Document ID: EPA-HQ-OPP-2012-0048-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2012-04-04T04:00Z

<EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE
PETITIONS PUBLISHED IN THE FEDERAL REGISTER  (5/5/2011)>

<EPA Registration Division contact: [Shaja Joyner (PM-20) 703-308-3194]>

 

<INSTRUCTIONS:  Please utilize this outline in preparing the pesticide
petition.  In cases where the outline element does not apply, please
insert “NA-Remove” and maintain the outline. Please do not change
the margins, font, or format in your pesticide petition. Simply replace
the instructions that appear in green and brackets, i.e., “[insert
company name],” with the information specific to your action.>

<TEMPLATE:>

<[Syngenta Crop Protection]>

<[Insert petition number]>

<	EPA has received a pesticide petition ([insert petition number]) from
[Syngenta Crop Protection], [P.O. Box 18300, Greensboro, NC 27409]
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.>

<(Options (pick one)>

<	1. by establishing a tolerance for residues of>

<	[cyprodinil:  2-pyrimidinamine, 4-cyclopropyl-6-methyl-N-phenyl-] in
or on the raw agricultural commodity [] at []  >

	

Leafy petioles subgroup 04B, at 30 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  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 cyprodinil is adequately
understood for the purpose of the proposed tolerances.  The metabolism
of cyprodinil has been characterized in plants and animals. No
toxicologically significant metabolites have been identified. The
metabolism profile supports the use of an analytical enforcement method
that accounts for only parent cyprodinil.

>

<2. Analytical method. Syngenta Crop Protection has developed and
validated analytical methodology for enforcement purposes. This method
(Syngenta Crop Protection Method AG-631B) has passed an Agency petition
method validation for several commodities and is currently the
enforcement method for cyprodinil. 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 tolerance, eight crop-field trials were
conducted with various commercially available celery cultivars, and the
soil types and meteorological conditions at the eight trial sites
adequately represented the diversity of conditions under which celery
may be commercially grown.  These trial sites satisfied the requirements
of OPPTS 860.1500 for number and regional distribution.  The study
design consisted of 2 plots at each trial site: a non-treated control
(UTC) plot and a treated (TRT) plot.  The TRT plot received four
broadcast foliar applications of 14 oz product/acre/application (or 56
oz product/acre/ season), which equates to 0.328 lb cyprodinil/acre +
0.219 lb fludioxonil/acre (or a seasonal rate of 1.3 lb cyprodinil/acre
+ 0.9 lb fludioxonil/acre).  The treatments were applied with a tank-mix
volume of 15 - 40 gallons/acre (GPA) at the minimum 7-day retreatment
interval (RTI), and the raw agricultural commodity (RAC) was harvested
on the day of the last application to support a 0-day pre-harvest
interval (PHI).  This use pattern would be the ‘worst-case’
application as per the proposed-use label.

                                                                        
                                                                        
                     

B. Toxicological Profile>

<>

An assessment of toxic effects caused by cyprodinil is discussed in Unit
III.A. and Unit III.B. of the Federal Register dated June 22, 2001 (66
FR 33478) (FRL-6778-7).    

The technical cyprodinil product is classified in toxicity categories
III & IV [CAUTION] based on acute oral, dermal, inhalation toxicity and
eye/skin irritation studies. The formulated end use products are also
classified in toxicity categories III & IV [CAUTION] based on similar
studies.

                                                                        
                                   

<1. Acute toxicity.  The acute toxicity data of cyprodinil show that
this chemical is >not acutely toxic by the oral, inhalation and dermal
routes of exposure. Technical cyprodinil, however, is a dermal
sensitizer.

<2. Genotoxicty. Cyprodinil was shown to be negative in studies for>
point mutation, for chromosome aberration, and for DNA repair.  These
results indicate that cyprodinil is unlikely to initiate cancer or cause
inheritable genetic defects.

