Fludioxonil Human - Health Risk Assessment DP# 389613

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### UNITED STA**TES ENVIRONMENTA L PROTECTION A** **GENCY**

**WA SHINGTON, 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 Frui t 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, 1 00 - 969, 100 - 1308 **Petition Nos.:** 1E7853, 1E7870 **Regulatory Action:** Section 3 Registration **Risk Assessment Type:** Single chemical/Aggregate **Case No.:** 7017 **T XR 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 fludioxoni l (4 - (2,2 - difluoro - 1,3 - benzodioxol - 4 - yl ) - 1 H - py rrole - 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 ,Fludioxonil Human - Health Risk Assessment DP# 389613

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### 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 b y George Kramer (RAB1); the hazard assessment by Anwar Dunbar (RAB1); the occupational/residential exposure assessment by L ata Venkateshwara (RAB1) ; and the drinking water assessm ent by

Cheryl Sutton of the Environmental Fate and Effects Division (EFED).Fludioxonil Human - Health Risk Assessment DP# 389613

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### TABLE OF CONTENTS **1.0 EXECUTIVE SUMMARY ................................**  **................................ ................................**  **..... 4**  **2.0 HED Recommendations ................................**  **................................ ................................**  **.......... 9**  **2.1 Dat a 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 C UMULATIVE 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** Fludioxonil Human - Health Risk Assessment DP# 389613

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### 1.0 EXECUTIVE SUMMARY Fludioxonil, 4 - (2,2 - difluoro - 1,3 - benzodioxol - 4 - yl ) - 1 H - py rrole - 3 - carbonitrile, is a phenyl py rrole 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 use s are also allowed on selected fruit and root crops. A total of 26 end - use products (EPs) containing fludioxonil are currently registered to Sy

ngenta 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 (WP s ), water- dispersible granules (WDG s ), flowable concentrates (FlC s ), 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, tropi cal 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, Sy ngenta 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 ; on ion, green, subgroup 3 - 07B; low - growing berry 13 - 07G crop subgroup; caneberry subgroup 13 - 07 A; 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. **Toxi cology/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. Itis 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 t oxicity . 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 developmentall y 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 quali tative 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 Human - Health Risk Assessment DP# 389613

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### Fludioxonil is classified as a Group D Chemic al; 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 n ot a strong indication of a positive effect. Further, statistical significance was onl y 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 poly ploidy in the in vitro Chinese hamster ovary

cell cy togenetic assay

and the suggestive evidence of micronuclei induction in rat hepatocy tes in vivo , additional mutagenicity testing was performed in three studies specificall y designed to address the concerns regarding aneuploidy . The results of these assay s 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, kidney s, 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

metab olites. 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 currentl y under review. HED’s H azard and S cience P olicy C ouncil (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 inhalatio n study

is submitted and reviewed, a 10X database uncertainty factor (UF DB 

### ) 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/resid ential exposure and risk assessment for fludioxonil are summarized in Tables 4.2.1 and 4.2.2, respectivel y. 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 10 X Safety Factor (SF) should be reduced to 1 X for oral exposures. Since the PODs are based on a common endpoint, oral and inhalation exposures can beFludioxonil Human - Health Risk Assessment DP# 389613

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### combined for aggregation of short - and intermediate - term risks. Since a POD wa s 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 Survey s of Food Intakes by Individual s (CSFII) from 1994 - 1996 and 1998. An unrefined acute dietary exposure and risk anal ysis was performed assuming tolerance - level residues, 100% crop - treated (CT), and DEEM TM 

### (ver. 7.81) default processing factors. The 1 - in 10 - ye ar acute drinking water es timate (i.e., relevant to acute exposure) of 0.0838 ppm, provided by EFED, was directl y incorporated into the acute assessment. This anal ys is was performed for females 13 to 49 ye ars old, the only subgroup of interest for acute exposure. The acute dietary (food plus water) risk for females 13 to 49 ye ars 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 lett uce, 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, gr apefruit, 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 w ater 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 ® 

### Fungicide ( EPA Reg. # 100 - 769 ) . Medallion ® 

### 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 expecte d from the use on residential turf.Fludioxonil Human - Health Risk Assessment DP# 389613

