EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE PETITIONS 

PUBLISHED IN THE FEDERAL REGISTER (1/18/2011)

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 pesticide 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 pesticide 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 0.04 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 tolerances. 

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 currently 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. 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 synthesis, 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.

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 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, ShortTerm 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 

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 female dogs
3

40%). (Residential). 

Short-Term (1-30 Days) 

Inhalation (Residential) 

Oral NOAEL = 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) 

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

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 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 longterm 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-FCIDTM, version 2.16) from Exponent. 

These exposure assessments included all current 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 minimum 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 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 used the DEEMTM 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 

databases 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 “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 intraand 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 

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 and proposed uses for 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 addition, 

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/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 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. 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 tolerance, 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 

professional 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 considered 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 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) 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 

reasonable 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 

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 subpopulation 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 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 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 shortterm 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/1000ft2) with a maximum of three applications allowed per year 
5

(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 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 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 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.” 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. 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 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 aggregate 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 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 606 or 16.5% 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 

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). The 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 reasonable 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 there is a reasonable certainty that no harm will result from aggregate exposure to 
6

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, melons (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.