Document ID: EPA-HQ-OPP-2011-0300-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2011-07-20T04:00Z

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EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE
PETITION

EPA Registration Division contact: Sidney Jackson (703) 305-7610

Interregional Research Project Number 4 

PP# 1E7852

	EPA has received a pesticide petition (PP) 1E7852 from Interregional
Research Project Number 4 (IR-4), IR-4 Project Headquarters, Rutgers,
The State University of New Jersey, 500 College Road East, Suite 201W, 
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 180.475 by establishing a tolerance for residues of Difenoconazole,
1-[2-[2-chloro-4-(4-chlorophenoxy)phenyl]-4-methyl-1,3-dioxolan-2-ylmeth
yl]-1H-1,2,4,-triazole, including its metabolites and degradates, in or
on the raw agricultural commodities; Vegetable, fruiting, group 8-10 at
0.6 parts per million (ppm), Fruit, citrus, group 10-10 at 0.6 (ppm),
Fruit, pome, group 11-10 at 1.0 (ppm) and Low growing berry subgroup
13-07G, except cranberry at 2.5 ppm, and by  amending the  established
tolerance in or on the raw agricultural commodity Vegetable, tuberous
and corm, subgroup 1C at 4.0 ppm.  In addition, the petition proposes to
remove established tolerance in or on the raw agricultural commodities; 
potato, processed waste at 0.04 ppm, vegetables, fruiting, group 8 at
0.6 ppm,  Fruit, citrus, group 10 at 0.6 ppm, Fruit, pome, group 11 at
1.0 ppm and strawberry at 2.5 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 support 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. i. Food.  Syngenta Crop Protection, Inc. has
submitted a practical analytical method (AG-575B, master record
identification (MRID) No. 428065-04) 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.  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. 

ii. Livestock.  Syngenta Crop Protection, Inc. 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. IR-4 conducted magnitude of residue trials on
potatoes under OPPTS 860.1500 to support the requested use of
difenoconzole. These residue trials satisfy the requested tolerance on
potato. 

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://edocket.access.gpo.gov/2010/2010-9759.htm.  A summary of the
toxicological endpoints for difenoconazole used for human risk
assessment is discussed in Unit III.A and B. of the final rule published
in the Federal Register of April 28, 2009 (75 FR pages 22256-22263)
(FRL-8817-3).

	1. Acute toxicity.  

	2. Genotoxicity. 

	3. Reproductive and developmental toxicity. 

	4. Subchronic toxicity. 

	5. Chronic toxicity. 

	6. Animal metabolism. 

	7. Metabolite toxicology. 

	8. Endocrine disruption. 

C. Aggregate Exposure

ctors utilized either the DEEM™ (version 7.87) default processing
factors or theoretical concentration factors listed in OPPTS860.1520. 
Anticipated residues in meat, milk, and eggs were calculated by
constructing a theoretical “maximum reasonably balanced diet” (MRBD)
using the OPPTS 860.1000 Table 1 feedstuffs (June 2008 revision). 
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.  All consumption data for these
assessments were taken from the USDA’s Continuing Survey of Food
Intake by individuals (CSFII) with the 1994-1996 consumption database
and the Supplemental CSFII children’s survey (1998) consumption
database.

	i. Food.  The difenoconazole acute food risk assessment was performed
using an acute reference dose (aRfD) of 0.25 mg/kg-bw/day based upon an
acute neurotoxicity study in rats with a no observed adverse effect
level (NOAEL) of 25 mg/kg-bw/day and an uncertainty factor of 100X.  The
100X safety factor includes intra- and inter-species variations; no
additional FQPA safety factor was applied.  For the purpose of 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 subpopulation.  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 864 (11.6% 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 481
(20.8% of the aRfD of 0.25 mg/kg-bw/day).  Because the Benchmark MOE for
this assessment is 100 and the EPA generally has no concern for
exposures above the Benchmark 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 all current
and pending uses plus the proposed post-harvest use on potatoes.

Chronic Exposure.  The difenoconazole chronic food risk assessment was
performed for all population subgroups using a chronic reference dose of
0.01 mg/kg-bw/day based upon 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 uncertainty factor of 100X.  The 100X safety factor
includes intra- and inter-species variations; no additional FQPA safety
factor was applied.  For the purpose of 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
subpopulation.  In addition, exposure was expressed as a percent of the
chronic reference dose (%cRfD).  Chronic food exposure to the U.S.
population resulted in a MOE of 603 (15.9% of the cRfD of 0.01
mg/kg-bw/day).  The most exposed subpopulation was children (1-2 years
old) with a MOE of 241 (39.9% of the cRfD of 0.01 mg/kg-bw/day). 
Because the Benchmark MOE for this assessment is 100 and the EPA
generally has no concern for exposures above the Benchmark 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 all current and pending uses plus the proposed post-harvest
use on potatoes.