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### Since HED did not select short - or intermediate - term dermal PODs, onl y residential adult handler inhalation exposure and incidental oral post - application exposure for children were assessed. All residential handler inh alation 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 anal ys is included both, no further calculations are necessary . Since the acute dietary risk does not excee d the LOC , the acute aggregate risk does not exceed the LOC . Short- term Aggregate Exposure (Food + Water + Residential) Due t o the application of fludioxonil on residential turf, there is potential for short - term handler and post - application exposure. S ince 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 di etary

(food + water) exposure with inhalation exposure (resulting from residential handlers treating lawns). The short - term aggregate exposure s and risk s 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 currentl y 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 anal ys is 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 re commended for use in predicting handler exposure that are used in this assessment, known as “unit exposures,” are outlined in the “Occupational Pesticide HandlerFludioxonil Human - Health Risk Assessment DP# 389613

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### Unit Exposure Surrogate Reference Table” (http://www.epa.gov/opp00001/science/handlerexposure - 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/p esticides/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, onl y 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 accepta ble 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 contro ls. 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 >1 000 . **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 Environm ental Justice in Minority Populations and L ow - 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. Inline 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 pestici de risk assessments for all registered food uses. These data are analyzed and categorized b y subgroups based on age, season of the ye ar, 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 b ys tanders 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 pes ticide 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 revi ewed 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 significantl y 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 allFludioxonil Human - Health Risk Assessment DP# 389613

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### 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 fr uit 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 Analy tic al Reference Standards

 An anal ytical reference standard for fludioxonil is currentl y 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 - carbox yl ic 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 /Anal ytical 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.Fludioxonil Human - Health Risk Assessment DP# 389613

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### 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 de termined 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 (HPL C/UV) methods (Sy ngenta Methods AG - 597 and AG - 597B) are available for enforcing tolerances for residues of fludioxonil in/on plant commodities. In the current field trials an d 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 conjunctio n with the anal ys is 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 Analy tical 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 - carbox yl ic acid). **International Harmonization:** There are currently no established Codex, Canadian, or Mexican maximum residue limits (MRL s) for fludioxonil in/ on tropical fruits. The following U.S., Canadian, and Codex tolerances/MRL s 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 vegeta bles 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/MRL s for residues of fludioxonil in/on bulb onions, caneberries, grapes (small vine cli mbing fruit, subgroup 13 - 07F) , strawberries (low - growing berry subgroup 13 - 07G), tomatoes, and leafy vegetables cannot be harmonized as the Canadian, and Codex MRL s differ. For leafy vegetables except Brassica subgroup 4A, the U.S. and Canada are harmoniz ed at 30 ppm, but a Codex MRLis 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 vineFludioxonil Human - Health Risk Assessment DP# 389613

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### 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/MRL s cannot be harmonized for green onions, to matoes, 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 d efinition 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 fludi oxonil . 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 b y measuring only fludioxonil, 4 - (2,2 - difluoro - 1,3 - benzodioxol - 4 - yl ) - 1 -H - p yrrole 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 b y measuring only the sum of fludioxonil, 4 - (2,2 - difluoro - 1,3 - benzodioxol - 4 - yl ) - 1 - H - py rrole - 3 - carbonitrile), and its metabolites converted to 2,2 - difluoro - l,3 - benzodioxole - 4 - carbox yl ic acid, calculat ed 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 20Fludioxonil Human - Health Risk Assessment DP# 389613

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Page 12 of 45 **Table 2.2.1. Tolerance Summary for Fludioxonil.** Commodity Proposed Tolerance (ppm) Recommended

Tolerance (ppm) Correct Commodity

Definition/Comments 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. Lo w 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, l eafy, 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 **Rem ove**  **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 Onion, green 7.0 Caneberry subgroup 13A 5.0 Bushberry subgroup 13B 2.0Fludioxonil Human - Health Risk Assessment DP# 389613

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Page 13 of 45 **Table 2.2.1. Tolerance Summary for Fludioxonil.** Commodity Proposed Tolerance (ppm) Recommended

