UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

     OFFICE OF

PREVENTION, PESTICIDES

AND TOXIC SUBSTANCES

Date: 01/31/07

MEMORANDUM

SUBJECT:	Fluopicolide:  Human Health Risk Assessment for Imported
Grapes.  PC Code: 027412, Petition No: 5E6903, DP Number: 315502.

		Regulatory Action:  Section 3 Action

Risk Assessment Type: Single Chemical/ No Aggregate

FROM:	Nancy Dodd, Chemist

		Registration Action Branch 3

		Health Effects Division (7509P)

			AND

		Amelia Acierto, Chemist

		Myron Ottley, Toxicologist

		Registration Action Branch 3

		Health Effects Division (7509P)

THROUGH:	Mary Elissa Reaves, Ph.D., Toxicologist

Christine Olinger, Chemist

Risk Assessment Review Committee

			AND

Paula Deschamp, Branch Chief

		Registration Action Branch 3

		Health Effects Division (7509P)

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

		Fungicide Branch

		Registration Division (7505P)

Bayer CropScience AG has submitted a petition for tolerances for the
fungicide fluopicolide in/on imported grapes and raisins.  The
Registration Division of the Office of Pesticide Programs (OPP) has
requested that HED evaluate hazard and exposure data and conduct dietary
exposure assessments to estimate the risk to human health that will
result from importation of fluopicolide-treated grapes.  Occupational,
residential, and aggregate exposure assessments have not been conducted
since HED has determined that they are not needed for fluopicolide on
imported grapes.

Fluopicolide is a new fungicide with no established U.S. tolerances.
This request for tolerances for imported grapes and raisins is being
followed by petitions for domestic uses on grapes and other crops.

The residue chemistry and the toxicological databases support the
establishment of tolerances for the fungicide fluopicolide of 2.0 ppm
in/on grape and 6.0 ppm in/on grape, raisin.  Provided the deficiencies
regarding the Sections B and F and the method validation which are
specified in Section 10.0 of this document are resolved, the tolerances
can be granted; deficiencies regarding storage stability can be resolved
after establishment of the tolerances.

One of the formulations used in the crop field trials, the 4.44%
water-dispersible granule (WDG) formulation of fluopicolide, also
contains fosetyl-aluminum.  A tolerance with regional registration is
established in 40 CFR §180.415(c) for residues of fosetyl-aluminum on
grapes at 10 ppm.  Based on a substantially lower use rate and
comparable preharvest interval for imported grapes as compared to the
registered fosetyl-aluminum use, residues of fosetyl-aluminum on
imported grapes are not likely to exceed the established 10 ppm
tolerance.

As part of every pesticide risk assessment, HED considers a large
variety of consumer subgroups.  These are broken into two main
categories: 1) subgroups based on dietary consumption patterns, and 2)
subgroups based on activity patterns in a residential setting.  In the
course of assessing the potential exposures resulting from the use of
fluopicolide, HED considered to the extent possible whether or not there
are population groups that may have unusually high exposure compared to
the general population.  HED did not identify any additional specialized
subgroup that would not be included in the generic models and approaches
utilized for this risk assessment.

A summary of the findings and an assessment of human risk resulting from
fluopicolide on imported grapes are provided in this document.  The
residue chemistry assessment was provided by Amelia Acierto, the dietary
exposure assessment and risk assessment by Nancy Dodd, and the hazard
characterization by Myron Ottley of RAB3/HED.

Table of Contents

  TOC \f  1.0	Executive Summary	  PAGEREF _Toc160520958 \h  5

2.0	Ingredient Profile	  PAGEREF _Toc160520959 \h  10

2.1	Summary of Registered/Proposed Uses	  PAGEREF _Toc160520960 \h  10

2.2	Structure and Nomenclature	  PAGEREF _Toc160520961 \h  11

2.3	Physical and Chemical Properties	  PAGEREF _Toc160520962 \h  12

3.0	Hazard Characterization/Assessment	  PAGEREF _Toc160520963 \h  13

3.1	Hazard and Dose-Response Characterization	  PAGEREF _Toc160520964 \h
 13

3.1.1	Database Summary	  PAGEREF _Toc160520965 \h  13

<IP_ADDRESS>	Studies available and considered (animal, human, general
literature)	  PAGEREF _Toc160520966 \h  13

<IP_ADDRESS>	Mode of action, metabolism, toxicokinetic data	  PAGEREF
_Toc160520967 \h  13

<IP_ADDRESS>	Sufficiency of studies/data	  PAGEREF _Toc160520968 \h  13

3.1.2	Toxicological Effects	  PAGEREF _Toc160520969 \h  14

3.1.3	Dose-response	  PAGEREF _Toc160520970 \h  15

3.1.4	FQPA	  PAGEREF _Toc160520971 \h  16

3.2	Absorption, Distribution, Metabolism, Excretion (ADME)	  PAGEREF
_Toc160520972 \h  16

3.3	FQPA Considerations	  PAGEREF _Toc160520973 \h  16

3.3.1	Adequacy of the Toxicity Database	  PAGEREF _Toc160520974 \h  16

3.3.2	Evidence of Neurotoxicity	  PAGEREF _Toc160520975 \h  17

3.3.3	Developmental Toxicity Studies	  PAGEREF _Toc160520976 \h  19

3.3.4	Reproductive Toxicity Study	  PAGEREF _Toc160520977 \h  21

3.3.5	Additional Information from Literature Sources	  PAGEREF
_Toc160520978 \h  23

3.3.6	Pre-and/or Postnatal Toxicity	  PAGEREF _Toc160520979 \h  23

<IP_ADDRESS>	Determination of Susceptibility	  PAGEREF _Toc160520980 \h  23

<IP_ADDRESS>	Degree of Concern Analysis and Residual Uncertainties for Pre-
and/or Postnatal Susceptibility	  PAGEREF _Toc160520981 \h  24

3.3.7	Recommendation for a Developmental Neurotoxicity Study	  PAGEREF
_Toc160520982 \h  24

3.4	Safety Factor for Infants and Children	  PAGEREF _Toc160520983 \h
24

3.5	Hazard Identification and Toxicity Endpoint Selection	  PAGEREF
_Toc160520984 \h  25

3.5.1	Acute Reference Dose (aRfD) - Females age 13-49	  PAGEREF
_Toc160520985 \h  25

3.5.2	Acute Reference Dose (aRfD) - General Population	  PAGEREF
_Toc160520986 \h  25

3.5.3	Chronic Reference Dose (cRfD) -	  PAGEREF _Toc160520987 \h  25

3.5.4	Incidental Oral Exposure (Short- and Intermediate-Term)	  PAGEREF
_Toc160520988 \h  26

3.5.5	Dermal Absorption	  PAGEREF _Toc160520989 \h  26

3.5.6	Dermal Exposure (Short-, Intermediate- and Long-Term)	  PAGEREF
_Toc160520990 \h  28

3.5.7	Inhalation Exposure (Short-, Intermediate- and Long-Term)
PAGEREF _Toc160520991 \h  28

3.5.8	Level of Concern for Margin of Exposure	  PAGEREF _Toc160520992 \h
 28

3.5.9	Recommendation for Aggregate Exposure Risk Assessments	  PAGEREF
_Toc160520993 \h  29

3.5.10	Classification of Carcinogenic Potential	  PAGEREF _Toc160520994
\h  29

3.5.11	Summary of Toxicological Doses and Endpoints for Fluopicolide for
Use in Human Risk Assessments	  PAGEREF _Toc160520995 \h  30

