Document ID: EPA-HQ-OPP-2014-0506-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2014-09-05T04:00Z

EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE
PETITIONS PUBLISHED IN THE FEDERAL REGISTER (11/25/2013)

Interregional Research Project Number 4 (IR-4) Petition Number, PP#,
4E8273

	EPA has received a pesticide petition, PP# 4E8273, from Interregional
Research Project Number 4, IR-4, 500 College Road East, Suite 201 W,
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 180.532 by establishing the tolerance for residues of
cyprodinil, 2-Pyrimidinamine, 4-cyclopropyl-6-methyl-N-phenyl-], in or
on the raw agricultural commodities artichoke, globe at 4.0 parts per
million (ppm); acerola at 1.5 ppm; feijoa at 1.5 ppm; guava at 1.5 ppm;
jaboticaba at 1.5 ppm; passionfruit at 1.5 ppm; starfruit at 1.5 ppm;
wax jambu at 1.5 ppm; fruit, stone group 12-12 at 2.0 ppm; and
pomegranate at 7.0 ppm. Upon approval of the aforementioned tolerances,
it is proposed that 40 CFR 180.532 be amended to remove the established
tolerance for the residues of cyprodinil in or on the raw agricultural
commodity fruit, stone, group 12 at 2.0 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, IR-4 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 fludioxonil 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 fludioxonil 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.  [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 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
current and pending uses plus proposed new IR-4 uses on artichoke,
guava, cucumbers (greenhouse), tomatoes (greenhouse and cherry), a
postharvest use on pomegranate, and an extension of existing stone fruit
tolerances to all of Crop Group 12-12.  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 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.  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 2,085 (4.8% 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
0.027 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 473 (21.1% of the cRfD of 0.027
mg/kg-bw/day).  Chronic food exposures to the most sensitive
subpopulation (children 1 - 2 years old) resulted in a MOE of 196 (51.1%
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 artichoke, guava,
green-house cucumbers, green-house tomatoes, and post-harvest
pomegranate 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
provided a combined EDWC of 0.0861 ppb (acute and chronic).   For
surface water, the registered use on peppers provided a combined acute
EDWC of 46.9 ppb and the currently registered use on grapes provided a
combined chronic EDWC of 27.1 ppb.  No Percent Cropped Area adjustments
were made to the surface water EDWCs.  Since the surface water EDWCs
exceed the ground water EDWC, the 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 EDWC of 46.9 ppb 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
201,072 (0.1% 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 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 and proposed uses of
cyprodinil.

Chronic Exposure from Drinking Water:  The chronic EDWC of 27.1 ppb was
incorporated with food residues as “water, direct and 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 4,758 (2.1% of the cRfD of
0.027 mg/kg-bw/day).  The most sensitive subpopulation was all infants
(<1 year old), with a MOE of 1,845 (5.4% 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 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 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.

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 430 (23.2% of the cRfD of 0.027 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 185 (54.1% of the cRfD of 0.027
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.

3. Females 13-49 years of age.  The acute aggregate exposure analysis
showed that exposure to all current and proposed cyprodinil uses would
result in a MOE of 2,064 (4.8% of the aRfD of 1.5 mg/kg-bw/day) for
females 13-49 years old, which exceeds the Benchmark MOE of 100.  The
chronic aggregate exposure analysis showed that exposure to all current
and proposed cyprodinil uses would result in a MOE of 483 (20.7% of the
cRfD of 0.027 mg/kg-bw/day) for females 13-49 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.

F. International Tolerances

In 2005 the 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.

  

 PAGE   

 PAGE   6