UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

	OFFICE OF PREVENTION, PESTICIDE

	AND TOXIC SUBSTANCES

  SEQ CHAPTER \h \r 1 MEMORANDUM

Date:  3/31/2008

SUBJECT:  Ingredient:  Uniconazole-P

		Title:  Petition for Establishment of a Tolerance for Use on Fruiting
Vegetables, Crop Group 8.  Summary of Analytical Chemistry and Residue
Data.

PC Code:  128976  	DP Barcode:  D347093

MRID No.:  47204101, 47204102, 4723102, 47245101, and 47245102
Registration No.:  59639-37

Petition No.:  7E7268	Regulatory Action:  Section 3

Assessment Type:  None	Reregistration Case No.:  None

TXR No.:  None	CAS No.:  83657-17-4

FROM:  	Douglas Dotson, Ph.D., Chemist

	RAB2

	Health Effects Division (7509P)	  SEQ CHAPTER \h \r 1

THROUGH:	William Drew, Chemist

		RAB2

		Health Effects Division (7509P)

		Richard Loranger, Ph.D., Senior Scientist

		RAB2

		Health Effects Division (7509P)

TO:		Shaja Brothers/Barbara Madden, PM Team 5

RIMUERB/Registration Division (7505P)

This document was originally prepared under contract by Dynamac
Corporation (2275 Research Blvd, Suite 300; Rockville, MD 20850;
submitted 01/09/2008).  The document has been reviewed by the Health
Effects Division (HED) and revised to reflect current Office of
Pesticide Programs (OPP) policies.

Executive Summary

Uniconazole
[(E)-(RS)-1-(4-chlorophenyl)-4,4-dimethyl-2-(1H-1,2,4-triazol-1-yl)pent-
1-en-3-ol] is a triazole Group 3 fungicide and plant growth regulator.
The resolved S-isomer, identified as uniconazole-P, is pesticidally
active and is the active ingredient in registered products.
Uniconazole-P reduces plant height by reducing internode elongation
through inhibition of gibberellin biosynthesis.  Under PP#7E7268, the
Interregional Research Project No. 4 (IR-4), in conjunction with Valent
U.S.A. Corporation, and on behalf of the Agricultural Experiment
Stations of Georgia and Oregon, is proposing the establishment of a
permanent tolerance for residues of uniconazole-P in/on Crop Group 8,
Fruiting Vegetables (Except Cucurbits).  The proposed use of
uniconazole-P on fruiting vegetables is the first food use for this
pesticide.  Currently, uniconazole-P is only registered for greenhouse
use on ornamental plants.

IR-4 is proposing the establishment of a permanent tolerance for
residues of the plant growth regulator uniconazole-P in/on:

Vegetable fruiting crop group 8	0.01 ppm

In conjunction with this petition, IR-4 is requesting amended
registration of the Valent end-use product, Sumagic® Plant Growth
Regulator (EPA Reg. No. 59639-37), a 0.055% emulsifiable concentrate
(EC) formulation.  The product is proposed for use on greenhouse-grown
fruiting vegetable transplants, including eggplant, groundcherry,
pepino, pepper, tomatillo, and tomato, as foliar spray applications at
up to 10 ppm in spray volumes of 2 qt/100 sq. ft.  No preharvest
interval (PHI) is specified.

No U.S. tolerances are established for uniconazole-P, and there are
currently no established Codex, Canadian, or Mexican MRLs.

Because uniconazole-P is a triazole compound, the Agency requires that
samples from any metabolism, livestock feeding, field trial, and/or
processing studies be analyzed for the triazole metabolites,
1,2,4-triazole, triazol alanine (TA), and triazol acetic acid (TAA).
The Agency issued guidance on the residue chemistry data requirements
for the triazole-based metabolites under Memo, D327788, 4/25/06, M.
Doherty.  Neither the metabolism studies nor the crop field trials
submitted under the current petition reflect analysis for the triazole
metabolites.  Because all of the studies were completed before the
Agency finalized its guidance for triazole compounds, the absence of
these data will not preclude conditional registration of the proposed
use for uniconazole-P.  In addition, the use of another triazole-derived
pesticide, myclobutanil, on fruiting vegetables at a much higher rate is
likely to result in higher residues of 1,2,4-triazole, TA, and TAA.

The qualitative nature of the residue in plants is adequately understood
for the purposes of this petition.  HED has determined that the residues
of concern in fruiting vegetables are uniconazole-P, its R-enantiomer,
and its Z-isomer.  In the apple and tomato metabolism studies,
uniconazole was the primary residue identified in all apple and tomato
matrices, accounting for 6.2-37.4% TRR in leaves, 44.0-88.9% TRR in
branches/stems,  42.1-43.5% TRR in pulp, and 13.1-16.4% TRR in juice.
The geometric Z-isomer of uniconazole was identified in apple matrices
at up to 3.0% TRR and in tomato matrices at 7.5-10.9% TRR.  Remaining
identified metabolites, including CH2OH-7E, CYC-4Cl, 7KE, and 7KZ were
identified at ≤7% TRR in apple and tomato matrices.  Based on the
submitted apple and tomato metabolism studies, the petitioner concluded
that the major metabolic pathway of uniconazole in plants is initial E/Z
isomerization to the Z-isomer followed by cyclization.  The minor
metabolic pathways are oxidation of the hydroxyl group to a ketone
group, hydroxylation at the terminal carbon, and conjugation of these
metabolites.  Because the nature of the residue has not been
investigated in three dissimilar crops, additional plant metabolism
studies might be required to support future food/feed uses of
uniconazole, depending on the crops for which tolerances are being
requested.

There are no livestock feedstuffs associated with the proposed use on
fruiting vegetables.  Therefore, no livestock metabolism data,
enforcement methods, storage stability data, or feeding studies are
required to support this petition.

