Cucumber	0.349-0.361

(0.391-0.405)	2	12	<0.01	0.057	0.050	0.020	0.024	0.0147

BAM

Cucumber	0.349-0.361

(0.391-0.405)	2	12	<0.01	<0.01	NA	NA	NA	NA

PCA

Cucumber	0.349-0.361

(0.391-0.405)	2	12	<0.01	<0.01	NA 	NA	NA 	NA

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

Fluopicolide

Summer squash 	0.354-0.367

[0.399-0.411]	2	12	0.0135	0.0506	0.0448	0.0322	0.0301	0.0120

BAM

Summer squash 	0.354-0.367

[0.399-0.411]	2	12	<0.01	<0.01	NA	NA	NA	NA

PCA

Summer squash 	0.354-0.367

[0.399-0.411]	2	12	<0.01	0.0207	0.0173	<0.01	<0.01	0.0060

1 HAFT = Highest average field trial result.

Grape (MRID 46708541)

Table <IP_ADDRESS>	Summary of Residue Data from Grape 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.

GRAPE (proposed use = 0.375 lb ai/A total application rate, 12-day
minimum RTI, 21-day PHI)

Fluopicolide

Grape	0.346-0.401

[0.387-0.449]	20-21	32	0.065	1.10	0.985	0.210	0.312	0.289

BAM

Grape	0.346-0.401

 [0.387-0.449]	20-21	32	<0.01	<0.01	NA	NA	NA	NA

PCA

Grape	0.346-0.401

 [0.387-0.449]	20-21	32	<0.01	0.013	0.012	<0.01	< 0.01	NA

1  HAFT = Highest average field trial result.

Processing Studies (MRIDs 46708542, 46708543, 46708544, and 46708545)

Adequate processing data for grapes, potatoes, tomatoes, and rotated
wheat are available pending submission of additional storage stability
data/information on residues of 3-OH-BAM and P1X on wheat grain stored
frozen for 20 months.  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 a tolerance
for wheat milled byproducts must be proposed at 0.07 ppm.

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
aspirated grain fractions (AGF) at 0.07 ppm is required.  HED could base
the tolerance for AGF on the available wheat processing data, but would
require confirmatory residue data on AGF as a condition of registration.

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.

  SEQ CHAPTER \h \r 1 Table <IP_ADDRESS>		Summary of Processing Factors for
Fluopicolide.

RAC	Processed Commodity	Average Processing Factor 1

Fluopicolide	BAM	PCA	3-OH-BAM	P1X

Grape

	Juice	<1x	≤1x	≤1x	NA	NA

	Raisins	3.4x	4x	4x	NA	NA

Potato	Chips	NC	NC	NC	NA	NA

	Flakes	NC	NC	NC	NA	NA

	Wet peels	4.0x2	NC	NC	NA	NA

Tomato	Paste	2.4x	NC	NC	NA	NA

	Puree	1.4x3	NC	≥1x	NA	NA

Wheat	Bran	3.0x	~1.7x	1.9x	3.0x	2.2x

	Flour	~0.4x	~0.7x	1x	~0.3x	0.6x

	Middlings	1.5x	~1.1x	1.3x	1x	1x

	Shorts	2.0x	~1.2x	1.8x	1.5x	1.4x

	Germ	4.7x	~1.8x	0.9x	1.5x	0.7x

1  NC = Not calculated; a processing factor could not be calculated for
this matrix as residues were below the LOQ in both the RAC and the
processed commodity.  NA = Not applicable.  Estimated (~) processing
factors were calculated when residues were reported below the LOQ in the
RAC and/or the processed matrix.

2  The observed processing factor (>4.9x) exceeded the theoretical value
of 4.0x; therefore, the theoretical value of 4.0x will be used.

3  The observed processing factors for puree (1.7-1.8x) exceeded the
theoretical value of 1.4x; therefore, the theoretical value of 1.4x will
be used.

Field Accumulation in Rotational Crops (46708547)

Wheat:  Pending submission of additional storage stability data,
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.

Additional storage stability data are needed reflecting the stability of
3-OH-BAM and P1X in wheat grain for 21 months and for all analytes
(fluopicolide, BAM, 3-OH-BAM, PCA and P1X) in wheat forage and straw for
24 months.  The available storage stability data for wheat straw will be
translated to wheat hay.

Twenty-one field trials were conducted on the rotational crop wheat in
the U.S.A.  Three broadcast foliar applications of a 4 lb ai/gal
suspension concentrate formulation [equivalent to a flowable concentrate
(FlC) formulation] were made to a primary crop of potatoes or to bare
ground (one TX trial only) for a total of 0.346-0.372 lb ai/A/season
(~1x the maximum proposed seasonal rate).  Potatoes were harvested ~7
days after the last application, and wheat was planted as a rotational
crop 29-37 days after the last application.  Residues in wheat forage,
hay, grain, and straw were determined at normal commercial harvest.
Considering all matrices, residues of fluopicolide (parent) were
<0.01-0.50 ppm.  Residues of the metabolites were individually lower
than the parent in all matrices.

Table <IP_ADDRESS>	Summary of Residue Data in Rotational Wheat Commodities
Following Treatment of a Primary Crop with Fluopicolide.

Commodity	Applic. Rate

(lb ai/A)

[g ai/ha]	PBI

(days)	Analyte	Residue Levels (ppm)

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

Wheat, forage	0.346-0.372

[388-417]	29-37	Fluopicolide	42	<0.01	0.213	0.160	0.027	0.044	0.047

	BAM	42	<0.01	0.123	0.106	0.019	0.028	0.027

	3-OH-BAM	42	<0.01	0.050	0.045	0.013	0.019	0.012

	PCA	42	<0.01	0.043	0.027	0.010	0.013	0.007

	P1X	42	<0.01	0.064	0.057	0.012	0.018	0.013

Wheat, hay	0.346-0.372

[388-417]	29-37	Fluopicolide	42	0.014	0.501	0.364	0.051	0.100	0.119

	BAM	42	<0.01	0.102	0.095	0.010	0.022	0.024

	3-OH-BAM	42	<0.01	0.160	0.133	0.032	0.048	0.044

	PCA	42	<0.01	0.064	0.055	0.010	0.018	0.013

	P1X	42	<0.01	0.073	0.070	0.025	0.028	0.017

Wheat, grain	0.346-0.372

[388-417]	29-37	Fluopicolide	42	<0.01	0.014	0.014	0.010	0.010	0.001

	BAM	42	<0.01	<0.01	<0.01	0.010	0.010	0.000

	3-OH-BAM	42	<0.01	<0.01	<0.01	0.010	0.010	0.000

	PCA	42	<0.01	0.062	0.060	0.011	0.016	0.011

	P1X	42	<0.01	0.075	0.075	0.019	0.025	0.020

Wheat, straw	0.346-0.372

[388-417]	29-37	Fluopicolide	42	<0.01	0.350	0.338	0.034	0.055	0.075

	BAM	42	<0.01	0.050	0.050	0.010	0.015	0.011

	3-OH-BAM	42	<0.01	0.081	0.078	0.026	0.031	0.019

	PCA	42	<0.01	0.043	0.040	0.010	0.012	0.007

	P1X	42	<0.01	0.055	0.049	0.020	0.021	0.011

1  HAFT = Highest average field trial result.

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, crops may not be
rotated to crops not listed on the label.

Limited field rotational crop studies must be conducted at a 12-month
PBI with 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 another cereal grain, preferably a small
grain, are needed to represent all grain crops other than wheat that may
be rotated at a 12-month PBI.)  If the results of the limited field
rotational crop studies indicate the potential for quantifiable
fluopicolide residues of concern in/on rotational crops at a 12-month
PBI, then extensive field rotational crop studies will be required for
all crops the petitioner wishes to allow for rotation at a 12-month PBI.

Meat, Milk, Poultry, and Eggs (MRIDs 46708528 and 46708529)

There are livestock feedstuffs associated with the proposed uses on
potato and rotated wheat.  The dietary burdens of fluopicolide to
livestock, based on reasonably balanced diets and tolerance-level
residues, are presented in Table <IP_ADDRESS>.  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 <IP_ADDRESS>   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 livestock 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 <IP_ADDRESS>  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.

Fluopicolide

Cattle:  Valent U.S.A. Corporation 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.

Samples of cattle matrices were analyzed for residues of fluopicolide,
AE C653711 (BAM), and AE C657188 (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.  HED
notes that, for Method No. AR 303-02 to be an enforcement method (for
any future livestock tolerances), radiovalidation data would be needed;
such data are not required for this petition since tolerances on
livestock commodities are not required.

The submitted dairy cattle feeding study data are acceptable.  At the
5.7 ppm dose level (the highest dose level), maximum residues of
fluopicolide (parent) were 0.024 ppm in milk and 0.018 ppm cream.
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
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.

Poultry:  Valent U.S.A. submitted a request to waive the requirements
for a poultry feeding study (MRID 46708529) on the basis that
anticipated residues in poultry would be far below the method LOQ of
0.05 ppm for tissues.

HED concurs with the request for a waiver of the poultry feeding study.
No poultry feeding study in which fluopicolide is fed is required based
on the poultry metabolism studies and the calculated dietary burden of
0.035 ppm (see Table <IP_ADDRESS>).  The available poultry metabolism data
(MRID 46708515) yielded maximum observed residues of fluopicolide
(parent) 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)
and maximum residues of BAM of 361 ppb parent equivalents (178 ppb BAM
equivalents) in liver following dosing at 10.7 ppm (306x the dietary
burden).  The expected maximum residues at a 1x dosing level would be
0.000019 ppm for fluopicolide in whole egg and 0.0012 ppm for BAM in
parent equivalents (0.00058 ppm in BAM equivalents) in liver.  These
calculated residues are <LOQ of the submitted analytical method, for
which the stated 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 available data indicate that a poultry feeding study is not
required to support the proposed uses.  There is no reasonable
expectation of finite residues of fluopicolide (parent) in poultry
commodities [40 CFR §180.6(a)(3)].

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 fluopicolide (refer to DP
#340366, N. Dodd, 11/21/07 and DP #345918, N. Dodd, 11/21/07), a 28-day
BAM ruminant feeding study must be submitted or referenced and livestock
tolerances must be proposed to support use of fluopicolide on crops with
associated livestock feed items and rotation to crops with associated
livestock feed items.  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.

To support uses with associated livestock feed items, 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.  To support uses with
associated livestock 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.

Note:  Potato and the rotational crop wheat are the only fluopicolide
crops with associated livestock feed items.  Provided that the potato
use will not be registered at this time and rotational crop restrictions
to limit rotation to crops on the label will be established at this
time, there will be no livestock feedstuffs associated with the proposed
fluopicolide uses.  In that case, this use would fall under 40 CFR
§180.6(a)(3) since there would be no reasonable expectation of finite
residues in livestock commodities from application of fluopicolide.

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)].

5.1.11	International Residue Limits TC \l3 "5.1.11	International Residue
Limits

No Codex, Canadian, or Mexican maximum residue limits (MRLs) or
tolerances have been established for fluopicolide.

5.2	Dietary Exposure and Risk TC \l2 "5.2	Dietary Exposure and Risk

References:

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 Number326080, Amelia Acierto,
11/19/07.

Fluopicolide Chronic Aggregate Dietary (Food and Drinking Water)
Exposure and Risk Assessment for the Section 3 Registration Action on
Tuberous and Corm Vegetables, Leafy Vegetables (except Brassica),
Fruiting Vegetables, Cucurbit Vegetables, Grapes, and the Rotational
Crop Wheat, DP Number 340365, N. Dodd, 11/21/07.

using the Dietary Exposure Evaluation Model DEEM-FCID™, Version 2.03,
which uses food consumption data from the U.S. Department of
Agriculture’s Continuing Surveys of Food Intakes by Individuals
(CSFII) from 1994-1996 and 1998.  Two dietary exposure assessments were
conducted:  one (discussed in this document) for residues of
fluopicolide (i.e., parent for water and most crops; for tuberous and
corm crops, parent and PCA; and for the grain used as human food of
cereal grains as rotational crops, parent, PCA, and P1X) in food and
drinking water, and one (discussed in a separate document) for combined
residues of BAM in food and drinking water from uses of both
fluopicolide and dichlobenil.

5.2.1	Acute Dietary (Food and Drinking Water) Exposure/Risk TC \l3
"5.2.1	Acute Dietary (Food and Drinking Water) Exposure/Risk

An acute dietary assessment was not conducted because an endpoint
attributable to a single dose was not identified from the available data
for fluopicolide.

5.2.2	Chronic Dietary (Food and Drinking Water) Exposure/Risk TC \l3
"5.2.2	Chronic Dietary (Food and Drinking Water) Exposure/Risk

The chronic dietary (food and drinking water) exposure analysis which
was conducted for fluopicolide residues on tuberous and corm vegetables,
leafy vegetables (except Brassica), fruiting vegetables, cucurbit
vegetables, grapes, and the rotational crop wheat was a conservative
assessment using the recommended tolerance levels (except for tuberous
and corm vegetables and wheat) and assuming that 100% of the crop was
treated.  Some processing studies were available; default processing
factors were used in cases where an adequate processing study was not
available for particular matrices in DEEMTM.  Since residues may be
expected to occur in rotational crops, a label restriction is
recommended against rotation to crops which are not on the label..
Based on a dairy cattle feeding study and a poultry metabolism study, no
livestock tolerances are required.

The results of the chronic dietary (food and drinking water) exposure
analysis which was conducted for fluopicolide residues on tuberous and
corm vegetables, leafy vegetables (except Brassica), fruiting
vegetables, cucurbit vegetables, grapes, and the rotational crop wheat
are reported in Table 5.2.2 below.  The chronic dietary (food and
drinking water) exposure to fluopicolide is below HED’s level of
concern for the general U.S. population and all population subgroups.
The chronic dietary exposure estimates are 6% cPAD for the general U.S.
population and 9% cPAD for children 1-2 years old, the most highly
exposed subgroup.

