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-difluoro-1,3-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 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 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 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-FCID™ 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/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 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 (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/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 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-FCID™ 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-FCID™ 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/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 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.  .  Residential exposure risk assessments were
performed for use of fludioxonil formulated as Palladium™ for
ornamentals and Medallion® for turf and ornamentals and and Medallion®
TL for turf.  Palladium™ 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.  Post-application 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 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/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 773 or 12.9% 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 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, 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.

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