Difenoconazole - Pesticide Petition Filing 4/99
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
ENVIRONMENTAL PROTECTION AGENCY
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 food commodities.
DATES: Comments, identified by the docket control number PF-870, must
be received on or before June 4, 1999.
ADDRESSES: By mail submit written comments to: Public Information and
Records Integrity Branch, Information Resources and Services Division
(7502C), Office of Pesticides Programs, Environmental Protection
Agency, 401 M St., SW., Washington, DC 20460. In person bring comments
to: Rm. 119, CM #2, 1921 Jefferson Davis Highway, Arlington, VA.
Comments and data may also be submitted electronically to: opp-
firstname.lastname@example.org. Follow the instructions under "SUPPLEMENTARY
INFORMATION." No confidential business information should be submitted
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. 119 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
Product Manager telephone number Address
Dani Daniel................... Rm. 211, CM #2, 703- 1921 Jefferson
305-5409, e- Davis Hwy,
mail:daniel.dani@epam Arlington, VA
Cynthia Giles-Parker (PM 22).. Rm. 249, CM #2, 703- Do.
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 food
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 granting of
the petition. Additional data may be needed before EPA rules on the
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-870] (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:
Electronic comments must be submitted as an ASCII file avoiding the
use of special characters and any form of encryption. Comments 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 notice 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: April 23, 1999.
Peter Caulkins, Acting
Director, Registration Division, Office of Pesticide Programs.
Summaries of Petitions
Petitioner summaries of the pesticide petitions are printed below
as required by section 408(d)(3) of the FFDCA. The summaries of the
petitions were prepared by the petitioners and represent the views of
the petitioners. EPA is publishing the petition summaries verbatim
without editing them in any way. 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.
1. Novartis Crop Protection, Inc.
EPA has received a pesticide petition (9F5045) from Novartis Crop
Protection, Inc., P.O.Box 18300, Greensboro, NC 27419-8300 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 by establishing a
tolerance for residues of difenoconazole ((2S,4R)/(2R,4S)/(2R,4R)/
dioxolan-2-yl)methyl-1H-1,2,4-triazole) in or on the raw agricultural
commodity (RAC) rapeseed at 0.01 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 the FFDCA; however, EPA has
not fully evaluated the sufficiency of the submitted data at this time
or whether the data support granting of the petition. Additional data
may be needed before EPA rules on the petition.
A. Residue Chemistry
1. Plant metabolism. The nature of the residues in plants is
understood for the purpose of the proposed tolerance. The metabolism of
14C-difenoconazole has been studied using both phenyl and
triazole labels in wheat, tomatoes, potatoes, grapes, and spring rape
The metabolic pathway was the same in these four separate and distinct
2. Analytical method--i. Food. Novartis Crop Protection, Inc. has
submitted a practical analytical method (AG-575B, master record
identification (MRID) No. 428065-04) for detecting and measuring levels
of difenoconazole in or on food with a limit of quantitation (LOQ) that
allows monitoring of food with residues at or above the levels set in
the proposed tolerances. EPA has validated this method and copies have
been provided to FDA for insertion into pesticide analytical manual
(PAM) II. The method is available to anyone who is interested, and may
be obtained from the Field Operations Division, Office of Pesticide
ii. Livestock. Novartis Crop Protection, Inc. has submitted a
practical analytical method (AG-544A, MRID-43292401) for detecting and
measuring levels of difenoconazole in or on cattle tissues and milk and
poultry tissues and eggs, with a LOQ that allows monitoring of food
with residues at or above the levels set in the proposed tolerances.
EPA has validated this method and copies have been provided to FDA for
insertion into PAM II. The method is available to anyone who is
interested, and may be obtained from the Field Operations Division,
Office of Pesticide Programs.
3. Magnitude of residues--i. Food. Six field trials were analyzed
in concordance with the OPPTS guidelines based on expected reduced
residues and environmental benefits of seed applications. The six
trials, held in areas representing approximately 84% of commercial
United States canola production (Agricultural Statistics, 1991), were
conducted in Georgia (2%), Minnesota (16%), North Dakota (53%), South
Dakota (2%), Idaho (6%), and Washington (5%). No residues were detected
in rape seed at either a 1x or 3x treatment rate.
ii. Livestock. No tolerances are necessary for grain commodities.
Tolerances in meat, milk, poultry or eggs were established for
B. Toxicological Profile
The following mammalian toxicity studies were conducted and
submitted in support of the establishment of tolerances for
1. Acute toxicity. Difenoconazole has a low order of acute
toxicity. The oral rat LD50 is 1,453 milligram/kilogram (mg/
kg). The rabbit acute dermal LD50 is > 2,010 mg/kg and the
rat inhalation LC50 is > 3.285 milligrams per liter (mg/L).