The petitioner has proposed an acceptable GC/NPD method, Method RM-25-1,
for the enforcement of tolerances in fruiting vegetables.  The method
determines residues of uniconazole.  The validated limit of quantitation
(LOQ) is 0.01 ppm.  An acceptable revision of the enforcement method,
Method RM-25-1a was used for data collection in the submitted crop field
trials.  The proposed enforcement method should be modified to clarify
which isomers of uniconazole are determined by the method.  From the
method description, it appears that it does not distinguish between the
R and S enantiomers or between the E and Z isomers.  In addition, the
method should be amended to include the confirmatory GC/MS procedures
used in the independent laboratory validation (ILV) and to incorporate
the revisions made by the ILV laboratory.  Alternatively, the petitioner
may propose the data collection method, which includes the confirmatory
procedures and the ILV recommendations, as an enforcement method.  The
proposed enforcement method was forwarded to the Analytical Chemistry
Branch (ACB/BEAD) for petition method validation.

No multiresidue methods testing data have been submitted.

The submitted uniconazole-P crop field trials are supported by
acceptable storage stability data, demonstrating that residues are
stable in/on bell pepper and tomato stored frozen for up to 395 days (13
months).

Provided that the label is modified to specify the total application
that may be made to the seedlings, and the timing of the last
application, adequate field trial data have been submitted to support a
conditional registration for the use of uniconazole-P.  Residues were
nondetectable (<0.005 ppm) in/on all samples of tomato and bell pepper
transplanted and harvested at maturity following one greenhouse
application of the 0.055% formulation of uniconazole-P at the 0.5x, 1x,
and 2x application rates.  The available data will support the proposed
tolerance of 0.01 ppm for fruiting vegetables.  Non-bell pepper data
will not be required for this very early season use before fruit are
present.  The tolerance spreadsheet could not be used to determine
tolerance levels for fruiting vegetables because residues were
nondetectable in/on all samples.

No processing data were submitted.  As residues were nondetectable in/on
all samples of tomatoes treated at up to a 2x rate, and fruit from
treated plants are unlikely to be processed, a tomato processing study
is not needed.

Because the proposed use of uniconazole-P on fruiting vegetables is
restricted to greenhouse application to plants intended to be
transplanted, and residues were nondetectable in/on all tomato and
pepper samples, no data pertaining to rotational crops are required to
support this petition.

  SEQ CHAPTER \h \r 1 Regulatory Recommendations and Residue Chemistry
Deficiencies

HED has examined the residue chemistry database for uniconazole-P.
Pending completion of a method validation by ACB/BEAD, submission of a
revised Section B (see requirements under Directions for Use), a revised
enforcement method (see requirements under Residue Analytical Methods),
and a revised Section F (see requirements under Proposed Tolerances),
there are no residue chemistry issues that would preclude granting
conditional registration for the requested uses of uniconazole-P or
establishment of the following tolerance for residues of uniconazole-P,
its R-enantiomer, and its Z-isomer:

Vegetable, Fruiting, Group 8	0.01 ppm

A human health risk assessment for uniconazole-P has been prepared
(D346558, E. Scollon, 3/31/2008).  This risk assessment addresses risk
of exposure to potential residues of the triazole metabolites
1,2,4-triazole, TA, and TAA, in/on crop commodities.

860.1200 Directions for Use

The following statements should be added to the fruiting vegetable
section of the label:

“If multiple applications are made to the transplants, the total
amount of uniconazole-P applied may not exceed that from a single
application of a 10 ppm spray concentration at 2 qts/100 sq ft
(equivalent to 0.000042 lb ai/100 sq ft or 0.018 lb ai/acre).  The final
application may not occur later than 14 days after the 2-4 true leaf
stage.”

The statement prohibiting application to food crops should be revised to
prohibit application to food crops other than those listed on the label.

860.1340 Residue Analytical Methods

Determination by ACB/BEAD that the enforcement method is adequate.

The proposed enforcement method, Method RM-25-1, should be modified to
clarify which isomers of uniconazole are determined by the method.  In
addition, the method should be modified to include the confirmatory
GC/MS procedures used in the ILV and to incorporate the revisions made
by the ILV laboratory.  Alternatively, the petitioner may propose the
data collection method, Method RM-25-1a, as an enforcement method for
fruiting vegetables, provided the method is modified to specify the
uniconazole isomers determined by the method.

860.1550 Proposed Tolerances

The petitioner should revise the proposed tolerance expression to
reflect the residues of concern:  uniconazole-P, its R-enantiomer, and
its Z-isomer.

The proposed commodity definition should be revised as follows:
Vegetable, Fruiting, Group 8.  The chemical name IR-4 used in the
proposed tolerance expression is the chemical name for the unresolved
enantiomers of uniconazole, and not the chemical names for
uniconazole-P, its R-enantiomer, and its Z-isomer.

Conversion of conditional registration to unconditional registration for
the requested use may be considered upon submission of the following
outstanding residue chemistry data.

860.1300 Nature of the Residue - Plants

Additional storage stability information pertaining to the dates of
sampling, extraction, and analysis, are required for the available apple
and tomato metabolism studies.

860.1360 Multiresidue Methods

Data pertaining to multiresidue methods testing for uniconazole should
be submitted.

The following data deficiencies are not conditions of registration.
However, if additional food uses are proposed in the future, the
following deficiencies should be resolved.

860.1300 Nature of the Residue - Plants

Additional plant metabolism studies will be needed for uses on crops
other than fruits or fruiting vegetables.  Such studies should include
use of uniconazole-P labeled in the triazole ring with analysis for the
triazole metabolites 1,2,4-triazole, TA, and TAA.

860.1340 Residue Analytical Methods

validated data collection method capable of achieving a limit of
quantitation of ≤0.01 ppm for these analytes should be submitted as
specified by the Agency under Memo, D327788, M. Doherty, 4/25/06.

860.1500 Crop Field Trials

Crop field trials for any future new uses should be conducted reflecting
analysis of samples for the triazole metabolites as specified by the
Agency under Memo, D327788, M. Doherty, 4/25/06.

Background

Uniconazole
[(E)-(RS)-1-(4-chlorophenyl)-4,4-dimethyl-2-(1H-1,2,4-triazol-1-yl)pent-
1-en-3-ol] is a triazole Group 3 fungicide and plant growth regulator.
The resolved S-isomer, identified as uniconazole-P, is pesticidally
active and is the active ingredient in registered products.
Uniconazole-P reduces plant height by reducing internode elongation
through inhibition of gibberellin biosynthesis.  Currently,
uniconazole-P is only registered for greenhouse use on ornamental
plants.  Under PP#7E7268, IR-4, in conjunction with Valent U.S.A.
Corporation, and on behalf of the Agricultural Experiment Stations of
Georgia and Oregon, is proposing the establishment of a permanent
tolerance for residues of uniconazole-P in/on Crop Group 8, Fruiting
Vegetables.  The proposed use of uniconazole-P on fruiting vegetables is
the first food use for this pesticide.

