §180.516(a)(1)]. Specifical ly, tolerances for residues of fludioxonil are established in/on rapeseed, crambe, and lesquerella at 0.01 pp m, flax seed at 0.05 ppm, and stone fruit group 12 at 5.0 ppm. Additionally, permanent toleranc es 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 a pplication. 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 ar e being extended to other member s of the rapeseed subgroup as fludioxonil is registered for use on rape seed wh ich 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, a nd 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 immuno toxicity when tested up to the limit dose. Fludioxonil was not mutagenic in the tests for ge ne 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 to xicology database for fludioxonil is adequate for characterizing toxicity and quan tification of risk fo r food and non-food uses; 2) there is minor evidence of neurotoxicity in fludioxonil hazard da tabase (convulsions in mi ce) but it is protected for by the point of departure (POD) chosen for th e chronic dietary exposure scenario; 3) there is no evidence of increased quantitativ e 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 toxico logical effects attributable to a single exposure (dose) observed in available oral toxicity studies, including maternal toxicity inFludioxonil Human Health Risk Assessment DP# 426863

Page 4 of 38 

### the developmental toxicity studie s. Therefore, a dose and endpoint were not identified for this risk assessment. The chronic reference dose (c RfD) 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 epithe lial 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 fludi oxonil exposure, the effects of concern in adults and offspring are adequately assessed in the de rmal toxicity study wher e no adverse dermal or systemic effects were observed up to the lim it dose (1000 mg/kg/day). The POD for the shortand intermediate-term incidental oral and inha lation endpoints is base d 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 ch emistry alterations (increased alpha-1 and alpha-2 globulin in females), increased liver weight s in both sexes, increased test es and ovary weights, and an increased severity (but not incidence) of bile duct proliferation. Fludioxo nil was classified as a Group D carcinogen; therefore, ther e is no need for a quantitative cancer risk assessment.

Dietary Risk Estimates (Food + Drinking Water) A chronic aggregate (food + drinking water) expo sure and risk assessment was conducted using the Dietary Exposure Evaluation Model - Food C onsumption 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 Su rvey, What We Eat in America, (USDA’s NHANES/WWEIA). This dietary survey wa s conducted from 2003 to 2008. The unrefined chronic analysis assumed DEEM (ver. 7.81) defau lt 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 Analys is 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 fiel d-grown ornamentals. An EDWC of 0.0385 ppm was used in the chronic analysis. The resulting chronic food plus drinking water risk es timates 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 Re g. No. 100-1242; containing 20.4 % fludioxonil) was evaluated in this assessment as a post-ha rvest fungicide for carrots. This product is formulated as a SC and is inte nded for use via dip/dren ch application for the control of white mold at a maximum applic ation rate of 0.0024 lbs ai/gallon of solution.

There is a potential for occupational exposure asso ciated 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 expo sure to fludioxonil is expected to occur for short- (1 to 30 days) and intermediate-term (1 to 6 months) dur ations. Chronic occupa tional exposures are not expected and were not assessed. The occupati onal exposure scenario s 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, fludioxonilFludioxonil Human Health Risk Assessment DP# 426863

Page 5 of 38 

### is registered for use in residentia l areas, including parks, golf cour ses, athletic fields, residential lawns, ornamentals, and greenhouses. The residen tial 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 hand lers 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, derm al and inhalation exposure is anticipated for workers performing sorting, culling, and packing tasks. Since the workers experience exposure following the treatment, this is technically “pos t-application” exposure; however, unlike other post-application activ ities (e.g., harvesting, scouti ng, etc.), this treatmen t is not governed by the Worker Protection Standard (WPS) and potential re-entry intervals (REIs). Additionally, for workers in the warehouse or packag ing facility not directly invol ved in the automated treatment process, there is potential for i ndirect inhalation exposur e. Exposures for these various scenarios are assessed using data from MR ID 43432901 (Maxey and Murphy, 1994).

HED’s level of concern (LOC) for non-cancer ri sks (i.e., level of c oncern for Margins of Exposure or MOEs) is defined by the uncertainty factors. Both residential and occupational inhalation exposure scenarios uti lized a 10x uncertainty factor fo r human to human extrapolation (UF H 

### ) and a 10x for animal to human extrapolation (UF A 

### ), for a total LOC of 100.

Residential Exposure/Risk: There are no new residential uses proposed for fludioxonil; howeve r, fludioxonil is registered for use in residential areas, including parks, golf courses, athletic fiel ds, residential lawns, ornamentals, and greenhouses. The residentia l uses were reassessed in a previous risk assessment (Memo, 01/19/14, L. Venkateshwara , D412253) to reflect updates to HED’s 2012 Residential Standard Operati ng 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 re sidential risk estimates of concern associated with the use of fludioxonil (i.e., MOEs ≥ 100).

Occupational Handler Exposure/Risk: Occupational handlers are anticipated to have shor t- and intermediate-ter m dermal and inhalation exposures. However, since no short- or interm ediate-term dermal PODs were selected, only inhalation exposures are assessed. There are no s hort- and intermediate-term occupational risk estimates of concern associated with th e proposed new use of fludioxonil (i.e., MOEs ≥ 100).

