Document ID: EPA-HQ-OPP-2007-0541-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2007-08-22T04:00Z

<COMPANY FEDERAL REGISTER DOCUMENT SUBMISSION TEMPLATE  (7/1/2006)>

<EPA Registration Division contact: [Janet Whitehurst, (703) 305-6129]>

 

<[ Syngenta Crop Protection, Inc.]>

<[6F7115 and 6E7120]>

<	EPA has received a pesticide petition ([PP]) from [Syngenta Crop
Protection, Inc], [Syngenta Crop Protection, Inc., PO Box 18300,
Greensboro, NC 27419] 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 by establishing tolerances for residues of
Difenoconazole,
(1-[2-[2-chloro-4-(4-chlorophenoxy)phenyl]-4-methyl-1,3-dioxolan-2-ylmet
hyl]-1H-1,2,4-triazole), in or on the following raw agricultural
commodities: Fruit, Pome , Group 11 at 0.6 parts per million (ppm),
Vegetable, Fruiting, Group 8 at 0.5 parts per million (ppm), Vegetables,
Tuberous and Corm, Subgroup 1C at 0.02 parts per million (ppm), Sugar
Beet Roots at 0.3 parts per million (ppm), Sugar Beet Tops at 7.0 parts
per million (ppm), and imported whole Papaya fruit at 0.3 parts per
million (ppm). EPA has determined that the petition contains data or
information regarding the elements set forth in section 408 (d)(2) of
the 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 difenocoanzole 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.  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. [The magnitude of residue studies are
submitted with this petition for Fruit, Pome , Group 11, Vegetables,
Fruiting, group 8, Vegetables, Tuberous and Corm, Subgroup 1C,
sugarbeets, and papaya.  All studies meet the requirements per EPA Test
Guideline 860.1000, 860.1500, and 860.1520.  The maximum difenoconazole
residues for each food commodity from any of the crops proposed in this
petition are as follows:  Pome fruit  - 0.59 ppm,  Fruiting vegetables
– 0.48 ppm, Tuberous and corm vegetables – 0.03 ppm, Sugarbeet roots
– 0.28 ppm, Sugarbeet tops - 5.8 ppm, Papaya – 0.10 ppm.]>

<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:   HYPERLINK
"http://www.epa.gov.fedrgstr/EPA-PEST/2000/September/Day-15/p23773.htm" 
http://www.epa.gov.fedrgstr/EPA-PEST/2000/September/Day-15/p23773.htm . 
A summary of the toxicological endpoints for difenoconazole used for
human risk assessment is discussed in Unit III.B. of the final rule
published in the Federal Register of September 15, 2000 (65 FR 55911)
(FRL-6589-3).

<	1. Acute toxicity.  [NA-Remove]>

<	2. Genotoxicty. [NA-Remove]>

<	3. Reproductive and developmental toxicity. [NA-Remove]>

<	4. Subchronic toxicity. [NA-Remove]>

<	5. Chronic toxicity. [NA-Remove]>

<	6. Animal metabolism. [NA-Remove]>

<	7. Metabolite toxicology. [NA-Remove]>

<	8. Endocrine disruption. [NA-Remove]>

<C. Aggregate Exposure>

<	1. Dietary exposure. [Tier I chronic and acute dietary exposure
evaluations were made for difenoconazole
(1-[2-[2-chloro-4-(4-chlorophenoxy)phenyl]-4-methyl-1,3-dioxolan-2-ylmet
hyl]-1H-1,2,4-triazole) using the Dietary Exposure Evaluation Model
(DEEM-FCIDTM), version 2.14 from Exponent for all registered and
proposed uses.  These assessments included established tolerances for
residues of difenoconazole in or on imported bananas (0.2 ppm), barley
grain (0.1 ppm), barley hay and straw (0.05 ppm), canola (0.01 ppm),
cottonseed and gin byproducts (0.05 ppm), imported grapes (0.1 ppm),
imported rye grain (0.1 ppm), sweet corn forage, stover, and kernel plus
cob with husks removed (0.01 ppm), and wheat (0.1 ppm).  These
assessments also included proposed tolerances for residues of
difenoconazole in or on foliar-treated pome fruit (0.6 ppm), fruiting
vegetables (0.5 ppm), tuberous and corm vegetables (0.02 ppm), sugar
beet roots (0.3 ppm), sugar beet tops (7.0 ppm), and imported whole
papaya fruit (0.3 ppm).  All tolerances were established or proposed as
a result of residue field trials conducted at the maximum labeled
treatment rate and harvested at the minimum pre-harvest interval (PHI). 
Experimental processing factors were used for sugar beet sugar (0.33X),
sugar beet molasses (0.58X), tomato paste (1.61X), tomato puree (0.55X),
and apple juice (0.03X); all other processing factors utilized either
the DEEM™ (version 7.87) default processing factors or theoretical
concentration factors listed in OPPTS 860.1520.  Anticipated residues in
meat, milk, and eggs were calculated by constructing a theoretical
worst-case diet containing tolerance-level residues that provides a
nutritionally balanced mixture of feeds (typically 30% protein and 70%
carbohydrates).  Percent of crop treated values were conservatively set
at 100% for all uses.  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 1994-96 consumption database and the
Supplemental CSFII children’s survey (1998) consumption database.]>

