UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

OFFICE OF

PREVENTION, PESTICIDES

AND TOXIC SUBSTANCES

MEMORANDUM

	Date:	11/19/07

	Subject:	Fluopicolide.  PP#5F7016.  Petition for Establishment of
Tolerances for Use on

		Tuberous and Corm Vegetables, Leafy Vegetables (except Brassica),
Fruiting Vegetables, Cucurbit Vegetables, and Grapes and for Indirect or
Inadvertent Residues on the Rotational Crop Wheat.  Summary of
Analytical Chemistry and Residue Data.

DP Numbers:	 326080, 327026,      339155	Decision Number:	362973

PC Code:	027412	MRID Nos.:	46708418, 46708514, 46708515, 46708516,
46708517, 46708518, 46708519, 46708520, 46708521, 46708522, 46708523,
46708524, 46708525, 46708526, 46708527, 46708528, 46708529, 46708530,
46708531, 46708532, 46708533, 46708534, 46708535, 46708536, 46708537,
46708538, 46708539, 46708540, 46708541, 46708542, 46708543, 46708544,
46708545, 46708546, 46708547, 47073701

40 CFR 180.	627

Chemical Class:	Benzamide/Pyridine

Fungicide

	From:	Amelia M. Acierto, Chemist

		Registration Action Branch 3/Health Effects Division (7509P)

	Through:	Donna S. Davis, Senior Chemist

		Reregistration Branch /Health Effects Division (7509P)

	To:	Janet Whitehurst/Tony Kish, RM-22

		Fungicide Branch/Registration Division (7505P)

This document was originally prepared under contract by Dynamac
Corporation (2275 Research Blvd, Suite 300; Rockville, MD 20850;
submitted 3/9/2007).  The document has been reviewed by the Health
Effects Division (HED) and revised to reflect current Office of
Pesticide Programs (OPP) policies.

Executive Summary

Valent U.S.A. Corporation has submitted a petition, PP#5F7016, proposing
the establishment of tolerances for residues of the fungicide
fluopicolide
[2,6-dichloro-N-[[3-chloro-5-(trifluoromethyl)-2-pyridinyl]methyl]benzam
ide] in/on the following raw agricultural commodities (RACs):

Commodity	ppm

Tuberous and corm vegetables subgroup 1C

Vegetable, leafy, except Brassica, group 4

Vegetable, fruiting, group 8

Vegetable, cucurbit, group 9

Grape

Raisins

Wheat forage

Wheat grain

Wheat hay

Wheat straw 	      0.02

     20

       0.8

       0.4

       2

       6

       0.2

       0.02                  0.5

       0.5

HED notes that the petitioner actually proposed separate tolerances for
the individual crops in the tuberous and corm vegetable, leafy
vegetable, fruiting vegetable, and cucurbit vegetable crop groups (see
Table 9 for a full list of proposed crops).

HED also notes that some crops in Crop Group 1C (bitter and sweet
cassava, dasheen, tanier, and true yam) are also in Group 2: Leaves of
Root and Tuber Vegetables (Human Food or Animal Feed) Group in 40 CFR
§180.41; however, tolerances are not needed for the leaves of these
crops since the leaves of these crops are not significant food/feed
items based on Agency guidelines (OPPTS 860.1000, Table 1; and Table 1
Feedstuffs, October 2006).

The petitioner is not proposing use of fluopicolide on wheat as a
primary crop; the proposed tolerances are for indirect or inadvertent
residues in rotational wheat commodities.

In conjunction with this petition, Valent U.S.A. has submitted a FIFRA
Section 3 request to register two end-use products, V-10161 4 SC, a 4 lb
ai/gal flowable concentrate (FlC) formulation with EPA File Symbol No.
59639-RUN; and V-10162 Premix, a FlC formulation containing 0.52 lb/gal
of fluopicolide and 5.2 lb/gal of propamocarb hydrochloride, with EPA
File Symbol No. 59639-RUE.  The products are proposed for use on grapes,
potatoes, sweet potatoes, the cucurbit vegetable crop group, the
fruiting vegetable crop group, and the leafy vegetable (except Brassica)
crop group, as multiple foliar applications at up to 0.125 lb
ai/A/application with a maximum seasonal rate of 0.375 lb ai/A.  The
petitioner has proposed preharvest intervals (PHIs) of 2 days for
cucurbit vegetables, fruiting vegetables, and leafy vegetables, 7 days
for potato and sweet potato, and 21 days for grape, and minimum
retreatment intervals (RTIs) of 7 days for fruiting vegetables, 10 days
for cucurbit vegetables, leafy vegetables, potato, and sweet potato, and
12 days for grape.  The 4 lb/gal FlC formulation (V-10161 4 SC) may be
applied in a tank mix with fungicides that are registered for the same
use.

Tolerances have been established (40 CFR §180.627) for residues of
fluopicolide,
2,6-dichloro-N-[[3-chloro-5-(trifluoromethyl)-2-pyridinyl]methyl]
benzamide, on grape at 2.0 ppm and grape, raisin at 6.0 ppm for use on
imported crops (see PP#5E6903; DP Number 321209, 1/23/2007, A. Acierto).
 No livestock tolerances have been established.  There are currently no
registered uses of fluopicolide in the U.S.   No Codex, Canadian, or
Mexican Maximum Residue Limits (MRLs) or tolerances have been
established for fluopicolide.

HED notes that one of the proposed products, V-10162 Premix (EPA File
Symbol No. 59639-RUE), is a multiple active ingredient (MAI) FlC
formulation containing propamocarb hydrochloride.  The proposed uses of
propamocarb hydrochloride on cucurbit vegetables, fruiting vegetables,
head and leaf lettuce, and potato are not evaluated in this document.
Tolerances do exist for residues of propamocarb hydrochloride on
cucurbit vegetables, fruiting vegetables, head and leaf lettuce, and
potato [40 CFR §180.499(a)].  The adequacy of the proposed use
directions for propamocarb hydrochloride and the availability of
adequate supporting residue data will be addressed in a separate review
for propamocarb hydrochloride.

The qualitative nature of the residues in primary plants is adequately
understood for the purposes of this petition based on acceptable grape,
lettuce, and potato metabolism studies.  HED has determined that the
tolerance expression for all primary crops is fluopicolide per se as an
indicator of combined residues of fluopicolide and its metabolite,
2,6-dichlorobenzamide (BAM).  For risk assessment purposes, the residue
of concern for the tuberous and corm vegetables includes the parent
compound, fluopicolide, and its metabolites,
3-chloro-5-trifluoromethylpyridine-2-carboxylic acid (PCA) and BAM.  For
all other primary crops, the residue of concern for risk assessment
purposes includes the parent compound and the metabolite, BAM.

The metabolism of fluopicolide in rotational crops has been adequately
delineated for the purpose of this petition.  HED has concluded that the
tolerance expression for inadvertent residues of fluopicolide in
rotational crops should be expressed as fluopicolide per se as an
indicator of combined residues of parent and its metabolite, BAM.  For
risk assessment purposes, the residue of concern in grain for human food
includes the parent compound, fluopicolide and its metabolites BAM, PCA
and 3-methylsulfinyl-5-trifluoromethylpyridine-2-carboxylic acid (P1X).
The residue of concern in forage/hay/straw and grain for livestock feed
is parent compound and the metabolite, BAM.  The residue of concern for
risk assessment purposes for all other rotational crops includes
fluopicolide (parent) and its metabolite, BAM.

There are livestock feed items associated with the requested new uses of
fluopicolide.  Additional information is needed to support the submitted
fluopicolide ruminant and poultry metabolism studies.  In ruminants, the
studies indicate that a large portion of the dosed radioactivity
(75-84%) was excreted.  Fluopicolide was the major residue identified in
milk (29% TRR) and fat (64-76%); it was found at low levels in muscle,
liver, and kidney (<3% TRR).  Fluopicolide appears to be metabolized in
ruminants via hydroxylation of the chlorophenyl ring in two positions to
form AE 0712556 and AE C643890; these metabolites were found in liver
and kidney at <7% TRR each.  Each of these metabolites is then
conjugated with sulfate or glucuronic acid, or hydroxylated in a second
position and then conjugated with sulfate or glucuronic acid.  Finite
residues of fluopicolide are not expected in ruminant commodities.  A
small amount of BAM was found in milk (4% TRR), and no PCA was found in
any cattle matrix. In poultry, based on the study conducted with
fluopicolide radiolabeled in the phenyl ring, a large portion of the
dosed radioactivity was excreted (up to 95%).  Fluopicolide was
identified at low levels in egg white, egg yolk, and fat (≤11% TRR);
it was not identified in liver or skin.  The major metabolite identified
in egg white and fat was Metabolite 1, a methyl sulfone metabolite of
fluopicolide, at 51% TRR in egg white and 38% TRR in fat.  The major
residue identified in liver was BAM, at 37% TRR; this metabolite was not
found in any other matrix.  Finite residues of fluopicolide are not
expected to occur in livestock commodities. Pending submission of the
required additional data, HED has tentatively determined that the
tolerance expression for livestock commodities should include residues
of the metabolite BAM only.  For risk assessment purposes, the residue
of concern for risk assessment purposes is fluopicolide and its
metabolite, BAM.

Acceptable data collection methods were used in the storage stability,
field trial, processing, and field rotational crop studies associated
with this petition.  The LC/MS/MS Method, RM-43C-1, which determines
residues of fluopicolide per se in plant commodities has been validated
and is adequate for enforcement purposes.

An adequate data collection method, LC/MS/MS Method 303-02, which
determines residues of fluopicolide and BAM, was submitted for cattle
commodities.  HED has determined that tolerances are not required for
poultry and swine; however, tolerances are required for ruminant
commodities.  Method 303-02 has been reviewed and is not acceptable as
an enforcement method.  A confirmatory procedure is required for the
LC/MS/MS Method 303-02 to be considered an adequate enforcement method
for ruminant commodities.

Multiresidue methods testing data have been submitted.  These data
indicate that the multiresidue methods are not appropriate for
determining residues of fluopicolide.

Adequate feeding study data for parent fluopicolide have been submitted.
 However, since measurable residues of the fluopicolid metabolite, BAM
are likely in cattle feed items, a ruminant feeding study conducted with
BAM must be submitted or referenced and tolerances for ruminant
commodities, at the limit of quantitation of the method, must be
proposed.  Tolerances for ruminant commodities were not proposed in the
registrant’s submission.

No poultry feeding study is required for fluopicolide based on the
poultry metabolism studies and the calculated dietary burden.  HED has
calculated a dietary burden to poultry based on BAM residues in
feedstuff items.  Given the very low dietary burden, a poultry feeding
study with BAM is not required at this time.  No tolerances are required
for poultry commodities.

Adequate field trial data for tuberous and corm vegetables, leafy
vegetables (except Brassica), fruiting vegetables, cucurbit vegetables,
and grapes are available, pending submission of additional storage
stability data/information for leafy vegetables and wheat.  An adequate
number of geographically representative field trials were conducted at
1x the proposed maximum seasonal rate for each crop.  The available
field trial data indicate that the proposed tolerances for tuberous and
corm vegetables and grapes are adequate, but that increased tolerances
are needed for the leafy vegetable, fruiting vegetable crop group 8, and
cucurbit vegetables crop group 9, at 25 ppm, 1.6 ppm, and 0.50 ppm,
respectively.

Adequate processing data for grapes, potatoes, tomatoes, and rotated
wheat are available pending submission of additional storage stability
data/information on wheat.  The available processing data indicate that
residues of fluopicolide are not likely to concentrate in grape juice,
potato chips and flakes, or wheat flour.  Residues of fluopicolide were
found to concentrate in raisins, processed potato waste (wet peels),
tomato paste and puree, and wheat milled byproducts (bran, germ,
middlings, and shorts).  The processing data indicate that the proposed
tolerance of 6 ppm for raisins is appropriate.  In addition, a tolerance
for processed potato waste must be proposed at 0.05 ppm, and tolerances
for wheat milled byproducts and aspirated grain fractions (AGF) must be
proposed at 0.07 ppm.  Since residues concentrate in wheat milled
byproducts, residue data and a tolerance are required for aspirated
grain fractions.  HED recommends setting the AGF tolerance at 0.07 ppm
based on the wheat processing data and requiring confirmatory residue
data on AGF.  Separate tolerances for tomato processed commodities are
not needed, as residues in these commodities are not expected to exceed
the recommended tolerance of 1.6 ppm for the fruiting vegetable group.

Pending submission of storage stability data/information, adequate field
rotational crop data have been submitted to support the proposed 30-day
plantback interval (PBI) for wheat.  The data indicate that rotational
crop tolerances are needed for wheat forage, hay, grain, and straw.  The
petitioner has proposed a PBI of one year for all crops other than
cucurbit vegetables, fruiting vegetables, grapes, leafy vegetables,
tuber vegetables, and wheat.  Because the confined rotational crop data
indicated the potential for quantifiable residues of fluopicolide in/on
rotated crops at a one-year PBI, additional field rotational crop data
must be submitted.  Until the data are submitted and livestock
tolerances are established, rotation should be restricted only to crops
listed on the label.

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

  SEQ CHAPTER \h \r 1 HED has examined the residue chemistry database
for fluopicolide.  Pending submission of a revised Section B and a
revised Section F (see requirements under Direction for Use and Proposed
Tolerances), there are no residue chemistry issues that would preclude
granting a registration for the requested uses of fluopicolide excluding
wheat and potato and establishment of tolerances for fluopicolide as
stated below.  The remaining deficiency regarding storage stability (see
requirement under Storage Stability) must be resolved as a condition of
registration.

Provided the forthcoming Human Health Risk Assessment does not identify
any risks of concern, HED recommends establishment of tolerances as
follows.

Tolerances to be established under 180. 627(a) General. (1)

Tolerances are established for residues of the fungicide fluopicolide
[2,6-dichloro-N-[[3-chloro-5-(trifluoromethyl)-2-pyridinyl]methyl]benzam
ide] as an indicator of combined residues of fluopicolide and its
metabolite, 2,6-dichlorobenzamide in/on the following raw agricultural
commodities (RACs):

            Grape
…………………………………………………………….
2.0 ppm

Grape, raisin
……………………………………………………...  6.0 ppm

Vegetable, cucurbit, group 9 …………………
…………………...  0.50 ppm

Vegetable, fruiting, group 8
………………………………………   1.6 ppm

Vegetable, leafy, except Brassica, group 4 ……………………
25 ppm

Vegetable, tuberous and corm, except potato, subgroup 1D …….
0.02 ppm

Note to RD:  HED is recommending a revision of the tolerance expression
for fluopicolide in/on RACs under (a) (1) to address issues of
quantifiable residues 2,6-dichlorobenzamide (BAM) in/on RACs resulting
from fluopicolide application.

DEFICIENCIES

860.1200 Directions for Use

Sufficient rotational crop data is not available to support the proposed
rotational crop restrictions.  The Section B/label must be modified to
state that rotation is limited only to those crops on the current label.

A revised Section B/label must be submitted to delete the proposed use
on potato.

860.1550 Proposed Tolerances

The petitioner should submit a revised Section F which reflects the crop
groups, tolerance levels and commodity definitions specified above and
in Table 9 of this document.

860.1380 Storage Stability

Additional storage stability data are needed for celery and spinach
reflecting a storage interval of 38 months.  One study should be
conducted on any representative leafy vegetable.

At this time, HED is unable to recommend in favor of the establishment
of tolerances on potato and wheat (inadvertent) due to the deficiencies
listed below.

Deficiencies

860.1200 Directions for Use

Until all field rotational crop data requirements have been satisfied,
the proposed

rotational crop restrictions must be modified to state that rotation is
limited only to those crops on the current label: cucurbit vegetables,
fruiting vegetables, grapes, leafy vegetables, tuberous and corm
vegetables, and wheat.  A 0-day PBI for cucurbit vegetables, fruiting
vegetables, grapes, leafy vegetables, and tuberous and corm vegetables,
and a 30-day PBI for wheat are supported by the available data.

