[Federal Register Volume 62, Number 33 (Wednesday, February 19, 1997)]
[Notices]
[Pages 7451-7454]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-3930]
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ENVIRONMENTAL PROTECTION AGENCY
[PF-703; FRL-5585-6]
Ciba-Geigy Corporation; Pesticide Tolerance Petition Filing
AGENCY: Environmental Protection Agency (EPA).
ACTION: Notice of filing.
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SUMMARY: This notice announces the initial filing of a pesticide
petition proposing the establishment of tolerances for residues of
difenoconazole in or on raw agricultural commodities of barley. This
notice includes a summary of the petition that was prepared by the
petitioner, Ciba-Geigy Corporation.
DATES: Comments, identified by the docket control number [PF-703], must
be received on or before March 21, 1997.
ADDRESSES: By mail, submit written comments to: Public Response and
Program Resources Branch, Field Operations Division (7506C), Office of
Pesticide Programs, Environmental Protection Agency, 401 M St., SW.,
Washington, DC 20460. In person, bring comments to: Crystal Mall #2,
Room 1132, 1921 Jefferson Davis Highway, Arlington, VA.
Comments and data may also be submitted electronically be sending
electronic mail (e-mail) to: [email protected]. 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 in 5.1 file format or ASCII file
format. All comments and data in electronic form must be identified by
the docket control number [PF-703]. Electronic comments on this notice
may be filed online at many Federal Depository Libraries. Additional
information on electronic submissions can be found in Unit II. of this
document.
Information submitted as a comment concerning this notice 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 Room 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: By mail, Cynthia Giles-Parker, Product
Manager (PM 22), Registration Division, Office of Pesticide Programs,
Environmental Protection Agency, 401 M St., SW., Washington, DC 20460.
Office location, telephone number, and e-mail address: Crystal Mall #2,
Room 229, 1921 Jefferson Davis Highway, Arlington, VA, 703-305-5540, e-
mail: [email protected].
SUPPLEMENTARY INFORMATION: EPA has received a pesticide petition (PP-
6F4748)) from Ciba-Geigy Corporation, 410 Swing Rd., Greensboro, NC
27401, 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 the fungicide,
difenoconazole, in or on the raw agricultural commodities barely
forage, hay, and straw at 0.05 parts per million (ppm) and barley grain
at 0.01 ppm.
EPA has determined that the petition contains data or information
regarding the elements set forth in section 408(d)(2) of FFDCA;
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.
As required by section 408(d) of the FFDCA, as recently amended by
the Food Quality Protection Act (FQPA) Pub. L. 104-170, Ciba-Geigy
Corporation (Ciba-Geigy) included in the petition a summary of the
petition and authorization for the summary to be published in the
Federal Register in a notice of receipt of the petition. The summary
represents the views of Ciba-Geigy. EPA is in the process of evaluating
the petition. As required by section 408(d)(3) of the FFDCA, EPA is
[[Page 7452]]
including the summary as a part of this notice of filing. EPA has made
minor edits to the summary for the purpose of clarity.
I. Petition Summary
The analytical method AG-575B (MRID 42806504) was used to determine
residues of difenoconazole in or on barley matrices. This method is
proposed as the regulatory enforcement method for barley. It is a
revised version of AG-575A that incorporates specificity data and
methodology for megabore column gas chromatography. The procedures in
AG-575A remain unaltered in the revised method, AG-575B. Procedural
recoveries on barley substrates, fortified prior to extraction at
levels ranging from 0.01 ppm to 5.0 ppm, ranged from 70% to 125% using
AG-575B.
One-year freezer storage stability was demonstrated in lettuce,
soybeans, and wheat forage. A 2-year stability study including wheat
forage, grain, and straw is now in progress.
A. Chemical Uses
Difenoconazole is the active ingredient in dividend 3FS,
a fungicide that offers broad-spectrum control of several seed, soil
borne, and foliar pathogens of wheat. In the current petition, dividend
is being developed as a seed treatment for barley and triticale. It is
highly active at rates of 0.5 to 1.0 fl. oz. of 3FS formulation/100 lb
of seed (0.0125 to 0.025 lb active ingredient (ai)/100 lb seed). In
barley, dividend controls barley stripe, general seed rots, fusarium
seed scab, and covered smut. Dividend also partially controls take-all,
common root rot, fusarium root rot, and fusarium crown rot. Dividend
controls general seed rots of triticale.
