EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE

PETITIONS PUB LISHED IN THE FEDERAL REGISTER ( 3 / 4 /20 11 )

EPA Registration Division contact: Laura Nollen, (703) 305

- 7390

Interregional Research Project Number 4 (IR

- 4)

Petition Number 1E7853

EPA has received a pesticide petition , 1E7853, from IR

- 4

, 500 College Road East, Suite 201 W, Princeton, NJ 08540 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 by establishing a tolerance for residues of fludioxonil ( 4

- (2, 2

- difluoro

- 1,3

- benzodioxol

- 4

- yl)

- 1 H

- pyrrole

- 3

- carbonitrile ) in or on the following raw agricultural commodit ies: a cero la, at 5.0 parts per million (ppm); at emoya, at 20 ppm; b iriba, at 20
ppm; c herimoya, at 20 ppm; cu stard apple, at 20 ppm; f eijoa, at 5.0 ppm; g uava, at 5.0 ppm; i lama, at 20 ppm; j aboticaba, at 5.0 ppm; p assionfruit, at 5.0 ppm; s oursop, at 20
ppm; s tarfr uit, at 5.0 ppm; s ugar apple, at 20 ppm; w ax jambu, at 5.0 ppm; gi nseng, at 3.0
ppm; o nion, bulb subgroup 3

- 07A at 0. 2 ppm; o nion, green subgroup 3

- 07B, at 7 .0 ppm;

c aneberry subgroup 13

- 07A, at 5 .0 ppm; b ushberry subgroup 13

- 07B, at 2 .0 ppm; fruit

, small vine climbing , except fuzzy kiwifruit, subgroup 13

- 07F, at 1 .0 ppm; berry , low growing, subgroup 13

- 07G, except cranberry, at 2 .0 ppm; ve getable, fruiting, group 8

- 10, except tomato, at 0.7 ppm; f ruit, citrus, group 10

- 10, at 10 ppm; f ruit, pome, group 11

- 10, at 5.0 ppm; leafy greens subgroup 4A, at 3 0 ppm; p otato, at 6.0 ppm; p ineapple, at 8.0 ppm; and d ragon fruit, at 1.0 ppm

. The petition additionally requests to amend 40 CFR part 180.516 by revising the tolerance for residues of f ludioxonil in or o n the following raw agricultural commodities:

a vocado, from 0.45 ppm to 5.0 ppm ; sapote, black from 0.45 ppm to 5.0 ppm ; c anistel, from 0.45 ppm to 5.0 ppm ; sapote, mamey from 0.45 ppm to 5.0 ppm ; m ango, from 0.45 ppm to 5.0 ppm ; p apaya, from 0.45 ppm to 5 .0 ppm ; s apodilla, from 0.45 ppm to 5.0
ppm ; s tar apple, from 0.45 ppm to 5.0 ppm ; l ongan, from 1.0 ppm to 20 ppm ; l ychee, from 1.0 ppm to 20 ppm ; p ulasan, from 1.0 ppm to 20 ppm ; r ambutan, from 1.0 ppm to 20 ppm ; Spanish lime, from 1.0 ppm to 20 ppm ; and t omato, from 0.50 ppm to 3.0 ppm.
Upon approval of the aforementioned tolerances, the petition finally requests to amend 40 CFR 180.5 16 by removing the established tolerances for residues of fludioxonil in or on the following raw agricultural commodit ies : o nion, bulb, at 0. 2 ppm; o nion, green, at 7 .0
ppm; c aneberry subgroup 13A, at 5 .0 ppm; b ushberry subgroup 13B, at 2 .0 ppm; Juneberry, at 2 .0 ppm; l ingonberry, at 2 .0 ppm; s alal, at 2 .0 ppm; g rape, at 1 .0 ppm;

s trawberry, at 2 .0 ppm; v egetable, fruiting, g roup 8, at 0.01 ppm; t omatillo, at 0. 50 ppm;2

f ruit, citrus, group 10, at 10 ppm; f ruit, pome, group 11, at 5.0 ppm; and l eafy greens subgroup 4A, except spinach, at 30 ppm.
EPA has determined that the petition contains data or information regarding the el ements 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 tolerances.

2. Analytical method. Syngenta has developed and validated analytical methodology for enforcement purp oses. This method (Syngenta Crop Protection Method AG

- 597B) has passed an Agency petition method validation for several commodities, and is currently the enforcement method for fludioxonil. This method has also been forwarded to the Food and Drug Administr ation 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.

In support of the requested tolerance, IR

- 4 has conducted the necessary trials in accordance with the requirements of the EPA Residue Chemistry Guidelines 860.1500 to determine the magnitude of residue of flu dioxonil in or on requested commodities.

