EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE PETITIONS

PUBLISHED IN THE FEDERAL REGISTER (1/1 8 /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 pestic ide 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 pest icide 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 amending the 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 []

Vegetable, tuberous and corm, subgroup 01C at 0.0 4 parts per million (ppm)

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 fully evaluated the sufficiency of the submitted data at this time or whether the data supports 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 tole rances.

2. Analytical 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 c urrently the enforcement method for fludioxonil. This method has also been forwarded to the Food and Drug Administration for inclusion into PAM II. An extensive database of method validation data using this method on various crop commodities is available.

3. Magnitude of residues. Complete residue data to support the requested tolerances have been submitted. The requested tolerances are adequately supported.2

In support of the requested tolerance, Syngenta Canada conducted sixteen field trials. Site Selection was determined according to the geographic Canadian Major and Minor Crop Field Trial Regions for potatoes in Zones 1, 5, 7A, 12, and 14. At two sites additional samples were collected to demonstrate residue decline.

B. Toxic ological 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 repeated in part below.

Carcinogenic and Other Toxicity

Study Type Results Carcino

- genicity 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 survival (F), decreased body weights (M), bile duct hyperplasia (M) and severe nephropathy(both sexes). No evidence of carcinogenicity. In vivo Rat hepatocyte micronucleus assay Male rats were orally dosed at 50, 250, and 1,250 mg/kg and hepatocytes were harvested. There was no evidence of a significant increase in micronucleated hepatocytes in treated groups in comparison to controls. Unscheduled DNA synthesis
assay There was no evidence that unscheduled DNA synthesis, as determined by nuclear silver grain counts, was indu ced in hepatocyte 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 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 years of age NOAEL = 100 mg/kg/day UF = 100 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 wi th 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 year chronic toxicity study

– dog LOAEL = 35.5 mg/k g/day based on decreased weight gain in female dogs

Incidental 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 Incidental Oral, Intermediate

- Term NOAEL = 3.3 mg/kg/day LOC for MOE = 100 1 year 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 days and 1

- 6 months) (Residen tial) None No systemic 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 = LOC for MOE = 100 (Occupational) LOC for MOE = 100 1 year chronic toxicity study

- dog LOAEL = 35.5 mg/kg/day based on decreased weight gain in femal e dogs3

40%). (Residential). Short

- Term (1

- 30 Days) Inhalation (Residential) Oral NOAEL = 10 mg/kg/ day (inhalation absorption rate = 100%) LOC for MOE = 100 (Oc cupational) 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) Inhalation (Residential) Oral NOAEL = 3.3 mg/kg/ da y (inhalation absorption rate = 100%) LOC for MOE = 100 (Occupational) LOC for MOE = 100(Residential). 1 year chronic toxicity study

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

Long

- Term (several months

- lifetime) Inhalation (Residential) Oral NOAEL = 3.3 mg/kg/day (inhalation absorption rate = 100%) LOC for MOE = 100(Occupational) LOC for MOE = 100(Re sidential). 1 year 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 disruption

. 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

- and long

term studies conducted with various mammalian species.

C. Aggr egate 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 c urrent uses as well as an increased domestic tolerance to accommodate the proposed new seed treatment use on imported potatoes grown in Canada from potato seed pieces treated with Maxim DTM brand fungicide product containing fludioxonil. These assessments utilized residue data from field trials where fludioxonil was applied at the maximum intended use rate and samples were harvested at the minim um pre - harvest interval (PHI) to obtain maximum residues. For the proposed use on potato seed pieces, an amended fludioxonil tolerance of 0.04 ppm was assumed for all potatoes in the dietary assessments. Empirically derived processing factors for apple j uice (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 factors used the DEEM TM def aults. 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 databases and the Supplemental CSFII children’s survey (1998) consumption database. Percent o f 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 and feeding studies.