860.1340 Residue Analytical Methods

HED has determined that tolerances are required for ruminant
commodities.  Method 303-02 has been reviewed and is not acceptable as
an enforcement method.  A confirmatory procedure is required for the
LC/MS/MS Method 303-02 to be considered an adequate enforcement method
for ruminant commodities.

An analytical reference standard for the metabolite
2,6-dichlorobenzamide (BAM) must be sent to USEPA, National Pesticide
Standards Repository/Analytical Chemistry Branch/OPP, 710 Mapes Road,
Fort George G. Meade, MD 20755-5350.

860.1550 Proposed Tolerances

The petitioner should submit a revised Section F which reflects the crop
groups, tolerance levels and commodity definitions specified in Table 10
of this document.

860.1300 Nature of the Residue - Livestock

For the fluopicolide phenyl-14C-labeled cow metabolism study (MRID
46708514), the

petitioner should provide complete sample history information for
samples from the study, including not only dates of collection, but also
dates of storage, radioassay, extraction, and analysis.  If sample
analyses were not completed within 6 months of sample collection, the
petitioner must provide data demonstrating that the metabolic profile
was stable in the affected matrices during storage.

For the fluopicolid pyridinyl-14C-labeled cow metabolism study (MRID
46708518):

Storage stability data are required to support the study.   If samples
were stored for greater than 6 months, the petitioner should provide
data showing stability of the metabolic profile of the affected matrices
for the duration of the storage period and under the conditions that the
samples were stored.

The petitioner must clarify the identification of two peaks in liver
methanol/water extract (retention times of 43 and 47 minutes) to state
whether the text on page 65 (which states that the metabolites are
sulfate conjugates) or the results reported in Table 10 of MRID 46708518
(which indicate that one is a sulfate conjugate and one is a glucuronide
conjugate) are correct, and to further explain how the retention times
for these metabolites were correlated with the identified metabolites in
urine and kidney.

The petitioner should correct the flowchart for omental fat (Figure 10)
to include the correct TRR value for this matrix (0.039 ppm).

The petitioner should recalculate the radioactivity levels and/or
clarify the results for the HPLC analysis of any extract in which the
calculated LOQ was too high to allow meaningful interpretation of the
chromatogram.

For the hen metabolism study reported in MRID 46708515:

The petitioner should provide complete sample history information for
samples from the study, including not only dates of collection but also
dates of storage, radioassay, extraction, and analysis.  If sample
analyses were not completed within 6 months of sample collection, the
petitioner should provide data demonstrating that the metabolic profile
was stable in the affected matrices during the storage period and under
the conditions that the samples were stored.

The petitioner should submit copies of the LC/MS chromatograms of
metabolite AE C653711 (BAM) in liver as well as the corresponding
chromatogram of the reference standard.  These chromatograms were
referenced in the submission (MRID 46708515, page 113) but were not
included.

The hen metabolism study conducted with [2,6-14C-pyridinyl]fluopicolide
(MRID 46708519) is incomplete but upgradeable.  The samples from this
study were not extracted until >6 months after sample collection.   The
petitioner should provide data showing stability of the metabolic
profile for the duration of the storage period and under the conditions
that the samples were stored.

860.1380 Storage Stability

To support the wheat field rotational crop study, storage stability data
are needed reflecting the stability of P1X in wheat grain for 21 months
and of fluopicolide and BAM in wheat forage and straw for 24 months.
The additional storage stability data for residues of P1X in wheat grain
is also required to support the wheat processing study.

860.1480 Meat, Milk, Poultry and Eggs

Since BAM may occur in livestock feed items and livestock (ruminant)
commodities, a BAM ruminant feeding study must be submitted or
referenced and livestock tolerances at the limit of quantitation of the
method must be proposed.

860.1520 Processed Food & Feed

No data have been submitted on aspirated grain fractions.  Since data
indicate that residues of fluopicolide concentrate in wheat milled
byproducts, HED concludes that residue data and a tolerance for AGF is
required.  HED will base the tolerance for AGF on the available wheat
process data, but requires confirmatory residue data on AGF as a
condition of registration.

860.1900 Field Accumulation in Rotational Crops

In the confined rotational crop study, residues of fluopicolide >0.01
ppm were observed in/on all rotational crop commodities at all PBIs,
with the exception of wheat grain at the 133- and 365-day PBIs.  Based
on these results and the proposed rotational crop restrictions, limited
field rotational crop studies should be conducted at 1, 4, and 12-month
PBIs with any representative leafy vegetable, root vegetable, and cereal
grain crops.  Although the petitioner is proposing a 30-day PBI for
wheat and has submitted supporting field rotational crop data, limited
field rotational crop data for wheat as a representative cereal grain
are also needed at 4- and 12-month PBIs.  If the results of the limited
field rotational crop study indicate the potential for quantifiable
fluopicolide residues of concern in/on rotational crops at the desired
PBI, then extensive field rotational crop studies will be required for
all crops.  Residues of parent, BAM, PCA and P1X should be determined in
the field rotational crop studies.

If the deficiencies cited above are resolved in full, the available data
support the following tolerances of fluopicolide:

	Tolerances to be established under 180. 627(a) General. (1)

Tolerances for residues of the fungicide fluopicolide
[2,6-dichloro-N-[[3-chloro-5-(trifluoromethyl)-2-pyridinyl]methyl]benzam
ide] as an indicator of combined residues of fluopicolide and its
metabolite, 2,6-dichlorobenzamide in/on the following raw agricultural
commodities (RACs):

Potato, processed potato waste                      …….…0.05 ppm

Vegetable, tuberous and corm, subgroup 1C …….…0.02 ppm

	Tolerances to be established under 180. 627(a) General. (2)

Tolerances for residues of 2,6-dichlorobenzamide in/on the following
food commodities:

Cattle, fat	…………………………………….          0.05
ppm

Cattle, meat	…………………………………..         0.02 ppm

Cattle, meat byproducts…………………………    0.05 ppm

Goat, fat…………………………………………    0.05 ppm

Goat, meat……………………………………….    0.02 ppm

Goat, meat byproducts…………………………..    0.05 ppm

Horse, fat………………………………………..    0.05 ppm

Horse, meat……………………………………..     0.02 ppm

Horse, meat byproducts…………………………    0.05 ppm

Milk……………………………………………..    0.01 ppm

Sheep, fat………………………………………..    0.05 ppm

Sheep, meat……………………………………..     0.02 ppm

Sheep, meat byproducts…………………………    0.05 ppm

Tolerances to be established under 180.627 “(d) Indirect or
inadvertent residues”:

Tolerances for indirect or inadvertent residues of the fungicide
fluopicolide
[2,6-dichloro-N-[[3-chloro-5-(trifluoromethyl)-2-pyridinyl]methyl]benzam
ide] as an indicator of combined residues of fluopicolide and its
metabolite, 2,6-dichlorobenzamide in/on the following raw agricultural
commodities (RACs):

Wheat, forage	…………………………………….   0.20 ppm

Wheat, grain……………………………………..    0.02 ppm

Wheat, hay	………………………………………    0.50 ppm

Wheat, milled byproducts ………………………. ..0.07 ppm

Wheat, straw …………………………………	…..  0.50 ppm

		Wheat, aspirated grain fractions …………………  0.07 ppm

Background

Fluopicolide is a benzamide/pyridine fungicide intended for the control
of plant diseases caused by Oomycetes.  Valent U.S.A. has applied for
registration of fluopicolide in the U.S. for use on cucurbit vegetables,
fruiting vegetables, grapes, leafy vegetables (except Brassica), potato,
and sweet potato.

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

Table 1.		Fluopicolide Nomenclature.

Chemical structure

Common name	Fluopicolide

Company experimental name	AE C638206

IUPAC name
2,6-dichloro-N-[3-chloro-5-(trifluoromethyl)-2-pyridylmethyl]benzamide

CAS name
2,6-dichloro-N-[[3-chloro-5-(trifluoromethyl)-2-pyridinyl]methyl]benzami
de

CAS registry number	239110-15-7

End-use products (EPs)	V-10161 4SC Fungicide (39.5% fluopicolide; EPA
File Symbol No. 59639-RUN)

V-10161 Premix Fungicide (5.54% fluopicolide and 55.4% propamocarb; EPA
File Symbol No. 59639–RUE)

Table 2.		Physicochemical Properties of Fluopicolide.

Parameter	Value	Reference

Melting point/range 	149 (C 	MRID 464740151

pH 	6.5 at 22.0 (C (1% suspension)	MRID 464740131

Density 	1.65 g/cm3 (30 (C)	MRID 464740161

Water solubility (20 (C) 	2.86 mg/L at pH 4

2.80 mg/L at pH 7

2.80 mg/L at pH 9 	MRID 464740211

Solvent solubility (g/L at 20 (C) 	n-Hexane:	0.20

Ethanol:	19.2

Toluene:	20.5

Ethyl acetate:	37.7

Acetone:	74.7

Dichloromethane:	126

Dimethyl sulfoxide:	183 	MRID 464740221

Vapor pressure at 25 (C 	8.03 x 10-7 Pa 	MRID 464740231

Dissociation constant (pKa) 	No evidence of ionization in the pH range
of 1.9 to 9.8 	MRID 464740171

Octanol/water partition coefficient Log(KOW) 	Log POW = 3.26 at pH 7.8
and 22 ± 1 (C 	MRID 464740181

	Log POW = 2.9 at pH 4.0, 7.3 and 9.1 and 40 (C 	MRID 464740191

UV/visible absorption spectrum 	Absorption maxima wavelengths (nm):

	In methanol:	203 and 271

	In methanol/HCl:	202 and 270

	In methanol/NaOH:	219 and 271 	MRID 464740141

1  DP Number 318332, 10/17/2006, S. Mathur.

HED notes that methods, field trial, storage stability and processing
data on residues of 3-OH-BAM were provided as part of this submission.
The HED RARC has determined that 3-OH-BAM should not be included in the
tolerance expression or risk assessment due to aspects of its
structure/nature (it’s a phenol, as a result of ring hydroxylation)
which increase its solubility, make it more readily conjugated and more
readily excreted.  References to 3-OH-BAM are included throughout this
document for completeness of information only.

The proposed uses of propamocarb hydrochloride on cucurbit vegetables,
fruiting vegetables, head and leaf lettuce, and potato are not evaluated
in this document; the adequacy of the proposed use directions and the
availability of adequate supporting residue data will be addressed in a
separate review.

860.1200 Directions for Use

Valent submitted proposed labels for two products to be used on
food/feed crops:  V-10161 4 SC (suspendable concentrate), a 4 lb ai/gal
FlC (an aqueous flowable concentrate) formulation with EPA File Symbol
No. 59639-RUN; and V-10162 Premix, a FlC (an aqueous flowable
concentrate) formulation containing 0.52 lb/gal of fluopicolide and 5.2
lb/gal of propamocarb hydrochloride, with EPA File Symbol No. 59639-RUE.

The proposed use directions for fluopicolide are presented in Table 3.

Table 3.		Summary of Directions for Use of Fluopicolide.

Trade Name	Application Timing	Application Rate

(lb ai/A)	Max. No. Applic. per Season	RTI1

(days)	Max. Seasonal Applic. Rate

(lb ai/A)	PHI

(days)	Use Directions and other Limitations

Cucurbit Vegetables [Acorn Squash; Balsam Apple; Balsam Pear;
Bittermelon; Butternut Squash; Calabaza; Cantaloupe; Chayote, Fruit;
Chinese Cucumber; Chinese Okra; Chinese Preserving Melon; Chinese
Waxgourd; Citron Melon; Cucumber; Cucuzza; Gherkin; Gourd, Edible;
Hechima; Hubbard Squash; Hyotan; Momordica spp; Muskmelon; Pumpkin;
Spaghetti Squash; Summer Squash; Watermelon; Winter Squash]

V-10161 4 SC	Postemergence	0.09-0.125	4	10	0.375	2	Application to be
made in a minimum of 20 gal/A using ground equipment or 5 gal/A using
aerial equipment.

V-10162 Premix	Postemergence	0.09-0.11	4	10	0.34	2	Application to be
made in a minimum of 20 gal/A using ground equipment or 5 gal/A using
aerial equipment.

Fruiting Vegetables [Bell Pepper; Chili Pepper; Cooking Pepper;
Eggplant; Groundcherry (Physalis spp.); Pepino; Pimento, Sweet Pepper;
Tomatillo; Tomato]

V-10161 4 SC	Postemergence	0.09-0.125	4	7	0.375	2	Application to be made
in a minimum of 20 gal/A using ground equipment or 5 gal/A using aerial
equipment.

V-10162 Premix	Postemergence	0.09-0.11	4	7	0.34	2	Application to be made
in a minimum of 20 gal/A using ground equipment or 5 gal/A using aerial
equipment.

Grapes

V-10161 4 SC	Postemergence	0.09-0.125	4	12	0.375	21	Application to be
made in a minimum of 20 gal/A using ground equipment or 5 gal/A using
aerial equipment.

Leafy Vegetables (except Brassica Vegetables) [Amaranth, Chinese
Spinach; Arugula, Roquette; Cardoon; Celery; Celtuce; Chinese Celery;
Chervil; Chrysanthemum, Edible-leaved; Chrysanthemum, Garland; Corn
Salad; Cress, Garden; Cress, Upland; Dandelion; Dock, Sorrel; Endive,
Escarole; Fennel; Florence; Lettuce, Head and Leaf; Orach; Parsley;
Purslane, Garden; Purslane, Winter; Radicchio, Red Chicory; Rhubarb;
Spinach; Spinach, New Zealand; Spinach, Vine; Swiss Chard]

V-10161 4 SC	Postemergence	0.09-0.125	4	10	0.375	21	Application to be
made in a minimum of 20 gal/A using ground equipment or 5 gal/A using
aerial equipment.

Lettuce, Head and Leaf

V-10162 Premix	Postemergence	0.09-0.11	4	10	0.34	2	Application to be
made in a minimum of 20 gal/A using ground equipment or 5 gal/A using
aerial equipment.

Potato

V-10161 4 SC	Postemergence	0.09-0.125	4	10	0.375	7	Application to be
made in a minimum of 20 gal/A using ground equipment or 5 gal/A using
aerial equipment.

V-10162 Premix	Postemergence	0.09-0.11	4	10	0.34	7	Application to be
made in a minimum of 20 gal/A using ground equipment or 5 gal/A using
aerial equipment.

Sweet Potato

V-10161 4 SC	Postemergence	0.09-0.125	4	10	0.375	7	Application to be
made in a minimum of 20 gal/A using ground equipment or 5 gal/A using
aerial equipment.

1  RTI = Retreatment interval

The proposed label for the 4 lb ai/gal FlC formulation (V-10161 4 SC)
specifies that the product should always be applied in a tank mix with
fungicides from different target site of action groups that are
registered for the same use and that are effective against the pathogens
of concern.  The label specifies that the minimum labeled rate of each
fungicide in the tank mix should be used.  The label for the 0.52 lb/gal
FlC formulation, which also contains propamocarb hydrochloride, states
that the product may be used in tank mixtures with fungicides from
different target site of action groups that are registered for the same
use.  The label specifies that the minimum labeled recommended rate of
each fungicide in the tank mix should be used.

Applications are to begin when crop and/or environmental conditions
favor disease development. A maximum of two sequential fluopicolide
applications are to be made before alternating with an effective
fungicide from a different resistance management group.

