Document ID: EPA-HQ-OPP-2016-0254-0007
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2017-02-27T05:00Z

EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE
PETITIONS PUBLISHED IN THE FEDERAL REGISTER  

EPA Registration Division contact: Tony Kish, 703-308-9443

Syngenta Crop Protection, LLC

6F8445

	EPA has received a pesticide petition (6F8445) from Syngenta Crop
Protection, LLC, P.O. Box 18300, Greensboro, NC 27419-8300 requesting,
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

	by establishing a tolerance for residues of

	Difenoconazole (1
[2-[2-chloro-4-(4-chlorophenoxy)]phenyl-4-methyl-1,3-dioxolan-2-ylmethyl
]-1H-1,2,4,-triazole) in or on the raw agricultural commodity Cottonseed
subgroup 20C at 0.40 parts per million (ppm); Cotton, gin byproducts at
15 parts per million (ppm), rice, grain at 7 parts per million (ppm) and
rice, wild, grain at 7 parts per million (ppm); Syngenta also proposes
that the currently established tolerance for residues of difenoconazole
in/on cotton, undelinted seed (0.05 ppm) for registered uses of
difenoconazole as a seed treatment be removed from 40 CFR §180.475,
because the proposed tolerance in/on these commodities reflecting foliar
uses will be adequate to cover the seed treatment uses. 

Syngenta further requests that the current tolerance for cotton, gin
byproducts be amended from 0.05 ppm to the proposed 15 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 nature of the residues in plants is understood
for the purpose of the proposed tolerance.  The metabolism of
14C-difenoconazole has been studied using both phenyl and triazole
labels in wheat, tomatoes, potatoes, grapes, and spring rape.  The
metabolic pathway was the same in these four separate and distinct
crops.  Therefore, the metabolism of difenoconazole is considered to be
adequately understood for all crops, per EPA Test Guideline 860.1300.

	2. Analytical method. Syngenta Crop Protection, LLC has submitted a
practical analytical method (AG-575B, master record identification
(MRID) No. 42806504) for detecting and measuring levels of
difenoconazole in or on food with a limit of quantitation (LOQ) that
allows monitoring of food with residues at or above the levels set in
the proposed tolerances.  Residues are quantified by gas chromatography
equipped with a nitrogen-phosphorous detector.  EPA has validated this
method and copies have been provided to FDA for insertion into pesticide
analytical manual (PAM) II. Method REM 147.08 (MRID 46950222) is also
available for enforcement method, for the determination of residues of
difenoconazole in crops. Residues are qualified by liquid chromatography
(LC)/mass spectrometry (MS)/(MS) The method is available to anyone who
is interested, and may be obtained from the Field Operations Division,
Office of Pesticide Programs.  Syngenta Crop Protection, LLC has
submitted a practical analytical method (AG-544A, MRID-43292401) for
detecting and measuring levels of difenoconazole in or on cattle tissues
and milk and poultry tissues and eggs, with a LOQ that allows monitoring
of food with residues at or above the levels set in the proposed
tolerances.  EPA has validated this method and copies have been provided
to FDA for insertion into PAM II.  The method is available to anyone who
is interested, and may be obtained from the Field Operations Division,
Office of Pesticide Programs.  Tolerances in meat, milk, poultry or eggs
were established for enforcement purposes.

	3. Magnitude of residues. Syngenta conducted adequate magnitude of
residue trials under OPPTS 860.1500 to support the requested uses of
difenoconazole. These

residue trials satisfy the requested tolerances on rice and cotton.

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 difenoconazole as well as the
no-observed-adverse-effect-level (NOAEL) from the toxicity studies can
be found at the following website: http://www.regulations.gov on page 37
of the document titled “Difenoconazole: Human Health Risk Assessment
for Proposed New Foliar Uses on Globe Artichoke, Ginseng and Greenhouse
Grown Cucumbers and Conversion of the Established Foliar Uses/Tolerances
for Stone Fruit Group 12 and Tree Nut Crop group 14 to Stone Fruit Group
12-12 and Tree Nut Group 14-12,’’ in Docket ID Number
EPA–HQ–OPP–2014-0470.  A summary of the toxicological endpoints
for difenoconazole used for human risk assessment is discussed in Table
1 of the final rule published in the Federal Register on April 2, 2015
(FR volume 80, No. 63, pages 17697-17703) (FRL-9923-82).

