Document ID: EPA-HQ-OPP-2011-0395-0008
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2012-08-15T04:00Z

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

MEMORANDUM

DATE:	21-MAY-2012

            SUBJECT:	Fludioxonil.  Tolerance Petitions for Residues in/on Ginseng, Leafy Petioles Crop Subgroup 4B, Pineapple (post-harvest treatment), Tuberous and Corm Vegetable Subgroup 1C, Tropical Fruit (post-harvest treatment), Bulb Onion Subgroup 3-07A, Green Onion subgroup 3-07B, Caneberry Subgroup 13-07A, Bushberry Subgroup 13-07B, Small Fruit Vine Climbing Subgroup 13-07F (except fuzzy kiwifruit), Low-Growing Berry Subgroup 13-07G (except cranberry), Fruiting Vegetable Group 8-10 (except tomato), Citrus Fruit Group 10-10, Pome Fruit Group 11-10, Leafy Vegetable (except Brassica) Subgroup 4A, Dragon Fruit, and Tomato (post-harvest treatment).  Human-Health Risk Assessment. 
            
PC Code:  071503
DP Barcode:  D389613
Decision Nos.:  447549, 448805
Registration Nos.:  100-953, 100-1242, 100-969, 100-1308
Petition Nos.:  1E7853, 1E7870
Regulatory Action:  Section 3 Registration
Risk Assessment Type:  Single chemical/Aggregate
Case No.:  7017
TXR No.:  None
CAS No.:  131341-86-1
MRID No.:  None
40 CFR:  §180.516

            Reviewer:	George F. Kramer, Ph.D., Senior Chemist
		Anwar Y. Dunbar, Ph.D., Pharmacologist
		Lata Venkateshwara Environmental Scientist
		Risk Assessment Branch 1 (RAB1)
		Health Effects Division (HED, 7509P)

Through:		David E. Hrdy, Acting Branch Chief
	RAB1/HED (7509P)

To:		Barbara Madden/Laura Nollen, RM 05
         		Mary Waller/Lisa Jones, RM 21
            	Registration Division (RD, 7505P)

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 new uses of fludioxonil (4-(2,2-difluoro-1,3-benzodioxol-4-yl)-1H-pyrrole-3-carbonitrile) on ginseng, leaf petioles, pineapple (post-harvest treatment), potato (post-harvest treatment), spinach, tropical fruit (post-harvest treatment), bulb onion, green onion, caneberry, bushberry, small fruit vine climbing (except fuzzy kiwifruit), low-growing berry (except cranberry), fruiting vegetables, citrus fruit, pome fruit, leafy vegetables (except Brassica), dragon fruit, and tomato (post-harvest treatment).

The risk assessment, dietary-exposure assessment, and the residue chemistry data review were provided by George Kramer (RAB1); the hazard assessment by Anwar Dunbar (RAB1); the occupational/residential exposure assessment by Lata Venkateshwara (RAB1); and the drinking water assessment by Cheryl Sutton of the Environmental Fate and Effects Division (EFED).
                               TABLE OF CONTENTS
1.0  EXECUTIVE SUMMARY	4
2.0  HED Recommendations	9
2.1  Data Deficiencies/Conditions of Registration	9
2.2  Tolerance Considerations	10
3.0  PHYSICAL/CHEMICAL PROPERTIES CHARACTERIZATION	13
3.1  Identification of Active Ingredient	13
3.2  Physical and Chemical Properties	14
4.0  HAZARD CHARACTERIZATION	14
4.1  FQPA Considerations	16
4.2  Toxicity Endpoint and Point of Departure Selection	16
5.0  EXPOSURE ASSESSMENT AND CHARACTERIZATION	18
5.1  Summary of Proposed Uses	18
5.2  Dietary Exposure/Risk Pathway	21
6.0  RESIDENTIAL (NON-OCCUPATIONAL) EXPOSURE/RISK CHARACTERIZATION	28
6.1  Residential Handler Exposure/Risk	28
6.2  Residential Post-application Exposure and Risk	29
6.3  Combined Exposure	30
6.4  Other (Spray Drift, etc.)	31
6.5  Residential Bystander Post-application Inhalation Exposure	32
7.0  AGGREGATE RISK ASSESSMENTS AND RISK CHARACTERIZATION	32
7.1  Acute Aggregate Risk	32
7.2  Short-Term Aggregate Risk	32
7.3  Intermediate-Term Aggregate Risk	33
7.4  Chronic Aggregate Risk	34
7.5  Cancer Aggregate Risk	34
8.0  CUMULATIVE RISK CHARACTERIZATION/ASSESSMENT	34
9.0  OCCUPATIONAL EXPOSURE/RISK PATHWAY	35
9.1  Occupational Handler Risk	35
9.2  Occupational Post-Application Risk	39
Appendix A:  Toxicity Profile	39
Appendix B:  International Residue Limits	43
                                       
1.0  EXECUTIVE SUMMARY

Fludioxonil, 4-(2,2-difluoro-1,3-benzodioxol-4-yl)-1H-pyrrole-3-carbonitrile, is a phenyl-pyrrole fungicide registered for use on a variety of field and vegetable crops, fruit trees, berries, herbs, and grasses.  It can be applied as a seed treatment, an at-planting soil application, and/or broadcast foliar application.  Post-harvest uses are also allowed on selected fruit and root crops.  A total of 26 end-use products (EPs) containing fludioxonil are currently registered to Syngenta Crop Protection for use on food/feed crops.  These EPs contain 0.13 to 50% fludioxonil as the active ingredient (ai) and are formulated as wettable powders (WPs), water-dispersible granules (WDGs), flowable concentrates (FlCs), and dusts.  Fludioxonil is also currently registered for use on residential turf and ornamentals.  A human-health assessment scoping document in support of fludioxonil registration review has recently been completed (DP# 384857, W. Wassell et al., 6/13/2011).

Permanent tolerances have been established for residues of fludioxonil per se in/on a variety of plant commodities, ranging from 0.01 ppm on numerous commodities to 500 ppm on citrus oil [40 CFR §180.516(a)].  There are currently no tolerances for fludioxonil residues in livestock commodities.

Interregional Research Project No. 4 (IR-4) has submitted a petition (1E7853) for the use of fludioxonil on ginseng, pineapple (post-harvest treatment), tuberous and corm vegetable subgroup 1C, spinach, tropical fruit (post-harvest treatment), bulb onion, green onion, caneberry, bushberry, small fruit vine climbing (except fuzzy kiwifruit), low-growing berry (except cranberry), fruiting vegetables, citrus fruit, pome fruit, leafy vegetables (except Brassica), dragon fruit, and tomato (post-harvest treatment).  In addition, Syngenta has submitted a petition (1E7870) for the use of fludioxonil on leafy petioles.  

No new data were submitted to support tolerances for residues in/on onion, bulb, subgroup 3-07A; onion, green, subgroup 3-07B; low-growing berry 13-07G crop subgroup; caneberry subgroup 13-07A; bushberry subgroup 13-07B; fruit, citrus, group 10; fruit, pome, group 11-10; or small fruit vine climbing subgroup 13-07F, except fuzzy kiwifruit.  IR-4 has requested that existing tolerances be expanded to their respective crop groups or crop subgroups.  Residue data for spinach, pepper, ginseng, and potato were reviewed with the Pest Management Regulatory Agency (PMRA) of Canada as part of a joint review.

Toxicology/Hazard

Fludioxonil is of low acute toxicity; the full battery of acute tests indicated that technical grade fludioxonil is in Toxicity Category III or IV.  It is not a dermal sensitizer.  For subchronic and chronic toxicity, the primary effects in the mouse and rat were similar and included decreased body weight and food consumption associated with clinical pathological and histopathological effects in the liver and kidney.  In the subchronic dog study, diarrhea was the most sensitive indicator of toxicity.  In contrast, in the chronic toxicity study in dogs, decreased body-weight gain in females was the most sensitive indicator of toxicity.  Liver toxicity was observed in both dog studies at higher doses.  Fludioxonil was not developmentally toxic in rabbits.  In a rat developmental toxicity study at the limit dose (1000 mg/kg/day), fludioxonil caused an increase in fetal incidence and litter incidence of dilated renal pelvis (in the presence of maternal toxicity).  There was no quantitative or qualitative evidence of increased susceptibility to rats and rabbits following in utero exposure.  There was no quantitative or qualitative evidence of increased susceptibility to rats following postnatal exposure.
Fludioxonil is classified as a Group D Chemical; not classifiable as to human carcinogenic potential.  Nonetheless, HED has determined that fludioxonil poses a negligible cancer risk.  This conclusion was based on the fact that cancer studies show evidence of cancer in one sex of one species.  There was no evidence of carcinogenicity in male rats, but there was a statistically significant increase, both trend and pairwise, of combined hepatocellular tumors in female rats.  The pairwise increase for combined tumors was significant at p=0.03, which is not a strong indication of a positive effect.  Further, statistical significance was only found when liver adenomas were combined with liver carcinomas.  Finally, the increase in these tumors was within, but at the high end, of the historical controls.  There was no evidence of carcinogenicity in mice when tested up to the limited dose 7,000 ppm.  Fludioxonil was not mutagenic in the tests for gene mutations.  However, based on the induction of polyploidy in the in vitro Chinese hamster ovary cell cytogenetic assay and the suggestive evidence of micronuclei induction in rat hepatocytes in vivo, additional mutagenicity testing was performed in three studies specifically designed to address the concerns regarding aneuploidy.  The results of these assays were negative for aneuploidy activity.

In a 28-day dermal toxicity study in rats, the no-observed adverse-effect level (NOAEL), based on no significant adverse effects in either sex, was equal to or greater than 1000 mg/kg/day [highest-dose tested (HDT)].  

In a rat metabolism study, tissue distribution showed that terminal residues were below the limit of detection (LOD) for most tissues except the liver, kidneys, blood, and lungs.  The major route of excretion was the feces; with approximately 80% of the administered radioactivity at both the low and high doses in male and female rats excreted by this route.  The remaining radioactivity was excreted through the urine.  Fludioxonil was well absorbed from the gastro-intestinal tract.  In bile-duct-cannulated rats, approximately 70% of an administered radioactive dose was excreted via this route; supporting the bile as the origin of the fecal radioactivity.  There were no apparent sex or dose related differences in the routes of excretion for fludioxonil.  Examination of urine for metabolites of fludioxonil showed at least 20 metabolites; each one comprised a minor fraction of the administered dose (0.1 to 3.1%).  There were no significant sex or dose differences in urinary metabolites.   

The fludioxonil risk assessment team evaluated the toxicology database, selected doses and endpoints for chronic dietary exposures, as well as occupational and residential exposure scenarios [short-, intermediate-, and long-term exposure (dermal and inhalation)], and addressed the sensitivity of infants and children from exposure to fludioxonil as required by the Food Quality Protection Act (FQPA) of 1996.  Since the last risk assessment, a guideline immunotoxicity study has been submitted and is currently under review.  HED's Hazard and Science Policy Council (HASPOC) used a weight-of-evidence approach to require a 90-day inhalation study and to not require the neurotoxicity screening battery studies (Memo, D. Smegal, 29-FEB-12, TXR# 0050679).  Until this 90-day inhalation study is submitted and reviewed, a 10X database uncertainty factor (UFDB) will be used to account for uncertainty stemming from the oral to inhalation route-to-route extrapolation.  Toxicological points of departure (PODs) for dietary, occupational/residential exposure and risk assessment for fludioxonil are summarized in Tables 4.2.1 and 4.2.2, respectively.  The potential enhanced sensitivity of infants and children from exposure to fludioxonil, as required by the FQPA of 1996, was also addressed.  The team concluded that the 10X Safety Factor (SF) should be reduced to 1X for oral exposures. 

Since the PODs are based on a common endpoint, oral and inhalation exposures can be combined for aggregation of short- and intermediate-term risks.  Since a POD was not identified for short- and intermediate-term dermal exposure risk assessments, assessment of dermal exposure and aggregation of dermal with inhalation and/or oral exposures is unnecessary.  

Dietary Exposure (Food Plus Water)

Acute and chronic dietary (food plus water) risk assessments were conducted using the Dietary Exposure Evaluation Model (DEEM-FCID[(TM)], Version 2.03) which uses food consumption data from the U.S. Department of Agriculture's (USDA's) Continuing Surveys of Food Intakes by Individuals (CSFII) from 1994-1996 and 1998.  

An unrefined acute dietary exposure and risk analysis was performed assuming tolerance-level residues, 100% crop-treated (CT), and DEEM[(TM)] (ver. 7.81) default processing factors.  The 1-in-10-year acute drinking water estimate (i.e., relevant to acute exposure) of 0.0838 ppm, provided by EFED, was directly incorporated into the acute assessment.  This analysis was performed for females 13 to 49 years old, the only subgroup of interest for acute exposure.  The acute dietary (food plus water) risk for females 13 to 49 years old utilizes 16% of acute population-adjusted dose (aPAD).

A partially refined chronic dietary exposure and risk assessment was performed assuming tolerance-level residues for most commodities [with the exception of celery, pineapple, potato, spinach, apple, grapefruit, lemon, lime, orange, pear, tomato, head lettuce, leaf lettuce, fresh parsley, Brassica leafy vegetables (crop group 5), grape, cherry, peach, and plum], 100% CT estimates, and DEEM[(TM)] (ver. 7.81) default processing factors [with the exception of citrus fruit juice (1X), apple juice (1X), grape juice (0.42X), raisin (1.65X), potato commodities (1X), and tomato commodities (1X), except dried tomato (14.3X)].  These processing factors are based on processing study data.  Anticipated residue estimates (ARs) for celery, pineapple, potato, spinach, apple, grapefruit, lemon, lime, orange, pear, tomato, head lettuce, leaf lettuce, fresh parsley, Brassica leafy vegetables (crop group 5), grape, cherry, peach, and plum were generated from field trial and processing study data.  The 1-in-10-year chronic drinking water estimate (i.e., relevant to chronic exposure) of 0.0385 ppm, provided by the EFED, was directly incorporated into the chronic assessment.  For the U.S. population the dietary risk (food plus water) utilizes 26% of the chronic PAD (cPAD).  The chronic dietary risk estimate for the highest reported exposed population subgroup, children 1 to 2 years old, utilizes 68% of the cPAD.  

Fludioxonil is classified as a Group D chemical - not classifiable as to human carcinogenicity; therefore, there is no need for a quantitative cancer risk assessment. 

Non-Occupational and Residential Exposure/Risks

The proposed uses will not result in residential exposures; however, fludioxonil is currently registered for use in residential areas, including parks, golf courses, athletic fields, residential lawns, ornamentals, and greenhouses.  The registered turf use has been reassessed in this document to reflect updates to HED's Residential Standard Operating Procedures (SOPs), 2012.  The currently registered label for turf is Medallion[(R)] Fungicide (EPA Reg. # 100-769).  Medallion[(R)] Fungicide is a 50% WP in water-soluble packaging.  The maximum single application rate is 0.50 oz per 1000 ft2 or 0.68 lbs ai/A.  

Residential handler and post-application exposure is expected from the use on residential turf.  Since HED did not select short- or intermediate-term dermal PODs, only residential adult handler inhalation exposure and incidental oral post-application exposure for children were assessed.  All residential handler inhalation exposures were above the level of concern (LOC) and are not of concern to HED.  In addition, post-application risk estimates do not exceed HED's LOC for any of the scenarios assessed.  

