UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

     OFFICE OF

PREVENTION, PESTICIDES

AND TOXIC SUBSTANCES

Date: 11/21/07

MEMORANDUM

SUBJECT:	Fluopicolide:  Human Health Risk Assessment for Proposed Uses
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.
PC Code: 027412, Petition No: 5F7016, DP Number: 325091.

		Regulatory Action:  Section 3 Registration Action

Risk Assessment Type: Single Chemical/Aggregate

FROM:	Nancy Dodd, Risk Assessor

		Registration Action Branch 3

		Health Effects Division (7509P)

			AND

		Amelia Acierto, Chemist

		Kelly O’Rourke, Biologist

		Myron Ottley, Toxicologist

		Registration Action Branch 3

		Health Effects Division (7509P)

THROUGH:	Paula Deschamp, Branch Chief

Registration Action Branch 3

Health Effects Division (7509P)

			AND

Christine Olinger, Chemist

Mary Elissa Reaves, Ph.D., Toxicologist

Risk Assessment Review Committee

Health Effects Division (7509P)

TO:		Janet Whitehurst/Tony Kish, RM Team #22

		Fungicide Branch

		Registration Division (7505P)

Valent U.S.A. Corporation has submitted a petition for tolerances for
the fungicide fluopicolide in/on tuberous and corm vegetables, leafy
vegetables (except Brassica), fruiting vegetables, cucurbit vegetables,
grapes, and the rotational crop wheat.  Uses on turf (residential,
commercial, golf course, and sod farms) and ornamental plants
(landscapes, commercial greenhouses, and nurseries) are also proposed.
The Registration Division of the Office of Pesticide Programs (OPP) has
requested that HED evaluate hazard and exposure data and conduct
dietary, occupational, residential, and aggregate exposure assessments,
as needed, to estimate the risk to human health that will result from
the requested uses of fluopicolide.

Tolerances have been established (40 CFR §180.627) for residues of
fluopicolide,
2,6-dichloro-N-[[3-chloro-5-(trifluoromethyl)-2-pyridinyl]methyl]benzami
de, on grape at 2.0 ppm and grape, raisin at 6.0 ppm for a use on
imported grapes (DP #315502, N. Dodd, 1/31/07).  No livestock tolerances
have been established.  No Codex, Canadian, or Mexican Maximum Residue
Limits (MRLs) or tolerances have been established for fluopicolide.

The residue chemistry and the toxicological databases support the
establishment of the following tolerances for the fungicide
fluopicolide.  Provided the deficiencies regarding the Sections B and F
are resolved (and provided that the Human Health Risk Assessment for BAM
is adequate), conditional registration for the requested uses of
fluopicolide can be granted and the tolerances as stated below can be
established.  The conditional registration can be converted to
unconditional registration when the remaining deficiency cited in
Section 10.0 of this document is resolved.

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

* These tolerances have been established for imported grapes (40 CFR
§180.627).

Note to RD:  HED is recommending a revision of the tolerance expression
for fluopicolide in/on plants to address issues of quantifiable residues
of 2,6-dichlorobenzamide (BAM) in/on plants resulting from fluopicolide
application.  BAM is also a metabolite of the registered herbicide
dichlobenil.

A summary of the findings and an assessment of human risk resulting from
fluopicolide uses on tuberous and corm vegetables, leafy vegetables
(except Brassica), fruiting vegetables, cucurbit vegetables, and grapes
are provided in this document.  The residue chemistry assessment was
provided by Amelia Acierto, the occupational and residential exposure
assessment by Kelly O’Rourke, the hazard characterization by Myron
Ottley, and the dietary exposure assessment and risk assessment by Nancy
Dodd of RAB3.

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

For V-10162 Premix (EPA File Symbol No. 59639-RUE), the proposed uses of
the second active ingredient on cucurbit vegetables, fruiting
vegetables, head and leaf lettuce, potato, turf, and ornamentals are not
evaluated in this document; the adequacy of the proposed use directions
and the availability of adequate supporting residue data will be
addressed in a separate review.

2,6-Dichlorobenzamide (BAM; AE C653711) is a metabolite and/or
environmental degradate of both the fungicide fluopicolide and the
herbicide dichlobenil.   Because the toxicological endpoints of BAM and
fluopicolide are different, a separate human health risk assessment (DP
#345918, N. Dodd, 11/21/07) for BAM is being concurrently conducted.
The BAM assessment evaluates BAM resulting from both fluopicolide and
dichlobenil; BAM from fluopicolide alone has not been assessed.
Registration of the proposed fluopicolide uses is dependent on the
adequacy of both  Human Health Risk Assessments.

Table of Contents

  TOC \f  1.0	Executive Summary	  PAGEREF _Toc185228014 \h  6

2.0	Ingredient Profile	  PAGEREF _Toc185228015 \h  12

2.1	Summary of Proposed Uses	  PAGEREF _Toc185228016 \h  12

2.2	Structure and Nomenclature	  PAGEREF _Toc185228017 \h  15

3.0	Hazard Characterization/Assessment	  PAGEREF _Toc185228018 \h  16

3.1	Hazard and Dose-Response Characterization	  PAGEREF _Toc185228019 \h
 16

3.1.1	Database Summary	  PAGEREF _Toc185228020 \h  16

<IP_ADDRESS>	Studies available and considered (animal, human, general
literature)	  PAGEREF _Toc185228021 \h  17

<IP_ADDRESS>	Mode of action, metabolism, toxicokinetic data	  PAGEREF
_Toc185228022 \h  17

<IP_ADDRESS>	Sufficiency of studies/data	  PAGEREF _Toc185228023 \h  17

3.1.2	Toxicological Effects	  PAGEREF _Toc185228024 \h  17

3.1.3	Dose-response	  PAGEREF _Toc185228025 \h  19

3.1.4	FQPA	  PAGEREF _Toc185228026 \h  19

3.1.5	The Report to the European Commission	  PAGEREF _Toc185228027 \h
20

3.2	Absorption, Distribution, Metabolism, Excretion (ADME)	  PAGEREF
_Toc185228028 \h  20

3.3	FQPA Considerations	  PAGEREF _Toc185228029 \h  21

3.3.1	Adequacy of the Toxicity Database	  PAGEREF _Toc185228030 \h  21

3.3.2	Evidence of Neurotoxicity	  PAGEREF _Toc185228031 \h  21

3.3.3	Developmental Toxicity Studies	  PAGEREF _Toc185228032 \h  23

3.3.4	Reproductive Toxicity Study	  PAGEREF _Toc185228033 \h  26

3.3.5	Additional Information from Literature Sources	  PAGEREF
_Toc185228034 \h  28

3.3.6	Pre-and/or Post-natal Toxicity	  PAGEREF _Toc185228035 \h  28

<IP_ADDRESS>	Determination of Susceptibility	  PAGEREF _Toc185228036 \h  28

<IP_ADDRESS>	Degree of Concern Analysis and Residual Uncertainties for Pre-
and/or Postnatal Susceptibility	  PAGEREF _Toc185228037 \h  28

3.3.7	Recommendation for a Developmental Neurotoxicity Study	  PAGEREF
_Toc185228038 \h  29

3.4	Safety Factor for Infants and Children	  PAGEREF _Toc185228039 \h
29

3.5	Hazard Identification and Toxicity Endpoint Selection	  PAGEREF
_Toc185228040 \h  29

3.5.1	Acute Reference Dose (aRfD) - Females age 13-49	  PAGEREF
_Toc185228041 \h  29

3.5.2	Acute Reference Dose (aRfD) - General Population	  PAGEREF
_Toc185228042 \h  30

3.5.3	Chronic Reference Dose (cRfD) -	  PAGEREF _Toc185228043 \h  30

3.5.4	Incidental Oral Exposure (Short- and Intermediate-Term)	  PAGEREF
_Toc185228044 \h  31

3.5.5	Dermal Absorption	  PAGEREF _Toc185228045 \h  31

3.5.6	Dermal Exposure (Short-, Intermediate- and Long-Term)	  PAGEREF
_Toc185228046 \h  32

3.5.7	Inhalation Exposure (Short-, Intermediate- and Long-Term)
PAGEREF _Toc185228047 \h  33

3.5.8	Level of Concern for Margin of Exposure	  PAGEREF _Toc185228048 \h
 33

3.5.9	Recommendation for Aggregate Exposure Risk Assessment	  PAGEREF
_Toc185228049 \h  34

3.5.10	Classification of Carcinogenic Potential	  PAGEREF _Toc185228050
\h  34

3.5.11	Summary of Toxicological Doses and Endpoints for Fluopicolide for
Use in Human Risk Assessments	  PAGEREF _Toc185228051 \h  35

3.6	Endocrine disruption	  PAGEREF _Toc185228052 \h  36

4.0	Public Health and Pesticide Epidemiology Data	  PAGEREF
_Toc185228053 \h  36

5.0	Dietary Exposure/Risk Characterization	  PAGEREF _Toc185228054 \h
36

5.1	Pesticide Metabolism and Environmental Degradation	  PAGEREF
_Toc185228055 \h  36

5.1.1	Metabolism in Primary Crops	  PAGEREF _Toc185228056 \h  36

5.1.2	Metabolism in Rotational Crops	  PAGEREF _Toc185228057 \h  37

5.1.3	Metabolism in Livestock	  PAGEREF _Toc185228058 \h  37

5.1.4	Analytical Methodology	  PAGEREF _Toc185228059 \h  38

5.1.5	Environmental Degradation	  PAGEREF _Toc185228060 \h  39

5.1.6	Comparative Metabolic Profile	  PAGEREF _Toc185228061 \h  40

5.1.7	Toxicity Profile of Major Metabolites and Degradates	  PAGEREF
_Toc185228062 \h  40

5.1.8	Pesticide Metabolites and Degradates of Concern	  PAGEREF
_Toc185228063 \h  41

5.1.9	Drinking Water Residue Profile	  PAGEREF _Toc185228064 \h  43

5.1.10	Food Residue Profile	  PAGEREF _Toc185228065 \h  44

5.1.11	International Residue Limits	  PAGEREF _Toc185228066 \h  56

5.2	Dietary Exposure and Risk	  PAGEREF _Toc185228067 \h  56

5.2.1	Acute Dietary (Food and Drinking Water) Exposure/Risk	  PAGEREF
_Toc185228068 \h  57

5.2.2	Chronic Dietary (Food and Drinking Water) Exposure/Risk	  PAGEREF
_Toc185228069 \h  57

5.2.3	Cancer Dietary Risk	  PAGEREF _Toc185228070 \h  58

5.3	Anticipated Residue and Percent Crop Treated (%CT) Information
PAGEREF _Toc185228071 \h  58

6.0	Residential (Non-Occupational) Exposure/Risk Characterization
PAGEREF _Toc185228072 \h  58

6.1. Residential Handler Exposure	  PAGEREF _Toc185228073 \h  58

6.2. Residential Postapplication Exposure	  PAGEREF _Toc185228074 \h  59

6.3 Other (Recreational Exposure; Spray Drift)	  PAGEREF _Toc185228075
\h  62

7.0	Aggregate Risk Assessments and Risk Characterization	  PAGEREF
_Toc185228076 \h  63

7.1 Acute Aggregate Risk	  PAGEREF _Toc185228077 \h  63

7.2 Short-Term Aggregate Risk	  PAGEREF _Toc185228078 \h  63

7.3 Intermediate-Term Aggregate Risk	  PAGEREF _Toc185228079 \h  64

7.4 Long-Term Aggregate Risk	  PAGEREF _Toc185228080 \h  64

7.5 Cancer Risk	  PAGEREF _Toc185228081 \h  64

8.0	Cumulative Risk Characterization Assessment	  PAGEREF _Toc185228082
\h  65

9.0 	Occupational Exposure/Risk Pathway	  PAGEREF _Toc185228083 \h  65

9.1 Short-/Intermediate-/Long-Term Handler Risk	  PAGEREF _Toc185228084
\h  65

9.2 Short-/Intermediate-/Long-Term Postapplication Risk	  PAGEREF
_Toc185228085 \h  69

10.0	Data Needs and Label Requirements	  PAGEREF _Toc185228086 \h  73

10.1	Toxicology	  PAGEREF _Toc185228087 \h  73

10.2	Residue Chemistry	  PAGEREF _Toc185228088 \h  73

10.3	Occupational and Residential Exposure	  PAGEREF _Toc185228089 \h
77

References:	  PAGEREF _Toc185228090 \h  77

Appendix A:  Toxicology Assessment	  PAGEREF _Toc185228091 \h  78

A.1	Toxicology Data Requirements	  PAGEREF _Toc185228092 \h  78

A.2	Toxicity Profiles	  PAGEREF _Toc185228093 \h  79

A.3	Executive Summaries	  PAGEREF _Toc185228094 \h  86

Appendix B:  Metabolism Assessment	  PAGEREF _Toc185228095 \h  113

B.1	Metabolism Guidance and Considerations	  PAGEREF _Toc185228096 \h
113

B.2	Tabular Summary of Fluopicolide and its Metabolites and Degradates
PAGEREF _Toc185228097 \h  114

Appendix C:  Tolerance Assessment Summary and Table	  PAGEREF
_Toc185228098 \h  127

Appendix D:  Review of Human Research	  PAGEREF _Toc185228099 \h  128

1.0	Executive Summary  TC \l1 "1.0	Executive Summary

Use Profile:  Fluopicolide is a fungicide that controls a wide range of
Oomycete (Phycomycete) diseases including downy mildews (Plasmopara,
Pseudoperonospara, Peronospora, and Bremia), late blight (Phytophthora),
and some Pythium species.  Fluopicolide appears to interfere with
mitosis and cell division resulting in the rapid destabilization of
fungal cell structures; this pesticidal mode of action has been
characterized as novel and unique and unlike the known modes of action
of other registered fungicides.

