cyprodinil Notice of Filing of Pesticide Petitions 3/97
Notice of Filing of Pesticide Petitions
AGENCY: Environmental Protection Agency (EPA).
SUMMARY: This notice announces the initial filing of pesticide petitions
proposing the establishment of regulations for residues of certain pesticide
chemicals in or on various agricultural commodities. DATES: Comments,
identified by the docket control number PF-723, must be received on or before
May 2, 1997.
ADDRESSES: By mail submit written comments to: Public Response and Program
Resources Branch, Field Operations Divison (7505C), Office of Pesticides
Programs, Environmental Protection Agency, 401 M St., SW., Washington, DC
20460. In person bring comments to: Rm. 1132, CM #2, 1921 Jefferson Davis
Highway, Arlington, VA.
Comments and data may also be submitted electronically by following the
instructions under "SUPPLEMENTARY INFORMATION." No confidential business
information should be submitted through e-mail.
Information submitted as a comment concerning this document may be claimed
confidential by marking any part or all of that information as "Confidential
Business Information" (CBI). CBI should not be submitted through e-mail.
Information marked as CBI will not be disclosed except in accordance with
procedures set forth in 40 CFR part 2. A copy of the comment that does not
contain CBI must be submitted for inclusion in the public record. Information
not marked confidential may be disclosed publicly by EPA without prior notice.
All written comments will be available for public inspection in Rm. 1132 at
the address given above, from 8:30 a.m. to 4 p.m., Monday through Friday,
excluding legal holidays.
FOR FURTHER INFORMATION CONTACT: The product manager listed in the table
Product Manager telephone number Address
Connie Welch (PM 21) 703-305-6226 Rm. 227, CM #2,
e-mail: 1921 Jefferson
email@example.com Davis Hwy,
Cynthia Giles-Parker (PM 22) Rm. 229, CM #2,
SUPPLEMENTARY INFORMATION: EPA has received pesticide petitions as follows
proposing the establishment and/or amendment of regulations for residues of
certain pesticide chemicals in or on various raw agricultural commodities
under section 408 of the Federal Food, Drug, and Comestic Act (FFDCA), 21
U.S.C. 346a. EPA has determined that these petitions contain data or
information regarding the elements set forth in section 408(d)(2); however,
EPA has not fully evaluated the sufficiency of the submitted data at this time
or whether the data supports grantinig of the petition. Additional data may be
needed before EPA rules on the petition.
The official record for this notice of filing, as well as the public version,
has been established for this notice of filing under docket control number PF-
723 (including comments and data submitted electronically as described below).
A public version of this record, including printed, paper versions of
electronic comments, which does not include any information claimed as CBI, is
available for inspection from 8:30 a.m. to 4 p.m., Monday through Friday,
excluding legal holidays. The official record is located at the address in
"ADDRESSES" at the beginning of this document.
Electronic comments can be sent directly to EPA at: firstname.lastname@example.org
Electronic comments must be submitted as an ASCII file avoiding the use of
special characters and any form of encryption. Comment and data will also be
accepted on disks in Wordperfect 5.1 file format or ASCII file format. All
comments and data in electronic form must be identified by the docket number
(insert docket number) and appropriate petition number. Electronic comments on
this proposed rule may be filed online at many Federal Depository Libraries.
List of Subjects
Environmental protection, Agricultural commodities, Food additives, Feed
additives, Pesticides and pests, Reporting and recordkeeping requirements.
Dated: March 24, 1997.
Stephen L. Johnson,
Director, Registration Division, Office of Pesticide Programs.
Summaries of Petitions
Below summaries of the pesticide petitions are printed. The summaries of the
petitions were prepared by the petitioners. The petition summary announces the
availability of a description of the analytical methods available to EPA for
the detection and measurement of the pesticide chemical residues or an
explanation of why no such method is needed.
2. Ciba Crop Protection
EPA has received pesticide petitions (PP) 6F4656/6H5746 from Ciba Crop
Protection, Ciba-Geigy Corporation, P.O. 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, to amend 40 CFR part 180 by establishing
tolerances for residues of the fungicide cyprodinil (4- cyclopropyl-6-methyl-
N-phenyl-2-pyrimidinamine) in or on the agricultural commodities almond
nutmeats at 0.04 ppm, almond hulls at 0.1 ppm, grapes at 3.0 ppm, raisins at
3.0 ppm, the pomefruit crop grouping at 0.1 ppm, apple pomace - wet at 0.4
ppm, and the stone fruit crop grouping at 2.0 ppm. The proposed analytical
method for determining residues uses high performance liquid chromatography
with UV detection. EPA has determined that the petition contains data or
information regarding the elements set forth in section 408(d)(2); 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. (PM 21)
A. Cyprodinil Uses
Cyprodinil is the first fungicide in a new chemical class known as the
anilinopyrimidine and is active against important Botrytis, Monilinia and
Venturia diseases of deciduous fruit and nut crops. Cyprodinil with a unique
mode of action, controls pathogens resistant to other chemical classes.
