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Propiconazole - Amending Existing Tolerance 6/93

Pesticide Tolerances for 1-[[2-(2,4-Dichlorophenyl)-4-Propyl-
1,3-Dioxolan-2-yl]Methyl]-1H-1,2,4-Triazole and its Metabolites
Determined as 2,4-Dichlorobenzoic Acid and Expressed as Parent
Compound
AGENCY: Environmental Protection Agency (EPA).
ACTION: Proposed rule.
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SUMMARY: This rule proposes amending existing tolerances (with
an expiration date of January 31, 1994) for the fungicide 1-
[[2-(2,4-dichlorophenyl)-4-propyl-1,3-dioxolan-2-yl]methyl]-
1H-1,2,4-triazole and its metabolites, determined as 2,4-dichlorobenzoic
acid and expressed as parent compound, in or on the raw agricultural
commodities grass forage, hay (straw) and seed screenings and
kidney and liver of cattle, goats, hogs, horses, and sheep by
extending the expiration date and raising several of the tolerance
levels. This rule to establish the maximum permissible levels
for residues of propiconazole in or on the commodities listed
above was requested in petitions submitted by the Ciba-Geigy
Corp.

DATES: Comments, identified by the document control number,
[PP 9F3706/P560], must be received on or before July 12, 1993.

ADDRESSES: By mail, submit written comments to: Public Document
and Freedom of Information Section, Field Operations Division
(H7506C), Office of Pesticide Programs, 401 M St., SW., Washington,
DC 20460. In person, bring comments to: Rm. 246, CM #2, 1921
Jefferson Davis Hwy., Arlington, VA 22202, (703)-305-6900.

   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).
Information so marked 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. 1128C
at the address given below, from 8 a.m. to 4 p.m., Monday through
Friday, excluding legal holidays.

FOR FURTHER INFORMATION CONTACT: By mail: Susan T. Lewis, Product
Manager (PM) 21, Registration Division (H7505C), Environmental
Protection Agency, 401 M St., SW.,Washington, DC 20460. Office
location and telephone number: Rm. 227, CM #2, 1921 Jefferson
Davis Hwy., Arlington, VA 22202, (703) 305-6900.