Table 5.2.2  Result of Chronic Dietary (Food and Drinking Water)
Exposure and Risk Estimates for Fluopicolide*

Population Subgroup	cPAD, mg/kg/day	DEEM-FCID

Exposure, mg/kg/day	% PAD

Chronic Dietary Estimates

U.S. Population	0.2	0.011999	6

All infants (< 1 yr old)

0.007826	4

Children 1-2 yrs old

0.018460	9

Children 3-5 yrs old

0.016718	8

Children 6-12 yrs old

0.012418	6

Youth 13-19 yrs old

0.009748	5

Adults 20-49 yrs old

0.011822	6

Adults 50+ yrs old

0.011590	6

Females 13-49 yrs old

0.012034	6

Cancer Dietary Estimate

U.S. Population	 Classification:  “Not Likely to be Carcinogenic to
Humans”

*Parent fluopicolide is included in the exposure calculation for all
crops and drinking water.  For

 tuberous and corm vegetables, parent and PCA are included.  For wheat
grain, parent, PCA, and

 P1X are included.  BAM is excluded because it is assessed in food and
drinking water in

DP #345918, N. Dodd, 11/21/07.

5.2.3	Cancer Dietary Risk TC \l3 "5.2.3	Cancer Dietary Risk

Fluopicolide is not likely to be carcinogenic to humans; therefore, a
cancer risk assessment was not conducted for parent fluopicolide.

5.3	Anticipated Residue and Percent Crop Treated (%CT) Information TC
\l2 "5.3	Anticipated Residue and Percent Crop Treated (%CT) Information

Anticipated residues/percent crop treated (% CT) data were not needed to
refine this risk assessment for fluopicolide so they were not used.

6.0	Residential (Non-Occupational) Exposure/Risk Characterization  TC
\l1	“6.0	Residential (Non-Occupational) Exposure/Risk
Characterization”

Occupational and Residential Risk Assessment to Support Request for
Registration of Fluopicolide on a Variety of Crops, Residential Turf and
Ornamentals, DP #326082, K. O’Rourke, 10/9/07.

Two products containing fluopicolide (i.e., V-10161 VPP Fungicide and
V-10162 VPP Fungicide) are proposed for application to residential
turfgrass and recreational sites.  They may be applied to turf at rates
ranging from 0.21 to 0.27 lb ai/A, for two applications at an interval
of 14 days.  The labels do not prohibit homeowners from using these
products; therefore, residential handlers may receive short-term dermal
and inhalation exposure to fluopicolide when mixing, loading and
applying the formulations.  Residential postapplication exposure via the
inhalation route is expected to be negligible; however, dermal exposure
is likely for adults and children entering treated lawns.  Toddlers may
also experience exposure via incidental non-dietary ingestion (i.e.,
hand-to-mouth, object-to-mouth (turfgrass), and soil ingestion) during
postapplication activities on treated turf.

Estimated short- and intermediate-term dermal, inhalation and incidental
oral (for toddlers) exposures were compared to the conservative oral
NOAEL of 20 mg/kg/day from a rabbit developmental toxicity study in
which death, abortions/premature deliveries, decreased food consumption,
and decreased body weight gain were observed at the LOAEL of 60
mg/kg/day.  Because this endpoint is from an oral study, the estimated
dermal exposures were adjusted by applying a 37 percent dermal
absorption rate (based on a dermal penetration study in the rat), while
inhalation toxicity is assumed to be equivalent to oral toxicity.  In
addition, this endpoint is applicable to all populations including
females 13+ years old; therefore, a 60-kg body weight was used in the
calculations.  Where appropriate, the resulting dermal, inhalation, and
incidental oral MOEs were combined into total MOEs because the same dose
and endpoint were chosen to evaluate all routes of exposure.  The FQPA
safety factor was removed (i.e., reduced to 1x) for all potential
exposure scenarios; therefore, the level of concern (LOC) for
non-occupational risk is for margins of exposure (MOEs) <100.

6.1	Residential Handler Exposure TC \l2 "6.1. Residential Handler
Exposure

HED’s Draft Standard Operating Procedures (SOPs) for Residential
Exposure Assessments, and Recommended Revisions (HED Policy Number 11,
revised 22 Feb 2001), were used as the basis for all residential handler
exposure calculations.   Data from the Outdoor Residential Exposure Task
Force (ORETF) (MRID # 44972201) were used in this assessment in place of
PHED data for the garden hose-end sprayer scenario, which provided more
confidence in the exposure estimate.  As shown in Table 6.1, the Total
MOEs for residential handlers are well above the LOC of 100, and are not
of concern.

Table 6.1.  Handler Exposure and Risk Estimates for Residential Lawn
Applicators

Handler Scenario	Application Rate 1

 (lb ai/A)	Area Treated 2

(acres/day)	Unit Exposure 3

(mg/lb ai)	Short-/Intermediate-Term

Daily Dose 4

(mg/kg/day)	Total MOE 5

(1) Mix/load and spot application of liquid formulation (low-pressure
hand sprayer)	0.27	0.023

(1,000 ft2)	Dermal:

100	Dermal:

0.0038	5,200

	Inhalation:

0.030	Inhalation:

0.0000031

	(2) Mix/load and broadcast application of liquid formulation (garden
hose-end sprayer)	0.27	0.50	Dermal:

11	Dermal:

0.0092	2,200

	Inhalation:

0.017	Inhalation:

0.000038

	1 Application rate is based on maximum values found in proposed labels:
V-10161 VPP Fungicide (Reg No. 59639-RUR), and V-10162 VPP Fungicide
(Reg. No. 59639-RUG).

2 Area treated is based on the area that can be reasonably treated in a
single day based on the application method (standard EPA/OPP/HED
values).

3 Dermal unit exposure values represent short pants and short-sleeved
shirt; inhalation values represent no respirator.  Values for
low-pressure handwand are reported in the PHED Surrogate Exposure Guide
dated August 1998, and those for hose-end sprayer were obtained from the
ORETF data.

4 Daily Absorbed Dose (mg/kg/day) = ([unit exposure * % absorption] *
Application rate * Area treated) / 60 kg, where dermal absorption is 37%
and inhalation absorption is assumed to be 100%.

5 Short-/Intermediate-Term Total MOE = NOAEL (20 mg/kg/day) / Total
Daily Absorbed Dose (dermal + inhalation).  The LOC is 100.

6.2.	Residential Postapplication Exposure TC \l2 "6.2. Residential
Postapplication Exposure

Residential postapplication exposure via the inhalation route is
expected to be negligible; however, dermal exposure is likely for adults
and children entering treated lawns.  Toddlers may also experience
exposure via incidental non-dietary ingestion (i.e., hand-to-mouth,
object-to-mouth [turfgrass], and soil ingestion) during postapplication
activities on treated turf.  The postapplication risk assessment is
based on generic assumptions as specified by the Recommended Revisions
to the Residential SOPs and recommended approaches by HED’s Science
Advisory Council for Exposure (ExpoSAC).

The following postapplication exposure scenarios resulting from lawn
treatment were assessed: (1) adult and toddler postapplication dermal
exposure; (2) toddlers’ incidental ingestion of pesticide residues on
lawns from hand-to-mouth transfer; (3) toddlers’ object-to-mouth
transfer from mouthing of pesticide-treated turfgrass; and (4)
toddlers’ incidental ingestion of soil from pesticide-treated
residential areas.

Turf transferable residue (TTR) data were not available.  The assessment
was based on generic assumptions per TTR and transfer coefficients, as
specified by the Recommended Revisions to the Residential SOPs and
recommended approaches by HED’s Science Advisory Council for Exposure
(ExpoSAC).

The exposure and risk estimates for the residential exposure scenarios
are assessed for the day of application (day “0”) because it is
assumed that adults and toddlers could contact the lawn immediately
after application.  The equations used for the exposure calculations and
the results are presented in Tables 6.2.1 through 6.2.5.

The exposure estimates are based on some upper-percentile (i.e., maximum
application rate, initial amount of transferable residue and duration of
exposure) and some central tendency (i.e., surface area and body weight)
assumptions and are considered to be representative of high-end
exposures.  The uncertainties associated with this assessment stem from
the use of an assumed amount of pesticide available from turf, and
assumptions regarding transfer of chemical residues and hand-to mouth
activity.  The estimated exposures are believed to be reasonable
high-end estimates based on observations from chemical-specific field
studies and professional judgement.

The short-/intermediate-term MOEs for each scenario are above the LOC of
100, and are not of concern.  As mentioned previously, the same toxicity
study was selected to evaluate all routes of exposure; therefore, the
MOEs were combined.  As shown in Table 6.2.5, the Total
short-/intermediate-term MOEs for adults (including handler exposure
which could co-occur with postapplication exposure) and children are 550
and 450, respectively.  These Total MOEs are greater than the LOC of 100
on the day of application, and therefore, are not of concern.

Table 6.2.1.  Postapplication Dermal Exposure and Risk from Treated
Lawns

Subgroup Exposed

Application Rate

 (lb ai/A)

Post-application day (t)

Fraction of ai Transferable from the Foliage

Turf Transferable Residue 1

(µg/cm2)

Dermal Transfer Coefficient

(cm2/hr)

 Body Weight

(kg)

 Daily Dermal Dose 2

(mg/kg/day)

Dermal MOE 3

Short-/

Intermediate-term

Adults	0.27	0	0.05	0.15	14,500

60	0.027	740

Children

	5,200

15	0.039	520

1 Turf Transferable Residue Postapplication day (µg/cm2)= Application
rate (lb ai/A) x Fraction of ai Transferable from the Foliage x (1-
Fraction of Residue That Dissipates Daily, 0.1) Postapplication day x
4.54E+8  µg/lb x 2.47E-8 A/cm2

2 Daily Dermal Dose = (Turf Transferable Residue (µg/cm2) x Absorption
Factor (0.37) x Dermal Transfer Coefficient (cm2/hr) x Exposure Time (2
hrs/day) x 0.001 mg/µg] / [Body Weight (kg)]

3 Dermal MOE = Dermal NOAEL / Daily Dermal Dose; where
Short-/Intermediate-term NOAEL = 20 mg/kg/day.

Table 6.2.2.  Postapplication Oral Hand-to-Mouth Exposure and Risk for
Children from Treated Lawns

Application Rate

 (lb ai/A)

Post-application day (t)

Fraction of ai Transferable from the Foliage

Turf Transferable Residue 1

(µg/cm2)

Hand Surface Area

(cm2/event)

Saliva Extraction Factor

 Frequency

(events/ hr)

Body Weight

(kg)

 Daily Dose2

(mg/kg/day)

Oral MOE3

	Short-/

Int-term

0.27

0

0.05

0.15

20

50%

20

15	0.0040	5,000

1 Turf Transferable Residue Postapplication day (µg/cm2)= Application
rate (lb ai/A) x Fraction of ai Transferable from the Foliage x (1-
Fraction of Residue That Dissipates Daily, 0.1) Postapplication day x
4.54E+8  µg/lb x 2.47E-8 A/cm2

2 Daily Dose = (Turf Transferable Residue (µg/cm2) x Hand Surface Area
(cm2/event) x Saliva Extraction factor x Frequency (events/hr) x 0.001
mg/ µg  x  Exposure time (2 hrs/day)] / [Body Weight (kg)]

3 Oral MOE = Oral NOAEL/Daily Dose; where Short-/Intermediate-term NOAEL
= 20 mg/kg/day.

Table 6.2.3.  Postapplication Oral Object-to-Mouth (Turfgrass) Exposure
and Risk for Children from Treated Lawns

Application Rate

 (lb ai/A)

Post-

application day

(t)

Fraction of ai Transferable from the Foliage

Grass/Object

Residue 1

(µg/cm2)

Ingestion Rate

(cm2/day)

Body

Weight

(kg)

 Daily Dose2

(mg/kg/day)

Oral MOE3

	Short-/

Int-term

0.27

0

0.29

0.88

25

15	0.0015	14,000

1Grass/Object residue Postapplication day (µg/cm2) = Application rate
(lb ai/A) x Fraction of ai Transferable from the Foliage (from MRID#:
46708641) x (1- Fraction of Residue That Dissipates Daily)
Postapplication day x  4.54E+8  µg/lb x 2.47E-8 A/cm2

2 Daily Dose  = [Grass reside (µg/cm2) x Ingestion rate (cm2/day) x
0.001 mg/µg] / [Body Weight (kg)]]

3Oral MOE = Oral NOAEL / Daily Dose; where Short-/Intermediate-term
NOAEL = 20 mg/kg/day.

Table 6.2.4. Postapplication Incidental Soil Ingestion Exposure and Risk
for Children from Treated Lawns

Application Rate

 (lb ai/A)

Fraction of ai Retained in the Soil

Soil

Residue 1

(µg/g)

Ingestion Rate

(mg/day)

Body

Weight

(kg)

 Daily Dose2

(mg/kg/day)

Oral MOE3

Short-/ Intermediate-term

0.27	1

2.0

100	15	0.000014	1,500,000

1 Soil residue Postapplication day zero (µg/cm2) = Application rate (lb
ai/A) x Fraction of ai Retained on the Soil x (4.54E+8 µg/lb x 2.47E-8
A/cm2 x 0.67 cm3/g soil

2 Daily Dose  = [Soil reside (µg/g) x Ingestion rate (mg/day) x
0.000001 g/µg] / [Body Weight (kg)]]

3 Oral MOE = Oral NOAEL/Daily Dose; where Short-/Intermediate-term NOAEL
= 20 mg/kg/day.

Table 6.2.5.  Aggregate Exposure and Risk Estimates from Residential
Lawns

Scenario

and

Pathway

TTR/GR/SR0 (µg/cm2 or g) 1

PDR0-norm

(mg/kg/day) 2

Short-/ Int-Term

 MOE 3

Total MOE 4

Short-/

Int-Term

Adult’s Scenarios

(1) Handler (Dermal) 	N/A	0.0092	2,200	550

(1) Handler (Inhalation) 	N/A	0.000038	520,000

(2) Dermal Postapplication	0.15	0.027	740

	Children’s Scenarios – All Postapplication

(1) Dermal 	0.15	0.039	520	450

(2) Hand-to-Mouth	0.15	0.0040	5,000

(3) Mouthing Grass/Object	0.88	0.0015	14,000

(4) Soil Ingestion	2.0	0.000014	1,500,000

	1 TTR=turf transferable residue on day “0"; GR=grass/object residue
on day “0"; SR0=soil residue on day “0".

2 PDR0norm=potential dose rate on day “0”.

3 MOE = NOAEL/PDR; where Short-/Intermediate-term NOAEL = 20 mg/kg/day.

4 Total MOE = 1/ [(1/MOEDermal) + (1/MOEHand-to-Mouth) + (1/MOEGrass) +
(1/MOESoil)]

6.3	Other (Recreational Exposure; Spray Drift) TC \l2 "6.3 Other
(Recreational Exposure; Spray Drift)

Recreational exposures to turf (including from playing golf) are
expected to be similar to, or in many cases less than, those evaluated
in section 5.2 Residential Postapplication Exposure and Risk; therefore,
a separate recreational exposure assessment was not included.