Occupational Post-appli cation Exposure/Risk: Since no short- or intermediate-term dermal PODs were selected, pos t-application dermal exposures and risks were not quantitatively as sessed for the proposed post-harvest uses on carrots. Post-application inhalati on exposure is expected for post- harvest sorters and packers as well as post-harvest ambient ai r exposure. There are no post- application inhalation risk estimates of concern associated with th e proposed new use of fludioxonil (i.e., MOEs ≥ 100).

There are no short- and intermediate-term occupati onal risk estimates of concern associated with the proposed new use of fludioxonil. There ar e no data gaps in the exposure database.

Aggregate-Risk EstimatesFludioxonil Human Health Risk Assessment DP# 426863

Page 6 of 38 

### Aggregate exposure risk assessments were done fo r the following scenarios: short-term (food + drinking water + residential) and chronic aggreg ate exposure (food + drinki ng water). An acute aggregate-risk assessment was not performed be cause no appropriate endpoint was available to determine the acute RfD for the general populatio n or any population subg roup. The short-term assessment is considered protective of intermedia te-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 reside ntial 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 chr onic aggregate risks do not exceed HED’s LOC.

Environmental-Justice Considerations Potential areas of environmental-ju stice concerns, to the extent possible, were considered in this human health risk assessment, in accordance w ith U.S. Executive Order 12898, “Federal Actions to Address Environmental Just ice in Minority Populations and Low-Income Populations” (http://www.epa.gov/compliance/en vironmentaljustice/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-esta blished procedures. In line with OPP policy, HED estimates risks to population subgroups fr om pesticide exposures that ar e based on patterns of that subgroup’s food and water consumption, and activ ities in and around the home that involve pesticide use in a residential se tting. 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 da ta are analyzed and categorized by subgroups based on age, season of the year, ethnic group, and region of the country. Additi onally, OPP is able to assess dietary exposure to smaller, specia lized 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 mode ls that consider exposure to bystanders and farm workers as well as lifesty le 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 pest icide to determine their dermal and inhalation exposure. As indicated in Appendix C, these studi es have been determined to re quire a review of their ethical conduct and have received that review.

2.0 HED Recommendations

There are no residue chemistry, t oxicological, or occupational/re sidential exposure issues that would preclude establishment of a registration and the followi ng permanent tolerance for the fungicide fludioxonil including its metabolites and de gradates, 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 ppmFludioxonil Human Health Risk Assessment DP# 426863

Page 7 of 38 

### The specific tolerance recommendations are discussed in Secti on 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 chromatogr aphy/ultraviolet (HPLC/UV) methods (Methods AG-597 and AG-597B) are available for enforc ing tolerances for fludioxonil on plant commodities. The limits of qua ntification (LOQs) for these methods range from 0.008 to 0.05 ppm depending on the plant commodity. Additi onally, 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 chromatogra phy and tandem mass-spectrometry detection (LCMS/MS) method (Analytical Met hod 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-be nzodioxole-4-carboxylic acid) for analysis.

2.2.2 Recommended Tolerances

Tolerances are currently established unde r 40 CFR §180.516 for residues of the fungicide fludioxonil, including its metabolit es and degradates, in or on th e 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-reco mmended 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 vegetabl e, 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 ar e included in the rapeseed subgroup 20A.

2.2.3 Revisions to Petitioned-For Tolerances

There are no revisions to the petitioned for tolerances.Fludioxonil Human Health Risk Assessment DP# 426863

Page 8 of 38 

### 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. to lerance 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 wher eas 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 harm onized. Canadian MRLs for fludioxonil in/on flax seed, mustard seed, and poppy seed are no t 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 fung icide registered for use on a variety of field and vegetable crops, fruit trees, berries, herbs, a nd 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 regist ered for seed treatment uses. These EPs contain 0.13 to 50% fludioxonil as the ai and are formulat ed as WPs, WDGs, FlCs, SCs, and dusts. The chemical structure and nomenclature for fludioxon il 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)Fludioxonil Human Health Risk Assessment DP# 426863

Page 9 of 38 

### 3.2 Physical and Chemical Properties

Table 3.2. Physicochemical Properties of Fludioxonil.
Parameter Valu e Reference Melting point 199.8°C DP# 325160, G. Kramer, 11/16/2006 pH 8-9 @ 25°C (1% aqueous dispersion) Density 1.54 g/cm 3 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, pK a pK a1 <0 pK a2 ~ 14.1 Octanol/water partition coefficient, Log(K OW ) 4.12 @ 25°C UV/visible absorption spectrum 12,384 L/mo l 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. N o. 100-1242) for the control of white mold on carrots. Appli cations are proposed as post-ha rvest in-line dip or drench applications at 16 fl oz (0.24 lbs ai) per 100 ga llons. 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 restricti on is included: do not make more than one post-harves t 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 20 0,000 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 em ulsion. 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 app lication 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 aque ous dilution of wax/oil emulsion. Use flooders, T-Jet, or similar application systems. The follo wing restrictions are incl uded: do not make more than one post-harvest applic ation to the fruit.

The currently registered use for Maxim ® 

### 4FS (EPA Reg. No. 100-758) on rapeseed, flax, crambe, and lesquerella is for protection agains t seed-borne and soil-bo rne fungi which cause decay, damping-off, and seedling blight. Applic ations are made at 0.08 to 0.16 fl oz (0.0025 to 0.0050 lbs ai) of formulated produc t per 100 pounds of seed.

The proposed and registered use patte rns are summarized in Table 3.3.Fludioxonil Human Health Risk Assessment DP# 426863

Page 10 of 38 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, fru it 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 notmake 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 ca rrots, 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 prop osed use directions.