The nomenclature of uniconazole is summarized in Table 1, and the
physicochemical properties of uniconazole-P are summarized in Table 2.
The chemical names and structures of uniconazole and its transformation
products are presented in Appendix I.

Table 1.		Uniconazole Nomenclature.

Chemical structure

Common name	Uniconazole (unresolved mixture)	Uniconazole-P (S-isomer)

Company experimental name	None	XE-1019D

IUPAC name
(E)-(RS)-1-(4-chlorophenyl)-4,4-dimethyl-2-(1H-1,2,4-triazol-1-yl)pent-1
-en-3-ol
(E)-(S)-1-(4-chlorophenyl)-4,4-dimethyl-2-(1H-1,2,4-triazol-1-yl)pent-1-
en-3-ol

CAS name
(βE)-β-[(4-chlorophenyl)methylene]-α-(1,1-dimethylethyl)-1H-1,2,4-tri
azole-1-ethanol
(αS,βE)-β-[(4-chlorophenyl)methylene]-α-(1,1-dimethylethyl)-1H-1,2,4
-triazole-1-ethanol

CAS registry number	83657-22-1	83657-17-4

End-use product (EP)	None	0.055% EC formulation (EPA Reg. No. 59639-37)

Based on product chemistry reviews by the Registration Division
(D322521, D. Rate, 12/12/2005, and D312831, S. Malak, 1/4/2006), at
least two uniconazole-P technical grade active ingredients contain about
78-80% S-isomer and 20% R-isomer.

Table 2. 	Physicochemical Properties of Uniconazole

Parameter	Value	Reference

Melting point/range	150ºC	MRID 46424905

pH	6.54 (1% suspension of uniconazole)	MRID 46424905

Density	1.256 g/mL @ 20ºC	MRID 46424905

Water solubility	11.1 mg/L at 20ºC	MRID 46424905

Solvent solubility	Not Submitted

	Vapor pressure	1.0 x 10-8 Pa @ 20ºC

2.3 x 10-8 Pa @ 25ºC 	MRID 46424907

Dissociation constant, pKa	Does not dissociate	MRID 46424905

Octanol/water partition coefficient, Log(KOW)	Log(KOW) = 3.67 @ 25ºC
MRID 46424905

UV/visible absorption spectrum	No significant differences were observed
between the spectra obtained for the acidic, alkaline, and neutral
samples.	MRID 46424905

860.1200  Directions for Use

IR-4 has submitted use directions under Section B of the petition as
well as draft labeling for the 0.055% EC formulation (Sumagic® Plant
Growth Regulator; EPA Reg. No. 59639-37).  The proposed use directions
for uniconazole-P are presented in Table 3.

Table 3.		Summary of Directions for Use of Uniconazole-P.

Applic. Timing, Type, and Equip.	Formulation

[EPA Reg. No.]	Applic. Rate 	Max. No. Applic. per Season	Max. Seasonal
Applic. Rate

	PHI

(days)	Use Directions and Limitations

Fruiting Vegetable Transplants:  Eggplant, Groundcherry, Pepino, Pepper,
Tomatillo, and Tomato

Foliar

Broadcast

Ground	0.055% EC

[59639-37]	2-10 ppm	2

(implied)*	2 qt./100 sq. ft

(implied)*

(0.000042 lb ai/100 sq ft)

(0.018 lb ai/A)	NS	Begin applications when 2-4 true leaves are present.
Apply in a spray volume of  2 qt/100 square feet.  A 7- to 14-day
retreatment interval is specified if sequential applications are made.
Mixing with pesticides, fertilizers, wetting agents, spreader stickers,
or other adjuvants is prohibited.

*Label does allow sequential applications at lower rates, but does not
explicitly state a maximum total rate.

The product is specified for use in commercial greenhouses, lathhouses,
and shadehouses (where plants are grown in containers).  Application
through any type of irrigation system is prohibited.  A reentry interval
of 12 hours is specified.

Under Restrictions and Limitations, the draft label contains the
following statement:  “Do not apply Sumagic to any food crops.”
This statement should be revised to prohibit application to food crops
other than those listed on the label.

Conclusions:  The submitted use directions are sufficient to allow
evaluation of the available residue data relative to the proposed use
provided that the following statements are added to the label:  “If
multiple applications are made to the transplants, the total amount of
uniconazole-P applied may not exceed that from a single application of a
10 ppm spray concentration at 2 qts/100 sq ft (equivalent to 0.000042 lb
ai/100 sq ft or 0.018 lb ai/acre).  The final application may not occur
later than 14 days after the 2-4 true leaf stage.”

Because applications are to be made to young plants in the greenhouse
prior to transplant, a PHI is not needed for the proposed use.  The
statement prohibiting application to food crops should be revised to
prohibit application to food crops other than those listed on the label.

860.1300 Nature of the Residue - Plants

DER References:	47204101.de1.doc (Apple)

		47204102.der.doc (Tomato)

Tomato

Valent U.S.A. Corporation submitted a report that discusses the results
of a study in which the metabolism of [phenyl-U-14C]uniconazole
(specific activity 27.1 mCi/mmol) in tomato was investigated.  The
radiolabeled test substance was dissolved in methanol, then applied as
two foliar broadcast applications with a 14-day retreatment interval to
tomato plants grown in one-gallon pots in a greenhouse.  Each
application was made at a rate of 1.35 mg/plant for a reported
application rate of 0.125 lb ai/A (total application rate of 0.25 lb
ai/A).  The plants bore 1-cm fruit at the time of treatment.  Samples of
tomato foliage, stems, and fruit were harvested at maturity, 49 days
after the last application.  Following harvest, tomatoes were rinsed
with a methanol wash to remove surface residues, and then separated into
juice and pulp.  The in-life and analytical phases of the study were
conducted by Chevron Chemical Company (Richmond, CA).  Based on the
reported R:S isomer ratio, the test substance consisted of 100% of the
S-isomer of uniconazole, uniconazole-P.  Because R:S isomerization was
not investigated in the study, the term uniconazole will be used to
describe the test substance and analyte in this report.