There are existing tolerances for residues of fluopicolide on imported
grapes.  This risk assessment addresses proposed domestic registrations
for agricultural crops [tuberous and corm vegetables, leafy vegetables
(except Brassica), fruiting vegetables, cucurbit vegetables, and
grapes], turf (residential, commercial, golf course, and sod farms), and
ornamental plants (landscapes, commercial greenhouses, and nurseries).

Four foliar applications of an SC (suspendable concentrate; also called
an aqueous flowable concentrate) or an FlC (an aqueous flowable
concentrate) are to be made at the maximum seasonal application rate of
0.34-0.375 lb active ingredient/acre (ai/A). Minimum retreatment
intervals of 7-12 days and a preharvest interval of 2-21 days are to be
observed.

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

For V-10162 Premix (EPA File Symbol No. 59639-RUE), the proposed uses of
the second active ingredient on cucurbit vegetables, fruiting
vegetables, head and leaf lettuce, potato, turf, and ornamentals are not
evaluated in this document; the adequacy of the proposed use directions
and the availability of adequate supporting residue data will be
addressed in a separate review.]

Human Health Risk Assessment:

This assessment includes fluopicolide residues of concern other than
BAM.  Because it has a different toxicity profile, BAM is assessed in a
separate Human Health Risk Assessment.

Fluopicolide Toxicity/Hazard:

The database for fluopicolide is adequate for purposes of risk
assessment.  Fluopicolide has demonstrated low to moderate acute
toxicity by the oral (Toxicity Category III), dermal (IV) and inhalation
routes (IV).  It is not an eye (IV) or dermal irritant (IV) and is not a
dermal sensitizer.  Repeat exposure studies result mainly in changes in
body weight and weight gain at oral dose levels of 109 mg/kg/day and
above in rats, mice and dogs.  No definitive cross-species target organ
was identified in subchronic or chronic studies with fluopicolide.
Adverse liver effects (hepatic oval cell proliferation and altered liver
cell foci) were observed in mice at dose levels of 551 mg/kg/day and
above.  A dermal subchronic toxicity study showed no systemic or local
effects at the limit dose.

Fluopicolide is not likely to be carcinogenic to humans.  There was no
evidence of carcinogenicity in rats, but hepatocellular adenomas were
observed in mice at dose levels of 551 mg/kg/day and above.
Developmental toxicity in the rabbit occurred only at doses that caused
severe maternal toxicity (including death).  In the rat, developmental
effects were seen only at high dose levels (700 mg/kg/day) in the
presence of maternal toxicity.  Similarly, offspring effects (body
weight, kidney) occurred only at levels causing toxicity in parents of
the multi-generation reproductive toxicity study.  No evidence of
neurotoxicity was seen in acute or subchronic oral rat neurotoxicity
studies.

Available in vivo dermal absorption data on fluopicolide indicated a
dermal absorption factor of 37% in rats.  In vitro dermal absorption
data suggested that fluopicolide will penetrate human skin at a
substantially lower rate (up to eight times less) than rat skin,
providing confidence that a 37% dermal absorption factor is conservative
for use in this risk assessment.

The rabbit developmental and rat chronic/carcinogenicity studies were
considered co-critical for endpoint selection.  The toxicological
profile for fluopicolide suggests that increased durations of exposure
(i.e., 90-day versus chronic) does not significantly increase the
severity of observed effects. The rabbit developmental and rat
chronic/cancer studies were therefore considered for all exposure
scenarios.  For the rabbit developmental study, the maternal LOAEL was
60 mg/kg/day based on death, abortions/premature deliveries (late-term),
decreased food consumption, and decreased body weight gain.  The
maternal NOAEL was 20 mg/kg/day.  In the combined chronic
toxicity/carcinogenicity study in rats the LOAEL was 109 mg/kg/day based
on decreased body weight gain and increased thyroid weight and increased
incidence of thyroid lesions with NOAEL of 31.5 mg/kg/day.  The
NOAEL/LOAEL from the rabbit developmental was used for the point of
departure since it is protective of effects observed from similar dosing
of the chronic/carcinogenicity rat study.

Uncertainty factors were 10x for extrapolation from animals to humans
(interspecies variation) and 10x for potential variation in sensitivity
among members of the human population (intraspecies variation).

HED recommends that the FQPA Safety Factor be reduced to 1X because
there is a complete toxicity database for fluopicolide and  there is no
evidence of susceptibility following in utero and/or postnatal exposure
in the rabbit and rat developmental toxicity studies or in the
2-generation rat reproduction study.  There is low concern for
qualitative susceptibility observed in the rat developmental toxicity
study because the offspring effects (reduced growth and skeletal

defects) and late-term abortions are well characterized and accompanied
by maternal toxicity near the limit dose.  Protection of the maternal
effects also protects for any effects that may occur during development.
 There are no residual uncertainties concerning pre- and post-natal
toxicity and there are no neurotoxicity concerns.  A conservative
endpoint from the rabbit developmental study was used for all exposure
scenarios.  Furthermore, the dietary food exposure assessment is also
conservative since it utilizes tolerance level residues and 100% crop
treated (CT).  Conservative (protective) assumptions were used in the
ground and surface water modeling to assess exposure to fluopicolide in
drinking water.  HED used similarly conservative assumptions to assess
post-application exposure of children as well as incidental oral
exposure of toddlers.

Dietary Exposure (Food and Drinking Water):

As determined by HED, the residue of concern for the tolerance
expression for domestic primary plants is fluopicolide (parent) as an
indicator of combined residues of fluopicolide and its metabolite
2,6-dichorobenzamide.  Residues considered in the risk assessment for
domestic primary plants except tuberous and corm vegetables are parent
and BAM.  For tuberous and corm vegetables, the residues of concern
include parent, BAM, and 3-chloro-5-trifluoromethylpyridine-2-carboxylic
acid (PCA; AE C657188).  Based on its structure, the metabolite PCA is
not expected to be more toxic than parent.

It should be noted that tolerances on livestock commodities will not be
established at this time because HED is not recommending for
establishment of tolerances on potato and the rotational crop wheat, the
only fluopicolide crops with livestock feed items.  Tolerances on
rotational crops will not be established at this time because HED is
recommending for rotational crop restrictions.

Residues included in the drinking water risk assessment are parent
fluopicolide and the metabolite BAM based on two aerobic soil metabolism
studies.  BAM was a major degradate in the aerobic soil metabolism
studies, present at levels up to 40%.

Since residues are expected from both fluopicolide and BAM, two dietary
assessments were conducted to be health protective.  One dietary
assessment was conducted for fluopicolide residues of concern in food
and drinking water from uses of fluopicolide (discussed in this
Assessment), and a second dietary assessment was conducted for residues
of BAM  in food and drinking water from uses of fluopicolide and
dichlobenil (discussed in the BAM Human Health Risk Assessment, DP
#345918, N. Dodd, 11/21/07).

The chronic dietary (food and drinking water) exposure assessment for
fluopicolide was a conservative assessment using the recommended
tolerance levels and assuming that 100% of the crop was treated.
Residues of fluopicolide are detectable in most crops and they tend to
be higher in leafy vegetables.  The available processing data indicate
that residues concentrate in raisins, processed potato waste, wheat
milled byproducts, and to a lesser degree in tomato processed
commodities. No residues are expected to occur in livestock commodities
since no crops in this petition have livestock feed items.

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%
of the chronic Population Adjusted Dose (cPAD) for the general U.S.
population and 9% cPAD for children 1-2 years old, the most highly
exposed subgroup.

Residential Exposure:

Fluopicolide is proposed for use on residential turfgrass and
recreational sites such as golf courses.  The proposed labels do not
prohibit application by home-owners; therefore, short-term
non-occupational handler exposure was evaluated.  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 total Margins of Exposure (MOEs) for residential handlers are well
above the LOC of 100, and are not of concern.  Residential
short-/intermediate-term postapplication MOEs were estimated for “Day
0” exposure (i.e., the day of application).  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.

Aggregate Risk:

In examining acute aggregate risk, HED assumed that the only pathway of
exposure relevant to the acute time frame is dietary exposure (i.e., any
non-dietary exposures are short- and/or intermediate-term duration).
Therefore, the acute aggregate risk would be composed of exposures to
residues in food and drinking water; however, an acute dietary
assessment was not conducted because an endpoint attributable to a
single dose was not identified from the available data for fluopicolide.

Short-term exposures (1-30 days of continuous exposure) may occur as a
result of activities on treated turf.  Exposures related to turf
activities have been combined with chronic dietary exposure estimates
(as an estimate of background dietary exposure) to assess short-term
aggregate exposure. Since the aggregate MOEs are greater than 100, they
represent risk estimates that are below HED’s level of concern.

The intermediate-term aggregate risk is the same as calculated for
short-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.  The chronic risk estimates are
below HED’s level of concern for all population subgroups.

Occupational Exposure/Risk:

The results of the handler occupational exposure and risk assessment
indicate that risks are not of concern with baseline clothing, or in
some cases, when gloves are worn (which is required on the proposed
labels).  The Total MOEs range from 100 to 19,000; and therefore, are
not of concern.

The results of the occupational postapplication exposure and risk
assessment indicate that:

MOEs for agricultural uses are greater than 100 on the day of
application (or the day after application for grapes, for which a
restricted entry interval of one day may be needed ), and therefore, are
not of concern.

MOEs for turf  and ornamental (nursery stock) uses are greater than 100
on the day of application, and are not of concern

Ornamental use (for cut flowers) at the maximum rate requires 6 days for
residues to decline to a level at which MOEs reach 100.  However, when
the minimum proposed rate is used, MOEs reach 100 on the day after
application.

Environmental Justice Considerations:

Potential areas of environmental justice concerns, to the extent
possible, were considered in this human health risk assessment, in
accordance with U.S. Executive Order 12898, "Federal Actions to Address
Environmental Justice in Minority Populations and Low-Income
Populations,"   HYPERLINK
"http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf"
http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf ).

As a part of every pesticide risk assessment, OPP considers a large
variety of consumer subgroups according to well-established procedures.
In line with OPP policy, HED estimates risks to population subgroups
from pesticide exposures that are based on patterns of that subgroup’s
food consumption.  Extensive data on food consumption patterns are
compiled by the USDA under the Continuing Survey of Food Intake by
Individuals (CSFII) and are used in pesticide risk assessments for all
proposed/registered food uses/tolerances of a pesticide.  These data are
analyzed and categorized by subgroups based on age, season of the year,
ethnic group, and region of the country.  Additionally, OPP is able to
assess dietary exposure to smaller, specialized subgroups and exposure
assessments are performed when conditions or circumstances warrant.
Further considerations are currently in development as OPP has committed
resources and expertise to the development of specialized software and
models that consider exposure from traditional dietary patterns among
specific subgroups.

Review of Human Research:

This risk assessment relies in part on data from studies in which adult
human subjects were intentionally exposed to a pesticide or other
chemical.  These studies (listed in Appendix D) have been determined to
require a review of their ethical conduct.  They are also subject to
review by the Human Studies Review Board.  The listed studies have
received the appropriate review.

Additional Data Needs:

Pending submission of revised Sections B and F (and provided that the
Human Health Risk Assessment for BAM is adequate), there are no data
gaps related to toxicology, residue chemistry, or
occupational/residential exposure that would preclude conditional
registrations and permanent tolerances for residues of the herbicide
fluopicolide.  SEQ CHAPTER \h \r 1

Residue Chemistry Deficiencies

The recommended conditional registrations can be converted to
unconditional registrations when the remaining deficiency concerning
storage stability, which is cited in Section 10.2 of this document, is
resolved.

Toxicology Deficiencies

None.

Occupational and Residential Exposure Deficiencies

None.

2.0	Ingredient Profile

  TC \l1 "2.0	Ingredient Profile

Fluopicolide
(2,6-dichloro-N-[[3-chloro-5-(trifluoromethyl)-2-pyridinyl]methyl]benzam
ide; AE C638206; V10161) is a fungicide which is placed in both the
benzamide and pyridine class of compounds.

Fluopicolide controls a wide range of Oomycete (Phycomycete) diseases
including downy mildews (Plasmopara, Pseudoperonospara, Peronospora, and
Bremia), late blight (Phytophthora), and some Pythium species.
Fluopicolide appears to interfere with mitosis and cell division
resulting in the rapid destabilization of fungal cell structures; this
pesticidal mode of action has been characterized as novel and unique and
unlike the known modes of action of other registered fungicides.  In the
plant, fluopicolide is a mesosystemic fungicide; it translocates toward
the stem tips via the xylem but it does not translocate toward the
roots.