Tolerance (ppm) Correct Commodity

Definition/Comments Juneberry 2.0 agricultural commodities (RACs) or a higher tolerance is required based on the proposed use pattern. Lingonberry 2.0 Salal 2.0 Grape 1.0 Straw berry 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 procedure s . 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 MRL s. **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 ® 62.5WG Fungicide (25% WDG; EPA Reg. No. 100 - 953) Scholar® 230SC Fungicide (20.5% SC; EPA Reg. No. 100 - 1242) Scholar® 50 WP Fungicide (50% WP; EPA Reg. No. 100 - 969) Cannonball ® WP (50% WP; EPA Reg. No. 100 - 1360) Graduate A+ TM (20.6% SC; EPA Reg. No. 100 - 1308) Compound

Company experimental name CGA192155 O O F F N

H C NFludioxonil Human - Health Risk Assessment DP# 389613

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Page 14 of 45 **Table 3.1. Fludioxonil Nomenclature.** 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. Physicochem ical 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/cm3 ty pical 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:** In2008, 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, tom ato, 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 currentl y 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 phy sical/chem ical properties of fludioxonil; (3) the toxicological profile of fludioxonil; and (4) signs of respiratory

toxicity (dys pnea) in the acute inhalation toxicity study . Until this 90 - day inhalation study

is submitted and reviewed, a 10X UF DB 

### 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 neurotoxici ty , 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 sy stem ; 3) no data are available for other structurally

similar chemicals (i.e., phenyl - py rrole fungicides) that showed concern for neurotoxicity ; 4) rats, the species of choice for conducting the neurotoxici ty battery , are not theFludioxonil Human - Health Risk Assessment DP# 389613

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Page 15 of 45 

### 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 fludioxo nil is in Toxicity Category I II 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 as sociated 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 developmentall y toxic in rabbits. In a rat developmental toxicity

study , fludioxonil caused an increase in fetal inci dence 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 C D - 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 statisticall y significant increase in tumor incidence only when hepatocellular adenomas and carcinomas were combined (not for individual tumor ty pes). 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 w as only found when liver adenomas were combined with liver carcinomas. Finall y, 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 c arcinogen; 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 o f 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 poly ploidy in the in vitro Chinese hamster ovary cell cy togenetic assay

and the suggestive evidence of micronuclei induction in rat hepatocy tes in vivo , additional mutagenicity testing was performed in three studies specificall y d esigned 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 NOAELwas equal to or greater than 1000 mg/kg/day

(HDT) based on no significant advers e 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, kidney s, 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 cannul ated 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. Ex amination of urine forFludioxonil Human - Health Risk Assessment DP# 389613

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### 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 UF DB 

### 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 rabbi ts 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 co nvulsions 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 anal y ses 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 o ral 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 (UF DB 

### ) 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 Hum** **an -**  **Health Risk Assessments.** Exposure/ Scenario P O D Uncertainty/ FQPA SFs RfD, PAD,

LOC for Risk Assessment Study and Toxicological Effects Ac ute 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. T herefore, a dose and endpoint were not identified for this risk assessment.Fludioxonil Human - Health Risk Assessment DP# 389613

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Page 17 of 45 **Table 4.2.1. Summary of Toxicological Doses and Endpoints for Fludioxonil for Use in Dietary and Non**  ****

**Occupational Hum an**  **- Health Risk Assessments.**  Exposure/ Scenario P O D Uncertainty/ FQPA SFs RfD, PAD,

LOC for Risk Assessment Study and Toxicological Effects Ac ute Dietary (Females 13 - 49 years of age) NOAEL = 100

mg/kg/day UF A = 10X

UF H = 10X FQPA SF = 1X Ac ute 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 UF A = 10X

UF H = 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 UF A = 10X

UF H = 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 mo nths) NOAEL = 3.3

mg/kg/day UF A = 10X

UF H = 10X FQPA S F = 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 mo nths) 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 UF A = 10X

UF H = 10X FQPA SF = 1X UF DB = 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 mo nths) Ora l NOAEL

