EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR 

PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER 

(5/5/2011)

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 establishing 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 14 parts per 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 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

2. Analytical method. Syngenta has developed and validated analytical methodology 

for enforcement purposes. This method (Syngenta Crop Protection Method AG597B) 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. 

In support of the requested tolerance, eight crop-field trials were conducted with 

various commercially available 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 cyprodinil/acre + 0.219 lb fludioxonil/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 the 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 proposed-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 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 
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 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, 

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 

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 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 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 NOAEL = 3.3 

mg/kg/ day

LOC for MOE = 

100 

1 year chronic toxicity study -

dog 
4

Inhalation 

(Residential)

(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 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 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 (DEEMFCIDTM, 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 postharvest uses on pineapples, potatoes, 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 preharvest 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 

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 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 “maximum reasonably balanced diets” and 

transfer information from metabolism 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 
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 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 1,182 or 8.5% of the aRfD (Benchmark MOE = 100; aRfD= 1.0 mg/kgbw/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/kgbw/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 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 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 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 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.
6

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 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 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 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 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 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 intermediateterm 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 (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 
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 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 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 

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 

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 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 years old) population 

subgroup (Benchmark MOE = 100). The intermediate- term aggregate assessment 

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 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.
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/kgbw/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 761 or 13.1% of the cRfD (Benchmark MOE = 100; cRfD= 0.033 mg/kgbw/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 761 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.

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, tomato, and potato.