3.6	Endocrine disruption	  PAGEREF _Toc160520996 \h  31

4.0	Public Health and Pesticide Epidemiology Data	  PAGEREF
_Toc160520997 \h  31

4.1	Incident Reports	  PAGEREF _Toc160520998 \h  31

4.2	National Health and Nutritional Examination Survey (NHANES)
PAGEREF _Toc160520999 \h  31

4.3	Agricultural Health Study (AHS)	  PAGEREF _Toc160521000 \h  31

4.4	Other Pesticide Epidemiology Published Literature	  PAGEREF
_Toc160521001 \h  31

5.0	Dietary Exposure/Risk Characterization	  PAGEREF _Toc160521002 \h
32

5.1	Pesticide Metabolism and Environmental Degradation	  PAGEREF
_Toc160521003 \h  32

5.1.1	Metabolism in Primary Crops	  PAGEREF _Toc160521004 \h  32

5.1.2	Metabolism in Rotational Crops	  PAGEREF _Toc160521005 \h  33

5.1.3	Metabolism in Livestock	  PAGEREF _Toc160521006 \h  33

5.1.4	Analytical Methodology	  PAGEREF _Toc160521007 \h  33

5.1.5	Environmental Degradation	  PAGEREF _Toc160521008 \h  33

5.1.6	Comparative Metabolic Profile	  PAGEREF _Toc160521009 \h  33

5.1.7	Toxicity Profile of Major Metabolites and Degradates	  PAGEREF
_Toc160521010 \h  34

5.1.8	Pesticide Metabolites and Degradates of Concern	  PAGEREF
_Toc160521011 \h  35

5.1.9	Drinking Water Residue Profile	  PAGEREF _Toc160521012 \h  35

5.1.10	Food Residue Profile	  PAGEREF _Toc160521013 \h  35

5.1.11	International Residue Limits	  PAGEREF _Toc160521014 \h  36

5.2	Dietary Exposure and Risk	  PAGEREF _Toc160521015 \h  36

5.2.1	Acute Dietary (Food Only) Exposure/Risk	  PAGEREF _Toc160521016 \h
 36

5.2.2	Chronic Dietary (Food Only) Exposure/Risk	  PAGEREF _Toc160521017
\h  36

5.2.3	Cancer Dietary Risk	  PAGEREF _Toc160521018 \h  37

5.3	Anticipated Residue and Percent Crop Treated (%CT) Information
PAGEREF _Toc160521019 \h  37

6.0	Residential (Non-Occupational) Exposure/Risk Characterization
PAGEREF _Toc160521020 \h  38

7.0	Aggregate Risk Assessments and Risk Characterization	  PAGEREF
_Toc160521021 \h  38

8.0	Cumulative Risk Characterization/Assessment	  PAGEREF _Toc160521022
\h  38

9.0	Occupational Exposure/Risk Pathway	  PAGEREF _Toc160521023 \h  38

10.0	Data Needs and Label Requirements	  PAGEREF _Toc160521024 \h  38

10.1	Toxicology	  PAGEREF _Toc160521025 \h  38

10.2	Residue Chemistry	  PAGEREF _Toc160521026 \h  38

10.3	Occupational and Residential Exposure	  PAGEREF _Toc160521027 \h
40

References:	  PAGEREF _Toc160521028 \h  40

Appendix A: Toxicology Assessment	  PAGEREF _Toc160521029 \h  41

A.1  Toxicology Data Requirements	  PAGEREF _Toc160521030 \h  41

A.2  Toxicity Profiles	  PAGEREF _Toc160521031 \h  42

A.3  Executive Summaries	  PAGEREF _Toc160521032 \h  48

Appendix B:  Metabolism Assessment	  PAGEREF _Toc160521033 \h  66

Appendix C:  Tolerance Assessment Summary and Table	  PAGEREF
_Toc160521034 \h  67

Appendix D:  Review of Human Research	  PAGEREF _Toc160521035 \h  68

Appendix E:  Sections 3.0, 4.0, 8.0, and 10.0 for BAM	  PAGEREF
_Toc160521036 \h  69

1.0	Executive Summary  TC \l1 "1.0	Executive Summary

Use Profile:  Fluopicolide is a fungicide to be used on imported grapes.
Three foliar applications are to be made to grapes in Europe at the
maximum seasonal application rate of 0.36 lb ai/A.  Minimum retreatment
intervals of 10 days and a preharvest interval of 21 days are to be
observed.

One of the formulations used in the crop field trials, the 4.44%
water-dispersible granule (WDG) formulation of fluopicolide, also
contains fosetyl-aluminum.  A tolerance with regional registration is
established in 40 CFR §180.415(c) for residues of fosetyl-aluminum on
grapes at 10 ppm.   Based on a substantially lower use rate and
comparable preharvest interval for imported grapes as compared to the
registered fosetyl-aluminum use, residues of fosetyl-aluminum on
imported grapes are not likely to exceed the established 10 ppm
tolerance.

Fluopicolide controls a wide range of Oomycete (Phycomycete) diseases
including downy mildews (Plasmopara, Pseudoperonospara, Peronospora,
Bremia), late blight (Phytophthora), and some Pythium species.

The mode of action of fluopicolide has not been determined; however, it
is a mode of action unlike the known modes of action of other registered
fungicides.

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) is a metabolite and/or environmental
degradate of both fluopicolide and dichlobenil.  As determined by the
HED Risk Assessment Review Committee (RARC1) on 12/21/06, BAM will not
be included in the tolerance or risk assessment for fluopicolide on
imported grapes because 1) as both a plant and rat metabolite of
fluopicolide, it has been included in the toxicology studies and
fluopicolide endpoint selections; and 2) residues of BAM in food
resulting from fluopicolide on imported grapes are expected to be
negligible since BAM is only 2.0% of the total radioactive residue in
the fluopicolide grape metabolism study and is a maximum of only 0.047
ppm in the fluopicolide grape field trials.  However, both parent
fluopicolide and BAM will be included in risk assessments for future
uses of fluopicolide on domestic crops since more exposure to BAM is
expected with domestic uses.