Difenoconazole is not a skin sensitizer in guinea pig and shows slight
eye and dermal irritation in the rabbit.
2. Genotoxicity. There was no evidence of the induction of point
mutations in an Ames test, no evidence of mutagenic effects in a mouse
lymphoma test or in a nucleus anomaly test with Chinese hamsters, and
no evidence of induction of DNA damage in a rat hepatocyte DNA repair
test or in a human fibroblast DNA repair test.
3. Reproductive and developmental toxicity. An oral teratology
study in rats had a maternal no-observed adverse effect level (NOAEL)
of 16 mg/kg/day based on excess salivation and decreased body weight
gain and food consumption. The developmental NOAEL of 85 mg/kg/day was
based on effects seen secondary to maternal toxicity including slightly
reduced fetal body weight and minor changes in skeletal ossification.
An oral teratology study in rabbits had a maternal NOAEL of 25 mg/kg/
day based on decreased body weight gain, death, and abortion. The
developmental NOAEL of 25 mg/kg/day was based on effects seen secondary
to maternal toxicity including a slight increase in post-implantation
loss and resorptions, and decreased fetal weight. A 2-generation
reproduction study in rats had a parental and reproductive NOAEL of 25
part per million (ppm) based on significantly reduced female body
weight gain, and reductions in male pup weights at 21-days.
4. Subchronic toxicity. A 13-week rat feeding study identified
liver as a target organ and had a NOAEL of 20 ppm. A 13-week mouse
feeding study also identified liver as a target organ and had a NOAEL
of 20 ppm. A 26-week dog feeding study further identified liver, and
also the eyes, as target organs and had a NOAEL of 100 ppm. A 21-day
dermal study in rabbits had a NOAEL of 10 mg/kg/day based on decreased
body weight gain at 100 and 1,000 mg/kg/day.
5. Chronic toxicity. A 24-month feeding study in rats had a NOAEL
of 20 ppm based on liver toxicity at 500 and 2,500 ppm. An 18-month
mouse feeding study had an overall NOAEL of 30 ppm based on decreased
body weight gain and liver toxicity at 300 ppm. A 12-month feeding
study in dogs had a NOAEL of 100 ppm based on decreased food
consumption and increased alkaline phosphatase levels at 500 ppm.
6. Carcinogenicity. A 24-month feeding study in rats had a NOAEL of
20 ppm based on liver toxicity at 500 and 2,500 ppm. There was no
evidence of an oncogenic response. An 18-month mouse feeding study had
an overall NOAEL of 30 ppm based on decreased body weight gain and
liver toxicity at 300 ppm. There was an increase in liver tumors only
at dose levels that exceeded the maximum tolerated dose (MTD). The
oncogenic NOAEL was 300 ppm.
7. Animal metabolism. The metabolism of difenoconazole is well
understood. Studies with 14C-difenoconazole in the rat,
goat, and hen demonstrate that the majority of the
administered dose (76 to > 98%) is eliminated via the excreta as parent
and metabolites. Very low concentrations of radioactivity, accounting
for < 1 to 4% of the applied dose, remain in tissues. The liver and
kidney typically show the highest radioactivity, but in the rat, the
highest concentration in any tissue was found in the fat.
Concentrations in goat milk reached a plateau on day 6 of the study at
0.043 ppm for the triazole label and 0.007 ppm for the phenyl label
when goats were fed approximately 5 ppm for 10 days. Similarly, very
little radioactivity was deposited in eggs; radioactivity reached a
plateau of 0.248 to 0.299 ppm in yolks after 7 to 8-days, and 0.007 to
0.153 ppm in whites after 5 days, in hens fed at a rate equivalent to 5
ppm in the diet for 14 consecutive days. CGA-205375, an alcohol
resulting from the deketalization of the dioxolane ring of
difenoconazole, is a major metabolite found in animal tissues, excreta,
milk, and eggs. The presence of CGA-71019, containing only the triazole
ring, and CGA-189138, containing only the phenyl ring, indicates that
bridge cleavage can occur in animals as well as plants. The metabolite
patterns in the excreta of hens, goats, and rats were similar.
8. Metabolite toxicology. The residue of concern for tolerance
setting purposes is the parent compound. Metabolites of difenoconazole
are considered to be of equal or lesser toxicity than the parent.