B. Difenoconazole Safety
1. Ciba-Geigy has submitted over 20 toxicity studies in support of
tolerances for difenoconazole. Difenoconazole has a low order of acute
toxicity, minimal irritation potential, and no sensitization potential.
There was no evidence of genotoxicity, and it is not fetotoxic,
embryolethal, or teratogenic. It is not a reproductive toxin. The main
target organ of toxicity was the liver in the species tested. There was
an increase in liver tumors only in mice, and only, according to the
EPA's Carcinogenicity Peer Review Committee (CPRC), at doses considered
excessively high for carcinogenicity testing. EPA has concluded that
for the purpose of risk characterization, the margin of exposure (MOE)
approach (threshold model) should be used for quantification of human
risk. MOEs are extremely high for the U.S. population and all
population subgroups for both chronic effects and acute toxicity.
2. The following mammalian toxicity studies were conducted and
submitted in support of tolerances for difenoconazole. No observed
effect levels (NOELs) are consistent with those published in the
Federal Register of August 24, 1994 (59 FR 43490, FRL-4906-2).
i. A rat acute oral study with an LD50 of 1,453 milligram/
kilogram (mg/kg).
ii. A rabbit acute dermal study with an LD50 of >2,010 mg/kg.
iii. A rat acute inhalation study with an LC50 of >3.285
milligram/liter (mg/L).
iv. A primary eye irritation study in the rabbit which showed
slight irritation.
v. A primary dermal irritation study in the rabbit which showed
slight irritation.
vi. A dermal sensitization study in the guinea pig which showed no
irritation.
vii. A 13-week rat feeding study identified liver as a target organ
and had a NOEL of 20 ppm.
viii. A 13-week mouse feeding study identified liver as a target
organ and had a NOEL of 20 ppm.
ix. A 26-week dog feeding study identified liver and eye as target
organs and had a NOEL of 100 ppm.
x. A 21-day dermal study in rabbits had a NOEL of 10 mg/mg/day
based on decreased body weight gain at 100 and 1,000 mg/kg/day.
xi. A 24-month feeding study in rats had a NOEL of 20 ppm based on
liver toxicity at 500 and 2,500 ppm. There was no evidence of an
oncogenic response.
3. An 18-month mouse feeding study had an overall NOEL 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 NOEL was 300 ppm.
4. A 12-month feeding study in dogs had a NOEL of 100 ppm based on
decreased food consumption and increased alkaline phosphatase levels at
500 ppm.
5. An oral teratology study in rats had a maternal NOEL of 16 mg/
kg/day based on excess salivation, decreased body weight gain, and food
consumption. The developmental NOEL 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.
6. An oral teratology study in rabbits had a maternal NOEL of 25
mg/kg/day based on decreased body weight gain, death, and abortion.
7. The developmental NOEL of 25 mg/kg/day was based on effects seen
secondary to maternal toxicity including slight increase in post-
implantation loss and resorptions and decreased fetal weight.
8. A two-generation reproduction study in rats had a parental and
reproductive NOEL of 25 ppm based on significantly reduced female body
weight gain, and reductions in male pup weights at 21 days.
9. There was no evidence of the induction of point mutations in an
Ames test.
10. There was no evidence of mutagenic effects in a mouse
lymphomatest.
11. There was no evidence of mutagenic effects in a nucleus anomaly
test with Chinese hamsters.
12. There was no evidence of induction of DNA damage in a rat
hepatocyte DNA repair test.
13. There was no evidence of induction of DNA damage in a human
fibroblast DNA repair test.
C. Threshold Effects
1. Chronic effects. Based on the data from chronic studies in rats,
mice, and dogs, the reference dose (RfD) for difenoconazole is 0.01 mg/
kg/day published in the Federal Register of August 24, 1994 (59 FR
43490). The RfD for difenoconazole is based on the chronic study in
rats with a threshold NOEL of 1 mg/kg/day and an uncertainty factor of
100.