3.4 Anticipated Exposure Pathways

The RD has requested an assessment of human hea lth 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 flud ioxonil may be applied directly to growing crops. Occupational exposures to fludioxonil ar e expected for short- and intermediate-term durations when conducting handling and post-applica tion activities. Furthermore, the currently registered residential uses are expected to resu lt in short-term handler exposures for adults and short-term post-application expos ures for adults and children.Fludioxonil Human Health Risk Assessment DP# 426863

Page 11 of 38 

### 3.5 Consideration of Environmental Justice

Potential areas of environmental ju stice concerns, to the extent possi ble, were considered in this human health risk assessment, in accordance w ith U.S. Executive Order 12898, “Federal Actions to Address Environmental Just ice in Minority Populations an d Low-Income Populations,” (http://epa.gov/complian ce/ej/resources/policy/ex ec_order_12898.pdf). As a part of every pesticide risk assessment, OPP considers a larg e 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 consumpti on patterns are compiled by the USDA under the NHANES/WWEIA (2003-2008) and are us ed in pesticide risk assessm ents for all registered food uses of a pesticide. These da ta are analyzed and categorized by subgroups based on age, season of the year, ethnic group, and region of the countr y. 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-diet ary exposures based on home use of pesticide products and associated ri sks for adult applicators and for toddlers, youths, and adults entering or playing on treated ar eas 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 traditiona l dietary patterns among specific subgroups.

4.0 Hazard Characterization and Dose-Response Assessment

Fludioxonil is a contact fungicide and is active through i nhibition of protein kinases leading to reduced fungal growth and development. In mammals, kinases are ubiq uitous enzymes and the effects in fludioxonil’s database are indicativ e 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 evalua ted 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 postnata l 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 i nhalation 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 upda ted endpoints and a waiver request from theFludioxonil Human Health Risk Assessment DP# 426863

Page 12 of 38 

### registrant, the HASPOC determined that a subchroni c inhalation study is not required at this time (TXR # 0053900).

4.2 Absorption, Distribution, Metab olism, & Elimination (ADME)

In the available data charact erizing the ADME for fludioxonil, a pharmacokinetic study was not performed allowing for the determination of the peak plasma concentration levels (C max 

### ), or the time to peak plasma concentration levels (T max 

### ). Absorption from the gastrointestinal (GI) tract was estimated from the excretion data. Tissue di stribution data showed that terminal residues were below the level of detection (LOD) for mo st tissues except the liver, kidneys, blood, and lungs. The major route of excretion was the fece s, with approximately 80% of the administered radioactivity excreted by this route in both sexes at the lo w and high doses. The remaining radioactivity was excreted through the urine. Fludioxonil was well ab sorbed 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 f ecal radioactivity. There were no apparent sex- or dose-related di fferences in the routes of excr etion 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 availabl e for fludioxonil; however, a dermal absorption factor is not needed since a quantitative dermal assessment wa s not required (see Section 4.5).

4.3 Toxicological Effects

In all species tested, the effects in the fludioxonil database are i ndicative of toxicity to the liver, kidney, and hematopoietic system (dogs only). There were also decreased body weights and clinical signs throughout the data base. 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 th e tests for gene mutations.

There was no quantitative or qualitative ev idence of increased susceptibility following in utero exposure to rats and rabbits or fo llowing pre-/postnatal exposure to rats. In a rat developmental toxicity study, fludioxonil caused an increase in fetal incidence and li tter 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 be ing transient and reversible which is consistent with the fludioxonil hazard data base (not seen in offspring in the 2-generation reproductive study). Under current policy, the agency consider s classification of these effects as treatmentrelated but conservative, and not indicative of an increased qualit ative susceptibility. Maternal toxicity occurred at the same dose and manife sted 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 bo dy weights in parental and offspring animals, as well as increased clinical signs in parental animals.

Fludioxonil is of low acute toxicit y, since technical grade fludioxon il is in Toxicity Category III or IV for the full battery of acute te sts and is not a dermal sensitizer.Fludioxonil Human Health Risk Assessment DP# 426863

Page 13 of 38 

### 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 de tail in the sections be low: 1) the toxicology database for fludioxonil is adequate for risk assessment; 2) there is no concern for increased preor postnatal quantitative or qualita tive sensitivity in rats or rabbits; 3) there is low concern for neurotoxicity in the fludioxonil database; and 4) the exposure databa ses are sufficient and unlikely to underestimate exposure.

4.4.1 Completeness of the Toxicology Database

The existing toxicology database for fludi oxonil is adequate for FQPA evaluation. Developmental toxicity studies in rats and rabbits and a tw o-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 carcinogeni city study at the mid- and hi gh-doses. The concern is low however since there was no supportive neuropathol ogy, 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 sele cted 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 exposur e 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 anal ysis assumed tolerance-level residues, DEEM (ver. 7.81) default processing factors, 100% cr op-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 fludi oxonil (Memo, G. Kramer, 05/12/2012, D389613), the scientific conclusions for the s ubchronic and chronic dog studies we re updated to reflect current policy (TXR #0054048). These changes subsequently led to revision of th e chronic dietary and inhalation endpoints described belo w. 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 si ngle dose; and 2) th e fetal effects in the developmental rat study occurred only at the limit dose (1000 mg/kg/day).Fludioxonil Human Health Risk Assessment DP# 426863