Aggregate Exposure/Risks

Acute Aggregate Exposure
Acute aggregate risk estimates do not exceed the LOC.  Since the acute aggregate risk assessment includes only food and water, and the acute dietary analysis included both, no further calculations are necessary.  Since the acute dietary risk does not exceed the LOC, the acute aggregate risk does not exceed the LOC.

Short-term Aggregate Exposure (Food + Water + Residential) 
Due to the application of fludioxonil on residential turf, there is potential for short-term handler and post-application exposure.  Since no dermal POD was selected, the short-term aggregate assessment for children includes exposure from food, water, and post-application non-dietary oral exposures (resulting from contact with treated lawns).  For adults, short-term aggregate combines dietary (food + water) exposure with inhalation exposure (resulting from residential handlers treating lawns).  The short-term aggregate exposures and risks do not exceed the LOC. 

Intermediate-term Aggregate Exposure (Food + Water + Residential)
Due to the application of fludioxonil on residential turf, there is potential for intermediate-term post-application exposure.  Since no dermal POD was selected and post-application inhalation exposure is expected to be minimal, the only intermediate-term residential exposure is incidental oral post-application exposure for children on treated lawns (resulting from the currently registered use).  The intermediate-term aggregate assessment for children includes exposure from food, water, and post-application non-dietary oral exposures resulting from contact with treated lawns.  The intermediate-term aggregate exposure and risk does not exceed the LOC. 

Chronic Aggregate Exposure
Chronic aggregate risk estimates do not exceed the LOC.  Since no chronic residential exposure is expected to result from the residential uses of fludioxonil, the chronic aggregate risk assessment includes only food and water.  As the chronic dietary analysis included both food and water, further estimates of risk are not necessary.  

Occupational Exposure/Risks

It is anticipated that there will be occupational hander and post-application exposure from the proposed uses on agricultural crops.  It is the policy of HED to use the best available data to assess handler exposure.  Sources of generic handler data, used as surrogate data in the absence of chemical-specific data, include the Pesticide Handlers Exposure Database Version 1.1 (PHED 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 the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA).  The standard values recommended for use in predicting handler exposure that are used in this assessment, known as "unit exposures," are outlined in the "Occupational Pesticide Handler Unit Exposure Surrogate Reference Table" (http://www.epa.gov/opp00001/science/handler-exposure-table.pdf), which, along with additional information on HED policy on use of surrogate data, including descriptions of the various sources, can be found at http://www.epa.gov/pesticides/science/handler-exposure-data.html.

Occupational handlers are anticipated to have short- and intermediate-term dermal and inhalation exposures.  However, since no short- or intermediate-term dermal PODs were selected, only inhalation exposures are assessed in this document.  HED has determined that risks are of concern for short-term exposures (i.e., MOEs <1000) for mixing/loading WPs for aerial and chemigation applications, and require a PF5 respirator with 80% protection factor to reach acceptable MOEs.  HED has also determined that for intermediate-term exposures, the personal-protective equipment (PPE) required to reach acceptable MOEs (i.e., MOEs >1000) for mixing/loading WPs for aerial and chemigation applications includes engineering controls.  Furthermore, for mixing/loading WPs for groundboom applications and for mixing/loading dry flowables (DFs) for aerial and groundboom applications, a PF5 respirator with 80% protection factor is required for intermediate-term exposures to reach MOEs >1000. 

Environmental Justice Consideration

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

As a part of every pesticide risk assessment in accordance with well-established procedures, OPP considers a large variety of consumer subgroups.  In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup's food and water consumption, and activities in and around the home that involve pesticide use in a residential setting.  Extensive data on food consumption patterns are compiled by the USDA under CSFII; and are used in pesticide risk assessments for all registered food uses.  These data are analyzed and categorized by subgroups based on age, season of the year, ethnic group, and region of the country.  Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups; and exposure assessments are performed when conditions or circumstances warrant.  Whenever appropriate, non-dietary exposures based on home use of pesticide products and associated risks for adult applicators and for young children, youths, and adults entering or playing on treated areas post-application are evaluated.  Further considerations are currently in development as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.

Review of Human Research

This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide to determine their dermal and inhalation exposure.  Many such studies, involving exposure to many different pesticides, comprise generic pesticide exposure databases such as PHED and the Agricultural Reentry Task Force (ARTF) database.  EPA has reviewed all the studies in these multi-pesticide generic exposure databases, and based on available evidence has found them to have been neither fundamentally unethical nor significantly deficient relative to standards of ethical research conduct prevailing when they were conducted.  There is no regulatory barrier to continued reliance on these studies, and all applicable requirements of EPA's Rule for the Protection of Human Subjects of Research (40 CFR Part 26) have been satisfied.

2.0  HED Recommendations

Provided revised Sections B and F are submitted, HED concludes that the toxicological, residue chemistry and occupational/residential databases support a conditional Section 3 registration and establishment of the tolerances listed in Section 2.2.   

2.1  Data Deficiencies/Conditions of Registration

Prior to Registration:  

Residue Chemistry

860.1200 Directions for Use

   * Adjuvants were not used in all of the submitted residue field trials.  Since adjuvants were not used in the ginseng, fruiting vegetables, bulb onion subgrcoup 3-07A, green onion subgroup 3-07B, caneberry subgroup 13-07A, bushberry subgroup 13-07B, small fruit vine climbing subgroup 13-07F (except fuzzy kiwifruit), low-growing berry subgroup 13-07G (except cranberry), and fruiting vegetable group 8-10 residue field trials, the label should prohibit adjuvant use on these crops.

860.1650 Submittal of Analytical Reference Standards

   * An analytical reference standard for fludioxonil is currently available at the EPA National Pesticide Standards Repository (personal communication with Theresa Cole, 8/15/11) with an expiration date of 5/30/13.  However, a reference standard of CGA192155 (2,2-difluoro-l,3-benzodioxole-4-carboxylic acid) should be sent to the Repository, which is located at Fort Meade, to the attention of Theresa Cole at the following address:

	USEPA
	National Pesticide Standards Repository/Analytical Chemistry Branch/OPP
	701 Mapes Road
	Fort George G. Meade, MD  20755-5350

(Note that the mail will be returned if the extended zip code is not used.)

860.1550 Proposed Tolerances

   * A summary of the recommended tolerance levels along with recommendations for commodity definitions are presented in Section 2.2.  The petitioner is required to submit a revised Section F to reflect the recommendations in Section 2.2.

Occupational Exposure

860.1200 Directions for Use

   * The occupational risk assessment indicates that risks are of concern for short-term exposures for mixing/loading WPs for aerial and chemigation applications, and require a PF5 respirator with 80% protection factor to reach acceptable MOEs.  HED has also determined that for intermediate-term exposures, the PPE required to reach acceptable MOEs for mixing/loading WPs for aerial and chemigation applications includes engineering controls.  Furthermore, for mixing/loading WPs for groundboom applications and for mixing/loading DFs for aerial and groundboom applications, a PF5 respirator with 80% protection factor is required for intermediate-term exposures to reach MOEs >1000.  RD should ensure that the proper PPE is listed on the label.   

As a Condition of Registration:  

Toxicology

   * A 90-day inhalation study (870.3465).

2.2  Tolerance Considerations

Enforcement Analytical Method:  Adequate high-performance liquid chromatography/ultraviolet light detector (HPLC/UV) methods (Syngenta Methods AG-597 and AG-597B) are available for enforcing tolerances for residues of fludioxonil in/on plant commodities.  In the current field trials and processing studies, residues of fludioxonil were determined using a liquid chromatography and tandem mass-spectrometry detection (LC-MS/MS) method, which is a modified version of Method AG-597B.  The LC-MS/MS method was adequately validated in conjunction with the analysis of field trial and processing study samples.  The validated limit of quantitation (LOQ) for fludioxonil was 0.01 or 0.02 ppm in each matrix, and the LOD was 0.003 or 0.006 ppm.  LC-MS/MS Analytical Method GRM025.03A (as modified in MRID# 48526508) is suitable as an enforcement method for livestock commodities as defined in SOP No. ACB-019 (9/15/08).  This is a common-moiety method in which fludioxonil and its metabolites of regulatory concern are converted to CGA192155 (2,2-difluoro-1,3-benzodioxole-4-carboxylic acid).

International Harmonization:  There are currently no established Codex, Canadian, or Mexican maximum residue limits (MRLs) for fludioxonil in/on tropical fruits.  The following U.S., Canadian, and Codex tolerances/MRLs for residues of fludioxonil are harmonized:  bushberries, grapes, citrus fruits, and pome fruits.  Additionally, the U.S. and Canadian tolerances/MRLs for tuberous and corm vegetables subgroup 1C, spinach, fruiting vegetables except tomato, and ginseng are being harmonized as part of this joint review.  

The U.S., Canadian, and Codex tolerances/MRLs for residues of fludioxonil in/on bulb onions, caneberries, grapes (small vine climbing fruit, subgroup 13-07F), strawberries (low-growing berry subgroup 13-07G), tomatoes, and leafy vegetables cannot be harmonized as the Canadian, and Codex MRLs differ.  For leafy vegetables except Brassica subgroup 4A, the U.S. and Canada are harmonized at 30 ppm, but a Codex MRL is established for head lettuce at 10 ppm.  For the bulb onion subgroup 3-07A, small vine climbing fruit subgroup 13-07F, and low-growing berry subgroup 13-07G, HED recommends that the U.S. tolerances be increased in order to harmonize with Codex; bulb onion subgroup 3-07A from 0.20 to 0.50 ppm, small vine climbing fruit subgroup 13-07F from 1.0 to 2.0 ppm and low-growing berry subgroup 13-07G from 2.0 to 3.0 ppm.  

The tolerances/MRLs cannot be harmonized for green onions, tomatoes, leafy vegetables except Brassica subgroup 4A, and leafy petioles as the U.S. residue data/use patterns necessitate a higher value.   

For livestock commodities, the U.S. and Codex residue definitions are harmonized; however, the Canadian residue definition is not harmonized.  The numerical values for the U.S. and Canadian livestock tolerances/MRLs are harmonized (see Appendix B).  

Recommended Tolerances:  Table 2.2.1 is a summary of the proposed and HED-recommended tolerance for residues of fludioxonil.  In accordance with the most recent guidance concerning tolerance expressions, HED recommends that the tolerance expression for 180.516 (a) be changed as indicated below.  A revised Section F specifying the new tolerance expression and the HED-recommended tolerances should be submitted.  

   40 CFR §180.516 (a) General. (1) should be as follows:  Tolerances are established for residues of the fungicide fludioxonil, including its metabolites and degradates, in or on the commodities in the table below.  Compliance with the tolerance levels specified below is to be determined by measuring only fludioxonil, 4-(2,2-difluoro-1,3-benzodioxol-4-yl)-1-H-pyrrole-3-carbonitrile).
   
   40 CFR §180.516 (a) General. (2) should be as follows:  Tolerances are established for residues of the fungicide fludioxonil, including its metabolites and degradates, in or on the commodities in the table below.  Compliance with the tolerance levels specified below is to be determined by measuring only the sum of fludioxonil, 4-(2,2-difluoro-1,3-benzodioxol-4-yl)-1-H-pyrrole-3-carbonitrile), and its metabolites converted to 2,2-difluoro-l,3-benzodioxole-4-carboxylic acid, calculated as the stoichiometric equivalent of fludioxonil.
   
Table 2.2.1.  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) 
Guava
                                       5
                                      5.0

Feijoa
                                       5
                                      5.0

Jaboticaba
                                       5
                                      5.0

Wax jambu
                                       5
                                      5.0

Starfruit
                                       5
                                      5.0

Passionfruit
                                       5
                                      5.0

Acerola
                                       5
                                      5.0

Avocado
                                       5
                                      5.0

Black sapote
                                       5
                                      5.0

Mamey sapote
                                       5
                                      5.0

Canistel
                                       5
                                      5.0

Mango
                                       5
                                      5.0

Papaya
                                       5
                                      5.0

Sapodilla
                                       5
                                      5.0

Star apple
                                       5
                                      5.0

Lychee
                                      20
                                      20

Longan
                                      20
                                      20

Spanish lime
                                      20
                                      20

Rambutan
                                      20
                                      20

Pulasan
                                      20
                                      20

Sugar apple
                                      20
                                      20

Atemoya
                                      20
                                      20

Custard apple
                                      20
                                      20

Cherimoya
                                      20
                                      20

Ilama
                                      20
                                      20

Soursop
                                      20
                                      20

Biriba
                                      20
                                      20

Ginseng
                                      3.0
                                      4.0

Onion, bulb subgroup 3-07A
                                      0.2
                                     0.50
Increased in order to harmonize with Codex MRL.
Onion, green subgroup 3-07B
                                      7.0
                                      7.0

Caneberry subgroup 13-07A
                                      5.0
                                      5.0

Bushberry subgroup 13-07B
                                      2.0
                                      2.0

Small fruit vine climbing subgroup 13-07F, except fuzzy kiwifruit
                                      1.0
                                      2.0
Fruit, small, vine climbing, subgroup 13-07F, except fuzzy kiwifruit.  Increased in order to harmonize with Codex MRL.
Low growing berry subgroup 13-07G, except cranberry
                                      2.0
                                      3.0
Increased in order to harmonize with Codex MRL.
Vegetable, fruiting group 8-10, except tomato
                                      0.7
                                     0.50

Tomato
                                      3.0
                                      5.0

Fruit, citrus, group 10-10
                                      10
                                      10

Fruit, pome, group 11-10
                                       5
                                      5.0

Vegetable, leafy, except brassica, subgroup 04A
                                      30
                                      30
Vegetable, leafy, except Brassica, subgroup 4A
Vegetable, tuberous and corm, subgroup 1C
                                      6.0
                                      6.0

Pineapple
                                      8.0
                                      20

Dragon-fruit
                                      1.0
                                      1.0
Dragon fruit
Leafy petioles crop subgroup 4B
                                      14
                                      15

To be established under 40 CFR §180.516 (a) General. (2)
Milk
                                       -
                                     0.01

Cattle, meat byproducts
                                       -
                                     0.05

Cattle, meat 
                                       -
                                     0.01

Cattle, fat 
                                       -
                                     0.05

Goat, meat byproducts
                                       -
                                     0.05

Goat, meat 
                                       -
                                     0.01

Goat, fat 
                                       -
                                     0.05

Horse, meat byproducts
                                       -
                                     0.05

Horse, meat 
                                       -
                                     0.01

Horse, fat 
                                       -
                                     0.05

Sheep, meat byproducts
                                       -
                                     0.05

Sheep, meat 
                                       -
                                     0.01

Sheep, fat 
                                       -
                                     0.05

Remove from 40 CFR §180.516 (a):
Onion, bulb
                                     0.20
                                       
These tolerances should be removed from 40 CFR §180.516 because tolerances are being established for crop groups that contain these raw agricultural commodities (RACs) or a higher tolerance is required based on the proposed use pattern.  
Onion, green
                                      7.0
                                       

Caneberry subgroup 13A
                                      5.0
                                       

Bushberry subgroup 13B
                                      2.0
                                       

Juneberry
                                      2.0
                                       

Lingonberry
                                      2.0
                                       

Salal
                                      2.0
                                       

Grape
                                      1.0
                                       

Strawberry
                                      2.0
                                       

Vegetable, fruiting group 8
                                     0.01
                                       

Tomatillo
                                     0.50
                                       

Fruit, citrus, group 10
                                      10
                                       

Fruit, pome, group 11
                                      5.0
                                       

Leafy greens subgroup 4A, except spinach
                                      30
                                       

Vegetable, tuberous and corn, except potato, subgroup 1D
                                      3.5
                                       

Revisions to Petition-For Tolerances:  Based on the proposed uses and the submitted data, HED concluded that crop group tolerances were appropriate.  The HED recommended tolerances are based on the submitted field trial data and the Organization for Economic Co-operation and Development (OECD) tolerance calculation procedures.  For the bulb onion subgroup 3-07A, small vine climbing fruit subgroup 13-07F, and low-growing berry subgroup 13-07G, HED recommends that the U.S. tolerances be increased in order to harmonize with the established Codex MRLs.