Spray drift is always a potential source of exposure to residents nearby
to spraying operations.  This is particularly the case with aerial
application, but, to a lesser extent, could also be a potential source
of exposure from the ground application method employed for
fluopicolide.  The Agency has been working with the Spray Drift Task
Force, EPA Regional Offices and State Lead Agencies for pesticide
regulation and other parties to develop the best spray drift management
practices.  The Agency is now requiring interim mitigation measures for
aerial applications that must be placed on product labels/labeling.  The
Agency has completed its evaluation of the new data base submitted by
the Spray Drift Task Force, a membership of U.S. pesticide registrants,
and is developing a policy on how to appropriately apply the data and
the AgDRIFT computer model to its risk assessments for pesticides
applied by air, orchard airblast and ground hydraulic methods.  After
the policy is in place, the Agency may impose further refinements in
spray drift management practices to reduce off-target drift and risks
associated with aerial as well as other application types where
appropriate.

Please note that as indicated in this assessment, fluopicolide is
directly applied to residential turf and does not result in exposures of
concern.  It is unlikely that the potential for risk of exposure to
spray drift from the agricultural uses would be higher than that
estimated for contact with treated turf.

7.0	Aggregate Risk Assessments and Risk Characterization  TC \l1	“7.0
Aggregate Risk Assessments and Risk Characterization”

Two products containing fluopicolide (i.e., V-10161 VPP Fungicide and
V-10162 VPP Fungicide) are proposed for application to residential
turfgrass and recreational sites.  There is a potential for short- and
intermediate-term non-occupational exposure to fluopicolide during
mixing, loading, application, and postapplication activities.  Chronic
exposure is not expected for the proposed use patterns associated with
fluopicolide.

7.1	Acute Aggregate Risk

 TC \l2 "7.1 Acute Aggregate Risk

An acute dietary assessment was not conducted because an endpoint
attributable to a single dose was not identified from the available data
for fluopicolide.

7.2	Short-Term Aggregate Risk. TC \l2 "7.2 Short-Term Aggregate Risk

Short-term exposures (1 to 30 days of continuous exposure) may occur as
a result of activities on treated turf.  The same dose and endpoint were
chosen to evaluate all routes of exposure (oral, dermal, and
inhalation); therefore, all exposures related to turf activities (Table
6.2.5) have been combined with chronic dietary exposure estimates (as an
estimated of background dietary exposure; Table 5.2.2) to assess
short-term aggregate exposure. Since aggregate MOEs in Table 7.2 are
greater than 100, they represent risk estimates that are below HED’s
level of concern.

Table 7.2.  Short-Term and Intermediate-Term Aggregate Risk Calculations

(Inhalation/Oral/Dermal Endpoints and NOAELs are  the Same)

Population	Short- or Intermediate-Term Scenario

	NOAEL

mg/kg/day	LOC1

	Max Allowable

Exposure2

mg/kg/day	Average

Food & Water

Exposure

mg/kg/day	Residential Exposure3

mg/kg/day	Aggregate MOE

(food and

residential)4

General U.S. Population	20	100	0.2	0.011999	0.036238	420

All Infants (<1 year old)	20	100	0.2	0.007826	0.044514	380

Children 1-2 years old	20	100	0.2	0.018460	0.044514	320

Children 3-5 years old	20	100	0.2	0.016718	0.044514	330

Children 6-12 years old	20	100	0.2	0.012418	0.044514	350

Youth 13-19 years old	20	100	0.2	0.009748	0.036238	440

Adults 20-49 years old	20	100	0.2	0.011822	0.036238	420

Adults 50+ years old	20	100	0.2	0.011590	0.036238	420

Females 13-49 years old	20	100	0.2	0.012034	0.036238	410

1 UFA  = 10x (extrapolation from animal to human (interspecies); UFH =
10x potential variation in sensitivity among members of the human
population (intraspecies); FQPA SF = 1x.  10 x 10 x 1 = 100.

2 Maximum Allowable Exposure (mg/kg/day) = NOAEL/LOC = 20 mg/kg/day ÷
100 = 0.2 mg/kg/day.

3 Residential Exposure = [Oral exposure + Dermal exposure + Inhalation
Exposure], calculated by adding PDR values shown in  Table 6.3.5 above.
Residential exposures were calculated for adults (60 mg bw) and children
(15 mg bw).

4 Aggregate MOE = [NOAEL / (Avg Food & Water Exposure + Residential
Exposure)]

7.3	Intermediate-Term Aggregate Risk

The intermediate-term aggregate risk is the same as calculated above for
the short-term aggregate risk. TC \l2 "7.3 Intermediate-Term Aggregate
Risk

7.4	Long-Term Aggregate Risk TC \l2 "7.4 Long-Term Aggregate Risk

In examining long-term aggregate risk, HED has assumed that the only
pathway of exposure relevant to that time frame is dietary exposure
(i.e., any non-dietary exposures are short- and/or intermediate-term in
duration).  Therefore, the long-term aggregate risk is composed of
exposures to fluopicolide residues in food and drinking water and is
equivalent to the chronic dietary risk discussed in Section 5.2.  As
shown in Table 5.2.2, the chronic risk estimates are below HED’s level
of concern for all population subgroups.

7.5	Cancer Risk TC \l2 "7.5 Cancer Risk

Fluopicolide has been classified as “not likely to be carcinogenic to
humans.”  As such, an estimate of cancer risk is not warranted for
parent fluopicolide.

8.0	Cumulative Risk Characterization/Assessment  TC \l1 "8.0	Cumulative
Risk Characterization Assessment

Unlike other pesticides for which EPA has followed a cumulative risk
approach based on a common mechanism of toxicity, EPA has not made a
common mechanism of toxicity finding as to fluopicolide (parent) and any
other substances and fluopicolide does not appear to produce a toxic
metabolite produced by other substances. For the purposes of this
tolerance action, therefore, EPA has not assumed that fluopicolide
(parent) has a common mechanism of toxicity with other substances. For
information regarding EPA’s efforts to determine which chemicals have
a common mechanism of toxicity and to evaluate the cumulative effects of
such chemicals, see the policy statements released by EPA’s Office of
Pesticide Programs concerning common mechanism determinations and
procedures for cumulating effects from substances found to have a common
mechanism on EPA’s website at   HYPERLINK
http://www.epa.gov/pesticides/cumulative/.
http://www.epa.gov/pesticides/cumulative/.

BAM, the common metabolite of fluopicolide and dichlobenil, is evaluated
in the concurrent document (DP #345918, N. Dodd, 11/21/07).

9.0	Occupational Exposure/Risk Pathway  TC \l1 "9.0 	Occupational
Exposure/Risk Pathway

Occupational and Residential Risk Assessment to Support Request for
Registration of Fluopicolide on a Variety of Crops, Residential Turf and
Ornamentals, DP #326082, K. O’Rourke, 10/9/07.

Estimated short- and intermediate-term dermal and inhalation exposures
were compared to the oral NOAEL of 20 mg/kg/day from a rabbit
developmental toxicity study in which death, abortions/premature
deliveries, decreased food consumption, and decreased body weight gain
were observed at the LOAEL of 60 mg/kg/day.  Because this endpoint is
from an oral study, the estimated dermal exposures were adjusted by
applying a 37 percent dermal absorption rate (based on a dermal
penetration study in the rat), while oral and inhalation toxicity is
assumed to be equivalent.  In addition, this endpoint is applicable to
all populations including females 13+ years old; therefore, a 60-kg body
weight was used in the calculations.  Where appropriate, resulting
dermal and inhalation MOEs were combined into total MOEs because the
same dose and endpoint were chosen to evaluate both routes of exposure.
The level of concern (LOC) for occupational risk is for margins of
exposure (MOEs) <100.

9.1	Short-/Intermediate-/Long-Term Handler Risk  TC \l2 "9.1
Short-/Intermediate-/Long-Term Handler Risk

There is a potential for short- and intermediate-term exposure to
fluopicolide during mixing, loading, and application activities.  No
chemical-specific handler exposure data were submitted in support of
this registration.  It is the policy of the HED to use data from the
Pesticide Handlers Exposure Database (PHED) Version 1.1 as presented in
PHED Surrogate Exposure Guide (8/98) to assess handler exposures for
regulatory actions when chemical-specific monitoring data are not
available (HED Science Advisory Council for Exposure Standard Operating
Procedure #7, dated 1/28/99).  The handler exposure data for the turf
handgun sprayer scenario are from the Outdoor Residential Exposure Task
Force (ORETF) (MRID # 44972201), rather than from PHED.  The ORETF data
were designed to replace the present PHED data with higher-confidence,
higher quality data that contain more replicates than the PHED data for
those scenarios.

The results of the handler occupational exposure and risk assessment
indicate that risks are not of concern with baseline clothing, or when
gloves are worn (which is required on the proposed labels).  Dermal and
inhalation MOEs were combined into Total MOEs because the same dose and
endpoint were chosen to evaluate both routes of exposure.  The level of
concern (LOC) for occupational risk is for margins of exposure (MOEs)
<100.  The Total Short/Intermediate-Term MOEs range from 100 to 19,000,
which reach or exceed the LOC of 100, and are not of concern.  Exposure
assumptions and MOEs for occupational handlers are summarized in Table
9.1.	Table 9.1.  Summary of  MOEs for Occupational Handlers of
Fluopicolide

Exposure Scenario (Scenario #)	Dermal Unit Exposure (mg/lb ai) 1
Inhalation

Unit

Exposure

(mg/lb ai)2	Use Site	Application

Rate

(lb ai/A)3	Area Treated

(A/day) 4	Daily Dose

(mg/kg/day) 5	Total

Short-/Int-term MOE 6

	Baseline	PPE

(gloves)

	Dermal	Inhalation	Baseline	PPE

(gloves)

Mixer/Loader

(1) Mixing/Loading Liquid for Aerial application or Chemigation	2.9
0.023	0.0012	Veg, Potatoes	0.13	350	0.81

0.0065 (gloves)	0.00091	25	2,700

(2) Mixing/Loading Liquid for Groundboom application or Chemigation	2.9
0.023	0.0012	Veg, Potatoes	0.13	80	0.19	0.00021	110	-

Turf	0.27	80	0.39

0.0031 (gloves)	0.00043	52	5,700

Ornamentals (drench)	27	40	19

0.15 (gloves)	0.021	1	110

Ornamentals	0.54	40	0.39

0.0031 (gloves)	0.00043	52	5,700

(3) Mixing/Loading Liquid for Airblast application	2.9	-	0.0012	Grapes
0.13	40	0.093	0.00010	210	-

Ornamentals	0.54	20	0.19	0.00022	100	-

Applicator

(4) Applying Sprays with Fixed-wing Aircraft	0.005	-	0.000068	Veg,
Potatoes	0.13	350	0.0014	0.000052	14,000	-

(5) Applying Sprays with Open Cab Groundboom 	0.014	-	0.00074	Veg,
Potatoes	0.13	80	0.00090	0.00013	19,000	-

Turf	0.27	80	0.0019	0.00027	9,400	-

Ornamentals	0.54	40	0.0019	0.00027	9,400	-

(6) Applying Sprays with Open Cab Airblast Sprayer	0.36	-	0.0045	Grapes
0.13	40	0.012	0.00039	1,700	-

Ornamentals	0.54	20	0.024	0.00081	810	-

Flagger

(7) Flagging to Support Aerial Applications	0.011	-	0.00035	Veg,
Potatoes	0.13	350	0.0031	0.00027	6,000	-

Mixer/Loader/Applicator

(8) Mixing/Loading Liquid and Applying with Handgun Sprayer	no data	0.50
0.0019	Turf	0.27	5	0.0042

(gloves)	0.000043	no data	4,800

(9) Mixing/Loading Liquid and Applying with Low-Pressure Handwand	100
0.43	0.03	Turf	0.0031

(lb ai/gal)	40

(gal/day)	0.076	0.000062	260	-

(10) Mixing/Loading Liquid and Applying with High-Pressure Handwand	no
data	2.5	0.12	Ornamentals	0.0025

(lb ai/gal)	1,000

(gal/day)	0.039

(gloves)	0.005	no data	460

(11) Mixing/Loading Liquid and Applying with Backpack Sprayer	no data
2.5	0.03	Turf	0.0031

(lb ai/gal)	40

(gal/day)	0.0019

(gloves)	0.000062	no data	10,000

Ornamentals	0.0025

(lb ai/gal)	40

(gal/day)	0.0015

(gloves)	0.000050	no data	13,000

1 Baseline dermal unit exposure values represent long pants, long
sleeved shirts, shoes, and socks; PPE values represent the addition of
chemical-resistant gloves for those scenarios in which the MOEs do not
reach 100 at baseline or those for which data are not available without
gloves.  Values are reported in the PHED Surrogate Exposure Guide dated
August 1998, except for the handgun value which was obtained from ORETF.

2 Inhalation unit exposure values represent no respirator.  Values are
reported in the PHED Surrogate Exposure Guide dated August 1998.

3 Application rates are based on maximum values found in proposed
labels: V-10161 4 SC (Reg No. 59639-RUN), V-10162 Premix (Reg. No.
59639-RUE), V-10161 VPP Fungicide (Reg No. 59639-RUR), and V-10162 VPP
Fungicide (Reg. No. 59639-RUG).

4 Daily area treated is based on the area or gallons that can be
reasonably applied in a single day for each exposure scenario of concern
based on the application method and formulation/packaging type.
(standard EPA/OPP/HED values).