TRR were 4.42 ppm in tomato leaves, 0.27 ppm in stems, 0.021 ppm in the
methanol surface wash, 0.15 ppm in pulp, and 0.013 ppm in juice.

Extraction with acetone released the majority of the radioactivity from
tomato leaves, stems, and pulp:  80.2% TRR (3.545 ppm) from leaves,
80.0% TRR (0.216 ppm) from stems, and 67.1% TRR (0.101 ppm) from pulp.
Additional residues were released from leaves, stems, and pulp by
sequential extraction with methanol (6.0-8.7% TRR), methanol/water
(3.0-4.6% TRR), and acidic methanol (1.9-3.4% TRR).  The nonextractable
residues of pulp were subjected to hydrolysis with 1 N HCl and 20% NaOH,
which released 3.5% and 7.6% TRR, respectively.  Extraction with ethyl
acetate released 44.7% TRR (0.006 ppm) from tomato juice.  Remaining
nonextractable residues were 6.8% TRR (0.301 ppm) in leaves, 9.1% TRR
(0.025 ppm) in stems, 5.5% TRR (0.008 ppm) in pulp, and 55.3% TRR (0.007
ppm) in tomato juice.  These procedures adequately extracted the
majority of residues from tomato matrices.  Extraction results were
normalized; therefore, accountabilities were 100%.  Residues were
identified and quantitated by two-dimensional TLC, and confirmed by
HPLC/UV.  Representative chromatograms were included in the submission.

The petitioner did not provide the dates of extraction or analysis for
the study; however, sufficient information was included in the
submission to suggest that initial characterization analysis was
completed within 6 months of harvest.  The petitioner needs to submit
the dates of extraction and analysis to confirm this conclusion.

The primary residue identified in all matrices was parent uniconazole,
accounting for 37.4% TRR (1.651 ppm) in leaves, 44.0% TRR (0.119 ppm) in
stems, 42.1% TRR (0.063 ppm) in pulp, 13.1% TRR (0.002 ppm) in juice,
and 57.1% TRR (0.012 ppm) in the methanol wash.  The geometric Z-isomer
of uniconazole was also a significant component, accounting for 9.2% TRR
(0.404 ppm) in leaves, 10.9% TRR (0.029 ppm) in stems, 8.9% TRR (0.013
ppm) in pulp, 7.5% TRR (0.001 ppm) in juice, and 10.0% TRR (0.0021 ppm)
in the methanol wash.  Metabolite CYC-4Cl accounted for 6.1-6.7% TRR in
leaves, stems, and pulp, and for 1.5% TRR in juice, and was present at
12.9% TRR (0.003 ppm) in the methanol wash.  Metabolites CH2OH-7E, 7KE,
and 7KZ were minor metabolites, accounting for 0.7-1.4% TRR in leaves
and 1.3-2.4% TRR (7KE and 7KZ only) in the methanol wash.  Conjugates of
the following metabolites were identified in leaves (following acid
hydrolysis of polar residues):  uniconazole (4.5% TRR), Z-isomer and
CYC-4Cl (2.3% TRR each), CH2OH-7E (4.5% TRR), and CH2OH-7Z (2.7% TRR).
Conjugates of uniconazole, the Z-isomer, and CYC-4Cl were also
identified at low levels in the nonextractable residues of juice
(following acid hydrolysis).  Unknown free metabolites (at least 2-4 in
each matrix) accounted for 11.1-11.9% TRR in leaves and stems, 2.7% TRR
in pulp, 4.8% TRR in juice, and 9.0% TRR in the methanol wash.
Remaining radioactivity was characterized as multicomponent polar and
conjugated unknowns, and accounted for up to 7.7% TRR (0.34 ppm) in
leaves, 17.3% TRR (0.047 ppm) in stems, 19.8% TRR (0.026 ppm) in pulp,
17.7% TRR (0.002 ppm) in tomato juice, and 9.0% TRR (0.002 ppm) in the
methanol wash.

Based on the submitted tomato metabolism study, the petitioner concluded
that the major metabolic pathway of uniconazole in plants is initial E/Z
isomerization to the Z-isomer followed by cyclization.  The minor
metabolic pathways are oxidation of the hydroxyl group to a ketone
group, hydroxylation at the terminal carbon, and conjugation of these
metabolites.  The petitioner noted that the metabolic pathway observed
in tomatoes was similar to that derived from plant metabolism studies in
apple, wheat, and rice.  As for apples, the petitioner noted that E/Z
isomerization and cyclization reactions are associated with
photoreactions that have been observed in uniconazole analogs, and that
the Z-isomer and CYC-4Cl metabolites were not among those identified in
the rat metabolism study.

Conclusions:  The apple and tomato metabolism data did not include
labeling/analysis for the triazole metabolites, 1,2,4-triazole, TA, and
TAA.  The Agency has determined that plant metabolism studies using
triazole-labeled parent compound with analysis for the triazole
metabolites are required for registrations of triazole pesticides for
uses associated with food and/or feed crops (Memo, D327788, 4/25/06, M.
Doherty).  For the proposed early season, low application rate use on
fruiting vegetable seedlings, the triazole data will not be required.
However, information is required pertaining to the dates of sampling
and/or extraction and analysis for the apple and tomato metabolism
studies.

The submitted metabolism studies indicate that the nature of the residue
is similar in apple and tomato.  Pending submission of the required
information pertaining to sample storage intervals, the nature of the
residue in fruiting vegetables is adequately understood.  For purposes
of this petition, the residues of concern for tolerance expression and
risk assessment in fruiting vegetables are uniconazole-P, its
R-enantiomer, and its Z-isomer.  The R-enantiomer is included because of
its presence in at least several technical grade active ingredients at
about 20%.

Additional plant metabolism studies might be required to support future
food/feed uses of uniconazole, depending on the crops for which
tolerances are being requested.  These studies should include triazole
ring labeling as described in the 4/25/2006 guidance.