The following tank mixes are recommended on the label for the 4 lb
ai/gal FlC formulation:  mefenoxam or other labeled product with
activity on downy mildew and Phytophthora for cucurbit and fruiting
vegetables;  Flint® (trifloxystrobin), Pristine® (pyraclostrobin and
boscalid), or Procure® (triflumizole), or other labeled products with
activity on downy mildew for grapes; strobilurin (Group 11 fungicides)
or Aliette® (fosetyl-Al), or other products listed on the label with
activity on downy mildew for leafy vegetables; and mefenoxam or other
products listed on the label with activity on Phytophthora for potato
and sweet potato.  The label specifies that all use directions specified
on each label should be followed for any product to be tank mixed with
V-10161 4 SC.

The 0.52 lb/gal FlC formulation allows tank-mixing with other labeled
pesticides although no specific tank mixes were recommended.

A restricted entry interval of 12 hours has been proposed.  The
following rotational crop restrictions are proposed for the 4 lb/gal FlC
formulation:  a 0-day PBI for cucurbit vegetables, fruiting vegetables,
grapes, leafy vegetables, and tuber vegetables; a 30-day PBI for wheat;
and a 12-month PBI for all other crops.  The 0.52 lb/gal FlC formulation
specifies the same rotational crop restrictions except that a 120-day
PBI is proposed for wheat.

Conclusions:  The submitted use directions are sufficient to allow
evaluation of the available residue data relative to the proposed uses.

The available data, which reflect three foliar applications of a FlC
(aqueous flowable concentrate) formulation at ~0.12 lb ai/A/application
for a total of ~0.36 lb ai/A/season, will support the proposed four
applications with a maximum of 0.34-0.37 lb ai/A/season to grapes, the
tuberous and corm vegetable subgroup 1C, leafy vegetable (except
Brassica) group 4, fruiting vegetable group 8, and cucurbit vegetable
group 9.  The data will also support:  a minimum retreatment interval of
5 days for all crops on the label; a PHI of 2 days for the leafy
vegetable (except Brassica) group 4, fruiting vegetable group 8, and
cucurbit vegetable group 9; a PHI of 7 days for the tuberous and corm
vegetable subgroup 1C; and a PHI of 21 days for grape.  The proposed use
directions for each crop are adequate.

Until all field rotational crop data requirements have been satisfied,
the proposed rotational crop restrictions should be modified to state
that rotation is permitted only to crops on the label. A 0-day PBI for
cucurbit vegetables, fruiting vegetables, grapes, leafy vegetables, and
tuberous and corm vegetables, and a 30-day PBI for wheat are supported
by the available data.

Since data on potato satisfies the data requirements for all commodities
in the tuberous and corm vegetable subgroup 1C, the petitioner may wish
to modify the proposed Section B/label to expand uses on potato and
sweet potato to include all members of the tuberous and corm crop
subgroup.

860.1300 Nature of the Residue - Plants

DER Reference:	46708520.der.doc (Lettuce)

		46708521.der.doc (Potato)

		  SEQ CHAPTER \h \r 1 Residue Chemistry Memo DP Number 321209,
1/23/2007, A. Acierto (PP#5E6903)

Valent U.S.A. submitted metabolism studies with lettuce and potato in
conjunction with this petition.  A metabolism study with grape had been
submitted previously.

Grape

A grape metabolism study with [2,6-14C-pyridinyl]fluopicolide and
[U-14C-phenyl]fluopicolide (specific activity 22 and 20 µCi/mg,
respectively) was submitted in conjunction with the grape import
petition.  The radiolabeled test substances were formulated as
suspension concentrates and applied to grape vines as three sequential
foliar treatments at a total application rates of  0.357 lb ai/A (~1x
the proposed maximum seasonal rate) and 3.56 lb ai/A (~10x the proposed
maximum seasonal rate).  In the grape metabolism study, the majority of
radioactivity was found to be on the surface of fruit and foliage
samples; surface washes with ACN released ~97-99% of the total
radioactive residues (TRR) from foliage samples collected immediately
after application, ~73-93% TRR from foliage samples collected 26-28 days
after application, ~50-75% TRR from mature foliage samples, and ~46-79%
TRR from mature fruit samples.  Fluopicolide was the primary residue
identified in fruit, accounting for ~87-91% TRR. The metabolites BAM and
PCA were found in fruit at <3% TRR each.  One additional metabolite, AE
C643890
(2,6-dichloro-N-[(3-chloro-5-trifluoromethylpyridin-2-yl)methyl]-3-hydro
xybenzamide), was identified at ≤0.2% TRR.  Fluopicolide appeared to
be metabolized slowly in grape vines to BAM and PCA, via cleavage of the
bond between the carbon attached to the pyridine ring and the amide
nitrogen of the parent compound, and AE C643890 is produced by the
hydroxylation of the phenyl ring in the parent compound.

Lettuce

Valent U.S.A. Corporation has submitted a study investigating the
metabolism of [2,6-14C-pyridinyl]fluopicolide (specific activity
40.1-40.2 µCi/mg) and [U-14C-phenyl]fluopicolide (specific activity
39.4-39.7 µCi/mg) in lettuce.  The radiolabeled test substances were
formulated as suspension concentrate formulations and diluted with
water, then applied to lettuce plants as two sequential foliar
treatments at 0.180-0.181 lb ai/A/application for a total of 0.361 lb
ai/A (~1x the proposed rate).  Total application rates for the pyridinyl
and phenyl labels were 0.360 and 0.362 lb ai/A, respectively.  A spray
adjuvant (Crodamol PC) was added to the spray mixtures at 0.05%.  The
first application was made 41 days after planting, and the second
application was made 21 days later.  A separate group of lettuce plants
received a single in-furrow soil drench application of the
phenyl-labeled formulation at 0.181 lb ai/A (203 g ai/ha) made 41 days
after planting (at the same time as the first foliar application).

Samples of immature lettuce were harvested immediately following the
first application (foliar applications only) and 21 days after the first
application (just prior to the second foliar application); samples of
mature lettuce were harvested 14 days after the second foliar
application (35 days after the first foliar application or soil-drench
application).  Samples from the foliar applications were surface washed
with acetonitrile (ACN) on the day of collection.  The in-life and
analytical phases of the study were conducted by AgrEvo USA Company
(Pikeville, NC).

The petitioner collected and analyzed two samples at each sampling
interval for all samples.  The values for total radioactive residues
(TRR) reported below reflect the range of values recovered for the
individual samples.  Because results for extraction and analysis were
similar for the duplicate samples, values for distribution,
characterization, and identification of residues reflect average values.

TRR in samples of immature lettuce following foliar application were
calculated by summing radioactivity in the surface wash, ACN extract,
and nonextractable residues.  TRR in samples of mature lettuce following
foliar application were calculated by adding radioactivity in the
surface wash to the radioactivity in the washed sample, determined by
combustion/LSC, and TRR in samples following soil drench application
were determined by combustion/LSC.  TRR were similar in samples
following foliar applications of pyridinyl- and phenyl-labeled
fluopicolide, but significantly different in foliar-treated and
soil-treated samples.  Following a single foliar application of the test
substances at ~0.180 lb ai/A, TRR were 9.583-15.640 ppm in samples
harvested immediately following application (0 day) and 1.143-1.470 ppm
in samples harvested 21 days after application.  In samples of mature
lettuce harvested 14 days following the second foliar application (35
days following the first foliar application; total application rate of
~0.360 lb ai/A), TRR were 12.647-14.821 ppm.  TRR were 0.075-0.076 ppm
in samples of immature lettuce harvested 21 days following a single soil
drench application of phenyl-labeled fluopicolide at 0.181 lb ai/A, and
0.142-0.208 ppm in mature lettuce harvested 35 days after soil
application.

le residues were ≤1.5% TRR (≤0.140 ppm) in lettuce samples following
foliar applications and ≤4.1% TRR (≤0.007 ppm) in lettuce samples
following soil drench application.  These procedures adequately
extracted the majority of the residues from lettuce matrices;
accountabilities were ~100%.

Residues were identified and confirmed using normal and reverse phase
TLC.  The petitioner did not report separate TLC results for surface
washes and extracts, although these fractions were analyzed separately
(based on representative chromatograms).  The petitioner should note for
future submissions that quantitative data for individual chromatograms
should be provided.  All analyses were completed within 2 months of
harvest; therefore, no supporting storage stability data are needed.

Fluopicolide was the primary residue identified in lettuce following all
treatments at all sampling intervals, accounting for 92.5-97.5% TRR
(1.227-13.979 ppm) in immature and mature lettuce harvested following
foliar applications and for 71.7-74.5% TRR (0.057-0.128 ppm) in immature
and mature lettuce harvested following soil drench application.  The
metabolites AE C653711 (BAM; phenyl label only) and AE C657188 (PCA;
pyridinyl label only) were found in foliar-treated lettuce at 0.1-3.9%
and 0.6-1.5% TRR, respectively; BAM was identified at higher percentage
(16.5-19.8% TRR, 0.013-0.034 ppm) in lettuce following a soil drench
application of phenyl-labeled fluopicolide.  A third metabolite, AE
C643890, was also identified in 21-day foliar-treated lettuce (both
labels) at 1.0-1.4% TRR and mature (35-day) soil-treated lettuce (phenyl
label) at 2.8% TRR.  The petitioner stated that no other single
metabolite comprised more than 1% of the TRR in any sample.

Based on the results of the lettuce metabolism study, the petitioner
proposed that fluopicolide is metabolized slowly in lettuce to BAM, PCA,
and AE C643890.  BAM and PCA result from the cleavage of the bond
between the carbon attached to the pyridine ring and the amide nitrogen
of the parent compound, and AE C643890 is produced by the hydroxylation
of the phenyl ring in the parent compound.  Fluopicolide is metabolized
in soil to BAM, which is then taken up by the lettuce plant.

Potato

Valent U.S.A. Corporation has submitted a study investigating the
metabolism of [2,6-14C-pyridinyl]fluopicolide (specific activity
40.0-40.08 µCi/mg) and [U-14C-phenyl]fluopicolide (specific activity
39.92-40.0 µCi/mg) in potato foliage and tubers.  The radiolabeled test
substances were formulated as suspension concentrate formulations and
diluted with water, then applied to potato plants as two sequential
foliar treatments at 0.179-0.182 lb ai/A/application (200-204 g
ai/ha/application) or 1.70-1.81 lb ai/A/application (1909-2029 g
ai/ha/application)...  Total application rates for the phenyl and
pyridinyl labels were 0.363 and 0.360 lb ai/A, respectively, for the ~1x
rate, and 3.60 and 3.51 lb ai/A, respectively, for the ~10x rate.  A
spray adjuvant (Crodamol PC) was added to the spray mixtures at 0.05%.
The first application was made 69 days before harvest at BBCH 31-35, and
the second application was made 49 days later (20 days before harvest).

Samples of immature potato foliage were harvested immediately following
the first application (0-day) and 40-41 days after the first application
(8-9 days prior to the second application).  Samples of mature potato
foliage and tubers were harvested 20 days after the second application.
Samples were surface washed with acetonitrile (ACN) on the day of
collection.  The in-life and analytical phases of the study were
conducted by AgrEvo USA Company (Pikeville, NC).

The petitioner collected and analyzed two samples at each sampling
interval for all samples except foliage harvested 0 and 41 days
following ~10x treatment with the pyridinyl label, for which four
samples were collected.  The values for total radioactive residues (TRR)
reported below reflect the range of values recovered for the individual
samples.  Because results for extraction and analysis were similar for
the duplicate/quadruplicate samples, values for distribution,
characterization and identification of residues reflect average values.

TRR in 0-day samples were calculated by summing radioactivity in the
surface wash, ACN extract, and nonextractable residues, and TRR in
40/41-day and mature potato samples were calculated by adding
radioactivity in the surface wash to the radioactivity in the washed
sample, determined by combustion/LSC.  TRR were similar in samples
following foliar applications of pyridinyl- and phenyl-labeled
fluopicolide for all samples except immature foliage harvested 40-41
days after the first application of the ~10x treatment, where the mean
TRR was ~3x higher in pyridinyl-treated samples than in phenyl-treated
samples.

Following treatment at the ~1x rate, TRR were 42.69-55.48 ppm in samples
of immature foliage harvested immediately following the first
application (0 day), and 7.08-11.39 ppm in foliage samples harvested
40-41 days after the first application.  In mature samples harvested 20
days following the second foliar application at the ~1x rate, TRR were
9.37 -12.57 ppm in foliage and 0.05-0.09 ppm in tubers.  Following
treatment at the ~10x rate, TRR were 395.65-567.51 ppm in 0-day foliage
samples.  In foliage samples harvested 40-41 days after the first
application, TRR were 55.87-175.70 ppm following treatment with the
pyridinyl label and 29.90-47.96 ppm following treatment with the phenyl
label.  In mature samples harvested 20 days following the second foliar
application at the ~10x rate, TRR were 75.17-382.07 ppm in foliage and
0.43-0.86 ppm in tubers.

dues were ≤4.7% TRR in immature foliage samples from both harvest
intervals, 3.8-3.9% TRR in ~1x mature foliage samples and 4.9-6.9% TRR
in ~1x tuber samples.  In ~10x tubers, which were not subjected to acid
hydrolysis, nonextractable residues were 7.8-10.1% TRR.

Residues were identified and confirmed using normal and reverse phase
TLC.  For 0-day foliage, only the ACN surface wash was analyzed.  For
all remaining samples, although both the surface wash and extracts were
analyzed, the petitioner only reported separate results for immature
foliage harvested 40-41 days following first application.  The
petitioner should note for future submissions that quantitative data for
individual chromatograms should be provided.  The petitioner stated that
preliminary chromatographic analysis of the principal extracts of the
RACs was completed within 2 months of final harvest, and analysis for
the entire study was completed within 3 months of final harvest; no data
were included in the submission to support this statement.  However,
based on the completion date of the study, all analyses were completed
within 6 months of collection; therefore, supporting storage stability
data are not needed.

Fluopicolide was the primary residue identified in potato matrices
following all treatments at all sampling intervals, accounting for
97.0-98.3% TRR (45.97-53.09 ppm for ~1x samples) in 0-day foliage,
88.8-94.6% TRR (6.78-9.03 ppm for ~1x samples) in 40/41-day foliage,
89.8-91.0% TRR (8.64-11.14 ppm) in ~1x mature foliage, and 51.1-70.2%
TRR (~0.041 ppm for ~1x samples) in tubers.  The metabolites PCA
(pyridinyl label only) and BAM (phenyl label only) were found in mature
foliage at 0.8% TRR and 1.9% TRR, respectively, and metabolite AE
C643890 was found in mature foliage from both labels at 0.6-0.7% TRR.
PCA and BAM were identified at higher percentage in ~1x and ~10x tubers,
at 12.0% and 26.1% TRR (0.01 and 0.19 ppm), respectively, for PCA and
25.4% and 22.2% TRR (0.021 and 0.116 ppm), respectively, for BAM. In
tubers (both labels), metabolite AE C643890 accounted for 1.7-2.4% TRR
(0.001-0.003 ppm) following ~1x treatment, and was not identified
following ~10x treatment.  The petitioner stated that no other single
metabolite comprised more than 2% of the TRR in any sample.

Based on the results of the potato metabolism study, the petitioner
proposed that fluopicolide is metabolized in potato to BAM, PCA, and
minor amounts of AE C643890.  BAM and PCA result from the cleavage of
the bond between the carbon attached to the pyridine ring and the amide
nitrogen of the parent compound, and AE C643890 is produced via the
hydroxylation of the phenyl ring in the parent compound.

Conclusions:   The grape, lettuce, and potato metabolism data are
adequate to satisfy nature of the residue data requirements in support
of the proposed uses on cucurbit vegetables, fruiting vegetables,
grapes, leafy vegetables (except Brassica), and tuberous and corm
vegetables.  The metabolism of fluopicolide was found to be similar in
the test crops.  Fluopicolide appears to be metabolized slowly to BAM
and PCA, via cleavage of the bond between the carbon attached to the
pyridine ring and the amide nitrogen of the parent compound, and AE
C643890 is produced by hydroxylation of the phenyl ring in the parent
compound.  Based on the results of the soil drench applications in
lettuce, it appears that fluopicolide is metabolized in soil to BAM,
which is then taken up by the lettuce plant.  HED notes that because of
the radiolabel of the test substance used for the soil drench
applications, the metabolite PCA would not have been observed.