5 Daily Dose (mg/kg/day) = Unit Exposure * % Absorption * Application
rate * Area treated} / 60 kg; where dermal absorption is 37% and
inhalation absorption is assumed to be 100%.

6 Short-/Intermediate-Term MOE = NOAEL (20 mg/kg/day) / (Daily Dermal
Dose + Daily Inhalation Dose).  The LOC is 100.

HED recognizes that it is feasible for the same individual to mix/load
and apply formulations with the groundboom and airblast sprayers,
however, appropriate data are not available in PHED for which unit
exposure values for these combined activities can be derived.  HED does
not recommend simply adding the unit exposure values for each job
function because any extrapolation error (i.e., exposure from the amount
ai handled in the study to that of a real-life application) would be
magnified, leading to greater uncertainty.  For information and
characterization purposes, even with the over-estimation uncertainty,
the MOEs for these combined activities for groundboom and airblast
application of fluopicolide would be above the LOC of 100 (i.e., ranging
from 110 to 3,600).

The minimum level of PPE for handlers is based on acute toxicity for the
end-use products.  Two of the products (V-10162 Premix and V-10162 VPP
Fungicide) contain a second active ingredient (propamocarb
hydrochloride) which may have additional PPE requirements.  The
Registration Division (RD) is responsible for ensuring that PPE listed
on the label is in compliance with the Worker Protection Standard (WPS)
relative to both fluopicolide and propamocarb hydrochloride exposure.

9.2	Short-/Intermediate-/Long-Term Postapplication Risk  TC \l2 "9.2
Short-/Intermediate-/Long-Term Postapplication Risk

This registration action for fluopicolide involves application to
agricultural crops as well as turf (residential and commercial lawns,
golf courses, and sod farms) and ornamentals (landscapes, commercial
greenhouses, and nurseries).  Postapplication inhalation exposure is
expected to be negligible; however, dermal exposure is possible for
workers entering treated areas to tend or harvest crops, mow/maintain
turfgrass, or tend ornamentals in nurseries and greenhouses.  A
dislodgeable foliar residue (DFR) study was submitted by the registrant
(MRID#: 46708641) for use in assessing postapplication activities.  The
study results are summarized below:

Dislodgeable Foliar Residue (DFR) Study on Leaf Lettuce (MRID#
46708641):

0.42 μg/cm2) and declined to 0.012 μg/cm2 after 14 days, with all
residues <LOQ by 21 days after the last treatment (note that rainfall
was 6 inches greater than the 10-year historical average during the
study period).  At the CA site, the maximum average residue was detected
1 day after the last treatment (0.45 μg/cm2) and declined to 0.0047
μg/cm2 after 35 days, with residues in two of three samples <LOQ by 21
and 35 days after the last treatment.  The estimated half-life values
were 2.5 days (r2 = 0.97) and 4.8 days (r2 = 0.77) for leaf lettuce at
the PA and CA sites, respectively.

This study is considered to be acceptable, and the data were used to
estimate exposure from activities associated with agricultural crops and
ornamentals.  The data regression analyses (assuming pseudo first-order
kinetics) from both sites indicate that the initial dislodgeable residue
is 29% of the application rate.  Because rainfall at the Pennsylvania
site was significantly above average during the study period, California
data were used to estimate the dissipation rate (14% per day).  A turf
transferable residue (TTR) study was not available.  Therefore, turf
scenario calculations were based on standard turf residue assumptions
(i.e., initial transferable fraction is 5% of the application rate, and
dissipation is 20% per day).

In addition to DFR and TTR, transfer coefficients (Tc) are used to
relate the residue values to activity patterns, which take place after
application, to estimate potential human exposure.  The transfer
coefficients used in this assessment are from an interim transfer
coefficient guidance document developed by HED’s Science Advisory
Council for Exposure using proprietary data from the Agricultural
Re-entry Task Force (ARTF) database (SOP# 3.1).

Postapplication MOEs were estimated for “Day 0" exposure (i.e., the
day of application).  In cases where the MOE was less than the LOC of
100 on Day 0, residue dissipation data/assumptions were used to
determine the day for which the MOE would reach 100 (i.e., not of
concern).  As shown in Table 5, the short-/intermediate-term MOEs are
greater than 100 on the day of application for all agricultural crops
except grapes, for which a restricted entry interval (REI) of one day
may be necessary to reach the LOC.  For turf and nursery stock
ornamentals (Table 6), MOEs reach 100 on the day of application and are
not of concern.  However, for cut flowers, an REI of 4 to 6 days may be
necessary to achieve an MOE of 100 when the maximum label application
rate is used.  Alternatively, when the minimum label rate is used, an
interval of only one day may be needed.  Note that ornamental-specific
DFR data were not available, and that the residues were based on data
from a lettuce DFR study which may have introduced extrapolation error.
The ornamental postapplication exposure estimates could be refined with
the use of ornamental-specific DFR data.

The fluopicolide technical material has been classified in Toxicity
Categories III-IV for acute dermal and primary skin irritation, and
Category III for primary eye irritation.  Per the Worker Protection
Standard (WPS), a 12-hr restricted entry interval (REI) is required for
chemicals classified under Toxicity Category III/IV.  The proposed
fluopicolide labels indicate an REI of 12 hrs, which is in compliance
with the WPS for uses that reach an MOE of 100 on the day of
application.

Fluopicolide is also intended for non-agricultural use sites (e.g., golf
course) to which the WPS does not apply; the labels appropriately
contain language cautioning unprotected persons to keep out of treated
areas until sprays have dried.

[Note:  Two of the products (V-10162 Premix and V-10162 VPP Fungicide)
contain a second active ingredient (propamocarb hydrochloride) which may
have a different REI requirement.  It is the responsibility of the
Registration Division to make certain that the label REIs for these
products is protective of both fluopicolide and propamocarb
hydrochloride exposure.]

Table 9.2.1.  Summary of Estimated Post-application MOEs for
Agricultural Crops

Crop	Application Rate

(lb ai/A) 1	DAT 2	DFR 3

(μg/cm2)	TC 4

(cm2/hr)	Activity 4	Short-/Int-

Term MOE 5

Fruiting Vegetables	0.13	0	0.42	500	Irrigation, scouting, thinning,
weeding immature plants	1,900

700	Irrigation and scouting mature plants	1,400

1,000	Hand harvesting, pruning, staking, tying	960

Cucurbit & Leafy Vegetables

0	0.42	500	Irrigation, scouting, thinning, weeding immature plants	1,900

1,500	Irrigation, scouting, weeding mature plants	640

2,500	Hand harvesting, pulling, pruning, and thinning mature plants	380

Grapes

0	0.42	500	Hedging, irrigation, scouting, hand weeding	1,900

1,000	Scouting	960

5,000	Hand harvest, leaf pulling, thinning, pruning, training/tying	190

10,000	Girdling and cane turning	96

1	0.36

	110

Potatoes & Sweet Potatoes

0	0.42	300	Irrigation, scouting, thinning, weeding immature plants	3,200

1,500	Irrigation and scouting mature plants	640

2,500	Hand harvesting	380

1 Maximum application rate from proposed labels: V-10161 4 SC (Reg No.
59639-RUN), V-10162 Premix (Reg. No. 59639-RUE)

2 DAT = Days after treatment needed to reach the LOC of 100; DAT 0 = The
day of treatment, after sprays have dried; assumed to be approximately
12 hours.

3: DFR (µg/cm2) = dislodgeable foliar residues corresponding to DAT,
based on results from a chemical-specific DFR study conducted on lettuce
(MRID 46708641).

4 TC (cm2/hr) = transfer coefficients and associated activities from
ExpoSAC Policy Memo #003.1 “Agricultural Transfer Coefficients”,
8/17/2000.

5 MOE = MOE on the corresponding DAT.  MOE = NOAEL / Daily Dose.

   Daily Dose = [(TTR or DFR x  TC x 37% Dermal absorption  x  8-hr
Exposure Time)] / [(CF: 1000 µg/mg) x (60-kg Body Weight)]

   Short-/intermediate-term NOAEL = 20 mg/kg/day.  The LOC is 100.

Table 9.2.2.  Summary of Estimated Post-application MOEs for Turf and
Ornamentals

Crop	Application Rate

(lb ai/A) 1	DAT 2	TTR or DFR 3

(μg/cm2)	TC 4

(cm2/hr)	Activity 4	Short-/Int-

Term MOE 5

Turf

Turf	0.27	0	0.15

3,400	Mowing and other maintenance activities	790

6,800	Sod harvesting and transplanting	390

Ornamentals – Nursery Stock

Nursery Stock	0.54	0	1.8	100	Hand pruning containerized ornamentals
2,300

400	Harvesting, ball/burlap containerized ornamentals	580

Ornamentals – Cut Flowers

Cut Flowers

(maximum rate)	0.54	0	1.8	500	Pinching	460

0	1.8	5,100	Hand harvesting, pruning, thinning, pinching	45

5	0.83

	96

6	0.71

	110

Cut Flowers

(minimum rate)	0.27	0	0.88	500	Pinching	920

0	0.88	5,100	Hand harvesting, pruning, thinning, pinching	91

1	0.75

	110

1 Maximum application rate from proposed labels: V-10161 VPP Fungicide
(Reg No. 59639-RUR), and V-10162 VPP Fungicide (Reg. No. 59639-RUG).
The foliar application rate was used for ornamentals.

2 DAT = Days after treatment needed to reach the LOC of 100; DAT 0 = The
day of treatment, after sprays have dried; assumed to be approximately
12 hours.

3 Turf transferable residues: TTR (µg/cm2) = Application rate (lb ai/A)
x CF (4.54E+8 µg/lb) x CF (2.47E-8 A/cm2) x Initial Fraction of ai
Retained on the Foliage (standard assumptions of 5% for turf)]

  Ornamental dislodgeable foliar residues corresponding to DAT, based on
results from a chemical-specific DFR study conducted on lettuce (MRID
46708641).

4 TC (cm2/hr) = transfer coefficients and associated activities from
ExpoSAC Policy Memo #003.1 “Agricultural Transfer Coefficients”,
8/17/2000.

5 MOE = MOE on the corresponding DAT.  MOE = NOAEL / Daily Dose.

   Daily Dose = [(TTR or DFR x  TC x 37% Dermal absorption  x  8-hr
Exposure Time)] / [(CF: 1000 µg/mg) x (60-kg Body Weight)]

   Short-/intermediate-term NOAEL = 20 mg/kg/day.  The LOC is 100.

10.0	Data Needs and Label Requirements  TC \l1 "10.0	Data Needs and
Label Requirements

10.1	Toxicology  TC \l2 "10.1	Toxicology

	None.

10.2	Residue Chemistry  TC \l2 "10.2	Residue Chemistry

Pending submission of revised Sections B and F (and provided that the
Human Health Risk Assessment for BAM is adequate), there are no Residue
Chemistry data gaps that would preclude conditional registrations and
permanent tolerances for residues of the fungicide fluopicolide as
follows.  The remaining deficiency (in Part A below) regarding storage
stability must be resolved as a condition of registration.  SEQ CHAPTER
\h \r 1

Tolerances to be established for residues of the fungicide fluopicolide
[2,6-dichloro-

N-[[3-chloro-5-(trifluoromethyl)-2-pyridinyl]methyl]benzamide] as an
indicator of combined residues of fluopicolide and its metabolite
2,6-dichlorobenzamide under “(a) General”:

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

Deficiencies (Part A)

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.

HED doe not recommend for the following tolerances at this time.
Provided the remaining deficiencies (in Part B below) are resolved, the
following tolerances could be established:

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 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 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

Deficiencies (Part B)

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 fluopicolide 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
aspirated grain fractions (AGF) is required.  HED could  base the
tolerance for AGF on the available wheat processing data, but would
require 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.

10.3	Occupational and Residential Exposure  TC \l2 "10.3	Occupational
and Residential Exposure

	None.

References:  TC \l1 "References:

Fluopicolide.  PP#5F7016.  Petition for Establishment of Tolerances for
Use on Tuberous and Corm Vegetables, Leafy Vegetables (except Brassica),
Fruiting Vegetables, Cucurbit Vegetables, Grapes and on the Rotational
Crop Wheat.  Summary of Analytical Chemistry and Residue Data,, DP
Number326080, Amelia Acierto,11/19/07.

Fluopicolide Chronic Aggregate Dietary (Food and Drinking Water)
Exposure and Risk Assessment for the Section 3 Registration Action on
Tuberous and Corm Vegetables, Leafy Vegetables (except Brassica),
Fruiting Vegetables, Cucurbit Vegetables, Grapes, and the Rotational
Crop Wheat, DP Number 340365, N. Dodd, 11/21/07.

Occupational and Residential Risk Assessment to Support Request for
Registration of Fluopicolide on a Variety of Crops, Residential Turf and
Ornamentals, DP #326082, K. O’Rourke, 10/9/07.

Drinking Water Exposure Assessment for Fluopicolide Uses on Grapes,
Vegetables, Potatoes and Turf, DP #325804, James Lin, 3/7/07.

Appendix A:  Toxicology Assessment tc  \l 1 "Appendix A:  Toxicology
Assessment"

A.1	Toxicology Data Requirements tc  \l 2 "A.1	Toxicology Data
Requirements"

The requirements (40 CFR 158.340) for food use for fluopicolide are in
Table 1. Use of the new guideline numbers does not imply that the new
(1998) guideline protocols were used.

