Interregional Research Project Number 4 (IR-4)

Petition #4E8272

EPA has received a pesticide petition (4E8272) 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-difluoro1,3-benzodioxol-4-yl)-1-H-pyrrole-3-carbonitrile] in or on the raw agricultural 

commodity carrot at 7.0 parts per million; and fruit, stone, group 12-12, at 5 parts per 

million. Upon approval of the aforementioned tolerances, it is proposed that 40 CFR 

180.516 be amended to remove the established tolerances for the residues of fludioxonil

in or on the raw agricultural commodity fruit, stone, group 12, at 5 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. 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 tolerances, 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

EPA has evaluated the available toxicity data and considered its validity, completeness, 

and reliability as well as the relationship of the results of the studies to human risk. EPA 

has also considered available information concerning the variability of the sensitivities of 

major identifiable subgroups of consumers, including infants and children. Specific 

information on the studies received and the nature of the toxic effects caused by
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fludioxonil as well as the no-observed-adverse-effect-level (NOAEL) from the toxicity

studies can be found at the following website: http://edocket.access.gpo.gov/2012/2012-

19988.htm. A summary of the toxicological endpoints for fludioxonil used for human 

risk assessment is discussed in Unit III.A and B. of the final rule published in the Federal 

Register of August 15, 2012 (77 FR pages 48907-48915) (FRL-9357-5).

C. Aggregate Exposure

1. Dietary exposure. Tier III acute and chronic dietary exposure evaluations were 

performed for fludioxonil using the using the Dietary Exposure Evaluation Model 

(DEEM-FCIDTM Version 3.16) from Exponent; consumption data was from the 

USDA NHANES “What We Eat in America” survey, 2003-2008. These exposure 

assessments included all current uses as well as a proposed post-harvest use on

carrots and stone fruit crop group 12-12. These assessments utilized residue data 

from field trials where fludioxonil was applied post-harvest at the maximum 

intended use rate. 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 

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). At the 99.9th percentile, acute (food only) exposure to the females 

13-49 years subpopulation resulted in a MOE of 1,683 (5.9% 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 above the Benchmark MOE or 

below 100% of the aRfD, Syngenta believes that there is a reasonable certainty that 

no harm will result from dietary (food only) exposure to residues arising from the 

current, pending and proposed uses for fludioxonil.

Chronic exposure. The chronic dietary (food only) risk assessment was performed 

for all population subgroups using a chronic reference dose (cRfD) of 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 to account for intra- and inter-species variations. 

No additional FQPA safety factor was applied. For the purpose of the chronic 

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 (food only) exposure to the U.S. population resulted in a MOE of 747 
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(13.4% of the cRfD of 0.033 mg/kg-bw/day). The most exposed sub-population was 

children (1-2 years old) with a MOE of 227 (44.0% of the cRfD of 0.033 mg/kgbw/day). Since the Benchmark MOE for this assessment was 100 and since the EPA 

generally has no concern for exposures above the Benchmark MOE or below 100% 

of the cRfD, Syngenta believes that there is a reasonable certainty that no harm will 

result from dietary (food only) 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 and PRZM-GW, 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 

post-harvest use on carrots. For ground water, the PRZM-GW model provided the 

highest EDWCs of 25.7 ppb and 24.6 ppb for acute and chronic, respectively, based 

on the currently registered use on turf. For surface water, the currently registered 

field grown and landscape ornamental provided the highest acute EDWC of 44.1 

ppb (no Percent Cropped Area (PCA) adjustment) and the currently registered use 

on turf provided the highest chronic EDWC of 34.8 ppb (adjusted for 0.95 PCA). 

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 44.1 ppb was incorporated 

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

DEEM-FCIDTM software to obtain acute dietary (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 94,073 (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 and proposed fludioxonil uses.

Chronic Exposure from Drinking Water: The chronic EDWC of 34.8 ppb was 

incorporated with food residues as “water, direct and indirect, all sources” directly 

into the DEEM-FCIDTM software to obtain chronic dietary (water) exposures. 

Chronic drinking water exposure to the U.S. population resulted in a MOE of 4,529 

(2.2% 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 1,756 (5.7% of the cRfD of 0.033 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 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 fludioxonil uses.

Cancer. A chronic cancer exposure analysis was not performed, since there is no 
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evidence of human carcinogenic potential for fludioxonil. 

2. Non-dietary exposure. . Residential exposure risk assessments were performed for 

use of fludioxonil formulated as PalladiumTM for ornamentals and Medallion®for 

turf and ornamentals and and Medallion® TLfor turf. PalladiumTM may not be used 

on residential ornamental plants; therefore, no residential handler exposure 

assessments are required for this product. Medallion®and Medallion® TL are 

intended primarily for professional use however, the product label does not exclude 

residential uses; therefore, a residential handler exposure assessment was 

conducted. The following endpoints were used: a 10 mg/kg/day NOAEL for adults 

(inhalation only) from a rabbit developmental tox study; a 10 mg/kg/day short-term 

NOAEL for children 1-6 years (incidental oral) from an oral rabbit developmental 

study; a 3.3 mg/kg/day intermediate-term NOAEL for children 1-6 years (incidental 

oral) from a one-year feeding study in dogs. Residential handler exposure risk from 

fludioxonil was acceptable (MOE = 69,140; short-term) for youths (13-19 years) 

and adults (19+ years) treating residential turf with a hose-end sprayer. Residential 

handler exposure scenarios are considered to be short-term only, due to the 

infrequent use patterns associated with homeowner products. Since no dermal 

endpoints were selected short- and intermediate-term assessments were not 

conducted for post-application exposure risk to children, youth or adults. Postapplication non-dietary oral hand-to-mouth exposure risks for children 1-6 years, 

resulting from contact with treated lawns were acceptable for short-term (MOE = 

911) and intermediate-term (MOE = 301) durations. Since the MOEs for children 

(1-6 years), youths (13-19 years) and adults (19+ years) were above the Benchmark 

MOE of 100, residential exposure risk for fludioxonil do not exceed the EPA’s Level 

of Concern.

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 
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current and proposed fludioxonil uses resulted in a MOE of 641 or 15.6% 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 641 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 212 or 47.2% 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 422, for the children (1-6 years old) population 

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

resulted in MOE of 139, for the children (1-6 years old) population subgroup 

(Benchmark MOE = 100). 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 139 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 1,654 or 6.1% 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 773 or 12.9% 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 773 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, apple pomace, dry, basil, basil, dry, 

beans (dry), beans, shelled, blackberries, blueberries, broccoli, cabbages, head, 

carrot, cereal grains, chives, chives, dry, citrus fruits, cotton seed, cucumber, 
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dewberries (including boysenberry and loganberry), edible offal (mammalian), 

eggplant, eggs, grapes, kiwifruit, lettuce, head, meat (from mammals other than 

marine mammals), melons, except watermelon, milks, mustard greens, onion, bulb, 

peas (dry), peas (pods and succulent=immature seeds), peas, shelled (succulent 

seeds), peppers, sweet (including pimento or pimiento), pistachio nuts, pome fruits, 

pomegranate, potato, poultry meat, poultry, edible offal of, rape seed, raspberries, 

red, black, soya bean (dry), squash, summer, stone fruits, straw and fodder (dry) of 

cereal grains, strawberry, sunflower seed, sweet corn (corn-on-the-cob), sweet 

potato, tomato, watercress, and yams.