<3. Reproductive and developmental toxicity.  >Reproductive Toxicity: 
In a two-generation reproduction study in rats, the NOEL for maternal
systemic toxicity is 1000 ppm and the NOEL for reproductive toxicity is
1000 ppm.  Developmental Toxicity:  Cyprodinil is not teratogenic. In
the rabbit developmental toxicity study, no developmental toxicity was
noted even at the highest dose tested (HDT) of 400 mg/k. In the rat
developmental toxicity study, the developmental and maternal NOELs were
both 200 mg/kg based on reduced ossification and body weight in pups and
decreased food consumption/weight gain in dams at 1000 mg/kg (HDT). 

<4. Subchronic toxicity. Subchronic Oral Toxicity: In subchronic
studies, the lowest NOEL is 50 ppm based on a rat study.  Subchronic
Dermal Toxicity: For female rats receiving dermal applications of
cyprodinil; NOEL was 5 mg/kg/.day; the NOEL for the male rats in this
study is 125 mg/kg/day. 

>

<5. Chronic toxicity. Chronic Oral Toxicity: Two chronic studies found
NOELs of 75 ppm in a 24-month rat study and 2500 ppm in a one-year
Beagle study. Neither study found evidence of carcinogenicity for
cyprodinil. 

>

<6. Animal metabolism. The metabolism of cyprodinil in rats is
adequately understood.   

                                            >

<7. Metabolite toxicology. The residue of concern for tolerance setting
purposes is the parent compound. The EPA has reviewed the hazard profile
of the pryimidine metabolites (CGA-249287, NOA-422054) of cyprodinil.
EPA has concluded that the toxicity of the CGA-249287 and NOA-422054
metabolites is no greater than that of the parent.

>

<8. Endocrine disruption. Cyprodinil does not belong to a class of
chemicals known or suspected of having adverse effects on the endocrine
system. Developmental toxicity studies in rats and rabbits and a
reproduction study in rats gave no indication that cyprodinil might have
any effects on endocrine function related to development and
reproduction. The chronic studies also showed no evidence of a long-term
effect related to the endocrine system.                                 
   

>

<C. Aggregate Exposure>

<1. Dietary exposure. Tier II acute and chronic dietary exposure
evaluations were performed for cyprodinil using the Dietary Exposure
Evaluation Model (DEEM-FCIDTM, version 2.16) from Exponent.  These
cyprodinil exposure assessments included all current and pending uses
and a proposed use on celery at a 0-day pre-harvest interval (PHI).  The
proposed celery and pending spinach uses combined with the existing use
on leafy vegetables (Group 4A) completes the representative crops for
all leafy vegetables (Crop Group 4).  These assessments utilized residue
data from field trials where cyprodinil was applied at the maximum
intended use rate and samples were harvested at the minimum PHI to
obtain maximum residues.  Empirically derived processing factors for
apple juice (0.39X), apple pomace (5.22X), grape juice (0.29X), dried
prune (2.05X), tomato puree (0.52X), and tomato paste (2.3X) were used
in these assessments.  All other processing factors used the DEEM-FCIDTM
Version 7.87 defaults.  All consumption data for these assessments was
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.  The percent of crop
treated value was assumed to be 100% for all commodities.  Secondary
residues in beef liver and kidney were estimated based on “maximum
reasonably balanced diets” and transfer information from feeding
studies.

>

<i. Food.  Acute exposure.  The acute dietary (food only) risk
assessment for females 13-49 years old (the only population subgroup for
which an acute toxicological endpoint has been established) was
performed using an acute reference dose (aRfD) of 1.5 mg/kg-bw/day,
based upon a rabbit study with a no observed adverse effect level
(NOAEL) of 150 mg/kg-bw/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 NOAEL by the exposure for each population
subgroup.  In addition, exposure was expressed as a percent of the acute
reference dose (%aRfD).  Acute food exposure to the females 13-49 years
subpopulation resulted in a MOE of 2,434 (4.1% of the aRfD of 1.5
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
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, pending, and proposed uses for cyprodinil.

                                                                        
                                                                        
                                                                        

Chronic exposure.  The chronic reference dose (RfD) for cyprodinil is
0.03 mg/kg-bw/day, based on a chronic rat study with a NOAEL of 2.7
mg/kg-bw/day and an uncertainly factor 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 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 exposures to the U.S.
population resulted in a MOE of 867 (10.4% of the cRfD of 0.03
mg/kg-bw/day).  Chronic food exposures to the most sensitive
subpopulation (children 1 - 2 years old) resulted in a MOE of 313 (28.7%
of the cRfD of 0.03 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 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 cyprodinil.