<Food. [Acute Exposure.  The difenoconazole acute dietary (food only)
risk assessment was performed for females 13 to 49 years old using an
acute reference dose (aRfD) of 0.25 mg/kg-bw/day based upon a
developmental toxicity study in rabbits with a no observable 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 population subgroup.  In addition,
exposure was expressed as a percent of the acute reference dose (%aRfD).
 An aRfD for the general population, including infants and children, has
not been established since an endpoint of concern attributable to a
single oral dose has not been identified.  At the 95th percentile, acute
(food only) exposure to females 13 to 49 years old resulted in a MOE of
9,730 (1.03% 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 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 and proposed uses for
difenoconazole.

Chronic Exposure.  The difenoconazole chronic dietary (food only) risk
assessment was performed for all population subgroups using a chronic
reference dose of 0.01 mg/kg-bw/day based upon a 2-year chronic feeding
study in rats with a no observable adverse effect level (NOAEL) of 1.00
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
population subgroup.  In addition, exposure was expressed as a percent
of the chronic reference dose (%RfD).  Chronic (food only) exposure to
the U.S. population resulted in a MOE of 787 (12.7% of the RfD of 0.01
mg/kg-bw/day).  The most exposed sub-population was children (1-2 years
old) with a MOE of 244 (41.0% of the RfD 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 below 100% of the RfD, Syngenta
believes that there is a reasonable certainty that no harm will result
from dietary (food only) exposure to residues arising from the current
and proposed uses for difenoconazole.

Cancer.  A cancer dietary assessment was not conducted for
difenoconazole because the cancer NOAEL is higher than the chronic RfD,
therefore the chronic dietary risk estimate is more protective.  (Reddy,
Levy, Dow, HED, 05-Aug-2005)]>

<	ii. Drinking Water. [The EPA uses FIRST (FQPA Index Reservoir
Screening Tool) as a Tier 1 screening model to estimate pesticide
concentrations in surface water, and SCI-GROW (Screening Concentration
In Ground Water) as a Tier 1 screening model to estimate pesticide
concentrations in ground water.  Neither model includes the impact of
processing raw water (mixing, dilution, or treatment) prior to
distribution as drinking water.  The primary use of these models by the
Agency is to provide a conservative approximation of the estimated
environmental concentration of specific pesticides in drinking water. 
The highest use rate for current or proposed crop uses adjusted for
percent cropped area (PCA) for difenoconazole in the United States is a
foliar application to ornamentals.  This use, along with a similar use
pattern for fruiting vegetables and potatoes, was used to assess the
potential environmental exposure to drinking water.  For ground water
(SCI-GROW) modelling, Syngenta has determined an Estimated Drinking
Water Concentration (EDWC) of difenoconazole at the highest use rate (4
x 0.13 lb a.i./A foliar applications) of 0.00845 ppb.  Using the same
difenoconazole foliar application use rate, with a 7-day interval
between applications, for surface water modelling (FIRST), the acute
EDWC was 10.753 ppb; using the fruiting vegetables and potatoes use rate
of 4 x 0.113 lb a.i./A with a 7-day interval by aerial application gave
the highest chronic (cancer and non-cancer, annual average) EDWC of
2.710 ppb.  Since the surface water EDWCs exceed the ground water EDWC,
the FIRST surface water values were used for comparison purposes and
will be considered protective for any ground water concentration
concerns.   

and proposed uses of difenoconazole directly into the DEEM-FCID™
software.  At the 95th percentile, acute exposure (food and water) for
females 13 to 49 years old resulted in a combined food and water MOE of
8,841 (1.13% 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 below 100% of the aRfD, Syngenta believes that there is a
reasonable certainty that no harm will result from acute aggregate (food
+ water) exposure to residues arising from the current and proposed uses
for difenoconazole.