	1. Acute toxicity.  [Insert text]

	2. Genotoxicty. [Insert text]

	3. Reproductive and developmental toxicity. [Insert text]

	4. Subchronic toxicity. [Insert text]

	5. Chronic toxicity. [Insert text.]

	6. Animal metabolism. [Insert text.]

	7. Metabolite toxicology. [Insert text.]

	8. Endocrine disruption. [Insert text.]

C. Aggregate Exposure  

	1. Dietary exposure. Tier III acute, short-term, and chronic dietary
exposure evaluations were performed for difenoconazole using the Dietary
Exposure Evaluation Model (DEEM-FCID™ Version 4.02) from EPA and
consumption data from the USDA NHANES “What We Eat in America”
survey, 2005-2010.  These difenoconazole exposure assessments included
all current uses plus proposed new foliar uses on rice and cotton. 
These assessments utilized residue data from field trials where
difenoconazole 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 were used in
these assessments when available; all other processing factors used the
DEEM-FCIDTM Version 7.87 defaults.  Secondary residues in beef liver and
kidney were estimated based on “maximum reasonably balanced diets”
and transfer information from feeding studies. Percent crop treated
(%CT) values were estimated based upon economic, pest, and competitive
pressures.  Drinking water estimates were selected using the higher of
the estimated drinking water concentrations (EDWCs) for surface and
ground water.

	i. Food. Acute exposure.  Acute (food only) risk assessments for
difenoconazole were performed for all population subgroups using an
acute reference dose (aRfD) of 0.25 mg/kg-bw/day, based upon a
neurotoxicity study in rats with a no observed adverse effect level
(NOAEL) of 25 mg/kg-bw/day and an uncertainty factor (UF) of 100X. The
100X safety factor includes 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 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 U.S. population
resulted in a MOE of 559 (17.9% of the aRfD of 0.25 mg/kg-bw/day).  The
most exposed sub population was children (1-2 years old) with a MOE of
281 (35.5% of the aRfD of 0.25 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 reference
dose, Syngenta believes that there is a reasonable certainty that no
harm will result from acute dietary (food) exposure to residues arising
from all current and proposed uses for difenoconazole.

Chronic exposure.  Chronic (food only) risk assessment for
difenoconazole were performed for all population subgroups using a
chronic reference dose (cRfD) of 0.01 mg/kg bw/day, based on a combined
chronic toxicity/carcinogenicity study in rats with a no observed
adverse effect level (NOAEL) of 0.96 mg/kg-bw/day and an uncertainly
factor of 100X.  The 100X safety factor includes intra- and
inter-species variations; 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 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) exposures to the
U.S. population resulted in a MOE of 996 (9.6% of the cRfD of 0.01
mg/kg-bw/day).  The most exposed sub population was all infants (<1 year
old) with a MOE of 273 (35.2% of the cRfD of 0.01 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 reference dose, Syngenta believes that there is a reasonable
certainty that no harm will result from chronic dietary (food) exposure
to residues arising from all current, pending, and proposed uses for
difenoconazole.