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 (aRfD) of 1.0 mg/kg

- bw/day, based upon a rat teratology study with a no observed adverse 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 the 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, exposure 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 1,916 or 5.2% of the aRfD (Benchmark MOE = 100; aRfD= 1.0 mg/kg

- bw/day). Since the Benchmark MOE for this

assessmen t 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 and proposed uses f or fludioxonil.4

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 population subgroup. In ad dition, exposure was expressed as a percent of the chronic reference dose (%cRfD). Chronic exposure to the most exposed subpopulation (children 1 and 2 years old) resulted in a MOE of 747 or 13.4% of the cRfD (Benchmark MOE = 100; cRfD = 0.033 mg/kg

- bw/da y). 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 residu es arising from the current and proposed uses for fludioxonil.

ii. Drinking water. The Estimated Drinking Water Concentrations (EDWCs) of fludioxonil were determined using Tier l SCI

- GROW, which estimates pesticide concentrations in ground water and Tie r II PRZM/EXAMS which estimates pesticide concentrations in surface water. EDWCs for fludioxonil from currently registered uses as well as the proposed use on potatoes grown in Canada from treated seed pieces were determined. For the amended potato toler ance, the imported potato tubers will be for human consumption, and possibly livestock cull consumption , only ; as such there will be no environmental exposure to ground water and/or surface water. For ground water, the currently registered use on professi onal turf provided the highest EDWC of 2.02E

- 01 ppb (acute and chronic). For surface water, the currently registered field grown and landscape ornamentals provided the highest acute EDWC of 44.102 ppb and the currently registered use on turf provided 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 will be co nsidered protective for any ground water exposure concerns.

Acute Exposure from Drinking Water : 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

- FCIDTM so ftware 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) resulted in a MOE of 69,735 or 0.1% 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

r easonable certainty that no harm will result from acute drinking water exposure to residues arising from all current and proposed uses for fludioxonil.

Chronic Exposure from Drinking Water : The chronic EDWC of 32.79 ppb (0.03279 ppm) was incorporated wi th food residues as “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 o f 0.033 mg/kg

- bw/day). The most sensitive sub

population was all infants (<1 year old), with a MOE of 1,456 or 6.9% 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 general ly 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 and proposed uses for fludioxonil.

Cancer

. A chronic cancer exposure analysis was not 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 fludioxonil. 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 grass of 0.68 lb a.i./A (0.50 oz product/1000ft 2 ) with a maximum of three applications allowed per year5

(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 study 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 d ermal 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 ingestion). 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 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 requi res that, when considering whether to establish, 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 toxicit y.” 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 produced 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. populat ion. An acute toxicological endpoint has 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 fl udioxonil uses resulted in a MOE of 1,697 or 5.9% 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 a ggregate MOE of 1,697 exceeds the benchmark 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 and proposed fludioxonil uses, including anticipated dietar y 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 606 or 16.5% of the cRfD (Benchmark MOE = 100; cRfD= 0.033 mg/kg

- bw/day) for children (1

- 2 years old). A cance r exposure analysis was not performed, since there is no evidence of human carcinogenic potential for fludioxonil. The short

- term aggregate assessment resulted in MOE of 579, for the children (1

- 6 years old) population subgroup (Benchmark MOE = 100). Th e intermediate

- term aggregate assessment resulted in MOE of 371, for the children (1

- 6 years old) population subgroup (Benchmark MOE = 100). Since the worst

- case aggregate MOE of 277 exceeds the Benchmark MOE of 100, Syngenta believes that there is a re asonable certainty that no harm will result from aggregate exposure to residues arising from all current and proposed fludioxonil uses, including anticipated dietary exposure from food, water, and all other types of non

- occupational exposures.

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 1,865 or 5.4% of the aRfD (Benchmark MOE = 100; aRfD= 1.0 mg/kg

- bw/day)) for females 13

- 49 years old. The chronic aggregate exposure analysis showed that exposure to all current and proposed fludioxonil uses would result in a MOE of 2,117 or 4.7% 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 performed, since there is no evidence of human carcinogenic potential for fludioxonil. Since the worst

- case aggregate MOE of 1,865 exceeds the Benchmark MOE of 100, Syngenta believes that the re is a reasonable certainty that no harm will result from aggregate exposure to6

residues arising from all current 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, melo ns (except watermelon), peas (dry), peas (pods and succulent=immature seeds), peas (pods and succulent seeds), peppers, sweet, pome fruits, squash, summer, straw and fodder (dry) of cereal grains and tomato.