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 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 s ynthesis, as determined by nuclear silver grain counts, was induced in hepatocyte cultures obtained from male rats dosed at 2,500 or 5,000 mg/kg.3

Summary of Toxicological Dose and Endpoints for Fludioxonil for Use in Human Risk Assessment
Exposure Scena rio 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

N OAEL = 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 increa sed 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 year chronic toxicity study

– dog LOAEL = 35.5 mg/kg/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) (Residential)

None No systemic

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

- day dermal toxicity study in
rats End point was not selected

Long

- Term (several months

- lifetime) Dermal (Residential)

Oral study NOAEL = 3.3 mg/kg/day (der mal penetration = 40%).

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

1 year chronic toxicity study

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

- Term (1

- 30 Days) Inhalation (Residential)

Oral NOAEL = 10 mg/kg/ day (inhalation absorptio n 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 Oral NOAEL = 3.3 LOC for MOE = 1 year chro nic toxicity study

-4

month

- 6 months) Inhalation (Residential) mg/kg/ day

(inhalation absorption rate = 100%)

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

dog LOAEL = 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(Residential).

1 year chronic toxicity study

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

6. Animal metabolism. The metaboli sm 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 mamma lian 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 proposed 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 tomatoe s. 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 processing f

actors 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 factors u sed 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) consumption dat abase. 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 studie s.

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) o f 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

-5

species variations; no additional FQPA safety factor was applied. For the pu rpose 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, exposur e 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 1,193 or 8.4% of the aRfD (Benchmark MOE = 100; aRfD= 1.0 mg/kg

- bw/day). Since the Benchmark MOE for this asse ssment 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
p roposed 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 fact or 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 su bgroup. 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 751 or 13.3% of the cRfD (Benchmark MOE = 100; cRfD = 0.033 mg/kg

- bw/day). Chronic exposure to t he most exposed subpopulation (children 1

- 2 years old) resulted in a MOE of 251 or 39.8% 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
expos ures 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 Estimated 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 asse ssment was conducted to assess all currently registered uses and the proposed uses on spinach, celery, peppers, ginseng, as well as the proposed post

- harvest uses on potatoes, pineapples, tropical fruits, and tomatoes. The post

- harvest uses have no impact on drinking water because post

- harvest treatment is an indoor use posing negligible impact to drinking water concentrations. 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 provided the highest chronic EDWC of 32.79 ppb. No Percent Cropped Area (PCA) adjust ments 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 considered protective for any ground water exposure concerns.

Acute Expos ure from Drinking Water : The acute EDWC of 44.102 ppb (0.044102 ppm)6

was incorporated with food residues as “water, direct and indirect, all sources” directly into the DEEM

- FCIDTM software to obtain acute dietary (food and water) exposures. Drinking water exposures at the 99.9th p ercentile 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 78,864 or 0.1% of the aRfD (Benchmark MOE = 100; aRfD= 1.0 mg/kg

- bw/day). Since the Ben chmark 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 acute drinking water exposure to residues arising from all current, pending and proposed uses for fludioxonil.

Chronic Exposure from Drinking Water : The chronic EDWC of 32.79 ppb (0.03279 ppm) was incorporated with food residues as “water, direct and indirect, all sources” directly into the DEEM

- FCIDTM s oftware 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/day). The most sensitive sub

- population was all infants (<1 year old), wit h 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 generally has no concern for exposures below 100% of the cRfD, Syngenta believes that there is a re asonable certainty that no harm will result from chronic drinking water exposure to residues arising from all current, pending 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 fo r 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 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 study was selected as well as an intermediate

- t erm 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 con cerns 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 ch ildren 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 fro m residential uses of fludioxonil.

D. Cumulative Effects7

Cumulative Exposure to Substances with a Common Mechanism of Toxicity

. Section 408(b)(2)(D)(v) of FFDCA requires that, when considering whether to establish, modify, or revoke a tolerance, the A gency 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 approac h 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. population. 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 fludioxonil uses resulted in a MOE of 649 or 15.4% of the cRfD (Benchmark MOE = 100; cR fD= 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 649 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, 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 a ll established and proposed fludioxonil uses resulted in a MOE of 233 or 43.0% 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 performed, since there is no evidence of human

carc inogenic potential for fludioxonil. The short

- term aggregate assessment resulted in MOE of 409, for the children (1

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

- term aggregate assessment resulted in MOE of 173, for the child ren (1

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

case aggregate MOE of 173 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, pending 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 1,176 or 8.5% 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 805 or 12.4% of8

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 805 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

curren t, 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 ha ve been established on a number of commodities, including apples, beans, berries, cabbage, citrus fruits, cucumber, egg plant, kiwifruit, lettuce, melons (except watermelon), peas (dry), peas (pods and succulent=immature seeds), peas (pods and succulent se eds), peppers, sweet, pome fruits, squash, summer, straw and fodder (dry) of cereal grains and tomato.