2,6-Dichlorobenzamide (BAM; AE C653711) is a metabolite and/or
environmental degradate of both fluopicolide and dichlobenil.  A
separate human health risk assessment is being concurrently conducted
for BAM from both fluopicolide and dichlobenil.

2.1	Summary of Proposed Uses  TC \l2 "2.1	Summary of Proposed Uses

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

Valent also submitted labels for non-food uses:  V-10161 VPP Fungicide
(EPA File Symbol No. 59639-RUR), an aqueous flowable formulation
containing 4 lb ai/gal, for use on turfgrass and ornamental plants, and
V-10162 VPP Fungicide (EPA File Symbol No. 59639-RUG), an aqueous
flowable formulation containing 0.52 lb/gal of fluopicolide and 5.2
lb/gal of propamocarb hydrochloride, for use on turfgrass and ornamental
plants.

The proposed use directions for fluopicolide are presented in Table 2.1
below.  Although a second active ingredient (propamocarb hydrochloride)
is included in two formulations, the application rates presented in the
table below reflect the ai fluopicolide only.  The proposed uses of
propamocarb hydrochloride on cucurbit vegetables, fruiting vegetables,
head and leaf lettuce, and potato (on the label for V-10162 Premix; EPA
File Symbol No. 59639-RUE) and on turfgrass and ornamental plants (on
the label for V-10162 VPP Fungicide; EPA File Symbol No. 59639-RUG) are
not evaluated in this document; the adequacy of the proposed use
directions and the availability of adequate supporting residue data will
be addressed in a separate review.

Table 2.1.	Summary of Directions for Use of Fluopicolide.

Applic. Timing, Type, and Equip.	Formulation

[EPA Reg. No.]	Applic. Rate

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

 (lb ai/A)

[g ai/ha]	PHI (days)	Use Directions and Limitations*

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

Postemergence

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

Retreatment Interval (RTI) is 10 days.

Postemergence	V-10162 Premix	0.09-0.11	4	0.34	2

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

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

RTI is 7 days.

Postemergence	V-10162 Premix	0.09-0.11	4	0.34	2

	Grapes

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

RTI is 12 days.

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

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

RTI is 10 days.

Lettuce, Head and Leaf

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

RTI is 10 days.

Potato

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

RTI is 10 days.

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

RTI is 10 days.

Sweet Potato

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

RTI is 10 days.

Turf (Residential, Commercial, Golf Course, Sod Farms)

Postemergence	V-10161

VPP Fungicide	0.27	2	0.54	N/A	Apply in a minimum volume of 2 gal/1000
ft2.  Application intervals are 14 days.

Postemergence	V-10162

VPP Fungicide	0.21	2	0.42	N/A

	Ornamental Plants (Bedding plants, Conifers, Flowering plants, Foliage
plants, Ground covers, Non-bearing fruit and nut trees, Ornamentals
[container-, bench-, or bed-grown in greenhouses or outdoor nurseries),
Ornamental trees, Shrubs, Vines)

Postemergence	V-10161

VPP Fungicide	Spray: 0.27-0.54

Drench: 6.8-27	No more than 2 applications per cropping cycle.	Not
stated	NA	Foliar spray:  Apply spray mixture to all plant surfaces to
the point of runoff (approximately 100 gal/20,000 ft2).  Minimum
application intervals are 14 days.

Drench:  Use enough solution to wet the root zones of plants (see label
charts for volume appropriate to pot, bed, and flat size).  Minimum
application intervals are 14 days.

Postemergence	V-10162

VPP Fungicide	Spray: 0.21-0.42

Drench: 5.3-21

Not stated	NA

	*Additional General Use Directions and Limitations:

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

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

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

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

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

HED concludes that the submitted use directions are sufficient to allow
evaluation of the available residue data relative to the proposed use;
however, until all field rotational crop and livestock data requirements
have been satisfied, the proposed rotational crop restrictions must be
modified to state that crops may not be rotated to any crops other than
cucurbit vegetables, fruiting vegetables, grapes, leafy vegetables, and
tuberous and corm vegetables (except potato) with a 0-day PBI.  Refer to
Section 10.2 for recommended label revisions.

2.2	Structure and Nomenclature  TC \l2 "2.2	Structure and Nomenclature

Table 2.2.		Fluopicolide Nomenclature.

Chemical structure

Empirical Formula	C14H8Cl3F3N2O

Common name	Fluopicolide

Company experimental name	AE C638206

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

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

CAS Registry Number	239110-15-7

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

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

Chemical Class	Fungicide

Known Impurities of Concern	None

2.3	Physical and Chemical Properties

Table 2.3.		Physicochemical Properties of Fluopicolide.

Parameter	Value	Reference

Molecular Weight	383.59	*

Melting point/range 	149 (C 	MRID 464740151

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

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

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

2.80 mg/L at pH 7

2.80 mg/L at pH 9 	MRID 464740211

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

Ethanol:	19.2

Toluene:	20.5

Ethyl acetate:	37.7

Acetone:	74.7

Dichloromethane:	126

Dimethyl sulfoxide:	183 	MRID 464740221

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

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

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

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

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

	In methanol:	203 and 271

	In methanol/HCl:	202 and 270

	In methanol/NaOH:	219 and 271 	MRID 464740141

*The molecular weight was calculated from the Periodic Table.

3.0	Hazard Characterization/Assessment   tc  \l 1 "3.0	Hazard
Characterization/Assessment"

3.1	Hazard and Dose-Response Characterization tc  \l 2 "3.1	Hazard and
Dose-Response Characterization"

3.1.1	Database Summary tc  \l 3 "3.1.1	Database Summary "

The toxicology database for fluopicolide (AC 638206) submitted by Bayer
CropScience AG is

complete and deemed adequate for hazard assessment and for FQPA
evaluation.

An important fluopicolide metabolite, 2,6-dichlorobenzamide (BAM) is
considered in this risk assessment, and its hazard
characterization/assessment appears in the BAM Human Health Risk
Assessment (DP #345918, N. Dodd, 11/21/07).

<IP_ADDRESS>	Studies available and considered (animal, human, general
literature)  tc  \l 4 "<IP_ADDRESS>	Studies available and considered (animal,
human, general literature)"

Fluopicolide (AC638206)

Acute- oral, dermal, inhalation, eye irritation, skin irritation, dermal
sensitization

Subchronic- oral 90-day rat, oral 90-day mouse (2 studies), oral 90-day
dog

Chronic- oral rat (combined chronic/carcinogenicity) and oral dog

Reproductive/developmental- oral developmental rat and rabbit, rat
reproduction/fertility

Other- acute and subchronic rat neurotoxicity, oral mouse
carcinogenicity, mutagenicity studies (in vitro and in vivo),
metabolism/pharmacokinetics studies and phenobarbital 28-day
hepatotoxicity mouse studies (2 studies)

<IP_ADDRESS>	Mode of action, metabolism, toxicokinetic data tc  \l 4 "<IP_ADDRESS>
Mode of action, metabolism, toxicokinetic data "

Fluopicolide is a fungicide that is effective in controlling plant
disease caused by Oomycetes.  The biological activity is mesosystemic in
that it controls pathogens on contact through translocation toward the
stem tips and not the roots. The exact mode of action of disease control
has not been fully determined. The test substance is mostly used on
grapes and raisins.   For detailed metabolism and toxicokinetic data,
please refer to Section 3.2.

<IP_ADDRESS>	Sufficiency of studies/data tc  \l 4 "<IP_ADDRESS>	Sufficiency of
studies/data "

The toxicity database is complete for fluopicolide (see Appendixes A-2
through A-4 for toxicity profile tables) and is adequate for risk
assessment evaluations and determination of FQPA.  All studies evaluated
were deemed acceptable and met guideline criteria except for one reverse
gene mutation study.  This study was unacceptable because purity of the
test material was not provided; however, there were enough adequate
studies for gene mutation that this does not constitute a data gap.

3.1.2	Toxicological Effects tc  \l 3 "3.1.2	Toxicological Effects "

NOAEL and LOAEL:  The no-observed-adverse-effect level (NOAEL) is the
dose level at which no adverse effects were noted. The
lowest-observed-adverse-effect level (LOAEL) is the lowest dose level at
which effects of toxicological significance are observed. These two
parameters are adequately provided in the studies for fluopicolide.

Acute toxicity:  Fluopicolide has moderate toxicity with no deaths noted
in male or female rats at doses of > 2000 mg/kg when given orally, and >
4000 mg/kg dermally. Following inhalation exposure, an LC50 of >1.789 to
< 5.16 mg/L was calculated. Toxicity was observed primarily in the
inhalation studies and included a decrease in body weight, decrease in
mean body temperature and signs of irritation (piloerection, hunched
posture, reddened nostrils).  Slight eye irritation occurred in the form
of chemosis and corneal opacities, but all effects were gone by 72
hours.  No dermal irritation occurred, and the test substance was not a
skin sensitizer.

Subchronic toxicity:  The most common effect observed in the 90 day
studies was a decrease in body weight gain. Weight gain was markedly
decreased in male and female rats in a subchronic study at doses that
exceeded the limit dose (1668-1673 mg/kg/day), and male and female rats
in a subchronic neurotoxicity study had reduced body weight gain at
doses of 780.6 and 125.2 mg/kg/day, respectively.  There was no effect
on weight gain in dogs or mice in subchronic studies. Besides effects on
body weight and body weight gain, no definitive cross-species target
organ was identified in subchronic studies with fluopicolide.  No organ
lesions were found in dogs administered up to 1000 mg/kg/day for 90
days. Male rats had hypertrophy of the zona glomerulosa in the adrenal
gland, trabecular hyperostosis of the bone joint, and decreased bone
marrow cellularity after exposure to 1668 mg/kg/day for 90 days.
Similar lesions in the adrenal gland and bone marrow were found in
female rats administered 119 mg/kg/day for 90 days. In mice, females
administered 965 mg/kg/day showed an increased incidence of hepatic oval
cell proliferation.

Chronic toxicity:  As in the subchronic studies, the main effect in the
chronic studies was a decrease in body weight gain with no definitive
cross-species target organ identified. Male dogs had reduced weight gain
after exposure to 1000 mg/kg/day for one year; body weight of females
was not affected.  Mice had severely decreased body weight and body
weight gain with administration of 551.0 and 772.3 mg/kg/day to males
and females, respectively, for 18 months. Male and female rats had
decreased weight gain after exposure to 109.4 and 142.2 mg/kg/day for 2
years, respectively. No organ lesions were found in dogs administered up
to 1000 mg/kg/day for 52 weeks.  Thyroid cystic follicular hyperplasia
was seen in male rats after 109.4 mg/kg/day for two years.  In mice,
altered liver cell foci were seen in males and females given 551.0 or
772.3 mg/kg/day, respectively, for 18 months.

Carcinogenicity:  No evidence for carcinogenicity was seen in rats
administered fluopicolide in food for 24 months.  Treatment of rats did
not result in an increase in overall tumor incidence or an increase in
the incidence of any specific type of tumor.  In contrast, mice had an
increased incidence of hepatocellular adenoma following administration
of 3200 ppm in the diet for 18 months (551.0 and 772.3 mg/kg/day for
males and females, respectively).

Developmental toxicity:  In developmental toxicity studies, maternal
toxicity was clearly evident only in rabbits as increased mortality,
abortion, and decreased body weight gain at 60 mg/kg/day, the highest
dose tested.  Minimal maternal toxicity was observed in rats dosed with
700 mg/kg/day; slightly reduced body weight gain did not result in lower
absolute body weight.  At the same dose affecting the dam, 700 mg/kg in
rats and 60 mg/kg in rabbits, fetal growth was affected in both species
and observed as decreases in body weight and crown-rump length. Also, at
700 mg/kg, delays in fetal ossification and increased incidence of
skeletal defects were observed in rat fetuses, with neither of these
effects seen in rabbit fetuses. No external or visceral abnormalities
were observed in either species.  In the rat, the developmental effects
observed (developmental delays and skeletal defects) were judged to be
qualitatively more severe than the minimal maternal toxicity (decreased
body weight gain) observed, suggesting a greater qualitative
susceptibility in the fetus compared to that of the dam.  This issue is
further discussed in Sections <IP_ADDRESS> and <IP_ADDRESS>.

Reproductive toxicity:  Reproductive performance was not affected in a
two-generation reproduction toxicity study in which fluopicolide was
administered to male and female rats at nominal dietary concentrations
of 0, 100, 500, or 2000 ppm (0, 7.4-8.8, 36.4-43.7, 144.6-179.9
mg/kg/day, respectively, for males and 0, 8.1-9.4, 41.0-46.9,
159.7-193.9 mg/kg/day, respectively, for females).  Evidence of parental
toxicity in the high-dose groups included decreased body weight gain in
F0 females and kidney toxicity in F0 and F1 males and females.  Kidney
lesions consisted of cortical tubular basophilia or dilation, medullary
granular casts, cortical scarring, interstitial inflammation, and/or
corticomedullary mineralization. Body weight of the high-dose F1 and F2
pups was significantly less than that of the controls beginning on
lactation day 14.  The high-dose pups had decreased weight gain
throughout the 28-day lactation interval.  Overall weight gain during
lactation was decreased by 8-9% of the control level in the high-dose F1
male and female pups and by 11-14% in the high-dose F2 male and female
pups.  No other effects on offspring growth or survival were noted in
either generation.