Test

	Technical

	Required	Satisfied

870.1100    Acute Oral Toxicity

870.1200    Acute Dermal Toxicity

870.1300    Acute Inhalation Toxicity

870.2400    Primary Eye Irritation

870.2500    Primary Dermal Irritation

870.2600    Dermal Sensitization		yes

yes

yes

yes

yes

yes	yes

yes

yes

yes

yes

yes

870.3100    Oral Subchronic (rodent)

870.3150    Oral Subchronic (nonrodent)

870.3200    28-Day Dermal

870.3250    90-Day Dermal

870.3465    90-Day Inhalation		yes

yes

yes

no

no	yes

yes

yes

-

-

870.3700a  Developmental Toxicity (rodent)

870.3700b  Developmental Toxicity (nonrodent)

870.3800    Reproduction		yes

yes

yes	yes

yes

yes

870.4100a  Chronic Toxicity (rodent)

870.4100b  Chronic Toxicity (nonrodent)

870.4200a  Oncogenicity (rat)

870.4200b  Oncogenicity (mouse)

870.4300    Chronic/Oncogenicity		yes

yes

yes

yes

yes	yes1

yes

yes1

yes

yes

870.5100    Mutagenicity—Gene Mutation - bacterial

870.5300    Mutagenicity—Gene Mutation - mammalian

870.5375    Mutagenicity—Structural Chromosomal Aberrations

870.5395   Mutagenicity—Other Genotoxic Effects		yes

yes

yes

yes	yes

yes

yes

yes

870.6100a  Acute Delayed Neurotox. (hen)

870.6100b  90-Day Neurotoxicity (hen)

870.6200a  Acute Neurotox. Screening Battery (rat)

870.6200b  90-Day Neuro. Screening Battery (rat)

870.6300    Develop. Neuro		no

no

yes

yes

no	-

-

yes

yes

-

870.7485    General Metabolism

870.7600    Dermal Penetration		yes

yes	yes

yes

Special Studies for Ocular Effects

Acute Oral (rat)

Subchronic Oral (rat)

Six-month Oral (dog)

no

no

no

-

-

-

1 Endpoint is met with combined chronic toxicity/carcinogenicity study
in rats.A.2	Toxicity Profiles tc  \l 2 "A.2	Toxicity Profiles

Table A.2.1	Acute Toxicity Profile of Fluopicolide Technical, and
Selected Metabolites and Formulations

Guideline No.	Study Type	MRID(s)	Results	Toxicity Category

870.1100	Acute oral [rat] Fluopicolide

Technical 98.3% (AE C638206)

Formulation SC 40 (AE C638206)

Formulation SC61 (AE B066752)

46708601

46709903

46709803

LD50≥  2000  mg/kg (f)

LD50 ≥ 2000  mg/kg (m/f)

LD50 ≥ 2000  mg/kg (m/f)

III

III

III

870.1100	Acute oral [rat] Metabolites

2,6-dichlorobenzamide (BAM)

1,3-chloro-5 (trifluoromethyl)

pyridine-2-carboxylic acid (PCA)

42940201

46708602

46708603

LD50 ≥ 1538/1144  mg/kg (m/f)

LD50 ≥ 2000/300 mg/kg (m/f)

LD50≥2000 mg/kg (m/f)

III

II

III

870.1200	Acute dermal [rat]

Technical 97.7% (AE C638206)

Formulation SC40 (AE C638206)

Formulation SC61 (AE B066752)

46708605

46709904

46709804

LD50 ≥ 5000 mg/kg

LD50 ≥ 4000 mg/kg

LD50 ≥4000 mg/kg

IV

III

III

870.1300	Acute inhalation [rat]

Technical (AE C638206)

Formulation SC40 (AE C638206)

Formulation SC61 (AE B066752)

46708606

46709905

46709805

LC50 ≥ 5.16 mg/L

LC50 ≥ 1.789 mg/L

LC50 ≥ 3.195 mg/L

IV

III

IV

870.2400	Acute eye irritation [rabbit]

Technical 97.7% (AE C638206)

Formulation SC40 (AE C638206)

Formulation SC61 (AE B066752)

46708607

46709906 46709806

slight conjuctival irritation

chemosis/corneal opacity in both studies

IV

III

III

870.2500	Acute dermal irritation [rabbit]

Technical 97.7% (AE C638206)

Formulation SC40 (AE C638206)

Formulation SC61 (AE B066752)

46708650

46709907

46709807

None (PDII = 0.00)

slight (PDII = 0.08)

slight (PDII = 0.25)

IV

IV

IV

870.2600	Skin sensitization [guinea pig]

Technical 97.7% (AE C638206)

Formulation SC40 (AE C638206)

Formulation SC61 (AE B066752)

46708608

46709908

46709808

Negative (Magnusson-Kligman)

Negative (Buehler)

Negative (Modified Buehler)

non-sensitizer

Table A.2.2	Subchronic, Chronic and Other Toxicity Profile of
Fluopicolide

Guideline No. 	Study Type	MRID No. (year)/ Classification /Doses	Results

870.3050	28-day dietary toxicity (mouse)	46708609 (2000)

Acceptable/Guideline

M/F: 0/0, 0.95/1.19, 10.4/12.9, 100/129,  980/1242 mg/kg/day 	NOAEL =
980/1242 mg/kg/day; the limit dose).

The LOAEL was not observed.

870.3050	28-day dietary toxicity (rat)	46708610 (2000)

Acceptable/Guideline

M/F: 0/0, 1.8/1.8, 17.4/17.9, 174/184, and 1720/1820 mg/kg/day	NOAEL =
17.4/17.9 mg/kg/day in males/females).

The LOAEL = 174/184 mg/kg/day (M/F) based on decreased body weight gain
and food conversion in females and nephrotoxicity in males.

870.3050	28-day dietary toxicity (rat)

AE 1344122 (Fluopicolide metabolite)	46708611 (2003)

Acceptable/Guideline

M/F: 0/0, 1.5/1.7, 14.9/16.8, 151.6/167.1, 1495.3/1615.5 mg/kg/day	NOAEL
= 151.6/167.1 mg/kg/day.

LOAEL = 1495.3/1615.5 mg/kg/day based on decreased body weights and body
weight gains in both sexes, and nephrotoxicity in females.

870.3050	28-day dietary toxicity (rat)

AE C657378 (a Fluopicolide metabolite)	46708612 (2003)

Acceptable/Guideline

M/F: 0/0, 1.6/2.1, 16.2/20.4, 159.2/230.6, and 1775.0/1930.8 mg/kg/day
NOAEL  =  159.2/230.6 mg/kg/day.

LOAEL = 1775.0/1930.8 mg/kg/day based on decreases in body weight and
body weight gain (males); increased absolute (females) and relative
liver weight (both sexes) and relative kidney weight (males); increased
cholesterol (both sexes); and histopathological effects in the liver
(females), the kidneys (males), and thyroid (both sexes).

870.3050	28-day oral toxicity (dog)

	46708613 (2000)

Acceptable/Non-guideline

0, 10, 100, 1000 mg/kg/day	NOAEL = 1000 mg/kg/day (limit dose).

LOAEL was not observed.

870.3100

	90-Day oral toxicity (rat)	46474112 (2000)

Acceptable/guideline

M: 0, 7.4, 109, 1668 mg/kg/d

F: 0, 8.4, 119, 1673 mg/kg/day	NOAEL = 109 mg/kg/day for males; 8.4
mg/kg/day for females

LOAEL = 1668 mg/kg/day for males and 119 mg/kg/day for females based on
hypertrophy of the zona glomerulosa in the adrenal gland (M/F),
decreased cellularity of the bone marrow (M/F), and trabecular
hyperostosis of the bone joint (M)

870.3100

1092 mg/kg/day (M/F)

LOAEL = not identified

870.3100

	90-Day oral toxicity (mouse)	46474116 (2001)

Acceptable/guideline

M: 0, 10.4, 37.8, 161, 770 mg/kg/d

F: 0, 12.6, 52.8, 207, 965 mg/kg/day	NOAEL = 770 mg/kg/day for males;
207 mg/kg/day for females

LOAEL = not identified for males; 965 mg/kg/day for females based on
increased incidence of liver oval cell proliferation

870.3150

	90-Day oral toxicity (dog)	46474118 (2000)

Acceptable/guideline

M&F: 0, 5, 70, 1000 mg/kg/day	NOAEL = 1000 mg/kg/day (M/F)

LOAEL = not identified (M/F)

870.3200

	21/28-Day dermal toxicity (species)	46708614 (2003)

Acceptable Guideline

0, 100, 250, 500, 1000 mg/kg/day	NOAEL = 1000 mg/kg/day

LOAEL > 1000 mg/kg/day

No local or systemic toxicity observed

870.3700a

	Prenatal developmental in (rat)

Pilot study	46708615 (2000)

Acceptable/non-guideline

F: 500, 1000 mg/kg/day (GD 7-20)	NOAEL/LOAEL not determined.  Only four
animals/group. Purpose of study was to determine high-dose level for
46474120.

870.3700a

	Prenatal developmental in (rat)	46474120 (2001)

Acceptable/guideline

F: 0, 5, 60, 700 mg/kg/day (GD 7-20)	Maternal NOAEL = 60 mg/kg/day

LOAEL = 700 mg/kg/day based on decreased body weight gain

Developmental NOAEL = 60 mg/kg/day

LOAEL = 700 mg/kg/day based on delayed fetal growth and skeletal defects

870.3700b

	Prenatal developmental in (rabbit)

Pilot study	46708616 (2000)

Acceptable/non-guideline

F: 25, 50, 100, 250, 500, or 1000 mg/kg bw/day

(GD 6-28)	Maternal NOAEL = 25 mg/kg/day

LOAEL = 50 mg/kg/day based on reduced defecation and abortion in a
single dose

Developmental NOAEL = 1000 mg/kg/day

LOAEL = not observed

870.3700b

	Prenatal developmental in (rabbit)	46474122 (2001)

Acceptable/guideline

F: 0, 5, 20, 60 mg/kg/day (GD 6-28)	Maternal NOAEL = 20 mg/kg/day

LOAEL = 60 mg/kg/day based on death, abortion/premature delivery,
decreased food consumption and weight gain

Developmental NOAEL = 20 mg/kg/day

LOAEL = 60 mg/kg/day based on abortion/premature delivery, decreased
fetal body weight and crown-rump length

870.3800

	Reproduction and fertility effects

(rat)	46474124 (2003)

46474125 (additional data, 2004)

46474126 (range-finding, 2002)

Acceptable/guideline

M: 0, 7.4, 36.4, 144.6 mg/kg/d

F: 0, 8.1, 41.0, 159.7 mg/kg/day	Parental/Systemic NOAEL = 36.4/41.0
mg/kg/day (M/F)

LOAEL = 144.6/159.7 mg/kg/day (M/F) based on kidney toxicity in males
and females and decreased weight gain in females.

Reproductive NOAEL = 144.6/159.7 mg/kg/day (M/F)

LOAEL = not identified.

Offspring NOAEL = 36.4/41.0 mg/kg/day (M/F)

LOAEL = 144.6/159.7 mg/kg/day (M/F) based on decreased body weight and
weight gain.

870.4100b

	Chronic toxicity (dog)	44674128 (2002)

Acceptable/guideline

M&F: 0, 70, 300, 1000 mg/kg/day	NOAEL = 300 mg/kg/day (M); 1000
mg/kg/day (F)

LOAEL = 1000 mg/kg/day based on decreased body weight gain (M); not
identified (F)

870.4200b

	Carcinogenicity

(mouse)	46474130 (2003)

Acceptable/guideline

M: 0, 7.9, 64.5, 551.0 mg/kg/d

F: 0, 11.5, 91.9, 772.3 mg/kg/day	NOAEL = 64.5/91.9 mg/kg/day (M/F)

LOAEL = 551.0/772.3 mg/kg/day (M/F) based on decreased body weight and
weight gain and liver lesions.

no evidence of carcinogenicity

870.4300

	Chronic/ Carcinogenicity

(rat)	46474139 (2003)

Acceptable/guideline

M: 0, 2.1, 8.4, 31.5, 109.4 mg/kg/day

F: 0, 2.8, 10.8, 41.0, 142.2 mg/kg/day	NOAEL = 31.5/41.0 mg/kg/day (M/F)

LOAEL = 109.4/142.2 mg/kg/day based on decreased body weight gain (M/F)
and thyroid toxicity (M).

no evidence of carcinogenicity

870.5100 	Gene Mutation

 (Salmonella typhimurium)	46474146 (2001)

Unacceptable/guideline

1.6- 5000 µg/plate

46474202 (2001)

Acceptable/guideline

1.6- 5000 µg/plate

46474148 (2001)

Acceptable/guideline

1.6- 5000 µg/plate

46474144 (2001)

Acceptable/guideline

1.6- 5000 µg/plate

46474142 (2004)

Acceptable/guideline

AE638206 (batch mixture of  PP/241067/1 and PP/241024)

5 - 5000 µg/plate

	negative (non-mutagenic) Upgradeable if purity for test material is
given.

negative (non-mutagenic)

negative (non-mutagenic)

negative (non-mutagenic

positive (mutagenic)

870.5300 	Gene mutation

 (Chinese hamster lung cells)	46474204 (2000)

Acceptable/guideline

AE638206 (batch mixture of  PP/241067/1 and PP/241024)

1.2- 3820 µg/mL	negative (non-mutagenic)

870.5375 	Cytogenetics

46474208 (2001)

Acceptable/guideline

1.22 to 625 µg/mL

46474206 (2004)

Acceptable/guideline

AE638206 (batch mixture of PP/241067/1 and PP/241024)

3.2 to 100 µg/mL

negative for chromosome aberrations

positive for aberrations without S9 activation

870.5395

	Micronucleus

 (mouse)

46474214 (2003)

Acceptable/guideline

150, 300 or 600 mg/kg/day

46474210 (2005)

Acceptable/guideline

AE638206 (batch mixture of PP/241067/1 and PP/241024)

200, 600 or 2000 mg/kg/day

46474212 (2005)

Acceptable guideline AE C638206 (Batch No.  OP 2050046 at 2000 mg/kg/day

negative at doses up to 600 mg/kg

negative at doses up to 2000 mg/kg

negative at dose of 2000 mg/kg

870.5550	Unscheduled DNA Synthesis

(rat hepatocytes)	42169839 (1989)

Acceptable/guideline	negative at concentration up to 300 µg/mL in
cultured rat hepatocytes

(no OPPTS no./ FIFRA test guideline 84-2)	Other Genotoxicity

Unscheduled DNA synthesis (rat hepatocytes)	46474216 (2000)

Acceptable/guideline

AE638206 (batch mixture of PP/241067/1 and PP/241024)

 600 or 2000 mg/kg	negative at concentrations up to 2000 mg/kg in
hepatocytes from treated rats

870.6200a

	Acute neurotoxicity screening battery

(rat)	46474218 (2002)

46474219 (range-finding, 2002)

Acceptable/guideline

M/F: 0, 10, 100, 2000 mg/kg	NOAEL = 100 mg/kg (M/F)

LOAEL = 2000 mg/kg (M/F) based on transiently lowered body temperature.

