Document ID: EPA-HQ-OPP-2005-0119-0003
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2007-09-28T04:00Z

EPA Registration Division contact: Barbara Madden, (703) 305-6463 

Interregional Research Project Number 4 (IR-4)

PP# 8E5012 

EPA has received a pesticide petition (8E5012) from IR-4, 500 College
Road, 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 tolerances for
residues of cyprodinil: 4-cyclopropyl-6-methyl-N-phenyl-2-pyrimidinamine
in or on the raw agricultural commodities Onion, dry bulb, at 0.60 part
per million (ppm), Onion, green, at 4.0 ppm, and Strawberry, at 5.0 ppm.
 It is proposed that 40 CFR 180 be amended by extending the  expiration
date for the existing time-limited tolerances established under the
pesticide petition, PP 8E5012, for an additional two year period from
December 31, 2007 to December 31, 2009 for the residues of cyprodinil
(4-cyclopropyl-6-methyl-N-phenyl-2-pyrimidinamine) in or on Onion, dry
bulb, at 0.60 part per million (ppm), Onion, green, at 4.0 ppm, and
Strawberry, at 5.0 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. 

This summary of the petition was prepared by Syngenta Crop Protection,
P. O. Box 18300, Greensboro, NC 27409 the registrant.  

 

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 for strawberry; onion, dry bulb; and onion, green have been
submitted. The 

requested tolerances are adequately supported. 

 

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 III acute and chronic dietary exposure
evaluations were performed for cyprodinil using the Dietary Exposure
Evaluation Model (DEEM-FCIDTM, version 2.14) from Exponent. 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. The apple juice
processing factor was used as a surrogate for pear juice. All other
processing factors used the DEEMTM 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. These exposure assessments included all current uses as well
as proposed pending uses for cyprodinil on tomato, tomatillo, avocado,
black sapote, canistel, mamey sapote, mango, papaya, sapodilla, star
apple, kiwifruit, fresh and dried herbs (Crop Group 19A), root
vegetables (Crop Group 1B), leaves of root and tuber vegetables (Crop
Group 2), lemon and lime. 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. Percent of crop treated values were
estimated based upon economic, pest and competitive pressures. Secondary
residues in animal commodities were estimated based on theoretical
worst-

case, yet nutritionally adequate animal 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 observable 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 exposure to the females 13-49
years subpopulation resulted in a MOE of 7,491 (1.3% of the acute RfD of
1.5 mg/kg-bw/day). Since the Benchmark MOE for this assessment was 100
and since 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) exposure to residues arising from the
current 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
reference dose (%RfD). Chronic exposure to the most exposed
sub-population (children 1 and 2 years old) resulted in a MOE of 1,007
(8.9% of the chronic RfD of 0.03 mg/kg-bw/day). Since the Benchmark MOE
for this assessment was 100 and since 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) exposure to residues arising
from the current and proposed uses for cyprodinil. 

ii. Drinking water. The Estimated Drinking Water Concentrations (EDWCs)
of cyprodinil and its major environmental degradate CGA-249287 were
calculated using Tier 1 SCI-GROW (Screening Concentration In GROund
Water) to provide ground water exposure estimates and Tier II PRZM
(Pesticide Root Zone Model) and EXAMS (Exposure Analysis Modeling
Systems) to provide surface water exposure estimates.  Model inputs were
chosen from environmental fate data submitted to the EPA, using EPA
guidance for selecting inputs, and application and use parameters of 4 X
0.328 lbs ai/A with 7-day intervals from the proposed new crop use of
tomatoes, the driving crop use. For surface water, utilizing the PRZM FL
tomatoes crop scenario, PRZM/EXAMS 



output provided peak (acute) EDWCs of 51.7 ppb for cyprodinil and 8.07
ppb for CGA-249287. The combined peak day (acute) surface water EDWC is
59.8 ppb. PRZM/EXAMS output provided annual average (chronic) surface
water EDWCs of 28.1 ppb for cyprodinil and 2.06 ppb for CGA-249287. The
combined annual average (chronic) surface water EDWC is 30.1 ppb. For
ground water, SCI-GROW output provided EDWCs (acute and chronic) of
0.0370 for cyprodinil and 0.435 ppb for CGA-249287. The combined ground
water (acute and chronic) EDWC is 0.472 ppb. Since the surface water
EDWCs exceed the ground water EDWC, the surface water values were 

used for risk assessment purposes and should be considered protective
for any ground 

water concentration concerns. 

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 120,773 (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. 

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 4,256 (2.1% of the RfD of 0.03 mg/kg-bw/day). The
most exposed sub-population was all infants <1 year old, with a MOE of
1,298 (6.9% of the RfD 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 and proposed uses of cyprodinil. 

 2. Non-dietary exposure. Residential exposures were not included in
these 

assessments since cyprodinil is not registered for any uses that would
result in residential 

exposure.  

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 1,918 (4.7% of the RfD 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 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 745 (12.1% of the RfD 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 and
proposed uses of cyprodinil. 

½

ü

a MOE of 7,053 (1.4% 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 2,212 (4.1% of the RfD of 0.03
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 

and proposed uses of cyprodinil. 

 F. International Tolerances 

  There are no Codex maximum residue levels established for cyprodinil.