Application rates range from 0.125 to 0.5 lb active ingredient per acre per
application depending upon disease and time of application.
B. Residue Chemistry
1. Metabolism. Ciba believes the metabolism of cyprodinil has been well
characterized in plants and animals. The metabolism profile supports the use
of an analytical enforcement method that accounts for only parent cyprodinil.
2. Analytical methodology. Ciba has submitted a practical analytical method
involving extraction, filtration, and solid phase cleanup of samples with
analysis by HPLC and UV. The limits of quantitation (LOQ) for various
commodities are as follows: fruit, grain, juice - 0.02 ppm; forage, fodder,
straw - 0.05 ppm; and grapes - 0.01 ppm.
C. Magnitude of Residue
This petition is supported by field residue trials conducted on almonds,
grapes, and representative members of the Pome Fruit and the Stone Fruit Crop
Groupings. All samples were analyzed for parent residues of cyprodinil.
Residues found in the almond nutmeats and hulls were all less than respective
LOQ's of 0.02 ppm and 0.05 ppm. Tolerances at twice the LOQ for these
commodities have been proposed. In grapes, the maximum residues found for
fresh fruit and raisins were 2.0 ppm and 2.9 ppm, respectively. Residues did
not concentrate in grape juice. Tolerances of 3.0 ppm for grapes and raisins
have been requested. In pome fruit, maximum residues ranged from 0.030 ppm to
0.061 ppm. The results of a processing study on apples using exaggerated rates
showed concentration of residues in wet pomace with an average concentration
factor of 4X. Residues in apple juice were not detectable at the LOQ (< 0.01
ppm). Tolerances of 0.1 ppm for the RAC of the Pome Fruit Crop Grouping and
0.4 ppm for wet apple pomace have been proposed. In stone fruit, maximum
residues ranged from 0.82 ppm to 1.7 ppm. A tolerance of 2.0 ppm has been
proposed for the Stone Fruit Crop Grouping. Based upon the results of a three
level dairy feeding study, Ciba believes no transfer of residue to animals is
expected through their diet and that tolerances in milk, meat, poultry, and
eggs are not required.
D. International Tolerances
There are no Codex Alimentarius Commission (CODEX) maximum residue levels
(MRL's) established for residues of cyprodinil in or on raw agricultural
E. Toxicological Profile of Cyprodinil
The following mammilian toxicity studies have been conducted to support the
tolerances of cyprodinil:
1. A rat acute oral study for cyprodinil with a LD50 of 2,796 mg/kg.
2. A rat acute dermal study for cyprodinil with a LD50 > 2,000 mg/kg.
3. A rat inhalation study for cyprodinil with a LC50 > 1.2 mg/ liter air.
4. A primary eye irritation study in rabbits showing cyprodinil as minimally
5. A primary dermal irritation study in rabbits showing cyprodinil as slightly
6. A skin sensitization study in guinea pigs showing cyprodinil as a weak
7. A 28-day dermal study in the rat with a NOEL of 5 mg/kg based on clinical
8. A 90-day feeding study in the dog with a NOEL of 1500 ppm (37.5 mg/kg)
based on reduced food intake and body weight.
9. A 90-day feeding study in the mouse with a NOEL of 500 ppm (75 mg/kg) based
on liver histologic changes.
10. A 90-day feeding study in the rat with a NOEL of 50 ppm (5 mg/ kg) based
on hematologic and histologic findings.
11. A 12-month feeding study in the dog with a NOEL of 2,500 ppm (62.5 mg/kg)
based on liver histologic changes.
12. An 18-month oncogenicity feeding study in the mouse with a NOEL of 2,000
ppm (300 mg/kg). The MTD was 5,000 ppm based on reduction in body weight gain
and no evidence of oncogenicity was seen.
13. A 24-month chronic feeding/oncogenicity study in the rat with a NOEL of 75
ppm (3.75 mg/kg) based on hematologic and histologic findings. The MTD was
2,000 ppm based on liver histopathology and no evidence of oncogenicity was
14. An oral teratology study in the rat with a maternal NOEL of 200 mg/kg
based on reductions in body weight gain and food consumption and a fetal NOEL
of 200 mg/kg based on decreased pup weight and delayed skeletal growth at
15. An oral teratology study in the rabbit with a maternal NOEL of 150 mg/kg
based on reduction in body weight gain and a fetal NOEL of 400 mg/kg based on
the absence of any fetal effects.
16. A 2-generation reproduction study in the rat with a systemic NOEL of 100
ppm and a fetal NOEL of 1,000 ppm (100 mg/kg). A slight decrease in pup weight
at birth and subsequent body weight gain during the lactation phase was
observed only at the maternally toxic dose of 4,000 ppm without any effects on
reproduction and fertility.
17. In vitro gene mutation test: Ames assay - negative; Chinese hamster V79
cell test - negative; rat hepatocyte DNA repair test - negative.