870.6200b

	Subchronic neurotoxicity screening battery	46474221 (2002)

46474222 (positive control, 2002)

Acceptable/guideline

M: 0, 15.0, 106.6, 780.6 mg/kg/day

F: 0, 18.0, 125.2, 865.8 mg/kg/day	NOAEL = 106.6/18.0 mg/kg/day (M/F)

LOAEL = 780.6/125.2 mg/kg/day based on decreased body weight gain, food
consumption, and food efficiency.

870.6300

	Developmental neurotoxicity	None

	870.7485

	Metabolism and pharmacokinetics

(rat)	46474242 (2004)-main studies

46474241 (2001)

46474244 (2003)

46474226 (2003)

46474239 (2003)

	rapid absorption, metabolism and excretion; main metabolites were
oxidative N-dealkylation cleavage products. Primary route of excretion
is fecal and urinary with little accumulation in the tissues.

870.7485

	Metabolism and pharmacokinetics

(rat)	46708632 (2002)

Acceptable Non-guideline	Most of the metabolites observed were
derivatives of AE C638206 fitting well with the prior known metabolites,
implying cysteine or N-acetyl-cysteine introduction on the phenyl ring
from gluthione conjugation, hydroxylation, or other conjugations.

870.7485

	Metabolism and pharmacokinetics

(rat)

AE C657188 (PCA)	46708636 (2002)

Acceptable Guideline	AE C657188 (PCA) showed high (87%) absorption but
low (14 – 21%) metabolism.  Excretion is mainly through the urine,
with a minor portion in the feces.

870.7485

	Metabolism and pharmacokinetics

(rat)

AE C653711 (2,6-dichloro-benzamide	46708633 (2003)

46708634 (2003)

46708635 (2003)

Acceptable Guideline	Absorption: 50-79%.  Metabolized extensively to 18
identified compounds.  The majority of the radioactivity was associated
with a mercapturic acid conjugate of hydroxyl-chlorobenzamide
(15-5-26.2%), present in the urine  Excretion mainly through urine and
feces.

870.7600	Dermal penetration

(rat)	46708638 (2003)

Acceptable Guideline

1.43, 659 ug/cm2 skin	In vivo study

Dermal Penetration rate:  37%

870.7600	Dermal penetration

(comparative)	46708637 (2003)

Acceptable Non-guideline

1.9, 744 ug/cm2 skin

	In vitro study

Rat skin dermal penetration rate  is 7.8 times greater than human skin.

A.3	Executive Summaries tc  \l 2 "A.3	Executive Summaries"

A.3.1	Subchronic Toxicity

	870.3050	28-day oral – mouse

In this 28-day oral toxicity study (MRID 46708609), 5 CRL CD-1 (ICR) BR
mice/sex/dose were treated daily with AE C638206 (Fluopicolide; 99.0%
a.i.; Batch No. CDB234187-1) in the diet at nominal concentrations of 0,
6, 64, 640, or 6400 ppm (equivalent to 0/0, 0.95/1.19, 10.4/12.9,
100/129, and 980/1242 mg/kg/day in males/females) for 28 days.

No adverse treatment-related effects were observed on mortality,
clinical signs, body weight, body weight gains, food consumption, food
conversion, hematology, clinical chemistry, organ weight, or gross or
histological pathology.

Alanine aminotransferase was increased (p<=0.01) in the >=640 ppm males
(incr 81-148%), and alkaline phosphokinase was increased (not
statistically significant [NS]) by 131% in the 6400 ppm males.  These
increases were outside the normal range (not reported) of historical
control data.  Absolute and relative to body liver weights were
increased (p<=0.01) by 33-58% in the 6400 ppm group.  Relative liver
weight was increased (p<=0.01) by 19% in the 640 ppm females. An
increase in incidence and severity of minimal to moderate centrilobular
hepatocyte hypertrophy was noted in the 640 and 6400 ppm groups.

Alanine aminotransferase was not increased sufficiently to categorize as
an adverse response, and, due to variation, it was unclear if the
alkaline phosphatase values were actually increased at 6400 ppm.
Centrilobular hepatocyte hypertrophy with increased liver weight is
characteristic of an adaptive response.  In the absence of definitive
evidence of hepatoxicity, all these effects were not considered adverse
in this 28-day study.

The LOAEL was not observed.  The NOAEL is 6400 ppm (equivalent to
980/1242 mg/kg/day; the limit dose).

This study is classified acceptable/guideline and satisfies the
guideline requirements (OPPTS 870.3050) for a repeated dose 28-day oral
toxicity study in rodents.  Although an adverse effect was not observed,
the limit dose was tested.

	870.3050	28-day oral – rat

In this 28-day oral toxicity study (MRID 46708610), 5 Sprague Dawley
rats/sex/dose were treated daily with AE C638206 (Fluopicolide; 99.9%
a.i.; Batch No. CDB234167-2) in the diet at nominal concentrations of 0,
20, 200, 2000, or 20,000 ppm (equivalent to 0/0, 1.8/1.8, 17.4/17.9,
174/184, and 1720/1820 mg/kg/day) for 4 weeks.

No adverse treatment-related effects were observed on mortality,
clinical signs, functional observational battery, motor activity,
opthalmoscopic examination, or hematology.

At >=2000 ppm, dose-dependent decreases (not statistically significant
[NS]; decr 7-15%) in body weights were noted throughout treatment in
females.  Overall (Days 1-29) body weight gains were also decreased in
the females by 30-36%.  Food conversion was decreased by 19-68% for
2-3/4 weeks in females.  Water consumption was increased in the males by
18-27%.  Pale kidneys were observed bilaterally in the males (3/5 each
treated group vs 0/5 controls).  Histological evidence of nephrotoxicity
in males included an increased incidence and severity of minimal to
severe renal tubular eosinophilic proteinaceous material (5/5 each
treated group vs 0/5 controls) and increased severity of minimal to
severe phloxine tartrazine positive granulation (4-5/5 moderate to
severe in treated groups vs 1/5 in controls).  Cholesterol levels
increased (p<=0.01) by 29-70% in both sexes, and was considered
equivocal evidence of hepatotoxicity with the corroborating evidence of
increased hepatocellular hypertrophy at >=200 ppm and increased liver
weights at 20,000 ppm.

At 20,000 ppm, the following findings of systemic toxicity were noted:
(i) decreased body weight throughout treatment and decreased overall
(Days 1-29) body weight gain in the males; (ii) transiently decreased
food consumption in both sexes during Week 1; (iii) decreased food
conversion in the males at Weeks 1 and 4; and (iv) increased water
consumption in the females.  Increased absolute liver weight was noted
in males and increased relative to body liver weights were observed in
both sexes; enlarged liver was observed in males.  An increased
incidence of slight to moderate hydronephrosis was noted in the male
kidney.

The LOAEL was 2000 ppm (equivalent to 174/184 mg/kg/day in
males/females) based on decreased body weight gain and food conversion
in females and nephrotoxicity in males.  The NOAEL is 200 ppm
(equivalent to 17.4/17.9 mg/kg/day in males/females).

This study is classified acceptable/guideline and satisfies the
guideline requirements (OPPTS 870.3050) for a repeated dose 28-day oral
toxicity study in rodents.

	870.3050	28-day oral – rat

In this 28-day oral toxicity study (MRID 46708611), 10 Wistar
rats/sex/dose were treated daily with AE 1344122 (Fluopicolide
metabolite; 98.8% a.i.; Batch No. YG3228) in the diet at nominal
concentrations of 0, 20, 200, 2000, or 20,000 ppm (equivalent to 0/0,
1.5/1.7, 14.9/16.8, 151.6/167.1, and 1495.3/1615.5 mg/kg/day) for 4
weeks.

No adverse, treatment-related effects were observed on mortality,
clinical signs, food consumption, ophthalmoscopic findings, hematology,
clinical chemistry, organ weights, or gross pathological findings.

Throughout treatment at 20,000 ppm, decreased body weights were observed
in both sexes.  On Day 28, body weight was decreased (p<=0.05) by 7% in
the males.  Overall (Days 1-28) body weight gains were decreased by
17-18% in the 20,000 ppm group.

Nephrotoxicity was evident in the 20,000 ppm females.  Urinary volume
was increased (p<=0.01) by 100%, and an increased number of coarsely
granular casts was observed in the urine (18-150 casts per rat in 9/10
treated females vs 0 casts in 10/10 controls).  Minimal to moderate
tubular degeneration/regeneration and single cell necrosis were each
seen in 8 females at 20,000 ppm and were not observed in any other dose
group.

In the 20,000 ppm males, increased incidences of scabs,
chromodacryorrhea, a mat aspect in the cornea, and soiled fur were
considered equivocal findings.

The LOAEL was 20,000 ppm (equivalent to 1495.3/1615.5 mg/kg/day in
males/females) based on decreased body weights and body weight gains in
both sexes, and nephrotoxicity in females.  The NOAEL is 2000 ppm
(equivalent to 151.6/167.1 mg/kg/day in males/females).

This study is classified acceptable/guideline and satisfies the
guideline requirements (OPPTS 870.3050) for a repeated dose 28-day oral
toxicity study in rodents.

28-day oral – rat

In a 28-day oral toxicity study (MRID 46708612), AE C657378 (a
Fluopicolide metabolite, 98.3% a.i.; Batch # 1119-DC/3) was administered
in the diet to 10 Wistar rats/sex/dose at dose levels of 0, 20, 200,
2000, or 20,000 ppm (equivalent to 0/0, 1.6/2.1, 16.2/20.4, 159.2/230.6,
and 1775.0/1930.8 mg/kg/day [M/F], respectively) for 4 weeks.

No treatment-related effects on mortality, clinical signs, food
consumption, ophthalmic findings, FOB, or gross pathology findings were
observed at any dose.

At 20,000 ppm, the males exhibited decreases (p<=0.05) in body weight
during Weeks 3 and 4 (decr 8-10%) and body weight gain during Week 2
(decr 19%) and overall (Days 1-29, calculated by reviewers; decr 18%).
Hematological effects were limited to increased (p<=0.05) platelets in
both sexes (incr 14-18%).

The liver was affected at 20,000 ppm as indicated by increased (p<=0.05)
absolute (incr 25%, females) and relative (incr 14-23%, both sexes)
organ weight and cytoplasmic change in the periportal hepatocytes (9/10
treated vs. 0 controls, females) accompanied by a concurrent reduction
in periportally stored fat (0/10 treated vs. 4 controls, females).  In
addition, cholesterol was increased (p<=0.05) by 40-44% in both sexes.

Additionally in the 20,000 ppm males, increases were noted in relative
kidney weight (incr 15%) and in incidence and severity of basophilic
cortical tubules (9/10 treated vs. 5 controls).  Mean urine volume was
decreased (p<=0.01) by 30% as well.

Histopathological effects noted in the thyroid at 20,000 ppm included
granular or clumpy alteration of the follicular colloid in the males (9
treated vs. 2 controls) and females (10 treated vs. 0 controls) and
flattening of the epithelium of the peripherally located follicles in
the males (2 treated vs. 0 controls).

In the thymus, increased histiocytosis was noted in both sexes (4-5
treated vs. 1-2 controls) at 20,000 ppm; however, as the mean severity
score was similar among the groups, this finding was considered to be
equivocal.

The LOAEL is 20,000 ppm (equivalent to 1775.0/1930.8 mg/kg/day [M/F])
based on decreases in body weight and body weight gain (males);
increased absolute (females) and relative liver weight (both sexes) and
relative kidney weight (males); increased cholesterol (both sexes); and
histopathological effects in the liver (females), the kidneys (males),
and thyroid (both sexes).  The NOAEL is 2000 ppm (equivalent to
159.2/230.6 mg/kg/day [M/F]).

This study is classified as acceptable/guideline and satisfies the
guideline requirements (OPPTS 870.3050; OECD 407) for a 28-day repeated
dose oral toxicity study in the rat.

28-day oral – dog

In this non-guideline 28-day oral toxicity study (MRID 46708613), AE
C638206 (Fluopicolide; 96.9% a.i.; Batch Nos. PP241024/2 and PP241067/1)
in 1% (w/v) aqueous methyl cellulose was administered daily via gavage
in a dose volume of 5 mL/kg to 2 beagle dogs/sex/dose group at dose
levels of 0, 10, 100, or 1000 mg/kg/day for at least 28 days.

No unscheduled deaths occurred during the study.  There were no effects
of treatment on clinical signs, body weights, body weight gains, food
consumption, ophthalmoscopy, hematology, urinalysis, or histopathology.

In one male at 1000 mg/kg/day:  cholesterol was increased on Days 14
(5.56 mmol/L) and 29 (7.72 mmol/L) compared to the mean values for this
animal during pre-treatment (3.76 mmol/L) and the mean for the two
control dogs during treatment (3.33 mmol/L).  Additionally in this dog:
absolute liver weight was increased by 34% over the mean of the two
control dogs; relative (to body) liver weight was increased by 44% over
the control mean; and liver enlargement was noted in all lobes at
necropsy.  There were no treatment-related microscopic findings in the
liver.  Therefore, the minor increases in cholesterol, liver weights,
and liver enlargement in this male are not considered adverse.  The
increased liver weights and the liver enlargement noted in this animal
may be indicative of an adaptive response to the test material.

The LOAEL was not observed.  The NOAEL is 1000 mg/kg/day (limit dose).

This 28-day repeated dose oral toxicity study in dogs is classified
acceptable/non-guideline.

	870.3100	90-Day Oral Toxicity – Rat

In a 90-day oral toxicity study (MRID 46474112) Fluopicolide (Lot # AE
C638206 00 1C99 0005; 97.2% a.i.) was administered to groups of 10 male
and 10 female Sprague Dawley rats in a diet containing 0, 100, 1400 or
20,000 ppm (equivalent to 0, 7.4, 109 or 1668 mg/kg/day for males, and
8.4, 119 or 1673 mg/kg/day for females) for 13 weeks. Ten additional
rats/sex from the control and high dose group were maintained on control
diet for a further four weeks to determine the reversibility of any
effects seen.