Cancer.  A cancer dietary assessment was not conducted.  Difenoconazole
is classified as a Group C, “possible human carcinogen,” with a
non-linear (MOE) approach for human risk characterization (CPRC
Document, 7/27/94, Memo, P. V. Shah, March 3, 2007, HED Doc. No.
0054532).

	ii. Drinking water. The Estimated Drinking Water Concentrations (EDWCs)
of difenoconazole determined as total toxic residues of difenoconazole
(CGA169374) and its degradate, CGA205375, were determined for ground
water using Tier 1 screening models SCI-GROW (version 2.3) and PRZM-GW
(version 1.07) and for surface water using Tier II Surface Water
Concentration Calculator (SWCC v1.106) for terrestrial uses and Modified
Tier 1 Rice Model for aquatic uses. The modelling was conducted to
identify the highest EDWCs of difenoconazole determined as total toxic
residues of difenoconazole (CGA169374) and its degradate, CGA205375,
from the proposed rice and cotton uses and all existing and pending
uses. For ground water, PRZM-GW provided an EDWC of 2.0 ppb for acute
and 0.66 ppb for chronic concentration based on the currently registered
use on turf. For surface water, Modified Tier-I Rice Model provided a
surface water acute EDWC of 33.4.ppb and a surface water chronic EDWC of
30.2 ppb for the proposed rice uses.  Since the surface water EDWCs
exceed the ground water EDWCs, 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 surface water EDWC of
33.4 ppb was input directly into the DEEM-FCID™ software as “water,
direct and indirect, all sources” to model the acute drinking water
exposures.  Exposure contributions at the 99.9th percentile of exposures
were determined by taking the difference between the aggregate (food +
drinking water) exposures and the food (alone) exposures for each
population subgroup.  Acute drinking water exposure U.S. population
resulted in a MOE of 25,432 (0.4% of the aRfD of 0.25 mg/kg-bw/day). 
The most exposed sub-population was all infants (<1 year old) with a MOE
of 12,723 (0.8% of the aRfD of 0.25 mg/kg/day).  Since the benchmark MOE
for this assessment was 100 and since 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 registered and proposed uses for
difenoconazole.

Chronic Exposure from Drinking Water.  The chronic surface water EDWC of
30.2 ppb was input directly into the DEEM-FCID software as “water,
direct and indirect, all sources” to model the chronic drinking water
exposures.  Chronic drinking water exposure to the U.S. population
resulted in a MOE of 1,573 (6.1% of the cRfD of 0.01 mg/kg-bw/day). 
Chronic drinking water exposure to the most exposed sub-population (all
infants, <1 year old) resulted in a MOE of 421 (22.8% of the cRfD of
0.01 mg/kg bw/day).  Since the Benchmark MOE for this assessment was 100
and since 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 registered and proposed uses for difenoconazole.

	2. Non-dietary exposure. The use of difenoconazole on ornamentals and
flower gardens (Inspire®, Ready-to-Use spray) and golf courses (Quadris
Top™, Heritage Top™, Briskway™) may result in residential handler
or post application exposures to selected subgroups.  A short-term
toxicological dermal and inhalation endpoint of 1.25 mg/kg-bw/day was
selected based upon the no observed adverse effect level (NOAEL) from a
2-generation reproductive study in rats with an uncertainty factor of
100X, which includes intra- and inter-species variations; no additional
FQPA safety factor was applied.  Exposure values were expressed in terms
of margin of exposure (MOE), which was calculated by dividing the NOAEL
by the exposure for each subgroup.  Adult gardeners (19+ years old) were
most exposed via post-application exposures from treated gardens, with a
short-term MOE of 251.  Youth gardeners (6-11 years old) were most
exposed via post-application exposures from treated gardens, with a
short term MOE of 367.  Youth golfers (11-16 years old) were most
exposed via post application exposures from treated golf course turf,
with a short-term MOE of 2,659.  Residential exposure assessments were
performed for difenoconazole to evaluate exposures resulting from
off-site drift of agricultural products into residential areas. 
Incidental exposure to consumers from spray drift from non-residential
uses were not included in the aggregate consumer risk; this approach
agrees with the EPA’s current policy and practice.  Since the
Benchmark MOE for this assessment was 100 and since the EPA generally
has no concern for exposures above the Benchmark MOE, Syngenta believes
that there is a reasonable certainty that no harm will result from
short-term residential exposure to residues arising from all current,
pending, and proposed uses for difenoconazole.