= 3.3 mg/kg/day (inhalation absorption = 100 %) a UF A = 10X

UF H = 10X FQPA SF = 1X UF DB = 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 d eparture (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. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). UF DB = to account for the absence of key date (i.e., lack of a critical study). FQPA SF = FQPA Safety Fa ctor. 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 .Fludioxonil Human - Health Risk Assessment DP# 389613

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Page 18 of 45 **Table 4.2.2. Summary of Toxicological Doses and Endpoints for Fludioxonil for Use in Occupational Hum an**  ****

**Health Risk Assessments.** Exposure/ Scenario P O D UFs LOC for Risk Assessment Study and Toxicological Effects Dermal Short - (1 - 30 days) and Intermediate Term (1 - 6 mo nths) 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 UF A = 10X

UF H = 10X UF DB = 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 mo nths) Oral NOAEL

= 3.3 mg/kg/day (inhalation absorption = 100 %) a UF A = 10X

UF H = 10X UF DB = 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 do g feeding study. Cancer (oral, dermal, inhalation) Classification: Group D chemical - not classifiable as to human carcinogenicity. Point of d eparture (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. UF A = extrapo lation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). UF DB = to account for the absence of key date (i.e., lack of a critical study). MOE = margin of exposure. LOC = l evel 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 S yngenta 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% cy prodinil. This formulation is registered in the U.S. under the trade name Switch ® 

### 62.5 WG (EPA Reg. No. 100 - 953). Other formulations include Cannonball ® 

### WP (EPA Reg. No. 100 - 1360), Scholar® 

### (EPA Reg. No. 100 - 969), Graduate A+ TM 

### (EPA Reg. No. 100 - 1308), and Scholar® 

### SC (EPA Reg. No. 100 - 1242). Information pertaining to the proposed end - use products is li sted in Table 5.1.1. A summary of the proposed use patterns is detailed in Table 5.1.2.Fludioxonil Human - Health Risk Assessment DP# 389613

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Page 19 of 45 **Table 5.1.1. Summary of Proposed End -**  **Use Products.** Trade Name Reg.

No. ai (% fludioxonil in formulation) Form

ulation Ty pe Target Crops Target Pests Label Date Switch ® 62.5WG 100 -

953 25 WG A variety of fruit, nut, vegetable, and herb crops Soil, crow n, and foliar diseases. Draft labels

submitted 3/28/11 Cannonball ® WP 100 -

1360 50 WP Onions, berries, ginseng Scholar® 100 -

969 50 WP Postharvest fruit, potatoes, tomatoes Postharvest fungal diseases Scholar® 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, Ty pe, and Equip. Form

ulation [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 em ulsion. 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 em ulsion. 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 tubersFludioxonil Human - Health Risk Assessment DP# 389613

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Page 20 of 45 **Table 5.1.2. Summary of Directions for Use of Fludioxonil.**  Applic. Timing, Ty pe, and Equip. Form

ulation [EPA Reg. No.] App. Rate Max. No. App. per Season Max. Seasonal

App. Rate PHI

(days) Use Directions and

Limitations **Tom ato**  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

em ulsion. 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

em ulsion. 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

em ulsion. 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 em ulsion. 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

em ulsion. 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 ® 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 su pport the use directions for the proposed uses.Fludioxonil Human - Health Risk Assessment DP# 389613

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Page 21 of 45 

### 5.2 Dietary Exposure/Risk Pathway The residue chemistry

assessment was completed by HED (Memo, G. Kramer, 05 /21 /20 12 ; 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 recentl y 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 climb ing (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, Sy

ngenta has submitted a petition (1E787 0) 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 jam bu 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 ppmFludioxonil Human - Health Risk Assessment DP# 389613

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Page 22 of 45 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 Lo w 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 adequatel y 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 Method s Adequate HPLC/UV methods (Sy ngenta 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 adequatel y validated in conjunction with the analy sis 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 Analy

tical 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 - carbox yl ic 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 unlikel y 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 reasonabl y balanced livestock diets (Memo, 6/30/08). Based upon this diet and the results of a newl y submitted ruminant feeding study, tolerances for total fludioxonil residues should be establishedFludioxonil Human - Health Risk Assessment DP# 389613

