Document ID: EPA-HQ-OPP-2015-0646-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2015-10-21T04:00Z

EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE
PETITIONS PUBLISHED IN THE FEDERAL REGISTER (3/30/2015)

EPA Registration Division contact: [Hope Johnson (PM-21) 703-305-5410]

 

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

5F8358

	EPA has received a pesticide petition (5F8358) 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 180.532.

	1. by establishing the tolerances for residues of

	

	cyprodinil:  4-cyclopropyl-6-methyl-N-phenyl-2-pyrimidinamine in or on
the raw agricultural commodity 

	

Vegetable, tuberous and corm, subgroup 1C; at 0.01 parts per million
(ppm)

Potato, wet peel; at 0.03 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, Syngenta 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
cyprodinil 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 cyprodinil 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/2012/2012-20235.htm.  A summary of the
toxicological endpoints for cyprodinil used for human risk assessment is
discussed in Unit III.A and B. of the final rule published in the
Federal Register of August 17, 2012 (77 FR pages 49732-49738)
(FRL-9359-7).

 

1. Acute toxicity.  

	2. Genotoxicty. 

	3. Reproductive and developmental toxicity. 

	4. Subchronic toxicity. 

	5. Chronic toxicity. 

	6. Animal metabolism. 

	7. Metabolite toxicology. 

	8. Endocrine disruption. 

                                                                        
                                 

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-FCID™ Version 3.16) from Exponent and
consumption data from the USDA NHANES “What We Eat in America”
survey, 2003-2008.  These cyprodinil exposure assessments included all
registered uses and pending uses, as well as a proposed new foliar use
for potatoes.  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 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.  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. 
Drinking water estimates were incorporated directly into the acute and
chronic dietary exposure assessments using the highest estimated
drinking water concentrations (EDWCs) for surface and ground water.  

i. Food.  Acute exposure.  The acute dietary (food only) risk
assessments for cyprodinil were performed for all population subgroups
using an acute reference dose of 2.0 mg/kg-bw/day based upon an acute
neurotoxicity study in rats with a no observed adverse effect level
(NOAEL) of 200 mg/kg-bw/day and an uncertainty factor of 100X to account
for intra- and inter-species variations.  No additional FQPA safety
factor was applied.  For the purpose of the acute aggregate risk
assessments, 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).  At the
99.9th percentile, acute (food only) exposure to the U.S. population
resulted in a MOE of 3,154 (3.2% of the aRfD of 2.0 mg/kg-bw/day).  The
most exposed sub-population was all infants <1 year old with a MOE of
1,536 (6.5% of the aRfD of 2.0 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 all
current, pending, and proposed uses of cyprodinil.

                                                                        
                                                                        
                                                                        

Chronic exposure.  The chronic dietary (food only) risk assessments were
performed for all population subgroups using a chronic reference dose of
0.027 mg/kg-bw/day based upon a two year chronic
toxicity/carcinogenicity study in rats with a no observed adverse effect
level (NOAEL) of 2.7 mg/kg-bw/day and an uncertainty factor of 100X to
account for 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 (%cRfD).  Chronic
(food only) exposure to the U.S. population resulted in a MOE of 796
(12.6% of the cRfD of 0.027 mg/kg-bw/day).  The most exposed
sub-population was children 1-2 years old with a MOE of 274 (36.6% of
the cRfD of 0.027 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 all current,
pending, and proposed uses of cyprodinil.

Cancer.  Cyprodinil is classified as “not likely” to be carcinogenic
to humans. Therefore, a cancer risk assessment was not performed 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 currently
registered uses (including almond and pistachio), all pending uses, and
proposed uses for representative crops of Tree Nut Crop Group 14-12. 
The Tier l SCI-GROW (version 2.3) model was used to estimate ground
water concentrations, and the Tier II Surface Water Concentration
Calculator (v. 1.106) was used to estimate surface water concentrations.
For ground water, the currently registered uses on almond and grapes
provided a combined EDWC of 0.086 ppb (acute and chronic).   For surface
water, the registered use on grapes provided a combined acute EDWC of
48.2 ppb and a combined chronic EDWC of 25.5 ppb.  No Percent Cropped
Area adjustments were made to the surface water EDWCs.  Since the
surface water EDWCs exceed the ground water EDWC, surface water values
were used for risk assessment purposes and considered protective for any
ground water exposure concerns.

Acute Exposure from Drinking Water:  The acute surface water EDWC of
48.2 ppb was input directly into the DEEM-FCID™ software as “water,
direct and indirect, all sources” to model the acute drinking water
exposures. The acute drinking water exposure contributions at the 99.9th
percentile of exposures was 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
to the U.S. population resulted in a MOE of 126,024 (0.1% of the aRfD of
2.0 mg/kg-bw/day). The most sensitive subpopulation was children 3-5
years old, with a MOE of 91,491 (0.1% of the aRfD of 2.0 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 acute drinking water exposure to residues
arising from all current, pending, and proposed uses of cyprodinil.

Chronic Exposure from Drinking Water:  The chronic surface water EDWC of
25.5 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 5,057 (2.0% of the cRfD of 0.027 mg/kg-bw/day). 
The most sensitive subpopulation was all infants (<1 year old), with a
MOE of 1,961 (5.1% of the cRfD of 0.027 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 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.  The 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. Residential
exposure assessments were performed for cyprodinil to evaluate exposures
resulting from off-site drift of agricultural products into residential
areas; the most-exposed subgroup was children 1-6 years old via
hand-to-mouth incidental oral exposures from play activities on turf,
with a MOE of 1,472 (Benchmark MOE = 100).  Incidental exposure to
consumers from spray drift from non-residential uses were not included
in the aggregate consumer risk estimates in accordance with EPA’s
current policy and practice.

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. The acute dietary exposure analysis (food plus
water) showed that exposure from all current, pending, and proposed uses
of cyprodinil would result in a MOE of 3,077 (3.3% of the aRfD of 2.0
mg/kg-bw/day) for the general U.S. population, 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 cyprodinil resulted in a MOE of 688 (14.6% of the cRfD of 0.027
mg/kg-bw/day) for the general U.S. population, which also 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 to
residues arising from all current, pending, and proposed uses of
cyprodinil.

2. Infants and children. The acute dietary exposure analysis (food plus
water) showed that exposure from all current, pending, and proposed uses
of cyprodinil resulted in a MOE of 1,522 (6.6% of the aRfD of 2.0
mg/kg-bw/day) for the most sensitive population subgroup, all infants <1
year old, which exceeds the Benchmark MOE of 100.  The chronic aggregate
dietary (food plus water) exposure analysis showed that exposure from
all current, pending, and proposed uses of cyprodinil would result in a
254 (39.5% of the cRfD of 0.027 mg/kg-bw/day) for the most sensitive
population subgroup, 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 to infants and children from aggregate exposure to
residues arising from all current, pending, and proposed uses of
cyprodinil.

F. International Tolerances

Codex Alimentarius Commission established Maximum Residue Limits (MRLs)
for cyprodinil in or on various agricultural commodities including
almond hulls, almonds, apple, barley, beans (except broad bean and soy
bean), cucumber, dried grapes (currants, raisins, and sultanas), edible
offal, eggplant, grapes, lettuce (head and leaf), bulb onion, pear,
sweet peppers, prunes, raspberries (red and black), summer squash, stone
fruits, straw and fodder of cereal grains, strawberry, tomato, wheat,
and various meat, milk, and egg commodities.

     

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