Neurotoxicity:  No evidence of neurotoxicity was seen in acute or
subchronic oral rat neurotoxicity studies with fluopicolide.  In the
acute study, a transient decrease in body temperature was the only
finding in male and female rats given a single dose of 2000 mg/kg.
Brain weight, brain morphometry, and neuropathology were not affected by
treatment.

Dermal toxicity:  Acute dermal toxicity studies showed that fluopicolide
was only a slight dermal irritant (Tox. Category IV).  A dermal
subchronic toxicity study showed no systemic or local effects at the
limit dose.

3.1.3	Dose-response tc  \l 3 "3.1.3	Dose-response"

HED has selected the most sensitive and protective endpoints from the
database to develop the risk assessment. Appropriate endpoints were
selected for the chronic dietary exposure scenario, incidental oral
short-term and intermediate-term scenarios, dermal all time periods, and
inhalation all time periods.  Further discussions in regards to the
studies chosen for each endpoint are included in Section 3.5.

3.1.4	FQPA tc  \l 3 "3.1.4	FQPA"

Data are adequate for evaluation of effects resulting from in utero and
post-natal exposure.  Acceptable developmental toxicity studies were
conducted in rodents and non-rodents, and a reproductive toxicity study
in rodents was available.  Developmental toxicity was found in both rats
and rabbits at doses equal to those resulting in maternal toxicity so no
quantitative susceptibility was observed.  Of the developmental studies,
rabbits were clearly more sensitive than rats.  In the rat developmental
study, the developmental effects observed (developmental delays and
skeletal defects) were judged to be qualitatively more severe than the
minimal maternal toxicity (decreased body weight gain) observed.  These
developmental effects occurred at 700 mg/kg with a NOAEL of 60 mg/kg.
In contrast, severe maternal toxicity was observed in rabbits and
therefore fetal loss was observed at 60 mg/kg with the maternal NOAEL of
20 mg/kg.  In the multigeneration rat study, neither quantitative nor
qualitative susceptibility was observed.  Although there was apparent
evidence of increased qualitative susceptibility in the rat
developmental study, the more sensitive species (rabbit) has been used
for the point of departure in the risk assessment.  Therefore, the 10X
FQPA safety factor may be reduced to 1X.

3.1.5	The Report to the European Commission

 tc  \l 3 "3.1.5	The Report to the European Commission"

The Report and Proposed Decision of the United Kingdom made to the
European Commission under article 8(1) of 91/414/ECC (EU Monograph, MRID
46821401) has set the following limits:

Acute RfD = 0.18 mg/kg/day based on impaired growth and
histopathological changes in the liver and kidney at the LOAEL of 106
mg/kg bw/day in a subchronic neurotoxicity study.  The NOAEL is 18
mg/kg/day, and the aRfD of 0.18 mg/kg bw/day allows for a 100-fold
uncertainty factor.

Chronic RfD = 0.08 mg/kg/day based on increased liver weights, enlarged
liver, masses and nodules and increased incidences of hepatocellular
hepatocyte hypertrophy at the LOAEL of 64.5 mg/kg/day for the males an
91.9 mg/kg/day for the females (the mid-dose level) in a 78-week mouse
study.  The NOAEL is 7.9 mg/kg/day (the low-dose level) and the chronic
RfD (Acceptable Daily Intake) of 0.08 allows for a 100-fold uncertainty
factor for inter- and intra-species differences.  A companion chronic
rat study showed adverse effects occurring at the LOAEL of 31.5
mg/kg/day (the mid-dose level), with a NOAEL of 8.4 mg/kg/day (the
low-dose level).

HED has not identified an endpoint in the available studies which can be
attributed to a single exposure; hence, HED has not set an acute RfD.

HED has reviewed the 78-week mouse study (MRID 46474130) mentioned
above, concluding that statistically- and toxicologically-significant
effects occurred at 551 mg/kg/day, (the high dose levels) only in both
studies, with the mid-dose level being the NOAEL. The EU Monograph
document identifies the mid-dose level as the LOAEL and the low-dose
levels as the NOAEL.

Since the developmental rabbit study provided endpoints at levels which
are more protective than the levels in these chronic studies
(NOAEL/LOAEL = 20/60 mg/kg/day), HED’s chronic endpoints are based on
the rabbit developmental toxicity study.   HED also considers the
104-week study in rats just mentioned (MRID 46474139) to be the
co-critical study for determining the chronic RfD.

3.2	Absorption, Distribution, Metabolism, Excretion (ADME)  tc  \l 2
"3.2	Absorption, Distribution, Metabolism, Excretion (ADME)"

Several studies were available on metabolism and disposition for
fluopicolide in rats. The studies

demonstrated rapid absorption, metabolism and excretion within 72 hours
after oral dosing. The

main metabolites were oxidative N-dealkylation cleavage products.  The
primary routes of excretion for the parent compound were fecal (68.8 -
72.4%) and urinary (18.8 - 21.4%) with metabolites identified in both
urine and feces. Up to 49 metabolites were identified in the urine,
while the main compound in the feces was identified as the parent.  No
gender-related variability was observed in any of the studies. Following
administration of the fluopicolide, highest concentrations were found in
the intestines and its contents.  The next highest concentrations were
found in the liver, kidneys and adrenals. However, based upon tissue
burden, neither the parent compound nor its metabolites appear to
undergo any significant tissue sequestration.

A metabolite of fluopicolide, 2,6-dichlorobenzamide or BAM, is formed
following hydroxylation of the parent molecule and cleavage of the
straight chain bridge to form the amide.  Following oral administration
of BAM itself, it is found in the kidney and liver, and most of the
radioactivity (82%) is found in the urine, with 13% found in the feces.

Existing data show that BAM produces toxicity at lower levels than
fluopicolide but it is a minor metabolite of fluopicolide.  When
fluopicolide is administered to the rat, only about 0.09% of the total
administered radioactivity 8 hours post-dosing is identified as BAM.

3.3	FQPA Considerations tc  \l 2 "3.3	FQPA Considerations"

3.3.1	Adequacy of the Toxicity Database tc  \l 3 "3.3.1	Adequacy of the
Toxicity Database"

Data for fluopicolide are adequate for evaluation of the FQPA factor.

3.3.2	Evidence of Neurotoxicity tc  \l 3 "3.3.2	Evidence of
Neurotoxicity"

Acute and subchronic neurotoxicity studies have been conducted with
fluopicolide in rats.  The

only notable functional observational battery (FOB) finding was a lower
body temperature in

males and females six hours after a single oral dose of 2000 mg/kg/day.
 No clinical signs of

toxicity or effects on motor activity were observed in either study. In
acute inhalation lethality

studies, there were no treatment-related effects on a battery of reflex
measurements evaluated the

day after exposure; however, mean body temperature was decreased after
exposure.

Acute Neurotoxicity in rats- fluopicolide

In an acute neurotoxicity study (MRID 46474218; summarized in MRID
46474217), groups of fasted, 6- to 7-week old CD rats (10/sex) were
given a single oral dose of AE C638206 (95.9% a.i., batch/lot
#OP2050046) in 1% methylcellulose at doses of 0, 10, 100, or 2000 mg/kg
bw and observed for 15 days.  Doses were based on a range-finding study
in which single doses of 50 mg/kg induced behavioral changes (MRID
46474219).  Neurobehavioral assessment (functional observational battery
[FOB] and motor activity testing) was performed in 10 animals/sex/group
pretreatment, on Day 1 (at six hours post-dosing, the time of peak
effect), and on Days 8 and 15.  Cholinesterase activity was not
determined.  At study termination, 5 animals/sex/group were euthanized
and perfused in situ for neuropathological examination.  Of the perfused
animals, the control and high-dose groups were subjected to
histopathological evaluation of brain and peripheral nervous system
tissues.

There was no effect of treatment on body weight, body weight gain, food
consumption, food efficiency, brain weight, brain measurements (cerebral
hemispheres), or incidence of gross or microscopic lesions.  Lower body
temperature in the high-dose males and females at the time of peak
effect (6 hours post-dosing) on the day of treatment (Day 1) was the
only treatment-related observation during the FOB.  This sign was not
observed on Days 8 or 15.  A statistically significant decrease in
forelimb grip strength in females in the 2000 mg/kg group on Day 8,
reduced motor activity of males in the 2000 mg/kg treatment group on Day
1, and increased motor activity in females in the 2000 mg/kg group on
Day 15 were considered incidental to treatment as these effects were not
clearly dose-related and were not observed in the other sex.

The LOAEL for AE C638206 in male and female rats was 2000 mg/kg, based
on the transient effect of lower body temperature.  The NOAEL for male
and female rats was 100 mg/kg.  Note:  HED has determined that a change
in body temperature is not a single dose effect.

This neurotoxicity study is classified as Acceptable/Nonguideline. Upon
receipt of provided positive control neuropathology data are submitted
by the conducting laboratory, this study can be upgraded to
Acceptable/Guideline, satisfying the guideline requirement for an acute
neurotoxicity study in rats (870.6200; OECD 424).

Subchronic Neurotoxicity in rats- fluopicolide

In a subchronic neurotoxicity study (MRID 46474221), Technical Grade AE
C638206 (97.8% a.i., Batch # OP2050046) was administered to 10 CD
rats/sex at dietary concentrations of 0, 200, 1400, or 10,000 ppm for 13
weeks.  Time-weighted average doses were 0, 15.0, 106.6, or 780.6
mg/kg/day, respectively, for males and 0, 18.0, 125.2, or 865.8
mg/kg/day, respectively, for females.  Neurobehavioral assessment
(functional observational battery [FOB] and motor activity testing) was
performed on all animals pre-test and at weeks 4, 8, and 13.  At study
termination, 6 animals/sex/group were euthanized and perfused in situ
for neuropathological examination.  Of the perfused animals, control and
high-dose rats were subjected to histopathological evaluation of brain
and peripheral nervous system tissues.  Positive control data for FOB
and motor activity testing were submitted in MRID 46474222 and were
summarized in MRID 46474220.

All animals survived to scheduled sacrifice.  No treatment-related
clinical signs of toxicity or gross lesions were observed in any group.
FOB findings and motor activity were similar between the treated and
control groups.

Mean body weight of the low-dose males and females was similar to the
controls throughout the study.  Mid- and high-dose males and females had
slightly lower body weight than that of the control group beginning at
week 1 but these data were not analyzed statistically.  Overall body
weight gain by the high-dose males and females and mid-dose females was
81%, 72%, and 87% (p ≤ 0.05 or 0.01), respectively, of the respective
control levels.  The most pronounced effect on body weight gain in the
high-dose groups was during weeks 0-1 when males and females gained 56%
and 63%, respectively, of the control level.  Weight gain by the
mid-dose groups appeared to be consistently less than that of controls
at each weekly interval.  Food consumption by the high-dose males and
females was slightly less than that of the controls for most weekly
intervals of the study.  Excessive food scatter was observed by the mid-
and high-dose males and by all treated female groups.  Overall food
conversion efficiency by the high-dose males and females and mid-dose
females was 87%, 79%, and 89%, respectively, of the respective control
levels.  The most pronounced effect on food efficiency in the high dose
groups was during week 1 when males and females were 62% and 69%,
respectively, of the control level.

Treatment-related lesions observed in the liver (hypertrophy) of males
and females and the male kidney (hyaline droplets) were not considered
adverse or relevant to humans.

Therefore, the systemic and neurotoxicity LOAEL for AE C638206 in male
and female rats is 10,000 and 1400 ppm, respectively (780.6 and 125.2
mg/kg/day for males and females, respectively) based on decreased body
weight gain, food consumption, and food efficiency.  The NOAEL for males
and females was 1400 and 200 ppm, respectively (106.6 and 18.0 mg/kg/day
for males and females, respectively).

This neurotoxicity study is classified as Acceptable/Nonguideline. Upon
submission of positive control neuropathology data by the conducting
laboratory, this study can be upgraded to Acceptable/Guideline,
satisfying the guideline requirement for a subchronic neurotoxicity
study in rats (870.6200; OECD 424).

3.3.3	Developmental Toxicity Studies tc  \l 3 "3.3.3	Developmental
Toxicity Studies "

Developmental toxicity studies have been conducted with fluopicolide in
the rat and rabbit.  The rabbit was clearly the more sensitive species.
For example, both maternal and developmental effects occurred at a much
lower dose level in the rabbit, compared to the rat.  The maternal and
developmental NOAELs/LOAELs are 60/700 mg/kg/day for the rat and 20/60
mg/kg/day for the rabbit.

In addition, the effects observed in both dams and offspring were more
severe in rabbit, compared with the rat. Maternal toxicity in the rat
was limited to marginally reduced body weight gain, while in the rabbit,
maternal toxicity consisted of death, abortions/premature deliveries,
decreased food consumption, and decreased body weight gain.
Developmental effects in the rat consisted of developmental delays and
skeletal defects.  In the rabbit, developmental delays, premature
deliveries and abortions were observed and were due to severe maternal
toxicity.