Two nontreatment-related mortalities were noted in the high dose group.
Body weight gain over the course of the 20,000 ppm treatment was reduced
by 41% in males and 29% in females, while the corresponding mean food
consumption was reduced by 22% and 19%  (p<0.01). Body weight gain was
dramatically affected the first week of the study as evidenced by
essentially no weight gain at the highest dose as compared to controls
that gained an average of 58 g for males and 39 g for females. Reduced
food consumption was also most dramatic during this week at about 50%
for both sexes. Water consumption was 43% higher for females relative to
the controls (p<0.01) during this same time frame and was somewhat
higher for the remainder of the study. An increase in urinary volume and
a slight decrease in specific gravity was observed in females only which
corresponds to the increased water intake. No toxicologically relevant
hematological or clinical chemistry findings were noted.   Microscopic
examination showed a minimal to slight hypertrophy of the zona
glomerulosa in the adrenal of 17/20 of the rats at the highest dose
level compared to one of each sex in the controls, and minimal changes
were seen in 3/10 females at the 1400 ppm level. Minimum to slight
trabecular hyperostosis of the bone joint was observed in 7/10 males and
all females at the 20,000 ppm level compared to 0/10 males and 3/10
females in the control group. Decreased cellularity of the bone marrow
was observed for 7/10 males and 9/10 females at 20,000 ppm, and in 8/10
females at 1400 ppm compared to 0/10 males and 1/10 females in the
control group. No treatment-related effects were observed at the 100 ppm
dose level.

Following the four week off-dose period there was a complete or partial
recovery of all treatment-related effects.

The LOAEL is 20,000 ppm in the diet (1668  mg/kg/day) for males based on
hypertrophy of the zona glomerulosa in the adrenal, trabecular
hyperostosis of the bone joint, and decreased cellularity of the bone
marrow. The LOAEL for females is 1400 ppm in the diet (119  mg/kg/day)
based on hypertrophy of the zona glomerulosa in the adrenal and
decreased cellularity of the bone marrow.  The NOAEL is 1400 ppm (109
mg/kg/day) for males and 100 ppm (7.9  mg/kg/day) for females.

This 90-day oral toxicity study in the rat is Acceptable/Guideline and
satisfies the guideline requirement for a 90-day oral toxicity study
(OPPTS 870.3100; OECD 408) in the rat.

	870.3100	90-Day Oral Toxicity – Mouse

96.9% a.i., batch/lot #AE C638206 00 1C99 0005) was administered to10
Crl: CD-1 (ICR) BR mice/sex/dose in diet at concentrations of 0, 32,
320, 3200, or 6400 ppm (equivalent to 0, 5.5, 53, 545, or 1092 mg/kg
bw/day).

There were no compound related effects on mortality, clinical signs of
toxicity or measured hematological parameters.  The overall body weight
gain was reduced by 22%-32% in females at 3200 ppm and 20% in males at
6400 ppm.  At 3200 ppm, there were statistically significant increases
in alanine aminotransferase activity in males and females (79%-98% and
116%-147%, respectively), and in aspartate aminotransferase (39%-69%)
activity in males.  A statistically significant increase was also noted
at 6400 ppm in alkaline phosphatase activity (106%) in males.

At 3200 ppm, both absolute and relative liver weights increased (33%-60%
and 36%-78%, respectively) in both sexes.  The microscopic examination
revealed hepatocellular hypertrophy in all males of the top two dose
groups, all females in the 6400 ppm dose group, and 9/10 females in the
3200 ppm dose group.  These findings were accompanied by the presence of
slight focal hepatocytic necrosis in 2/10 females at 3200 ppm and 3/10
males and 3/10 females at 6400 ppm.  Minimal to slight centrilobular
hepatocytic hypertrophy in the liver was also seen in 9/10 males and
minimal hypertrophy in 1/10 females at 320 ppm.  A LOAEL was not
identified in this study.  The NOAEL is the highest dose tested, 6400
ppm (1092 mg/kg/day).

This 90-day oral toxicity study in the mouse is Acceptable/Guideline,
and satisfies the guideline requirement for a 90-day oral toxicity study
(OPPTS 870.3100; OECD 408) in mice.

In a 90-day oral toxicity study (MRID 46474116, summarized in MRID
46474115), AE C638206 (Fluopicolide, 95.9% a.i., Batch # OP2050046) was
administered to 10 C57BL/6JICO mice/sex/dose in the diet at
concentrations of 0, 50, 200, 800, or 3200 ppm (approximately 10.4,
37.8, 161, or 770 mg/kg/day for males and 12.6, 52.8, 207, or 965
mg/kg/day for females, respectively).  Doses were selected based on
previous results from a 90-day mouse dietary study with AE C638206 using
Crl:CD1 (1 CR) Br mice (MRIDs 46474114 and 46474113).

There were nine deaths that appeared unrelated to treatment (no
dose-response relationship).   There were no adverse effects on clinical
signs or neurological parameters noted for the surviving animals.
Although body weight of males and females in the 3200 ppm group was
lower by 7-10% early in the study, final mean body weights were
comparable with the controls (both 97% of controls).  The overall weight
gain was slightly reduced in males in the 800 and 3200 ppm groups and in
females in the 3200 ppm group (86-93% of control gain).  There were some
clinical chemistry variations such as slight decreases in the
concentration of albumin and total cholesterol in animals treated with
800 ppm of AE C638206 and slightly increased alkaline phosphatase enzyme
activity in males in the 3200 ppm group.

There was a slight dose-related increase in absolute (110 - 125% of
control) and relative (114 - 130% of control) liver weight in animals
treated with 800 ppm of AE C638206.  These weight changes were
associated with a diffused centrilobular hepatocellular liver
hypertrophy.  Microscopic examination revealed this lesion in 4/8 and
8/8 surviving male mice (control: 0/8) and in 8/9 and 10/10 surviving
female mice (control: 0/8) at 800 and 3200 ppm of AE C638206,
respectively. In addition, there was a dose-related increase in liver
oval cell proliferation in females: 2/9, 2/9, 3/10, 4/9, and 8/10 in the
control through the high dose groups, respectively.  The toxicological
significance of dark coloration of the liver in 4/8 males and 9/10
females treated with 3200 ppm was not determined.

Under the conditions of this study, the LOAEL for AE C638206 in male
mice is not established; the LOAEL for female is 3200 ppm based on liver
oval cell proliferation.  The NOAEL for AE C638206 in male mice is 3200
ppm and for female mice is 800 ppm.

This 90-day oral toxicity study in the mouse is Acceptable/Guideline,
and satisfies the guideline requirement for a 90-day oral toxicity study
(OPPTS 870.3100; OECD 408).

	870.3150	90-Day Oral Toxicity – Dog

In a subchronic oral toxicity study (MRID 46474118) AE C638206 (97.7%,
Lot Nos. PP/241024/2 and PP/241067/1) was administered to 4 beagle
dogs/sex/dose by oral gavage at concentrations of 0, 5, 70 and 1000
mg/kg/day for 13 weeks.

There were no significant compound-related effects on mortality,
clinical signs, food consumption, food efficiency, body weight/body
weight gain, opthalmoscopic examinations, urinalysis, hematology,
clinical chemistry, organ weight, gross pathology or histopathology.
Increased liver weight in males and females receiving 1000 mg/kg/day AE
C 638206 was considered an exposure-related effect, however, there were
no correlative changes in clinical pathology or histopathology.  A
marginal effect on body weight gain was also seen in males and females
dosed with 70 and 1000 mg/kg/day.

A LOAEL was not determined for AE C638206 in male and female dogs in
this study.  The NOAEL was 1000 mg/kg/day, the highest dose
administered.

This 90-day oral toxicity study in the dog is Acceptable/Guideline and
satisfies the requirement for a 90-day oral toxicity study (OPPTS
870.3150; OECD 409) in a non-rodent.

	870.3200	21/28-Day Dermal Toxicity – Rat

In a 28-day dermal toxicity study (MRID 46708614) AE C638206
(fluopicolide; 97.7% a.i., Batch # 2050190/PP241024/2) was applied to
the shaved skin of 10 Wistar rats/sex/dose at dose levels of 0, 100,
250, 500,  or 1000 mg/kg/day (limit dose), 6 hours/day for 5days/week
during a 28-day period.

No compound-related effects were observed in mortality, clinical signs
of toxicity, body weight, body weight gain, food consumption,
ophthalmoscopic exams, hematology, clinical chemistry, absolute or
relative organ weights, or gross or microscopic pathology in either sex.

The LOAEL was not observed.  The NOAEL for local and systemic toxicity
is 1000 mg/kg/day.

This study is classified as acceptable guideline and satisfies the
guideline requirement for a 28-day dermal toxicity study (OPPTS
870.3200; OECD 410) in rats.

	870.3465	90-Day Inhalation – Rat

No studies available.

A.3.2	Prenatal Developmental Toxicity

	870.3700a Prenatal Developmental Toxicity Study – Rat

In a developmental toxicity study (MRID 46474120), AE C638206  (97.6 and
97.8% a.i., lot/batch # PP/241024/2 & PP241067/1) was administered to 23
female Sprague-Dawley rats/dose by gavage at dose levels of 0, 5, 60, or
700 mg/kg bw/day from days 7 through 20 of gestation.  On gestation day
(GD) 21, dams were sacrificed and subjected to gross necropsy.
Approximately one-half of the fetuses were fixed in alcohol, examined
for external defects, checked for visceral anomalies, and then fixed and
examined for skeleton and cartilage defects.  The remaining one-half of
the fetuses were examined for external defects and then examined for
visceral abnormalities by Wilson’s slicing technique.  The total
number of fetuses examined (number of litters) was 284(22), 291(21),
297(22), and 274(21) for the 0, 5, 60, and 700 mg/kg bw/day groups,
respectively.

Treatment with 700 mg/kg bw/day was only minimally toxic to the pregnant
dams.  Mean absolute body weight values were statistically decreased
(p<0.05) at several time points as compared to controls, but were not
biologically relevant at only 97-98% of control levels.  No
statistically significant differences were noted in body weight gain at
any intervals.  However, body weight gain over GD 7-21, both corrected
and not corrected for the gravid uterine weight, was bordering on
biological significance at 92% and 88%, respectively, of controls.  No
significant differences were noted in clinical signs and feed
consumption, or during gross necropsy.

Therefore, the maternal toxicity LOAEL for AE C638206 in rats is 700
mg/kg bw/day based on slightly reduced body weight gain, and the
maternal toxicity NOAEL is 60 mg/kg bw/day.

No adverse, treatment-related, statistically significant effects on
pregnancy rates, number of corpora lutea, pre- or post implantation
losses, resorptions/dam, fetuses/litter, or fetal sex ratio were
observed in the treated groups compared with the controls.  No dams had
complete litter resorption.  No treatment-related malformations or
external or visceral variations were observed in any group.

Decreased fetal growth was noted in the high-dose group as evidenced by
significant decreases in mean fetal weight (3.4 g vs. 3.7 g for
controls), crown/rump length (34.8 mm vs. 36.2 mm for controls), mean
placental weight (0.52 g vs. 0.57 for controls), and delays in
ossification of sacral vertebra (arch/centra), sternebra, and 5th
metacarpal or 5th metatarsal of the forepaw or hindpaw, respectively.
The high-dose group also had slightly elevated litter incidences of
skeletal defects of the thoracic vertebra (arch: aplasia, dysplasia,
fused, fused with attached rib; 4 fetuses from 3/21 litters affected),
thoracic vertebra (centra: aplasia, dysplasia, fragmented, fused,
dislocated; 10 fetuses from 6/21 litters affected), and ribs (aplasia,
dysplasia, shortened, fused, anlage of only 9; 6 fetuses from 3/21
litters affected) compared to the control incidence of 0/22 litters
affected.

Therefore, the developmental toxicity LOAEL for AE C638206 in rats is
700 mg/kg bw/day based on delays in fetal growth (decreased fetal
weight, crown/rump length, delays in ossification) and skeletal defects
of the thoracic vertebra, and ribs and the developmental  toxicity NOAEL
is 60 mg/kg bw/day.

The developmental toxicity study in the rat is classified
Acceptable/Guideline and satisfies the guideline requirement for a
developmental toxicity study (OPPTS 870.3700; OECD 414) in the rat.

	870.3700a Prenatal Developmental Toxicity Study – Rat

In a developmental toxicity study (MRID 46708615), AE C638206
(Fluopicolide; 97.6% w/w, Batch #s PP/241024/2 and PP/241067/1) in 1%
(w/v) aqueous methyl cellulose was administered via gavage to 4 Hsd:
Sprague Dawley rats/dose group at dose levels of 500 or 1000 mg/kg
bw/day at a dose volume of 5 mL/kg from gestation days (GD) 7-20.  On GD
21, females were euthanized to perform a cesarean section, and their
uterine contents were examined.

All animals survived until scheduled termination.  At 1000 mg/kg/day,
pultaceous feces was observed in 2/4 rats from GD 10 through GD 12 and
in 1/4 rats on GD 13.  There were no clinical signs of toxicity in the
500 mg/kg/day group.

Body weight gains were lower than normal throughout the treatment period
at 1000 mg/kg/day.  However, the lack of concurrent or historical
control data made interpretation of the data problematic.  Weight gain
was comparable prior to treatment (19.6-22.0 g) for GD 1-7.  At 500 and
1000 mg/kg/day, respectively, body weight gains were:  7.0 and 3.0 g for
GD 7-10; 17.0 and 15.4 g for GD 10-14; 23.5 and 19.3 g for GD 14-17;
31.8 and 12.0 for GD 17-19; and 25.5 and 19.7 g for GD 19-21.  Thus,
body weight gains at 1000 mg/kg/day were consistently lower than at 500
mg/kg/day throughout the study.  Body weight gains for the overall
treatment period (GD 7-21) were 104.8 g at 500 mg/kg/day and 69.4 g at
1000 mg/kg/day.