Apple

Valent U.S.A. Corporation submitted a report that discusses the results
of a study in which the metabolism of [phenyl-U-14C]uniconazole
(specific activity 27.1 mCi/mmol) in apple was investigated.  The
radiolabeled test substance was isotopically diluted with nonlabeled
standard, dissolved in methanol, and applied as a 25-mg stem injection
treatment to the trunks of apple trees grown outdoors in pots.  Samples
of branches, leaves, and mature apples were harvested 86 days after
treatment.  Apples were separated into juice and pulp.  The in-life and
analytical phases of the study were conducted by Chevron Chemical
Company (Richmond, CA).  Based on the reported R:S isomer ratio, the
test substance consisted of 100% of the S-isomer of uniconazole,
uniconazole-P.  Because R:S isomerization was not investigated in the
study, the term uniconazole will be used to describe the test substance
and analyte in this report.

TRR were 9.88 ppm in leaves, 14.6 ppm in branches, 0.074 ppm in apple
pulp, and 0.011 ppm in juice.  The low residues in apples suggest that
uniconazole was very slowly translocated in apple trees.  The petitioner
noted that <1% of the [14C]uniconazole injected into the trunk
translocated to the fruit.

Extraction with acetone released the majority of the radioactivity
(54.4-75.5% TRR) from leaves, branches, and apple pulp; sequential
extraction with methanol and methanol/water released additional
radioactivity:  4.6-18.7% TRR and 3.3-9.2% TRR, respectively.  Remaining
nonextractable residues were ≤9.4% TRR (≤1.21 ppm) in leaves and
branches, and 37.7% TRR (0.028 ppm) in pulp.  The nonextractable
residues of pulp were subjected to additional acid and base hydrolysis
procedures, which released 2.4% TRR and 29.4% TRR, respectively.
Extraction with ethyl acetate released 48.1% TRR (0.005 ppm) from juice;
the remaining nonextractable residues of juice (51.9% TRR, 0.006 ppm),
were not further investigated.  These procedures adequately extracted
the majority of residues from apple matrices.  Extraction results were
normalized; therefore, accountabilities were 100%.

Residues were identified and quantitated using two-dimensional TLC, and
confirmed by HPLC/UV.  Representative chromatograms were included in the
submission.

The petitioner did not provide the dates of sampling, extraction, or
analysis for the study; however, sufficient information was included in
the submission to suggest that initial characterization analysis was
completed within 6 months of harvest.  The petitioner should submit the
dates of sampling, extraction, and analysis to confirm this conclusion.

Uniconazole was the primary residue identified in all apple matrices,
accounting for 6.2% TRR (0.61 ppm) in leaves, 88.9% TRR (12.98 ppm) in
branches, 43.5% TRR (0.032 pm) in pulp, and 16.4% TRR (0.0018 ppm) in
juice.  In leaves, 11.4% TRR (1.13 ppm) was identified as a uniconazole
conjugate (following acid hydrolysis of polar residues).  The geometric
Z-isomer of uniconazole and a hydroxylated metabolite, CH2OH-7E, were
identified in all matrices at 0.5-4.0% TRR, and metabolite CYC-4Cl was
identified in leaves, branches, and pulp at ≤2.3% TRR.  Conjugates of
the following metabolites were identified in leaves and juice,
respectively (following acid hydrolysis of polar residues):  Z-isomer
(5.9% and 1.4% TRR), CYC-4Cl (1.4% and 1.0% TRR), CH2OH-7Z (9.7% and
0.9% TRR), and CH2OH-7E (5.9% TRR, leaves only).  Unknown free
metabolites accounted for 4.0% TRR in leaves, 0.3% TRR in branches, and
12.7% TRR in juice.  Remaining radioactivity was characterized as
multicomponent polar and conjugated unknowns, and accounted for up to
24.5% TRR in leaves, 0.4% TRR in branches, and ≤9.9% TRR in pulp and
juice.

Based on the results of the apple metabolism study, the petitioner
concluded that the major metabolic pathway in plants was initial E/Z
isomerization to the Z-isomer followed by cyclization and hydroxylation
at the terminal carbon, followed by conjugation.  The petitioner noted
that the metabolic pathway observed in apples was similar to that
derived from plant metabolism studies in tomato, wheat, and rice.  The
wheat and rice metabolism studies have not been reviewed by HED.  The
petitioner further noted that E/Z isomerization and cyclization
reactions are associated with photoreactions that have been observed in
uniconazole analogs, and that the Z-isomer and CYC-4Cl metabolites were
not among those identified in rats.

860.1300 Nature of the Residue - Livestock

There are no livestock feedstuffs associated with the proposed use on
fruiting vegetables.  Therefore, data requirements for livestock
metabolism are not relevant to this tolerance petition.

860.1340 Residue Analytical Methods

DER Reference:	47204101.de2.doc (also includes review of MRIDs 47204102
and 47232102)

Enforcement method:  Valent U.S.A Corporation submitted GC/NPD Method
RM-25-1, “Determination of XE-1019D (S-3307) In Crops” for the
determination of residues of

uniconazole-P in/on various crop commodities.  Valent is proposing
Method RM-25-1 as a tolerance enforcement method, and has submitted
radiovalidation data and an ILV.

Briefly, samples of dry crops (e.g., leaves or mulch) are extracted
twice with methanol.  The combined extracts are filtered through sodium
sulfate and concentrated.  Samples of high moisture crops (e.g., tomato
or apple) are mixed with anhydrous sodium sulfate and then extracted
twice with acetone.  The combined extracts are filtered through sodium
sulfate and concentrated.  All extracts are diluted with 10% NaCl
solution and partitioned twice with dichloromethane (DCM).  The DCM
phases are filtered through sodium sulfate, combined, and evaporated to
dryness.  For dry crops, the residue is dissolved in hexane and
partitioned twice with acetonitrile (ACN).  The ACN phases are combined,
washed with hexane, and evaporated to dryness.  The resulting residue
from dry crops and the residue from high moisture crops are dissolved in
ethyl acetate, diluted with hexane, and applied to a Florisil column.
Residues of uniconazole are eluted with ethyl acetate.  The eluate is
evaporated to dryness and dissolved in ethyl acetate for GC/NPD
analysis.