3.0  PHYSICAL/CHEMICAL PROPERTIES CHARACTERIZATION

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 product (EP)
Switch[(R)] 62.5WG Fungicide (25% WDG; EPA Reg. No. 100-953)
Scholar[(R)] 230SC Fungicide (20.5% SC; EPA Reg. No. 100-1242)
Scholar[(R)] 50 WP Fungicide (50% WP; EPA Reg. No. 100-969)
Cannonball[(R)] WP (50% WP; EPA Reg. No. 100-1360)
Graduate A+[(TM)] (20.6% SC; EPA Reg. No. 100-1308)
Compound
                                       
Company experimental name
CGA192155
IUPAC name
2,2-difluoro-benzo[l,3]dioxole-4-carboxylic acid
CAS name
2,2-difluoro-1,3-benzodioxole-4-carboxylic acid
CAS registry number
126120-85-2

3.2  Physical and Chemical Properties

Table 3.2.  Physicochemical Properties of Fludioxonil.
Parameter
Value
Reference
Melting point
199.8 °C
DP# 348539, D. Rate, 09/10/08
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 (g/L at 20 C)
Ethanol	44,000
Acetone	190,000
Toluene	2,700
n-Octanol	20,000
n-Hexane	7.8

Vapor pressure at 25 C
2.9 x 10[-9] mm Hg

Dissociation constant (pKa)
pKa1 <0
pKa2 ~14.1

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

UV/visible absorption spectrum
12,384 L/mol x cm @ 266 nm (neutral solution)
12,327 L/mol x cm @ 265 nm (acidic solution)
11,790 L/mol x cm @ 271 nm (basic solution)

4.0  HAZARD CHARACTERIZATION

NOTE:  In 2008, the Alternative Risk Integration and Assessment (ARIA) Team of RD completed a Section 3 risk assessment for the application of fludioxonil to avocado, carrot, cucurbit, lemon, parsley, radish, sweet potato, tomato, and Brassica vegetables (Memo, 7/10/2008, B. Hanson, et al.; D342827).  A complete discussion of the hazard assessment can be found in this previous risk assessment.  Since the last risk assessment, a guideline immunotoxicity study has been submitted and is currently under review.  HED's HASPOC used a weight-of-evidence approach to require a 90-day inhalation study and to not require the neurotoxicity screening battery studies (Memo, D. Smegal, 29-FEB-12, TXR# 0050679).  For the inhalation study, this approach considered all of the available hazard and exposure information for fludioxonil, including:  (1) the use of an oral POD that results in MOEs as low as 70 for risk via the inhalation route resulting from occupational exposure; (2) the physical/chemical properties of fludioxonil; (3) the toxicological profile of fludioxonil; and (4) signs of respiratory toxicity (dyspnea) in the acute inhalation toxicity study.  Until this 90-day inhalation study is submitted and reviewed, a 10X UFDB will be used to account for uncertainty stemming from the oral to inhalation route-to-route extrapolation.  For the neurotoxicity screening battery, the decision included the following considerations:  1) lack of evidence for clinical signs of neurotoxicity, changes in brain weight or neuropathology in the available toxicology studies for fludioxonil except for some convulsions in mice following handling at high doses that were considered to be agonal in nature; 2) target organs of toxicity are the liver, kidney, and to a less degree, the hematopoietic system; 3) no data are available for other structurally similar chemicals (i.e., phenyl-pyrrole fungicides) that showed concern for neurotoxicity; 4) rats, the species of choice for conducting the neurotoxicity battery, are not the most sensitive species; and 5) considering the potential impact of the neurotoxicity studies providing a POD lower than those used in the overall risk assessment.

Fludioxonil is of low acute toxicity, since technical grade fludioxonil is in Toxicity Category III or IV for the full battery of acute tests and is not a dermal sensitizer.  For subchronic and chronic toxicity, the primary effects in the mouse and rat were similar and included decreased body weight and food consumption associated with clinical pathological and histopathological effects in the liver and kidney.  In the subchronic dog study, diarrhea was the most sensitive indicator of toxicity.  In contrast, decreased weight gain in females was the most sensitive indicator of toxicity in the chronic toxicity study in dogs.  Liver toxicity was observed in both dog studies at higher doses.  Fludioxonil was not developmentally toxic in rabbits.  In a rat developmental toxicity study, fludioxonil caused an increase in fetal incidence and litter incidence of dilated renal pelvis at the limit dose (1000 mg/kg/day).  Maternal toxicity occurred at the same dose and manifested as a reduction in corrected body-weight gain.  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.  There was no evidence of immunotoxicity when tested up to including the limit dose.

There was no evidence of carcinogenicity in male or female CD-1 mice and male Sprague-Dawley rats following dietary administration at doses that were adequate for assessing the carcinogenic potential of fludioxonil.  In female Sprague-Dawley rats, there was a statistically significant increase in tumor incidence only when hepatocellular adenomas and carcinomas were combined (not for individual tumor types).  The pairwise increase for combined tumors was significant at p=0.03, which is not a strong indication of a positive effect.  Further, statistical significance was only found when liver adenomas were combined with liver carcinomas.  Finally, the increase in these tumors was within, but at the high end, of the historical controls.  Based on these findings and in accordance with the Agency's 1986 "Guidelines for Carcinogen Risk Assessment," fludioxonil was classified as a Group D carcinogen; therefore, there is no need for a quantitative cancer risk assessment.  The cancer classification of fludioxonil was not re-assessed since no new information on carcinogenicity of the compound was required.  The classification is based on the guidance used when this assessment was completed (1996) and should continue to be considered scientifically sound.  

Fludioxonil was not mutagenic in the tests for gene mutations.  However, based on the induction of polyploidy in the in vitro Chinese hamster ovary cell cytogenetic assay and the suggestive evidence of micronuclei induction in rat hepatocytes in vivo, additional mutagenicity testing was performed in three studies specifically designed to address the concerns regarding aneuploidy.  The results of these assays were negative for aneuploidy activity.

In a 28-day dermal toxicity study in rats, the NOAEL was equal to or greater than 1000 mg/kg/day (HDT) based on no significant adverse effects in either sex.  

In a rat metabolism study, tissue distribution showed that terminal residues were below the LOD for most tissues except the liver, kidneys, blood, and lungs.  The major route of excretion was the feces, with approximately 80% of the administered radioactivity excreted by this route in male and female rats at both the low and high dose.  The remaining radioactivity was excreted through the urine.  Fludioxonil was well absorbed from the gastro-intestinal tract.  In bile duct-cannulated rats, approximately 70% of an administered radioactive dose was excreted via this route, supporting the bile as the origin of the fecal radioactivity.  There were no apparent sex- or dose-related differences in the routes of excretion for fludioxonil.  Examination of urine for metabolites of fludioxonil showed at least 20 metabolites, each comprising a minor fraction of the administered dose (0.1 to 3.1%).  There were no significant differences in urinary metabolites with sex or dose.   

4.1  FQPA Considerations

Based on the weight-of-evidence considerations for both hazard and exposure, the Agency has determined that the overall assessment does not underestimate risk for the current uses and, therefore, a UFDB in the form of the FQPA SF is reduced to 1X for oral exposures.  This recommendation is based on the following considerations:

   * The toxicology database is adequate for FQPA assessment.  
   * There was no evidence of increased susceptibility following in utero exposure to rats and rabbits or following pre-/post-natal exposure to rats.  In rats, developmental effects occurred in the presence of maternal effects.  In rabbits, no developmental toxicity was seen up to the highest dose tested which demonstrated maternal toxicity.  In the two-generation rat reproduction study, offspring toxicity was seen at the dose that produced parental toxicity.  There are no residual uncertainties of pre- and/or post-natal toxicity.  
   * The only potential indicator of neurotoxicity for fludioxonil was some convulsions in mice following handling at high doses that were considered to be agonal in nature.  
   * A developmental neurotoxicity study is not required.
   * There are no residual uncertainties in the exposure database.  The dietary and residential exposure analyses are conservative in nature.  The dietary exposure assessment assumes 100% crop treated and uses tolerance-level residues or made use of average residues derived from crop field trial studies (maximum application rate and minimum pre-harvest interval).  
   * The residential exposure assessment uses chemical-specific turf-transferable residue data and the 2012 Residential SOPs and is considered health-protective.
   * Although an inhalation study is required for fludioxonil, the oral PODs used for assessing inhalation risk are based on the most sensitive endpoints established in the most sensitive species.  Furthermore, an additional 10X uncertainty factor (UFDB) will be used to further protect for the uncertainty from this oral to inhalation route-to-route extrapolation.  Based on these oral PODs, all residential handler inhalation exposures were well above the LOC and are not of concern to HED.  Therefore, the risk estimate is conservative and will not underestimate risk via the inhalation route.
  
4.2  Toxicity Endpoint and Point of Departure Selection

Table 4.2.1.  Summary of Toxicological Doses and Endpoints for Fludioxonil for Use in Dietary and Non-Occupational Human-Health Risk Assessments.
Exposure/
Scenario
                                      POD
                                 Uncertainty/
                                   FQPA SFs
                       RfD, PAD, LOC for Risk Assessment
                       Study and Toxicological Effects 
Acute Dietary (General Population, including Infants and Children)
There were no appropriate toxicological effects attributable to a single exposure (dose) observed in available oral toxicity studies, including maternal toxicity in the developmental toxicity studies.  Therefore, a dose and endpoint were not identified for this risk assessment.
Acute Dietary
(Females 13-49 years of age)
NOAEL = 100 mg/kg/day
UFA = 10X
UFH = 10X
FQPA SF = 1X
Acute RfD = 1 mg/kg/day
aPAD = 1 mg/kg/day
Prenatal developmental toxicity in rats.
LOAEL = 1000 mg/kg/day based on the increased incidence of fetuses and litters with dilated renal pelvis and dilated ureter in rat developmental study.
Chronic Dietary (All Populations)
NOAEL = 3.3 mg/kg/day
UFA = 10X
UFH = 10X
FQPA SF = 1X
Chronic RfD = 0.033
mg/kg/day
cPAD = 0.033 mg/kg/day
Chronic toxicity in dogs.
LOAEL = 35.5 mg/kg/day based on decreased weight gain in female dogs during weeks 1-52 of one-year dog feeding study.
Incidental Oral Short-Term (1-30 days)
NOAEL = 10 mg/kg/day
UFA = 10X
UFH = 10X
FQPA SF = 1X
Residential LOC for MOE = 100
Rabbit developmental study.
LOAEL = 100 mg/kg/day based on decreased weight gain during dosing period.
Incidental Oral Intermediate-Term (1-6 months)
NOAEL = 3.3 mg/kg/day
UFA = 10X
UFH = 10X
FQPA SF = 1X
Residential LOC for MOE = 100
Chronic toxicity in dogs.
LOAEL = 35.5 mg/kg/day based on decreased weight gain in female dogs during weeks 1-52 of one-year dog feeding study.
Dermal Short- (1-30 days) and Intermediate-Term (1-6 months)
No hazard identified and therefore quantification is not required.  There are no developmental concerns via the dermal route and no systemic toxicity was seen following dermal exposure.
Inhalation Short- Term (1-30 days)
Oral NOAEL = 10 mg/kg/day

(inhalation absorption = 100%)[a]
UFA = 10X
UFH = 10X
FQPA SF = 1X
UFDB = 10X
Residential LOC for MOE = 1000
Rabbit developmental study.
LOAEL = 100 mg/kg/day based on decreased weight gain during dosing period.
Inhalation Intermediate-Term (1-6 months)
Oral NOAEL = 3.3 mg/kg/day

(inhalation absorption = 100%)[a]
UFA = 10X
UFH = 10X
FQPA SF = 1X
UFDB = 10X

Residential LOC for MOE = 1000
Chronic toxicity in dogs.
LOAEL = 35.5 mg/kg/day based on decreased weight gain in female dogs during weeks 1-52 of one-year dog feeding study.
Cancer (oral, dermal, inhalation)
Classification:  Group D chemical - not classifiable as to human carcinogenicity.  
 Point of departure (POD) = A data point or an estimated point that is derived from observed dose-response data and  used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures.  NOAEL = no-observed adverse-effect level.  LOAEL = lowest-observed adverse-effect level.  UF = uncertainty factor.  UFA = extrapolation from animal to human (interspecies).  UFH = potential variation in sensitivity among members of the human population (intraspecies).  UFDB = to account for the absence of key date (i.e., lack of a critical study).  FQPA SF = FQPA Safety Factor.  PAD = population-adjusted dose (a = acute, c = chronic).  RfD = reference dose.  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.

Table 4.2.2.  Summary of Toxicological Doses and Endpoints for Fludioxonil for Use in Occupational Human-Health Risk Assessments.
Exposure/
Scenario
POD
UFs
LOC for Risk Assessment
Study and Toxicological Effects
Dermal Short- (1-30 days) and Intermediate-Term (1-6 months)
No hazard identified and therefore quantification is not required.  There are no developmental concerns via the dermal route and no systemic toxicity was seen following dermal exposure.
Inhalation Short-Term (1-30 days)
Oral NOAEL = 10 mg/kg/day

(inhalation absorption = 100%)[a]
UFA =10X
UFH = 10X
UFDB = 10X
Occupational LOC for MOE = 1000
Rabbit developmental study
LOAEL = 100 mg/kg/day based on Decreased weight gain during dosing period.
Inhalation Intermediate-term (1-6 months)
Oral NOAEL = 3.3 mg/kg/day

(inhalation absorption = 100%)[a]
UFA =10X
UFH = 10X
UFDB = 10X
Occupational LOC for MOE = 1000
Chronic toxicity in dogs
LOAEL = 35.5 mg/kg/day based on decreased weight gain in female dogs during weeks 1-52 of one-year dog feeding study.
Cancer (oral, dermal, inhalation)
Classification:  Group D chemical - not classifiable as to human carcinogenicity.  
Point of departure (POD) = A data point or an estimated point that is derived from observed dose-response data and  used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures.  NOAEL = no-observed adverse-effect level.  LOAEL = lowest-observed adverse-effect level.  UF = uncertainty factor.  UFA = extrapolation from animal to human (interspecies).  UFH = potential variation in sensitivity among members of the human population (intraspecies).  UFDB = to account for the absence of key date (i.e., lack of a critical study).  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.