Human Health Risk Assessment:

Toxicity/Hazard:  An appropriate endpoint was identified for the chronic
dietary exposure scenario based on a NOAEL in a developmental toxicity
study in rabbits and uncertainty factors of 10x for extrapolation from
animals to humans (interspecies variation) and 10x for potential
variation in sensitivity among members of the human population
(intraspecies variation).  A LOAEL in that study was based on death,
abortions/premature deliveries, decreased food consumption, and
decreased body weight gain.  No appropriate endpoint was identified for
an acute dietary assessment.  Incidental oral, dermal, and inhalation
endpoints were selected but are not applicable to this risk assessment
because residential and occupational exposures are not anticipated for
an imported crop.  Fluopicolide is not likely to be carcinogenic to
humans.

Dietary Exposure (Food Only):  A dietary exposure assessment was
conducted using the Dietary Exposure Evaluation Model DEEM-FCID™,
Version 2.03, which uses food consumption data from the U.S. Department
of Agriculture’s Continuing Surveys of Food Intakes by Individuals
(CSFII) from 1994-1996 and 1998.  The dietary exposure assessment was
conducted for residues of fluopicolide (parent only) in food (only).
Since U.S. registration is not required for an imported crop and there
are no existing U.S. registrations for fluopicolide, no fluopicolide
residues are expected to occur in drinking water.

The chronic dietary (food only) exposure assessment for fluopicolide on
imported grapes was a conservative assessment using the recommended
tolerance levels and assuming that 100% of the crop was treated and 100%
of the crop was imported.  An adequate processing study was conducted on
grapes indicating no concentration in grape juice but concentration in
raisins.  No default processing factors were used since an adequate
processing study was available; tolerance levels of 2.0 ppm and 6.0 ppm
were used for grapes and raisins, respectively.  Since grapes are
imported, no fluopicolide residues are expected to occur in rotational
crops.  Since no livestock feed items are associated with grapes, no
fluopicolide residues are expected to occur in livestock commodities.

The chronic dietary (food only) 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 <1%
cPAD for the general U.S. population and 3% cPAD for children 1-2 years
old, the most highly exposed subgroup.

Residential Exposure:  There are no U.S. registrations for fluopicolide;
therefore, no residential exposure is expected.

Aggregate Risk:  No aggregate exposure is expected to occur in the U.S.
as a result of fluopicolide on imported grapes since exposure is
expected to occur only from food.

Occupational Exposure/Risk:  No occupational exposure to fluopicolide is
expected to occur in the U.S. as a result of fluopicolide on imported
grapes.

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 (as it relates to an imported crop), 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 does not rely on any data from studies in which
human subjects were intentionally exposed to a pesticide or other
chemical.

Additional Data Needs:

Pending the resolution of Residue Chemistry Deficiencies #’s 1a and 1b
(pertaining to directions for use), Deficiency # 2 (pertaining to the
requirement for a proposed confirmatory method or an interference
study), Deficiency #3 (pertaining to the need for the proposed
enforcement method, Method 00782/M002, to undergo a successful petition
method validation by ACB/BEAD), and Deficiency #6 (pertaining to a
revised Section F), there are no Residue Chemistry data gaps that would
preclude permanent tolerances for residues of fluopicolide as follows:
SEQ CHAPTER \h \r 1

Grape	2.0 ppm

Grape, raisin	6.0 ppm

This decision is based on use of water dispersible granular (WDG) or
emulsifiable concentrate (EC) formulations without adjuvants.  To use
other formulations (other than WDG and EC formulations) or spray
adjuvants, additional residue data (or review of additional residue
data) would be required as indicated in Deficiencies 1c and 1d.

Deficiency #4 (pertaining to storage stability data for fluopicolide in
juice or must [i.e., the unfiltered liquid that results from pressing
grapes] and raisins) and Deficiency #5 (pertaining to length of storage
information for the processed commodities) are confirmatory data
requirements which must be resolved but can be resolved after
establishment of the tolerances.

Residue Chemistry Deficiencies

860.1200  Directions for Use

1a.	Residue data were submitted which reflected use of a 4.44% WDG
formulation (WG71) and a 95 g/L suspo-emulsion formulation (SE10), which
is similar to an emulsifiable concentrate (EC) formulation.  The
petitioner should submit representative labels or a revised Section B to
indicate the types of formulations to be used on imported grapes.

1b.	A Section B was submitted which provided some information regarding
the proposed use pattern on imported grapes, including the maximum
number of applications per season (3), the maximum seasonal application
rate (0.36 lb ai/A), the minimum preharvest interval (PHI; 21 days), and
retreatment intervals (10-14 days).  The petitioner should submit a
representative label or a revised Section B to more fully describe the
use pattern(s) to be applied to grapes and raisins to be exported to the
USA.  The additional information to be provided to the Agency should
include the maximum single application rate, application timing (as it
relates to the plant growth stage), names and quantities of stickers,
spreaders, and other adjuvants (if any) to be added to the spray
solution, application tank-mix preparation, volume of spray mix per unit
area (hectare or acre), and type of application equipment.

1c.	No spray adjuvants were used in the crop field trials submitted to
support this petition.  If the petitioner intends to recommend use of
spray adjuvants, residue data reflecting use of spray adjuvants should
be submitted.

1d.	The submitted residue data reflect use of WDG and EC types of
formulations.  If other types of formulations are to be used on grapes
to be imported, additional residue data would be needed to reflect use
of those other types of formulations.

860.1340  Residue Analytical Methods

2.	The petitioner must propose confirmatory procedures for the proposed
enforcement method, or submit an interference study for fluopicolide.

3.	The proposed enforcement method, Method 00782/M002, must be validated
as an adequate enforcement method by ACB/BEAD.

860.1380  Storage Stability

4.	The petitioner must submit data demonstrating the stability of
residues of fluopicolide in grape juice (or must) and raisins stored
frozen for 29 months or the maximum storage interval for each of these
commodities.

860.1520  Processed Food and Feed

5.	The petitioner should submit the actual dates of collection,
extraction, and analysis for each sample of grape juice (or must) and
raisins from the processing studies to determine the storage interval
required for the storage stability study.

860.1550  Proposed Tolerances

6.	The proposed tolerances should be revised to reflect the recommended
tolerance levels and correct commodity definitions as specified in
Appendix C.

Toxicology 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 belongs to the benzamide
class and the pyridine class.  Another fungicide in the benzamide class
is zoxamide.

Fluopicolide controls a wide range of Oomycete (Phycomycete) diseases
including downy mildews (Plasmopara, Pseudoperonospara, Peronospora,
Bremia), late blight (Phytophthora), and some Pythium species.

The mode of action of fluopicolide has not been determined; however, it
is a mode of action unlike the known modes of action of other registered
fungicides.

Fluopicolide is a mesosystemic fungicide; it translocates toward the
stem tips via the xylem but it does not translocate toward the roots.

2.1	Summary of Registered/Proposed Uses

  TC \l2 "2.1	Summary of Registered/Proposed Uses

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

Grapes

Foliar (application timing and equipment not specified)	Not specified
Not specified	3	0.36

[400]	21	A minimum retreatment interval of 10 days is specified.