SUPPLEMENTARY INFORMATION: EPA issued a notice, published in
the Federal Register of February 22, 1989 (54 FR 7597), which
announced that the Ciba-Geigy Corp., P.O. Box 18300, Greensboro,
NC 27419, had submitted a pesticide petition (PP 9F3706) to
EPA requesting that the Administrator, pursuant to section 408(d)
of the Federal Food, Drug, and Cosmetic Act, 21 U.S.C. 346a(d),
propose to amend 40 CFR 180.434 by establishing tolerances for
the fungicide 1-[[2-(2,4dichlorophenyl)-4-propyl-1,3-dioxolan-
2-yl]methyl]-1H-1,2,4-triazole and its metabolites, determined
as 2,4-dichlorobenzoic acid and expressed as parent compound,
in or on the commodities grass hay at 5.0 parts per million
(ppm) and grass forage at 0.5 ppm. EPA issued a notice, published
in the Federal Register of April 19, 1989 (54 FR 15802), which
announced that the petition was subsequently amended by Ciba-
Geigy Corp. by retaining the previously proposed tolerances
for grass hay and grass forage while proposing to increase the
established tolerance level for kidney and liver of cattle,
goats, hogs, horses, and sheep to 2.0 ppm. EPA issued a notice,
published in the Federal Register of March 15, 1989 (54 FR 10715),
which announced that Ciba-Geigy amended the petition by proposing
a tolerance for residues of the fungicide for the commodity
grass seed screenings at 10 ppm.
   In the Federal Register of June 21, 1989 (54 FR 26044), EPA
established tolerances, on an interim basis, in 40 CFR 180.434
for residues of this chemical in or on the raw agricultural
commodities grass forage, hay, and seed screenings and liver
and kidney of cattle, goats, hogs, horses, and sheep. An expiration
date of June 21, 1991, was imposed for the tolerances. The interim
tolerances were established based upon the condition that data
be submitted to the Agency to fully support permanent tolerances
for these commodities. Available data were insufficient to completely
characterize the metabolism of the compound in ruminants, and
residue data were inadequate due to insufficient geographic
distribution and grass species representation.
   Data were submitted in response to the conditions of the
interim tolerances within the required time imposed. However,
review of these data indicated that the data did not reflect
use of the chemical according to label use direction, and the
data were considered to be inadequate. The reasons for the inadequacies
in the submitted data were not under the control of the company.
Because of excessively heavy rainfall during the grass-growing
season, the label directions could not be followed, e.g., both
the application interval and the prescribed preharvest interval
were shortened.
   Subsequently, EPA issued a document, published in the Federal
Register of July 1, 1991 (56 FR 29900), which announced that
the tolerances described above were extended from June 21, 1991
to June 21, 1993.
   The Ciba-Geigy Corp. has submitted a petition (PP 1F3974)
to EPA proposing tolerances for residues of the fungicide in
or on grass hay (straw) at 40 ppm, and in or on grass seed screenings
at 60 ppm, and grass forage at 2.0 ppm. These increased tolerance
levels are based on the most recent residue data submitted and
are intended to avoid any possible overtolerance residues in
the affected commodities. Notice of the filing of this petition
was published in the Federal Register of May 15, 1991 (56 FR
22428). The Agency did not receive any objections in response
to this notice.
   Once adequate residue data are submitted, the Agency will
review all of the required data and reach a regulatory position
on the appropriateness of permanent tolerances for this chemical
in or on these commodities. If EPA decides permanent tolerances
are appropriate, EPA will issue permanent tolerances in response
to the petition. These tolerances will be in the form of a final
rule and subject to the objections and hearing procedures under
the Federal Food, Drug, and Cosmetic Act (FFDCA).
   The data submitted in the petition and other relevant materials
have been evaluated. The data considered include the following:
   1. Plant and animal metabolism studies.
   2. Residue data for crop and livestock commodities.
   3. Two enforcement methodologies and a multiresidue method
of analysis.
   4. A rat oral lethal dose (LD50) of 1,517 milligrams/kilogram
(mg/kg) of body weight.
   5. A 90-day rat feeding study with a no-observable-effect
level (NOEL) of 12 mg/kg/day.
   6. A 90-day dog feeding study with a NOEL of 1.25 mg/kg/day.
   7. A rabbit developmental toxicity study with a maternal
NOEL of 100 mg/kg/day and a developmental toxicity NOEL of greater
than 400 mg/kg/day (highest dose tested (HDT)).
   8. A rat teratology study with a maternal toxicity NOEL of
30 mg/kg/day and a developmental toxicity NOEL of 30 mg/kg/day.
   9. A two-generation rat reproduction study with a reproductive
NOEL of 125 mg/kg/day (HDT) and a developmental toxicity NOEL
of 25 mg/kg/day.
   10. A 1-year dog feeding study with a NOEL of 1.25 mg/kg/day.
   11. A 2-year rat chronic feeding/carcinogenicity study with
a NOEL of 5 mg/kg/day with no carcinogenic potential under the
conditions of the study up to and including approximately 125
mg/kg, the highest dose tested.
   12. A 2-year mouse chronic feeding/carcinogenicity study
with a NOEL of 15 mg/kg/day and with a statistically significant
increase in combined adenomas and carcinomas of the liver in
male mice at approximately 375 mg/kg/day, the highest dose tested.
   13. Ames test with and without activation, negative.
   14. A mouse dominant-lethal assay, negative.
   15. Chinese hamster nucleus anomaly, negative.
   16. Cell transformation assay, negative.
   Data currently lacking concern the nature of residue in ruminants,
explanation of recovery calculations, and an explanation of
crop field trial protocol. Also, data gaps exist concerning
dosing in the mouse carcinogenicity study. The latter data requirements
were required under reregistration, pursuant to the Federal
Insecticide, Fungicide, and Rodenticide Act, 7 U.S.C. 136 et
seq.
   As part of EPA's evaluation of potential human health risks
propiconazole has been the subject of five Peer Reviews and
one Scientific Advisory Panel (SAP) meeting.
   Propiconazole was originally evaluated by the Peer Review
Committee on January 15, 1987 and classified as a Group C (possible
human) carcinogen with a recommendation made for the quantification
of estimated potential human risk using a linearized low-dose
extrapolation. The method resulted in the establishment of a
Q* of 7.9 X 10.-2 (mg/kg/day).-1.
   The Peer Review Committee's decision was presented to the
FIFRA Scietific Advisory Panel on March 2, 1988. The Panel did
not concur with the committee's overall assessment of the weight-
of-evidence on the carcinogenicity of propiconazole. The Panel
recommended placing the chemical in Group D, indicating that
the Group C classification was based on minimal evidence. The
Panel's determination that EPA's Group C classification was
based on minimal evidence was due to the fact that the incidence
of liver tumors in male mice only occurred when the mice were
given an excessive chemical dose.
   In the second, third, and fourth Peer Reviews that followed,
the Peer Review Committee considered recommendations of the
SAP as well as rebuttals by the registrant. Its conclusion,
however, that propiconazole should be classified as a Group
C carcinogen with a quantification of potential human risk remained
unchanged.
   As part of a fifth Peer Review, EPA considered additional
information provided by the registrant in support of the registrant's
argument that the high dose was excessively toxic in the mouse
carcinogenicity study. It further argued that the data from