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### at 0.05 ppm for residues in fat and meat b yp roducts 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 - 07 A; bushberry subgroup 13 - 07 B; 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 representativ e 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 anal yz ed 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 pro cessed 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 currentl y required for rotational crops. Tolerance Summary There are currently

no established Codex, Canadian, or Mexican MRL s 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/MRL s 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/MRL s for residues of fludioxonil in/on bulb onions, caneberries, grapes (small vine climbing f ruit, subgroup 13 - 07F) , strawberries (low - growing berry subgroup 13 - 07G), tomato es, and leafy vegetable s cannot be harmonized as the Canadian, and Codex MRL s 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 f ruit 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. 2 0 to 0. 5 0 ppm , small vine climbing f

ruit subgroup 13 - 07F from 1 .0 to 2 .0 ppm and low - growing berry subgroup 13 - 07G from 2.0 to 3.0 ppm.Fludioxonil Human - Health Risk Assessment DP# 389613

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### The tolerances/MRL s cannot be harmonized for green onions , tomato es , leafy vegetables except Brassica subgroup 4A , and leafy petioles as the U.S. residue data/use pattern s 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 har monized. **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 Analy sis Modeling Sy stem (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. Th e PRZM model simulates pesticide movement and transformation on and across the agricultural field resulting from crop applications. Percentcropped areas (PCA) that account for the maximum area within a watershed that may be planted with the modeled crop are applied to concentrations predicted by PRZM/EXAMS. The models and their descriptions are available at the EPA internet site: http://www.epa.gov/oppefed1/models/water/ . Screening Concentration in Ground Water (SCI - GROW v2.3, 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 propo sed uses (for onion subgroups 3 - 07A and 3 - 07B) is 0.25 lbs ai/A/application, applied four times per ye ar 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 previousl y 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 Sy ngenta’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 fro m 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 valu es in the Tier I DWA are based on the use of fludioxonil on field- grown ornamentals at one application of 2 lb ai/A/y r. The resulting acute and chronic EDWCs in surface water were 83.8 ppb (1 - in - 10 - ye ar acute estimate) and 38.5 ppb (1 - in - 10 - ye ar chronic e stimate), respectivel y. The EDWC for groundwater (for both acute and chronic anal ys is) 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 an d 0.0385 ppm, respectivel y, for all water sources (direct and indirect).Fludioxonil Human - Health Risk Assessment DP# 389613

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Page 25 of 45 **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**  **(m odel)**  **Use 1**  **- in**  **- 10**  **- year acute**  **( μg/L**  **) 1**  **- in**  **- 10**  **- year chronic**  **( μg/L**  **)** Surface water (PRZM/EXAMS) Container - grown ornamental 83.8 38.5 Groundwater (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 day s. 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 publicl y 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 anal ys is 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 ye ar old), ch ildren 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 dail y 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 expos ure 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 anal ysis. 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 anal ysis was performed assuming tolerance - level residues, 100% CT, and DEEM TM 

### (ver. 7.81 ) default processing factors. The 1 - in - 10 - ye ar acute drinking water estimate (i.e., relevant to acute exposure) of 0.0838 ppm, previously provided b yFludioxonil Human - Health Risk Assessment DP# 389613

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### EFED, was directl y incorporated into the acute assessment. This anal ys is 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 p lus water) risk utilizes 16% of a PAD for females 13 to 49 ye ars 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 subgro ups 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 fac tors [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 proce ssing study

data for the chronic anal ys is. The 1 - in - 10 - ye ar 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 ye ars old, is 68 % of the cPAD. The results of the acute and chronic dietary exposure anal ys es are reported in the Summary Table (Table 5.2.3.2, below). **Table 5.2.3.2. Summ ary of Dietary Exposure (Food Plus Water) and Risk Assessment for Fludioxonil.**  **Population Subgroup Acute Dietary**  **(95th Percentile) Chronic Dietary**  **Dietary Exposure**  **(m g/kg/day)**  **% aPAD*** **Dietary Exposure (m**  **g/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 **Fem ales 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.Fludioxonil Human - Health Risk Assessment DP# 389613