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)	1.  WG71 Formulation (4.44% AE C638206 + 66.7%
fosetyl-aluminum)

2.  SE10 (Suspo-Emulsion; similar to an emulsifiable concentrate; 95
g/L)

Chemical Class	Fungicide

Known Impurities of Concern	None

2.3	Physical and Chemical Properties

The physical/chemical properties of fluopicolide as they affect
inhalation or dermal exposure are not relevant for an imported crop.  TC
\l2 "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 46474015

pH 	6.5 at 22.0 (C 	MRID 46474013

Density 	1.65 g/cc 	MRID 46474016

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 46474021

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 46474022

Vapor pressure at 25 (C 	8.03 x 10-7 Pa 	MRID 46474023

Dissociation constant (pKa) 	No evidence of ionization in the pH range
of 1.9 to 9.8 	MRID 46474017

Octanol/water partition coefficient Log(KOW) 	Log POW = 3.26 at pH 7.8
and 22 ± 1 (C 	MRID 46474018

	Log POW = 2.9 at pH 4.0, 7.3 and 9.1 and 40 (C 	MRID 46474019

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 46474014

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 Appendix E.

<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 in which no adverse effects were noted. The
lowest-observed-adverse-effect level (LOAEL) is the 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). Moderate eye irritation occurred in the
form of chemosis and corneal opacities, but all effects were gone by 72
hours. Slight dermal irritation occurred, but 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 malformations 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 rats the adverse
effect was judged to be greater in the fetus than in the dam, suggesting
a greater susceptibility in the fetus compared to that of the dam.

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.  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
chronic dietary exposure scenario, incidental oral short-term and
intermediate-term, 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.  In
the rat developmental study, the developmental effects, developmental
delays and skeletal defects, were judged to be qualitatively more severe
than the minimal maternal toxicity (decreased body weight gain)
observed.  In the multigeneration study, neither quantitative nor
qualitative susceptibility was observed.  Although there was evidence of
increased qualitative susceptibility in the rat developmental study, the
concern is low and there are no residual uncertainties.  The 10X FQPA
Safety Factor is reduced to 1X.  (See section <IP_ADDRESS> for details.)

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.

BAM also is a plant and soil metabolite of other compounds such as
dichlobenil, and concern has been expressed about the contribution of
fluopicolide to total environmental levels of BAM.  When fluopicolide is
administered to the rat, only about 0.09% of the total administered
radioactivity 8 hrs post dosing is identified as BAM, mitigating against
this concern.

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 FQPA.

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.

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
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 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 high dose approached the limit dose for rats but
was well below the limit dose for rabbits.  Minimal maternal toxicity
was evident in rats but was marked in rabbits.  At the highest dose
tested, pregnant rats had slightly reduced body weight gain that did not
affect absolute body weight.  In contrast, rabbits demonstrated
increased mortality, abortion/premature delivery, decreased food
consumption, and decreased body weight gain or weight loss at the
highest dose.

Developmental toxicity was observed at the highest dose tested in both
species. In rats, maternal

administration of 700 mg/kg, resulted in delayed fetal growth and
skeletal malformations but no

treatment-related structural external or visceral abnormalities. In
fetal rabbits, maternal treatment

with 60 mg/kg/day resulted in increased abortion/premature delivery and
delayed fetal growth

with no treatment-related structural external, visceral, or skeletal
abnormalities.

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 malformations or
external or visceral variations were observed in any group.

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

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

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

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
(in g/100 g bw) was decreased to 73-89% of controls during GD 8-23
(n.s) and to 46-57% of controls during GD 23-29 (p<0.05).  Red
discoloration of the urine was noted from two additional high-dose
animals at necropsy for a total of five affected (3 in life and 2 post
mortem); this finding is considered treatment-related and possibly
adverse.

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

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

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

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

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"

No additional information on the toxicity of fluopicolide was identified
in the open literature.

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

It is concluded that there is concern for prenatal toxicity resulting
from exposure to fluopicolide.

<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 maternal toxicity.  There was no prenatal susceptibility in the
rat multi-generation reproduction study either; adverse effects in the
offspring occurred at doses that also caused maternal toxicity.

There was qualitative, but not quantitative susceptibility 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.

<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 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 because:  the offspring toxicity was well characterized
and was accompanied by maternal toxicity;  there was a clear NOAEL/LOAEL
for offspring toxicity;  and because the dose/endpoint selected for
long- term risk assessments is considerably lower and would address the
concerns for offspring toxicity seen in this study.  Therefore, there
are no residual uncertainties for pre- and/or postnatal 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 because the offspring
effects (reduced growth and skeletal defects) are well characterized and
accompanied by maternal toxicity.  There are no residual uncertainties
concerning pre- and post-natal toxicity and no neurotoxicity concerns.
The dietary food exposure assessment utilizes tolerance level residues
and 100% CT.  There is no potential for drinking water exposure.  There
is no potential for residential exposure.  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.

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) - "

Study Selected:   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.

Comments on Study/Endpoint/Uncertainty Factors:  A chronic study in rats
(MRID 46474139) provided a NOAEL of 31.5/41.0 mg/kg/day (M/F) based on
decreased weight gain in males and females and thyroid lesions in males
at 109.4/142.2 mg/kg/day (M/F).  The duration of dosing and the chronic
endpoint are appropriate for this scenario, and represents the highest
level at which toxicity is not seen, based on the available data.
However, this rabbit developmental study provides valid endpoints which
are more protective of populations than any other available study.

                              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:  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"

Two studies are available (MRID 46708638 and 46708637 summarized below)
which show that 1) dermal absorption through rat skin (in vivo) is as
high as 37%, and 2) that human skin (in vitro) is about eight times less
permeable than rat skin.

 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% (low dose) to 22-37% (high 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:  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:  This rabbit
developmental study provides endpoints appropriate of short,
intermediate, and long-term exposure.  A rat dermal subchronic study
(MRID 46708614) 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:  An inhalation study is
not available for this risk assessment.  The rabbit developmental study
provides endpoints appropriate of short, intermediate, and long-term
exposure and is considered appropriate for this risk assessment.  100%
absorption rate is assumed.

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

There is no concern for margins of exposure because there is no
occupational or residential exposure anticipated in this risk
assessment.  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

Not applicable. tc  \l 3 "3.5.9	Recommendation for Aggregate Exposure
Risk Assessments "

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 <IP_ADDRESS>  Summary of Toxicological Doses and Endpoints for
Fluopicolide for Use in Dietary and Non-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 = 60 mg/kg/day based death, abortions/ premature deliveries,
decreased food consumption, decreased body weight gain.

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 = 60 mg/kg/day based death, abortions/ premature deliveries,
decreased food consumption, decreased body weight gain.

Dermal Short-  Intermediate- and Long-Term (1-30 days and 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 = 60 mg/kg/day based death, abortions/ premature deliveries,
decreased food consumption, decreased body weight gain.

Inhalation Short- Intermediate- and Long-term (1-30 days and 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 = 60 mg/kg/day based death, abortions/ premature deliveries,
decreased food consumption, decreased body weight gain.