      5.0  EXPOSURE ASSESSMENT AND CHARACTERIZATION

5.1  Summary of Proposed Uses

There are currently 26 EPs containing fludioxonil that are registered to Syngenta Crop Protection in the U.S. for use on food/feed crops.  These EPs contain 0.13 to 50% fludioxonil and are formulated as WPs, WDGs, FlCs, and dusts.  One of the formulations registered for foliar application on a variety of fruit, nut, vegetable, and herb crops is a 62.5% WDG, a multiple-active-ingredient (MAI) formulation that contains 25% fludioxonil and 37.5% cyprodinil.  This formulation is registered in the U.S. under the trade name Switch[(R)] 62.5 WG (EPA Reg. No. 100-953).  Other formulations include Cannonball[(R)] WP (EPA Reg. No. 100-1360), Scholar[(R)] (EPA Reg. No. 100-969), Graduate A+[(TM)] (EPA Reg. No. 100-1308), and Scholar[(R)] SC (EPA Reg. No. 100-1242).  Information pertaining to the proposed end-use products is listed in Table 5.1.1.  A summary of the proposed use patterns is detailed in Table 5.1.2.  

Table 5.1.1.  Summary of Proposed End-Use Products.
Trade Name
                                   Reg. No.
                       ai (% fludioxonil in formulation)
                               Formulation Type
                                 Target Crops
                                 Target Pests
                                  Label Date
Switch[(R)] 62.5WG
                                    100-953
                                      25
                                      WG
              A variety of fruit, nut, vegetable, and herb crops
Soil, crown, and foliar diseases.
                        Draft labels submitted 3/28/11
Cannonball[(R)] WP
                                   100-1360
                                      50
                                      WP
                           Onions, berries, ginseng

Scholar[(R)]
                                    100-969
                                      50
                                      WP
                     Postharvest fruit, potatoes, tomatoes
Postharvest fungal diseases

Scholar[(R)] SC 
                                   100-1242
                                     20.4
                                      SC
                                       

Graduate A+[(TM)]
                                   100-1308
                                     20.6
                                      SC
                                    Citrus

Table 5.1.2.  Summary of Directions for Use of Fludioxonil.
                       Applic. Timing, Type, and Equip.
                                  Formulation
                                [EPA Reg. No.]
                                   App. Rate
                           Max. No. App. per Season
                            Max. Seasonal App. Rate
                                      PHI
                                    (days)
                        Use Directions and Limitations
                      Leafy Vegetables (except Brassica)
Broadcast foliar application, ground equipment only
                                  25% WDG[1]
                                   [100-953]
                                     0.225
                                 (lb ai/acre)
                                       4
                                      0.9
                                 (lb ai/acre)
                                       0
7- to 10-day retreatment interval (RTI)
                              Fruiting Vegetables
Broadcast foliar application, ground equipment only
                                  25% WDG[1]
                                   [100-953]
                                     0.225
                                 (lb ai/acre)
                                       4
                                      0.9
                                 (lb ai/acre)
                                       0
14- to 21-day RTI
Do not apply to small tomatoes in greenhouse
                                    Ginseng
                               Drip irrigation 
                              or ground drenching
                                    50% WP
                                  [100-1360]
                                     0.25
                                 (lb ai/acre)
                                       4
                                      1.0
                                 (lb ai/acre)
                                      14
Applications are to be made in >=3 gal/acre using ground or aerial equipment.  
                                   Pineapple
                                  Postharvest
                             high-volume (dilute)
                                   20.4% SC
                                  [100-1242]
                               0.24 lb ai/50 gal
                                       1
                               0.24 lb ai/50 gal
                                       
Mix in water or wax/water emulsion.
                                       
                                    50% WP
                                   [100-969]
                               0.25 lb ai/50 gal
                                       
                               0.25 lb ai/50 gal
                                       

                                  Postharvest
                            peduncle spray (dilute)
                                   20.4% SC
                                  [100-1242]
                               0.24 lb ai/50 gal
                                       1
                               0.24 lb ai/50 gal
                                       
Mix in water or wax/water emulsion.
Use T-jet application system
                                       
                                    50% WP
                                   [100-969]
                               0.25 lb ai/50 gal
                                       
                               0.25 lb ai/50 gal
                                       

                                    Potato
                                  Postharvest
                             in-line aqueous spray
                                   20.4% SC
                                  [100-1242]
                            0.009 lb ai/ton tubers
                                       1
                            0.009 lb ai/ton tubers
                                       
Must tank mix with difenoconazole or azoxystrobin.
Use T-jet application system.
                                       
                                    50% WP
                                   [100-969]
                            0.009 lb ai/ton tubers
                                       
                            0.009 lb ai/ton tubers
                                       

                                    Tomato
                                  Postharvest
                              in-line drip/drench
                                   20.4% SC
                                  [100-1242]
                              0.48 lb ai/100 gal
                                       1
                              0.48 lb ai/100 gal
                                       
Mix in water or wax/water emulsion.
Must tank mix with propiconazole.
                                       
                                    50% WP
                                   [100-969]
                               0.5 lb ai/100 gal
                                       
                               0.5 lb ai/100 gal
                                       

                                  Postharvest
                             high-volume (dilute)
                                   20.4% SC
                                   100-1242
                          0.25 lb ai/50,000 lbs fruit
                                       1
                          0.25 lb ai/50,000 lbs fruit
                                       
Mix in water or wax/water emulsion.
Use T-jet application system. 
Must tank mix with propiconazole.
Not for processing tomatoes.
                                       
                                    50% WP
                                   [100-969]
                          0.24 lb ai/50,000 lbs fruit
                                       
                          0.24 lb ai/50,000 lbs fruit
                                       

                                Tropical Fruit 
                                  Postharvest
                              in-line drip/drench
                                   20.4% SC
                                  [100-1242]
                              0.48 lb ai/100 gal
                                       1
                              0.48 lb ai/100 gal
                                       
Mix in water or wax/water emulsion.
Dip for ~30 seconds.
                                       
                                    50% WP
                                   [100-969]
                               0.5 lb ai/100 gal
                                       
                               0.5 lb ai/100 gal
                                       

                                 Citrus Fruit
                                  Postharvest
                              in-line drip/drench
                                   20.4% SC
                                  [100-1242]
                               1.0 lb ai/100 gal
                                       2
                               2.0 lb ai/100 gal
                                       
Mix in water or wax/water emulsion. 
Dip for 30 seconds minimum.
                                       
                                    50% WP
                                   [100-969]
                               1.0 lb ai/100 gal
                                       
                               2.0 lb ai/100 gal
                                       

                                       
                                   20.6% SC
                                  [100-1308]
                               1.0 lb ai/100 gal
                                       
                               2.0 lb ai/100 gal
                                       

                                  Postharvest
                in-line aqueous fruit coating spray application
                                   20.4% SC
                                   100-1242
                          1.0 lb ai/250,000 lbs fruit
                                       2
                          2.0 lb ai/250,000 lbs fruit
                                       
Mix in water or wax/water emulsion.
Use T-jet application system. 
                                       
                                    50% WP
                                   [100-969]
                          1.0 lb ai/250,000 lbs fruit
                                       
                          2.0 lb ai/250,000 lbs fruit
                                       

                                       
                                   20.6% SC
                                  [100-1308]
                          1.0 lb ai/250,000 lbs fruit
                                       
                          2.0 lb ai/250,000 lbs fruit
                                       

[1]	Switch[(R)] 62.5 WG is an MAI formulation containing 25% fludioxonil and 37.5% cyprodinil.
[2]	A minimum plant-back interval (PBI) is 30 days for crops not listed on the label.

Conclusions:  The proposed use directions are sufficient to allow for evaluation of the available residue data.  Provided that the use directions for ginseng, fruiting vegetables, bulb onion subgroup 3-07A, green onion subgroup 3-07B, caneberry subgroup 13-07A, bushberry subgroup 13-07B, small fruit vine climbing subgroup 13-07F (except fuzzy kiwifruit), low-growing berry subgroup 13-07G (except cranberry), and fruiting vegetable group 8-10 are revised to prohibit the use of adjuvants, the available field trial data support the use directions for the proposed uses.

5.2  Dietary Exposure/Risk Pathway

The residue chemistry assessment was completed by HED (Memo, G. Kramer, 05/21/2012; DP# 389980).  The drinking water assessment was completed by EFED (Memo, C. Sutton, 10/27/2011; DP# 389616).  The dietary-exposure assessment was completed by HED (Memo, G. Kramer, 05/21/2012; DP# 389981).

5.2.1  Residue Profile

Background
A human-health assessment scoping document in support of fludioxonil registration review has recently been completed (DP# 384857, W. Wassell et al., 6/13/2011).  In that document, it was noted that permanent tolerances have been established for residues of fludioxonil per se in/on a variety of plant commodities, ranging from 0.01 ppm on numerous commodities to 500 ppm on citrus oil [40 CFR §180.516(a)].  There are currently no tolerances for fludioxonil residues in livestock commodities.

IR-4 has submitted a petition (1E7853) for the use of fludioxonil on ginseng, pineapple (post-harvest treatment), tuberous and corm vegetable subgroup 1C, spinach, tropical fruit (post-harvest treatment), bulb onion, green onion, caneberry, bushberry, small fruit vine climbing (except fuzzy kiwifruit), low-growing berry (except cranberry), fruiting vegetables, citrus fruit, pome fruit, leafy vegetables (except Brassica), dragon fruit, and tomato (post-harvest treatment).  In addition, Syngenta has submitted a petition (1E7870) for the use of fludioxonil on leafy petioles.  The petitioners request that the following tolerances be established as a result of the proposed uses for the residues of fludioxonil in/on:

                                  PP# 1E7853
Guava
5 ppm
Feijoa
5 ppm
Jaboticaba
5 ppm
Wax jambu
5 ppm
Starfruit
5 ppm
Passionfruit
5 ppm
Acerola
5 ppm
Avocado
5 ppm
Black sapote
5 ppm
Mamey sapote
5 ppm
Canistel
5 ppm
Mango
5 ppm
Papaya
5 ppm
Sapodilla
5 ppm
Star apple
5 ppm
Lychee
20 ppm
Longan
20 ppm
Spanish lime
20 ppm
Rambutan
20 ppm
Pulasan
20 ppm
Sugar apple
20 ppm
Atemoya
20 ppm
Custard apple
20 ppm
Cherimoya
20 ppm
Ilama
20 ppm
Soursop
20 ppm
Biriba
20 ppm
Ginseng
3.0 ppm
Onion, bulb subgroup 3-07A
0.2 ppm
Onion, green subgroup 3-07B
7.0 ppm
Caneberry subgroup 13-07A
5.0 ppm
Bushberry subgroup 13-07B
2.0 ppm
Small fruit vine climbing subgroup 13-07F, except fuzzy kiwifruit
1.0 ppm
Low growing berry subgroup 13-07G, except cranberry
2.0 ppm
Vegetable, fruiting group 8-10, except tomato
0.7 ppm
Tomato
3.0 ppm
Fruit, citrus, group 10-10
10 ppm
Fruit, pome, group 11-10
5 ppm
Vegetable, leafy, except brassica, subgroup 4A
30 ppm
Vegetable, tuberous and corm, subgroup 1C
6.0 ppm
Pineapple
8.0 ppm
Dragon-fruit
1.0 ppm
                                  PP# 1E7870
Leafy petioles crop subgroup 4B
14 ppm

Nature of the Residue in Plants 
The nature of the fludioxonil residues in plants is adequately understood based on adequate metabolism studies on peaches, grapes, onions, and head lettuce.  Based on the results from these studies, HED has determined that the residue of concern in plants following foliar applications, for tolerance enforcement and risk assessment purposes, is fludioxonil per se.

Nature of the Residue in Livestock 
The nature of the residues in livestock is also understood based on the adequate goat and hen metabolism studies.  For purposes of tolerance enforcement and risk assessment, the residues of concern in ruminants are fludioxonil and Metabolite B-1, and the residues of concern in poultry are fludioxonil, CGA-344623, and Metabolite I-1.

Residue Analytical Methods
Adequate HPLC/UV methods (Syngenta Methods AG-597 and AG-597B) are available for enforcing tolerances of fludioxonil in plant commodities.  In the current field trials and processing studies, residues of fludioxonil were determined using a LC-MS/MS method, which is a modified version of Method AG-597B.  The LC-MS/MS method was adequately validated in conjunction with the analysis of field trial and processing study samples.  The validated LOQ for fludioxonil was 0.01 or 0.02 ppm in each matrix, and the LOD was 0.003 or 0.006 ppm. 

LC-MS/MS Analytical Method GRM025.03A (as modified in MRID# 48526508) is suitable as an enforcement method for livestock commodities as defined in SOP No. ACB-019 (9/15/08).  This is a common-moiety method in which fludioxonil and its metabolites of regulatory concern are converted to CGA192155 (2,2-difluoro-1,3-benzodioxole-4-carboxylic acid).

Magnitude of the Residue in Livestock
Based on the available goat and poultry metabolism data and the previously calculated dietary exposures of livestock to fludioxonil residues, HED had concluded that quantifiable residues of fludioxonil were unlikely to occur in livestock commodities.  As processed potato waste is a significant feedstuff for livestock (ruminants only), the dietary burden of fludioxonil was recalculated for this petition using the Agency's most recent guidance on constructing reasonably balanced livestock diets (Memo, 6/30/08).  Based upon this diet and the results of a newly submitted ruminant feeding study, tolerances for total fludioxonil residues should be established at 0.05 ppm for residues in fat and meat byproducts of cattle, goats, horses, and sheep and at 0.01 ppm for milk and for the meat of cattle, goats, horses, and sheep.

Magnitude of the Residue in Plants
No new data were submitted to support tolerances on onion, bulb, subgroup 3-07A; onion, green, subgroup 3-07B; low-growing berry 13-07G crop subgroup; caneberry subgroup 13-07A; bushberry subgroup 13-07B; fruit, citrus, group 10-10; fruit, pome, group 11-10; or small fruit vine climbing subgroup 13-07F, except fuzzy kiwifruit.  IR-4 has requested that existing tolerances be expanded to their respective crop groups or crop subgroups.

The submitted field trial residue data for ginseng, celery as a representative crop of the leaf petioles crop subgroup 4B, bell and non-bell peppers as a representative crop of the fruiting vegetable group 8-10 (except tomato), pineapple, potatoes as a representative crop of the tuberous and corm vegetable subgroup 1C, spinach as a representative commodity of leafy vegetable (except Brassica) subgroup 4A, and tomatoes are adequate.  The field trial data reflect the proposed use pattern, an adequate number of trials were conducted in the appropriate geographic regions, and samples were analyzed for the residue of concern using validated data-collection methods (storage intervals were also validated).  Using the OECD tolerance calculation procedures for the residue data sets indicate that the requested tolerance levels are not appropriate for several commodities.  A revised Section F is requested.

Magnitude of the Residue in Processed Fractions
The submitted pineapple and potato processing studies are also adequate.  Separate tolerances are not required for any of the processed fractions.

Magnitude of the Residue in Rotational Crops
Adequate confined and limited field rotational crop trials are available and support the label-specified 30-day PBI for crops without uses on the fludioxonil label.  The available data indicate that tolerances are not currently required for rotational crops.

Tolerance Summary
There are currently no established Codex, Canadian, or Mexican MRLs for fludioxonil in/on tropical fruits.  The following U.S., Canadian, and Codex tolerances/MRLs for residues of fludioxonil are harmonized:  bushberries, grapes, citrus fruits, and pome fruits.  Additionally, the U.S. and Canadian tolerances/MRLs for potatoes, spinach, fruiting vegetables except tomato, and ginseng are being harmonized as part of this joint review.