Page 14 of 38 

### Acute dietary endpoint (all populations): There were no appropriate toxicological effects at tributable to a single exposure (dose) observed in available oral toxicity studi es, 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 wei ghts, increased platelet s and fibrin in both sexes, cholesterol in males, and alkaline phosphata se release in both sexes. Enlarged livers in two females were observed along with biliary epithe lial cell proliferation in one female. A total UF of 100X (10X for interspecies extrapolation, 10X for intraspecies vari ability, 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 ad verse effects were observe d 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/suscepti bility to offspring from fludi oxonil 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 incident al oral and inhalation endpoints: The POD for the short- and intermediate-term in cidental oral and inha lation endpoints is based upon the NOAEL of 50 mg/kg/day in the subc hronic dog study. At the LOAEL of 250 mg/kg/day, there were decreased absolute body we ights in both sexes, diarrhea, hematological alterations (increased platelet s and fibrin, decreased red ce lls, hemoglobin, and packed cell volume), clinical chemistry alterations (increas ed alpha-1 and alpha-2 globulin in females), increased liver weights in both sexes, increased testes and ov ary weights, and an increased severity (but not incidence) of bile duct prolif eration. This endpoint is protective of adverse effects seen in rats, mice, and dogs after subchr onic 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 und er current policy. A total UF of 100X (10X for interspecies extrapolation, 10X for intraspeci es variability, and a 1X FQPA SF) was applied to the NOAEL of 50 mg/kg/day. Inhalation exposure is assu med to be equivalent to oral exposure.

4.5.1 Recommendation for Combining Routes of Exposure for Risk Assessment

When there are potential occupational and resi dential exposures to a pesticide, the risk assessment must address exposures from three ma jor 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 ma le or female CD-1 mice and male SpragueDawley rats following dietary ad ministration at doses that were adequate for assessing the carcinogenic potential of fludioxonil. In female Sprague-Dawle y rats, there was a statisticallyFludioxonil Human Health Risk Assessment DP# 426863

Page 15 of 38 

### significant increase in tumor incidence only when hepatocellular adenomas and carcinomas were combined (not for individual tumor types). Th e pairwise increase for combined tumors was significant at p=0.03, which is not a strong indicati on of a positive effect. Further, statistical significance was only found when liver adenomas were combined with liver carcinomas. Finally, the increase in these tumo rs was within, but at the high-e nd, 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 classifica tion of fludioxonil was not re-assessed since no new information on carcin ogenicity of the compound was required. The classification is based on the guidance used wh en this assessment was completed (1996) and should continue to be consid ered scientifically sound.

4.5.3 Summary of Points of Departure and Toxici ty 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 toxicol ogical effects attributable to a single exposure (dose) observed in available oral toxicity studies, including ma ternal 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 UF A = 10X UF H = 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) andIntermediateTerm (1-6 months) NOAEL = 50 mg/kg/day UF A = 10X UF H = 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) andIntermediateTerm (1-6 months) No hazard identified and therefor e 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

Page 16 of 38Table 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) andIntermediateTerm (1-6 months) Oral NOAEL = 50 mg/kg/day Inhalation assumed equivalent to oral. UF A = 10X UF H = 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 clas sifiable 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 dete rmine risk associated with lo wer environmentally relevant human exposures. NOAEL = no-observed adverse-effect level. LOAEL = lowest-observed adverse-effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intra species). 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) andIntermediateTerm (1-6 months) No hazard identified and therefor e 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) andIntermediateTerm (1-6 months) Oral NOAEL = 50 mg/kg/day (inhalation absorption = 100%) a UF A =10X UF H = 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 clas sifiable 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 en vironmentally relevant human exposures. NOAEL = no-observed adverse-effect level. LOAEL = lowest-observed adverse-effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation inFludioxonil Human Health Risk Assessment DP# 426863

Page 17 of 38 sensitivity among members of the human population (intrasp ecies). 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 fo llowed 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 fludi oxonil 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 m echanism of toxicity with other substances. For information regarding EPA’s efforts to determine which chemicals have a common mechanism of toxicity and to ev aluate the cumulative effects of such chemicals, see the policy statements released by EPA’s Office of Pe sticide Programs concerning common mechanism determinations and procedures for cumulating e ffects 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 plan ts 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 concer n 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 sulfat e conjugates. Based on the results of these studies, HE D has concluded that the residues of concern in ruminants, for purposes of tolerance expression and risk as sessment, are fludioxonil and Metabolite B-1 [4- (2',2'-difluoro-1',3'-benzdioxol-4'-yl)-1 H -pyrrole-3-carbonitrile, 2- O -glucuronide]. The residues of concern in poultry, for purposes of tolerance expression and risk asse ssment, are fludioxonil, CGA-344623 [2-cyano-3-(2,2-difluor o-1,3-benzdioxol-4-yl)succinami c 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, fl udioxonil 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 carro ts. The registered use on stone fruit group 12 is being expanded to the redefined group 12-12. The registered use on rapeseed is beingFludioxonil Human Health Risk Assessment DP# 426863

