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Propiconazole - Pesticide Tolerances 1/94

40 CFR Part 180
[PP 1F3974/R2040; FRL-4757-8]
RIN 2070-AC18
Pesticide Tolerances for 1-[[2-(2,4-Dichlorophenyl)-4-Propyl-
1,3-Dioxolan-2-yl]Methyl]-1H-1,2,4-Triazole and its Metabolites
known as prpicanazole
AGENCY: Environmental Protection Agency (EPA).
ACTION: Final rule.
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SUMMARY: This rule establishes tolerances for the fungicide
1-[[2-(2,4-dichlorophenyl)-4-propyl-1,3-dioxolan-2yl-]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.
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.

EFFECTIVE DATE: This regulation is effective January 28, 1994.

ADDRESSES: Written objections, identified by the document control
number, [PP 1F3974/R2040], may be submitted to: Hearing Clerk
(A-110), Environmental Protection Agency, Rm. M3708, 401 M St.,
SW., Washington, DC 20460.

FOR FURTHER INFORMATION CONTACT: By mail: Sidney C. Jackson,
Acting Product Manager (PM) 21, Registration Division (7505C),
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-(2,4-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 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
but a result of excessively heavy rainfall during the grass
growing season. Label directions pertaining to both the application
interval and the prescribed preharvest interval could not be
followed.
   Subsequently, EPA issued a notice, 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.
   A notice of filing to establish tolerance levels in or on
grass seed screenings at 70 ppm, grass straw at 40 ppm, and
grass forage at 2.0 ppm 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. On January 14, 1993,
Ciba-Geigy proposed revisions to the earlier published tolerances
to include 60 ppm for grass seed screenings, 40 ppm for grass
straw, and 0.5 ppm for grass forage. These revised tolerance
levels are based on the most recent residue data submitted and
are intended to avoid any possible over-tolerance residues in
the affected commodities.
   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 multiresidue method
testing data.
   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.
   Ciba-Geigy submitted information which resolved the previously
outstanding concerns about the nature of the residue in ruminants,
an explanation of recovery calculations, and an explanation
of the crop field trial protocol. Data gaps exist concerning
dosing in the mouse carcinogenicity study. These 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 Scientific 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 tolerances and the commodities
which have established tolerances using data on anticipated
residues and percent crop treated data. 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 4 percent of the
RfD is being utilized for the general U.S. population. The tolerances
are expected to elicit only a minor increase in the percent
utilization of the RfD for the general U.S. population. The
most highly exposed subgroups, nursing and nonnursing infants
< 1 year, have Anticipated Residue Contributions (ARCs) from
all published tolerances of 1.9 X 10.-3 and 3.7 X 10.-3 mg/kg
bwt/day. These ARCs represent 15% and 28% of the Reference Dose
for these subgroups, respectively.
   The nature of the residue in plants and animals is adequately
understood, and adequate analytical methods (gas chromatography)
are 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 (7506C),
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 establishing tolerances 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.
   Based on the above information the Agency concludes that
the tolerances will protect the public health. Therefore, the
tolerances are proposed as set forth below.
   Any person adversely affected by this regulation may, within
30 days after publication of this document in the Federal Register,
file written objections with the Hearing Clerk, at the address
given above (40 CFR 178.20). The objections submitted must specify
the provisions of the regulation deemed objectionable and the
grounds for the objections (40 CFR 178.25). Each objection must
be accompanied by the fee prescribed by 40 CFR 180.33(i). If
a hearing is requested, the objections must include a statement
of the factual issue(s) on which a hearing is requested, the
requestor's contentions on such issues, and a summary of any
evidence relied upon by the objector (40 CFR 178.27) A request
for a hearing will be granted if the Administrator determines
that the material submitted shows the following: There is a
genuine and substantial issue of fact; there is a reasonable
possibility that available evidence identified by the requestor
would, if established, resolve one or more of such issues in
favor of the requestor, taking into account uncontested claims
or facts to the contrary; and resolution of the factual issue(s)
in the manner sought by the requestor would be adequate to justify
the action requested (40 CFR 178.32).
   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 Executive Order 12866.
List of Subjects in 40 CFR Part 180
   Environmental protection, Administrative practice and procedures,
Agricultural commodities, Pesticides and pests, Reporting and
recordkeeping requirements.

   Dated: January 28, 1994.

Douglas D. Campt,
Director, Office of Pesticide Programs.

   Therefore, 40 CFR part 180 is 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. In . 180.434, by revising paragraph (a), 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.
   (a) Tolerances are established 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:
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                           Commodity                              Parts per
                                                                   million
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Apricots.......................................................          1.0
Bananas........................................................          0.2
Barley, grain .................................................          0.1
Barley, straw .................................................          1.5
Cattle, fat....................................................          0.1
Cattle, kidney.................................................          2.0
Cattle, liver..................................................          2.0
Cattle, meat...................................................          0.1
Cattle, mbyp (except kidney and liver).........................          0.1
Celery.........................................................          5.0
Eggs...........................................................          0.1
Goats, fat.....................................................          0.1
Goats, kidney..................................................          2.0
Goats, liver...................................................          2.0
Goats, meat....................................................          0.1
Goats, mbyp (except kidney and liver)..........................          0.1
Grass, forage..................................................          0.5
Grass, hay (straw).............................................         40.0
Grass, seed screenings.........................................         60.0
Hogs, fat......................................................          0.1
Hogs, kidney...................................................          2.0
Hogs, liver....................................................          2.0
Hogs meat......................................................          0.1
Hogs, mbyp (except kidney and liver)...........................          0.1
Horses, fat....................................................          0.1
Horses, kidney.................................................          2.0
Horses, liver..................................................          2.0
Horses, meat...................................................          0.1
Horses, mbyp (except kidney and liver).........................          0.1
Milk...........................................................          0.05
Nectarines.....................................................          1.0
Peaches........................................................          1.0
Pecans.........................................................          0.1
Plums..........................................................          1.0
Poultry, fat...................................................          0.1
Poultry, kidney................................................          0.2
Poultry, liver.................................................          0.2
Poultry, meat..................................................          0.1
Poultry, mbyp (except kidney and liver)........................          0.1
Prunes, fresh..................................................          1.0
Rice, grain....................................................          0.1
Rice, straw....................................................          3.0
Rye, grain.....................................................          0.1
Rye, straw.....................................................          1.5
Sheep, fat.....................................................          0.1
Sheep, kidney..................................................          2.0
Sheep, liver...................................................          2.0
Sheep, meat....................................................          0.1
Sheep, mbyp (except kidney and liver)..........................          0.1
Wheat, grain...................................................          0.1
Wheat, straw...................................................          1.5
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[FR Doc. 94-3761 Filed 2-17-94; 8:45 am]