the high dose (2,500 ppm) should not be included in the evaluation
of carcinogenic potential of propiconazole. In support of these
arguments, the registrant provided two subchronic oral toxicity
studies in mice. Ciba-Geigy also provided a reread of the pathology
slides from a mouse oncogenicity study which it felt indicated
sufficient concurrent liver toxicity at 2,500 ppm to document
that this dose was excessive. These findings were not present
in the original pathology report. Owing to the inconsistency
in Ciba-Geigy's report and the original report, the Agency requested
that an independent (third) evaluation of the pathology slides
be made to determine if the pathology reported could be confirmed.
The results of this (third) pathology evaluation were used in
the fifth Peer Review in place of data resulting from the earlier
evaluations provided by Ciba-Geigy.
   The Peer Review Committee considered the following facts
regarding the toxicology data on propiconazole in a weight-of-
evidence determination of carcinogenic potential:
   1. Increased numbers of adenomas (increased trend and pairwise
comparison) were found in the livers of male CD1 mice given
2,500 ppm of propiconazole in the diet.
   2. The treated animals had earlier fatalities than the controls.
   3. The numbers of carcinomas were increased (trend only)
in male mice only at the 2,500 ppm dose level. Tumors were not
significantly increased at the 500 ppm dose level. Adenomas
observed in the treated animals were larger and more numerous
than those in controls; however, the tumor type (adenoma) was
the same.
   4. No excessive number of tumors was found in female mice.
   5. In a rat study conducted with acceptable doses of propiconazole,
no excessive numbers of tumors were found.
   The Peer Review Committee determined, based on the additional
information submitted by Ciba-Geigy from two 90-day subchronic
studies in mice that: The 2,500-ppm dose used in the 2-year
chronic study exceeded the maximum-tolerated dose (MTD) based
on the endpoint of hepatic necrosis, and the 500-ppm dose used
in the chronic study was inadequate to assess the carcinogenicity
of propiconazole. Based on the third pathology evaluation of
the chronic study, the Peer Review Committee disagreed with
Ciba-Geigy's argument that the study showed excessive toxicity
at the 2,500 ppm-dose. However, the Peer Review Committee concluded
that the 90-day subchronic studies are a better measure of what
would be an MTD.
   Based upon these findings, the Peer Review Committee agreed
that the classification for propiconazole should remain a Group
C (possible human) carcinogen and recommended against the previously
used Q* (viz. 0.079) for risk assessment purposes. For the
purpose of risk characterization the Peer Review Committee recommended
that the reference dose (RfD) approach should be used for quantification
of human risk. This decision was based on the disqualification
of the high dose (2,500 ppm), making the data inappropriate
for the calculation of Q*. Because the middle dose (500 ppm)
was not considered sufficiently high enough for assessing the
carcinogenetic potential of propiconazole, EPA has requested
an additional mouse study at intermediate dose levels in male
mice only. EPA does not expect that these data will significantly
change the above cancer assessment that propiconazole poses
a negligible cancer risk to humans.
   The reference dose (RfD) for propiconazole is 0.013 mg/kg/day,
based on a no-observable-effect level (NOEL) of 1.25 mg/kg/day
and an uncertainty factor of 100. The NOEL is taken from a 1-
year feeding study in dogs which demonstrated as an effect irritation
of the stomach in males.
   The Agency has evaluated dietary exposure to the fungicide
residues based on the proposed increased tolerances and the
commodities which have established tolerances using data on
anticipated residues. The livestock burden was calculated using
anticipated residues in feed items multiplied by the expected
percent contribution to the diet. This dietary burden was then
compared with available data from feeding studies to determine
anticipated residues in meat and milk. Based on current registered
uses of this chemical only 2.46 percent of the RfD is being
utilized. The proposed tolerance increases are expected to elicit
only a minor increase in the percent utilization of the RfD.
   The nature of the residue in plants is adequately understood,
and an adequate analytical method (gas chromatography) is available
for enforcement purposes. Because of the long lead time for
establishing these tolerances and food additive regulations
to publication of the enforcement methodology in the "Pesticide
Analytical Manual," Vol. II, the analytical methodology is
being made available in the interim to anyone interested in
pesticide enforcement when requested from: Calvin Furlow, Public
Information Branch, Field Operations Division (H7506C), 401
M St., SW., Washington, DC 20460. Office location and telephone
number: Rm. 1128C, CM #2, 1921 Jefferson Davis Hwy., Arlington,
VA 22202, (703)-305-5232.
   The pesticide is considered useful for the purpose for which
the tolerances are being sought. For the reasons described above,
the Agency is proposing tolerances (with an expiration date)
for residues of 1-[[2-(2,4-dichlorophenyl)-4-propyl-1,3-dioxolan-
2-yl]methyl]-1H-1,2,4-triazole and its metabolites, determined
as 2,4-dichlorobenzoic acid and expressed as parent compound,
in or on the following raw agricultural commodities: grass forage,
0.5 ppm; grass hay (straw), 40 ppm; grass seed screenings, 60
ppm; kidney and liver of cattle, goats, hogs, horses, and sheep,
2.0 ppm. Available data/information are inadequate concerning
the nature of the residue in ruminants, explanation of recovery
calculations, and the field trial protocol. Therefore, these
tolerances are being proposed with an expiration date of January
31, 1994. Available residue data indicate that these revised
interim tolerances will not be exceeded.
   Based on the above information the Agency concludes that
the revised interim tolerances (with expiration date of January
31, 1994) will protect the public health. Therefore, the tolerances
are proposed as set forth below.
   Any person who has registered or submitted an application
for registration of a pesticide, under the Federal Insecticide,
Fungicide, and Rodenticide Act (FIFRA), as amended, which contains
any of the ingredients listed herein, may request within 30
days after publication of this document in the Federal Register
that the rulemaking proposal for the above tolerances be referred
to an Advisory Committee in accordance with section 408(e) of
the Federal Food, Drug, and Cosmetic Act.
   Interested persons are invited to submit written comments
on the proposed regulations. Comments must bear a notation indicating
the document control number, [PP 9F3706/P560]. All written comments
filed in response to this petition will be available in the
Public Docket and Freedom of Information Section, at the address
given above, from 8 a.m. to 4 p.m., Monday through Friday, except
legal holidays.
   Pursuant to the requirements of the Regulatory Flexibility
Act (Pub. L. 96-354, 94 Stat. 1164, 5 U.S.C. 601-612), the Administrator
has determined that regulations establishing new tolerances
or food additive regulations or raising tolerance levels or
food additive regulations or establishing exemptions from tolerance
requirements do not have a significant economic impact on a
substantial number of small entities. A certification statement
to this effect was published in the Federal Register of May
4, 1981 (40 FR 24950). The Office of Management and Budget has
exempted this rule from the requirements of section 3 of Executive
Order 12291.