Page 18 of 38 

### expanded to the rapeseed subgroup 20A. Fludioxon il 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 th e suppression of certain f ungal diseases in soil, crown, and foliar. When used as a foliar applicat ion, 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 es tablished for residues of fludioxonil per se in/on a variety of plant commodities, ranging from 0.01 ppm on nu merous commodities to 500 ppm on citrus oil [40 CFR §180.516(a)(1)]. Additionally, permanent to lerances have been established for residues of fludioxonil and its metabolites converted to 2,2-difluoro-l,3-benzodi oxole-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 resi dues 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 fo r fludioxonil on carrot. Based on the results of these trials, the appropriate to lerance for residues of fludioxon il in/on carrot is 7.0 ppm. Tolerances for residues in stone fruit group 12 an d 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 vegetabl e. root, except sugar beet and carrot, subgroup 1B. Additionally, tolerances fo r residues of fludioxonil in/on rapeseed, crambe, lesquerella, and flax seed should be deleted as the tolerance fo r residues on rapeseed s ubgroup 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 Mo deling 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 ag ricultural field resulting fromcrop applications. Percentcropped areas (PCA) that account for the maximum area within a watershed that may be planted with the modeled crop are applied to concentr ations 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 pesticid e concentrations found in groundwater used as drinking water. The output of SCI-GROW repres ents the concentratio ns of fludioxonil that might be expected in shallow unc onfined aquifers under sandy soils , which is representative ofFludioxonil Human Health Risk Assessment DP# 426863

Page 19 of 38 

### the groundwater most vulnerable to pesticide co ntamination 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 r ecommended 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 Respons e 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 appl ication 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 we ll as the use of containers, resu lts in attenuation of pesticide movement from the containers to the underlying soil in the field, ther eby reducing potential runoff of the pesticide. Thus, EFED now recomm ends that the values from the Tier I DWA of 6/22/2009 (D364264) be used in HED’s human health di etary assessment. The values in the Tier I DWA are based on the use of fludioxonil on field-gr own ornamentals at one application of 2 lb ai/A/yr. The resulting acute and chronic ED WCs in surface water were 83.8 ppb (1-in-10-year acute estimate) and 38.5 ppb (1-in-10-year chroni c estimate), respectively. The EDWC for groundwater (for both acute and chronic an alysis) is 0.2 ppb. Since the surface water concentrations were the highe st; 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 Con centrations (EDWCs) Result ing 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 dos e and endpoint appropriate for th e 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 c onsumption data from USDA’s NHANES/WWEIA (2003-2008). The chronic analysis assumed DEEM (ver. 7.81) defa ult 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. Th e 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 th e dietary assessment.Fludioxonil Human Health Risk Assessment DP# 426863

Page 20 of 38 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, ther e are existing residential uses that have been reassessed in previous documen ts to reflect updates to HED’s 2012 Residential SOPs 1 

### along with policy changes for body weight a ssumptions. 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 reside ntial handlers did not exceed HED’s LOC for all scenarios (i.e., MOEs ≥ 100). Post-application inci dental 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 fl udioxonil 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 list ed below in table 6.1.

1 Available: http://www.epa.gov/pesticides/scien ce/residential-exposure-sop.htmlFludioxonil Human Health Risk Assessment DP# 426863

Page 21 of 38 Table 6.1. Short-term Residential Handler Ex posure and Risk Estima tes for Fludioxonil.

Exposure Scenario Application Rate 1 Area Treated Daily 2 Baseline Unit Exposures 2,3

(mg/lb ai) Baseline Dose 4 (mg/kg/day) Baseline MOE 5

Inhalation Inhalation Inhalation Mixer/Loader/Applicator Mixing/Loading/Applying Wettable Powder in Water-soluble Packaging with Manually-pressurized Handwand to Turf 6 0.0000156 lb ai/ ft 2 1000 ft 2 0.018 3.5E-06 14,000,000

Mixing/Loading/Applying Wettable Powder in Water-soluble Packaging with Backpack Sprayer to Turf 6 0.0000156 lb ai/ ft 2 1000 ft 2 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/ ft 2 1000 ft 2 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/ft 2 1200 ft 2 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/ft 2 1200 ft 2 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/ft 2 1200 ft 2 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/ft 2 1200 ft 2 0.034 0.00048 100,000

1. Application rates based on label for fludioxoni l (Medallion® Fungicide, EPA Reg. No. 100-769).

2. Based on HED’s SOP for Resi dential Pesticide Exposure A ssessment; Lawns/Turf (Feb. 2012).

3. Baseline inhalation: no respirator.

4. Dose (mg/kg/day) = daily unit exposure (mg/lbs ai) x applicatio n rate (lbs ai/area treated or amount handled) x area treated or amount handled * absorption factor (i nhalation = 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 thes e 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 ft 2 was assumed for the area treated, representing a worst-case broadcast spray.Fludioxonil Human Health Risk Assessment DP# 426863

Page 22 of 38 

### 6.2 Residential Post-application Exposure and Risk

There is the potential for post-app lication exposure for individuals e xposed as a result of being in an environment that has been prev iously treated with fludioxonil. Th e lifestages selected for each post-application scenario are based on an analysis provided as an Appendix in the 2012 Residential SOPs 2 

### . While not the only life stage potenti ally 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 pote ntially exposed life stag e. The quantitative exposure/risk assessment for residential post-appl ication exposures are su mmarized 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 MOEs 4

Child 1 to 2 years old Turf -

sprays Hand to Mouth 1 0.0101 4,800 Object to Mouth 2 0.00031 160,000 Incidental Soil Ingestion 2.2E-05 2,200,000

1. Hand-to-Mouth = [hand residue loading (mg/cm 2 )*(fraction hand surface area mouthed/ event (0.127/event)*typical surface

area of one hand (150 cm 2 ))*(exposure time (1.5 hrs/day)*numbe r of replenishment intervals/hr (4 intervals/hr)*(1-(1-saliva extraction factor (0.5)^(number of hand-to-mout h 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)*der mal exposure (mg))/typical surface area of one hand (150 cm 2 ).

