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Difenoconazole - Pesticide Tolerance Petition Filing 2/97

CHEMICAL PROFILES/FUNGICIDES/difenoconazole
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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: opp-docket@epamail.epa.gov. 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: giles-
parker.cynthia@epamail.epa.gov.

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 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
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 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-Docket@epamail.epa.gov

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]