The nature of the residue in primary crop plants is adequately
understood.  In HED’s RARC1 meeting held on 7/19/07, HED determined
that the tolerance for all primary crops should be expressed in terms of
fluopicolide per se.  However, since there are quantifiable residues of
the metabolite, BAM in some primary crops, and this metabolite is a
regulated metabolite of the registered pesticide, diclobenil, the
Fluopicolide Team recommends that the numerical value for the tolerance
be expressed in terms of the parent compound as a marker or indicator of
total residue.  The Team recommends that the tolerance expression read
“Tolerances are established for residues of the fungicide fluopicolide
[2,6-dichloro-N-[[3-chloro-5-(trifluoromethyl)-2-pyridinyl]methyl]benzam
ide] as an indicator of combined residues of fluopicolide and its
metabolite, 2,6-dichlorobenzamide in/on the following raw agricultural
commodities (RACs):”

For risk assessment purposes, the residue of concern in tuberous and
corm vegetables treated directly with fluopicolide is parent compound
and its PCA and BAM metabolites.  For all other primary crops, the
residue of concern for risk assessment purposes is the parent compound
and its BAM metabolite (BAM and Fluopicolide. Report of the Risk
Assessment Review Committee (RARC1), Sarah Winfield, 7/19/07).

860.1300 Nature of the Residue - Livestock

DER Reference:	46708514.der.doc (Cow; phenyl label)

		46708515.der.doc (Hen; phenyl label)

		46708518.der.doc (Cow; pyridinyl label)

		46708519.der.doc (Hen; pyridinyl label)

Ruminant (phenyl label)

Valent U.S.A. Corporation has submitted a study investigating the
metabolism of [U-14C-phenyl]fluopicolide (specific activity 5.572
MBq/mg) in lactating cows.  The test substance was orally administered
twice daily to two cows for 7 consecutive days, one at 1.1 ppm and one
at 10.6 ppm in the diet.  The 1.1 ppm dosing level corresponds to 5.2x
and 3.8x the dietary burden for beef cattle and dairy cattle,
respectively.  The 10.6 ppm dosing level corresponds to 50x and 37x the
dietary burden for beef cattle and dairy cattle, respectively.  Milk was
collected twice daily throughout the study, and tissues (muscle, fat,
liver, and kidney) were collected at sacrifice, 23.25-23.75 hours after
the final dose.  The in-life and analytical phases of the study were
conducted at Covance Laboratories, Ltd. (Harrogate, England).

Total radioactive residues (TRR) following dosing at 1.1 ppm were
0.9-1.8 ppb in milk, 5.1-5.7 ppb in fat, 3.4-4.3 ppb in muscle, 90 ppb
in liver, and 26 ppb in kidney.  TRR following dosing at 10.6 ppm were
3.5-19 ppb in milk, 40-43 ppb in fat, 23-25 ppb in muscle, 644 ppb in
liver, and 302 ppb in kidney.  Radioactivity was highest in liver and
appeared to plateau in milk after 5 days of dosing.  The majority of the
administered dose was excreted, with urine, feces, and cage wash
accounting for a total of ~75% of the administered dose.

Metabolic profiling was conducted on milk and tissues from the high-dose
cow.  The majority of the radioactivity (85-86% TRR) was extracted from
milk and fat using acetonitrile (ACN); ACN extracted 14% of the TRR from
muscle.  In liver and kidney, the majority of the radioactivity (89-91%
TRR) was extracted using water.  Separate aliquots of the water extracts
of liver and kidney were subjected to solvent extraction, acid
hydrolysis, base hydrolysis, and enzyme hydrolysis.  Nonextractable
residues accounted for ≤0.03 ppm in fat, muscle, and kidney, and 11%
TRR (72 ppb) in liver.

These procedures adequately extracted the majority of the residues from
cow matrices.  Residues were identified and quantitated by HPLC.  Milk
samples were assayed fresh prior to sub-sampling and storage.  Animal
tissues were processed on the day of collection and stored frozen
(<-100C) prior to analysis.

Approximately 76% TRR was identified in fat, and ~3-33% TRR was
identified in milk, muscle, liver, and kidney.  Fluopicolide was the
major residue identified in milk at 29% TRR (5 ppb) and fat at 76% TRR
(31 ppb); fluopicolide was also identified in muscle, liver, and kidney
at 0.9-2.9% TRR (0.7-5.5 ppb).  Metabolite AE C653711 (BAM) was
identified in milk at 3.9% TRR, and metabolites AE C643890 and AE
0712556 were identified in liver and kidney at 1.2-6.8% TRR each (7.6-21
ppb).  In milk, fat, and muscle, the remainder of the extractable
radioactivity consisted of unknowns and polar material totaling <8 ppb
in each matrix.  In liver and kidney, HPLC unknowns accounted for 6-11%
TRR (32-41 ppb) and polar material accounted for 17-19% TRR (57-108
ppb).  A large portion of the radioactivity in these tissues appeared to
have been lost, or distributed into fractions that were not HPLC
analyzed; accountability in terms of total identified/characterized plus
total nonextractable was 38% for liver and 50% for kidney.

Enzyme hydrolysis of liver and kidney indicated that radioactivity in
the water-extractable fraction was not associated with glucuronide
conjugates.  Protease digestion of liver and kidney yielded mostly polar
material which did not match any reference standards.  Cellular
fractionation of these tissues indicated that portions of radioactivity
were associated with low molecular weight proteins, amino acids, and
peptides (33% TRR in kidney, 16.9% in liver); lipids (11.8% TRR in
kidney, 15.4% TRR in liver); RNA (0.9% TRR in kidney, 0.5%TRR in liver);
sulfurated glucosaminoglycans ( 13.6% TRR in kidney, 15.2% in liver);
carbohydrates (2.4% TRR in kidney, 3.0% TRR in liver); DNA (1.7% in
kidney, 2.1% in liver); and the final nonextractable radioactivity was
associated with protein (36.0% TRR in kidney, 46.4% in liver).

tudy 2014/004) and rat (Bayer Report No. TOX/00283-24), where one of the
main metabolite residues was the S-methyl analogue probably produced via
glutathione conjugation.  The glutathione metabolites produced could
then undergo cleavage by β-lyase leaving a product that could bind to
proteins.

Ruminant (pyridinyl label)

Valent U.S.A. Corporation has submitted a study investigating the
metabolism of [2,6-14C-pyridinyl]fluopicolide (specific activity 49.12
(Ci/mg for the low-dose dose cow and 24.76 (Ci/mg for the high-dose cow)
in lactating cows.  The test substance was administered orally to two
cows, one at 1 ppm and one at 10 ppm in the diet.  The 1 ppm dosing
level corresponds to 4.8x and 3.4x the dietary burden for beef cattle
and dairy cattle, respectively.  The 10 ppm dosing level corresponds to
48x and 34x the dietary burden for beef cattle and dairy cattle,
respectively.  The cows were dosed twice daily for 7 consecutive days.
Milk was collected twice daily throughout the study, and tissues
(muscle, fat, liver, and kidney) were collected at sacrifice, 23 hours
after the final dose.  The in-life and analytical phases of the study
were conducted at Inveresk Research (Tranent, Scotland).

Total radioactive residues (TRR) following dosing at 1 ppm were 0.001
ppm in milk, 0.005 ppm in fat, 0.001 ppm in muscle, 0.058 ppm in liver,
and 0.033 ppm in kidney.  TRR following dosing at 10 ppm were
0.004-0.010 ppm in milk, 0.039-0.042 ppm in fat, 0.012 ppm in muscle,
0.449 ppm in liver, and 0.196 ppm in kidney.  Radioactivity was highest
in liver and kidney, and lowest in milk and muscle; residues in milk
appeared to reach a plateau after 1 day of dosing.  The majority of the
administered dose was excreted, with urine, feces, and cage wash
accounting for a total of ~80-84% of the administered dose.

Metabolic profiling was conducted on liver, kidney, and renal fat from
the low-dose cow and on milk and tissues from the high-dose cow.  The
majority of the radioactivity (78-89% TRR) was extracted from milk and
fat using methanol (MeOH)/water.  MeOH/water extracted 15-36% of the TRR
from liver, kidney, and muscle.  A large portion of radioactivity was
extracted from liver and kidney using pepsin and protease hydrolysis
(total of 7-38% TRR) and strong acid hydrolysis (5-40% TRR).
Nonextractable residues accounted for ≤0.02 ppm in liver, kidney, and
renal fat from the low-dose cow, and milk, renal and omental fat,
muscle, and kidney from the high-dose cow; nonextractable residues
remaining following strong acid hydrolysis were 32% TRR (0.142 ppm) in
liver from the high-dose cow.

These procedures adequately extracted the majority of residues from cow
matrices.  Although nonextractable residues in liver accounted for a
significant portion of the radioactivity, the petitioner made sufficient
attempts to release residues (pepsin and protease hydrolysis, and
hydrolysis in 6 N HCl at reflux).  Because the petitioner normalized
extraction results, accountabilities were generally 100%.  Residues were
identified and quantitated by HPLC and confirmed by LC/MS/MS.  Samples
were stored up to 12.5 months prior to analysis; no supporting storage
stability data were submitted.

The extracts of milk, omental fat, and muscle from the high-dose cow,
and the extracts of kidney from the low-dose cow were not analyzed due
to low radioactivity levels.

In tissues from the high-dose cow, approximately 73% TRR was identified
in renal fat, and 14% and 24% TRR was identified in liver and kidney,
respectively.  Fluopicolide was the only residue identified in fat at
73% TRR (0.034 ppm); fluopicolide was also identified in liver and
kidney at <3% TRR (<0.02 ppm).  A dihydroxy glucuronide of fluopicolide
was identified in kidney at 10% TRR (0.019 ppm); this metabolite was not
found in liver.  All other metabolites identified in liver and kidney
accounted for <6% TRR each (<0.03 ppm).  Identified metabolites included
a hydroxy glucuronide of fluopicolide, a hydroxy sulfate of
fluopicolide, a dihydroxy sulfate of fluopicolide, AE C643890, and AE
0712556.

In renal fat from the low-dose cow, fluopicolide was the only identified
metabolite, at 64.4% TRR.  No metabolites were identified in liver or
kidney from the low-dose cow.

The combined enzyme hydrolysates of liver from the low- and high-dose
cow, comprising 33.2% and 38.2% TRR, respectively, were analyzed by
HPLC, which resolved a number of unknown peaks, each below the LOQ
(low-dose cow) or <0.04 ppm (high-dose cow); similar results were
observed for the combined enzyme hydrolysates of kidney from the
high-dose cow (17.6% TRR). The acid hydrolysate of liver from the
high-dose cow was analyzed by HPLC which yielded four components, each
<2% TRR.  The petitioner reported that HPLC analysis of the acid
hydrolysate of kidney from the high-dose cow yielded a single peak,
accounting for 37.9% TRR (0.074 ppm); however, the HPLC chromatogram of
this fraction showed several peaks.

Based on the results of the study, the petitioner proposed that
fluopicolide is metabolized in ruminants via hydroxylation of the
chlorophenyl ring in two positions to form AE 0712556 and AE C643890.
Each of these metabolites is then conjugated with sulfate or glucuronic
acid, or hydroxylated in a second position and then conjugated with
sulfate or glucuronic acid.

Poultry (phenyl label)

Valent U.S.A. Corporation has submitted a study investigating the
metabolism of [U-14C-phenyl]fluopicolide (specific activity 5.81 MBq/mg)
in laying hens. Two dose formulations (low and high) were prepared in
capsule form to allow daily dose administration of 0.15 mg/day (specific
activity equivalent to 0.857 MBq/day) and 1.5 mg/day (specific activity
equivalent to 5 MBq/day).  Two groups of five hens each were dosed daily
for 14 consecutive days, one group at 1.2 ppm and one group at 10.7 ppm
in the diet.  The 1.2 ppm dosing level corresponds to 34x the dietary
burden for poultry.  The 10.7 ppm dosing level corresponds to 306x the
dietary burden for poultry.  Eggs were collected twice daily throughout
the study, and tissues (fat, liver, skin with subcutaneous fat, and
muscle) were collected at sacrifice, 23-24 hours after the final dose.
The in-life and analytical phases of the study were conducted at Covance
Laboratories, Ltd. (Harrogate, England).

Total radioactive residues (TRR) following dosing at 1.2 ppm were
0.002-0.018 ppm in egg white, 0.001-0.024 ppm in egg yolk, 0.004-0.007
ppm in fat, 0.086-0.224 ppm in liver, 0.004-0.011 ppm in skin (including
subcutaneous fat), and 0.003-0.006 ppm in muscle.  TRR following dosing
at 10.7 ppm were 0.005-0.072 ppm in egg white, 0.003-0.224 ppm in egg
yolk, 0.042-0.099 ppm in fat, 0.602-1.69 ppm in liver, 0.060-0.087 ppm
in skin, and 0.031-0.047 ppm in muscle.  Radioactivity was highest in
liver and appeared to plateau in eggs after 10-11 days of dosing.  The
majority of the administered dose was excreted; with excreta and cage
wash accounting for an average total of ~83% of the administered dose in
the low-dose hens and ~95% of the administered dose in the high-dose
hens.

es accounted for ≤0.05 ppm in egg white, egg yolk, skin, fat, and
muscle, and 22% TRR (0.214 ppm) in liver.  Residues were identified and
quantitated by HPLC.  Samples were stored frozen prior to analysis, but
no information pertaining to storage intervals was provided.

 ppm).  The remainder of the radioactivity consisted of unknowns (each
present at ≤0.06 ppm) and polar compounds.

Although metabolite AE C653711 was found in liver following enzyme
hydrolysis, comparative analysis of an extract of liver with or without
glucuronidase hydrolysis indicated that metabolite AE C653711 was not
present in liver as a glucuronide conjugate.  Additional
characterization procedures with liver indicated that the largest
portion of radioactivity (≥90% TRR) could be extracted with water;
however, only ~40% TRR was organosoluble.  The remainder was assumed to
be associated with polar material.  Cellular fractionation of liver
indicated that the largest portions of radioactivity were associated
with low molecular weight proteins, amino acids, and peptides (23% TRR),
sulfurated glucosaminoglycans (29% TRR), and protein (26% TRR; released
upon base hydrolysis).

The procedures of the study adequately extracted the majority of
residues from hen matrices.  The petitioner proposed that fluopicolide
is metabolized in hens via ring hydroxylation to form AE C643890,
cleavage of the pyridinyl ring moiety to form AE C653711, or formation
of Metabolite 1.

Poultry (pyridinyl label)

Valent U.S.A. has submitted a study investigating the metabolism of
[2,6-14C-pyridinyl]fluopicolide (specific activity 183 (Ci/mg) in laying
hens.  The test substance was administered orally to two groups of five
hens each, one at 1 ppm and one at 10 ppm in the diet.  The dosing
levels correspond to 29x and 286x the dietary burden to poultry.  The
hens were dosed daily for 14 consecutive days.  Eggs were collected
daily throughout the study, and tissues (fat, liver, skin with fat, and
muscle) were collected at sacrifice, 23 hours after the final dose.