2. Object-to-mouth = ((object residue (μg/cm 2 )*CF1 (1.0E-3 mg/μg)*object surfa ce area mouthed/event (10

cm 2 /event))*(exposure time (1.5 hrs/day) *number of replenishment intervals/ hr (4))*(1-((1-extraction by saliva (0.48))^(number of object-to-mout h events/hr (8.8 events/hr)/ number of repl enishment intervals/hr))))/body weight (11 kg).

3. Soil ingestion = (soil residue (7.0746975 μg/g) *ingestion rate (5 0 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 recomme nded for use in the aggregate assessment for fludioxonil.

6.3 Residential Bystander Post-Application Inhalation Exposure

Volatilization of pes ticides may be a source of post-ap plication inhala tion exposure to individuals nearby pesticide app lications. The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insec ticide, Fungicide, and Rodenticide Act (FIFRA) Scientific Advisory Pa nel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 (http://www.epa.gov/scipoly/SA P/meetings/2009/120109meeting.html). The Agency has evaluated the SAP report and has de veloped a Volatilization Screening Tool and a subsequent Volatilization Screening Analysis (http://www.regulations.gov/#!docke tDetail;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 pest icide applications. This is particularly the case with aerial application, but, to a lesser exte nt, spray drift can also be a potential source of exposure from the ground application methods (e.g., groundboom and airblast) employed for prohexadione calcium. Th e Agency has been working with the Spray Drift Task Force (a task force composed of va rious 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/scien ce/residential-exposure-sop.htmlFludioxonil 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 sp ray 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 approa ch 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 residen tial (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 th e 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 aR fD 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 mi xing/loading/applying a wetta ble powder in water-soluble packaging with hose end sprayer/sp rinkler can to gardens and trees.

 The recommended residential exposure for childr en 1 to 2 years old aggregate assessment reflects incidental oral expos ures (hand-to-mouth) from post-application exposure to outdoor treated turf.

Table 7.2.1 Recommenda tions for the Residential Exposures fo r the Fludioxonil Aggregate Assessment.

Lifestage Exposure Scenario Dose (mg/kg/day) 1 MOE 2

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 re sidential scenarios assessed. Total = dermal + inhalation + in cidental 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.htmFludioxonil Human Health Risk Assessment DP# 426863

Page 24 of 38 

### Short-term aggregate risk is calculated in Ta ble 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 LOC 1 Max Allowable Exposure 2 mg/kg/day Average Food and

Water Exposure mg/kg/day Residential Exposure mg/kg/day 3 Total Exposure mg/kg/day 4 Aggregate MOE (food, water, and residential) 5

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 in ter- and intra-species UFs (UF A and UF H , 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 asse ssments were not performed because there are no registered or proposed uses of fludioxonil that re sult in intermediate- or long-term residential exposures. The chronic aggregat e exposure assessment consists of exposure from food and water only. The chronic dietar y 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 fo llowed 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 ot her substances; and prohexadione calcium does not appear to produce a toxic metabolite produced by other substa nces. For the purposes of this tolerance action, therefore, EPA has assumed that pr ohexadione 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 mech anism 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 mechan ism determinations and procedures for cumulating effects from substances found to ha ve 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; theref ore, there is potential for occupational handler and post-application exposure. Application methods, maximum app lication rates, and use sites are summarized in Table 3.3. Occupational hand ler and post-application exposure is expected and based on the use pattern and information provide d on the labels, is expect ed to be short- or intermediate-term based on the use pattern and information provide d on the labels.

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

Page 25 of 38 

### HED uses the term handlers to describe those individuals who are invo lved in the pesticide application process. HED believe s 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 ha ndler can cause exposure levels to differ in a manner specific to each application event.

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

 Mixing and loading liquid formulation for a pplication 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 detail ed 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 applica tion rate: 16 fl oz formulated pr oduct/100 gal solution with 1.92 lbs ai/gal solution.

 Conversion: (16 fl oz/100 gal solu tion) x (1 gal/128 fl oz) = 0.125 gal 0.125 gal x 1.92 lbs ai/gal soluti on = 0.0024 lbs ai/gal solution.

Unit Exposures: It is the policy of HED to use the best av ailable data to assess handler exposure. Sources of generic handler data, used as surrogate data in the absence of chemical-specific data, include Pesticide Handlers E xposure 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 pred icting handler exposure that are used in this assessment, known as unit exposures, are outlined in the Occupational Pesticide Handler Unit Exposure Surrogate Reference Table 4 

### , 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 website 5 

### . For this assessment, HED’s draft Post Harvest Treatment SOP (03/23/2012) was used with inhalation un it of exposures of 0.083 and 0.219 μ g/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.htmlFludioxonil Human Health Risk Assessment DP# 426863

Page 26 of 38 

### 15,000 lbs of pears (300 boxes/day, 50 lbs/box). Use of this estimate assumes a worker is producing a fresh batch of pestic ide per treatment. In most cas es, one batch can be used for several treatments, so it is unlikely that this am ount 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-t erm. Exposure duration is determined by many things, including the exposed population, the use site , the pest pressure tr iggering the use of the pesticide, and the cultural prac tices surrounding that use site. Fo r 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 pr oduct 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 a pplication method, and (2) maximum number of applications per year.