Chronic Exposure from Drinking Water.  The annual average surface water
EDWC of 2.710 ppb was used to calculate the acute drinking water
exposure values for all population subgroups.  Chronic EDWCs were
incorporated as “water, direct and indirect, all sources” with food
residues for all current and proposed uses of difenoconazole directly
into the DEEM-FCID™ software.  Chronic exposure (food and water) to
the U.S. population resulted in a combined food and water MOE of 753
(13.3% of the RfD of 0.01 mg/kg-bw/day).  The most exposed
sub-population was children 1 to 2 years old with a combined food and
water MOE of 239 (41.8% of the chronic RfD 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 below 100% of the RfD, Syngenta
believes that there is a reasonable certainty that no harm will result
from chronic aggregate (food + water) exposure to residues arising from
the current and proposed uses for difenoconazole.]>

<	2. Non-dietary exposure. [Risk assessments were conducted for
non-dietary uses of difenoconazole because it is proposed for use on
residential landscape ornamentals and for use indoors as a materials
protection additive to paint, wallboard, paper, caulk, rubber, wood,
etc.  Difenoconazole may be applied up to five times to landscape
ornamentals at up to 0.13 lbs. a.i./A (not to exceed 0.56 lbs. a.i./A
per year).  For materials protection uses, difenoconazole may be added
to paint or other substrate at up to 0.01% a.i. by weight.  Short-term
handler risk assessments were required for residential exposure to
difenoconazole used for ornamental landscape plants around the home and
the application of paint treated with DIFENO-Shield.  The exposure
scenarios assessed included adults making hand-wand or hose end
applications to ornamentals, and adults applying paint with a roller or
an airless sprayer.  A dermal penetration factor (DPF) of 48% was used
in the landscape ornamental assessment, and a rate of 75% was used in
the paint assessment.  A non-dietary short-term NOAEL of 25 mg/kg/day
was used.  These exposures were of short-term duration only; there were
no intermediate-term exposures based on these use patterns.  The target
population was adults; toddlers were not anticipated to be exposed in
these use scenarios.    

The worse case short-term margin of exposure (MOE) was for adults using
an airless sprayer to apply paint, with a combined (inhalation and
dermal) MOE of 1,940.  Since 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 either proposed residential use.]>

<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. [Using the conservative assumptions described
above, and based on the completeness and reliability of the toxicity
data, the chronic aggregate exposure analysis (food and water) showed
that exposure from all current, pending, and proposed uses of
difenoconazole resulted in a chronic aggregate MOE of 753 for the U.S.
population.  Since the worst case chronic aggregate MOE of 753 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 chronic
aggregate exposures arising from all current, pending, and proposed uses
of difenoconazole.  An acute aggregate exposure analysis (food and
water) was not performed for the U.S. population because the only
population subgroup for which a toxicological endpoint of concern has
been established is females 13-49 years old.]>

<	2. Infants and children. [Using the conservative assumptions described
above, and based on the completeness and reliability of the toxicity
data, the chronic aggregate exposure analysis (food and water) showed
that exposure from all current, pending, and proposed uses of
difenoconazole uses resulted in a chronic aggregate MOE of 239 for
children 1-2 years old.  Since the worst case chronic aggregate MOE of
239 for children 1-2 years exceeds the benchmark MOE of 100, Syngenta
believes that there is a reasonable certainty that no harm will occur to
infants and children from chronic aggregate exposures arising from all
current, pending, and proposed uses of difenoconazole.  An acute
aggregate exposure analysis (food and water) was not performed for
infants or children because the only population subgroup for which a
toxicological endpoint of concern has been established is females 13-49
years old.]>

<F. International Tolerances>

<	[There are no Codex maximum residue levels (MRLs) established for
residues of difenoconazole in any commodity.  In Canada, MRLs have been
established for residues of difenoconazole in barley (0.01 ppm),
canola/rapeseed (0.03 ppm), eggs (0.05 ppm), corn grain, field (0.01
ppm), meat and meat by-products of cattle, goats, hogs, poultry and
sheep (0.05 ppm), milk (0.01 ppm), mustard seed (0.05 ppm), and wheat
(0.1 ppm).  Mexico relies upon current U.S. tolerances and has not
established national MRLs for difenoconazole in any commodity. 
Difenoconazole is currently registered for foliar uses on grapes in
France and Switzerland, and proposed for use in Chile and South Africa. 
Difenoconazole is also currently registered for foliar uses on pome
fruit in Australia, France, New Zealand, South Africa, and Switzerland,
and proposed for registration in Chile and Germany.

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n the United States, tolerances are either pending or established for
residues of difenoconazole in imported bananas (0.2 ppm), barley grain
(0.1 ppm), barley forage and hay (0.05 ppm), canola (0.01 ppm),
cottonseed and gin byproducts (0.05 ppm), imported grapes (0.10 ppm),
imported rye grain (0.1 ppm), sweet corn (0.01 ppm), and wheat (0.1
ppm).  When established U.S. tolerances are compared to Canadian MRLs, a
3X difference is observed in canola (0.03 ppm Canada, 0.01 ppm USA) and
a 10X difference is observed in barley (0.10 ppm USA, 0.01 ppm
Canada).]>