TRR following dosing at 1 ppm were 0.001-0.004 ppm in egg white,
0.001-0.018 ppm in egg yolk, 0.002-0.004 ppm in fat, 0.031-0.052 ppm in
liver, 0.002-0.003 ppm in skin (with fat), and 0.001-0.002 ppm in
muscle.  TRR following dosing at 10 ppm were 0.004-0.023 ppm in egg
white, 0.004-0.104 ppm in egg yolk, 0.014-0.044 ppm in fat, 0.237-0.357
ppm in liver, 0.013-0.039 ppm in skin, and 0.007-0.015 ppm in muscle.
Radioactivity was highest in liver and appeared to plateau in eggs after
11-12 days of dosing. The majority of the administered dose was
excreted, with excreta and cage wash accounting for an average total of
~94-95% of the administered dose.

in and protease hydrolysis (total of 51-52% TRR) and strong acid
hydrolysis (10-17% TRR); pepsin and protease hydrolysis released a total
of 29-37% TRR from egg yolk.  Nonextractable residues accounted for
≤0.01 ppm in egg white, egg yolk, skin, fat, muscle, and liver
(low-dose hens), and 20% TRR (0.06 ppm) in liver from high-dose hens.

These procedures adequately extracted the majority of residues from hen
matrices.  Although nonextractable residues in liver accounted for a
significant portion of the radioactivity, the petitioner made sufficient
attempts to release residues (pepsin and protease hydrolysis, and
hydrolysis in 6 N HCl at reflux).  Because the petitioner normalized
extraction results, accountabilities, in terms of extractable plus
nonextractable residues, were generally 100%.  However, some
radioactivity appeared to be “lost” in the various extraction steps;
accountabilities in terms of total identified/characterized residues
plus nonextractable residues ranged from 52-103%.  The petitioner should
note for future submissions that attempts should be made to account for
all radioactivity during extraction procedures.

Residues were identified and quantitated by HPLC and confirmed by
LC/MS/MS.  Samples were stored frozen for 6.2-6.7 months prior to
extraction and for a total of 7.8-13.1 months prior to completion of
analysis.  No supporting storage stability data were provided.

Approximately 10-64% TRR was identified in egg white, egg yolk, liver,
skin, and fat; no compounds were identified in muscle.  Fluopicolide was
identified at low levels in egg yolk, fat, and skin (3.3-16% TRR;
0.003-0.005 ppm); it was not identified in liver or egg white.  The
major metabolite identified in egg white, fat, and skin was AE 0712556,
at 41% TRR (0.005 ppm) in egg white, 47% TRR (0.012 ppm) in fat, and 30%
TRR (0.007 ppm) in skin; this metabolite was also identified in egg yolk
at 10-16% TRR (0.004-0.014 ppm) and in liver at 6% TRR (0.016 ppm).  A
metabolite determined to be a dihydroxy sulfate of fluopicolide, or two
metabolites that were both dihydroxy sulfates of fluopicolide, was a
major portion of the residue in egg white (23% TRR, 0.003 ppm) and egg
yolk (15-34% TRR, 0.013-0.015 ppm); it was also found in liver at 2%
TRR.  A hydroxy sulfate of fluopicolide was observed in egg yolk and
liver at low levels (1.0-7.1% TRR), and a second hydroxy sulfate of
fluopicolide was observed as a minor metabolite in liver (1.4% TRR).
The remainder of the radioactivity consisted of unknowns (each present
at <0.03 ppm).  The majority of the radioactivity in liver (51-52% TRR)
was released upon pepsin and protease hydrolysis, with an additional
10-17% released via strong acid hydrolysis; the hydrolysates were found
to consist of several unknowns, each <0.03 ppm.

The petitioner proposed that fluopicolide is metabolized in hens via
hydroxylation of the chlorophenyl ring in two positions to form AE
0712556 and AE C643890 (AE C643890 was only observed in excreta).  Each
of these metabolites is then conjugated with sulfate or hydroxylated in
a second position, to form a proposed dihydroxy intermediate, which is
conjugated with sulfate.

Conclusions:  The submitted livestock metabolism studies are incomplete
but upgradeable.  Additional information is required for three of the
studies; the required additional information is detailed below.

If sample analyses of any of the ruminant and poultry metabolism studies
were not completed within 6 months of sample collection, the petitioner
should provide data demonstrating that the metabolic profile was stable
in the affected matrices during storage.

For the phenyl-14C-labeled cow metabolism study (MRID 46708514), the
petitioner should provide complete sample history information for
samples from the study, including not only dates of collection but also
dates of storage, radioassay, extraction, and analysis.

For the pyridinyl-14C-labeled cow metabolism study (MRID 46708518),
additional information should be submitted to address storage stability
requirements and to correct errors and inconsistencies in the study
submission.  Storage stability data are required to support the study.
In addition, the petitioner should clarify the identification of two
peaks in the liver MeOH/water extract (retention times of 43 and 47
minutes) to state whether the text on page 65 (which states that the
metabolites are sulfate conjugates) or the results reported in Table 10
(which indicate that one is a sulfate conjugate and one is a glucuronide
conjugate) are correct, and to further explain how the retention times
for these metabolites were correlated with the identified metabolites in
urine and kidney.  The petitioner should correct the flowchart for
omental fat (Figure 10) to include the correct TRR value for this matrix
(0.039 ppm).  Finally, the petitioner should recalculate the
radioactivity levels and/or clarify the results for the HPLC analysis of
any extract in which the calculated LOQ was too high to allow meaningful
interpretation of the chromatogram.  For example, the HPLC analysis of
the acid hydrolysate of kidney, Figure 24, showed diffuse radioactivity
over the entire chromatogram (based on the dpm results in each collected
fraction).  The petitioner’s calculated results for this chromatogram
showed only one spot in which the radioactivity was above the LOQ
(fraction 24) and so the petitioner reported that HPLC analysis yielded
one peak, comprising the entire analyzed fraction. This reported result
is misleading.

The hen metabolism study conducted with [2,6-14C-pyridinyl]fluopicolide
(MRID 46708519) and U-14C-phenyl]fluopicolide (MRID 46708515) are
incomplete but upgradeable.   In addition to the data demonstrating the
stability of the metabolic profile, the petitioner should provide
complete sample history information for samples from the study conducted
with [U-14C-phenyl]fluopicolide including not only dates of collection
but also dates of storage, radioassay, extraction, and analysis.  In
addition, the petitioner should submit copies of the LC/MS chromatograms
of metabolite AE C653711 (BAM) in liver as well as the corresponding
chromatogram of the reference standard.  These chromatograms were
referenced in the submission (MRID 46708515, page 113) but were not
included.

Provided the requested information to support the fluopicolid metabolism
studies noted above are submitted, HED tentatively concludes that the
nature of the residue in livestock has been adequately delineated for
the purpose of this petition.  The Fluopicolide Risk Assessment Team has
concluded that tolerance expression in livestock should include the
metabolite, 2,6-dichlorobenzamide (BAM) only.  For risk assessment
purposes, the residue of concern is parent compound and BAM.

860.1340 Residue Analytical Methods

Plant commodities

DER Reference:	46708522.der.doc (includes review of MRIDs 46708523 and
46708524)

  SEQ CHAPTER \h \r 1 Residue Chemistry Memo DP Number 321209,
1/23/2007, A. Acierto (PP#5E6903)

Residue Chemistry Memo DP Number 329686, A. Acierto, 6/8/2006

Enforcement method:  Valent U.S.A. has submitted an LC/MS/MS method,
Method RM-43C-1, for the determination of residues of fluopicolide per
se in/on crops.  The petitioner has noted that this method is based on
Bayer CropScience Method 00782, and three modified versions of the
method:  Method 00782/M001, Method 00782/M002, and Method 00782/M003.
HED notes that the method most closely follows Method 00782/M002, with
modifications made to incorporate some of the changes recommended during
the independent laboratory validation (ILV).  Adequate method validation
data have been submitted for Method 00782/M002 (46474027.der.doc,
11/29/06, A. Acierto).

Radiovalidation data have been submitted previously for Method
00782/M003; these data indicate that the extraction procedures of Method
00782/M003 adequately extract aged residues of fluopicolide, BAM, and
PCA, as well as P1X and 3-OH-BAM (rotational crop metabolites), from
grape and wheat straw samples (46474027.der.doc, 11/29/06, A. Acierto).

Adequate ILV data for fluopicolide have been submitted for Methods
00782/M002 and 00782/M003 using samples of wheat forage; adequate data
were also submitted for fluopicolide metabolites BAM and 3-OH-BAM using
samples of wheat forage.  Adequate ILV data for fluopicolide, BAM, and
PCA have been submitted previously for Method 00782/M002 using samples
of tomato.  HED notes that the ILV laboratory did not validate Methods
00782/M002 and 00782/M003 in wheat forage for fluopicolide metabolites
PCA and P1X.

In Method RM-43C-1, chopped plant commodities are mixed with
acetone/water, and the mixture is acidified to pH <2 with 2 M sulfuric
acid.  An aqueous solution of L-cysteine hydrochloride is added, and the
sample is extracted by blending, shaking, or vortexing.  The extract is
isolated by gravity filtration and diluted to volume with acetone and
water.  An aliquot of the extract is concentrated to remove the acetone,
and the concentrated extract is partitioned twice with methyl t-butyl
ether (MTBE).  The MTBE phases are combined, and an aliquot is
evaporated to dryness, redissolved in acetonitrile/water, and then
filtered for LC/MS/MS analysis.  Fluopicolide is detected and quantified
using the daughter ion.  The validated LOQ is 0.01 ppm for crop
matrices.

The ACB/BEAD reviewed the proposed enforcement method, Method RM-43C-1,
and reported that the method was not considered specific enough to
positively confirm analyte identity since the tandem mass spectrometric
analysis only monitored a single ion transition.  ACB recommended that
the petitioner provide information for a second ion transition to
provide confirmation of analyte identities, or provide an alternate
chromatographic column and/or mobile phase combination to add an
additional degree of specificity. (Memo, Charles Stafford, 3/1/07).

In response to the ACB/BEAD review of Method RM-43C-1, the petitioner
has now submitted a revised enforcement method (Method RM-43C-2; MRID
47073701) in which the primary analytical column is a reversed-phase C18
packing while the alternative column is a mixed phase of C18 plus a
strong cation exchange packing material.  The difference of polarity
between the primary and alternate columns provides an additional degree
of method selectivity which satisfies the guideline requirement for a
confirmatory method (Memo, DP #339155, Charles Stafford, 3/14/07).

Data collection methods:  Samples of crop commodities from the storage
stability, crop field trial, processing, and field rotational studies
associated with this petition were analyzed for residues of fluopicolide
and its metabolites using LC/MS/MS Methods 00782, 00782/M001,
00782/M002, and/or 00782/M003, or a modified version of 00782/M001.

Samples of tomato commodities from the tomato and grape crop field trial
and tomato processing studies were analyzed for residues of
fluopicolide, BAM, and PCA using Method 00782.

For the bell pepper, chili pepper, cantaloupe, cucumber, head lettuce,
leaf lettuce, and summer squash crop field trials, samples were analyzed
by Pyxant Labs Inc. for residues of fluopicolide, BAM, and PCA using a
modified version of Method 00782/M001.  The method was modified from
00782/M001 in the following ways:  (1) a smaller volume of solvent was
used for extraction; (2) the MTBE liquid/liquid partition step was
eliminated; and (3) the same diluted sample was used for the analysis of
all three compounds by LC/MS/MS.

Samples of potato commodities from the potato crop field trial and
processing studies were analyzed for residues of fluopicolide, BAM, and
PCA using Method 00782/M001.

For the celery and spinach crop field trials, samples were analyzed for
residues of fluopicolide, BAM, and PCA using a method identified as
Pyxant method METH 1611-00.02.  A complete copy of the method was
included in the submissions.  Although not stated in METH 1611-00.02,
the method is clearly a modified version of 00782/M001, and is identical
to the modified version used by Pyxant for the bell pepper, chili
pepper, cantaloupe, cucumber, head lettuce, leaf lettuce, and summer
squash crop field trials.

Samples of wheat straw, grain, and forage from the storage stability
study were analyzed for residues of fluopicolide, 3-OH-BAM, BAM, and P1X
using LC/MS/MS Methods 00782/M001, 00782/M002, and 00782/M003.

Samples of wheat forage, hay, grain, straw, and processed commodities
from the extensive field rotational crop study and rotated wheat
processing study   SEQ CHAPTER \h \r 1 were analyzed for residues of
fluopicolide and its metabolites BAM, PCA, P1X, and 3-OH-BAM using a
combined and modified version of LC/MS/MS Methods 00782/M002 (for
determination of fluopicolide, BAM, PCA, and P1X) and 00782/M003 (for
determination of 3-OH-BAM).  The extraction steps of the methods were
modified to minimize ion suppression, and the same final extract was
used for determination of all analytes.

HED notes that for the storage stability, crop field trial, processing,
and field rotational crop submissions associated with this petition,
residues of each analyte were reported in terms of the analyte (i.e.,
residues of metabolites were not converted to parent equivalents).

Conclusions:  Acceptable plant data collection methods were used to
generate field trial, storage stability, and processing data.

An acceptable LC/MS/MS plant enforcement method (Method RM-43C-2) is
available for fluopicolide (parent) in plants.  The LOQ for fluopicolide
(parent) is 0.01 ppm.   Method RM-43C-2 will be forwarded to FDA for
inclusion in PAM II.

Livestock commodities

DER Reference:	46708516.der.doc

Valent U.S.A. Corporation has submitted an LC/MS/MS method, Method AR
303-02, for the determination of residues of fluopicolide and its
metabolites AE C653711 (BAM) and AE C657188 (PCA) in/on milk, meat, fat,
liver, and kidney of cattle.  This method was used for data collection
in samples of beef commodities from the livestock feeding study
submitted in conjunction with DP Number 327026.

The method includes instructions for determining free compounds and
bound compounds; bound compounds are to be determined in liver and
kidney samples only.  Because the procedure for determination of bound
compounds involves acid hydrolysis of the samples followed by extraction
of the hydrolysate, the procedure determines free + bound compounds in
liver and kidney.

For the determination of free compounds in beef tissues (meat, fat,
liver, and kidney), samples are extracted twice with water, acetonitrile
(ACN), and 0.1% formic acid.  The extracts are combined and diluted to
volume with water and 0.1% formic acid.  The final extract is filtered
and diluted prior to analysis by LC/MS/MS.

For the determination of free compounds in milk, samples are extracted
with water, ACN and 0.3% formic acid and then extracted twice with ACN
and 0.5% formic acid.  The extracts are combined and diluted to volume
with water and 0.1% formic acid.  The final extract is filtered and
diluted prior to analysis by LC/MS/MS.

For the determination of free + bound compounds in liver and kidney,
samples are mixed with water and concentrated HCl and then heated at 100
(C for one hour.  After cooling, the mixture is extracted twice with
ACN.  The combined extracts are neutralized and diluted to volume with
water.  The final extract is filtered and diluted prior to analysis by
LC/MS/MS.

The validated limits of quantitation (LOQs) for each analyte are 0.01
ppm for milk, 0.02 ppm for meat, and 0.05 ppm for fat, liver, and
kidney.

The method was adequately validated using samples of milk, meat, fat,
liver, and kidney of cattle.  Recoveries of fluopicolide, BAM, and PCA
averaged 93% (standard deviation of 8.0%), 102% (standard deviation of
9.2%), and 99% (standard deviation of 10.4%), respectively, from samples
of milk, meat, fat, liver, and kidney fortified at the LOQ and 10x LOQ
and analyzed using the procedures for free compounds.  Recoveries of
fluopicolide, BAM, and PCA averaged 92% (standard deviation of 7.2%),
101% (standard deviation of 12.3%), and 83% (standard deviation of
6.6%), respectively, from samples of beef liver and kidney fortified at
the LOQ and 10x LOQ and analyzed using the procedures for free + bound
compounds.  Based on the method validation data, LC/MS/MS (Method AR
303-02) is adequate for data collection.