D. Cumulative Effects

	Cumulative Exposure to Substances with a Common Mechanism of Toxicity. 
Section 408(b)(2)(D)(v) 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”.  An ongoing series of studies being
conducted by the U.S. Triazole Task Force (USTTF) are designed to
provide the Agency with more complete toxicological and residue
information for 1,2,4 triazole and two conjugates, triazolylalanine and
triazolyl acetic acid, metabolites common to most of the triazole
fungicides.  Upon completion of review of those data, EPA will prepare a
more sophisticated assessment based on the revised toxicological and
exposure databases.  For the purposes of this tolerance action, the EPA
has not assumed that difenoconazole has a common mechanism of toxicity
with other substances.

E. Safety Determination

	1. U.S. population. The acute dietary exposure analysis (food plus
water) showed that exposure from all current and proposed uses of
difenoconazole would result in a MOE of 547 (18.3% of the aRfD of 0.25
mg/kg-bw/day) for the U.S. population, which exceeds the Benchmark MOE
of 100.  For the short-term aggregate exposure analysis the
corresponding food, water and residential MOEs were aggregated using the
inverse MOE approach.  The short-term aggregate exposure analysis (food,
drinking water, and residential) showed that exposure from all current
and proposed uses of difenoconazole resulted in a MOE of 191 for the
U.S. population, which exceeds the Benchmark MOE of 100.  The chronic
dietary exposure analysis (food plus water) showed that exposure from
all current and proposed uses of difenoconazole resulted in a MOE of 610
(15.7% of the cRfD of 0.01 mg/kg-bw/day) for the U.S. population, which
exceeds the Benchmark MOE of 100.  Based on the completeness and
reliability of the toxicity data supporting these petitions, Syngenta
believes that there is a reasonable certainty that no harm will result
from aggregate exposure to residues arising from all current and
proposed uses of difenoconazole, including anticipated dietary exposure
from food, water, and all other types of non-occupational residential
exposures.

	2. Infants and children. The acute dietary exposure analysis (food plus
water) showed that exposure from all current, pending and proposed uses
of difenoconazole would result in a MOE of 278 (36.0% of the aRfD of
0.25 mg/kg-bw/day) for the most sensitive population subgroup, children
1-2 years old, which exceeds the Benchmark MOE of 100.  For the
short-term aggregate exposure analysis the corresponding food, water and
residential MOEs were aggregated using the inverse MOE approach.  The
short term aggregate (food, drinking water, and residential) MOE was 215
for all infants (<1 year), which exceeds the Benchmark MOE of 100.  The
chronic dietary exposure analysis (food plus water) showed that exposure
from all current, pending, and proposed uses of difenoconazole resulted
in a MOE of 166 (58.0% of the cRfD of 0.01 mg/kg-bw/day) for the most
sensitive population subgroup, all infants <1 year old, which exceeds
the Benchmark MOE of 100.  Based on the completeness and reliability of
the toxicity data supporting these petitions, Syngenta believes that
there is a reasonable certainty that no harm will result to infants and
children from aggregate exposure to residues arising from all current
and proposed uses of difenoconazole, including anticipated dietary
exposure from food, water, and all other types of non-occupational
exposures.

F. International Tolerances

	Codex Alimentarius Commission established Maximum Residue Limits (MRLs)
for difenoconazole in various agricultural commodities including
asparagus, banana, beans, except broad bean and soya bean,  broccoli,
Brussels sprouts, cabbages, head, carrot, cauliflower,  celeriac,
celery, cherries, edible offal (mammalian), eggs, garlic,  ginseng,
grapes, leek, lettuce, head, lettuce, leaf, mango, meat, milks,
nectarine, olives, papaya, passion fruit, peach, peas (pods and
succulent/immature seeds), plums (including prunes), pome fruits,
potato, poultry meat, poultry, edible offal of, rape seed, soya bean
(dry), sugar beet, sunflower seed, tomato, tree nuts, wheat, and wheat
straw and fodder, dry..

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