**EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR**

**PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER (**  **5 /**  **5 /20**  **11 )**  **EPA Registration Division contact: [Shaja Joyner (PM**  **- 20) 703**  **- 308**  **- 3194]** 

**INSTRUCTIONS: Please utilize this outline in preparing the pesticide petition. In**  **cases where the outline element does not apply, please insert “NA -**  **Remove” and maintain the outline. Please do not change the margins, font, or format in your**  **pestici de petition. Simply replace the instructions that appear in**  **green and brackets,**  **i.e., “ [**  **insert company name ]**  **,” with the information specific to your action. TEMPLATE:**  **[Syngenta Crop Protection] [Insert petition number]**  EPA has received a pesti cide petition **( [insert petition number]**  **)** from **[Syngenta Crop Protection]**  **, [P. O. Box 18300, Greensboro, NC 27409]**  proposing, pursuant to section 408(d) of the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR part 180 .516

. **(Options (pick one)** 1. by establish ing a tolerance for residues of **[fludioxonil: [4 -**  **(2, 2 -**  **difluoro -**  **1,3 -**  **benzodioxol -**  **4 -**  **yl) -**  **1H -**  **pyrrole -**  **3 -**  **carbonitrile]** in or on the raw agricultural commodity **[]** at **[] Leafy petioles subgroup 04B**  **, at 1**  **4 parts p**  **er million** EPA has determined that the petition contains data or information regarding the elements set forth in section 408 (d)(2) of FDDCA; however, EPA has not full y evaluated the sufficiency

of the submitted data at this time or whether the data supp orts granting of the petition. Additional data may be needed before EPA rules on the petition. A. Residue Chemistry 1. Plant metabolism **. The metabolism of fludioxonil is adequately understood for**  **the purpose of the proposed tolerances.**2

2. Analy tical method. **Syngenta has developed and validated analytical methodology for enforcement purposes. This method (Syngenta Crop Protection Method AG**  **** **597B) has passed an Agency petition method validation for several commodities, and is currently the enforcem**  **ent method for fludioxonil. This method has also been forwarded to the Food and Drug Administration for inclusion into PAM II. An**  **extensive database of met hod valida**  **tion data using this method on various crop commodities is available.**  3. Magnitude o

f residues. **Complete residue data to support the requested tolerances have been submitted. The requested tolerances are adequately supported.**  **In support of the requested tolerance, eight crop**  **- field trials were conducted with**  **various commercially availa ble celery cultivars, and the soil types and**  **meteorological conditions at the eight trial sites adequately represented the diversity of conditions under which celery may be commercially grown. These trial sites**  **satisfied the requirements of OPPTS 860.1500 for number and regional distribution.**  **The study design consisted of 2 plots at each trial site: a non -**  **treated control (UTC) plot and a treated (TRT) plot. The TRT plot received four broadcast foliar**  **applications of 14 oz product/acre/application (or 56 oz product/acre/ season), which**  **equates to 0.328 lb c**  **yprodinil/acre + 0.219 lb f**  **ludioxonil/acre (or a seasonal rate of 1.3 lb Cyprodinil/acre + 0.9 lb Fludioxonil/acre). The treatments were applied with**  **a tank -**  **mix volume of 15 -**  **40 gallons/acre (GPA) at t he minimum 7**  **- day retreatment**  **interval (RTI), and the raw agricultural commodity (RAC) was harvested on the day of the last application to support a 0**  **- day pre**  **- harvest interval (PHI). This use**  **pattern would be the ‘worst -**  **case’ application as per the propose d**  **- use label.**  B. Toxicological Profile **An assessment of toxic effects caused by fludioxonil is discussed in Unit III. A. and Unit III. B. of the Federal Register published by EPA dated August 2, 2002 (67 FR**  **50354) (FRL -**  **7188 -**  **7) and is repeate d in part below.**  **Carcinogenic and Other Toxicity** Study Ty pe Results Carcino

- genicit y rats NOAEL = 590 mg/kg/day (M) and 715 mg/kg/day (F). LOAEL: 851 mg/kg/day