>

<ii. Drinking water. The Estimated Drinking Water Concentrations (EDWCs)
of cyprodinil and its degradate CGA249287, reported as combined total
residues (cyprodinil plus CGA249287), were determined for the currently
registered uses as well as proposed uses on celery, spinach, and peppers
using Tier l SCI-GROW (version 2.3), which estimates pesticide
concentrations in ground water and Tier II PRZM/EXAMS (PE version 5.0)
which estimates pesticide concentrations in surface water.  For ground
water, the currently registered uses on almond and grapes and the
pending use on tree nuts provided the highest combined EDWC of 0.1076
ppb (acute and chronic).  For surface water, the proposed use on peppers
provided the highest combined acute EDWC of 46.314 ppb and the currently
registered use on grapes provided the highest combined chronic EDWC of
22.691 ppb.  The surface water EDWCs have been corrected for a 0.87 PCA
factor.  Since the surface water EDWCs exceed the ground water EDWC, the
surface water values will be used for risk assessment purposes and
considered protective for any ground water exposure concerns.

 was incorporated with food residues as “water, direct and indirect,
all sources” directly into the DEEM-FCID™ software to model the
aggregate (food and water) exposures.  The acute drinking water 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 (only) exposures for each population subgroup. 
Acute drinking water exposure at the 99.9th percentile for females
(13-49 years), the only population subgroup for which an acute
toxicological endpoint has been established, resulted in a MOE of 42,206
(0.2% of the aRfD of 1.5 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, pending, and proposed
uses of cyprodinil.

nd indirect, all sources” directly into the DEEM-FCID™ software to
obtain chronic dietary (food and water) exposures.  Chronic drinking
water exposure to the U.S. population resulted in a MOE of 5,645 (1.6%
of the cRfD of 0.03 mg/kg-bw/day).  The most sensitive subpopulation was
all infants, with a MOE of 1,722 (5.2% of the cRfD of 0.03
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 drinking water exposure to residues arising
from all current, pending and proposed uses of cyprodinil.

>

<2. Non-dietary exposure.  Cyprodinil is not currently registered for
any uses that would result in residential handler
(mixer/loader/applicator) exposure.  A new product label for
Palladium®, containing cyprodinil and fludioxonil, allows professional
applications to ornamental plants in residential settings.  No
post-application residential exposure assessment is required because
post-application exposure to adults and children from ornamental
applications is negligible.

>

<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”.  The EPA does not have, at this time,
available data to determine whether cyprodinil has a common mechanism of
toxicity with other substances or how to include this pesticide in a
cumulative risk assessment.  For the purposes of this tolerance action,
the EPA has not assumed that cyprodinil 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 cyprodinil
uses resulted in a MOE of 752 (12.0% of the cRfD of 0.03 mg/kg-bw/day)
for the U.S. population, which exceeds the Benchmark MOE of 100.  A
cancer exposure analysis was not performed, since there is no evidence
of human carcinogenic potential for cyprodinil.  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 from all current, pending,
and proposed uses of cyprodinil.

>

<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
cyprodinil uses resulted in a MOE of 289 (31.1% of the cRfD of 0.03
mg/kg-bw/day) for children 1-2 years old, which exceeds the Benchmark
MOE of 100.  A cancer exposure analysis was not performed, since there
is no evidence of human carcinogenic potential for cyprodinil.  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 from all current, pending,
and proposed uses of cyprodinil.

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>

<F. International Tolerances>

<Codex maximum residue levels have been established for residues of
cyprodinil in or on almonds, apples, barley, beans (except broad bean
and soya bean), cucumbers, dried grapes (currants, raisins and
sultanas), eggplant, eggs, grapes, lettuce (head & leaf), meat &
meat-by-products, milk, onions (bulb), pears, peppers (sweet), poultry,
prunes, raspberries, squash (summer), stone fruits, straw and fodder of
cereal grains, strawberries, tomatoes, wheat, and wheat bran.

  >

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