The U.S., Canadian, and Codex tolerances/MRLs for residues of fludioxonil in/on bulb onions, caneberries, grapes (small vine climbing fruit, subgroup 13-07F), strawberries (low-growing berry subgroup 13-07G), tomatoes, and leafy vegetables cannot be harmonized as the Canadian, and Codex MRLs differ.  For leafy vegetables except Brassica subgroup 4A, the U.S. and Canada are harmonized at 30 ppm, but a Codex MRL is established for head lettuce at 10 ppm.  For the bulb onion subgroup 3-07A, small vine climbing fruit subgroup 13-07F, and low-growing berry subgroup 13-07G, HED recommends that the U.S. tolerances be increased in order to harmonize with Codex; bulb onion subgroup 3-07A from 0.20 to 0.50 ppm, small vine climbing fruit subgroup 13-07F from 1.0 to 2.0 ppm and low-growing berry subgroup 13-07G from 2.0 to 3.0 ppm.  

The tolerances/MRLs cannot be harmonized for green onions, tomatoes, leafy vegetables except Brassica subgroup 4A, and leafy petioles as the U.S. residue data/use patterns necessitate a higher value.  

For livestock commodities, the U.S. and Codex residue definitions are harmonized; however, the Canadian residue definition is not harmonized.  The numerical values for the U.S. and Canadian livestock tolerances/MRLs are harmonized.   

5.2.2  Drinking Water Residue Profile

Estimated drinking water concentrations (EDWCs) were generated using EFED's standard suite of models (DP#389616, C. Sutton, 10/27/2011).  The Pesticide Root Zone Model (PRZM, v3.12.2, May 2005) and Exposure Analysis Modeling System (EXAMS, v2.98.4.6, April 2005) are simulation models used to generate EDWCs of fludioxonil residues that may occur in surface water used as drinking water.  The PRZM model simulates pesticide movement and transformation on and across the agricultural field resulting from crop applications.  Percent-cropped areas (PCA) that account for the maximum area within a watershed that may be planted with the modeled crop are applied to concentrations predicted by PRZM/EXAMS.  The models and their descriptions are available at the EPA internet site: http://www.epa.gov/oppefed1/models/water/.  

Screening Concentration in Ground Water (SCI-GROW v2.3, Jul. 29, 2003) is a regression model used as a screening tool to estimate pesticide concentrations found in groundwater used as drinking water.  The output of SCI-GROW represents the concentrations of fludioxonil that might be expected in shallow unconfined aquifers under sandy soils, which is representative of the groundwater most vulnerable to pesticide contamination and likely to serve as a drinking water source.  

The maximum proposed application rate among all new proposed uses (for onion subgroups 3-07A and 3-07B) is 0.25 lbs ai/A/application, applied four times per year with a 7-day application interval, for a maximum total annual application rate of 1.0 lb ai/A/yr.  Because the maximum proposed application rate among all of the uses considered for this assessment is less than the rates previously assessed by EFED for ornamentals, the EDWCs based on use on ornamentals are recommended for use in the human-health dietary assessment.  However, based on information provided in Syngenta's 9/9/2011 submission "Fludioxonil Registration Review Public Comments Response to Initial 60-Day Comment Period, Case Number: 7017, Docket Number: EPA-HQ-OPP-2010-1067," EFED concurs that the use of the container-grown ornamentals application rate is not appropriate for estimating EDWCs.  As noted by the registrant, the strong adsorption of the pesticide to the potting media used for container-grown ornamentals, as well as the use of containers, results in attenuation of pesticide movement from the containers to the underlying soil in the field, thereby reducing potential runoff of the pesticide.  Thus, EFED now recommends that the values from the Tier I DWA of 6/22/2009 (D364264) be used in HED's dietary exposure and risk assessment.  The values in the Tier I DWA are based on the use of fludioxonil on field-grown ornamentals at one application of 2 lb ai/A/yr.  The resulting acute and chronic EDWCs in surface water were 83.8 ppb (1-in-10-year acute estimate) and 38.5 ppb (1-in-10-year chronic estimate), respectively.  The EDWC for groundwater (for both acute and chronic analysis) is 0.2 ppb.  Since the surface water concentrations were the highest, the acute and chronic dietary runs were conducted assuming surface water residues of 0.0838 ppm and 0.0385 ppm, respectively, for all water sources (direct and indirect). 
Table 5.2.2.  Tier II EDWCs Resulting From Applications of Fludioxonil on Ornamentals (Total Rate of 4 lb ai/A/yr).
Drinking water source (model)
                                       
                                      Use
                          1-in-10-year acute (ug/L)
                         1-in-10-year chronic (ug/L)
Surface water (PRZM/EXAMS)
Container-grown ornamental
                                     83.8
                                     38.5
Groundwater (SCIGROW)
Container-grown ornamental
                                      0.2
                                      0.2

5.2.3  Dietary Exposure and Risk

Fludioxonil acute and chronic dietary exposure assessments were conducted using the DEEM-FCID[(TM)] model, Version 2.03, which incorporates consumption data from USDA's CSFII, 1994-1996 and 1998.  The 1994-96, 98 data are based on the reported consumption of more than 20,000 individuals over two non-consecutive survey days.  Foods "as consumed" (e.g., apple pie) are linked to EPA-defined food commodities (e.g., apples, peeled fruit - cooked; fresh or N/S; baked; or wheat flour - cooked; fresh or N/S, baked) using publicly available recipe translation files developed jointly by USDA/ARS and EPA.  For chronic exposure assessment, consumption data are averaged for the entire U.S. population and within population subgroups, but for acute exposure assessment are retained as individual consumption events.  Based on analysis of the 1994-96, 98 CSFII consumption data, which took into account dietary patterns and survey respondents, HED concluded that it is most appropriate to report risk for the following population subgroups: the general U.S. population, all infants (<1 year old), children 1-2, children 3-5, children 6-12, youth 13-19, adults 20-49, females 13-49, and adults 50+ years old.

For chronic dietary exposure assessment, an estimate of the residue level in each food or food-form (e.g., orange or orange juice) on the food commodity residue list is multiplied by the average daily consumption estimate for that food/food form to produce a residue intake estimate.  The resulting residue intake estimate for each food/food form is summed with the residue intake estimates for all other food/food forms on the commodity residue list to arrive at the total average estimated exposure.  Exposure is expressed in mg/kg body weight/day and as a percent of the cPAD.  This procedure is performed for each population subgroup.

For acute exposure assessments, individual one-day food consumption data are used on an individual-by-individual basis.  The reported consumption amounts of each food item can be multiplied by a residue point estimate and summed to obtain a total daily pesticide exposure for a deterministic exposure assessment, or "matched" in multiple random pairings with residue values and then summed in a probabilistic assessment.  The resulting distribution of exposures is expressed as a percentage of the aPAD on both a user (i.e., only those who reported eating relevant commodities/food forms) and a per-capita (i.e., those who reported eating the relevant commodities as well as those who did not) basis.  In accordance with HED policy, per capita exposure and risk are reported for all tiers of analysis.  However, for Tiers 1 and 2, any significant differences in user vs. per capita exposure and risk are specifically identified and noted in the risk assessment.

5.2.3.1  Acute Dietary Exposure/Risk

An unrefined acute dietary exposure and risk analysis was performed assuming tolerance-level residues, 100% CT, and DEEM[(TM)] (ver. 7.81) default processing factors.  The 1-in-10-year acute drinking water estimate (i.e., relevant to acute exposure) of 0.0838 ppm, previously provided by EFED, was directly incorporated into the acute assessment.  This analysis was performed for the population subgroup females 13 to 49 years old, which is the only subgroup of interest for acute exposure.  The acute dietary (food plus water) risk utilizes 16% of a PAD for females 13 to 49 years old.

There were no appropriate toxicological effects attributable to a single exposure (dose) for the general population or any other population subgroups; therefore, these population subgroups were not included in this assessment.  

5.2.3.2  Chronic Dietary Exposure/Risk

A partially refined chronic dietary exposure and risk assessment was performed assuming tolerance-level residues for most commodities [with the exception of celery, pineapple, potato, spinach, apple, grapefruit, lemon, lime, orange, pear, tomato, head lettuce, leaf lettuce, fresh parsley, Brassica leafy vegetables (crop group 5), grape, cherry, peach and plum], 100% CT estimates, and DEEM[(TM)] (ver. 7.81) default processing factors [with the exception of citrus fruit juice (1X), apple juice (1X), grape juice (0.42X), raisin (1.65X), potato commodities (1X), and tomato commodities (1X), except dried tomato (14.3X)].  These processing factors are based upon processing study data.  ARs for celery, pineapple, potato, spinach, apple, grapefruit, lemon, lime, orange, pear, tomato, head lettuce, leaf lettuce, fresh parsley, Brassica leafy vegetables (crop group 5), grape, cherry, peach, and plum were generated from field trial and processing study data for the chronic analysis.  The 1-in-10-year chronic drinking water estimate (i.e., relevant to chronic exposure) of 0.0385 ppm, provided by the EFED, was directly incorporated into the chronic assessment.  For the U.S. population the dietary risk (food plus water) utilizes 26% of the cPAD.  The chronic dietary risk estimate for the highest reported exposed population subgroup, children 1 to 2 years old, is 68% of the cPAD.

The results of the acute and chronic dietary exposure analyses are reported in the Summary Table (Table 5.2.3.2, below).  

Table 5.2.3.2.  Summary of Dietary Exposure (Food Plus Water) and Risk Assessment for Fludioxonil.
Population Subgroup
                        Acute Dietary (95th Percentile)
                                Chronic Dietary

                         Dietary Exposure (mg/kg/day)
                                    % aPAD*
                               Dietary Exposure
                                  (mg/kg/day)
                                    % cPAD*
General U.S. Population
                                      N/A
                                   0.008711
                                      26
All Infants (<1 year old)
                                       
                                   0.018891
                                      57
Children 1-2 years old
                                       
                                   0.022497
                                      68
Children 3-5 years old
                                       
                                   0.017817
                                      54
Children 6-12 years old
                                       
                                   0.011011
                                      33
Youth 13-19 years old
                                       
                                   0.006547
                                      20
Adults 20-49 years old
                                       
                                   0.006943
                                      21
Adults 50+ years old
                                       
                                   0.007778
                                      24
Females 13-49 years old
                                   0.163378
                                      16
                                   0.007073
                                      21
 * % PADs are reported to 2 significant figures.  The values for the highest exposed population for each type of risk assessment are bolded.

5.2.3.3  Cancer Dietary Risk

Fludioxonil is classified as a Group D chemical - not classifiable as to human carcinogenicity; therefore, a cancer dietary exposure and risk assessment was not performed for fludioxonil.

5.2.4  Anticipated Residue and Percent Crop Treated (%CT) Information

The acute and chronic dietary assessments for fludioxonil assumed 100% CT.  The chronic assessment was based on the assumption of tolerance-level residues for most commodities with existing and recommended tolerances.  ARs for apple, grapefruit, lemon, lime, orange, pear, head lettuce (with wrapper), leaf lettuce, fresh parsley, Brassica leafy vegetables (crop group 5), grape, cherry, peach, and plum were previously generated from field trials (D. Rate, DP#379936, 07/14/2010).  ARs for tomato, celery, pineapple, potato, and spinach were also generated from field trial data for this assessment; see Table 5.2.4, below.  For Brassica leafy vegetables (crop group 5), the field trial data were translated from the representative commodities in the crop groups to the non-representative commodities according to HED SOP 2000.1:  "Guidance for Translation of Field Trial Data from Representative Commodities in the Crop Group Regulation to Other Commodities in Each Crop Group/Subgroup."  ARs were determined for apple, grapefruit, lemon, and lime juices (J. Sullivan and M. Papathakis, 02/27/2004) using average residues from field trials and processing studies.  As a result, processing factors were set to 1X for these juices.  The value for orange juice was set to 0.0 ppm as fungicide-treated fruit are not processed and Pesticide Data Program (PDP) monitoring data reported no detectable residues in orange juice (16th Annual Summary, data from calendar year 2006).  The submitted grape processing study indicated that fludioxonil residues do not concentrate in juice or appreciably in raisin.  The processing factors were set to 0.42X for grape juice and 1.65X for raisin.  The submitted tomato, pineapple, and potato processing study indicated that fludioxonil residues do not appreciably concentrate in processed commodities made from treated tomato, pineapple, and potato samples; therefore, separate tolerances are not required for tomato, pineapple, and potato processed commodities.  Processing factors were set to 1X for these processed commodities (pineapple juice; tomato paste, juice, and puree; and potato chips, flakes, and flour).  DEEM[(TM)] (ver. 7.81) default processing factors were used for all other processed commodities for which they are available.

Table 5.2.4.  AR Values Used for the Chronic Assessment.
Commodity
                                  AR (ppm)[2]
Apple, whole
            juice
                                      1.1
                                      0.1
Grapefruit, whole
                   juice
                                      2.6
                                     0.74
Lemon, whole
              juice
                                      1.7
                                     0.02
Lime, whole
           juice
                                      1.7
                                     0.02
Orange[1], whole
               juice
                                      1.5
                                      0.0
Pear, whole         
                                      1.6
Tomato 
                                     0.89
Lettuce, head (with wrapper leaves)
                                     2.09
Lettuce, leaf
                                     10.77
Parsley, fresh
                                     1.23
Brassica leafy vegetables (crop group 5)
       Cabbage
       Mustard greens
       Broccoli
                                       
                                       
                                     0.34
                                     1.03
                                     0.13
Grape
                                     0.33
Cherry 
                                     0.82
Peach
                                     0.40
Plum
                                     0.51
Celery
                                      4.9
Pineapple
                                     5.64
Potato
                                     1.82
Spinach
                                      7.1
	      [1]  Also represents tangerine.
            [2]  ARs calculated for the current memo were taken from field trial data associated with the following
              MRID Nos.:  48478501, 48437302, 48437101, 48437305, and 48438204.

6.0  RESIDENTIAL (NON-OCCUPATIONAL) EXPOSURE/RISK CHARACTERIZATION

The proposed uses will not result in residential exposures; however, fludioxonil is currently registered for use in residential areas, including parks, golf courses, athletic fields, residential lawns, ornamentals, and greenhouses.  

HED previously assessed the use of fludioxonil in residential use scenarios to control certain diseases of turfgrass and certain foliar, stem and root diseases in ornamentals in residential landscapes and greenhouses (Memo, 11/10/09, W. Wassell, et al., D362493; 05/06/02, T. Swackhammer, D282570; and 9/30/08, M. Dow, D356221).  A Human-Health Assessment Scoping Document in Support of the Registration Review (W. Wassell, D384857) was completed in 2011.  As noted in the recent scoping document, in addition to the conventional uses of fludioxonil is residential areas, there are also antimicrobial uses.  The antimicrobial uses in residential areas will be further reviewed and assessed during Registration Review.  The residential turf uses of fludioxonil are expected to result in the highest potential exposure of all registered residential uses of fludioxonil and, therefore, were reassessed in this risk assessment.  The registered turf use has been reassessed in this document to reflect updates to HED's Residential SOPs, 2012 and the revised UFDB for inhalation risks (Memo, L Venkateshwara, D389982).  The currently registered label for turf is Medallion[(R)] Fungicide EPA Reg. # 100-769.  Medallion[(R)] Fungicide is a 50% WP in water-soluble packaging.  The maximum single application rate is 0.50 oz per 1000 ft2 or 0.68 lbs ai/A.  For a complete review of the calculations associated with the residential turf uses of fludioxonil, see the aforementioned L. Venkateshwara memo. 