(M) and 1,008 mg/kg/ day (F) based on reduced su rvival (F), decreased bod y weights (M), bile duct hy perplasia (M) and severe nephropath y(both sexes). No evidence of carcinogenicity. In vivo Rat hepatocy

te micronucleus assay Male rats were orally dosed at 50, 250, and 1,250 mg/kg and hep atocy tes were harvested. There was no evidence of a significant increase in micronucleated hepatocytes in treated groups in comparison to controls. Unscheduled DNA sy nthesis assay There was no evidence that unscheduled DNA s yn thesis, as determined by nu clear silver grain counts, was induced in hepatocy te cultures obtained from male rats dosed at 2,500 or 5,000 mg/kg. **Summary of Toxicological Dose and Endpoints for Fludioxonil for Use in Human**3

**Risk Assessment** Exposure Scenario Dose Used in Risk

Assessment, UF

FQPA SF and Level of Concern for Risk Assessment Study and Toxicological Effects Acute Dietary females 13

- 50 y ears of age

NOAEL = 100 mg/kg/day UF = 10 0 Acute RfD = 1.0 mg/kg/day

.

FQPA SF = 1X aPAD = acute RfD ÷ FQPA SF = 1.0 mg/kg/day

.

Developmental Toxicity

Study

– rat Developmental LOAEL =1,000 mg/kg/day

based on increased incidence of fetuses and litters dilated renal pelvis and with dilated ureter Chronic Dietary

all populations

NOAEL= 3.3 mg/kg/day

UF = 100 Chronic RfD = 0.03 mg/ kg/day

. FQPA SF = 1X

cPAD = chronic RfD FQPA SF = 0.03 mg/kg/day

.

1 y ear chronic tox icity

study

– dog LOAEL = 35.5 mg/kg/day based on decreased weight gain in female dogs In cidental Oral, Short

- Term

NOAEL = 10 mg/kg/day LOC for MOE =

100 Rabbit developmental study

LOAEL = 100 mg/kg/day based on decreased weight gain during gestation In cidental Oral, Intermediate

- Term

NOAEL = 3.3 mg/kg/day LOC for MOE =

100 1 y ear chronic toxicity study

- dog LOAEL = 35.5 mg/kg/day based on decreased weight gain in female dogs Short

- and Intermediate Term Dermal (1

- 30 day s and 1

- 6 months) (Residential)

None No sy stemic

toxicity was seen at the limit dose (1,000 mg/kg/day ) in the 28

- day dermal toxicity study in rats Endpoint was not selected

Long

- Term (several months

- lifetime) Dermal (Residential)

Oral study NOAEL = 3.3 mg/kg/day

(dermal penetration = 40%). LOC for MOE =

100 (Occupational) LOC for MOE = 100 (Residential).

1 y ear chronic toxicity

study

- dog LOAEL = 35.5 mg/kg/day base d on decreased weight gain in female dogs Short

- Term (1

- 30 Day s) Inhalation (Residential)

Oral NOAE L = 10 mg/kg/ day (inhalation absorption rate = 100%) LOC for MOE =

100 (Occupational) LOC for MOE = 100(Residential).

Rabbit developmental study LOAEL = 100 mg/kg/day based on decreased weight gain during gestation Intermediate

- term (1 month

- 6 months) Oral NOAE L = 3.3

mg/kg/ day LOC for MOE =

100 1 y ear chronic toxicity study

- dog4

Inhalation (Resi dential) (inhalation absorption

rate = 100%)

(Occupational) LOC for MOE = 100(Residential).

LOAEL = 35.5 mg/kg/day based on decreased weight gain in female dogs Long

- Term (several months

- lifetime) Inhalation (Residential) Oral NOAE L = 3.3

mg/kg/day (inhalation absorption rate = 100%) LOC for MOE =

100( Occupational) LOC for MOE = 100(Residential).

1 y ear chronic toxicity

study

– dog LOAEL = 35.5 mg/kg/day based on decreased weight gain in female dogs 6. Animal metabolism. **The metabolism of fludioxonil in rats is adequately**  **understood.** 7. Metabolite toxicology