2. Acute toxicity. i. EPA has concluded that the dietary acute MOE
for developmental toxicity was 25,000 for high exposure in the females
13+ subgroup. The agency is generally not concerned unless the MOE is
below 100 for substances whose acute NOEL is based on animal studies.
ii. Ciba-Geigy concurs, and has also considered that since the
percentage of the RfD utilized in the chronic exposure analysis for all
population subgroups is less than 10, it is highly unlikely that any
acute dietary exposure scenario would utilize a significant percentage
of the RfD.
iii. Since MOEs of 100 or more are considered satisfactory, there
is no concern for acute dietary exposure for the U.S. population, for
various population subgroups, or for either gender.
D. Non-Threshold Effects
1. The Health Effects Division, CPRC evaluated the weight of the
evidence on difenoconazole with reference to its carcinogenic
potential. The CPRC concluded that difenoconazole should be classified
a Group C carcinogen, and
[[Page 7453]]
for the purpose of risk characterization the MOE approach should be
used for quantification of human risk.
2. In the 18-month study with CD-1 mice, there was a statistically
significant increase in hepatocellular adenomas, carcinomas, and
combined adenomas/carcinomas in both sexes, but only at dose levels
which were considered excessively high for carcinogenicity testing.
This is considered very weak evidence of carcinogenic potential.
Additionally, there was no evidence of carcinogenicity in either sex of
CD rat after 24 months, and there was no evidence of genotoxicity.
Therefore, a threshold model should be used for estimating risk. The
CPRC determined that a NOEL of 4.7 mg/kg/day, based on endpoints
related to hepatic tumor development, should be used for calculating
MOEs. The calculated margin of exposure, using worst case assumptions,
was 9,958 for the U.S. population.
E. Aggregate Exposure
1. When the potential dietary exposure to difenoconazole is
calculated, the theoretical maximum residue concentration (TMRC) of
0.00041 mg/kg/day utilizes 4% of the RfD for the overall U.S.
population. For the most exposed population subgroups, children and
non-nursing infants, the TMRC is 0.000946 mg/kg/day, utilizing 9% of
the RfD published in the Federal Register of August 24, 1994 (59 FR
43490).
2. Ciba-Geigy has conducted another exposure analysis using
additional crops and similar conservative assumptions. In this
analysis, oats, barley, and bananas (pending import tolerance) were
included in addition to wheat. Tolerances or proposed tolerances were
0.1 ppm each for wheat, oats, and barley, and 0.2 ppm for bananas.
Tolerances were 0.01 ppm for milk and 0.05 ppm for all other
commodities: beef, goat, horse, rabbit, sheep, pork, turkey, eggs,
chicken, and other poultry. Very conservative assumptions were used to
estimate residues (i.e. 100% of all wheat, oats, barley, and imported
bananas used for human consumption or forage was treated and all raw
agricultural commodities contained tolerance level residues). These
estimates result in a extreme overestimate of human dietary exposure.
Calculated TMRC values from these assumptions utilize 4.7% of the RfD
for the U.S. population and 12.51% of the RfD for non-nursing infants.
3. Other potential sources of exposure of the general population to
residues of pesticides are drinking water and non-occupational sources.
Difenoconazole is currently used as a seed treatment and residues are,
therefore, incorporated into the soil at very low rates (0.0125 to
0.025 lb ai/100 lb of seed). The likelihood of contamination of surface
water from run-off is essentially negligible. In addition, parent and
aged leaching, soil absorption/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 water are not anticipated.
4. Non-occupational exposure for 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.
5. Ciba-Geigy has considered the potential for cumulative effects
of difenoconazole and other substances of common mechanism of toxicity.
Ciba-Geigy has concluded that consideration of a common mechanism of
toxicity in aggregate exposure assessment is not appropriate at this
time. Ciba-Geigy has no 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, Ciba-Geigy is
considering only the potential risk of difenoconazole from dietary
exposure in its aggregate and cumulative exposure assessment.