Mitigation/Personal Protective Equipment: Estimates of inhalation e xposure were calculated for various levels of personal prot ective equipment (PPE). Results are presented for “baseline,” defined as a single layer of clot hing consisting of a long-sleeved shirt, long pants, shoes plus socks, no protective gloves, and no respirator. The fludioxonil product la bels direct mixers, loaders, applicators, and other ha ndlers to wear long-sleeved shir ts and long pants, shoes plus socks, chemical-resistant gloves and protectiv e eyewear such as goggl es or face shield.

Occupational Handler Non-Cancer Expos ure and Risk Estimate Equations: The algorithms used to estimate non-cancer exposure and dos e for occupational handlers can be found in Appendix B.

Summary of Occupational Handler Non-C ancer Exposure and Risk Estimates: For label specified occupational exposure scenarios, the lo west short- and intermediate-term occupational handler inhalation exposure and ri sk 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 ( μ g/lb ai) 1 Maximum Application Rate 2 Area Treated or Amount Handled Daily 3 Inhalation

Mitigation

Level Dose (mg/kg/day) 4 MOE 5

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 Handl er 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 Polic y: Post Harvest draft SOP (3/23/2012). 4. Inhalation dose = inhalation unit exposure ( μ g/lbs ai) × conversion factor (0.001 mg/ μ g) × application rate (lbs ai/gal) × amount handled

(gal/day) ÷ body weight (80 kg). 5. Inhalation MOE = inhala tion NOAEL (50 mg/kg/day) ÷ inhalation dose (mg/kg/day).Fludioxonil Human Health Risk Assessment DP# 426863

Page 27 of 38 

### 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 pe sticide (also referred to as reentry exposure). Such exposures may occur when workers enter previously treated areas to perform job functions, including ac tivities related to crop producti on such as scouting for pests or harvesting. In the case of a post-harvest tr eatment, post application ac tivities include sorting and packing the treated commodity. Post-applica tion exposure levels vary over time and depend on such things as the type of activ ity, the nature of the crop or targ et that was treated, the type of pesticide application, and the chemi cal’s degradation properties.

Occupational Post-Application Inhalati on 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 appl ication via dip/drench application equipment. Post application ac tivities include packers, sorters, a nd ambient air exposure scenarios. Based on the proposed us e, 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 De rmal Exposure and Risk Estimate Equations: The algorithms used to estimat e non-cancer exposure and dose fo r occupational post-application workers can be found in Appendix B.

Occupational Post-application Non-C ancer Inhalation Risk Estimates: Post application exposure scenarios include post-harv est packers and sorters. Post a pplication exposures to sorters and packers (MOE = 20,000), as well as ambi ent 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 ( μ g/% ai) Baseline Inhalation Dose (mg/kg/day) 2

Baseline MOE 3

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 μ g/ % 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 labe l is based on the acute toxicityFludioxonil 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, a nd 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-appli cation 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 In halation Toxicity .............................................. 870.2400 Primar y Eye Irr itation

.................................................... 870.2500 Primar y Dermal Irr itation

.............................................. 870.2600 Derm al Sensiti zation ..................................................... Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes 870.3100 Oral Su bchronic (rodent) ............................................... 870.3150 Oral Su bchronic (nonr odent) ......................................... 870.3200 21-Day Dermal .............................................................. 870.3465 90-D ay Inhala tion .......................................................... Yes Yes Yes No 1 Yes Yes Yes

- 870.3700a Developmental Toxicity (rodent) .................................. 870.3700b Developmental Toxicity (nonrodent) ............................ 870.3800 Reproduc tion ................................................................. Yes Yes Yes Yes Yes Yes 870.4100a Chronic T oxicity (rodent) .............................................. 870.4100b Chronic Toxi city (nonrodent) ........................................ 870.4200b Oncogenicity (mouse) ................................................... 870.4300 Chronic/ Oncogenicity (rat) ............................................ No Yes Yes Yes - Yes Yes Yes 870.5100 Mutagenicity—G ene Mutation - bacterial ..................... 870.5300 Mutagenicity—Gene Mutation - mammalian ................ 870.5375 Mutagenicity—Struc tural 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 No 2
No 2
No -

-

-

-

- 870.7485 Gene ral Metabo lism ...................................................... 870.7600 Derm al Penetr ation ........................................................ 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 accor ding to current HED policy (e.g., body weight gain). These updates, however, would result in higher NOA EL/LOAEL values and would not impact the selected endpoints. Consequently, given the curre nt 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

Page 31 of 38 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 F 0 F 1 M: 2.19, 22.13, 221.61 mg/kg/day F 0 F 1 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

Page 32 of 38 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 14 C-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 approxim ately 80% of the administered radioactiv ity excreted by this route in male and female rats at both the low and high dose. The remaining radioactivitywas excreted through urine. In bile ductcannulated rats, approximately 70% of an administered radioactiv e 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

Page 33 of 38 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 formula tions 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 appl y treatments with powered handguns; that scenario is not further discussed as it does not apply to the current petitions. In th e 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 Occupa tional Pesticide Handler Unit Exposure Surrogate Reference Table 6 

### found on EPA’s webpage detailing occupational handler exposure assessment 7 

### . Values are formulation-speci fic, 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 us ing the application ra te and, depending on the units given for the applicati on 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/sci ence/handler-exposure-table.pdf

7 http://www.epa.gov/pesticides/science/handler-exposure-data.htmlFludioxonil Human Health Risk Assessment DP# 426863

Page 34 of 38 

### percent solution). Rates ma y also appear as mass of product per mass of commodity (e.g., gallons product/ton of commodity). Rega rdless, rates should be converted in the equation to account for units in te rms of amount of ai handled.