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### 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 an d 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 transl ated 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 fo r 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 ye ar 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 p rocessing study indicated that fludioxonil residues do not appreciabl y 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). DEEMTM 

### (ver. 7.81) default processing factors were used for all other processed commodi ties for which they are available. **Table 5.2.4. AR Values Used for the Chronic Assessment. Comm**  **odity 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 w

rapper 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 0.40Fludioxonil Human - Health Risk Assessment DP# 389613

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Page 28 of 45 **Table 5.2.4. AR Values Used for the Chronic Assessment. Comm**  **odity AR (ppm)**  **2** 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 previousl y 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., D3 62493; 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 expe cted 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 UF DB 

### for inhalation risks (Memo, L Venkateshwara , D389982). The currentl y registered label for turf is Medallion ® 

### Fungicide EPA Reg. # 100 - 769. Medallion ® 

### 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 resi dential 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 han dler 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.Fludioxonil Human - Health Risk Assessment DP# 389613

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###  Homeowner handlers are expected to complete all task s 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/appl yi ng WP in water- soluble packaging with manually pressurized handwand , (2) Mixing/loading/appl ying WP in water- soluble packaging with backpack sprayer , (3) Mixing/loading/appl yi ng WP in water- soluble packaging with hose end sprayer, and (4) Mixing/loading/appl yi ng WP in wat er- 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 likel y because of the intermittent nature of applications by homeowners. Short - term inhalation risk estimates to residential handlers do not excee d HED’s LOC for all scenarios. Although an inhalation study is required for fludioxonil, the o ral PODs used for assessing inhalation risk are based on the most sensitive endpoints established in the most sensitive species. Furthermore, an additional 10X UF DB 

### 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 Estim ates 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 (m**  **g/k g/day)**  **Baseline MOE e**  **Inhalation c**  **Inhalation c**  **Inhalation c**  **Mixer/Loader/Applicator** Mixing/Loading/Applying WP in Water- soluble Packaging with Manuallypressurized 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 S prayer 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 ® Fungicide, EPA Reg.# 100 - 769). b. Based on HED’s SOPs for Residential Pesticide Exposure Assessment; Lawns/Turf (February , 2012). c. Baseline I

nhalation: 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 = 100 0 . 

### 6.2 Residential Post**- application Exposure and Risk**  Fludioxonil can be used in many areas that can be frequented by the general population includingFludioxonil Human - Health Risk Assessment DP# 389613

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### residential areas (e.g., h ome 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 nearb y 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 policie s 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 ® 

### label specifies that the product may

be applied at 14 - day

application intervals, with an annual maximum rate of 2 lbs ai/A/y r, which equates to about three applications at the maximum per application rate. F ludioxonil has exhibited half - lives ranging from 95 to 440 day s 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 .  Phy sical activities on turf: children 1 < 2 ye ars old (incidental oral). The lifestage (i.e., children 1 < 2 years old) selected for this post - application scenario is based on an anal ys is 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 in cidental 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 -**  **applicatio n Exposure and Risk Estim**  **ates 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 associatedFludioxonil Human - Health Risk Assessment DP# 389613

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### with the exposed population and when the toxicological effects are similar. For fludioxonil, there is no dermal POD ; therefore, the onl y 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 overl y conservative because of the conservative nature of each individual assessment. Therefore, onl y the hand - to - mouth scenario was ch osen 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 -**  **Ter m**  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 alway s 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 D rift 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/factshe ets/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 appropriatel y apply the data and the AgDRIFT ® 

### computer model to its risk assessments for pesticides applied b y 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 residenti al 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 w orse case inhalation (drift) exposure and may be considered protective of most outdoor agricultural and commercial post - application inhalation exposure scenarios .Fludioxonil Human - Health Risk Assessment DP# 389613

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### 6.5 Residential Bystander Post**- application Inhalation Exposure**  Based on the Agency's current practices, a quantitative residential b ys tander 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 s ource of post - application inhalation exposure to individuals nearb y 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 co nsiders both the route and duration of exposure. **7.1 Acute Aggregate Risk** Based on the exposure pathway s, the acute aggregate risk assessment should include exposure from food and water onl y. Since the acute dietary anal ys is 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 inhalatio n 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 handl ers (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 , bec ause the short -Fludioxonil Human - Health Risk Assessment DP# 389613