Again, the lack of concurrent or historical control data made
interpretation of the food consumption data difficult.  It was stated
that food consumption showed a marked initial decrease in the 1000
mg/kg/day group during GD 7-10 and a slight decrease in the 500
mg/kg/day during this interval.  During pre-treatment, food consumption
in both groups averaged from 13.3-15.0 g/animal/day during GD 1-4 and
from 18.2-19.7 g/animal/day during GD 4-7.   In contrast to the
Sponsor’s assertion, food consumption at the beginning of treatment
during GD 7-10 (16.5-17.07 g/animal/day) was comparable to these
pre-treatment values (13.3-19.7 g/animal/day) in both dose groups.
However, food consumption during GD 17-19 (19.8 g/animal/day) and 19-21
(20.2 g/animal/day) at 1000 mg/kg/day was lower than the 500 mg/kg/day
group during GD 17-19 (25.2 g/animal/day) and 19-21 (22.9g/animal/day).
Food consumption was comparable between the two groups and consistent
across time during the remaining treatment intervals.

There were no abortions, premature deliveries, or dead fetuses in either
group.  One animal in the 1000 mg/kg/day group had only a single
implantation site which was empty.  This total litter loss was excluded
from all calculations.  At 1000 mg/kg/day, the number of early
resorptions (17 total; 5.7/dam) resulted in a post-implantation loss of
31.7%, leaving a total of 28 fetuses (9.3/litter).  At 500 mg/kg/day,
the post-implantation loss was 0% because there were no early
resorptions, late resorptions, or fetal deaths, resulting in a total of
52 fetuses (13.0/litter).  The lower number of live fetuses at 1000
mg/kg/day was reflected in the lower litter weight at this dose (26.9 g)
compared to the 500 mg/kg/day group (40.6 g).  Fetal and placental
weights and crown/rump length were only minimally lower at 1000
mg/kg/day compared to the 500 mg/kg/day group.  Because the skeleton was
not examined, any possible delays in ossification could not be assessed.
 There were no remarkable external findings in the fetuses.

In summary, the available data indicate that:  body weights, food
consumption, and fetal growth were lower at 1000 mg/kg/day than at 500
mg/kg/day; post-implantation loss was higher at 1000 mg/kg/day than at
500 mg/kg/day; and incidences of pultaceous feces were noted at 1000
mg/kg/day.  Thus, the reviewers conclude that the high dose in the
definitive developmental toxicity study in the rat should be between 500
and 1000 mg/kg/day.  However, the reviewers considered it inappropriate
to determine a NOAEL and LOAEL based on the lack of a control group and
the fact that only two dose groups were employed.

This range-finding study is classified as acceptable/non-guideline.

	870.3700b Prenatal Developmental Toxicity Study – Rabbit

In a developmental toxicity study (MRID 46474122) AE C638206
[Fluopicolide; 97.8% a.i.; batch numbers PP/241024/2 and PP241067/1
(mixed sample)] was administered to 23 mated female Chbb:HM(SPF)
Kleinrusse (Himalayan) rabbits/dose by gavage in 1% (w/v)
methylcellulose in deionized water at dose levels of 0, 5, 20, or 60
mg/kg bw/day on gestation days (GDs) 6 through 28, inclusive.  On GD 29,
the surviving dams were sacrificed and necropsied.  Gravid uterine
weight, corpora lutea counts, and the numbers and positions of live and
dead fetuses, early resorptions and late resorptions, empty implantation
sites and “conceptuses” were recorded.  Fetuses were weighed,
measured crown-to-rump, subjected to external, visceral, and skeletal
examinations, including cross-sectioning of the eyes, brain, heart, and
kidneys.  The number of fetuses (litters) examined in the control, low-,
mid-, and high-dose groups was 157 (22), 132 (20), 147 (21), and 32 (5),
respectively.

Treatment-related clinical signs included deaths of 3 high-dose animals
(on GDs 24, 25, and 29) following hypoactivity, decreased defecation
and/or decreased hay consumption over the preceding 1-5 days; one
decedent also had a bristling haircoat and red discoloration of the
urine on the day prior to death.  Fifteen high-dose animals aborted or
delivered prematurely (during GD 22-28); five of these also showed
hypoactivity, decreased defecation, decreased hay consumption, abnormal
(“pultaceous”) feces, and/or red discoloration of the urine.  One
surviving high-dose animal had increased salivation on GD 14.  At the
highest dose level, there were treatment-related decreases in body
weight gain during GD 10-23 (approximately 54-70% of the control levels)
and mean weight loss by this group during GD 23-29 (-41.4 g. vs. +123.6
g. for controls).  Mean daily food consumption of the high dose-animals
(in g/100 g bw) was decreased to 73-89% of controls during GD 8-23
(n.s) and to 46-57% of controls during GD 23-29 (p<0.05).  Red
discoloration of the urine was noted from two additional high-dose
animals at necropsy for a total of five affected (3 in life and 2 post
mortem); this finding is considered treatment-related and possibly
adverse.

The maternal LOAEL for Fluopicolide in Himalayan rabbits is 60 mg/kg
bw/day, based on death, abortions/premature deliveries, decreased food
consumption, and decreased body weight gain.  The maternal NOAEL is 20
mg/kg bw/day.

At the highest dose level, there were significant decreases in mean
fetal crown-rump length (94% of controls; p<0.05) and mean fetal weight
(86%; p<0.05).  There were no treatment-related effects on live litter
size, numbers of dead fetuses or resorptions, or postimplantation loss.
Fetal sex ratio and placental weight were not affected by treatment.
There were no treatment-related increases in the fetal or litter
incidences of major or minor defects, variations, or retardations, and
no evidence of altered ossification was seen.

The developmental LOAEL for Fluopicolide in Himalayan rabbits is 60
mg/kg bw/day, based on abortions, premature deliveries, and decreased
fetal body weight and crown-rump length.  The developmental NOAEL is 20
mg/kg bw/day.

This developmental toxicity study in the rabbit is classified
Acceptable/Guideline and satisfies the guideline requirement for a
developmental toxicity study (OPPTS 870.3700b; OECD 414) in the rabbit.
Excessive maternal toxicity was seen at the highest dose level; however,
the dose levels were appropriately spaced, and the small number of
litters did not preclude the evaluation of the potential developmental
toxicity of fluopicolide.

	870.3700b Prenatal Developmental Toxicity Study – Rabbit

In a range-finding developmental toxicity study (MRID 46708616), AE
C638206 (Fluopicolide; 97.6-97.8% w/w, Batch #s PP/241024/2 and
PP/241067/1) in 1% (w/v) aqueous methyl cellulose was administered daily
via oral gavage to 4 Himalayan rabbits/dose group at dose levels of 25,
50, 100, 250, 500, or 1000 mg/kg bw/day at a dose volume of 5 mL/kg from
gestation days (GD) 6-28.  On GD 29, females were euthanized to perform
a cesarean section, and their uterine contents were examined.

At 100 mg/kg/day, one female was killed following abortion on GD 22.
All remaining animals in the 100 mg/kg/day groups and above were found
dead or killed moribund between GD 13 and 23.  Prior to death, these
animals exhibited general clinical signs of toxicity, including:
uncoordinated gait/movements, prone position, hypoactivity,
hyperactivity, discolored urine, stupor, coat bristling, ataxia,
respiratory sounds, and decreased defecation and hay consumption.

At 50 mg/kg/day, one animal had decreased defecation on GD 28 and
discoloration in the cage tray on GD 29.  This animal aborted on GD 29.
There were no other mortalities, abortions, moribund animals or clinical
signs of toxicity in the 25 and 50 mg/kg/day groups.

It was stated that body weight gains and food consumption were decreased
during the treatment period at 100 mg/kg/day and above.  However, the
lack of concurrent or historical control data made interpretation of the
data problematic.  During pre-treatment, food consumption in all groups
ranged from 42.8-107.1 g/animal/day during GD 0-3 and from 62.7-104.3
g/animal/day during GD 3-6, and all groups gained weight (30.7-81.8 g)
from GD 0-6.  For the first week of treatment (GD 6-13), body weight
gains were -11.7, 30.8, -96.5, -50.0, -124.5, and -198.8 g in the 25,
50, 100, 250, 500, and 1000 mg/kg/day groups, respectively.  After this
point, body weight gains in the 100 mg/kg/day groups and above were not
presented due to mortality.  Body weight gains for the overall (GD 6-29)
treatment period were 173.3 g at 25 mg/kg/day and 12.5 g at 50
mg/kg/day.  Food consumption for GD 6-8 and GD 8-10 was lower at 500 and
1000 mg/kg/day (17.3-34.4 g/animal/day) compared to the remaining groups
(72.6-103.6 g/animal/day).  For GD 10-13, food consumption was lower at
100 mg/kg/day and above (2.2-37.2 g/animal/day) compared to the lower
dose groups (87.8-90.4 g/animal/day).  A dose-dependent decrease in
total food consumption was evident in all dose groups, with 2540.0,
2106.0, 1015.3, 941.0, 577.8, and 589.5 g/animal/day consumed in the 25,
50, 100, 250, 500, and 1000 mg/kg/day groups, respectively.  The
apparent effect on total food consumption at 100 mg/kg/day and above is
confounded by the mortalities in these groups.

The maternal LOAEL is 50 mg/kg/day based on reduced defecation and
abortion in a single doe.  The maternal NOAEL is 25 mg/kg/day.

The 50 mg/kg/day doe which aborted had 6 dead fetuses.  There were no
other findings which could be attributed to treatment.  The numbers of
litters, live fetuses, dead fetuses, and resorptions, and
post-implantation loss were similar between the two groups.  The litter,
placental, and fetal weights were comparable between the two groups.
There were no remarkable external findings in the fetuses.

The developmental LOAEL was not observed.  The developmental NOAEL is
1000 mg/kg/day (limit dose).

Based on the 100% mortality in the animals at 100 mg/kg/day and above
and the minimal findings at 50 mg/kg/day, the reviewers conclude that
the high dose in the definitive developmental toxicity study in the
rabbit should be 50 mg/kg/day.

This range-finding study is classified as acceptable/non-guideline.

A.3.3	Reproductive Toxicity

	870.3800 Reproduction and Fertility Effects – Rat

In a two-generation reproduction study (MRID 46474124 and 46474125), AE
C638206 (95.9% a.i., batch/lot # OP2050046) was administered to 28 F0
generation and 24 F1 generation male and female Crl:CD®(SD)IGS BR rats
at concentrations of 0, 100, 500, or 2000 ppm.  The dietary levels
corresponded to doses of 0, 7.4, 36.4, and 144.6 mg/kg bw/day,
respectively, for F0 males; 0, 8.8, 43.7, and 179.9 mg/kg bw/day for F1
males; 0, 8.1, 41.0, and 159.7 mg/kg bw/day for F0 females; and 0, 9.4,
46.9, and 193.9 mg/kg bw/day for F1 females.  The premating period was
10 weeks.  The males received the treated or control diets continuously
until sacrificed when almost all their litters were weaned, and the
females received the diets during premating, mating, gestation, and
lactation until sacrifice after weaning their litters.

No treatment-related effects were observed on survival or clinical signs
in any group of parental male or female rats in either generation.
Absolute body weight and weight gain were significantly decreased but
were within 10% of that of controls in F0 and F1 males during
premating/postmating periods and in female rats during premating except
as noted below.  High-dose F0 females gained up to 14% (p<0.01) less
weight than controls and high-dose F1 males weighed 11% (p<0.01) less
than controls on day 4 of premating because of the significantly
decreased male pup weight at weaning.  Food consumption was
significantly decreased during a few weekly intervals in high-dose F0
and F1 males and females, but was within 10% of that of controls.  Food
efficiency was not significantly affected by treatment of male or female
rats in either generation.  No treatment-related effect was observed on
body weight, weight gain, food

consumption, or food efficiency in low- or mid-dose male or female rats
of either generation.

In high-dose pregnant females, body weight was significantly decreased
by 7% on GD 6 and 13 in the F0 generation and by 10-11% throughout
gestation in the F1 generation compared with that of controls.  Both
generations gained 14-16% (p<0.01) less weight than controls during the
first 13 days of gestation, but weight gain was similar to or greater
than that of controls after GD 13.  A 13% decrease in body weight gain
in mid-dose F0 females during GD 0-6 was not accompanied by a decrease
in body weight.  High-dose  F0 and F1 lactating females had body weight
up to 8% and 13% (p<0.01) less, respectively, than controls, but weight
gain was not significantly affected.  High-dose F0 and F1 females
consumed up to 12% (p<0.01) less food than controls during the first 13
days of lactation.

Postmortem evaluation showed treatment-related and toxicologically
significant effects only in the kidneys.  High-dose F0 and F1 males had
small, statistically significant increases in absolute and relative
kidney weights and high-dose F0 and F1 females had significant increases
in relative kidney weight.  No treatment-related gross lesions were
observed in male or female rats in either generation.  Treatment-related
and toxicologically significant histopathologic lesions were observed in
the kidneys of high-dose F0 and F1 male and female rats.  The incidences
of  cortical tubular basophilia, medullary granular casts, and cortical
scarring were significantly increased in high-dose F0 and F1 males
compared with the control incidences.  The incidence of interstitial
inflammation was significantly increased in high-dose F0 males.  The
increased incidences of cortical tubular dilatation and cortical
granular casts in high-dose F1 males did not reach statistical
significance but were considered treatment related.  In high-dose F0 and
F1 female rats, the incidences of cortical tubular basophilia and
cortical tubular dilatation were significantly increased and the
increased incidence of  corticomedullary mineralization was not
statistically significant but was considered treatment related.

The lowest-observed-adverse-effect level (LOAEL) for systemic toxicity
of AE C638206 in rats is 2000 ppm (144.6-179.9 mg/kg bw/day in males and
159.7-193.3 mg/kg bw/day in females) based on decreases in weight gain
in F0 females and kidney toxicity in F0 and F1 males and females.  The
no-observed-adverse-effect level (NOAEL) is 500 ppm (36.4-43.7 mg/kg
bw/day in males and 41.0-46.9 mg/kg bw/day in females).

Evaluation of reproductive parameters showed no treatment-related
effects on estrous cycle periodicity or length, sperm measures (motility
or sperm count), precoital interval, gestation length, or reproductive
indices (mating, conception, fertility, and gestation) in either