. **The residue of concern for tolerance setting purposes is the parent compound. Consequently, there is no additional concern for toxicity of**  **metabolites.** 8. Endocrine disrupti on . **Fludioxonil does not belong to a class of chemicals known for having adverse effects on the endocrine system. No estrogenic effects have been**  **observed in the various short -**  **an d long**  **- ter**  **m studies conducted with various ma**  **mmalian species.** C. Aggregate Exposure 1. Dietary exposure. **Tier III acute and chronic dietary exposure evaluations were performed for fludioxonil using the Dietary Exposure Evaluation Model (DEEM**  **** **FCID TM**  **, version 2.16) from Exponent. These**  **exposure assessments included all current uses as well as a proposed foliar use on celery plus pending foliar uses on**  **peppers (bell and non -**  **bell) and spinach, a irrigation use on ginseng, and post**   ** harvest uses on pineapples, potatoes, tropical fruits and t** **omatoes. These**  **assessments utilized residue data from field trials where fludioxonil was applied at the maximum intended use rate and samples were harvested at the minimum pre**  **** **harvest interval (PHI) to obtain maximum residues. Empirically derived process ing**  **factors for apple juice (0.09X), apple pomace (6.77X), tomato puree (0.34X), tomato paste (1.1X), and citrus oil (50X) were used in these assessments. The apple juice**  **processing factor was used as a surrogate for pear juice. All other processing fact**  **ors used the DEEM TM**  **defaults. All consumption data for these assessments was taken from the USDA’s Continuing Survey of Food Intake by individuals (CSFII)**  **with the 1994 -**  **96 consumption database and the Supplemental CSFII children’s survey (1998) consumptio**  **n database. Percent of crop treated values were estimated based upon economic, pest and competitive pressures. Secondary residues in animal**  **commodities were estimated based on “maximum reasonably balanced diets” and transfer information from metabolism s**  **tudies.** i. Food. Acute exposure

. **The acute dietary (food only) risk assessment for females 13 to 49 years old (the only population subgroup for which an acute toxicological**  **endpoint has been established) was performed using an acute reference dose (aR fD)**  **of 1.0 mg/kg -**  **bw/day, based upon a rat teratology study with a no observed adverse**5

**effect level (NOAEL) of 100 mg/kg/day and an uncertainty factor (UF) of 100X for intra**  **- and inter**  **- species variations; no additional FQPA safety factor was applied.**  **For t he purpose of the aggregate risk assessment, the exposure value was expressed**  **in terms of margin of exposure (MOE), which was calculated by dividing the no observed adverse effect level (NOAEL) by the exposure for each population**  **subgroup. In addition, ex posure was expressed as a percent of the acute reference**  **dose (% aRfD). Acute exposure to the females 13 -**  **49 years subpopulation resulted in a MOE of 1,182 or 8.5% of the aRfD (Benchmark MOE = 100; aRfD=**  **1.0 mg/kg**  **** **bw/day). Since the Benchmark MOE for this assessment was 100 and since the EPA**  **generally has no concern for exposures below 100% of the aRfD, Syngenta believes that there is a reasonable certainty that no harm will result from dietary (food)**  **exposure to residues arising from the current, pending and proposed uses for**  **fludioxonil.** Chronic exposure. **The chronic reference dose (RfD) for fludioxonil is 0.033 mg/kg**   ** bw/day, based upon a one** **- year study in dogs with a NOAEL of 3.3 mg/kg**  **- bw/day**  **and an uncertainly factor of 100X; no additional FQPA safety factor was applied.**  **For the purpose of the aggregate risk assessment, the exposure values were expressed in terms of margin of exposure (MOE), which was calculated by dividing**  **the no observed adverse effect level (NOAEL) by the exposure for each populati on**  **subgroup. In addition, exposure was expressed as a percent of the chronic reference dose (%cRfD). Chronic exposure to the U.S. population resulted in a MOE of 708**  **or 14.1% of the cRfD (Benchmark MOE = 100; cRfD = 0.033 mg/kg -**  **bw/day). Chronic exposure**  **to the most exposed subpopulation (children 1 -**  **2 years old) resulted in a MOE of 243 or 41.1% of the cRfD (Benchmark MOE = 100; cRfD =**  **0.033 mg/kg -**  **bw/day). Since the Benchmark MOE for this assessment was 100 and since the EPA generally has no concern for**  **exposures below 100% of the cRfD, Syngenta believes that there is a reasonable certainty that no harm will result from**  **dietary (food) exposure to residues arising from the current, pending and proposed uses for fludioxonil.**  ii. Drinking water. **The Estim ated Drinking Water Concentrations (EDWCs) of**  **fludioxonil were determined using Tier l SCI -**  **GROW, which estimates pesticide concentrations in ground water and Tier II PRZM/EXAMS which estimates**  **pesticide concentrations in surface water. This drinking water assessment was**  **conducted to assess all currently registered uses, the**  **pending uses on spinach, peppers, ginseng, potatoes, pineapples, tropical fruits, and tomatoes as well as the**  **proposed use on celery. For ground water, the currently registered use on professional turf provided the highest EDWC of 2.02E**  **- 01 ppb (acute and chronic).**  **For surface water, the currently registered field grown and landscape ornamental provided the highest acute EDWC of 44.102 ppb and the currently registered use on**  **turf provid ed the highest chronic EDWC of 32.79 ppb. No Percent Cropped Area**  **(PCA) adjustments were made for the surface water EDWCs. Since the surface water EDWCs exceed the ground water EDWC, the surface water values were used**  **for risk assessment purposes and wil l be considered protective for any ground water**  **exposure concerns.**6