6.1  Residential Handler Exposure/Risk

The residential handler exposure assessment estimates only inhalation exposures for individuals using fludioxonil on residential turfgrass as there are no dermal endpoints for fludioxonil.  The following are key differences between residential and occupational handler assessments include the following:  

   * Residential handler exposure scenarios are considered to be short-term only, due to the infrequent use patterns associated with homeowner products.

   * A tiered approach for personal protection using increasing levels of PPE is not used in residential handler risk assessments.  Homeowner handler assessments are based on the assumption that individuals are wearing shorts, short-sleeved shirts, socks, and shoes.

   * Homeowner handlers are expected to complete all tasks associated with the use of a pesticide product including mixing/loading if needed as well as the application.

The quantitative exposure/risk assessment developed for residential handlers is based on the following scenarios: 

(1) Mixing/loading/applying WP in water-soluble packaging with manually pressurized handwand,
(2) Mixing/loading/applying WP in water-soluble packaging with backpack sprayer, 
(3) Mixing/loading/applying WP in water-soluble packaging with hose end sprayer, and 
(4) Mixing/loading/applying WP in water-soluble packaging with a sprinkler can.

Unit exposure values and estimates for area treated were taken from the HED's 2012 SOPs for Residential Pesticide Exposure Assessment for Lawns/Turf.  

Short-term risks for residential handlers are presented in Table 6.1.1.  Intermediate-term exposures are not likely because of the intermittent nature of applications by homeowners.  Short-term inhalation risk estimates to residential handlers do not exceed HED's LOC for all scenarios.  Although an inhalation study is required for fludioxonil, the oral PODs used for assessing inhalation risk are based on the most sensitive endpoints established in the most sensitive species.  Furthermore, an additional 10X UFDB will be used to further protect for the uncertainty from this oral to inhalation route-to-route extrapolation.  Based on these oral PODs, all residential handler inhalation exposures were well above the LOC and are not of concern to HED.  Therefore, the risk estimate is conservative and will not underestimate risk via the inhalation route.

Table 6.1.1.  Residential Handler Exposure and Risk Estimates for Fludioxonil Applications to Turfgrass.
                               Exposure Scenario
                         Application Rate (lb ai/A)[a]
                         Area Treated Daily (acres)[b]
                     Baseline Unit Exposures[b] (mg/lb ai)
                         Baseline Dose[d] (mg/kg/day)
                                Baseline MOE[e]
                                       
                                       
                                       
                                 Inhalation[c]
                                 Inhalation[c]
                                 Inhalation[c]
                            Mixer/Loader/Applicator
Mixing/Loading/Applying WP in Water-soluble Packaging with Manually-pressurized Handwand 
                                     0.68
                                     0.023
                                     0.018
                                    3.5E-06
                                   2,800,000
 Mixing/Loading/Applying WP in Water-soluble Packaging with Backpack Sprayer 
                                     0.68
                                     0.023
                                     0.018
                                    3.5E-06
                                   2,800,000
  Mixing/Loading/Applying WP in Water-soluble Packaging with Hose-end Sprayer
                                     0.68
                                      0.5
                                     0.034
                                    1.5E-04
                                    69,000
   Mixing/Loading/Applying WP in Water-soluble Packaging with Sprinkler Can
                                     0.68
                                     0.023
                                     0.034
                                    6.7E-06
                                   1,500,000
a.	Application rates based on label for fludioxonil (Medallion[(R)] Fungicide, EPA Reg.# 100-769).
b.	Based on HED's SOPs for Residential Pesticide Exposure Assessment; Lawns/Turf (February, 2012).
c.	Baseline Inhalation:  no respirator.  
d.	Dose (mg/kg/day) = daily unit exposure (mg/lb ai) x application rate (lb ai/A) x acres treated * absorption factor (inhalation = 100%) / body weight (80 kg).
e.	MOE = NOAEL (10 mg/kg/day) / daily dose (mg/kg/day).  Level of concern = 1000.

6.2  Residential Post-application Exposure and Risk

Fludioxonil can be used in many areas that can be frequented by the general population including residential areas (e.g., home lawns).  As a result, individuals can be exposed by entering these areas if they have been previously treated.  

6.2.1  Post-application Inhalation

Based on the Agency's current practices, a quantitative post-application inhalation exposure assessment was not performed for fludioxonil at this time.  However, volatilization of pesticides may be a potential source of post-application inhalation exposure to individuals nearby to pesticide applications.  The Agency sought expert advice and input on issues related to volatilization of pesticides from its FIFRA Scientific Advisory Panel (SAP) in December 2009.  The Agency received the SAP's final report on March 2, 2010 (http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html).  The Agency is in the process of evaluating the SAP report and may, as appropriate, developing policies and procedures, to identifying the need for and, subsequently, the way to incorporate post-application inhalation exposure into the Agency's risk assessments.  If new policies or procedures are put into place, the Agency may revisit the need for a quantitative post-application inhalation exposure assessment for fludioxonil.

6.2.2  Post-application Dermal and Incidental Oral

Dermal post-application exposure/risk has not been assessed because there is no dermal POD.  Short- and intermediate-term incidental oral exposure and risk estimates have been assessed here.  Intermediate-term exposures may be possible as the Medallion(R) label specifies that the product may be applied at 14-day application intervals, with an annual maximum rate of 2 lbs ai/A/yr, which equates to about three applications at the maximum per application rate.  Fludioxonil has exhibited half-lives ranging from 95 to 440 days in thatch sod based on field-dissipation studies (05/06/02, T. Swackhammer, D282570).  Therefore, this assessment included a residential post-application assessment for toddler incidental ingestion exposures related to residential lawn applications.

   * Physical activities on turf:  children 1 < 2 years old (incidental oral).

The lifestage (i.e., children 1 < 2 years old) selected for this post-application scenario is based on an analysis provided as an Appendix in the 2012 Residential SOPs.  This lifestage is not the only lifestage that could be potentially exposed for these post-application scenarios; however, the assessment of this lifestage is health protective for the exposures and risks for any other potentially exposed lifestages.  Table 6.2.2.1 presents the post-application incidental oral MOE values calculated for children 1 < 2 years old after applications of fludioxonil to turf.  Post-application risk estimates do not exceed HED's LOC for any of the scenarios assessed. 

Table 6.2.2.1.  Short-Term Residential Post-application Exposure and Risk Estimates for Fludioxonil.
                                   Lifestage
                      Post-application Exposure Scenario
                               Dose (mg/kg/day)
                                Short-term MOEs
                            Intermediate-term MOEs
                            Child 1 < 2 year old
                                 Turf - sprays
                                 Hand-to-Mouth
                                    0.0101
                                      990
                                      330
                                       
                                       
                                Object-to-Mouth
                                    0.00031
                                    32,000
                                    11,000
                                       
                                       
                           Incidental Soil Ingestion
                                    2.2E-05
                                    450,000
                                    150,000

6.3  Combined Exposure

HED combines risk estimates resulting from separate post-application exposure scenarios when it is likely they can occur simultaneously based on the use pattern and the behavior associated with the exposed population and when the toxicological effects are similar.  For fludioxonil, there is no dermal POD; therefore, the only route of exposure is incidental oral for children.  

The incidental oral scenarios (i.e., hand-to-mouth, object-to-mouth, and soil ingestion) should be considered inter-related and it is likely that they occur interspersed amongst each other across time.  Combining all three of these scenarios would be overly conservative because of the conservative nature of each individual assessment.  Therefore, only the hand-to-mouth scenario was chosen as a health protective estimate of children's exposure to pesticides used on turf.

Table 6.3.1.  Short- and Intermediate-Term Residential Exposures for the Fludioxonil Combined Residential Turf Risk Estimates.
                                  Population
                        Handler Exposure (mg/kg/day)[1]
               Residential Handler Total Exposure (mg/kg/day)[3]
                         Residential Handler Total MOE
                   Post-application Exposure (mg/kg/day)[2]
          Residential Post-application Total Exposure (mg/kg/day)[3]
                    Residential Post-application Total MOE
                                       
                                  Inhalation
                                       
                                       
                                    Dermal
                                    Inhal.
                                     Oral
                                       
                                       
                                  Short-Term
                                  Adult Male
                                    1.5E-04
                                    1.5E-04
                                    69,000
                                      NA
                                      N/A
                                      N/A
                                      NA
                                      NA
                           Child 1 < 2 years old
                                      N/A
                                      NA
                                      N/A
                                    0.0101
                                    0.0101
                                      990
                               Intermediate-Term
                           Child 1 < 2 years old
                                      N/A
                                      N/A
                                      N/A
                                    0.0101
                                    0.0090
                                      370
[1]  Handler exposure represents high-end inhalation handler exposure, where the exposure duration is appropriate to assess.
[2]  Post-application exposure represents high-end incidental oral exposure for the relevant exposure duration.
[3]  For adults, residential total exposure combines the highest inhalation exposures, where applicable.  For young children, total residential exposure combines high-end post application incidental oral AND dermal exposure, where applicable.

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

Although a quantitative residential post-application inhalation exposure assessment was not performed as a result of pesticide drift from neighboring treated agricultural fields, an inhalation exposure assessment was performed for flaggers.  This exposure scenario is representative of a worse case inhalation (drift) exposure and may be considered protective of most outdoor agricultural and commercial post-application inhalation exposure scenarios.   

6.5  Residential Bystander Post-application Inhalation Exposure

Based on the Agency's current practices, a quantitative residential bystander post-application inhalation exposure assessment was not performed for fludioxonil this time primarily because it is applied at a low use rate.  However, volatilization of pesticides may be a potential source of post-application inhalation exposure to individuals nearby to pesticide applications.  The Agency sought expert advice and input on issues related to volatilization of pesticides from its FIFRA SAP in December 2009.  The Agency received the SAP's final report on March 2, 2010 (http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html).  The Agency is in the process of evaluating the SAP report and may, as appropriate, develop policies and procedures, to identify the need for and, subsequently, the way to incorporate post-application inhalation exposure into the Agency's risk assessments.  If new policies or procedures are put into place, the Agency may revisit the need for a quantitative post-application inhalation exposure assessment for fludioxonil.

      
7.0  AGGREGATE RISK ASSESSMENTS AND RISK CHARACTERIZATION

In accordance with the FQPA, HED must consider and aggregate pesticide exposures and risks from non-occupational sources, including food, drinking water, and residential pathways.  In an aggregate assessment, exposures from relevant sources are added together and compared to quantitative estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can be aggregated.  When aggregating exposures and risks from various sources, HED considers both the route and duration of exposure.
      
      7.1  Acute Aggregate Risk

Based on the exposure pathways, the acute aggregate risk assessment should include exposure from food and water only.  Since the acute dietary analysis included both food and water exposures, no further estimates of risk are necessary.  The acute dietary risk does not exceed the LOC; therefore, the acute aggregate risk does not exceed the LOC.

      7.2  Short-Term Aggregate Risk

In aggregating short-term risk, HED considers background chronic dietary exposure (food + water) and short-term, residential exposures.  Fludioxonil is registered for use in residential areas; therefore, there is the potential for residential handler and post-application exposure.  Because the registered use on turf represents the higher potential exposure of all registered residential uses, potential exposures resulting from the turf use are included in the short-term aggregate assessment.  Aggregating residential turf exposure with potential dietary exposures provided a conservative assessment that is protective of all potential aggregate exposures to fludioxonil.  Since no dermal POD was selected and post-application inhalation exposure is expected to be minimal, the only short-term residential exposures are (1) incidental oral post-application exposures for children on treated lawns (resulting from the currently registered use) and (2) inhalation exposure for residential handlers (resulting from the currently registered use).  The short-term aggregate assessment for children includes exposure from food, water, and post-application non-dietary oral exposures using an MOE approach.  Table 7.2.1 summarizes the short-term aggregate exposure estimates to fludioxonil residues for children (1-2 years old).  For adults, short-term aggregate combines dietary (food + water) exposure with inhalation exposure resulting from residential handlers treating lawns.  For the adult assessment, because the short-term oral and inhalation risks are estimated using the same oral POD, these routes of exposure can be combined.  However, because the LOCs for oral and inhalation routes of exposure are not the same (an MOE of <100 defines the LOC for incidental oral risk while inhalation risk is defined by an MOE of <1000) an aggregate risk index (ARI) was required to estimate aggregate risk for adults.  EPA identifies as a LOC ARIs that fail to reach or exceed the level of one.  ARIs below one result in a risk estimate of concern.  Table 7.2.2 summarizes the short-term aggregate exposure estimates to fludioxonil residues for adults.

Table 7.2.1.  Short-Term Aggregate Risk (Food, Drinking Water, and Residential Exposure).
Population
                              Short-Term Scenario

                                     NOAEL
                                   mg/kg/day
                                      LOC
                                    MOE[1]
                                    Average
                                 Food + Water
                                   Exposure
                                   mg/kg/day
                      Inhalation Residential Exposure[2]
                                   mg/kg/day
                         Oral Residential Exposure[3]
                                   mg/kg/day
                                 Aggregate MOE
                                 (food, water
                             & residential)[4]
Children (1-2 years old)
                                      10
                                      100
                                   0.022497
                                       -
                                    0.0101
                                      310
   [1] The LOC MOE is 100, based on inter- and intra-species SFs totaling 100.
   [2] Inhalation exposure from Table 6.3.1.
   [3] Oral residential exposure = [incidental oral exposure].  From Table 6.3.1.
   [4] Aggregate MOE = [NOAEL / (avg. food + water exposure + residential exposure)].

Table 7.2.2.  Short-Term Aggregate Risk (Food, Drinking Water, and Residential Exposure).
                                  Population
                            Level of Concern ARI[1]
                             ARI (Food + Water)[2]
                              Residential ARIs[3]
                            Total Aggregate ARI[4]
                                       
                                       
                                       
                                   Handlers
                       Post Application Dermal Exposure
                                       
                                       
                                       
                                       
                                Dermal Exposure
                              Inhalation Exposure
                                       
                                       
                            General U.S. Population
                                       1
                                      11
                                       -
                                      69
                                       -
                                      9.5
                             Adults 50+ years old
                                       1
                                      13
                                       -
                                      69
                                       -
                                      11
[1]  ARI (Aggregate Risk Index) = MOECalculated / MOEAcceptable.
[2]  ARIFood + Water = (10 mg/kg/day/0.008711 mg/kg/day) / 100 = 11 (general U.S. population); and (10 mg/kg/day/0.007778 mg/kg/day) / 100 = 13 (adults 50+ years old).
[3]  ARIDermal =MOE / 100 and, ARIInhalation = MOE / 1000.
[4]  ARITotal Aggregate = 1/[(1/ARIFood + water) + (1/ARIResidential Handler Deraml ) + (1/ARIResidential Handler Inhalation) + (1/ARIPost Application Dermal)].

All short-term aggregate risk estimates result a MOE >100 or an ARI >1.  Short-term aggregate exposure to fludioxonil, as a result of all registered and proposed uses, is thus below HED's LOC.