Based on the method description, the method does not distinguish between
the R and S enantiomers of uniconazole.  In addition, the original
residue method, RM-25, reportedly does not distinguish between
uniconazole and its Z-isomer.  The registrant needs to revise Method
RM-25-1 so that it states more clearly that it does not distinguish
between the uniconazole isomers.

The reported LOQ was 0.02 ppm (based on the lowest limit of method
validation; LLMV), and the reported limit of detection (LOD) was 0.002
ppm based on the results of the ILV.

No method validation data were submitted for GC/NPD Method RM-25-1;
however, the method was successfully validated for tomato fortified at
0.02, 0.04, and 0.2 ppm in the ILV.  Recoveries ranged from 82.0 to
88.5%, with an overall average recovery of 86.2% and an overall standard
deviation of 2.6%.  Acceptable concurrent recovery data reflecting
fortification of bell pepper at 0.01 ppm and tomato at 0.01 and 0.02 ppm
were also submitted for the modified data collection method, Method
RM-25-1a, in conjunction with the tomato and pepper crop field trials.
Together, the ILV and concurrent recovery data are sufficiently
representative of the expected residue levels for fruiting vegetables.
No additional method validation data are required.

Radiovalidation data were generated for the original residue method,
Method RM-25, in conjunction with the apple and tomato metabolism
studies submitted under PP#7E7268.  The submitted data are acceptable
and indicate that the method adequately recovered weathered residues of
uniconazole from samples of apple and tomato leaves and pulp.

Data collection method:  Samples of tomato and bell pepper from the
submitted crop field trials were analyzed for residues of uniconazole-P
using GC/NPD Method RM-25-1a, entitled “Determination of Uniconazole-P
in Fruiting Vegetables” (revision dated 4/10/03).  Method RM-25-1a is
a modification of the proposed enforcement method, RM-25-1 which
incorporates the ILV recommendations and includes GC/MS confirmatory
procedures.  Adequate concurrent recovery data were submitted for the
method.

Conclusions.  Pending review by ACB/BEAD, the submitted residue
analytical method data are adequate to satisfy data requirements for the
tolerance petition.  The proposed enforcement method, Method RM-25-1,
needs to be revised so that it states more clearly that it does not
distinguish between the isomers.  In addition, the method should be
modified to include the confirmatory GC/MS procedures used in the ILV
and to incorporate the revisions made by the ILV laboratory.
Alternatively, the petitioner may propose the data collection method,
revised Method RM-25-1a, as an enforcement method for fruiting
vegetables, provided the method is modified to specify the uniconazole
isomers determined by the method.  The proposed enforcement method and
the ILV recommendations were forwarded to the Analytical Chemistry
Branch (ACB/BEAD) for petition method validation.

An acceptable method was used for data collection for the bell pepper
and tomato crop field trial studies submitted under this action.  When
any future field trial data reflecting analysis for residues of the
triazole metabolites are submitted, a validated data collection method
capable of achieving a limit of quantitation of ≤0.01 ppm for these
analytes should be submitted as specified by the Agency under Memo,
D327788, M. Doherty, 4/25/06.

860.1360 Multiresidue Methods

No data pertaining to multiresidue methods were submitted with this
petition, and the FDA PESTDATA database (dated 06/05) does not contain
any information for uniconazole.  Data pertaining to multiresidue
methods testing for uniconazole should be submitted.

860.1380 Storage Stability

DER Reference:  None

IR-4 conducted concurrent storage stability studies with the bell pepper
and tomato field trials.  The results indicated that residues of
uniconazole-P are relatively stable in/on bell pepper and tomato for up
to 395 days (13 months).

The storage durations and conditions of samples from the crop field
trials submitted to support this petition are presented in Table 4.

Table 4.	   Summary of Storage Conditions and Durations of Samples from
Crop Field Trial Studies

Matrix 	Storage Temperature

 (°C)	Actual Storage Duration	Interval of Demonstrated Storage
Stability

Tomato	< -25 to -15	84-316 days

(2.8-10.4 months)	Residues of uniconazole were relatively stable in/on
tomato stored for 396 days and in/on bell pepper stored for 395 days

Bell pepper

133-335 days

(4.4-11.0 months)

Conclusions:  The available storage stability data for uniconazole-P are
adequate to support the storage conditions and durations of samples of
tomato and bell pepper from the submitted crop field trials.  There are
no storage stability issues, and no corrections for storage stability
need to be applied to the field trial studies.

860.1400 Water, Fish, and Irrigated Crops

There are no proposed/registered uses that are relevant to this
guideline topic.

860.1460 Food Handling

There are no proposed/registered uses that are relevant to this
guideline topic.

860.1480 Meat, Milk, Poultry, and Eggs

There are no livestock feedstuffs associated with the proposed use on
fruiting vegetables.  Therefore, data requirements pertaining to meat,
milk, poultry, and eggs are not relevant to this tolerance petition.

860.1500 Crop Field Trials

DER Reference:  47245101.der.doc (also includes review of MRID 47245102)

IR-4 submitted field trial data for uniconazole on fruiting vegetables
from 18 field trials conducted in the United States during the 2002
growing season.  Twelve tomato trials were conducted in EPA Growing
Zones 2 (NJ; 1 trial), 3 (FL; 2 trials), 5 (MI; 1 trial), 6 (TX; 1
trial), and 10 (CA and NM; 7 trials).  Six bell pepper trials were
conducted in Zones 2 (NJ; 1 trial), 3 (FL; 1 trial), 5 (MI; 1 trial), 6
(TX; 1 trial), and 10 (CA and NM; 2 trials).  No non-bell pepper field
trials were conducted.

At each test location, greenhouse-grown tomato and bell pepper plants at
the 2- to 4-leaf growth stage were treated with the 0.055% EC
formulation of uniconazole-P, in a single foliar broadcast application
made to separate plots using 5 and 10 ppm solutions.  Applications were
made using backpack sprayers in spray volumes of 1.97-4.09 qt/100 sq.
ft, without an adjuvant.  Tomato and bell pepper plants were
transplanted to the field 20-41 days after application.  Samples of
mature tomatoes and peppers were harvested at PHIs of 91-128 days for
tomatoes and 85-116 days for peppers.  In the tomato trials, 22 samples
were taken from 1x treated plots, 2 samples were taken from 0.5x treated
plots, and 2 samples were taken from 2x treated plots.  In the pepper
trials, 10 samples were taken from 1x treated plots and 2 samples were
taken from 2x treated plots.