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).  UFL = use of a LOAEL to extrapolate a NOAEL.  UFS = use
of a short-term study for long-term risk assessment.  UFDB = to account
for the absence of key data (i.e., lack of a critical study).  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.  TC \l1 "4.0	Public
Health and Pesticide Epidemiology Data

4.1	Incident Reports  TC \l2 "4.1	Incident Reports

No information is available since fluopicolide is not registered for use
in the U.S.

4.2	National Health and Nutritional Examination Survey (NHANES)   TC \l2
"4.2	National Health and Nutritional Examination Survey (NHANES)

No information is available since fluopicolide is a new pesticide.

4.3	Agricultural Health Study (AHS)   TC \l2 "4.3	Agricultural Health
Study (AHS)

No information is available since fluopicolide is a new pesticide.

4.4	Other Pesticide Epidemiology Published Literature  TC \l2 "4.4	Other
Pesticide Epidemiology Published Literature

No information is available since fluopicolide is a new pesticide.

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 residue of fluopicolide in grapes is
adequately understood.  As determined by the HED Risk Assessment Review
Committee (RARC1) on 12/21/06, the residue of concern for the tolerance
and the risk assessment for fluopicolide on imported grapes (only) is
fluopicolide (parent).  2,6-Dichlorobenzamide (BAM) is a metabolite
and/or environmental degradate of both fluopicolide and dichlobenil.  As
determined by the RARC1,  BAM will not be included in the tolerance or
risk assessment for fluopicolide on imported grapes because 1) as both a
plant and rat metabolite, it has been included in the toxicology studies
and fluopicolide endpoint selections; and 2) residues of BAM in food
resulting from fluopicolide on imported grapes are expected to be
negligible since BAM is only 2.0% of the total radioactive residue in
the fluopicolide grape metabolism study and is a maximum of only 0.047
ppm in the fluopicolide grape field trials.  However, both parent
fluopicolide and BAM will be included in risk assessments for future
uses of fluopicolide on domestic crops since more exposure to BAM is
expected with domestic uses.

Metabolism studies were conducted on greenhouse-grown grapes using
suspension concentrate formulations of [2,6-14C-pyridinyl]fluopicolide
and [U-14C-phenyl]fluopicolide.  The formulations were applied to grape
vines as three sequential foliar applications at nominal rates of 0.149,
0.104, and 0.104 lb ai/A or 1.49, 1.04, and 1.04 lb ai/A.  The total
application rates were 0.357 lb ai/A (1x the proposed maximum seasonal
rate) and 3.56 lb ai/A (10x the proposed maximum seasonal rate).  In
mature samples (21-day PHI) at the 1X rate, total radioactive residues
(TRR) were 11.754-24.397 ppm in/on forage and 1.012-1.344 ppm in/on
fruit.  TRR in samples treated at the higher rate were approximately 10x
greater than in samples treated at the lower rate.

The majority of radioactivity was found to be on the surface of fruit
and foliage samples.  Surface washes with acetonitrile (ACN) released
~50-75% TRR from mature foliage samples and ~46-79% TRR from mature
fruit samples.  Fluopicolide was the primary residue identified in the
fruit, accounting for 87-91% TRR (0.91-1.15 ppm) in/on fruit at the 1x
treatment rate.  Three minor metabolites were identified in fruit at 1X:
 2,6-dichlorobenzamide (BAM; AE C653711) at 2.0% TRR (0.026 ppm);
3-chloro-5-trifluoromethylpyridine-2-carboxylic acid (PCA; AE C657188)
at 2.3% TRR (0.024 ppm), and
2,6-dichloro-N-[(3-chloro-5-trifluoromethylpyridin-2-yl)methyl]-3-hydrox
ybenzamide (AE C643890) at 0.2% TRR (0.002 ppm).  Based on these grape
metabolism studies, fluopicolide appears to be metabolized slowly in
grapes to BAM and PCA, via cleavage of the amide bond, and to AE C643890
by hydroxylation of the phenyl ring in the parent compound.

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

No data pertaining to rotational crops are required for an imported crop
(HED SOP 98.6, Data Requirements for Import Tolerances, Table 3,
12/3/98).

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

Since no livestock feedstuffs are associated with grapes (Table 1
Feedstuffs, October 2006), no livestock metabolism data are required.

5.1.4	Analytical Methodology  TC \l3 "5.1.4	Analytical Methodology

The petitioner has proposed an LC/MS/MS method, Method 00782/M002, for
the enforcement of tolerances in grapes and raisins.  This method
separately determines residues of fluopicolide, BAM, PCA, and AE 1344122
(P1X, a rotational crop metabolite;
3-methylsulfinyl-5-trifluoromethylpyridine-2-carboxylic acid).  The
validated limit of quantitation (LOQ) is 0.01 ppm for each analyte in
each commodity.  Confirmatory procedures for the method, or an
interference study, are needed.  Method 00782/M002 has been forwarded to
the Analytical Chemistry Branch (ACB/BEAD) for petition method
validation.  Acceptable data collection methods, Methods 00782 and
00782/M001 (earlier versions of the proposed enforcement method), were
used in the storage stability, field trial, and processing studies.

Since there are no livestock feedstuffs associated with grapes, no
livestock enforcement methods are required to support use on grapes.

5.1.5	Environmental Degradation TC \l3 "5.1.5	Environmental Degradation

Because the proposed use of fluopicolide is on an imported crop, the
environmental degradation of fluopicolide is not relevant to this risk
assessment.  Since U.S. registration is not required for an imported
crop and there are no existing U.S. registrations for fluopicolide, no
fluopicolide residues are expected to occur in drinking water.

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.

The metabolic profiles of fluopicolide in ruminants and poultry are not
relevant to this risk assessment since no livestock feedstuffs are
associated with grapes.

In grapes, fluopicolide (parent) was the major residue identified in the
fruit, accounting for ~87-91% TRR at the 1X treatment rate.  Three minor
metabolites were identified in the fruit at 1X:  2,6-dichlorobenzamide
(BAM) at 2.0% TRR; 3-chloro-5-trifluoromethylpyridine-2-carboxylic acid
(PCA) at 2.3% TRR, and
2,6-dichloro-N-[(3-chloro-5-trifluoromethylpyridin-2-yl)methyl]-3-hydrox
ybenzamide (AE C643890) at 0.2% TRR.  Fluopicolide appeared to be
metabolized slowly in grapes to BAM and PCA, via cleavage of the amide
bond, and to AE C643890 via hydroxylation of the phenyl ring in the
parent compound.

The metabolic profile of fluopicolide in rotational crops is not
relevant to this risk assessment since grapes are an imported crop.

The degradation of fluopicolide in the environment is not relevant to an
imported crop.  No residues are expected to occur in drinking water.

