EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE 

PETITIONS PUBLISHED IN THE FEDERAL REGISTER (3/4/2011)

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)-1H-pyrrole-3-carbonitrile) in or on the following raw agricultural 

commodities: acerola, at 5.0 parts per million (ppm); atemoya, at 20 ppm; biriba, at 20 

ppm; cherimoya, at 20 ppm; custard apple, at 20 ppm; feijoa, at 5.0 ppm; guava, at 5.0 

ppm; ilama, at 20 ppm; jaboticaba, at 5.0 ppm; passionfruit, at 5.0 ppm; soursop, at 20 

ppm; starfruit, at 5.0 ppm; sugar apple, at 20 ppm; wax jambu, at 5.0 ppm; ginseng, at 3.0 

ppm; onion, bulb subgroup 3-07A at 0.2 ppm; onion, green subgroup 3-07B, at 7.0 ppm; 

caneberry subgroup 13-07A, at 5.0 ppm; bushberry 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; vegetable, fruiting, group 8-10, 

except tomato, at 0.7 ppm; fruit, citrus, group 10-10, at 10 ppm; fruit, pome, group 11-10, 

at 5.0 ppm; leafy greens subgroup 4A, at 30 ppm; potato, at 6.0 ppm; pineapple, at 8.0 

ppm; and dragon fruit, at 1.0 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; papaya, 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; lychee, 

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, the petition finally requests to amend 40 

CFR 180.516 by removing the established tolerances for residues of fludioxonil in or on 

the following raw agricultural commodities: onion, bulb, at 0.2 ppm; onion, green, at 7.0 

ppm; caneberry subgroup 13A, at 5.0 ppm; bushberry subgroup 13B, at 2.0 ppm; 

Juneberry, at 2.0 ppm; lingonberry, at 2.0 ppm; salal, at 2.0 ppm; grape, at 1.0 ppm; 

strawberry, at 2.0 ppm; vegetable, fruiting, group 8, at 0.01 ppm; tomatillo, at 0.50 ppm; 
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fruit, citrus, group 10, at 10 ppm; fruit, pome, group 11, at 5.0 ppm; and leafy greens 

subgroup 4A, except spinach, at 30 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.

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 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.
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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, 

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 Oral NOAEL = 3.3 LOC for MOE = 1 year 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 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 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 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-harvest 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/kgbw/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-
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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 1,193 or 8.4% 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, 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 751 or 13.3% 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 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 

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 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) 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) 
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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 78,864 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, 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 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 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, 

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 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/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-tomouth 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
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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 649 or 15.4% 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 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 nonoccupational 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 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 

carcinogenic 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 

children (1-6 years old) population subgroup (Benchmark MOE = 100). Since the worstcase 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% of 
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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 

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 and tomato.