Samples of tomatoes and peppers from all 10-ppm treatment plots and
samples of tomatoes from one 5-ppm treatment plot were analyzed for
residues of uniconazole-P using GC/NPD Method RM-25-1a.  The LOQ,
determined as the LLMV, was 0.01 ppm for uniconazole-P in/on tomato and
pepper; the experimental LOD was 0.005 ppm.  The method is adequate for
data collection based on acceptable concurrent recovery data.  Samples
were not analyzed for the triazole metabolites, 1,2,4-triazole, TA, and
TAA.

The maximum storage durations of crop samples, from harvest to analysis,
were 316 days (10.4 months) for tomato and 335 days (11.0 months) for
bell pepper.  To support sample storage conditions and durations, the
petitioner conducted a concurrent storage stability study which
indicated that residues of uniconazole-P were relatively stable during
frozen storage for up to 395 days (13 months) in/on tomato and pepper.
These data are adequate to support the storage durations and conditions
for the fruiting vegetable field trials.

Residues of uniconazole-P were nondetectable (<0.005 ppm) in/on all
samples of tomato and bell pepper harvested 91-128 and 85-116 days,
respectively, following a single foliar broadcast application of the
0.055% EC formulation of uniconazole at 0.5x, 1x, and 2x the maximum
label application rate.  The results of the analyses are given in Table
5, below.

Table 5.	  Summary of Residue Data from Crop Field Trials with
Uniconazole-P

Commodity	PHI

(days)	Total Applic. Rate

 (lb ai/A)	Residue Levels1

 (ppm)

	n	Min.	Max.	HAFT2	Median

(STMdR)	Mean

(STMR)	Std. Dev.

Tomato	91-128	0.0091	2	<0.01	<0.01	0.01	0.01	0.01	--

0.0178-0.0198	22	<0.01	<0.01	0.01	0.01	0.01	0

0.0363	2	<0.01	<0.01	0.01	0.01	0.01	--

Bell pepper	85-116	0.0183-0.0198	10	<0.01	<0.01	0.01	0.01	0.01	0

0.0384	2	<0.01	<0.01	0.01	0.01	0.01	--

1  For calculation of median, mean, and standard deviation, the LOQ
(0.01 ppm) was used for results reported as ND in the field trial DERs.

2  HAFT = Highest Average Field Trial.

From the submission, it is unclear as to whether the method determines
uniconazole-P or the unresolved mixture of the two enantiomers.  Based
on the method description and information reported with the original
residue method, it appears that the method probably determines combined
residues of all uniconazole isomers (R/S enantiomers and E/Z isomers).

No small-size tomato varieties were used in the field trials; however,
because the proposed use pattern reflects greenhouse application to
plants made prior to fruit formation and transplanting (i.e., surface
residues are not of concern), no additional tomato trials will be
required.

No residue decline data were submitted; however, no data are required
because of the long PHIs reflected in the study and the absence of
detectable residues in all samples.

Conclusions.  The residue data reflect a single application of
uniconazole-P using the maximum proposed spray concentration of 10 ppm.
With the exception of a few samples, most of the data also reflect the
proposed spray volume of 2 qts/100 sq ft, which in conjunction with the
10 ppm concentration equates to 0.018 lb ai/A.  The proposed label also
has the option of sequential applications at lower recommended rates,
which presumably involve use of concentrations as low as 2 ppm based on
the rate table for fruiting vegetables.  First time users are advised to
use the lowest rate to determine the optimal rate for individual
cultivars under local conditions.  If additional growth regulation is
needed, a sequential spray application at the lowest rate should be made
7 to 14 days after the initial treatment.  HED notes that the data do
not reflect multiple applications or any applications later than the 2-4
leaf stage.  However, the second of the sequential applications would be
made at a rate considerably below the rate used in the field trials and
would still occur at an early growth stage before transplanting.
Furthermore, some of the field trial samples had applications of the 10
ppm spray concentration at volumes of 4 qts/100 sq ft or 2x the maximum
requested rate.  Taking into account these factors, HED concludes the
residue data are adequate to support the proposed 0.01 ppm tolerance
provided that the following statements are added to the label:  “If
multiple applications are made to the transplants, the total amount of
uniconazole-P applied may not exceed that from a single application of a
10 ppm spray concentration at 2 qts/100 sq ft (equivalent to 0.000042 lb
ai/100 sq ft or 0.018 lb ai/acre).  The final application may not occur
later than 14 days after the 2-4 true leaf stage.”  With the latter
statement on the label, a preharvest interval does not need to be
specified.

Geographic representation for the submitted tomato and bell pepper field
trials is adequate.  Although one tomato trial was conducted in Region 6
instead of in Region 1, as specified under OPPTS Guideline 860.1500,
because the proposed use is for pretransplant application in the
greenhouse, no additional data are required.

Samples were analyzed for the residue of concern, uniconazole; however,
samples were not analyzed for the triazole metabolites 1,2,4-triazole,
TA, and TAA.  Crop field trials for any future new uses should be
conducted reflecting analysis of samples for the triazole metabolites as
specified by the Agency under Memo, D327788, M. Doherty, 4/25/06.  Such
data are not required for the proposed uses because the registered use
of the triazole fungicide myclobutanil on fruiting vegetables at rates
of 0.125 to 0.50 lb ai/A is likely to produce higher residues of the
triazole metabolites.

No trials were conducted on non-bell peppers.  IR-4 argued that these
data are not required because, given the very early season application
and long PHI, residues would be unlikely to result regardless of variety
or fruit size.  HED concurs with IR-4’s argument.  Because residues of
uniconazole were nondetectable in/on all samples from all 18 tomato and
pepper field trials, no additional trials on non-bell peppers will be
required at this time.

Provided that the label is amended as specified in Directions for Use
(860.1200), the available field trial data will support a tolerance for
residues of uniconazole in/on Crop Group 8, Fruiting Vegetables, at the
method LOQ of 0.01 ppm.