F. Determination of Safety for U.S. Population
1. Using the very conservative exposure assumptions described in
Unit I.E. of this document, and based on the completeness of the
toxicity data base for difenoconazole, Ciba-Geigy calculates that
aggregate exposure to difenoconazole utilizes <5% of the RfD for the
U.S. population based on chronic toxicity endpoints (NOEL = 1 mg/kg/
day). When using the carcinogenic NOEL of 4.7 mg/kg/day and the MOE
approach recommended by the CPRC, approximately 1% of the RfD is
utilized.
2. 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 highest exposed population subgroup. EPA generally has no
concern for exposures below 100% of the RfD. Therefore, Ciba-Geigy
concludes that there is reasonable certainty that no harm will result
from daily aggregate exposure to residues of difenoconazole over a
lifetime.
G. Determination of Safety for Infants and Children
Developmental toxicity and two-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 which 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
two-generation reproduction study. Therefore, Ciba-Geigy 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.
H. Estrogenic Effects
1. Developmental toxicity studies in rats and rabbits and a two-
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.
2. Difenoconazole has not been found in raw agricultural
commodities at the limit of quantitation (LOQ). Based on the available
toxicity information and the lack of detected residues, it is concluded
that difenoconazole has no potential to interfere with the endocrine
system, and there is no risk of endocrine disruption in humans.
I. Chemical Residues
1. The nature of the residue is adequately understood in plants and
animals. The metabolism of difenoconazole has been studied in wheat,
tomatoes, potatoes, and grapes. The metabolic pathway was the same in
these four separate and distinct crops. There are no Codex maximum
residue levels established for residues of difenoconazole in barley.
Ciba-Geigy has submitted a practical analytical method for detecting
and measuring levels of difenoconazole in or on food with a LOQ that
allows monitoring of food with residues at or above the levels
[[Page 7454]]
set in the proposed tolerances. EPA will provide information on this
method to the Food and Drug Administration (FDA). The method is
available to anyone who is interested in pesticide residue enforcement
from EPA's Field Operations Division, Office of Pesticide Programs.
2. Nine-barley trials were conducted in eight states. Fifty-four
one-time treated grain, hay, and straw samples (fed commodities) were
analyzed. In addition, eighteen one-time treated forage samples were
analyzed. Residues of difenoconazole in barley grown from seed treated
with difenoconazole were below the LOQ in forage, hay, and straw (<0.05
ppm), and grain (<0.01 ppm). The feeding of difenoconazole-treated
barley products to beef or dairy cattle will not require an increase in
existing beef tissue or milk tolerances. Similarly, the feeding of
difenoconazole-treated barley grain to poultry will not require
increasing existing established poultry tissue and egg tolerances.
J. Environmental Fate
Since the Agency classifies seed treatment uses as ``indoor,'' the
only environmental fate data requirement is hydrolysis. Difenoconazole
is hydrolytically stable in solution at 25 deg.C at pH 5, 7, or 9.
II. Public Record
EPA invites interested persons to submit comments on this notice of
filing. Comments must bear a notification indicating the docket control
number [PF-703].
A record has been established for this notice under docket control
number [PF-703] 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 public
record is located in Room 1132 of the Public Response and Program
Resources Branch, Field Operations Division (7506C), Office of
Pesticide Programs, Environmental Protection Agency, Crystal Mall #2,
1921 Jefferson Davis Highway, Arlington, VA.
Electronic comments can be sent directly to EPA at:
opp-D[email protected]
Electronic comments must be submitted as an ASCII file avoiding the
use of special characters and any form of encryption.
The official record for this notice, as well as the public version,
as described above will be kept in paper form. Accordingly, EPA will
transfer all comments received electronically into printed, paper form
as they are received and will place the paper copies in the official
record which will also include all comments submitted directly in
writing.
The official record is the paper record maintained at the address
in ``ADDRESSES'' at the beginning of this notice.
List of Subjects
Environmental protection, Administrative practice and procedure,
Agricultural commodities, Pesticides and pests, Reporting and
recordkeeping requirements.
Dated: February 4, 1997.
Stephen L. Johnson,
Director, Registration Division, Office of Pesticide Programs.
[FR Doc. 97-3930 Filed 2-18-97; 8:45 am]
BILLING CODE 6560-50-F