 If the application rate is given ba sed on the amount of commodity (e.g., per ton of fruit) to be treate d, 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 concentr ation of ai in application solution and does not provide information on the am ount 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 assume s 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 ba sed 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% absorpti on of external exposure is typically assumed when an oral toxicity study is used to estim ate 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 inha lation exposure is anticipated for workers performing sorting, culling, and packing tasks. Since the workers experience exposure following the treatment, this is technical ly “post-application” exposur e; however, unlike other postapplication activities (e. g., harvesting, scouting, etc.), this tr eatment 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 as sessed using data from MRID 43432901 (Maxey and Murphy, 1994).

Given the potential effects of these different variables, it is a reas onable approach to group sorters and packers for the purposes of expos ure 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/ae184Fludioxonil 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 prov ided 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 rout ine 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: Recomme nded Unit Exposures (μg/percent ai; arithmetic mean) a

Exposure Route PPE b 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 f actor 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 (percen t 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 GM 1 8300 4020 823 374 GSD 1 3.99 5.13 7.76 11.1

AM 1 Empirical 2 16800 9760 2500 1810 Parametric 3 21600 15300 6720 6760 95 th Percentile Empirical 4 47800 22900 6690 4130 Parametric 5 80700 59100 23900 19600

1 GM = geometric mean; GSD = geometric standard deviat ion; 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 measur ements 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 95 th = GM * GSD^1.645.

6 Calculated as sum of inner dosimeter, outer arm dosimeter, and hand rinse m easurements, normalized to percent ai in solution. Exposure monitoring is reflective of individua ls 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/m 3 * m 3 /minute * minutes), normalized to percent ai in solution. Exposure monitoring reflects workers without respirat ors (NR = no respirator). See Table B.2 for estimates that co nsider protection by respirators.Fludioxonil Human Health Risk Assessment DP# 426863

Page 36 of 38 

### Where:

UE = unit exposure (expressed as amount of expos ure per concentration of ai in solution).

Table B.2. presents the recommended defau lt 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 expr ess rates in terms of mass ai per volume solution.

AF = absorption factor (route-specific).

If no information is available, 100% absorpti on of external exposure is typically assumed when an oral toxicity study is used to estim ate 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 ba sed on a chemical’s toxicity. Both reflect current HED policy (HED Hot Sheet #31).

Indirect Inhalation Exposure Ambient/area air monitoring was also conduc ted 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 proce ss. 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 Result s for Ambient Air Samples.

Statistic Inhalation Exposure (μg/% ai) 6 (n=22) Range 2.71 – 1570 GM 1 96.7 GSD 1 4.57

AM 1 Empirical 2 235 Parametric 3 307

95 th Percentile Empirical 4 702 Parametric 5 1180

1 GM = geometric mean; GSD = geometric standard deviat ion; 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 95 th = 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/m 3 * m 3 /minute * minutes), normalized to % ai in solution. Exposure monitoring re flects workers without respirators (NR = no respirator). See Table B.4 for estimates that co nsider protection by respirators.



### In terms of exposure assessment categories, th e 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, si nce the results do not allow differentiation by crop or any other treatment charact eristic, 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 expos ure is as follows:

Dose (μg) = [UE (μg/percent ai) * AR (% ai in solution) * AF] ÷ BW (kg)

Where:

UE = unit exposure (expressed as amount of e xposure 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 expres s rates in terms of mass of ai per volume solution.

AF = absorption factor (route-specific).

If no information is available, 100% absorpti on of external exposure is typically assumed when an oral toxicity study is used to estim ate 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 chemi cal’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 exposur e to many different pesticides, comprise generic pesticide exposure databases such as Pesticide Handlers Exposure Database (PHED) , Outdoor Residential Exposure Task Force (ORETF), Agricultural Hand lers Exposure Task Force (AHETF), and the Agricultural Reentry Task Force (ARTF) database s. 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 re lative to standards of ethical research conduct prevailing when they we re conducted. There is no regulatory barrier to continued reliance on these studi es, and all applicable require ments of EPA’s Rule for the Protection of Human Subject s of Research (40 CFR §26) have been satisfied.

Appendix D. International Resi due Limit (IRL) Status Form

Fludioxonil (071503; 10/30/2014) Summary of US and International Tol erances and Maximum Residue Limits Residue Definition : US Canada Mexico 2 Codex 3 40 CFR §180.490: Plant: 4-(2,2-difluoro-1,3- benzodioxol-4-yl) 1 H -pyrrole-3- carbonitrile Livestock: N/A 4-(2,2-difluoro-1,3- benzodioxol-4-yl) 1 H

pyrrole-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.
Commodity 1 Tolerance (ppm) /Maximum Residue Limit (mg/kg) US Canada Mexico 2 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 co mmodity, 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.