860.1520 Processed Food and Feed

DER Reference:	None

No processing study was included in the subject petition, nor was the
need for a processing study addressed.  The proposed use reflects an
early-season application to tomatoes prior to fruit formation, and
residues were nondetectable (<0.005 ppm) in/on all tomato samples from
the crop field trials conducted at up to a 2x rate.  However, the
maximum theoretical concentration factor for tomato is 5.5x (Table 1,
OPPTS 860.1520).  Application of this factor to the method LOD of 0.005
ppm suggests that detectable residues (up to 0.028 ppm) could
potentially be present in tomato processed commodities.  However, HED
believes that very few tomato plants treated with a growth regulator to
control their height would end up in the processing market (electronic
communication, B. Schneider, 3/11/2008).

Conclusions:  A tomato processing study is not needed to support the
proposed use of uniconazole-P on fruiting vegetables.  This waiver is
based on residues being nondetectable in the crop field trials and the
minimal likelihood of treated tomatoes being processed.

  SEQ CHAPTER \h \r 1 860.1650 Submittal of Analytical Reference
Standards

Analytical standards for uniconazole-P (expiration 6/2009) and
uniconazole (expiration 5/2008) are currently available in the EPA
National Pesticide Standards Repository (electronic communication from
Dallas Wright, ACB, 2/26/2008).  The Agency requires that the registrant
submit new analytical standards upon expiration of the old ones.

860.1850 and 860.1900 Confined and Field Accumulation in Rotational
Crops

Because the proposed use of uniconazole-P on fruiting vegetables is
restricted to greenhouse application to plants intended to be
transplanted, and because no detectable residues of uniconazole were
found in/on any sample in any of the crop field trials, no data
pertaining to rotational crops are required to support this petition.

860.1550 Proposed Tolerances

HED has determined that the residues of concern in fruiting vegetables
are uniconazole-P, its R-enantiomer, and its Z-isomer.  IR-4 is
proposing establishment of a tolerance for residues of uniconazole-P
[(E)-(RS)-1-(4-chlorophenyl)-4,4-dimethyl-2-(1H-1,2,4-triazol-1-yl)pent-
1-en-3-ol].  The petitioner should revise the proposed tolerance
expression to reflect the residues of concern.  The chemical name IR-4
used in the proposed tolerance expression is the chemical name for the
unresolved enantiomers of uniconazole, and not the chemical names for
uniconazole-P, its R-enantiomer, and its Z-isomer.

No Codex, Canadian, or Mexican MRLs have been established for
uniconazole.

The available field trial data for tomato and bell pepper are adequate,
pending revision of the label as specified under 860.1200.  The
available data will support a tolerance of 0.01 ppm for residues of
uniconazole-P in/on Crop Group 8, Fruiting Vegetables (Except
Cucurbits).  Because residues were nondetectable in/on all samples of
tomato and bell pepper, the tolerance spreadsheet in the Agency’s
Guidance for Setting Pesticide Tolerances Based on Field Trial Data was
not needed to determine the tolerance level.  The proposed tolerance is
set at the method LOQ.

Tolerances are not needed for tomato processed commodities.

The proposed tolerance should be revised to reflect the correct
commodity definition specified in Table 6, below.

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References

Triazole-Based Metabolites:  Guidance On Residue Chemistry Data
Submissions, D327788, M. Doherty,   SEQ CHAPTER \h \r 1 4/25/06.

  SEQ CHAPTER \h \r 1 Attachments:

International Residue Limit Status sheet

Appendix I - Chemical Name and Structure Table

INTERNATIONAL RESIDUE LIMIT STATUS

Chemical Name:
(E)-(RS)-(4-chlorophenyl)-4,4-dimethyl-2-(1H-1,2,4-triazol-1-yl)pent-1-e
n-3-ol	Common Name:

Uniconazole or uniconazole-P	X Proposed tolerance

□  Reevaluated tolerance

□  Other	Date: 12/10/07

Codex Status (Maximum Residue Limits)	U. S. Tolerances

√No Codex proposal step 6 or above

□ No Codex proposal step 6 or above for the crops requested	Petition
Number:  PP#7E7268

DP#:  347093

√ No Limits

□No Limits for the crops requested	√ No Limits

□No Limits for the crops requested

Residue definition:  N/A

	Residue definition:  N/A

Crop(s)	MRL (mg/kg)	Crop(s)	MRL (mg/kg)

	Notes/Special Instructions:

S. Funk, 12/10/2007.

APPENDIX I.	Chemical Names and Structures of Uniconazole and
Metabolites.

Common name;

Company code	Chemical name	Chemical structure

Uniconazole

(XE-1019D)
(E)-(S)-1-(4-chlorophenyl)-4,4-dimethyl-2-(1H-1,2,4-triazol-1-yl)-pent-1
-en-3-ol

Z-isomer
(Z)-(S)-1-(4-chlorophenyl)-4,4-dimethyl-2-(1H-1,2,4-triazol-1-yl)-pent-1
-en-3-ol

CYC-4Cl

(XE-1145)
1-(9-chloro-s-triazolo[5,1a]-isoquinoline-5-yl)-2,2-dimethylpropan-1-ol

CH2OH-7E

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(E)-(S)-1-(4-chlorophenyl)-4-methyl-4-hydroxymethyl-2-(1H-1,2,4-triazol-
1-yl)-pent-1-en-3-ol

CH2OH-7Z

(XE-1179; as a conjugate only)
(Z)-(S)-1-(4-chlorophenyl)-4-methyl-4-hydroxymethyl-2-(1H-1,2,4-triazol-
1-yl)-pent-1-en-3-ol

7KE

(XE-1169)
(E)-1-(4-chlorophenyl)-4,4-dimethyl-2-(1,2,4-triazol-1-yl)-penten-3-one

7KZ

(XE-1170)
(Z)-1-(4-chlorophenyl)-4,4-dimethyl-2-(1,2,4-triazol-1-yl)-penten-3-one

Page   PAGE  6  of   NUMPAGES  21

Uniconazole-P	Summary of Analytical Chemistry and Residue Data	DP#:
347093