18. In vitro chromosome test: Chinese hamster ovary cell cytogenetic test -
19. In vivo mutagenicity test: mouse bone marrow test - negative.
F. Threshold Effects
1. Chronic effects. Based on the available chronic toxicity data, Ciba Crop
Protection believes the Reference dose (RfD) for cyprodinil is 0.0375
mg/kg/day. This RfD is based on a 2-year feeding study in rats with aNo-
Observed Effect Level (NOEL) of 3.75 mg/kg/day (75 ppm) and an uncertainly
factor of 100. No additional modifying factor for the nature of effects was
judged to be necessary as liver sinusoidal dilatation was the most sensitive
indicator of toxicity in that study.
2. Acute toxicity. The risk from acute dietary exposure to cyprodinil is
considered to be very low. The lowest NOEL in a short term exposure scenario,
identified as 150 mg/kg in the rabbit teratology study, is fortyfold higher
than the chronic NOEL. Since chronic exposure assessment did not result in any
margin of exposure less than 400 for even the most impacted population
subgroup, Ciba believes the margin of exposure is greater than 100 for any
population subgroups; EPA considers margins of exposure of 100 or more as
G. Non-threshold Effects
Using the Guidelines for Carcinogenic Risk Assessment published September 24,
1986 (51 FR 33992), Ciba believes cyprodinil to be in Group "E"( no evidence
of carcinogenicity. There was no evidence of carcinogenicity in an 18-month
feed study in mice and a 24-month feeding in rats. Dosage levels in both the
mouse and the rat studies were adequate for identifying a cancer risk.
H. Aggregate Exposure
1. Dietary exposure. For the purposes of assessing the potential dietary
exposure under the proposed tolerances, Ciba has estimated aggregate exposure
based upon the Theoretical Maximum Residue Concentration (TMRC) from the
requested tolerances: Almonds -- 0.04 ppm for the raw agricultural commodity
(RAC) and 0.1 ppm for hulls; Grapes -- 3.0 ppm for the RAC and 3.0 ppm for
raisins; Pome Fruit Crop Grouping -- 0.1 ppm for the RAC and 0.4 ppm for apple
wet pomace; and Stone Fruit Crop Grouping -- 2.0 ppm for the RAC. The TMRC is
a "worst case" estimate of dietary exposure since it assumes 100 % of all
crops for which tolerances are established are treated and that pesticide
residues are at the tolerance levels. In conducting this exposure assessment,
Ciba has made very conservative assumptions -- 100% of all almonds, grapes,
pome fruit and stone fruit commodities will contain cyprodinil residues at
tolerance levels -- which result in an overestimate of human exposure.
2. Drinking water exposure. Cyprodinil is rapidly degraded in the environment
via photolysis and microbial degradation; aqueous and soil photolysis half
lives for cyprodinil are 12 days and 67 days, respectively. The aerobic
metabolism half life is 25 days and the leaching potential for cyprodinil is
low (Koc = 1,550 to 2,030). Based on these data, Ciba does not anticipate
exposure to residue of cyprodinil in drinking water.
3. Non-dietary exposure. Ciba believes that the potential for non-
occupational exposure to the general public is unlikely except for potential
residues in food crops discussed above. The proposed uses for cyprodinil are
for agricultural crops and the product is not used residentially in or around
Ciba believes that consideration of a common mechanism of toxicity is not
appropriate at this time since there is no information to indicate that toxic
effects produced by cyprodinil would be cumulative with those of any other
chemicals. Consequently, Ciba is considering only the potential exposure to
cyprodinil in its aggregate risk assessment.
I. Safety To the U.S. Population
Reference dose. Using the conservative exposure assumptions described above
and based on the completeness and reliability of the toxicity data base for
cyprodinil, Ciba has calculated aggregate exposure levels for this chemical.
Based on chronic toxicity endpoints, only 4% of the RfD will be utilized for
the U.S. general population. EPA usually has no concern for exposures below
100 % of the RfD because the RfD represents the level at or below which daily
aggregate dietary exposure over a lifetime will not pose appreciable risks to
human health. Ciba concludes that there is a reasonable certainty that no harm
will result from aggregate exposure to cyprodinil residues.
J. Safety to Infants and Children
Developmental delays (reduced pup weight and ossification) were observed in
the rat teratology study and 2-generation rat reproduction study at maternally
toxic doses. The lowest NOEL for this effect was established in the 2-
generation study at 100 mg/kg (1,000 ppm). The finding is judged to be a
nonspecific, secondary effect of maternal toxicity. No developmental toxicity
was observed in the rabbit teratology study.
Reference dose. Using the same conservative exposure assumptions as employed
for the determination in the general population, Ciba has calculated the
utilization of RfD by aggregate exposure to residues of cyprodinil to be 12%
for nursing infants less than 1 year old, 22% for non-nursing infants less
than 1 year old, 12% for children 1 to 6 years old, and 6% for children 7 to
12 years old. Ciba believes that under the worst case assumptions which
overestimate exposure to infants and children, there is a reasonable certainty
that no harm will result to infants and children from aggregate exposure to
K. Estrogenic effects
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.
[FR Doc. 97-8397 Filed 4-1-97; 8:45 am]