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

**PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER (**  **2 /**  **2 /20**  **1 2**  **) EPA Registration Division contact:**  **Laura Nollen , (703) 305**  **- 7390**  **Interregional Research Projec t 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 the tolerance for residues of fludioxonil , [4
- (2, 2
- difluoro
1,3
- benzodioxol
- 4
- yl )
- 1H
- py rrole
- 3
- carbonitrile] in or o n the raw agricultural commodities a cerola, at 5.0 parts per million (ppm); at emoy a, at 20 ppm ; b iriba, at 20 ppm; c herimoy a, at 20 ppm; c ustard apple, at 20 ppm; f eijoa, at 5.0 ppm; guava, 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 tarfruit, 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; f ruit, s mall fruit vine climbing , except fuzzy ki wifruit, subgroup 13
- 07F, at 1 .0 ppm; b erry, l ow growing , subgroup 13
- 07G, except cranberry , at 2 .0 ppm; v egetable, 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; l eaf

y green subgroup 4A, at 3 0 ppm; p ineapple, at 8.0 ppm; dragon fruit, at 1.0 ppm; and v egetable, tuberous and corm, subgroup 1C, at 6.0 ppm . The petition additionally

requests to amend 40 CFR part 180.516 by revising the tolerance for residues of fludioxonil in or on the following raw agricultural commodities: avocado, from 0.45 ppm to 5.0 ppm; sapote, black from 0.45 ppm to 5.0 ppm; canistel, from 0.45 ppm to 5.0 ppm; sapote, mamey from 0.45 ppm to 5.0 ppm; mango, from 0.45 ppm to 5.0 ppm; papay a, from 0.45 ppm to 5.0 ppm; sapodilla, from 0.45 ppm to 5.0 ppm; star apple, from 0.45 ppm to 5.0 ppm; longan, from 1.0 ppm to 20 ppm; ly chee, from 1.0 ppm to 20 ppm; pulasan, from 1.0 ppm to 20 ppm; rambutan, from 1.0 ppm to 20 ppm; Spanish lime, from 1.0 ppm to 20 ppm; and tomato, from 0.50 ppm to 3.0 ppm. Upon approval of the aforementioned tolerances, it is proposed that 40 CFR 180.5 16 be amended to remove the established tolerances for the residues of fludioxonil in or on the raw agricultural commodities 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; grape, at 1 .0 ppm; s trawberry , at 2 .0 ppm; v egetable, fruiting, group 8, at 0.0 1 ppm; t omatillo, at 0. 50 ppm; f ruit, citrus, group 10, at 10 ppm; f ruit, pome, group 11, at 5.0 ppm; l eaf y greens2

subgroup 4A, except spinach, at 30 ppm; and v egetable, tuberous and corm, subgroup 1D, at 3.5 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 full y evaluated the sufficiency

of the submitted data at this time or whether the data supports granting of the petition. Additional data may b e 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 an al yt ical methodology for enforcement purposes. This method (Sy ngenta Crop Protection Method AG
- 597B) has passed an Agency

petition method validation for several commodities, and is currentl y 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 reque sted tolerances have been submitted. The requested tolerances are adequatel y 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 fludioxonil in or on requested commodities. B. Toxicological Profile An assessment of toxic effects caused b y 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 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 survival (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 hepatocy 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 The re was no evidence that unscheduled DNA s yn thesis, as determined by nuclear silver grain counts, was induced in hepatocy te 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 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 = 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 Development al 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

N OAEL= 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 toxicity

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 gestat ion 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 dec reased 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 2 8
- 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 based on decreased weight gain in female dogs Short
- Term (1
- 30 Day s) Inhalation (Residential)

Oral NO AE 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 dur ing gestation Intermediate
- term (1 Oral NOAE L = 3.3 LOC for MOE = 1 y ear chronic 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 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 dog s 6. Animal metabolism. The metabolism of fludioxonil in rats is adequatel y 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 s ys tem. No estrogenic effects have been observed in the various short
- and long
- term studies conducted with various mammalian 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, an irrigation use on ginsen g, and post
- harvest uses on Crop Group 1C, pineapples, tropical fruits and tomatoes. 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
- har vest interval (PHI) to obtain maximum residues. Empirically derived processing 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 processi ng factor was used as a surrogate for pear juice. All other processing factors used the DEEM TM defaults. All consumption data for these assessments was taken from the USDA’s Continuing Survey of Food Intake b y individuals (CSFII) with the 1994
- 96 consump tion database and the Supplemental CSFII children’s survey (1998) consumption database. Percent of crop treated values were estimated based upon economic, pest and competitive pressures. Secondary