List of Subjects in 40 CFR Part 180

   Administrative practice and procedures, Agricultural commodities,
Pesticides and pests, Reporting and recordkeeping requirements.

Dated: June 3, 1993.

Douglas D. Campt,
Director, Office of Pesticide Programs.
   Therefore, 40 CFR part 180 is proposed to be amended as follows:

PART 180-[AMENDED]

   1. The authority citation for part 180 continues to read
as follows:

   Authority: 21 U.S.C. 346a and 371.

   2. Section 180.434 is amended in the table therein by revising
the entries for cattle kidney and liver; goat kidney and liver;
grass forage, hay, and seed screenings; hog kidney and liver;
horse kidney and liver; and sheep kidney and liver, to read
as follows:

. 180.434 1-[[2-(2,4-dichlorophenyl)-4-propyl-1,3-dioxolan-2-
yl]methyl]-1H-1,2,4-triazole; tolerances for residues.
 *     *     *     *

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                     Commodity                       Parts per    Expiration
                                                      million        date
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               *              *              *              *              *
Cattle, kidney....................................          2.0     01/31/94
Cattle, liver.....................................          2.0     01/31/94

               *              *              *              *              *
Goats, kidney.....................................          2.0     01/31/94

Goats, liver......................................          2.0     01/31/94

               *              *              *              *              *
Grass, forage.....................................          0.5     01/31/94
Grass, hay (straw)................................           40     01/31/94
Grass, seed screenings ...........................           60     01/31/94

               *              *              *              *              *
Hogs, kidney......................................          2.0     01/31/94
Hogs, liver.......................................          2.0     01/31/94

               *              *              *              *              *
Horses, kidney....................................          2.0     01/31/94
Horses, liver.....................................          2.0     01/31/94

               *              *              *              *              *
Sheep, kidney.....................................          2.0     01/31/94
Sheep, liver......................................          2.0     01/31/94

               *              *              *              *              *
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*     *     *     *     *

[FR Doc. 93-13860 Filed 6-10-93; 8:45 am]