Developmental Toxicity in rats- fluopicolide

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 marginally 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 defects 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.  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.

Developmental Toxicity in rabbits- fluopicolide

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
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.

3.3.4	Reproductive Toxicity Study tc  \l 3 "3.3.4	Reproductive Toxicity
Study"

Reproductive performance was not affected in a two-generation
reproduction toxicity study in

which fluopicolide was administered to male and female rats.  The most
common effect was a

decrease in body weight gain in both the parental animals and offspring.

Reproductive Toxicity in rats- fluopicolide

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
generation. The numbers of implantation sites and viable litters were
similar in the treated and control groups in both generations.  No
treatment-related gross or microscopic lesions were observed in
reproductive organs.

The lowest-observed-adverse-effect level (LOAEL) for reproductive
toxicity of AE C638206 in rats was not determined; therefore the
no-observed-adverse-effect level (NOAEL) is >2000 ppm (>179.9 mg/kg
bw/day in males and >193.3 mg/kg bw/day in females).

No treatment-related effects were observed on the behavior or other
clinical signs of offspring of  either generation.  No treatment-related
effects were observed on litter size, sex ratio, or any survival index
(postimplantation survival, live birth, viability, and lactation
indices) in F1 or F2 offspring.  The day of attainment of sexual
maturation and the body weight at attainment were not affected by
treatment with the test material in male or female F1 offspring.  Body
weight was  significantly reduced by 7-13% in high-dose group F1 and F2
male and female pups 14, 21, and 28 days old.  Weight gain over the
28-day postnatal period was significantly decreased by 8-9% in high-dose
F1 male and female pups and by 11-14% in high-dose F2 male and female
pups compared with that of controls due primarily to decreases in weight
gain occurring after postnatal day 7.  Statistically significant changes
in organ weights in F1 and F2 weanlings (absolute and/or relative
spleen, thymus and/or brain) were not accompanied by gross lesions in
these organs and microscopic examinations were not conducted.

The lowest-observed-adverse-effect level (LOAEL) for offspring toxicity
of AE C638206 in rats is 2000 ppm (144.6-179.9 mg/kg by/day in males and
159.7-193.3 mg/kg bw/day in females) based on decreases in body weight
and weight gain F1 and F2 male and female pups.  The
no-observed-adverse-effect level (NOAEL) is 500 ppm (36.4–43.7 mg/kg
bw/day for males and 41.0-46.9 mg/kg bw/day in females).

Kidney toxicity was observed in the parental animals at the high-dose
level; therefore, the animals in this study were adequately dosed to
assess both reproductive and offspring toxicity.

This study is Acceptable/Guideline and it satisfies the guideline
requirement for a two-generation reproductive study (OPPTS 870.3800);
OECD 416 in rats.

3.3.5	Additional Information from Literature Sources tc  \l 3 "3.3.5
Additional Information from Literature Sources"

Available is The Report and Proposed Decision of the United Kingdom made
to the European Commission under article 8(1) of 91/414/ECC (EU
Monograph, MRID 46821401).  This monograph is discussed briefly in
Section 5.1.11.

3.3.6	Pre-and/or Post-natal Toxicity tc  \l 3 "3.3.6	Pre-and/or
Post-natal Toxicity"

There was evidence of qualitative susceptibility in the prenatal rat
study.  However, no prenatal susceptibility (quantitative or
qualitative) was observed in the more sensitive species (rabbit).
Therefore, this risk assessment is protective of the potential
qualitative (but not quantitative) susceptibility that was observed in
the rat prenatal study.

<IP_ADDRESS>	 Determination of Susceptibility tc  \l 4 "<IP_ADDRESS>	Determination
of Susceptibility "

There was no prenatal susceptibility in the developmental rabbit study
with fluopicolide; developmental effects occurred only at doses that
caused severe maternal toxicity.  Additionally, there also was no pre-
and/or post-natal susceptibility in the rat multi-generation
reproduction study; adverse effects in the offspring occurred at doses
that also caused maternal toxicity.

There was qualitative, but not quantitative susceptibility observed in
the developmental rat study with fluopicolide.  At a dose of 700
mg/kg/day, pregnant rats showed only minimally decreased body weight
gain, while the fetuses showed reduced growth and skeletal defects.
This was determined to be qualitative susceptibility.

<IP_ADDRESS>	 Degree of Concern Analysis and Residual Uncertainties for Pre-
and/or Postnatal Susceptibility tc  \l 4 "<IP_ADDRESS>	Degree of Concern
Analysis and Residual Uncertainties for Pre- and/or Postnatal
Susceptibility"

Since there was evidence of increased susceptibility of offspring
following exposure to fluopicolide in the rat developmental study, a
Degree of Concern Analysis was performed to: 1) determine the level of
concern for the effects observed when considered in the context of all
available toxicity data;  and  2) identify any residual uncertainties
after establishing toxicity endpoints and traditional uncertainty
factors to be used in the risk assessment for this chemical.  If
residual uncertainties are identified, an examination is made whether
these residual uncertainties can be addressed by an FQPA safety factor
and, if so, the size of the factor needed.

It is concluded that there is low concern for the qualitative
susceptibility that was observed in the rat because:

the offspring toxicity was well characterized and was accompanied by
maternal toxicity;

there was a clear NOAEL/LOAEL for offspring toxicity;

the developmental effects were observed at a high dose level only (700
mg/kg/day) which is close to the limit dose;

there was an absence of corroborating evidence from other studies, in
that qualitative susceptibility was not demonstrated in the rabbit
developmental study or the rat multigeneration reproduction study;

the dose/endpoint selected for all risk assessments is considerably
lower (rabbit maternal NOAEL 20 mg/kg/day) and would address the
concerns for offspring toxicity seen in this rat study.

Therefore, there are no residual uncertainties for pre- and/or
post-natal toxicity.

3.3.7	Recommendation for a Developmental Neurotoxicity Study

 tc  \l 3 "3.3.7	Recommendation for a Developmental Neurotoxicity Study"

The available data on the toxicity of fluopicolide do not support the
recommendation for a developmental neurotoxicity study.  Prenatal
exposure resulting in delayed growth and skeletal effects did not result
in central nervous system malformations.  While offspring growth was
affected at the same dose that also affected parental animals, no
functional or behavioral changes were reported in adults or pre- or
post-weaning pups (complete neurotoxicity evaluation not done).
Clinical signs suggestive of neurotoxicity were not observed in any
study at doses that caused systemic toxicity such as decreased body
weight or histopathologic lesions.  No gross or microscopic pathology
was found in neurologic tissues from animals on acute and subchronic
neurotoxicity studies or on general subchronic and chronic studies.

3.4	Safety Factor for Infants and Children

 tc  \l 2 "3.4	Safety Factor for Infants and Children"

Based on the hazard and exposure data, the fluopicolide risk assessment
team has recommended that the FQPA Safety Factor be reduced to 1X
because there is a complete toxicity database for fluopicolide and
exposure data are complete or are estimated based on data that
reasonably account for potential exposures.  There is no evidence of
susceptibility following in utero and/or postnatal exposure in the
rabbit developmental toxicity study or in the 2-generation rat
reproduction study.  There is low concern for qualitative susceptibility
observed in the rat developmental toxicity study for a number of reasons
discussed in Section <IP_ADDRESS>, including the position that the regulatory
point of departure (20 mg/kg/day) for the expected exposure scenarios is
well below the LOAEL (700 mg/kg/day) for rat developmental toxicity.
There are no residual uncertainties concerning pre- and post-natal
toxicity and no neurotoxicity concerns.  The dietary food exposure
assessments were performed based on 100%CT and tolerance-level residues
and conservative (protective) assumptions in the ground and surface
water modeling were used to assess exposure to fluopicolide in drinking
water.  HED used similarly conservative assumptions to assess
post-application exposure of children as well as incidental oral
exposure of toddlers.  Based on these data and conclusions, the FQPA
Safety Factor can be reduced to 1X.

3.5	Hazard Identification and Toxicity Endpoint Selection tc  \l 2 "3.5
Hazard Identification and Toxicity Endpoint Selection"

3.5.1	Acute Reference Dose (aRfD) - Females age 13-49 tc  \l 3 "3.5.1
Acute Reference Dose (aRfD) - Females age 13-49"

Study Selected:  None.  An endpoint attributable to a single dose was
not identified from the available data.

MRID No:  None

Executive summary:  None

Dose and Endpoint for Risk Assessment:  None

Comments on Study/Endpoint/Uncertainty Factors:  None

3.5.2	Acute Reference Dose (aRfD) - General Population tc  \l 3 "3.5.2
Acute Reference Dose (aRfD) - General Population "

Study Selected:  None.  An endpoint attributable to a single dose was
not identified from the available data.  Note:  HED has determined that
a change in body temperature in the acute neurotoxicity study is not a
single dose effect.

MRID No:  None

Executive summary:  None

Dose and Endpoint for Risk Assessment:  None

Comments on Study/Endpoint/Uncertainty Factors:  None

3.5.3	Chronic Reference Dose (cRfD)  tc  \l 3 "3.5.3	Chronic Reference
Dose (cRfD) - "

Two studies were selected for establishing points of departure and are
considered co-

critical.  Each study is discussed below.

Study Selected (one of two):   developmental toxicity -- rabbit		OPPTS
3700b

MRID No:  46474122

Executive summary:  See Section 3.3.3.

Dose and Endpoint for Risk Assessment:  Maternal NOAEL of 20 mg/kg/day,
based on death, abortions/premature deliveries, decreased food
consumption and decreased body weight at 60 mg/kg/day.

Study Selected (two of two):   chronic/oncogenicity -- rat		OPPTS 4200a

MRID No:  46474139

Executive summary:  See Appendix A.3.5.

Dose and Endpoint for Risk Assessment:  NOAEL of 31.5 mg/kg/day, based
on decreases in body  weight gain and an increase in thyroid organ
weight with corresponding increases in the incidence of thyroid lesions
at the LOAEL of  109.4 mg/kg/day.

Comments on Study/Endpoint/Uncertainty Factors:  The rabbit
developmental and rat chronic/cancer study were used to determine the
Chronic RfD.  The dosing scheme was similar between these two studies
with a NOAEL/LOAEL of 20 / 60mg/kg/day in rabbits and a NOAEL/LOAEL of
31.5 / 109.4 mg/kg/day for the chronic/cancer rat study.  Although the
chronic study matches the chronic exposure scenario more appropriately
than the rabbit developmental study, the rabbit is the more sensitive
species for fluopicolide.  The rabbit developmental study therefore
provides conservative endpoints for the chronic exposure scenario.

                              Chronic RfD =     20.0 mg/kg/day   =
0.2 mg/kg/day

                                                                     100

3.5.4	Incidental Oral Exposure (Short- and Intermediate-Term)  tc  \l 3
"3.5.4	Incidental Oral Exposure (Short- and Intermediate-Term) "

Study Selected:   developmental toxicity -- rabbit		OPPTS 870.3700b

MRID No:  46474122

Executive summary:  See Section 3.3.3.

Dose and Endpoint for Risk Assessment:  Maternal NOAEL of 20 mg/kg/day,
based on death, abortions/premature deliveries, decreased food
consumption and decreased body weight at 60 mg/kg/day.

Comments on Study/Endpoint/Uncertainty Factors:  The rabbit is the most
sensitive species for fluopicolide.  This rabbit developmental study
provides endpoints appropriate of short and intermediate term exposure
which are more protective of populations than any other available study

3.5.5	Dermal Absorption tc  \l 3 "3.5.5	Dermal Absorption"

For the purposes of this risk assessment, a dermal absorption factor of
37% can be used.  It is the highest level of absorption reported in a
guideline rat dermal penetration study (MRID 46708638, summarized below)
and, therefore, the most conservative/protective number available.  In
addition, an in vitro study (MRID 46708637) using human skin suggests
that dermal penetration of fluopicolide is expected to be considerably
less for humans, compared with rats.  This provides confidence that the
dermal absorption factor of 37% for fluopicolide will not be exceeded.

 μg/cm2 skin) was applied to 12 cm2 skin and removed after 8 hours.
The animals were sacrificed at 8, 24, 72, or 144 hours after
application.  Additionally, 2 male rats/time point/dose were treated
similarly in a preliminary study and were sacrificed at 24, 72, or 144
hours, except only 1 rat was treated with the low dose in the 144 hour
group.

Recovery of the applied dose was 91-109%.  The distribution profile of
radioactivity was qualitatively similar between the two dose groups.
The majority of the administered dose (41-69% of the low dose and 87-91%
of the high dose) was recovered from the swabs used to remove the test
compound from the skin after 8 hours of treatment.  A total of 56-81%
(low dose) or 92-95% (high dose) was considered not absorbed.  After 144
hours, only 2-7% remained at the dose site and was considered available
for absorption.  Estimates of dermal absorption were based on the sum of
urine + feces + cage wash + tissues + treated skin + stratum corneum.
Dermal absorption ranged from 3-8% (high dose) to 22-37% (low dose).  In
the main studies, dermal absorption was greatest at 24 hours after
application, but there was no clear evidence for increased dermal
absorption with time at either dose.  Although there was not a
time-dependent increase in total dermal absorption at either dose, there
was a time-dependent increase in absorption through the stratum corneum
at the low dose (but not the high dose).