residues in animal commodities were estimated based on “m aximum reasonabl y balanced diets” and transfer information from metabolism studies. i. Food. Acute exposure
. The acute dietary (food only) risk assessment for females 13 to 49 y ears old (the onl y population subgroup for which an acute toxicological en dpoint 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 uncertaint y factor (UF) of 100X for intra
- and inter -5

species variations; no additional FQPA safet y 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 b y dividing the no observed adverse effect level (NOAEL) b y 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 y ears subpopulation resulted in a MOE of 1,182 or 8.5% of the aRfD (Ben chmark 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, S yn genta believes that there is a reasonable certaint y 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 uncertainl y factor of 100X; no additional FQPA safet y 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 th e no observed adverse effect level (NOAEL) b y the exposure for each population 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 y ears 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 generall y has no concern for exposures below 100% of the cRfD, S yn genta 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 whi ch estimates pesticide concentrations in surface water. This drinking water assessment was conducted to assess all currentl y 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 o n 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 currentl y registered use on turf prov ided 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 w ill be considered protective for an y ground water exposure concerns. Acute Exposure from Drinking W ater : 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
- F CI DTM software to obtain acute dietary (food and water) exposures. Drinking water exposures at the 99.9th percentile to fludioxonil for females 13
- 49 y ears old (the only

population subgroup for which an acute toxicological endpoint has been established) re sulted 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, Sy ngenta 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 fludioxonil uses. Chronic Exposure from Drinking W ater : 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 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/day). The most sensitive sub
- population was all infants (<1 ye ar 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 generall y has no concer n for exposures below 100% of the cRfD, S yn genta believes that there is a reasonable certaint y that no harm will result from chronic drinking water exposure to residues arising from all current, pending and proposed uses for fludioxonil. Cancer . A chroni c cancer exposure anal ys is 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 currentl y registered for professionall y applied uses on turf grass and ornamentals in residential landscapes. The Sy ngenta 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 ye ar (0.68 lb a.i./A x 3 apps = 2 lb a.i./A/y ear). 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 stud y. Residential post
- application dermal assessments were not conducted since short
- term and intermediate
- term dermal e ndpoints were not established by the EPA and there were no developmental concerns with fludioxonil. The residential risk assessments were limited to children since the onl y route of exposure was incidental oral ingestion via hand
- to mouth activity

and obj ect - to - mouth (grass and soil ingestion). The combined short
- term MOE for children 1
- 6 y ears was 784 and the combined intermediate
- term MOE for children 1
- 6 y ears was 445. Since the Benchmark MOE for this assessment was 100, Sy ngenta believes that there i s a reasonable certainty that no harm will result from exposures arising from 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 Agency consider “available information” concerning the cumulative effects of a particular pesticide’s residues and “other substances that have a common mechanism of toxicity .” Unli ke 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 t o produce a toxic metabolite produced b y 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 a cute 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 anal ys is 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 anal ys is was not performed since there is no evidence of human carcinogenic potential for fludioxonil. Since the worst
- case aggregate M OE of 617 exceeds the benchmark MOE of 100, Sy ngenta 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 e xposure from food, water, and all other ty pes 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 ch ildren. The chronic aggregate exposure anal ys is 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 y ears old). A cancer e xposure anal ysis was not performed, 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 y ears old) population subgroup (Benchmark MOE = 100). The i ntermediate
- term aggregate assessment resulted in MOE of 169, for the children (1
- 6 y ears 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 reaso nable 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 ty pes of non
- occupational exposures. 3. Fe males 13
- 49 years of age
. The acute aggregate exposure anal ys is 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 ye ars old. The chronic aggregate exposure analy sis 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 y ears8

old. A cancer ex posure analy sis was not performed, 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, Sy ngenta believes that there is a reasonable certaint y 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 ty pes of non
- occupational exposures. F. International Tolerances Codex Maximum Residue L imits (MRL s) 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 (dry), peas (pods and succulent=immature seeds), peas (pods and succul ent seeds), peppers, sweet, pome fruits, squash, summer, straw and fodder (dry) of cereal grains and tomato.