ACB/BEAD has reviewed Method AR 303-02 to determine if it would be
suitable for enforcement purposes (email from C. Stafford to A. Acierto
dated 11/15/07) for cattle commodities.  ACB concluded the method is not
suitable for enforcement purposes since the method quantitates parent
and BAM by monitoring only one MRM ion transition for each analyte.  The
method does not meet the Agency criteria as a confirmatory method since
it doesn’t monitor two or more transition for each analyte.  Further,
there are some large, close-eluting peaks in the liver and kidney
controls, leading to the potential for false positives supporting the
need for a confirmatory step.  ACB/BEAD recommends that the petitioner
revise the method to include an alternate LC column as they did for the
plant method.

No method to determine residues of fluopicolid in poultry commodities
has been proposed.

 Conclusions:  Adequate method validation data have been submitted for
LC/MS/MS (Method AR 303-02); the data are sufficiently representative of
the expected residue levels for the beef commodities included in the
petition associated with DP Number 327026.  No radiovalidation data were
submitted for the method; however, HED has concluded that
radiovalidation data are not required because the extraction solvents
used in the method are similar to those used in the cattle metabolism
study.

Based on the method validation data, the LC/MS/MS method AR 303-02 for
livestock is adequate for data collection purposes. The validated limits
of quantitation (LOQs) for each analyte are 0.01 ppm for milk, 0.02 ppm
for meat, and 0.05 ppm for fat, liver, and kidney.

 Method 303-02 has been reviewed and is not acceptable as an enforcement
method.  A confirmatory procedure is required for the LC/MS/MS Method
303-02 to be considered an adequate enforcement method for ruminant
commodities.

860.1360 Multiresidue Methods

  SEQ CHAPTER \h \r 1 Residue Chemistry Memo DP Number 321209,
1/23/2007, A. Acierto (PP#5E6903; MRID 46708525)

Adequate multiresidue method testing data for fluopicolide and its
metabolites BAM, PCA, P1X, and BAM-OH were submitted in conjunction with
the previous petition (PP#5E6903).  Based on the results of the testing,
the multiresidue methods are not appropriate for determining residues of
fluopicolide or its metabolites (BAM, PCA, P1X, and BAM-OH).  The data
have been forwarded to FDA for further evaluation.

860.1380 Storage Stability

Plant commodities

DER Reference:	46708418.der.doc (Wheat commodities)

		46708526.der.doc (Extrapolation of storage stability to 48 months)

		46708527.der.doc (Potato, sugar beet, tomato, and wheat processed
commodities)

  SEQ CHAPTER \h \r 1 Residue Chemistry Memo DP Number 321209,
1/23/2007, A. Acierto (PP#5E6903)

Storage stability studies

The available storage stability data are summarized below and presented
in Table 4.

etabolites BAM and PCA are stable at ≤-18 (C for up to 30 months in
cabbage leaves, grape, potato tuber, and wheat grain.

P1X.  Samples were placed in frozen storage at ≤-18 ºC and analyzed
at storage intervals of approximately 0, 30, 90, 180 and 360 days.

Samples of wheat straw, grain, and forages were analyzed for residues of
fluopicolide, 3-OH-BAM, BAM, and P1X using LC/MS/MS Methods 00782/M001,
M002, and M003.  The reported LOQ was 0.01 ppm for each analyte in each
matrix.  The methods were adequate for data collection based on
acceptable concurrent method recoveries.

≤-18 (C for up to 12 months in wheat straw, and residues of 3-OH-BAM
and P1X are stable at ≤-18 (C for up to ~12 months in wheat grain and
forage.  The petitioner has stated that additional storage intervals of
18 months and 24 months will be investigated, and the final storage
stability study will be submitted upon completion.

Valent U.S.A. also submitted the results of a storage stability study
with fluopicolide and its metabolites BAM and PCA in sugar beet, tomato,
wheat, and potato processed commodities.  Untreated samples of sugar
beet dried pulp, molasses, and refined sugar, tomato paste and puree,
wheat bran, flour, and shorts, and potato chips, dried flakes, and wet
peel were fortified with a mixed standard of
[phenyl-UL-14C]fluopicolide, [phenyl-UL-14C]BAM, and
[pyridine-2,6-14C]PCA, at fortification levels of 0.30-0.31, 0.17-0.18,
and 0.26-0.35 ppm, respectively.  Samples were placed in frozen storage
at ≤-10 ºC and analyzed at storage intervals of 0-7, 29-36, and
911-925 days.

Samples of sugar beet, tomato, wheat, and potato processed commodities
were extracted using 0.1 M sulfuric acid or acetone/0.1 M sulfuric acid.
 Following solid-phase extraction cleanup, the extracts were
radioassayed by LSC and then analyzed by HPLC.  The recovered residue
for each sample was determined by multiplying the total radioactivity,
determined by radioassay, by the relative percentage of each analyte in
each extract, determined by HPLC.  An LOQ was not reported for this
method.  The method was adequate for data collection based on acceptable
concurrent method recoveries.

The storage stability data indicate that residues of fluopicolide and
its metabolites BAM and PCA are stable at ≤-10 (C for up to 30 months
in sugar beet, tomato, wheat, and potato processed commodities.

Valent U.S.A. Corporation also submitted a study in which the results of
a previously submitted storage stability study were extrapolated to a
longer storage interval.  The data from the previously submitted
30-month storage stability study (46474036.Der.doc, 11/29/06, A.
Acierto) with fluopicolide and its metabolites BAM and PCA in cabbage
leaves, grape, potato tuber, and wheat grain were used to extrapolate to
a 48-month storage interval for each analyte in each crop.

 after 48 months of frozen storage (≤-18 (C); the linear regression
analyses yielded lines with negative slopes for these commodities.  The
data also indicated that fluopicolide residues are likely to be stable
in wheat grain, residues of BAM are likely to be stable in cabbage
leaves, grapes, and potato tubers, and residues of PCA are likely to be
stable in grapes and wheat grain during 48 months of frozen storage; the
linear regression analyses for these commodities yielded lines with
positive slopes.

 the correlation coefficients.  The correlation coefficients were
determined to be ≤0.48.  Because the proposed extrapolation represents
a much longer interval (1.6x) than is supported by actual storage
stability data and in consideration of the low correlation coefficients,
HED does not believe it would be appropriate to use the extrapolated
data to make conclusions regarding the stability of residues of
fluopicolide and PCA in cabbage and potato tuber, residues of
fluopicolide in grape, or residues of BAM in wheat grain following 48
months of storage.

Sample storage intervals and conditions

All samples from the crop field trial and field rotational crop studies
associated with this petition were stored frozen prior to analysis.
Samples from the potato, tomato, and wheat processing studies were
stored frozen.  The maximum storage intervals of samples from the crop
field trial, processing, and field rotational crop studies associated
with this petition are presented below.  Unless otherwise noted, samples
were stored at the analytical lab at < -20oC.

Tuberous and corm vegetable subgroup:  The maximum storage interval from
harvest to analysis was 896 days (~30 months).  For the potato
processing study, the maximum storage interval of the samples from
processing to extraction was 589 days (20 months).

Leafy vegetables, except Brassica, group:  The maximum storage intervals
from harvest to extraction were 1,149 days (38 months) for celery, 878
days (29 months) for head lettuce, 877 days (29 months) for leaf
lettuce, and 1,169 days (38 months) for spinach.

Fruiting vegetable group:  The maximum storage intervals from harvest to
analysis were 554 days (19 months) for bell pepper, 508 days (17 months)
for chili pepper, and 646 days (21 months) for tomato.  For the tomato
processing study, the maximum storage interval from harvest to
extraction for analysis of tomatoes and the processed commodities was
378 days (12 months).  Tomatoes (MRID 46708536) were stored at < -15oC.

Cucurbit vegetable group:  The maximum storage interval from harvest to
extraction was 560 days (19 months) for cantaloupe, 597 days (20 months)
for cucumber, and 624 days (21 months) for summer squash.

Grape:  The maximum storage interval from harvest to extraction was 219
days (7 months).  Grapes were stored at < -15oC.

Rotational wheat commodities:  Maximum storage intervals from harvest to
analysis were 24.0 months for wheat forage, 24.5 months for wheat hay,
20.7 months for wheat grain, and 24.4 months for wheat straw.  For the
wheat processing study, maximum storage intervals from harvest (RAC) or
processing to analysis were ~20 months for wheat grain and 17 months for
wheat processed commodities.

TABLE 4.	Summary of Stability of Residues of Fluopicolide, BAM, and PCA
in Cabbage Leaves, Grape, Potato Tuber, Sugar Beet, Tomato, and Wheat,
and Processed Commodities.

RAC	Spike Level (ppm)	Storage Interval (months)	Processed Commodity
Spike Level (ppm)	Storage Interval (months)

Fluopicolide

Cabbage leaves	0.1	30

	Grape	0.1	30

	Potato tuber	0.1	30

	Wheat grain	0.1	30	Wheat straw	0.1	12

	Refined sugar	0.3	30	Sugar beet molasses	0.3	30

Tomato paste	0.3	30	Beet dried pulp	0.3	30

Tomato puree	0.3	30	Wheat flour	0.3	30

Wheat bran	0.3	30	Wheat shorts	0.3	30

Potato flakes	0.3	30	Potato chips	0.3	30

	Potato wet peel	0.3	30

BAM

Cabbage leaves	0.1	30

	Grape	0.1	30

	Potato tuber	0.1	30

	Wheat grain	0.1	30	Wheat straw	0.1	12

	Refined sugar	0.18	30	Sugar beet molasses	0.18	30

Tomato paste	0.18	30	Beet dried pulp	0.18	30

Tomato puree	0.18	30	Wheat flour	0.18	30

Wheat bran	0.18	30	Wheat shorts	0.18	30

Potato flakes	0.18	30	Potato chips	0.18	30

	Potato wet peel	0.18	30

PCA

Cabbage leaves	0.1	30

	Grape	0.1	30

	Potato tuber	0.1	30

	Wheat grain	0.1	30

Refined sugar	0.35	30	Sugar beet molasses	0.35	30

Tomato paste	0.35	30	Beet dried pulp	0.35	30

Tomato puree	0.35	30	Wheat flour	0.35	30

Wheat bran	0.35	30	Wheat shorts	0.35	30

Potato flakes	0.35	30	Potato chips	0.35	30

	Potato wet peel	0.35	30

P1X

	Wheat grain	0.10	12

	Wheat straw	0.10	12

	Wheat forage	0.10	12

3-OH-BAM

	Wheat grain	0.10	12

	Wheat straw	0.10	12

	Wheat forage	0.10	12

Conclusions:  The submitted storage stability studies are adequate to
demonstrate that residues of fluopicolide and its metabolites 3-OH-BAM,
BAM, and P1X are stable at ≤-18 (C for up to 12 months in wheat straw;
that residues of 3-OH-BAM and P1X are stable at ≤-18 (C for up to ~12
months in wheat grain and forage.  Further, the submitted storage
stability results adequately demonstrate that residues of fluopicolide
and its metabolites BAM and PCA are stable at ≤-10 (C for up to 30
months in sugar beet, tomato, wheat, and potato processed commodities

Storage stability data submitted previously (PP#5E6903) indicate that
residues of fluopicolide and its metabolites BAM and PCA are stable at
≤-18 (C for up to 30 months in cabbage leaves, grape, potato tuber,
and wheat grain.  The petitioner presented data extrapolating the
results of the 30-month storage stability study to a 48-month storage
interval for each analyte in each crop. HED does not believe that a
general conclusion regarding the stability of fluopicolide, BAM, and PCA
in cabbage, grape, potato, and wheat grain following 48 months of frozen
storage can be made using these data.  The available storage stability
data should be considered interim data.  Storage stability data to
support the full duration of the study period should be submitted.

The available storage stability data for fluopicolide, BAM, and PCA
in/on cabbage, grape, and potato tuber, which indicate stability for 30
months, are adequate to support the submitted grape, cucurbit vegetable,
leafy vegetable (except celery and spinach), and potato field trials.
The available storage stability data on tomato paste and puree can be
used in lieu of storage stability data on the tomato RAC, and can be
used along with the data on cabbage and grapes to support the submitted
fruiting vegetable field trials.  All field trial samples from these
crops (except celery and spinach) were stored ≤30 months prior to
analysis.

Additional storage stability data are needed for celery and spinach.
Samples of celery and spinach were stored up to 38 months prior to
analysis; HED concludes that the available 30-month storage stability
data may not be extrapolated to 38 months to support these crop field
trials; storage stability data for any representative leafy vegetable
should be submitted to support the full duration of the study period for
celery and spinach.

Adequate storage stability data are available for residues of
fluopicolide, BAM and PCA in/on wheat grain and bran, flour and shorts.
Interim data are available for residues of 3-OH-BAM and P1X in/on wheat
grain, forage, and straw (for up to 12 months).  However, to support the
wheat field rotational crop study, storage stability data are needed
reflecting the stability of P1X in wheat grain for 21 months and for
fluopicolide and BAM in wheat forage and straw for 24 months.  While
storage stability data for 21 months are not available for 3-OH-BAM in
wheat grain, and P1X and PCA in wheat forage and straw, these are not
regulated metabolites; therefore additional storage stability data are
not required for these metabolites.  The requested additional storage
stability data for residues of P1X in wheat grain is also needed to
support the wheat processing study. The available and requested storage
stability data for wheat straw will be translated to wheat hay.  Storage
stability data on wheat grain can be translated to the wheat processed
commodities.

Livestock commodities

DER Reference:	46708528.de2.doc

Valent U.S.A. has submitted the results of a storage stability study
with fluopicolide and its metabolites in cattle commodities.

Samples of homogenized milk, muscle, fat, liver, and kidney from undosed
cattle were separately fortified with fluopicolide and a mixed standard
of BAM and PCA at 0.1 ppm each for milk and muscle and 0.5 ppm each for
fat, liver, and kidney.  Samples were stored frozen (~-18 (C) and
analyzed at intervals of 13, 51, and 83 days for milk, 4 months for
muscle and fat, or 9 months for kidney and liver.

The results indicate that under these conditions, residues of
fluopicolide and its metabolites BAM and PCA are stable for up to 83
days in milk, for up to 4 months in muscle and fat, and for up to 9
months in liver and kidney.

Samples of cattle matrices were analyzed for residues of fluopicolide
and its metabolites (BAM and PCA) using LC/MS/MS Method No. AR 303-02.
This method is adequate for data collection based on acceptable method
recoveries.  The validated LOQs were 0.010 ppm for each analyte in milk,
0.020 ppm for each analyte in muscle, and 0.050 ppm for each analyte in
fat, liver, and kidney.

In the cattle feeding study, milk and tissue samples were stored frozen
prior to analysis; maximum storage intervals were 30 days for milk, 20
days for cream, 13 days for skim milk, 66 days for muscle, 95 days for
fat, and 277-280 days for liver and kidney.

Conclusions:  The submitted storage stability data are adequate to
support the storage intervals and conditions of samples from the cattle
feeding study.

860.1400 Water, Fish, and Irrigated Crops

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

860.1460 Food Handling

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

860.1480 Meat, Milk, Poultry, and Eggs

DER Reference:	46708528.de1.doc

		46708529.der.doc

There are livestock feedstuffs associated with the proposed new uses on
potato and rotated wheat.  The dietary burdens of fluopicolide per se to
livestock, based on reasonably balanced diets, are presented in Table 5.
 The dietary burdens are 0.21 ppm for beef cattle, 0.29 ppm for dairy
cattle, and 0.035 ppm for swine and poultry (e-mail, J. Stokes,
4/30/07).

Table 5.   Calculation of Dietary Burdens of Fluopicolide Residues to
Livestock.