This study is classified as acceptable/guideline and satisfies the
guideline requirements (OPPTS 870.7600; OECD none) for a dermal
penetration study in rats.

In a non-guideline in vitro dermal penetration study (MRID 46708637),
[14C-Phenyl]-AE C638206 (Fluopicolide; 99.8% radiochemical purity; Batch
No. SEL/1200) was applied to excised human and rat skin in a suspension
concentrate formulation (EXP 11120A) at 2 dose concentrations, 1.9 and
744 μg/cm2 skin.  Flow-through diffusion cells were prepared for each
skin type at each dose level (n=7/group).  Dermatomed membranes of
approximately 300 µm thickness were tested for permeability prior to
treatment.  Receptor fluid samples were collected each hour after
treatment for 24 hours.  At 8 hours after test compound application, the
skin was swabbed with a mild detergent solution.  After 24 hours, the
experiment was terminated, and the skin membranes were tape stripped.
The initial 2 tape strips were assumed to represent the residual
(non-absorbed) dose.  Subsequent tape strips, the remaining skin, and
the receptor fluid remaining in the cell and outlet tubing at the end of
the experiment were also assayed.  Radioactivity was determined by
liquid scintillation counting.  Results for 5-7 skin
samples/species/dose were reported.

Total recovery was 92.3-96.5%.  The total amounts of applied
radioactivity absorbed within 24 hours at the high dose level were
0.022% in humans and 0.172% in rats, while at low dose levels the
amounts absorbed were 1.454% in humans and 14.26% in rats.  Therefore,
the amount of radioactive material absorbed was 7.8 times greater for
rat skin than for human skin at the high dose level, and 9.8 times
greater for rat skin than human skin at the low dose level.  These data
indicate that dermal penetration studies in the rat will provide a very
conservative estimate of dermal absorption in humans for risk
assessment.

This study is acceptable/non-guideline.

3.5.6	Dermal Exposure (Short-, Intermediate- and Long-Term)  tc  \l 3
"3.5.6	Dermal Exposure (Short-, Intermediate- and Long-Term)"

Study Selected:   developmental toxicity -- rabbit		OPPTS 870.3700b

MRID No:  46474122

Executive summary:  See Section 3.3.3.

Dose and Endpoint for Risk Assessment:  Although the rat dermal toxicity
study (28-day; MRID 46708614) resulted in no systemic toxicity or local
effects at the limit dose (1000 mg/kg/day), the rabbit developmental
toxicity study was chosen since the rabbit is the most sensitive species
for fluopicolide.  The maternal NOAEL is 20 mg/kg/day, based on death,
abortions/premature deliveries, decreased food consumption and decreased
body weight at 60 mg/kg/day.

Comments on Study/Endpoint/Uncertainty Factors:  This rabbit
developmental study provides endpoints protective of short,
intermediate, and long-term exposure.  Based on available data, a dermal
absorption factor of 37% can be used.  A rat dermal subchronic study
showed no local or systemic effects at dose levels up to 1000 mg/kg/day,
indicating that the use of the rabbit developmental study endpoint(s)
provides adequate protection to all populations.

3.5.7	Inhalation Exposure (Short-, Intermediate- and Long-Term)  tc  \l
3 "3.5.7	Inhalation Exposure (Short-, Intermediate- and Long-Term)"

Study Selected:   developmental toxicity -- rabbit		OPPTS 870.3700b

MRID No:  46474122

Executive summary:  See Section 3.3.3.

Dose and Endpoint for Risk Assessment:  Maternal NOAEL of 20 mg/kg/day,
based on death, abortions/premature deliveries, decreased food
consumption and decreased body weight at 60 mg/kg/day.

Comments on Study/Endpoint/Uncertainty Factors:  A repeat dose
inhalation toxicity study is not available for this risk assessment.
The rabbit developmental study provides endpoints protective of short,
intermediate, and long-term exposure and is considered appropriate for
this risk assessment.  Inhalation and oral toxicity are assumed to be
equivalent.

3.5.8	Level of Concern for Margin of Exposure tc  \l 3 "3.5.8	Level of
Concern for Margin of Exposure "

The following MOEs would apply to the non-dietary endpoints selected in
this section (Section 3.5) but not used for this risk assessment.

Table 3.5.8   Summary of Levels of Concern for Risk Assessment.

Route	Short-Term

(1 - 30 Days)	Intermediate-Term

(1 - 6 Months)	Long-Term

(> 6 Months)

Occupational (Worker) Exposure

Dermal	100	100	100

Inhalation	100	100	100

Incidental oral	100	100	100

Residential Exposure

Dermal	100	100	100

Inhalation	100	100	100

3.5.9	Recommendation for Aggregate Exposure Risk Assessments tc  \l 3
"3.5.9	Recommendation for Aggregate Exposure Risk Assessment"

Residential exposure from dermal, inhalation and incidental oral
exposure routes can be aggregated, because the endpoint (death,
abortions/premature deliveries, decreased food consumption and decreased
body weight) for these routes was selected from a single study.

Similarly, for occupational (worker) exposure, dermal and inhalation
exposures can be combined because the endpoint (death,
abortions/premature deliveries, decreased food consumption and decreased
body weight) and study are the same for each.

3.5.10	Classification of Carcinogenic Potential tc  \l 3 "3.5.10
Classification of Carcinogenic Potential"

In accordance with the EPA’s Final Guidelines for Carcinogen Risk
Assessment (March, 2005), the HED Cancer Assessment Review Committee
classified Fluopicolide as “not likely to be carcinogenic to humans”
based on convincing evidence that a non-genotoxic, mitogenic mode of
action for liver tumors was established in the mouse and that the
carcinogenic effects were not likely at doses that do not cause
perturbations of the liver.  Quantification of carcinogenic potential is
not required. The cRfD, which is based on the developmental rabbit
study, is protective of both chronic and carcinogenic effects.

3.5.11	Summary of Toxicological Doses and Endpoints for Fluopicolide
for Use in Human Risk Assessments tc  \l 3 "3.5.11	Summary of
Toxicological Doses and Endpoints for Fluopicolide for Use in Human Risk
Assessments "

Table 3.5.11   Summary of Toxicological Doses and Endpoints for
Fluopicolide for Use in Dietary and Occupational Human Health Risk
Assessments

Exposure/

Scenario	Point of Departure	Uncertainty/FQPA Safety Factors	RfD, PAD,
Level of Concern for Risk Assessment	Study and Toxicological Effects

Acute Dietary

(all populations)	None	None	None	An endpoint attributable to a single
dose was not identified from the available data.

Chronic Dietary (all populations)	Maternal

NOAEL=20 mg/kg/day

	UFA=10x

UFH=10x

FQPA SF = 1X	Chronic RfD =

0.2 mg/kg/day

cPAD = 0.2 mg/kg/day	Developmental Toxicity Study in Rabbits

LOAEL (maternal) = 60 mg/kg/day based on death, abortions/ premature
deliveries, decreased food consumption and body weight gain.

Co-critical: Chronic/Oncogenicity Study in Rats

NOAEL = 31.5 mg/kg/day.

LOAEL = 109.4 mg/kg/day based on decreased body weight gain and
increased thyroid weight and increased incidence of thyroid lesions.

Incidental Oral Intermediate-Term

(1 - 6 months)	Maternal  NOAEL = 20 mg/kg/day	UFA=10x

UFH=10x

FQPA SF = 1X	MOE = 100 (occupational)

MOE = 100 (residential)	Developmental Toxicity Study in Rabbits

LOAEL (maternal) = 60 mg/kg/day based on death, abortions/ premature
deliveries, decreased food consumption and body weight gain.

Dermal Short-  Intermediate- and Long-Term (1-30 days, 1-6 months, and
>6 months)	Maternal  NOAEL = 20 mg/kg/day

	UFA=10x

UFH=10x

FQPA SF = 1X

37% dermal absorption	MOE = 100 (occupational)

MOE = 100 (residential)	Developmental Toxicity Study in Rabbits

LOAEL (maternal) = 60 mg/kg/day based on death, abortions/ premature
deliveries, decreased food consumption and body weight gain.

Co-critical: Chronic/Oncogenicity Study in Rats

NOAEL = 31.5 mg/kg/day.

LOAEL = 109.4 mg/kg/day based on decreased body weight gain and
increased thyroid weight and increased incidence of thyroid lesions.

Inhalation Short- Intermediate- and Long-term (1-30 days,  1-6 months,
and >6 months)	Maternal  NOAEL = 20 mg/kg/day

	UFA=10x

UFH=10x

FQPA SF = 1X

(inhalation and oral toxicity are assumed to be equivalent)	MOE = 100
(occupational)

MOE = 100 (residential)	Developmental Toxicity Study in Rabbits

LOAEL (maternal) = 60 mg/kg/day based on death, abortions/ premature
deliveries, decreased food consumption and body weight gain.

Co-critical: Chronic/Oncogenicity Study in Rats

NOAEL = 31.5 mg/kg/day.

LOAEL = 109.4 mg/kg/day based on decreased body weight gain and
increased thyroid weight and increased incidence of thyroid lesions.

Cancer (oral, dermal, inhalation)	Classification:  “Not Likely to be
Carcinogenic to Humans”.

Point of Departure (POD) = A data point or an estimated point that is
derived from observed dose-response data and  used to mark the beginning
of extrapolation to determine risk associated with lower environmentally
relevant human exposures.  NOAEL = no observed adverse effect level.
LOAEL = lowest observed adverse effect level.  UF = uncertainty factor.
UFA = extrapolation from animal to human (interspecies).  UFH =
potential variation in sensitivity among members of the human population
(intraspecies).  FQPA SF = FQPA Safety Factor.  PAD = population
adjusted dose (a = acute, c = chronic).  RfD = reference dose.  MOE =
margin of exposure.  LOC = level of concern.  N/A = not applicable.

3.6	Endocrine disruption tc  \l 2 "3.6	Endocrine disruption"

EPA is required under the FFDCA, as amended by FQPA, to develop a
screening program to determine whether certain substances (including all
pesticide active and other ingredients) may have an effect in humans
that is similar to an effect produced by a naturally occurring estrogen,
or other such endocrine effects as the Administrator may designate.
Following recommendations of its Endocrine Disruptor and Testing
Advisory Committee (EDSTAC), EPA determined that there was a scientific
basis for including, as part of the program, the androgen and thyroid
hormone systems, in addition to the estrogen hormone system.  EPA also
adopted EDSTAC’s recommendation that the Program include evaluations
of potential effects in wildlife.  For pesticide chemicals, EPA will use
FIFRA and, to the extent that effects in wildlife may help determine
whether a substance may have an effect in humans, FFDCA authority to
require the wildlife evaluations.  As the science develops and resources
allow, screening of additional hormone systems may be added to the
Endocrine Disruptor Screening Program (EDSP).

4.0	Public Health and Pesticide Epidemiology Data.

No information is available since fluopicolide has not been previously
registered for use in the U.S.A.    TC \l1 "4.0	Public Health and
Pesticide Epidemiology Data

5.0	Dietary Exposure/Risk Characterization  TC \l1 "5.0	Dietary
Exposure/Risk Characterization

5.1	Pesticide Metabolism and Environmental Degradation  TC \l2 "5.1
Pesticide Metabolism and Environmental Degradation

5.1.1	Metabolism in Primary Crops  TC \l3 "5.1.1	Metabolism in Primary
Crops

The qualitative nature of the residues of fluopicolide in the primary
plants [cucurbit vegetables, fruiting vegetables, grapes, leafy
vegetables (except Brassica), and tuberous and corm vegetables] is
adequately understood based on adequate metabolism studies on grape,
lettuce, and potato.  The metabolism in grape, lettuce, and potato was
found to be similar.  The majority of radioactivity was found on the
surface of foliage samples (grape, lettuce, and potato) and fruit
samples (grape).  Fluopicolide was the primary residue identified in
grape fruit, lettuce leaves, and potato tubers, accounting for ~51-98%
TRR.  The metabolites 2,6-dichlorobenzamide (BAM;AE C653711) and
3-chloro-5-trifluoromethylpyridine-2-carboxylic acid (PCA; AE C657188)
were found in foliarly-treated grape fruit and lettuce leaves at <4% TRR
each (refer to Appendix B for chemical structures of fluopicolide
metabolites).  In lettuce which had received soil drench application,
BAM was found (17-20% TRR), and both BAM and PCA were found in potato
tubers (12-26% TRR each).  One additional metabolite (AE C643890;
2,6-dichloro-N-[(3-chloro-5-trifluoromethylpyridin-2-yl)methyl]-3-hydrox
ybenzamide) was identified in grape, lettuce, and potato commodities at
<3% TRR.

Fluopicolide is metabolized slowly to 2,6-dichlorobenzamide (BAM; AE
C653711) and 3-chloro-5-trifluoromethylpyridine-2-carboxylic acid (PCA;
AE C657188), via cleavage of the bond between the carbon attached to the
pyridine ring and the amide nitrogen of the parent compound, and to AE
C643890
(2,6-dichloro-N-[(3-chloro-5-trifluoromethylpyridin-2-yl)methyl]-3-hydro
xybenzamide) via hydroxylation of the phenyl ring in the parent
compound.  Based on the results of the soil drench applications in
lettuce, fluopicolide is metabolized in soil to BAM, which is then taken
up by the lettuce plant.  (HED notes that because of the radiolabel of
the test substance used for the soil drench applications, the metabolite
PCA would not have been observed.)