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### term oral and inhalation risk s 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 b y 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 + residenti al 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 AR I (Aggregate Risk I

ndex) = MOE Calculated / MOE Acceptable . 2 AR I Food + 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 AR IDermal =MOE / 100 and, ARIInhalation = MOE / 1000 . 4 AR ITotal Aggregate = 1/[(1/ARI Food + water) + (1/ARIResidential Handler Deraml ) + (1/ARIResidential Handler Inhalation ) + (1/ARI Post 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 interme diate 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 - a pplication 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 currentl y 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 treatedFludioxonil Human - Health Risk Assessment DP# 389613

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### lawns. Table 7.3 summarizes the intermediate - term aggregate exposure estimates to fludioxonil residues. **Table 7.3. Interm ediate**  **- 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 1 05

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 onl y. As the chronic dietary

analy sis 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 mechanis m 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 b y other substances. For the purposes of this tolerance action, there fore, 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 ch emicals, see the policy statements released b y 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/.Fludioxonil Human - Health Risk Assessment DP# 389613

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### 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/L oader: 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 spray s via aerial application; 10. application of spray s via groundboom applications; 11. application of spray s via airblast application; Flagger: 12. flagging for aerial application; Mixer/L oader/Applicator: 13. mixing/loading/appl ying WP with backpack sprayer; 14. mixing/loading/appl ying DF/WDG with a backpack sprayer; 15. mixing/loading/appl ying WP with mechanically- pressurized handgun sprayer; 16. mixing/loading/appl ying DF/WDG with mechanically- pressurized handgun sprayer; 17. mixing/loading/appl ying WP with manuall y- pressurized handgun; 18. mixing/loading/appl ying 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 asses sment, known as “unit exposures,” are outlined in the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table”Fludioxonil Human - Health Risk Assessment DP# 389613

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### (http://www.epa.gov/opp00001/science/handler- exposure - table.pdf), which, along with additional information on HED policy on use o f 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 “base line” 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 fo r 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 exposure s (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 accep table 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 PF 5 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**  **(m g/lb ai)**  **e Inhalation** 

**Doses (m** **g/k g/day)**  **c Short**  **- term** 

**Inhalation MOEs**  **d Intermediate** 

**- term**  **Inhalation MOEs**  **d Mi** **xer/Loader** Mixing/Loading WPs for Aerial Applications 0.25 Cannonball® (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® (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 1400Fludioxonil Human - Health Risk Assessment DP# 389613

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Page 37 of 45 **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**  **(m g/lb ai)**  **e Inhalation** 

**Doses (m** **g/k g/day)**  **c Short**  **- term** 

**Inhalation MOEs**  **d Intermediate** 

**- term**  **Inhalation MOEs**  **d** Mixing/Loading WPs for Chemigation 0.25 Cannonball® (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® (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® (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® (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® (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® (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® (100 - 1360) and Switch® (100 - 953) 80 0.00034 0.00019 53000 18000 Applying Sprays via Aerial Equipment 0.25 Cannonball® (100 - 1360) on strawberries (foliar applied) 350 Engineering Control: 0.000068 0.000075 130000 44000 Applying Sprays via Airblast Equipment 0.22 Switch® (100 - 953) on grapes, tropical fruit 40 0.00471 0.00052 19000 66000

**Flagger** Flagging for Aerial Sprays Applications 0.25 Cannonball® (100 - 1360) on strawberries (foliar applied 350 0.00035 0.00039 26000 8600 **Mi xer/Loader/Applicator**  Applying WP with backpack

sprayer 0.000625 lb

ai/gal Cannonball® (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® (100 - 1360)

on bushberries (greenhouse use) 1000 gallons Baseline: 0.120 0.00094 11000 3500 Applying WP with manuallypressurized handwand 0.000625 lb ai/gal Cannonball® (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® (100 - 953 on tomato, peppers, eggplant and other fruiting vegetables (greenhouse use) 5 Baseline: 0.140 0.0019 5200 1700Fludioxonil Human - Health Risk Assessment DP# 389613