      7.3  Intermediate-Term Aggregate Risk

In aggregating intermediate-term risk, HED considers background chronic dietary exposure (food + water) and intermediate-term, residential exposures.  Fludioxonil is registered for use in residential areas; therefore, there is the potential for intermediate-term residential exposure.  Because the registered use on turf represents the higher potential exposure of all registered residential uses, potential exposures resulting from the turf use are included in the intermediate-term aggregate assessment.  Aggregating residential turf exposure with potential dietary exposures provided a conservative assessment that is protective of all potential aggregate exposures to fludioxonil.  Since no dermal POD was selected and post-application inhalation exposure is expected to be minimal, the only intermediate-term residential exposure is incidental oral post-application exposures for children on treated lawns (resulting from the currently registered use).  The intermediate-term aggregate assessment for children includes exposure from food, water, and post-application non-dietary oral exposures resulting from contact with treated lawns.  Table 7.3 summarizes the intermediate-term aggregate exposure estimates to fludioxonil residues.

Table 7.3.  Intermediate-Term Aggregate Risk (Food, Drinking Water, and Residential Exposure).
Population
                              Short-Term Scenario

                                     NOAEL
                                   mg/kg/day
                                      LOC
                                    MOE[1]
                                    Average
                                 Food + Water
                                   Exposure
                                   mg/kg/day
                      Inhalation Residential Exposure[2]
                                   mg/kg/day
                         Oral Residential Exposure[3]
                                   mg/kg/day
                                 Aggregate MOE
                                 (food, water
                             & residential)[4]
Children (1-2 years)
                                      3.3
                                      100
                                   0.022497
                                       -
                                    0.0090
                                      105
   [1]  The LOC MOE is 100, based on inter- and intra-species SFs totaling 100.
   [2]  Inhalation exposure from Table 6.3.1.
   [3]  Oral residential exposure = [incidental oral exposure].  From Table 6.3.1.
   [4]  Aggregate MOE = [NOAEL / (avg. food + water exposure + residential exposure)].

All intermediate-term aggregate risk estimates result in MOEs greater than 100.  Intermediate-term aggregate exposure to fludioxonil, as a result of all registered and proposed uses, is below HED's LOC.

7.4  Chronic Aggregate Risk

Since chronic residential exposure is not expected to result from the residential uses of fludioxonil, the chronic aggregate risk assessment includes exposures from food and water only.  As the chronic dietary analysis that was performed included both food and water, no further calculations are necessary.  Since the chronic dietary risk does not exceed the LOC, the chronic aggregate risk does not exceed the LOC.

7.5  Cancer Aggregate Risk

Fludioxonil is classified as a Group D chemical - not classifiable as to human carcinogenicity; therefore, there is no need for a quantitative cancer risk assessment.

8.0  CUMULATIVE RISK CHARACTERIZATION/ASSESSMENT

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as to fludioxonil and any other substances, and fludioxonil does not appear to produce a toxic metabolite produced by other substances.  For the purposes of this tolerance action, therefore, EPA has not assumed that fludioxonil has a common mechanism of toxicity with other substances.

For information regarding EPA's efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA's Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on EPA's website at http://www.epa.gov/pesticides/cumulative/.
      
      
9.0  OCCUPATIONAL EXPOSURE/RISK PATHWAY

The potential uses are on agricultural crops; therefore, there is potential for occupational handler and post-application exposure.  For a complete review of the calculations associated with the occupational uses of fludioxonil, see the co-pending HED memo (L. Venkateshwara, D389982).

      9.1  Occupational Handler Risk

Occupational handlers may experience short- and intermediate-term dermal exposure to fludioxonil while performing tasks involving applications to agricultural crops.  The quantitative exposure/risk assessment developed for occupational handlers is based on the following scenarios:

Mixer/Loader:
   1. open mixing/loading WP for aerial application; 
   2. open mixing/loading WP for groundboom application;
   3. open mixing/loading WP for chemigation application;
   4. open mixing/loading DF for aerial application;
   5. open mixing/loading DF for groundboom application;
   6. open mixing/loading DF for airblast application;
   7. open mixing/loading WP for dip application;
   8. open mixing/loading DF for dip application;

Applicator:
   9. application of sprays via aerial application;
   10. application of sprays via groundboom applications; 
   11. application of sprays via airblast application;

Flagger:
   12. flagging for aerial application;

Mixer/Loader/Applicator:
   13. mixing/loading/applying WP with backpack sprayer;
   14. mixing/loading/applying DF/WDG with a backpack sprayer;
   15. mixing/loading/applying WP with mechanically-pressurized handgun sprayer;
   16. mixing/loading/applying DF/WDG with mechanically-pressurized handgun sprayer;
   17. mixing/loading/applying WP with manually-pressurized handgun;
   18. mixing/loading/applying DF/WDG with manually-pressurized handwand;

Post-harvest Handler Scenarios:
   19. open mixing/loading liquids for post-harvest commodity treatment; and
   20. open mixing/loading WP for post-harvest commodity treatment.

It is the policy of HED to use the best available data to assess handler exposure.  Sources of generic handler data, used as surrogate data in the absence of chemical-specific data, include PHED 1.1, the AHETF database, the ORETF database, or other registrant-submitted occupational exposure studies.  Some of these data are proprietary (e.g., AHETF data), and subject to the data protection provisions of FIFRA.  The standard values recommended for use in predicting handler exposure that are used in this assessment, known as "unit exposures," are outlined in the "Occupational Pesticide Handler Unit Exposure Surrogate Reference Table" (http://www.epa.gov/opp00001/science/handler-exposure-table.pdf), which, along with additional information on HED policy on use of surrogate data, including descriptions of the various sources, can be found at http://www.epa.gov/pesticides/science/handler-exposure-data.html.

For pesticide handlers, it is HED standard practice to present estimates of exposure for "baseline" (i.e., workers wearing a single layer of work clothing consisting of a long-sleeved shirt, long pants, shoes plus socks and no protective gloves and no respirator), as well as for "baseline" and the use of protective gloves or other PPE as might be necessary (e.g., respirator).  The five proposed labels involved in this assessment directs applicators and other handlers to wear long-sleeved shirt, long pants, shoes plus socks, and chemical-resistant gloves.  

Handler exposure is expected to be short- or intermediate-term based on information provided on proposed labels.  Long-term exposures are not expected; therefore, a long-term assessment was not conducted.  The average adult body weight of 80 kg was used for estimating the inhalation dose.  Since the short- and intermediate-term inhalation PODs are based on an oral study and no inhalation absorption data are available, toxicity by the inhalation route is considered equivalent to the estimated toxicity by the oral route of exposure.

Table 9.1.1 presents the estimated risks for workers based on the short and intermediate-term inhalation exposures with baseline attire, or with additional PPE.  HED has determined that risks are of concern for short-term exposures (i.e., MOEs <1000) for mixing/loading WPs for aerial and chemigation applications, and require a PF5 respirator with 80% protection factor to reach acceptable MOEs.  HED has also determined for intermediate-term exposures, the PPE required to reach acceptable MOEs (i.e., MOEs >1000) for mixing/loading WPs for aerial and chemigation applications includes engineering controls.  Furthermore, for mixing/loading WPs for groundboom applications and mixing/loading DFs for aerial and groundboom applications, a PF5 respirator with 80% protection factor is required for the intermediate-term exposures to reach MOEs >1000.  

Table 9.1.1.  Fludioxonil Occupational Inhalation Exposures and Risks.
                               Exposure Scenario
               App Rate (lb ai/acre, unless otherwise noted)[a]
                           Source of Maximum Rate[f]
             Area Treated Daily (acres, unless otherwise noted)[b]
                           Inhalation Unit Exposures
                                 (mg/lb ai)[e]
                        Inhalation Doses (mg/kg/day)[c]
                         Short-term Inhalation MOEs[d]
                     Intermediate-term Inhalation MOEs[d]
                                 Mixer/Loader
                 Mixing/Loading WPs for Aerial Applications  
                                     0.25
           Cannonball(R) (100-1360) on strawberries (foliar applied)
                                      350
                                    0.0434
                                     0.054
                                      210
                                      70
                                       
                                       
                                       
                                       
                                 PF5: 0.00868
                                    0.0095
                                     1100
                                      350
                                       
                                       
                                       
                                       
                                     PF10:
                                    0.00438
                                    0.0047
                                     2100
                                      700
                                       
                                       
                                       
                                       
                             Engineering Control:
                                    0.00024
                                    0.00026
                                     38000
                                     13000
                      Mixing/Loading WPs for Groundboom  
                                     0.55
                   Cannonball(R) (100-1360) on onions, garlic
                                (soil directed)
                                      80
                                    0.0434
                                     0.024
                                      420
                                      140
                                       
                                       
                                       
                                       
                                 PF5: 0.00868
                                    0.0047
                                     2100
                                      700
                                       
                                       
                                       
                                       
                                     PF10:
                                    0.00438
                                    0.0024
                                     4200
                                     1400
                      Mixing/Loading WPs for Chemigation
                                     0.25
                      Cannonball(R) (100-1360) on ginseng
                                (soil directed)
                                      350
                                    0.0434
                                     0.054
                                      210
                                      70
                                       
                                       
                                       
                                       
                                 PF5: 0.00868
                                    0.0095
                                     1100
                                      350
                                       
                                       
                                       
                                       
                                     PF10:
                                    0.00438
                                    0.0047
                                     2100
                                      700
                                       
                                       
                                       
                                       
                             Engineering Control:
                                    0.00024
                                    0.00026
                                     38000
                                     13000
                    Mixing/Loading WPs for Dip Applications
                                    0.00125
        Cannonball(R) (100-1360) on strawberries (dip/crown treatments)
                                      100
                                    0.0434
                                   0.000068
                                    150000
                                     49000
                                       
                                       
                                       
                                     1000
                                    0.0434
                                    0.00068
                                     15000
                                     4900
                  Mixing/Loading DFs for Aerial Applications 
                                     0.22
Switch(R) (100-953) on berries, bushberries, caneberries, grapes, strawberries, tropical fruit)
                                      350
                                    0.00896
                                    0.0087
                                     1200
                                      380
                                       
                                       
                                       
                                       
                                     PF5:
                                   0.001792
                                    0.0017
                                     5800
                                     1900
                      Mixing/Loading DFs for Groundboom 
                                     0.55
Switch(R) (100-953) on berries, bushberries, caneberries, leafy vegetables, onions, garlic, strawberries, tomato, peppers, eggplant and other fruiting vegetables
                                      80
                                    0.00896
                                     0.005
                                     2000
                                      670
                                       
                                       
                                       
                                       
                                     PF5:
                                   0.001792
                                    0.00099
                                     10000
                                     3300
                        Mixing/Loading DFs for Airblast
                                     0.22
                 Switch(R) (100-953) on grapes, tropical fruit
                                      40
                                    0.00896
                                    0.00099
                                     10000
                                     3300
                    Mixing/loading DFs for Dip Applications
                               0.00125 lb ai/gal
          Switch(R) (100-953) on strawberries (dip/crown treatments) 
                                      100
                                    0.00896
                                   0.000014
                                    710000
                                    230000
                                       
                                       
                                       
                                     1000
                                    0.00896
                                    0.00014
                                     71000
                                     23000
                                  Applicator
                   Applying Sprays via Groundboom Equipment 
                                     0.55
                Cannonball(R) (100-1360) and Switch(R) (100-953)
                                      80
                                    0.00034
                                    0.00019
                                     53000
                                     18000
                     Applying Sprays via Aerial Equipment 
                                     0.25
           Cannonball(R) (100-1360) on strawberries (foliar applied)
                                      350
                             Engineering Control:
                                   0.000068
                                   0.000075
                                    130000
                                     44000
                    Applying Sprays via Airblast Equipment
                                     0.22
                 Switch(R) (100-953) on grapes, tropical fruit
                                      40
                                    0.00471
                                    0.00052
                                     19000
                                     66000
                                    Flagger
                   Flagging for Aerial Sprays Applications 
                                     0.25
            Cannonball(R) (100-1360) on strawberries (foliar applied
                                      350
                                    0.00035
                                    0.00039
                                     26000
                                     8600
                            Mixer/Loader/Applicator
                      Applying WP with backpack sprayer 
                              0.000625 lb ai/gal
            Cannonball(R) (100-1360) on bushberries (greenhouse use)
                                  40 gallons
                                Baseline: 0.140
                                   0.000044
                                    230000
                                     75000
          Applying WP with mechanically-pressurized handgun sprayer 
                              0.000625 lb ai/gal
            Cannonball(R) (100-1360) on bushberries (greenhouse use)
                                 1000 gallons
                                Baseline: 0.120
                                    0.00094
                                     11000
                                     3500
                Applying WP with manually-pressurized handwand
                              0.000625 lb ai/gal
                    Cannonball(R) (100-1360) on bushberries
                               (greenhouse use)
                                  40 gallons
                                Baseline: 0.030
                                   0.0000094
                                    1100000
                                    350000
                   Applying DF/WDG with a backpack sprayer 
                                     0.22
 Switch(R) (100-953 on tomato, peppers, eggplant and other fruiting vegetables
                               (greenhouse use)
                                      5 
                                Baseline: 0.140
                                    0.0019
                                     5200
                                     1700
        Applying DF/WDG with mechanically-pressurized handgun sprayer 
                                     0.22
 Switch(R) (100-953) on tomato, peppers, eggplant and other fruiting vegetables
                               (greenhouse use)
                                      5 
                                Baseline: 0.120
                                    0.0017
                                     6000
                                     2000
               Applying DF/WDG with manually-pressurized handwand 
                                     0.22
 Switch(R) (100-953) on tomato, peppers, eggplant and other fruiting vegetables
                               (greenhouse use)
                                       5
                                Baseline: 0.030
                                    0.00042
                                     24000
                                     8000
a.	Application rate = maximum application rate from labels.
b.	Amount handled per day values are HED estimates of acres treated per day based on ExpoSAC SOP #9 "Standard Values for Daily Acres Treated in Agriculture," industry sources, and HED estimates.
c.	Inhalation Dose (mg/kg/day) = daily unit exposure (mg/lb ai) x application rate (lb ai/A or lb ai/gallon) x amount handled or area treated/day (acres/day or gallons/day) x absorption factor (100%) / body weight (80 kg adult).
d.	Inhalation MOE = NOAEL (10 mg/kg/day for short-term exposure and 3.3 mg/kg/day for intermediate-term exposure) / inhalation daily dose (mg/kg/day).  LOC = 1000.
e.	Based on "Occupational Pesticide Handler Unit Exposure Surrogate Reference Table" September 26, 2011.  Baseline inhalation:  no respirator.  PF5:  respirator that reduces exposure by 80%.  Engineering control:  enclosed cockpit for aerial applicators.
f.	Maximum rates are from labels:  Cannonball[(R)] WP (EPA Reg. # 100-1360) is a 50 % WP and Switch[(R)] 62.5 WG (EPA Reg. # 100-953) is a combination product which contains 37.5 %, by weight, cyprodinil ai and 25.0 %, by weight, fludioxonil ai.  It is formulated as a WDG.  