5.1.2	Metabolism in Rotational Crops  TC \l3 "5.1.2	Metabolism in
Rotational Crops

The qualitative nature of the residues of fluopicolide in rotational
crops is adequately understood based on adequate confined rotational
crop studies on lettuce, radish, and wheat.  The metabolism of
fluopicolide in rotational crops appears to be more extensive than that
observed in primary crops (grapes, lettuce, and potato).  In addition to
fluopicolide, BAM, and PCA, four other metabolites
[2,6-dichloro-3-hydroxybenzamide (AE C657378; 3-OH-BAM),
3-methylsulfinyl-5-trifluoromethylpyridine-2-carboxylic acid (AE
1344122; P1X), 3-chloro-5-(trifluoromethyl)-2-pyridine carboxamide (AE
C653598), and 3-chloro-5-(trifluoromethyl)-2-pyridinol (AE B102859)]
were observed in the confined rotational crop studies that were not
observed in the primary crop metabolism studies.  The confined
rotational crop data indicate the potential for quantifiable
fluopicolide and metabolites to occur in rotational crops.

 ≥0.01 ppm in all rotated crop matrices.  TRR were highest in 29-day
PBI matrices, and ranged from 0.083 ppm in radish root and wheat grain
to 13.56 ppm in wheat straw.  TRR decreased at the 133-day PBI, ranging
from 0.02 ppm in radish root to 0.84 ppm in wheat straw.  Residues
increased slightly at the 365-day PBI, ranging from 0.02 ppm in radish
root to 2.37 ppm in wheat straw.  The principal residues identified were
fluopicolide, AE C653711 (BAM), AE C657188 (PCA), AE C657378 (3-OH-BAM),
and AE 1344122 (P1X).  Fluopicolide was found at >0.01 ppm in all
matrices at all PBIs with the exception of wheat grain at the 133- and
365-day PBIs.

5.1.3	Metabolism in Livestock  TC \l3 "5.1.3	Metabolism in Livestock

In ruminants, a large portion of the dosed radioactivity (75-84%) was
excreted.  Fluopicolide was the major residue identified in milk (29%
TRR) and fat (64-76%); it was found at low levels in muscle, liver, and
kidney (<3% TRR).  Fluopicolide appears to be metabolized in ruminants
via hydroxylation of the chlorophenyl ring in two positions to form AE
0712556 and AE C643890; these metabolites were found in liver and kidney
at <7% TRR each.  Each of these metabolites is then conjugated with
sulfate or glucuronic acid, or hydroxylated in a second position and
then conjugated with sulfate or glucuronic acid.  A small amount of BAM
was found in milk (4% TRR).  No PCA was found in any cattle matrix.

 was identified at low levels in egg white, egg yolk, and fat (≤11%
TRR); it was not identified in liver or skin.  The major metabolite
identified in egg white and fat was Metabolite 1, a methyl sulfone
conjugate of fluopicolide, at 51% TRR(0.022 ppm) in egg white and 38%
TRR (0.023 ppm) in fat.  The major residue identified in liver was BAM,
at 37% TRR (0.361 ppm); this metabolite was not found in any other
matrix.

Deficiencies were noted in both the ruminant and poultry metabolism
studies including sample storage and storage stability.  Further details
may be found in the referenced residue chemistry summary document.

5.1.4	Analytical Methodology  TC \l3 "5.1.4	Analytical Methodology

Plant Methods

Enforcement method:  The LC/MS/MS method, Method RM-43C-2 (MRID
47073701), is an adequate enforcement method for determination of
fluopicolide (parent) in plants (DP #329578, C. Stafford, Analytical
Chemistry Branch/Biological and Economic Analysis Division (ACB/BEAD),
3/14/06[07]).  The LOQ for fluopicolide (parent) is 0.01 ppm.

Data Collection Methods:  Acceptable data collection methods, LC/MS/MS
Methods 00782, 00782/M001, 00782/M002, and 00782/M003, or modified
versions of these methods, were used in the storage stability, crop
field trial, processing, and field rotational crop studies associated
with this petition.  Method 00782/M002 determines residues of
fluopicolide (parent), BAM, PCA, and P1X.  Method 00782/M003 determines
3-OH-BAM.  Radiovalidation data have been submitted which indicate that
the extraction procedures of Methods 00782/M002 and 00782/M003
adequately extract aged residues of fluopicolide, BAM, PCA, P1X, and
3-OH-BAM from grape and wheat straw samples.  Adequate method validation
data were submitted.  An independent laboratory validation was conducted
on Method 00782/M002.  All methods were validated with an LOQ of 0.01
ppm for each analyte in each commodity.

Livestock Methods

Enforcement Method:   Method AR 303-02, the LC/MS/MS method described
below, is not acceptable as an enforcement method.  A confirmatory
procedure is required.  Also, 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.

Data Collection Method:  Valent U.S.A. Corporation’s LC/MS/MS method,
Method AR 303-02 (MRID 46708516), which determines residues of
fluopicolide and its metabolites AE C653711 (BAM) and AE C657188 (PCA)
in/on milk, meat, fat, liver, and kidney of cattle, is adequate for data
collection.  Adequate method validation data (recovery data) have been
submitted.  Radiovalidation data are not required because the extraction
solvents used in the method are similar to those used in the cattle
metabolism study.  The validated limits of quantitation (LOQs) for each
analyte are 0.01 ppm for milk, 0.02 ppm for meat, and 0.05 ppm for fat,
liver, and kidney.

Multiresidue Methods

Adequate multiresidue method testing data (MRID 46708525) have been
submitted for fluopicolide and BAM.  These data indicate that the
multiresidue methods are not appropriate for determining residues of
fluopicolide and BAM using some matrices.  Protocol C testing of
fluopicolide and BAM indicated that these compounds were found to
chromatograph with sufficient response on all tested modules except
DG18.  Fluopicolide and BAM were tested under Protocol D, using tomato
as the representative nonfatty matrix, and F, using potato chips as the
representative fatty matrix.  Fluopicolide and BAM were found to be
unrecoverable when tested under Protocol D due to matrix interference.
Therefore, further testing under Protocol E was not conducted.  BAM was
found to be unrecoverable when tested under Protocol F.  Fluopicolide
had small recoveries (29-42%) from a representative fatty matrix, potato
chips, under Protocol F.  The data will be forwarded to FDA.

The FDA PESTDATA database dated 1/94 (PAM,  Volume I, Appendix I)
indicates that BAM is completely recovered (>80%) using Section 302, and
not recovered using Sections 303 and 304.

5.1.5	Environmental Degradation TC \l3 "5.1.5	Environmental Degradation

The fate and behavior in the environment were summarized in DP#325804
(J. Lin, 3/7/07):  “Based on chemical properties and laboratory
environmental fate studies, fluopicolide will not volatilize from soil
or aqueous solution.  Neither photolysis nor hydrolysis is expected to
be a significant degradative pathway for the dissipation of
fluopicolide. Photolysis does, however, enhance the degradation of
fluopicolide soil degradates.  The primary pathway for dissipation of
fluopicolide is by microbial or mineral-catalyzed degradation in soil.
Fluopicolide is unlikely to leach in soil but its moderate water
solubility suggests the potential for runoff in storm or irrigation
water. This potential is significantly mitigated by an increase in
fluopicolide soil binding over time. Laboratory studies suggest moderate
persistence in soil and persistence in sediment under anaerobic
conditions.  However field studies, with multiple degradative pathways
operating simultaneously, suggest only moderate persistence.

“The major routes of degradation for fluopicolide and its degradates
in laboratory studies are photodegradation in water and on soil and
aerobic microbial degradation. Laboratory studies predict that
fluopicolide should persist in soil and aquatic environments.
Degradation in soil was slow with a mean half-life of 413 days. In an
aerobic aquatic system, fluopicolide slowly partitioned into the
sediment and degraded from the water-sediment system with half-lives of
699 to 866 days. In an anaerobic aquatic system, fluopicolide partitions
from water into sediment (water dissipation half-lives of 21.6 to 24.7
days), then slowly degrades with system half-lives of 967 to 1553 days.
A mean KOC value of 340 suggests that fluopicolide could leach in soil
but this leaching potential should abate due to a time dependent
increase in KOC. Field studies support the conclusion that fluopicolide
will not leach. In the soil environment, fluopicolide degradation was
faster with half-lives of 72 to 315 days (mean 181 days) in terrestrial
field studies with no significant leaching of parent.”

BAM can be produced by aerobic soil metabolism.  After formation, there
is a potential for BAM to move into ground water.  BAM can be very
mobile and persistent under aerobic and anaerobic conditions.

5.1.6	Comparative Metabolic Profile  TC \l3 "5.1.6	Comparative Metabolic
Profile

In the rat, fluopicolide was readily absorbed and rapidly excreted.  The
major metabolites identified appeared to be oxidative N-dealkylation
cleavage products, including BAM at 0.09% of the total administered dose
in rats.  The radioactivity concentrations in any given tissue
consistently represented considerably less than 1% of the administered
dose within 24 hours of administration.

Residues are not expected to occur in livestock commodities (ruminants
and poultry) as a result of the proposed and established uses.  In the
livestock metabolism studies, the major residues (> 10% TRR) in
ruminants were fluopicolide (parent) and the dihydroxy glucuronide of
fluopicolide; the major residues in poultry were fluopicolide (parent),
BAM, AE 0712556
(2,6-dichloro-N-[(3-chloro-5-trifluoromethyl-2-pyridyl)methyl]-4-hydroxy
benzamide), Metabolite 1
(2,6-dichloro-N-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]methyl}-3-(me
thylsulfonyl)benzamide), and the dihydroxy sulfate of fluopicolide.

With the possible exception of potatoes, residues are expected to occur
in primary (treated) plants.  In the plant metabolism studies,
fluopicolide (parent) is the major residue in plants after foliar
application.  In the potato metabolism study, BAM and PCA also occurred
at levels > 10% TRR.  Fluopicolide is metabolized slowly to BAM, PCA,
and AE C643890
(2,6-dichloro-N-[(3-chloro-5-trifluoromethylpyridin-2-yl)methyl]-3-hydro
xybenzamide).  The majority of the residue after foliar application and
short preharvest intervals is on the surface of the plant.

More extensive metabolism was observed in rotational crops than in
primary crops.  In addition to residues found in primary crops, four
additional metabolites were found in the confined rotational crop study.
 The confined rotational crop studies indicate the potential for
occurrence of quantifiable residues of fluopicolide and metabolites in
rotational crops.  The major residues (>10% TRR) found in the confined
rotational crop study were fluopicolide (parent), BAM, PCA, AE C643840
(in wheat), 3-OH-BAM, and P1X.

5.1.7	Toxicity Profile of Major Metabolites and Degradates TC \l3 "5.1.7
Toxicity Profile of Major Metabolites and Degradates

The metabolites/degradates included in the risk assessment for one or
more matrices include BAM, PCA, and P1X.

BAM (2,6-dichlorobenzamide; AE C653711) is a metabolite and/or
environmental degradate of both fluopicolide and dichlobenil.  The
toxicity of BAM has been recently reviewed (BAM Human Health Risk
Assessment, DP #345918, N. Dodd, 11/21/07).  The acute and chronic
studies were sufficient to evaluate human hazard potential.  BAM
demonstrated moderate acute toxicity (Category III) via the oral route
of exposure.  Because the subchronic and chronic toxicity of BAM is
considered less than or equal to that of dichlobenil (parent herbicide)
based on submitted and published toxicity studies, the acute toxicity of
BAM via the inhalation and dermal routes is expected to be less than or
equal to that of dichlobenil.  In the case of fluopicolide, the toxicity
profile is different from that of BAM.  The small cPAD (0.0045
mg/kg/day) for BAM is based on decreased body weight and decreased body
weight gain in the chronic oral toxicity study (dog).  There was no
evidence that BAM was either mutagenic or clastogenic in submitted
genotoxicity studies.  In the absence of carcinogenicity study data for
a second species, HED considers the carcinogenic potential of BAM to be
similar to that of dichlobenil, the parent compound having the greatest
carcinogenic potential.  Dichlobenil is classified as “Group C,
possible human carcinogen”, with the RfD approach utilized for
quantification of human cancer risk.  BAM is considered to be
neurotoxic.  No evidence of endocrine modulation was observed in any
study with BAM.  An FQPA SF of 10X for database uncertainty is applied
to acute and chronic dietary and incidental oral exposure scenarios for
incompleteness of the database with regard to the systemic neurotoxic
potential of BAM, including olfactory toxicity) and also, in the case of
acute dietary exposure, use of a LOAEL to extrapolate to a NOAEL.

PCA (3-chloro-5-trifluoromethylpyridine-2-carboxylic acid; AE C657188)
is not expected to be more toxic than parent fluopicolide, based on its
structure.