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Page 38 of 45 **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**  **(m g/lb ai)**  **e Inhalation** 

**Doses (m** **g/k g/day)**  **c Short**  **- term** 

**Inhalation MOEs**  **d Intermediate** 

**- term**  **Inhalation MOEs**  **d** Applying DF/WDG with mechanically- pressurized handgun sprayer 0.22 Switch® (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® (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 = 100 0 . 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 ® WP (EPA Reg. # 100 - 1360) is a 50 % WP and Switch® 62.5 WG (E PA Reg. # 100 - 953)

is a combination product which contains 37.5 %, by weight, cyprodinil ai and 25.0 %, by weight, fludioxonil ai. I t is formul ated 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 Day2 (1 gal/lbs of crop) Amount Processed

per Day3 (lbs boxes/hr) Inhalation

UE 4 (μg/lb ai) ST & IT Inhalation

Daily Dose 5 (mg ai/kg/day) ST MOE 6 IT MOE 7 **Open Mixing/Loading WP: Scholar® 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 To mato 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 To mato 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 Expo SAC 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).Fludioxonil Human - Health Risk Assessment DP# 389613

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### 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 in dividuals nearb y 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/scip oly /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 risk s 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, subsequentl y, 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 lo w 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 expo sures 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:RAB1Fludioxonil Human - Health Risk Assessment DP# 389613

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### 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 Ac ute Oral 43124105 LD50 > 5000 mg/kg IV 870.1200 Ac ute Dermal 43124106 LD50 > 2000 mg/kg III 870.1300 Ac ute 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.Fludioxonil Human - Health Risk Assessment DP# 389613

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Page 41 of 45 **Guideline No./ Study Type**  **MRID No. (year)/ Classification /Doses**  **Results** 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 F 0 F 1 M: 2.19, 22.13, 221.61 mg/kg/day F 0 F 1 F: 2.45, 24.24, 249.67 mg/kg/day Parental/Systemic NOAEL = 22.13 mg/kg/day (M) and 24.24 mg/kg/day (F). LOAEL = 221.61 mg/kg/day (M) and 249.67 mg/kg/day (F) based on increased clinical signs, decreased body weights, decreased weight gain, and decreased food consumption in both sexes Reproductive/Offspring NOAEL = 22.13 mg/kg/day (M) and 24.24 mg/kg/day (F). LOAEL = 221.61 mg/kg/day (M) and 249.67 mg/kg/day (F ) based on reduced pup weights during lactation. 870.4100b Chronic toxicity 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 Com bined 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/d ay (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 carcinog enicity in male rats, but there wa s 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, o r 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 μg/plate in absence and presence of metabolic activation. 870.5300 Gene mutation in mammalian cells in culture 43152501 (1989) Acceptable/guideline Chinese hamster V79 ovary cells were tested from 0.50 to 60 μg/mL. Negative up to limit of solubility and cytotoxicity. 870.5375 in vitro Chromosome aberration 43080040 (1989) Acceptable/guideline Chinese hamster ovary cells were tested with and without metabolic activation from 1.37 to 700 μg/mL. Positive for non disjunction of chromosomes both in the presence and absence of activation.Fludioxonil Human - Health Risk Assessment DP# 389613

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Page 42 of 45 **Guideline No./ Study Type**  **MRID No. (year)/ Classification /Doses**  **Results** 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 hep atocyte 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 dos e 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 μg/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 remaini ng 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 dos e - 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.Fludioxonil Human - Health Risk Assessment DP# 389613

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### 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 . Com pliance 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 f

ludioxonil 4 - (2,2 - difluoro - 1,3 -benzodioxol 4 - yl) - 1 H -py

rrole - 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 20Fludioxonil Human - Health Risk Assessment DP# 389613

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Page 44 of 45 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, dew berries (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 Lo w growing berry subgroup 13 - 07G, except cranberry 3.0 2 blueberries, lingonberries, straw berries 2 blueberries 3 straw berry 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, dryFludioxonil Human - Health Risk Assessment DP# 389613

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Page 45 of 45 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 revie w.