9. Endocrine disruption. Developmental toxicity studies in rats and
rabbits and a 2-generation reproduction study in rats gave no specific
indication that difenoconazole may have effects on the endocrine system
with regard to development or reproduction. Furthermore, histologic
investigations were conducted on endocrine organs (thyroid, adrenal,
and pituitary, as well as endocrine sex organs) from long-term studies
in dogs, rats, and mice. There was no indication that the endocrine
system was targeted by difenoconazole, even when animals were treated
with maximally tolerated doses over the majority of their lifetime.
Difenoconazole has not been found in RAC at the LOQ. Based on the
available toxicity information and the lack of detected residues, it is
concluded that difenoconazole has no potential for interfering with the
endocrine system, and there is no risk of endocrine disruption in
C. Aggregate Exposure
1. Dietary exposure--i. Food. When the potential dietary exposure
to difenoconazole from established and pending tolerances (assuming
100% treated) is calculated, the theoretical maximum residue
concentration (TMRC) of 0.000583 mg/kg/day utilizes 5.83% of the
reference dose (RfD) for the overall U. S. population. For the most
exposed population subgroups, non-nursing infants, the TMRC is 0.001656
mg/kg/day, utilizing 16.56% of the RfD, followed by children (1-6 years
old), who are exposed to 14.58% of the RfD. In this analysis, canola
does not contribute to exposure.
ii. Drinking water. Other potential sources of exposure of the
general population to residues of pesticides are in drinking water and
from non-occupational activities. Difenoconazole is currently used as a
seed treatment and residues are, therefore, incorporated into the soil.
The likelihood of contamination of surface water from run-off is
essentially negligible. In addition, parent and aged leaching, soil
adsorption/desorption, and radiolabeled pipe studies indicated that
difenoconazole has a low potential to leach in the soil and it would
not be expected to reach aquatic environments. For these reasons, and
because of the low use rate, exposures to residues in ground and
surface water are not anticipated to contribute significantly to the
aggregate exposure profile for difenoconazole.
2. Non-dietary exposure. Non-occupational exposure to
difenoconazole has not been estimated since the current registration is
limited to seed treatment. Therefore, the potential for non-
occupational exposure to the general population is insignificant.
D. Cumulative Effects
Novartis has considered the potential for cumulative effects of
difenoconazole and other substances of common mechanism of toxicity.
Novartis has concluded that consideration of a common mechanism of
toxicity in aggregate exposure assessment is not appropriate at this
time. Novartis has no reliable information to indicate that the toxic
effects (generalized liver toxicity) seen at high doses of
difenoconazole would be cumulative with those of any other compound.
Thus, Novartis is considering only the potential risk of difenoconazole
from dietary exposure in its aggregate and cumulative exposure
E. Safety Determination
1. U.S. population. Using very conservative exposure assumptions
(tolerance levels for 100% of the United States market) described and
based on the completeness of the toxicity data base for difenoconazole,
Novartis calculates that aggregate exposure to difenoconazole utilizes
< 6% of the RfD for the U.S. population based on chronic toxicity
endpoints (NOAEL = 1 mg/kg/day). If more realistic assumptions were
used to estimate anticipated residues and appropriate market share,
this percentage would be considerably lower, and would be significantly
lower than 100%, even for the most highly exposed population subgroup.
EPA generally has no concern for exposures below 100% of the RfD.
Therefore, Novartis concludes that there is a reasonable certainty that
no harm will result from daily aggregate exposure to residues of
difenoconazole over a lifetime of exposure.
2. Infants and children. Developmental toxicity and 2-generation
toxicity studies were evaluated to determine if there is a special
concern for the safety of infants and children from exposure to
residues of difenoconazole. There was no evidence of embryotoxicity or
teratogenicity, and no effects on reproductive parameters, including
number of live births, birth weights, and post-natal development, at
dose levels that did not cause significant maternal toxicity. In
addition, there were no effects in young post-weaning animals that were
not seen in adult animals in the 2-generation reproduction study.
Therefore, Novartis concludes that it is inappropriate to assume that
infants and children are more sensitive than the general population to
effects from exposure to residues of difenoconazole, and also concludes
that the use of an additional safety factor to protect infants and
children is unnecessary.
F. International Tolerances
There are pending Codex maximum residue levels (MRLs) for this
compound in Mexico for oats, wheat, and barley. There are also MRLs for
this compound in Australia for carrots at 0.02 ppm, and bananas at 0.05
[FR Doc. 99-11169 Filed 5-4-99; 8:45 am]
BILLING CODE 6560-50-F