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

The major residue from use of fluopicolide on grapes is parent.  Three
minor metabolites have been identified: 2,6-dichlorobenzamide (BAM; AE
C653711), 3-chloro-5-trifluoromethylpyridine-2-carboxylic acid (PCA; AE
C657188), and
2,6-dichloro-N-[(3-chloro-5-trifluoromethylpyridin-2-yl)methyl]-3-hydrox
ybenzamide (AE C643890).

BAM is a metabolite and/or environmental degradate of both fluopicolide
and dichlobenil.  The toxicity of BAM has been recently reviewed
(Appendix E, R. Mitkus, 7/27/06).  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.
The small cPAD (0.0045 mg/kg/day) 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 mutagenic or clastogenic in either in
vitro or in vivo assays.  A statistically marginal increase (p<0.049) in
the incidence of adenomas was observed in female high-dose rats.  In the
absence of carcinogenicity study data for a second species, HED
considers the carcinogenic potential of BAM to be similar to that of a
parent compound, dichlobenil (possible human carcinogen); an RfD
approach is appropriate 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 all exposure scenarios, in most cases for
absence of key data.

As determined by the HED Risk Assessment Review Committee (RARC1) on
12/21/06, BAM will not be included in the tolerance or risk assessment
for fluopicolide on imported grapes because 1) as both a plant and rat
metabolite of fluopicolide, it has been included in the toxicology
studies and fluopicolide endpoint selections; and 2) residues of BAM in
food resulting from fluopicolide on imported grapes are expected to be
negligible since BAM is only 2.0% of the total radioactive residue in
the fluopicolide grape metabolism study and is a maximum of only 0.047
ppm in the fluopicolide grape field trials.  However, both parent
fluopicolide and BAM will be included in risk assessments for future
uses of fluopicolide on domestic crops since more exposure to BAM is
expected to occur with domestic uses.

Based on its structure, PCA is not expected to be more toxic than
parent.

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

Table 5.1.8  Summary of Fluopicolide Residues to be included in the Risk
Assessment and Tolerance Expression for Imported Grapes

Matrix	Residues included in Risk Assessment	Residues included in
Tolerance Expression

Imported Grapes

	Primary Crop	fluopicolide per se1	fluopicolide per se

	Rotational Crop	Not applicable for an import2	Not applicable for an
import2

Livestock

	Ruminant	Not applicable since no livestock feedstuffs are associated
with grapes.2, 3	Not applicable since no livestock feedstuffs are
associated with grapes.2, 3

	Poultry

Drinking Water	Not applicable for an import	Not applicable

1   The risk assessment for domestic crops will include both
fluopicolide (parent) and 2,6-dichlorobenzamide (BAM).

2   HED SOP 98.6, Data Requirements for Import Tolerances, Table 3,
12/3/98.

3    OPPTS 860.1000, Table 1 Feedstuffs (October 2006)

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

Since U.S. registration is not required for an imported crop and there
are no existing U.S. registrations for fluopicolide, no residues from
fluopicolide are expected to occur in drinking water.

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

Reference:

PP#5E6903.  Petition for Tolerances on Imported Grapes and Raisins.
Summary of Analytical Chemistry and

Residue Data.  DP Number 321209, Amelia Acierto, 1/23/07.

In a grape metabolism study, the majority of radioactivity was found to
be on the surface of fruit and foliage samples; surface washes with ACN
released ~97-99% of the total radioactive residues (TRR) from foliage
samples collected immediately after application, ~73-93% TRR from
foliage samples collected 26-28 days after application, ~50-75% TRR from
mature foliage samples, and ~46-79% TRR from mature fruit samples.

In the crop field trials, detectable residues were found in grapes.  The
majority of the residue was fluopicolide (parent).  Residues are not
expected to exceed 2.0 ppm in grapes and 6.0 ppm in raisins based on
field trials and processing studies summarized below.

Adequate field trial data for grapes are available.  A total of 34 grape
field trials were conducted in Europe during 2000, 2001, and 2002, with
14 trials conducted in northern Europe (6 trials in Germany and 8 trials
in northern France) and 20 trials conducted in southern Europe (8 trials
in southern France, 3 trials in Italy, 5 trials in Spain, and 4 trials
in Greece).  Maximum residues of fluopicolide in/on grapes treated at
total rates of 0.34-0.37 lb ai/A and harvested at the proposed 21-day
PHI were 1.2 ppm; maximum residues of BAM and PCA were 0.047 ppm and
0.06 ppm, respectively, in/on the same samples.

The submitted grape processing data are adequate, pending submission of
supporting storage stability data and information pertaining to
individual sample storage intervals.  The data indicate that
fluopicolide residues do not concentrate in must.  Must, which is the
unfiltered liquid that results from pressing grapes, is considered to be
a surrogate for juice.  Fluopicolide residues do concentrate in raisins,
with average processing factors of 3.4x for fluopicolide, 4x for BAM,
and 4x for PCA.

No rotational crop data are required for an imported crop (HED SOP 98.6,
Data Requirements for Import tolerances, Table 3, 12/3/98).

No residues are expected to occur in livestock commodities since no
livestock feedstuffs are associated with grapes (Table 1 Feedstuffs,
October 2006).

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

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

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

References:

Fluopicolide Chronic Dietary Exposure and Risk Assessment for the
Section 3 Registration Action on Imported Grapes, DP Number 334710, N.
Dodd, 1/31/07.

Dietary exposure assessments were conducted using the Dietary Exposure
Evaluation Model DEEM-FCID™, Version 2.03, which uses food consumption
data from the U.S. Department of Agriculture’s Continuing Surveys of
Food Intakes by Individuals (CSFII) from 1994-1996 and 1998.  Since U.S.
registration is not required for an imported crop and there are no
existing U.S. registrations for fluopicolide, no fluopicolide residues
are expected to occur in drinking water.

5.2.1	Acute Dietary (Food Only) Exposure/Risk TC \l3 "5.2.1	Acute
Dietary (Food Only) Exposure/Risk

An appropriate endpoint for fluopicolide was not identified from the
available data.

5.2.2	Chronic Dietary (Food Only) Exposure/Risk TC \l3 "5.2.2	Chronic
Dietary (Food Only) Exposure/Risk

The chronic dietary (food only) exposure assessment for fluopicolide on
imported grapes was a conservative assessment using the recommended
tolerance levels and assuming that 100% of the crop was treated and 100%
of the crop was imported.  The recommended tolerance levels of 2.0 ppm
and 6.0 ppm were used for grapes and raisins, respectively.  An adequate
processing study was conducted on grapes indicating no concentration in
grape juice but concentration in raisins.  Since residues of
fluopicolide do not concentrate in juice, 2.0 ppm was also used for
grape juice and wine.  No default processing factors were used since an
adequate processing study was available.  No residues are expected to
occur in rotational crops since the grapes are imported.  Since no
livestock feed items are associated with grapes, no residues are
expected to occur in livestock commodities.