Feedstuff	Type1	% Dry Matter2	% Diet2	Recommended Tolerance (ppm)
Dietary Contribution (ppm)3

Beef Cattle   R: 15%; CC:  75 %;  PC: 10%

Wheat, hay	R	88	15	0.50	0.08

Potato, processed waste	CC	15	30	0.05	0.10

Wheat, milled byproducts	CC	88	40	0.07	0.032

CC (untreated)	CC	N/A	5	N/A	--

PC (untreated)	PC	N/A	10	N/A	--

TOTAL BURDEN	--	--	100	--	0.21

Dairy Cattle R: 45%; CC: 45 %;  PC: 10%

Wheat, hay	R	88	40	0.50	0.23

R (untreated)	R	N/A	5	N/A	--

Potato, processed waste	CC	15	10	0.05	0.033

Wheat, milled byproducts	CC	88	35	0.07	0.028

PC (untreated)	PC	N/A	10	N/A	--

TOTAL BURDEN	--	--	100	--	0.29

Poultry  CC: 75 %;  PC: 25%

Wheat, milled byproducts	CC	88	50	0.07	0.035

CC (untreated)	CC	N/A	25	N/A	--

PC (untreated)	PC	N/A	25	N/A	--

TOTAL BURDEN	--	--	100	--	0.035

Swine CC: 85 %;  PC: 15%

Wheat, milled byproducts	CC	88	50	0.07	0.035

CC (untreated)	CC	N/A	35	N/A	--

PC (untreated)	PC	N/A	15	N/A	--

TOTAL BURDEN	--	--	100	--	0.035

1  R:  Roughage; CC:  Carbohydrate concentrate; PC:  Protein
concentrate.

2  OPPTS 860.1000 Table 1 Feedstuffs (October 2006).

3  Contribution = ([tolerance /% DM] X % diet) for beef and dairy
cattle; contribution = ([tolerance] X % diet) for poultry and swine.

4  N/A:  Not applicable.  Tolerances/uses of fluopicolide have not been
registered or proposed for this feedstuff.

In addition, since there are likely to be measurable residues of the
fluopicolide metabolite, BAM in livestock feedstuffs, and HED has
determined that the residues of concern in animal commodities includes
BAM, HED has also calculated a BAM dietary burden in connection with the
Human Health risk assessment for BAM (2,6-Dichlorobenzamide (BAM ) as a
Metabolite/Degradate of Fluopicolide and Dichlobenil.  Human Health Risk
Assessment for Proposed Uses of Fluopicolide on Tuberous and Corm
Vegetables, Leafy Vegetables (except Brassica), Fruiting Vegetables,
Cucurbit Vegetables, Grapes, Turf, and Ornamentals, and for Indirect or
Inadvertent Residues on the Rotational Crop Wheat, DP #345918, N. Dodd,
11/21/07).

Wet apple pomace is the only livestock feed associated with crops with
established/pending dichlobenil tolerances.  Wet apple pomace is fed to
beef and dairy cattle.  There are no poultry or swine feedstuffs
associated with the established/pending uses of dichlobenil.

Feed items from potatoes (potato culls and processed potato waste) and
wheat (grain, forage, hay, straw, aspirated grain fractions, milled
byproducts) are the only livestock feeds from fluopicolide uses on
tuberous and corm vegetables, leafy vegetables, fruiting vegetables,
cucurbit vegetables, grapes, and the rotational crop wheat.

The dietary burdens of BAM residues in livestock from dichlobenil and
fluopicolide uses, based on reasonably balanced diets, are presented in
the table below.  The dietary burdens of BAM are 0.13 ppm for beef
cattle, 0.12 ppm for dairy cattle, and 0.009 ppm for swine and poultry.

Table 6.  Calculation of Dietary Burdens of BAM Residues in Livestock
from Fluopicolide and Dichlobenil Uses.*

Feedstuff	Type1	% Dry Matter2	% Diet2	BAM Maximum Residues (ppm)	Dietary
Contribution (ppm)3

Beef Cattle   R: 15%; CC:  75 %;  PC: 10%

Wheat, hay	R	88	15	0.102	0.017

Potato, processed waste	CC	15	30	 0.054	0.10

Wheat, milled byproducts	CC	88	40	0.0185	0.0082

CC (untreated)	CC	N/A	5	N/A6	--

PC (untreated)	PC	N/A	10	N/A	--

TOTAL BURDEN	--	--	100

0.13

Dairy Cattle R: 45%; CC: 45 %;  PC: 10%

Wheat, hay	R	88	40	0.102	0.046

R (untreated)	R	N/A	5	N/A	--

Wet apple pomace	CC	40	10	0.271	0.068

Wheat, milled byproducts	CC	88	35	0.0185	0.0072

PC (untreated)	PC	N/A	10	N/A	--

TOTAL BURDEN	--	--	100

0.12

Poultry  CC: 75 %;  PC: 25%

Wheat, milled byproducts	CC	88	50	0.0185	0.009

CC (untreated)	CC	N/A	25	N/A	--

PC (untreated)	PC	N/A	25	N/A	--

TOTAL BURDEN	--	--	100

0.009

Swine CC: 85 %;  PC: 15%

Wheat, milled byproducts	CC	88	50	0.0185	0.009

CC (untreated)	CC	N/A	35	N/A	--

PC (untreated)	PC	N/A	15	N/A	--

TOTAL BURDEN	--	--	100

0.009

1  R:  Roughage; CC:  Carbohydrate concentrate; PC:  Protein
concentrate.

2  OPPTS 860.1000 Table 1 Feedstuffs (October 2006).

3  Contribution = ([tolerance /% DM] X % diet) for beef and dairy
cattle; contribution = ([tolerance] X % diet) for poultry and swine.

4The value of 0.05 ppm for processed potato waste is based on a
concentration factor for wet peel of 4.9x and the LOQ (0.01 ppm) as the
BAM residue in the RAC samples.

5 Residues of BAM in wheat grain (field accumulation in rotational wheat
study: MRID 46708547) were below the calculated LOD of 0.0029-0.0077
ppm; the LOQ is 0.01 ppm.  BAM concentration factors are 1.7x for wheat
bran, 0.7x for flour, 1.1x for middlings, 1.2x for shorts, and 1.8x for
germ.   The value of 0.018 ppm for wheat milled byproducts and aspirated
grain fractions is based on the highest concentration factor of 1.8x for
BAM and a grain (RAC) residue of 0.01 ppm (LOQ) for BAM.

6 N/A:  Not applicable.

Fluopicolid

Cattle:  Valent U.S.A. Corporation has submitted a cattle feeding study
with fluopicolide.  Three treatment groups of three dairy cows each were
dosed orally with fluopicolide in the feed at dose rates corresponding
to 0.5, 1.7, and 5.7 ppm (dry feed weight) for 28 consecutive days.
(These dosing levels as compared to the dietary burden are 1.7x, 5.9x,
and 20x , respectively, for dairy cattle and 2.4x, 8.1x, and 27x,
respectively, for beef cattle.  Cows were milked twice daily, and
samples were composited daily for each cow.  Cows were sacrificed within
17 hours of the final dose.  Samples of liver, kidneys, fat (composite
of mesenterial, perirenal, and subcutaneous), and muscle (composite of
round and loin) were collected from each cow.  Samples of milk collected
on study days 1, 4, 7, 10, 13, 16, 19, 22, 25, and 28 from all dose
levels were reserved for analysis.   Samples of cream and skim milk were
generated from milk samples collected on study day 22 (high dose group
only).

Samples of cattle matrices were analyzed for residues of fluopicolide,
BAM, and PCA using LC/MS/MS Method No. AR 303-02.  This method is
adequate for data collection based on acceptable method recoveries.  The
validated limits of quantitation (LOQs) were 0.010 ppm for each analyte
in milk, 0.020 ppm for each analyte in muscle, and 0.050 ppm for each
analyte in fat, liver, and kidney.

Milk and tissue samples were stored frozen prior to analysis; maximum
storage intervals were 30 days for milk, 20 days for cream, 13 days for
skim milk, 66 days for muscle, 95 days for fat, and 277-280 days for
liver and kidney.  To support the sample storage intervals, the
petitioner conducted a storage stability study with milk, muscle, fat,
liver, and kidney; the results of this study are reported in the
860.1380 DER for this MRID (46708528.de2.doc).  The storage stability
results indicate that fortified residues of fluopicolide, BAM, and PCA
are stable during frozen storage for up to 83 days in milk, 4 months in
fat and muscle, and 9 months in liver and kidney.  These data are
adequate to support the storage intervals and conditions of samples from
this feeding study.

Residues of fluopicolide were below the LOQ (<0.010 ppm) in all samples
of milk and skim milk from the 5.7 ppm dose group, except for one sample
of milk from study day 4 (0.013 ppm) and one sample from study day 28
(0.024 ppm).  Residues of fluopicolide were below the LOQ in all samples
of milk tested from the 0.5 ppm dose group (study days 1 and 4) and the
1.7 ppm dose group (study days 1, 4, 7, and 10).  Residues of
fluopicolide were 0.012-0.018 ppm in cream samples (study day 22) from
the 5.7 ppm dose group.  Fluopicolide residues were below the LOQ
(<0.020 ppm) in all samples of muscle from all three dose groups, and
residues were below the LOQ (<0.050 ppm) in all samples of fat, liver,
and kidney from the 5.7 ppm dose group.  Samples of fat, liver, and
kidney from the 0.5 and 1.7 ppm dose groups were not analyzed.

Residues of BAM and PCA were below the LOQ (<0.010 ppm each) in all
samples of milk, cream, and skim milk from the 5.7 ppm dose group, and
in all samples of milk tested from the 0.5 ppm dose group (study days 1
and 4) and the 1.7 ppm dose group (study days 1, 4, 7, and 10).
Residues of BAM and PCA were below the LOQ (<0.020 ppm each) in all
samples of muscle from all three dose groups, and residues were below
the LOQ (<0.050 ppm each) in all samples of fat, liver, and kidney from
the 5.7 ppm dose group.  Samples of fat, liver, and kidney from the 0.5
and 1.7 ppm dose groups were not analyzed.

BAM

A BAM ruminant feeding study was not submitted with this petition.
Given the likelihood of measurable residues of BAM in livestock feed
items as a result of treating RACs with fluopicolid, a 28-day BAM
feeding study must be submitted or referenced.  HED has determined that
tolerances, at the limit of quantitation of the analytical method, are
needed for ruminant commodities.

Conclusions:  The submitted fluopicolide dairy cattle feeding study data
are acceptable.  At the 5.7 ppm dose level, residues of fluopicolide
(parent) were 0.024 ppm in milk and 0.018 ppm cream.  Residues of
fluopicolide were below the LOQ in all tissue samples (<0.020 ppm in
muscle and <0.050 ppm in fat, liver, and kidney) from the highest dosing
level, and residues of BAM and PCA were below the LOQ in all milk
samples (<0.010 ppm) and tissue samples (<0.020 ppm in muscle and <0.050
ppm in fat, liver, and kidney) from the highest dosing level.

A BAM ruminant feeding study must be submitted or referenced.  Pending
review of the 28-day BAM ruminant feeding study, HED tentatively
concludes that finite residues of BAM may be present in ruminant
commodities as a result of feeding fluopicolide treated feed items.  The
petitioner should propose tolerances for milk, meat by products, fat and
muscle of cattle, goat, horse, and sheep at the analytical method limit
of quantitation (LOQ) for each commodity.  The validated limits of
quantitation (LOQs) for the LC/MS/MS method 303-02 for BAM are 0.01 ppm
for milk, 0.02 ppm for meat, and 0.05 ppm for fat, liver, and kidney.

Poultry:  Valent U.S.A. submitted a request to waive the requirements
for a poultry feeding study (MRID 46708529).

EPA calculated a poultry dietary burden of 0.035 (see Table 5).  The
poultry feeding levels of 1 and 10 ppm in the poultry metabolism study
using [2,6-14C-pyridinyl]fluopicolide correspond to 29x and 286x ,
respectively, of the dietary burden.  The poultry feeding levels of 1.2
and 10.7 ppm in the poultry metabolism study using
[U-14C-phenyl]fluopicolide correspond to 34x and 306x , respectively, of
the dietary burden.  TRR following dosing at 1 ppm using
[2,6-14C-pyridinyl]fluopicolide were 0.001-0.004 ppm in egg white,
0.001-0.018 ppm in egg yolk, 0.002-0.004 ppm in fat, 0.031-0.052 ppm in
liver, 0.002-0.003 ppm in skin (with fat), and 0.001-0.002 ppm in
muscle.  TRR following dosing at 10 ppm using
[2,6-14C-pyridinyl]fluopicolide were 0.004-0.023 ppm in egg white,
0.004-0.104 ppm in egg yolk, 0.014-0.044 ppm in fat, 0.237-0.357 ppm in
liver, 0.013-0.039 ppm in skin, and 0.007-0.015 ppm in muscle.  Total
radioactive residues (TRR) following dosing with
[U-14C-phenyl]fluopicolide at 1.2 ppm were 0.002-0.018 ppm in egg white,
0.001-0.024 ppm in egg yolk, 0.004-0.007 ppm in fat, 0.086-0.224 ppm in
liver, 0.004-0.011 ppm in skin (including subcutaneous fat), and
0.003-0.006 ppm in muscle.  TRR following dosing with
[U-14C-phenyl]fluopicolide at 10.7 ppm were 0.005-0.072 ppm in egg
white, 0.003-0.224 ppm in egg yolk, 0.042-0.099 ppm in fat, 0.602-1.69
ppm in liver, 0.060-0.087 ppm in skin, and 0.031-0.047 ppm in muscle.
The maximum fluopicolide (parent) residues found were in egg:  17 ppb in
egg yolk, equivalent to 5.8 ppb in whole egg  (31.0% yolk x 17 ppb
+58.0% egg white x 1 ppb = 5.8 ppb in whole egg; North, M.O, and Bell,
D. D., Commercial Chicken Production Manual, 4th ed., 1990).  The
maximum residues of BAM  were 361 ppb parent equivalents (178 ppb BAM
equivalents) in liver following dosing with [U-14C-phenyl]fluopicolide
at 10.7 ppm (306x the dietary burden).

No poultry metabolism data for the fluopicolide metabolite, BAM was
submitted or referenced.  However, given the very low calculated dietary
BAM dietary burden, HED concludes that it is unlikely that there will be
measurable residues of BAM in poultry commodities as a result of the
proposed uses on fluopicolide.

Conclusions:  No poultry feeding studies are required for either
fluopicolide or BAM based on the available metabolism studies and the
calculated dietary burdens.  There is no reasonable expectation of
finite residues of fluopicolide (parent) in poultry commodities [40 CFR
§180.6(a)(3)].

860.1500 Crop Field Trials

Tuberous and corm vegetable, subgroup 1C

DER Reference:	46708537.der.doc

HED notes that the petitioner has requested tolerances for only potato
and sweet potato, however, the submitted data support the establishment
of a tolerance for the tuberous and corm vegetable crop subgroup 1C.

Valent U.S.A. Corporation has submitted field trial data for
fluopicolide on potatoes.  Nineteen field trials (seventeen harvest and
two decline) were conducted during the 2001 growing season in the United
States encompassing Zones 1 (1 trial in Pennsylvania and 1 trial in New
York), 2 (1 trial in New Jersey), 3 (1 trial in Florida), 5 (1 trial in
Minnesota, 1 trial in Ohio, 1 trial in Illinois, 2 trials in Wisconsin,
and 1 trial in Michigan), 9 (1 trial in Colorado), 10 (1 trial in
California) and 11 (2 trials in Oregon, 1 trial in Washington and 4
trials in Idaho).  At each test location, there was one untreated and
one treated plot.  The treated plots received three broadcast foliar
applications of fluopicolide, formulated as a 40% suspension
concentrate.  Each application was made at a nominal rate of 0.119 lb
ai/A for a total seasonal application rate of 0.357 lb ai/A/season (~1x
the proposed rate) and the retreatment interval was 5 ± 2 days. An
adjuvant was added to the spray mixture for all applications. At each
trial location, one untreated control and two treated mature raw
agricultural commodity (RAC) samples were collected 7 ± 1 days
following the last test substance application.  In addition, at two of
the test sites, one control and duplicate treated RAC samples were also
harvested at 2, 5, 10, and 14 days after the last application (DALA) to
determine residue decline.