Acute Exposure from Drinking W ater : **The acute EDWC of 44.102 ppb (0.044102 ppm) was incorporated with food residues as “water, direct and indirect, all**  **sources” directly into the DEEM -**  **FCI DTM software to obtain acute dietary (food and**  **water) exposures. Drinking water exposures at the 99.9th percentile to fludioxonil for females 13**  **- 49 years old (the only population subgroup for which an acute**  **toxicological endpoint has been established) resu lted in a MOE of 97,847 (0.1% of**  **the aRfD of 1.0 mg/kg -**  **bw/day). Since the Benchmark MOE for this assessment was 100, and since the EPA generally has no concern for exposures below 100% of the**  **aRfD, Syngenta believes that there is a reasonable certainty th at no harm will result**  **from acute drinking water exposure to residues arising from all current, pending and proposed fludioxonil uses.**  Chronic Exposure from Drinking W ater : **The chronic EDWC of 32.79 ppb (0.03279 ppm) was incorporated with food residues a**  **s “water, direct and indirect, all sources” directly into the DEEM**  **- FCIDTM software to obtain chronic dietary (food**  **and water) exposures. Chronic drinking water exposure to the U.S. population resulted in a MOE of 4,775 (2.1% of the cRfD of 0.033 mg/kg**  **- bw/d**  **ay). The most sensitive sub**  **- population was all infants (<1 year old), with a MOE of 1,456 (6.9% of**  **the cRfD of 0.033 mg/kg -**  **bw/day). Since the Benchmark MOE for this assessment was 100 and since the EPA generally has no concern for exposures below 100% of**  **the cRfD, Syngenta believes that there is a reasonable certainty that no harm will result from chronic drinking water exposure to residues arising from all current,**  **pending and proposed fludioxonil uses.** Cancer

. **A chronic cancer exposure analysis was n ot performed, since there is no**  **evidence of human carcinogenic potential for fludioxonil.** 2. Non

- dietary exposure

. **There is a potential for residential post -**  **application exposure to adults and children entering residential areas treated with fludioxo**  **nil. Fludioxonil is currently registered for professionally applied uses on turf grass and**  **ornamentals in residential landscapes. The Syngenta short -**  **term and intermediate**   ** term residential risk assessments were based on the maximum label rate for turf** **gra ss of 0.68 lb a.i./A (0.50 oz product/1000ft**  **2 ) with a maximum of three**  **applications allowed per year (0.68 lb a.i./A x 3 apps = 2 lb a.i./A/year). In these residential risk assessments, a short**  **- term NOAEL of 10 mg/kg**  **- bw/day from a**  **rabbit developmental stu dy was selected as well as an intermediate**  **- term NOAEL of**  **3.3 mg/kg -**  **bw/day from a one year dog feeding study. Residential post -**  **application dermal assessments were not conducted since short**  **- term and intermediate**  **- term**  **dermal endpoints were not established by the EPA and there were no developmental**  **concerns with fludioxonil. The residential risk assessments were limited to children since the only route of exposure was incidental oral ingestion via hand**  **- to**  **- mouth**  **activity and object -**  **to -**  **mouth (grass and soil ing estion). The combined short**  **- term**  **MOE for children 1 -**  **6 years was 784 and the combined intermediate -**  **term MOE for children 1**  **- 6 years was 445. Since the Benchmark MOE for this assessment was 100,**  **Syngenta believes that there is a reasonable certainty that no harm will result from** 7

**exposures arising from residential uses of fludioxonil.** D. Cumulative Effects Cumulative Exposure to Substances with a Common Mechanism of Toxicity