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 were determined using Tier 1 screening model SCI-GROW
(version 2.3) which estimates pesticide concentration in ground water
and Tier II PRZM/EXAMS (PE version 5.0) which estimates surface water
exposures.  EDWCs for difenoconazole from currently registered and
pending uses were determined.  For the proposed post-harvest use on
potatoes, there will be no environmental exposure to ground water and/or
surface water.  Based on the SCI-GROW modeling results, the highest
groundwater EDWC for difenoconazole was 0.0123 ppb (acute and chronic)
based on the currently registered citrus use.   Based on Tier II
PRZM/EXAMS modeling for surface water conducted by EPA (D367382), the
currently registered grape use provided the highest EDWCs of 15.8 ppb
and 10.4 ppb for acute and chronic, respectively (adjusted for 0.87
Percent Cropped Area, 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.  

The annual average (chronic) EDWC of 10.4 ppb (0.0104 ppm) for surface
water was input into the DEEM-FCID™ software as “water, direct and
indirect, all sources” to obtain the chronic dietary exposure from
water.  Drinking water exposures were determined by taking the
difference between the aggregate exposures (food + drinking water) and
food exposures (food only) for each population subgroup.  Chronic
drinking water exposure to the U.S. population resulted in a MOE of
4,379 (2.2% 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 1,336 (7.2% of
the cRfD of 0.01 mg/kg-bw/day).  Because the Benchmark MOE for this
assessment is 100 and the EPA generally has no concern for exposures
above the Benchmark or below 100% of the cRfD, Syngenta believes that
there is a reasonable certainty that no harm will result from chronic
exposure to drinking water residues arising from all current and pending
uses plus the proposed post-harvest use on potatoes.

	2. Non-dietary exposure. Difenoconazole is a broad spectrum fungicide
used in residential applications for landscape ornamentals and materials
protection.  Difenoconazole is formulated in Difenoconazole 2EC for
protection of landscape ornamentals and in DIFENO-Shield™ as an
additive to paint.  For landscape ornamentals, these residential
exposure assessments were run in support of registered uses of
Difenoconazole 2EC at a maximum single application rate of 8.0 oz
product/A (0.13 lb ai/A) for prevention of diseases in roses.  For
paints containing DIFENO-Shield™, these exposure assessments assumed a
maximum application rate of 0.01% ai w/w.  The toxicological endpoints
established by the EPA in the August 2007 HED difenoconazole risk
assessment were used (NOAEL = 1.25 mg/kg-bw/day).  The worse case
short-term margin of exposure (MOE) for all uses assessed was for adults
applying paint with an airless sprayer, with a combined (inhalation and
dermal) MOE of 387.  Because the residential MOE exceeds the EPA’s
Benchmark MOE of 100, Syngenta believes that there is a reasonable
certainty that no harm will result from short-term exposures arising
from all current and pending uses plus the proposed post-harvest use on
potatoes.

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

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and proposed uses of difenoconazole resulted in a MOE of 530 for the
U.S. population.  Because the worst case aggregate MOE of 205 for
short-term aggregate exposures exceeds the Benchmark MOE of 100,
Syngenta believes that there is a reasonable certainty that no harm will
occur to the U.S. Population from acute, short-term, and chronic
aggregate exposures arising from all current and pending uses plus the
proposed post-harvest use on potatoes.

	2. Infants and children. Using the conservative assumptions described
above, and based on the completeness and reliability of the toxicity
data, the acute aggregate exposure analysis for all current, pending and
proposed uses of difenoconazole resulted in a MOE of 466 for children
1-2 years old.  The short-term aggregate exposure analysis for all
current, pending and proposed uses of difenoconazole resulted in a MOE
of 333 for children 1-6 years old.  The chronic aggregate exposure
analysis for all current, pending and proposed uses of difenoconazole
resulted in a MOE of 223 for children 1-2 years old.  Because the worst
case aggregate MOE for chronic exposures of 223 for children 1-2 years
old exceeds the Benchmark MOE of 100, Syngenta believes that there is a
reasonable certainty that no harm will occur to infants and children
from acute, short-term, and chronic aggregate exposures arising from all
current and pending uses plus the proposed post-harvest use on potatoes.

F. International Tolerances

	Codex Maximum Residue Limits (MRLs) for residues of difenoconazole per
se have been established on a number of commodities including banana,
grapes, meat milk eggs, milks, peach, plums, pome fruit, potatoes,
soybeans, tomatoes, and wheat.

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