The results of the chronic dietary exposure analysis for fluopicolide on
imported grapes are reported in Table 5.2.2 below.  The chronic dietary
(food only) 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 <1% cPAD for the general U.S.
population and 3% cPAD for children 1-2 years old, the most highly
exposed subgroup.

Table 5.2.2.  Result of Chronic Dietary (Food Only) Exposure and Risk
Estimates for Fluopicolide.

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

Exposure, mg/kg/day	% PAD

Chronic Dietary Estimates

U.S. Population	0.20	0.001129	<1

All infants (< 1 yr)

0.001742	<1

Children 1-2 yrs

0.006272	3

Children 3-5 yrs

0.003827	2

Children 6-12 yrs

0.001456	<1

Youth 13-19 yrs

0.000513	<1

Adults 20-49 yrs

0.000697	<1

Adults 50+ yrs

0.000828	<1

Females 13-49 yrs

0.000748	<1

Cancer Dietary Estimate

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

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

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

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

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

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

There are no U.S. registrations for fluopicolide; therefore, no
residential exposure is expected.

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

Since exposure is expected to occur only from food, no aggregate
exposure is expected to occur in the U.S. as a result of fluopicolide on
imported grapes.

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

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

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

No occupational exposure to fluopicolide is expected to occur in the
U.S. as a result of fluopicolide on imported grapes.

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

10.1	Toxicology  TC \l2 "10.1	Toxicology

	None

10.2	Residue Chemistry  TC \l2 "10.2	Residue Chemistry

Pending the resolution of Residue Chemistry Deficiencies #’s1a and 1b
(pertaining to directions for use), Deficiency # 2 (pertaining to the
requirement for a proposed confirmatory method or an interference
study), Deficiency #3 (pertaining to the need for the proposed
enforcement method, Method 00782/M002, to undergo a successful petition
method validation by ACB/BEAD), and Deficiency #6 (pertaining to a
revised Section F), there are no Residue Chemistry data gaps that would
preclude permanent tolerances for residues of fluopicolide as follows:
SEQ CHAPTER \h \r 1

Grape	2.0 ppm

Grape, raisin	6.0 ppm

This decision is based on use of water dispersible granular (WDG) or
emulsifiable concentrate (EC) formulations without adjuvants.  To use
other formulations (other than WDG and EC formulations) or spray
adjuvants, additional residue data (or review of additional residue
data) would be required as indicated in Deficiencies 1c and 1d.

Deficiency #4 (pertaining to storage stability data for fluopicolide in
juice or must and raisins) and Deficiency #5 (pertaining to length of
storage information for the processed commodities) are confirmatory data
requirements which must be resolved but can be resolved after
establishment of the tolerances.

Residue Chemistry Deficiencies

860.1200  Directions for Use

1a.	Residue data were submitted which reflected use of a 4.44% WDG
formulation (WG71) and a 95 g/L suspo-emulsion formulation (SE10), which
is similar to an emulsifiable concentrate (EC) formulation.  The
petitioner should submit representative labels or a revised Section B to
indicate the types of formulations to be used on imported grapes.

1b.	A Section B was submitted which provided some information regarding
the proposed use pattern on imported grapes, including the maximum
number of applications per season (3), the maximum seasonal application
rate (0.36 lb ai/A), the minimum preharvest interval (PHI; 21 days), and
retreatment intervals (10-14 days).  The petitioner should submit a
representative label or a revised Section B to more fully describe the
use pattern(s) to be applied to grapes and raisins to be exported to the
USA.  The additional information to be provided to the Agency should
include the maximum single application rate, application timing (as it
relates to the plant growth stage), names and quantities of stickers,
spreaders, and other adjuvants (if any) to be added to the spray
solution, application tank-mix preparation, volume of spray mix per unit
area (hectare or acre), and type of application equipment.

1c.	No spray adjuvants were used in the crop field trials submitted to
support this petition.  If the petitioner intends to recommend use of
spray adjuvants, residue data reflecting use of spray adjuvants should
be submitted.

1d.	The submitted residue data reflect use of WDG and EC types of
formulations.  If other types of formulations are to be used on grapes
to be imported, additional residue data would be needed to reflect use
of those other types of formulations.

.

860.1340  Residue Analytical Methods

2.	The petitioner must propose confirmatory procedures for the proposed
enforcement method, or submit an interference study for fluopicolide.

3.	The proposed enforcement method, Method 00782/M002, must be validated
as an adequate enforcement method by ACB/BEAD.

860.1380  Storage Stability

4.	The petitioner must submit data demonstrating the stability of
residues of fluopicolide in grape juice (or must) and raisins stored
frozen for 29 months or the maximum storage interval for each of these
commodities.

860.1520  Processed Food and Feed

5.	The petitioner should submit the actual dates of collection,
extraction, and analysis for each sample of grape juice (or must) and
raisins from the processing studies to determine the storage interval
required for the storage stability study.

860.1550  Proposed Tolerances

6.	The proposed tolerances should be revised to reflect the recommended
tolerance levels and correct commodity definitions as specified in
Appendix C.

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

	None.

References:  TC \l1 "References:

PP#5E6903.  Petition for Tolerances on Imported Grapes and Raisins.
Summary of Analytical Chemistry and

Residue Data.  DP Number 321209, Amelia Acierto, 1/23/07.

Fluopicolide Chronic Dietary Exposure and Risk Assessment for the
Section 3 Registration Action on Imported Grapes, DP Number 334710, N.
Dodd, 1/31/07.

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

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

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

Test

	Technical

	Required	Satisfied

870.1100    Acute Oral Toxicity

870.1200    Acute Dermal Toxicity

870.1300    Acute Inhalation Toxicity

870.2400    Primary Eye Irritation

870.2500    Primary Dermal Irritation

870.2600    Dermal Sensitization		yes

yes

yes

yes

yes

yes	yes

yes

yes

yes

yes

yes

870.3100    Oral Subchronic (rodent)

870.3150    Oral Subchronic (nonrodent)

870.3200    21-Day Dermal

870.3250    90-Day Dermal

870.3465    90-Day Inhalation		yes

yes

no

no

no	yes

yes

-

-

-

870.3700a  Developmental Toxicity (rodent)

870.3700b  Developmental Toxicity (nonrodent)

870.3800    Reproduction		yes

yes

yes	yes

yes

yes

870.4100a  Chronic Toxicity (rodent)

870.4100b  Chronic Toxicity (nonrodent)

870.4200a  Oncogenicity (rat)

870.4200b  Oncogenicity (mouse)

870.4300    Chronic/Oncogenicity		yes

yes

yes

yes

yes	yes1

yes

yes1

yes

yes

870.5100    Mutagenicity—Gene Mutation - bacterial

870.5300    Mutagenicity—Gene Mutation - mammalian

870.5375    Mutagenicity—Structural Chromosomal Aberrations

870.5395   Mutagenicity—Other Genotoxic Effects		yes

yes

yes

yes	yes

yes

yes

yes

870.6100a  Acute Delayed Neurotox. (hen)

870.6100b  90-Day Neurotoxicity (hen)