Potato samples were analyzed for residues of fluopicolide (parent) and
its metabolites BAM and PCA using high pressure liquid
chromatography/triple stage quadropole mass spectrometry (HPLC/MS/MS)
Method 00782/M001. The method was adequate for data collection based on
acceptable method validation and concurrent method recoveries.

 at ≤-18oC; therefore, adequate storage stability data are available
to support the storage conditions and intervals of samples from the
potato field trials.

The maximum residues of fluopicolide (parent)   SEQ CHAPTER \h \r 1 were
0.013 in/on potatoes harvested 7-days after the last of three foliar
applications of the 40% SC formulation at a total rate of 0.350 to 0.372
lb ai/A.  The maximum residues of PCA were 0.045 ppm.  (There are
nineteen potato field trials and 38 samples.  PCA was found in two
samples in one field study in Pennsylvania at 0.0429 and 0.0447 ppm.
The other field trials have <0.01 ppm PCA.)  Residues of BAM were less
than the LOQ (<0.01 ppm) in all samples.  Fluopicolide-derived residues
were not detected above the LOQ (0.01 ppm) in either of the two residue
decline studies; therefore, residue decline could not be assessed.

The results from these field trials are discussed below and summarized
in Table 6.1.

TABLE 6.1.	Summary of Residue Data from Crop Field Trials with
Fluopicolide.

Matrix	Total Applic. Rate

(lb a.i./A)	PHI (days)	Residue Levels*

(ppm)

	n	Min.	Max.	HAFT	Median

(STMdR)	Mean

(STMR)	Std. Dev.

Fluopicolide

Potatoes	0.350 to 0.372	6 to 8	38	<0.01	0.0126	<0.01 	<0.01	<0.01	0.0012

BAM (AE C653711)

Potatoes	0.350 to 0.372	6 to 8	38	<0.01	<0.01	NA	NA	NA	NA

PCA (AE C657188)

Potatoes	0.350 to 0.372	6 to 8	38	<0.01	0.0447	0.0438	<0.01	< 0.010
0.009

HAFT = Highest Average Field Trial.

Statistical calculations were performed using a value of ½ LOQ when
residues were reported as <LOQ or <LOD.

LOQ = 0.01 ppm for fluopicolide, BAM and PCA.

LOD = 0.003 ppm for fluopicolide, 0.004 ppm for BAM and 0.002 ppm for
PCA.

Note:  BAM and PCA are not expressed as parent equivalents.

PCA was found in two samples in one field study in Pennsylvania at
0.0429 and 0.0447 ppm.  The other field trials have <0.01 ppm PCA.

Conclusions:  The maximum residues of fluopicolide (parent)   SEQ
CHAPTER \h \r 1 were 0.013 in/on potatoes harvested 7-days after the
last of three foliar applications of the 40% SC formulation at a total
rate of 0.350 to 0.372 lb ai/A.  The maximum residues of PCA were 0.045
ppm.  (There are nineteen potato field trials and 38 samples.  PCA was
found in two samples in one field study in Pennsylvania at 0.0429 and
0.0447 ppm.  The other field trials have <0.01 ppm PCA.)  Residues of
BAM were less than the LOQ (<0.01 ppm) in all samples.
Fluopicolide-derived residues were not detected above the LOQ (0.01 ppm)
in either of the two residue decline studies; therefore, residue decline
could not be assessed.

for up to ~30 months at ≤-18 (C.  The available storage stability data
support the storage intervals of samples from the potato field trials.

The number and locations of the potato field trials are in accordance
with OPPTS Guideline 860.1500 to support a tolerance for the tuberous
and corm crop subgroup 1C.  The use pattern of the field trials
adequately reflects the use pattern proposed for tuberous and corm
vegetables.  The residues values of fluopicolide were below the LOQ
in/on all potato tuber samples, except for one sample in which the
residue was detected at 0.013, ppm.  Therefore, the tolerance setting as
specified by the Guidance for Setting Pesticide Tolerances Based on
Field Trial Data SOP was not used since dataset with LOQ >60% would be
unreliable.  However, the available field trial data will support a
tolerance of 0.02 ppm for residues of fluopicolide per se in/on tuberous
and corm vegetables, subgroup 1C, based on the highest residue value
observed in the field trial data.

Leafy vegetable, except Brassica, group 4

DER Reference:	46708533.der.doc (Head lettuce)

		46708534.der.doc (Leaf lettuce)

		46708539.der.doc (Celery)

		46708540.der.doc (Spinach)

Valent has submitted magnitude of the residue studies for celery, head
lettuce, leaf lettuce, and spinach, the representative crops of group 4.
 The results from these field trials are discussed below and summarized
in Table 6.2.  HED notes that the field trial data were conducted prior
to a determination of the metabolites to be regulated in leafy
vegetables.  Subsequently, the Fluopicolide Risk Assessment Team
concluded that PCA was not a regulated metabolite in leafy vegetables;
however, the data on PCA residues are included here since they were
provided by the petitioner.

Table 6.2.	Summary of Residue Data from Group 4 Crop Field Trials with
Fluopicolide.

Commodity	Total Applic. Rate

 (lb ai/A)

[kg ai/ha]	PHI (days)	Residue Levels (ppm)

	n	Min.	Max.	HAFT1	Median	Mean	Std. Dev.

CELERY (proposed use = 0.375 lb ai/A total application rate, 10-day
minimum RTI, 2-day PHI)

Fluopicolide

Celery	0.354-0.365

[0.397-0.410]	2	12	0.325	13.6	9.9	3.13	4.05	3.93

BAM

Celery	0.354-0.365

[0.397-0.410]	2	12	<0.01	0.041	0.039	NA	NA	NA

PCA

Celery	0.354-0.365

[0.397-0.410]	2	12	<0.01	0.024	0.020	NA	NA	NA

HEAD LETTUCE (proposed use = 0.375 lb ai/A total application rate,
10-day minimum RTI, 2-day PHI)

Fluopicolide

Head lettuce	0.350-0.368 (0.392-0.414)	2	14	0.455	7.15	6.34	2.39	2.68
2.06

BAM

Head lettuce	0.350-0.368 (0.392-0.414)	2	14	<0.01	0.0132	0.012	<0.01
<0.01	NA

PCA

Head lettuce	0.350-0.368 (0.392-0.414)	2	14	<0.01	<0.01	NA	NA	NA	NA

LEAF LETTUCE (proposed use = 0.375 lb ai/A total application rate,
10-day minimum RTI, 2-day PHI)

Fluopicolide

Leaf lettuce	0.349-0.364

[0.391-0.408]	2	14	0.444	11.7	9.78	6.43	6.37	2.96

BAM

Leaf lettuce	0.349-0.364

[0.391-0.408]	2	14	<0.01	0.038	0.031	<0.01	0.012	0.010

PCA

Leaf lettuce	0.349-0.364

[0.391-0.408]	2	14	<0.01	<0.01	<0.01	NA	NA	NA

SPINACH (proposed use = 0.375 lb ai/A total application rate, 10-day
minimum RTI, 2-day PHI)

Fluopicolide

Spinach	0.357-0.365

[0.400-0.410]	2	14	5.43	16.8	16.2	8.53	9.71	3.87

BAM

Spinach	0.357-0.365

[0.400-0.410]	2	14	0.022	0.188	0.170	0.065	0.072	0.047

PCA

Spinach	0.357-0.365

[0.400-0.410]	2	14	<0.01	0.119	0.076	0.013	0.022	0.025

1  HAFT = Highest average field trial result.

Celery:  Valent U.S.A. Corporation has submitted field trial data for
fluopicolide on celery. Seven field trials (six harvest and one decline)
were conducted in the United States during the 2002 growing season in
Zones 3 (1 trial in Florida), 5 (1 trial in Michigan) and 10 (5 trials
in California).  At each test location, there was one untreated and one
treated plot. The treated plots received three broadcast foliar
applications of fluopicolide formulated as a 40% suspension concentrate
of fluopicolide (active ingredient), with a 5 ± 2 day retreatment
interval. Each application was made at a nominal rate of 0.119 lb ai/A
for a total seasonal application rate of 0.357 lb ai/A/season (~1x the
proposed rate). An adjuvant was added to the spray mixture for all
applications. At each trial location, one untreated control and two
treated mature celery raw agricultural commodity (RAC) samples were
collected 2 days following the last test substance application [2-day
pre-harvest interval (PHI)].  In addition, at one of the California test
sites, one control and one treated RAC sample were also harvested at 1,
3, 5, and 7 days after the last application (DALA) to determine residue
decline.

Celery samples were analyzed for residues of fluopicolide (parent) and
its metabolites BAM  and PCA using high pressure liquid
chromatography/triple stage quadropole mass spectrometry (HPLC/MS/MS),
method METH1611-00.02.  The method was adequate for data collection
based on acceptable method validation and concurrent method recoveries.
The LOQ was 0.01 ppm for each analyte in celery).

d frozen at ≤-18 (C for up to 30 months.  The storage interval in the
cabbage leaf/grape storage stability study was approximately 8 months
less than the maximum storage interval in the celery crop field trial
study.

The maximum average residues of fluopicolide (parent), BAM, and PCA
SEQ CHAPTER \h \r 1 were 9.85 ppm, 0.039 ppm and 0.020 ppm in/on celery
harvested 2 days after the last of three foliar applications of the 40%
SC formulation (EXP 11067B) at a total rate of 0.354 to 0.365 lb ai/A.

Residues of fluopicolide increased as PHI increased in the decline study
samples. The petitioner did not provide an explanation for this
observation.

Head lettuce:  Valent U.S.A. Corporation has submitted field trial data
for fluopicolide on head lettuce.  Seven field trials (six harvest and
one decline) were conducted during the 2002 growing season in the United
States: 1 trial in New York (Zones 1), 1 trial in Florida (Zone 3 ), and
5 trials in California (Zone 10).  Each test location contained control
and treated plots. EXP 11067B is formulated as a 4 lb ai/gal suspension
concentrate (SC).  Three foliar spray applications were made with
fluopicolide  5 ± 2 days apart to each treated plot at a target rate of
0.119 lb ai/A/application.  The achieved total seasonal rates ranged
from 0.350 to 0.368 lb ai/A (~1x the proposed rate).  An adjuvant was
added to the spray mixture for all applications.

At each trial location, two control and four treated mature head lettuce
raw agricultural commodity (RAC) samples were collected 2 days following
the last test substance application [2-day preharvest interval (PHI)].
One control and two treated samples were harvested with wrapper leaves
intact, and one control and two treated samples were harvested and all
wrapper leaves were removed.  In addition, at the Florida test site,
head lettuce RAC samples were harvested with and without wrapper leaves
at 1, 3, 5, and 7 days after the last application to determine residue
decline.

Head lettuce samples were analyzed to quantify residues of fluopicolide
(parent) and its metabolites AE C653711 (BAM) and AE C657188 (PCA) with
high pressure liquid chromatography/triple stage quadropole mass
spectrometry (HPLC/MS/MS) Method 00782/M001.  Method verification was
performed prior to sample analysis and concurrent recoveries were
performed during sample analysis to demonstrate acceptable method
performance.  The limit of quantitation (LOQ) was 0.01 ppm for each
analyte for head lettuce.

Head lettuce samples were stored frozen prior to analysis; the maximum
storage interval from harvest to analysis was 878 days (29 months).  The
Analytical Report stated that the samples were stored frozen at <-20 oC.
 No storage stability data are available for head lettuce; however,
residues of fluopicolide, BAM, and PCA are stable in/on cabbage leaves
[Brassica (Cole) leafy crop vegetable Crop Group] and grapes stored
frozen at ≤ -18 oC for up to 30 months.  Adequate storage stability
data are available on cabbage and grapes to support the storage
conditions and intervals of samples from the head lettuce field trials.

In head lettuce samples collected with wrapper leaves, the highest
average field trial fluopicolide-derived residue was 6.34 ppm with a
maximum residue of 7.15 ppm at the proposed PHI of 2 ± 1 days.
Residues of BAM were less than the LOQ in all but two samples.  The
maximum BAM residue of these two samples was 0.0132 ppm.  Residues of
PCA were less than the LOQ in all samples.  In head lettuce samples
collected without wrapper leaves, the highest average field trial
fluopicolide-derived residue was 0.31 ppm with a maximum residue of
0.324 ppm.  Residues of BAM and PCA were less than the LOQ in all
samples.  Residue decline data showed no general tendency to increase or
decline with increasing pre-harvest intervals.  However, it should be
noted that for both the head lettuce samples collected with wrappers and
those collected without wrappers, residues spiked at 2-3 days after the
last application (DALA) and then decreased to 1 DALA levels.

The results of the head lettuce field trials are presented in Table 6.2.
 In/on samples of head lettuce with wrapper leaves harvested 2 days
after the last of three foliar applications of the 4 lb/gal FlC
formulation at a total rate of 0.350-0.368 lb ai/A (~1x), the maximum
residues of fluopicolide were 7.15 ppm.  The maximum residues of BAM
were 0.013 ppm and residues of PCA were <LOQ in/on all samples.  In/on
samples of head lettuce without wrapper leaves, the maximum fluopicolide
residues were 0.324 ppm; residues of BAM and PCA were <LOQ in/on all
samples.

In the residue decline samples, the maximum observed fluopicolide
residues occurred at the 3-day PHI in/on samples with wrapper leaves and
at the 2-day PHI in/on samples without wrapper leaves.  Residues of BAM
and PCA were below the LOQ in/on all residue decline samples.

Leaf lettuce:  Valent U.S.A. Corporation has submitted field trial data
for fluopicolide on leaf lettuce.  Seven field trials (six harvest and
one decline) were conducted in the United States encompassing Zones 1 (1
trial in New York), 3 (1 trial in Florida) and 10 (5 trials in
California) during the 2002 growing season.  At each test location,
there was one untreated and one treated plot.  The treated plots
received three broadcast foliar spray applications of fluopicolid,
formulated as a 40% suspension concentrate (SC) of fluopicolide (active
ingredient), at 5 ± 2 day retreatment intervals.  Each application was
performed at a nominal application rate of 0.119 ai/A, in spray volumes
ranging from 19.2 to 23.9 gal/A.  The achieved total seasonal
application rates ranged from 0.349 to 0.364 lb a.i./A/season (~1x the
proposed rate).  An adjuvant was added to the spray mixture for all
applications.

At each trial location, one untreated control and two treated mature
leaf lettuce raw agricultural commodity (RAC) samples were collected 2
days following the last test substance application [2-day preharvest
interval (PHI)].  In addition, at one of the California test sites, one
control and duplicate treated mature leaf lettuce samples were also
harvested at 1, 3, 5 and 7 days after the last application to determine
residue decline.

Leaf lettuce samples were analyzed for residues of fluopicolide (parent)
and its metabolites BAM (AE C653711) and PCA (AE C657188) using high
pressure liquid chromatography/triple stage quadropole mass spectrometry
(HPLC/MS/MS) Method 00782/M001.  Method validation was performed prior
to sample analysis using head lettuce samples and concurrent recoveries
were performed during sample analysis.  The limit of quantitation (LOQ)
was 0.01 ppm for each analyte for leaf lettuce.  The method was adequate
for data collection based on acceptable method validation and concurrent
method recoveries.

Leaf lettuce samples were stored frozen (< -20oC) prior to analysis; the
maximum storage interval from harvest to extraction was 877 days (29
months).  No storage stability data are available for leaf lettuce;
however, residues of fluopicolide, BAM and PCA are stable in/on cabbage