. **Section 408(b)(2)(D)(v) of FFDCA requires that, when considering whether to e**  **stablish, modify, or revoke a tolerance, the Agency consider “available information”**  **concerning the cumulative effects of a particular pesticide’s residues and “other substances that have a common mechanism of toxicity.” Unlike other pesticides for**  **which the EPA has followed a cumulative risk approach based on a common**  **mechanism of toxicity, the 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 p roduced by other substances. For the purposes of**  **this tolerance action, the EPA has not assumed that fludioxonil has a common mechanism of toxicity with other substances.**  E. Safety Determination 1. U.S. population. **An acute toxicological endpoint ha s not been established for the**  **U.S. population, so an acute exposure assessment was not performed for the U.S. population. The chronic aggregate exposure analysis showed that exposure from all**  **current and proposed fludioxonil uses resulted in a MOE of 617 or 16.2% of the**  **cRfD (Benchmark MOE = 100; cRfD= 0.033 mg/kg -**  **bw/day). A cancer exposure analysis was not performed since there is no evidence of human carcinogenic**  **potential for fludioxonil. Since the worst -**  **case aggregate MOE of 617 exceeds the benchmar**  **k MOE of 100, Syngenta believes that there is a reasonable certainty that no harm will result from aggregate exposure to residues arising from all current,**  **pending and proposed fludioxonil uses, including anticipated dietary exposure from food, water, and**  **all other types of non -**  **occupational exposures.** 2. Infants and children

. **An acute toxicological endpoint has not been established for infants and children, so an acute exposure assessment was not performed for infants**  **and children. The chronic aggregate exposure analysis showed that exposure from**  **all established and proposed fludioxonil uses resulted in a MOE of 226 or 44.2% of the cRfD (Benchmark MOE = 100; cRfD= 0.033 mg/kg**  **- bw/day) for children (1**  **- 2**  **years old). A cancer exposure analysis was not perfo rmed, since there is no evidence**  **of human carcinogenic potential for fludioxonil. The short -**  **term aggregate assessment resulted in MOE of 403, for the children (1**  **- 6 years old) population**  **subgroup (Benchmark MOE = 100). The intermediate -**  **term aggregate as sessment**  **resulted in MOE of 169, for the children (1 -**  **6 years old) population subgroup (Benchmark MOE = 100). Since the worst**  **- case aggregate MOE of 169 exceeds the**  **Benchmark MOE of 100, Syngenta believes that there is a reasonable certainty that no harm w**  **ill result from aggregate exposure to residues arising from all current, pending and proposed fludioxonil uses, including anticipated dietary exposure from**  **food, water, and all other types of non -**  **occupational exposures.**8

3. Females 13

- 49 years of age

. **The acute aggregate exposure analysis showed that**  **exposure to all current, pending and proposed fludioxonil uses would result in a MOE of 1,168 or 8.6% of the aRfD (Benchmark MOE = 100; aRfD=**  **1.0 mg/kg**  **** **bw/day)) for females 13 -**  **49 years old. The chronic aggreg ate exposure analysis**  **showed that exposure to all current and proposed fludioxonil uses would result in a MOE of 761 or 13.1% of the cRfD (Benchmark MOE = 100; cRfD= 0.033 mg/kg**  **** **bw/day) for females 13 -**  **49 years old. A cancer exposure analysis was not perfor med,**  **since there is no evidence of human carcinogenic potential for fludioxonil. Since the worst**  **- case aggregate MOE of 761 exceeds the Benchmark MOE of 100, Syngenta**  **believes that there is a reasonable certainty that no harm will result from aggregate exp**  **osure to residues arising from all current, pending and proposed fludioxonil uses, including anticipated dietary exposure from food, water, and all other types of**  **non -**  **occupational exposures.** F. International Tolerances **Codex Maximum Residue Limits (MRLs) for residues of fludioxonil per se**  **have been established on a number of commodities, including apples, beans, berries,**  **cabbage, citrus fruits, cucumber, egg plant, kiwifruit, lettuce, melons (except watermelon), peas (dr**  **y), peas (pods and succulent=immature seeds), peas (pods and succulent seeds), peppers, sweet, pome fruits, squash, summer, straw and fodder**  **(dry) of cereal grains ,**  **tomato , and potato**  **.**