P1X (3-methylsulfinyl-5-trifluoromethylpyridine-2-carboxylic acid; AE
1344122) is not expected to be more toxic than parent fluopicolide,
based on its structure.

5.1.8	Pesticide Metabolites and Degradates of Concern  TC \l3 "5.1.8
Pesticide Metabolites and Degradates of Concern

As shown in Table 5.1.8 below, HED has determined that the residue of
concern for the tolerance expression in the domestic primary plants
(cucurbit vegetables, fruiting vegetables, grapes, leafy vegetables, and
tuberous and corm vegetables) is fluopicolide (parent) as an indicator
of combined residues of fluopicolide and its metabolite
2,6-dichlorobenzamide.  For the risk assessment, the residues of concern
in the domestic primary plants except tuberous and corm vegetables are
fluopicolide (parent) and 2,6-dichlorobenzamide (BAM).  For tuberous and
corm vegetables, the residues of concern for the risk assessment are
fluopicolide (parent), BAM, and
3-chloro-5-trifluoromethylpyridine-2-carboxylic acid (PCA).

As determined by HED, the residue of concern for the tolerance
expression for rotational crops is fluopicolide (parent) as an indicator
of combined residues of fluopicolide and its metabolite
2,6-dichlorobenzamide.  The residues of concern for the risk assessment
are fluopicolide (parent) and BAM for all rotational crops except the
grain of cereal grains used as human food.  The residues of concern for
the risk assessment for the grain portion of cereal grain rotational
crops used as human food are fluopicolide (parent), BAM, PCA, and
3-methylsulfinyl-5-fluoromethylpyridine-2-carboxylic acid (P1X; AE
1344122).

BAM is a metabolite and/or environmental degradate of both fluopicolide
and dichlobenil.  BAM is a minor metabolite of fluopicolide.  BAM is
included in the tolerance expression for dichlobenil because it is a
major metabolite/degradate of dichlobenil.

The residues of concern in livestock commodities are tentative since
additional information is needed to support the ruminant and poultry
metabolism studies.  Pending submission of the required additional data,
HED has tentatively determined that the residue of concern in livestock
commodities for a tolerance expression is 2,6-dichlorobenzamide (BAM).
For the risk assessment, the residues of concern are fluopicolide
(parent) and BAM.

Based on two aerobic soil metabolism studies, fluopicolide (parent) and
BAM are the residues of concern in drinking water.  BAM was a major
metabolite in these aerobic soil metabolism studies, present at levels
up to 40%.

Table 5.1.8.  Summary of Metabolites and Degradates to be included in
the Risk Assessment and Tolerance Expression

Matrix	Residues included in Risk Assessment1	Residues included in
Tolerance Expression1

Plants

(Tuberous and Corm Vegetables, Leafy Vegetables (except Brassica),
Fruiting Vegetables, Cucurbit Vegetables, and

Grapes)	Primary Crops

	All primary crops except Tuberous and Corm Vegetables	fluopicolide
(parent) and BAM	fluopicolide (parent) as an indicator of combined
residues of fluopicolide and BAM

	Tuberous and Corm Vegetables	fluopicolide (parent), BAM, and PCA

Rotational Crops

	All rotational crops except cereal grains	fluopicolide (parent) and BAM
fluopicolide (parent) as an indicator of combined residues of
fluopicolide and BAM

	Cereal grains: grain for human food	fluopicolide (parent), BAM, PCA,
and P1X

Cereal grains: forage/hay/straw and grain for livestock feed
fluopicolide (parent) and BAM

	Livestock	Ruminant	fluopicolide (parent) and BAM 	BAM

	Poultry

Drinking Water	fluopicolide (parent) and BAM	Not applicable

1 The residues of concern for primary and rotational crops were
determined in a RARC1 meeting on 7/19/07.  The residues of concern in
livestock were discussed in a meeting on 11/5/07; the residues of
concern in livestock are tentative since additional information is
needed to support the ruminant and poultry metabolism studies.

5.1.9 Drinking Water Residue Profile  TC \l3 "5.1.9	Drinking Water
Residue Profile

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

No monitoring data were available for fluopicolide.  Drinking water
residues of fluopicolide (parent) were modeled for exposures resulting
from uses on grapes, vegetables, and turf.  The drinking water residues
were incorporated directly into the dietary assessment, i.e., the water
residues were incorporated in the Dietary Exposure Evaluation Model
(DEEM-FCID) into the food categories “water, direct, all sources”
and “water, indirect, all sources.”

Surface water concentrations were estimated using the Tier II model PRZM
(Pesticide Root Zone Model) version 3.12/ EXAMS (Exposure Analysis
Modeling System) version 2.98.  Ground water concentrations were
estimated using the Tier I SCI-GROW (Screening Concentration in Ground
Water) model.

Based on modeling results, the estimated surface water (drinking water)
concentrations for fluopicolide are:

26.81 ug/L for the 1 in 10 year annual peak concentration (acute)

8.34 ug/L for the 1 in 10 year annual mean concentration (non-cancer
chronic) and

6.14 ug/L for the 30 year annual mean concentration (cancer/chronic).

The 1 in 10 year annual peak (acute) was derived from modeling
fluopicolide use on Florida peppers with ground applications.  The 1 in
10 year annual mean (non-cancer chronic) was derived from modeling
fluopicolide use on California lettuce with aerial applications.  The
30-year annual mean concentration (cancer/chronic) was derived from
fluopicolide use on California lettuce with aerial applications.  These
values were highest among all modeling scenarios examined.

The SCI-GROW estimated ground water (drinking water) concentrations for
fluopicolide are not expected to exceed 0.64 μg/L, which was based on 2
applications to turf of 0.270 lb ai/acre per application.

This chronic dietary assessment used the value of 8.34 ug/L (ppb) for
drinking water.

HED (Paula Deschamp, Amelia Acierto, Nancy Dodd, Kelly O’Rourke, and
Myron Ottley) and EFED (Thuy Nguyen and James Lin) met on April 12, 2007
to determine the residues to include in the drinking water risk
assessment.  It was determined, based on two aerobic soil metabolism
studies, that the residues of concern in drinking water are parent
fluopicolide and the degradate BAM.  BAM was a major degradate, present
at levels up to 40%.  Table 5.1.9 below presents the estimations of
parent fluopicolide only.  Estimated concentrations of BAM in drinking
water are addressed in the BAM Human Health Risk Assessment (DP#345918,
N. Dodd, 11/ 21/07).

Table 5.1.9	Summary of Estimated Surface Water and Groundwater
Concentrations for Fluopicolide (Parent).

	Fluopicolide (parent)

	Surface Water Conc., ppb a	Groundwater Conc., ppb b

Acute	26.81	0.64

Chronic (non-cancer)	8.34	0.64

Chronic (cancer)	6.14	0.64

a From the Tier II PRZM-EXAMS - Index Reservoir model.  Input parameters
are based on CA lettuce with aerial application and a maximum seasonal
use rate of 0.375 lb ai/A.

b From the SCI-GROW model assuming a maximum seasonal use rate of 0.54
lb ai/A, a Koc of 349 mL/g, and a half-life of 413 days.

5.1.10	Food Residue Profile  TC \l3 "5.1.10	Food Residue Profile

Reference:

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 Number 326080, Amelia Acierto,
11/19/07.

Crop Field Trials

Adequate field trial data for tuberous and corm vegetables, leafy
vegetables (except Brassica), fruiting vegetables, cucurbit vegetables,
and grapes are available, pending submission of additional storage
stability data/information for leafy vegetables.  In all field trials,
three foliar applications of a 40% suspension concentrate (SC)
formulation were made for a total of 0.35-0.40 lb ai/A/season (~1x the
proposed seasonal rate).  An adequate number of geographically
representative field trials were conducted:

nineteen field trials on potato (the representative crop for the
tuberous and corm vegetable subgroup 1C);

twenty-eight field trials on the representative crops for the leafy
vegetables crop group: seven field trials on celery, seven on head
lettuce, seven on leaf lettuce, and seven on spinach;

twenty-two field trials on the representative crops of the fruiting
vegetable crop group: seven field trials on bell pepper, three on a
non-bell pepper (chili pepper), and twelve on tomato;

twenty-one field trials on the representative commodities of the
cucurbit vegetable crop group:  nine field trials on muskmelon
(cantaloupe), six on cucumber, and six on summer squash;

and sixteen field trials on grapes.

Tuberous and corm vegetable, subgroup 1C (MRID 46708537)

TABLE <IP_ADDRESS>	  Summary of Residue Data from Crop Field Trials with
Fluopicolide.

Matrix	Total Applic. Rate

(lb a.i./A)

[kg a.i./ha]	PHI (days)	Residue Levels*

(ppm)

	n	Min.	Max.	HAFT	Median

(STMdR)	Mean

(STMR)	Std. Dev.

Fluopicolide

Potatoes	0.350 to 0.372

[0.392 to 0.417]	6 to 8	38	<0.01	0.0126	<0.01 (0.0088)	<0.01	<0.01
0.0012

BAM (AE C653711)

Potatoes	0.350 to 0.372

[0.392 to 0.417]	6 to 8	38	<0.01	<0.01	NA	NA	NA	NA

PCA (AE C657188)

Potatoes	0.350 to 0.372

[0.392 to 0.417]	6 to 8	38	<0.01	0.0447	0.0438	<0.01	< 0.010	0.009

*HAFT = Highest Average Field Trial.

  BAM and PCA are not expressed as parent equivalents.

Leafy vegetable, except Brassica, group 4 (MRIDs 46708533, 46708534,
46708539, 46708540)

Table <IP_ADDRESS>	Summary of Residue Data from Group 4 Crop Field Trials
with Fluopicolide.

Commodity	Total Applic. Rate

 (lb ai/A)

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

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

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

Fluopicolide

Celery	0.354-0.365

[0.397-0.410]	2	14	0.037	13.6	9.9	1.23	2.73	3.70

BAM

Celery	0.354-0.365

[0.397-0.410]	2	14	<0.01	0.041	0.039	NA	NA	NA

PCA

Celery	0.354-0.365

[0.397-0.410]	2	14	<0.01	0.024	0.020	NA	NA	NA

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

Fluopicolide

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

BAM

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

PCA

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

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

Fluopicolide

Leaf lettuce	0.349-0.364

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

BAM

Leaf lettuce	0.349-0.364

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

PCA

Leaf lettuce	0.349-0.364

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

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

Fluopicolide

Spinach	0.357-0.365

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

BAM

Spinach	0.357-0.365

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

PCA

Spinach	0.357-0.365

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

1  HAFT = Highest average field trial result.

Fruiting vegetable, group 8 (MRIDs 46708530, 46708535, and 46708536)

Table <IP_ADDRESS>	Summary of Residue Data from Group 8 Crop Field Trials
with Fluopicolide.

Commodity	Total Applic. Rate

 (lb ai/A)

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

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

BELL PEPPER (proposed use = 0.375 lb ai/A total application rate, 7-day
minimum RTI, 2-day PHI)

Fluopicolide

Bell pepper	0.349-0.358

[0.391-0.401]	2	14	0.0411	0.557	0.523	0.099	0.156	0.163

BAM

Bell pepper	0.349-0.358

[0.391-0.401]	2	14	<0.01	<0.01	NA	NA	NA	NA

PCA

Bell pepper	0.349-0.358

[0.391-0.401]	2	14	<0.01	<0.01	NA	NA	NA	NA

CHILI PEPPER (proposed use = 0.375 lb ai/A total application rate, 7-day
minimum RTI, 2-day PHI)

Fluopicolide

Chili pepper	0.355-0.363

[0.398-0.407]	2	6	0.0837	0.576	0.516	0.300	0.302	0.198

BAM

Chili pepper	0.355-0.363

[0.398-0.407]	2	6	<0.01	<0.01	NA	NA	NA	NA

PCA

Chili pepper	0.355-0.363

[0.398-0.407]	2	6	<0.01	<0.01	NA	NA	NA	NA

TOMATO (proposed use = 0.375 lb ai/A total application rate, 7-day
minimum RTI, 2-day PHI)

Fluopicolide

Tomato	0.356-0.368

[398.9-412.8]	2	24	0.015	0.420	0.375	0.145	0.150	0.094

BAM

Tomato	0.356-0.368

[398.9-412.8]	2	24	<0.01	<0.01	NA	NA	NA	NA

PCA

Tomato	0.356-0.368

[398.9-412.8]	2	24	<0.01	0.013	0.012	NA	NA	NA

1  HAFT = Highest average field trial result.

Cucurbit vegetable, group 9 (MRIDs 46708531, 46708532, and 46708538)

Table <IP_ADDRESS>	Summary of Residue Data from Group 9 Crop Field Trials
with Fluopicolide.

Commodity	Total Applic. Rate

 (lb ai/A)

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

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

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

Fluopicolide

Cantaloupe	0.352-0.362

[0.395-0.406]	2	18	<0.01	0.258	0.181	0.055	0.068	0.061

BAM

Cantaloupe	0.352-0.362

[0.395-0.406]	2	18	<0.01	<0.01	NA	NA	NA	NA

PCA

Cantaloupe	0.352-0.362

[0.395-0.406]	2	18	<0.01	<0.01	NA	NA	NA	NA

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

Fluopicolide