Table 9.1.2.  Occupational Handler Short- and Intermediate-Term Inhalation Exposure and Risk Estimates for the Post-Harvest Use of Fludioxonil.
                                     Crop
                  Solution Concentration[1] (lb ai/gal soln)
                 Amount Treated per Day[2] (1 gal/lbs of crop)
                  Amount Processed per Day[3] (lbs boxes/hr)
                         Inhalation UE[4] (ug/lb ai)
               ST & IT Inhalation Daily Dose5 (mg ai/kg/day)
                                   ST MOE[6]
                                   IT MOE[7]
             Open Mixing/Loading WP:  Scholar(R) 50% WP (100-969) 
                                    Citrus
                                     0.01
                                   0.000125
                                    180,000
                                     43.4
                                   0.001116
                                     9,000
                                     3,000
                                   Pineapple
                                     0.005
                                   0.000125
                                    180,000
                                       
                                   0.000558
                                    18,000
                                     5,900
                                  Pome Fruit
                                    0.0025
                                   0.000125
                                    180,000
                                       
                                   0.000279
                                    36,000
                                    12,000
                                    Potato
                                    0.01875
                                   0.000125
                                    180,000
                                       
                                   0.0020925
                                     4,800
                                     1,600
                                    Tomato
                                     0.005
                                   0.000125
                                    180,000
                                       
                                   0.000558
                                    18,000
                                     5,900
                                Tropical Fruit
                                     0.005
                                   0.000125
                                    180,000
                                       
                                   0.000558
                                    18,000
                                     5,900
Open Mixing/Loading Liquids:  Graduate A+(TM) 20.6 % or 1.99 lbs ai per gallon (EPA Reg. # 100-1308) 
                                    Citrus
                                    0.00995
                                   0.000125
                                    180,000
                                     0.219
                                   5.58E-06
                                   1,800,000
                                    590,000
                                   Pineapple
                                    0.0048
                                   0.000125
                                    180,000
                                       
                                   2.70E-06
                                   3,700,000
                                   1,200,000
                                  Pome Fruit
                                    0.0024
                                   0.000125
                                    180,000
                                       
                                   1.35E-06
                                   7,400,000
                                   2,400,000
                                    Potato
                                     0.018
                                   0.000125
                                    180,000
                                       
                                   1.01E-05
                                    990,000
                                    330,000
                                    Tomato
                                    0.0048
                                   0.000125
                                    180,000
                                       
                                   2.70E-06
                                   3,700,000
                                   1,200,000
                                Tropical Fruit
                                    0.0048
                                   0.000125
                                    180,000
                                       
                                   2.70E-06
                                   3,700,000
                                   1,200,000
1.	Solution concentration  -  (a) for WP product:  application rate (oz product/gal water) x 1 lb/16 oz x % ai; (b) for liquid product:  	application rate (fl oz product/gal water) x lb ai/gal x 1 gal/128 fl oz.
2.	Amount treated per day  -  assumption from ExpoSAC draft policy on post harvest use (D. Jaquith, 11/2005); 1 gallon treats 8,000 lbs fruit.
3.	Amount processed per day - lbs boxes per hour.  Assumed that a packing facility could potentially pack 2,000 boxes per hour, each weighing 90 	lbs (2,000 boxes/hr x 90 lbs each = 180,000 lbs boxes/hr).  
4.	Based on "Occupational Pesticide Handler Unit Exposure Surrogate Reference Table" September 26, 2011.  Baseline = no respirator.
5.	Daily dose = [amount processed (lb boxes/hr) x amount treated daily (gal/lb) x soln. concentration (lb ai/gal soln.) x unit exposure x 8 (hr/day) 	x absorption factor (1.0)]/body weight (80 kg).
6.	Short-term MOE = NOAEL (10 mg/kg/day)/daily dose (mg ai/kg/day).
7.	Intermediate-term MOE = NOAEL (3.3 mg/kg/day)/daily dose (mg ai/kg/day).

      

      9.2  Occupational Post-Application Risk

Based on the Agency's current practices, a quantitative post-application inhalation exposure assessment was not performed for fludioxonil at this time primarily because it has a low vapor pressure (2.9 x 10[-9] mm Hg @ 25°C) and it is applied at low application rates.  However, volatilization of pesticides may be a potential source of post-application inhalation exposure to individuals nearby pesticide applications.  The Agency sought expert advice and input on issues related to volatilization of pesticides from its FIFRA SAP in December 2009.  The Agency received the SAP's final report on March 2, 2010 (http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html).  Although a quantitative occupational post-application inhalation exposure assessment was not performed, an inhalation exposure assessment was performed for occupational handlers.  This assessment resulted in risks that did not exceed HED's LOC at baseline inhalation PPE.  Handler exposure resulting from application of pesticides outdoors is likely to result in higher exposure than post-application exposure.  Therefore, it is expected that these handler inhalation exposure estimates would be protective of most occupational post-application inhalation exposure scenarios.  The Agency is in the process of evaluating the SAP report as well as available post-application inhalation exposure data generated by the Agricultural Reentry Task Force and may, as appropriate, develop policies and procedures, to identify the need for and, subsequently, the way to incorporate occupational post-application inhalation exposure into the Agency's risk assessments.  If new policies or procedures are put into place, the Agency may revisit the need for a quantitative occupational post-application inhalation exposure assessment for fludioxonil.  HED assumes that inhalation exposures are minimal following outdoor applications of an ai with low vapor pressure; therefore, post-application inhalation exposures and risks were not quantitatively assessed.  

There is potential for dermal post-application exposure; however, since no short-term dermal POD was selected, no post-application dermal exposures and risks are assessed.

Attachment A:  Toxicology Profile Tables.
Appendix B:  International Residue Limits for Fludioxonil.

cc:  G. Kramer (RAB1), L. Venkateshwara (RAB1), A. Dunbar (RAB1)
RDI:  Branch (2/2/12)
G.F. Kramer:S10957:PY-S:(703)305-5079:7509P:RAB1
Appendix A:  Toxicity Profile

Acute Toxicity Profile.

Table A1.  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 m/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
-

Toxicity Profile of Fludioxonil.

Guideline No./ Study Type
MRID No. (year)/ Classification /Doses
Results
870.3100a
90-Day oral toxicity in rats
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).
870.3100b
90-Day oral toxicity in mice
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).
870.3100c
90-Day oral toxicity in dogs
43080029 (1990)
Acceptable/guideline
0, 200, 2000, 15,000/10,000 ppm
M & F:  5, 50, 375/250 mg/kg/day
NOAEL = 5 mg/kg/day (both sexes).
LOAEL = 50 mg/kg/day based on an increased incidence of diarrhea (both sexes).
870.3200
21/28-Day dermal toxicity in rats
43080030 (1990)
Acceptable/guideline
M & F:  0, 40, 200, or 1000 mg/kg/day
NOAEL 1000 mg/kg/day for both sexes.

870.3250
90-Day dermal toxicity in rats
NA
NA
870.3465
90-Day inhalation toxicity in rats
NA
NA
870.3700a
Prenatal developmental toxicity in rats
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 toxicity in rabbits
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.
870.3800
Reproduction and fertility effects in rats
43080036 (1992)
Acceptable/guideline
0, 30, 300, or 3,000 ppm
F0F1 M:  2.19, 22.13, 221.61 mg/kg/day
F0F1 F:  2.45, 24.24, 249.67 mg/kg/day 
Parental/Systemic NOAEL = 22.13 mg/kg/day (M) and 24.24 mg/kg/day (F).
LOAEL = 221.61 mg/kg/day (M) and 249.67 mg/kg/day (F) based on increased clinical signs, decreased body weights, decreased weight gain, and decreased food consumption in both sexes
Reproductive/Offspring NOAEL = 22.13 mg/kg/day (M) and 24.24 mg/kg/day (F).
LOAEL = 221.61 mg/kg/day (M) and 249.67 mg/kg/day (F) based on reduced pup weights during lactation.
870.4100b
Chronic toxicity in dogs
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 = 3.3 mg/kg/day (F) and 33.1 mg/kg/day (M).
LOAEL = 35.5 mg/kg/day (F) and 297.8 mg/kg/day (M) based upon decreased weight gain (F) and decreased body weight,  reduction in hematological parameters (platelets), increase in cholesterol and alkaline phosphatase, and increased relative liver weight (M).
870.4300
Combined Chronic Toxicity/
Carcinogenicity in rats
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.  There was no evidence of carcinogenicity in male rats, but there was a statistically significant increase, both trend and pairwise, of combined hepatocellular tumors in female rats.  Classified as a Group D chemical by HED Cancer Peer Review Committee.
870.4200a
Carcinogenicity in Mice
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). Statistically significant trend for malignant lymphomas in females.
870.4200b
Carcinogenicity in mice
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.
870.5100
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 ug/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 ug/mL.  Negative up to limit of solubility and cytotoxicity.
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 ug/mL.  Positive for non-disjunction of chromosomes both in the presence and absence of activation.
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.
870.5550
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 ug/mL.
870.5450 
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 in rats
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 approximately 80% of the administered radioactivity excreted by this route in male and female rats at both the low and high dose.  The remaining radioactivity was excreted through urine.  In bile duct-cannulated rats, approximately 70% of an administered radioactive dose was excreted via this route, supporting the bile as the origin of the fecal radioactivity.  There were no apparent sex- or dose-related differences in the routes of excretion for fludioxonil.  Examination of urine for metabolites of fludioxonil showed at least 20 metabolites, each comprising a minor fraction of the administered dose (0.1-3.1%). 
870.7600
Dermal penetration
NA
NA
870.7800
Immunotoxicity
48478502 (2011) 
Classification pending formal review
0, 1000, 2000, 5000 ppm (equivalent to 0, 253.8, 454, 1230 mg/kg/day [F])
Preliminary NOAEL = 1230 mg/kg/day.
Preliminary LOAEL = not established.
No evidence of immunotoxicity.

Appendix B:  International Residue Limits 

               Fludioxonil (118203; Date of Request: 08/29/2011)
Summary of US and International Tolerances and Maximum Residue Limits 
Residue Definition:
US
Canada
Mexico[2]
Codex[3]
40 CFR 180.516:
Plant:  fludioxonil, 4-(2,2-difluoro-1,3-benzodioxol-4-yl)-1-H-pyrrole-3-carbonitrile)

Livestock:  fludioxonil, including its metabolites and degradates, in or on the commodities in the table below. Compliance with the tolerance levels specified below is to be determined by measuring only the sum of fludioxonil, 4-(2,2-difluoro-1,3-benzodioxol-4-yl)-1-H-pyrrole-3-carbonitrile), and its metabolites converted to 2,2-difluoro-l,3-benzodioxole-4-carboxylic acid, calculated as the stoichiometric equivalent of fludioxonil
4-(2,2-difluoro-1,3-benzodioxol-4-yl)-1H-pyrrole-3-carbonitrile

Plant : fludioxonil.
Livestock : fludioxonil and metabolites determined as 2,2-difluoro-1,3-
benzodioxole-4-carboxylic acid and calculated as fludioxonil.
The residue is fat-soluble.

Commodity[1]
Tolerance (ppm)/Maximum Residue Limit (mg/kg)

                                      US
                                    Canada
                                   Mexico[2]
                                   Codex[3]
Guava
                                      5.0

Feijoa
                                      5.0

Jaboticaba
                                      5.0

Wax jambu
                                      5.0

Starfruit
                                      5.0

Passionfruit
                                      5.0

Acerola
                                      5.0

Avocado
                                      5.0

Black sapote
                                      5.0

Mamey sapote
                                      5.0

Canistel
                                      5.0

Mango
                                      5.0

Papaya
                                      5.0

Sapodilla
                                      5.0

Star apple
                                      5.0

Lychee
                                      20

Longan
                                      20

Spanish lime
                                      20

Rambutan
                                      20

Pulasan
                                      20

Sugar apple
                                      20

Atemoya
                                      20

Custard apple
                                      20

Cherimoya
                                      20

Ilama
                                      20

Soursop
                                      20

Biriba
                                      20

Ginseng
                                      4.0

Onion, bulb subgroup 3-07A
                                     0.50
0.02 Chinese onions, garlic, great headed garlic, potato onions, shallots

0.2 dry bulb onions

0.5 onion, bulb
Onion, green subgroup 3-07B
                                      7.0
0.02 Chinese, chives, chive leaves, leeks, green onions, Welsh onion tops

Caneberry subgroup 13-07A
                                      5.0
4.2 blackberries, loganberries, raspberries 

5 blackberries, raspberries, red, black, dewberries (including boysenberry and loganberry) 
Bushberry subgroup 13-07B
                                      2.0
2.0 blueberries, currant, elderberries, gooseberries, huckleberries, salal berries, saskatoon berries (juneberries)

2 blueberries 
Fruit, small, vine climbing, subgroup 13-07F, except fuzzy kiwifruit
                                      2.0
1 gooseberries 
1 grape
20 kiwifruit

2 grapes
15 kiwifruit Po
Low growing berry subgroup 13-07G, except cranberry
                                      3.0
2 blueberries, lingonberries, strawberries

2 blueberries
3 strawberry
Vegetable, fruiting group 8-10, except tomato
                                     0.50
**0.01 bell peppers, eggplants, ground cherries, non-bell peppers, pepinos, pepper hybrids

0.3 eggplant
1 peppers, sweet (including pimento or pimiento) 
Tomato
                                      5.0
0.01 tomatoes, tomatillos

0.5 
Fruit, citrus, group 10-10
                                      10
10 calamondin, citrus citron, citrus hybrids, grapefruits, kumquats, lemons, limes, oranges, pummelos, tangerines, Satsuma mandarins

500 citrus oil

7 citrus fruits 

10 citrus fruits Po (proposed)
Fruit, pome, group 11-10
                                      5.0
5.0 apples, crabapples, loquats, mayhaws, pears, quinces

5 pome fruits Po
0.7 pear 
20 apple pomace, dry
Vegetable, leafy, except Brassica, subgroup 4A
                                      30
30 amaranth, arugula, corn salad, dandelion leaves, dock, edible leaved chrysanthemum, endives, fresh chervil leaves,  fresh parsley leaves, garden cress, garden purslane, garland chrysanthemum, head lettuce, leaf lettuce, orach leaves, radicchio, upland cress, winter purslane

**0.01 New Zealand spinach, spinach, vine spinach

10 lettuce, head
Vegetable, tuberous and corm, subgroup 1C
                                      6.0
**0.02 potato

0.02 potato
Pineapple
                                      20

Dragon fruit
                                      1.0

Leafy petioles crop subgroup 04B
                                      15
0.01 cardoon, celery, celtuce, Chinese celery, fresh Florence fennel leaves and stalks, rhubarb, Swiss chard 

Milk
                                     0.01
0.01

0.01 milks
Cattle, Goat, Horse, Sheep:  meat byproducts
                                     0.05
0.05 kidney and liver of cattle, goats, horses, sheeps

0.05 edible offal (mammalian) (*)
Cattle, Goat, Horse, Sheep:  fat
                                     0.05
0.05 fat of cattle, goats, horses, sheeps

Cattle, Goat, Horse, Sheep:  meat
                                     0.01
0.01 meat of cattle, goats, horses, sheeps

0.01 (*) meat from mammals other than marine mammals)
Completed:  M. Negussie; 09/01/2011
[1] Includes only commodities of interest for this action.  Tolerance values should be the HED recommendations and not those proposed by the applicant.
2 Mexico adopts US tolerances and/or Codex MRLs for its export purposes.

3 * = absent at the limit of quantitation; Po = postharvest treatment, such as treatment of stored grains.  PoP = processed postharvest treated commodity, such as processing of treated stored wheat.  (fat) = to be measured on the fat portion of the sample.  MRLs indicated as proposed have not been finalized by the CCPR and the CAC.

** = Levels to be harmonized as part of this joint review.