870.6200a  Acute Neurotox. Screening Battery (rat)

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

870.6300    Develop. Neuro		no

no

yes

yes

no	-

-

yes

yes

-

870.7485    General Metabolism

870.7600    Dermal Penetration		yes

no	yes

-

Special Studies for Ocular Effects

Acute Oral (rat)

Subchronic Oral (rat)

Six-month Oral (dog)

no

no

no

-

-

-

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

≥ 2000  mg/kg (m/f)

LD50≥  2000  mg/kg (f)

LD50 ≥ 2000  mg/kg (m/f)	III

III

III

870.1100	Acute oral [rat] - studies with metabolites

1) 2,6-dichlorobenzamide

2) 1,3-chloro-5 (trifluoromethyl)pyridine-2-carboxylic acid

3) 3-methylsulfinyl-5-trifluoromethylpyridine-2-carboxylic acid	46708602

46708603

46708604	LD50 ≥ 2000  mg/kg (m) and  LD50 ≥300 mg/kg (f)

LD50≥2000  mg/kg (m/f)

LD50≥ 2000  mg/kg (f)	II

III

III

870.1200	Acute dermal [rat]	46709904

46708605

46709804	LD50 ≥ 4000 mg/kg

LD50 ≥ 5000 mg/kg

LD50 ≥4000 mg/kg	III

IV

III

870.1300	Acute inhalation [rat]	46709905

46708606

46709805	LC50 ≥ 1.789 mg/L

LC50 ≥ 5.16 mg/L

LC50 ≥ 3.195 mg/L	III

IV

IV

870.2400	Acute eye irritation [rabbit]	46709906 46709806
chemosis/corneal opacity in both studies	III

III

870.2500	Acute dermal irritation [rabbit]	46709907

46709807	slight (PDII = 0.08)

slight (PDII = 0.25)	IV

IV

870.2600	Skin sensitization [guinea pig]	46709908

46708608

46709808	Negative (Buehler method)

Negative (Magnusson-Kligman Design method)

Negative (modified Buehler method)	non-sensitizer

non-sensitizer

non-sensitizer

Table A.2.2	Subchronic, Chronic and Other Toxicity Profile

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

870.3100

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

Acceptable/guideline

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

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

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

870.3100

	90-Day oral toxicity (mouse)	46474114 (2000)

Acceptable/guideline

1092 mg/kg/day (M/F)

LOAEL = not identified

870.3100

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

Acceptable/guideline

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

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

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

870.3150

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

Acceptable/guideline

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

LOAEL = not identified (M/F)

870.3200

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

Acceptable Guideline

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

LOAEL > 1000 mg/kg/day

No local or systemic toxicity observed

870.3700a

	Prenatal developmental in (rat)	46474120 (2001)

Acceptable/guideline

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

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

Developmental NOAEL = 60 mg/kg/day

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

870.3700b

	Prenatal developmental in (rabbit)	46474122 (2001)

Acceptable/guideline

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

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

Developmental NOAEL = 20 mg/kg/day

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

870.3800

	Reproduction and fertility effects

(rat)	46474124 (2003)

46474125 (additional data, 2004)

46474126 (range-finding, 2002)

Acceptable/guideline

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

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

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

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

LOAEL = not identified.

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

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

870.4100b

	Chronic toxicity (dog)	44674128 (2002)

Acceptable/guideline

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

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

870.4200b

	Carcinogenicity

(mouse)	46474130 (2003)

Acceptable/guideline

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

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

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

no evidence of carcinogenicity

870.4300

	Chronic/ Carcinogenicity

(rat)	46474139 (2003)

Acceptable/guideline

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

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

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

no evidence of carcinogenicity

870.5100 	Gene Mutation

 (Salmonella typhimurium)	46474146 (2001)

Unacceptable/guideline

1.6- 5000 µg/plate

46474202 (2001)

Acceptable/guideline

1.6- 5000 µg/plate

46474148 (2001)

Acceptable/guideline

1.6- 5000 µg/plate

46474144 (2001)

Acceptable/guideline

1.6- 5000 µg/plate

46474142 (2004)

Acceptable/guideline

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

5 - 5000 µg/plate

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

negative (non-mutagenic)

negative (non-mutagenic)

negative (non-mutagenic

positive (mutagenic)

870.5300 	Gene mutation

 (Chinese hamster lung cells)	46474204 (2000)

Acceptable/guideline

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

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

870.5375 	Cytogenetics

46474208 (2001)

Acceptable/guideline

1.22 to 625 µg/mL

46474206 (2004)

Acceptable/guideline

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

3.2 to 100 µg/mL

negative for chromosome aberrations

positive for aberrations without S9 activation

870.5395

	Micronucleus

 (mouse)

46474214 (2003)

Acceptable/guideline

150, 300 or 600 mg/kg/day

46474210 (2005)

Acceptable/guideline

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

200, 600 or 2000 mg/kg/day

negative at doses up to 600 mg/kg

negative at doses up to 2000 mg/kg

870.5550	Unscheduled DNA Synthesis

(rat hepatocytes)	42169839 (1989)

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

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

Unscheduled DNA synthesis (rat hepatocytes)	46474216 (2000)

Acceptable/guideline

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

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

870.6200a

	Acute neurotoxicity screening battery

(rat)	46474218 (2002)

46474219 (range-finding, 2002)

Acceptable/guideline

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

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

870.6200b

	Subchronic neurotoxicity screening battery	46474221 (2002)

46474222 (positive control, 2002)

Acceptable/guideline

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

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

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

870.6300

	Developmental neurotoxicity	None

	870.7485

	Metabolism and pharmacokinetics

(rat)	46474242 (2004)-main studies

46474241 (2001)

46474244 (2003)

46474226 (2003)

46474239 (2003)

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

870.7600	Dermal penetration

(rat)	46708638 (2003)

Acceptable Guideline

1.43, 659 ug/cm2 skin	In vivo study

Dermal Penetration rate:  37%

870.7600	Dermal penetration

(comparative)	46708637 (2003)

Acceptable Non-guideline

1.9, 744 ug/cm2 skin

	In vitro study

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

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

A.3.1	Subchronic Toxicity

	870.3100	90-Day Oral Toxicity – Rat

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

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

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

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

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

	870.3100	90-Day Oral Toxicity – Mouse

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

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

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

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

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

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

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

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

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

	870.3150	90-Day Oral Toxicity – Dog

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

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

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

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

	870.3200	21/28-Day Dermal Toxicity – Rat

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

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

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

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

	870.3465	90-Day Inhalation – Rat

No studies available.

A.3.2	Prenatal Developmental Toxicity

	870.3700a Prenatal Developmental Toxicity Study – Rat

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

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

Therefore, the maternal toxicity LOAEL for AE C638206 in rats is 700
mg/kg bw/day

based on slightly reduced body weight gain, and the maternal toxicity
NOAEL is 60 mg/kg

bw/day.

No adverse, treatment-related, statistically significant effects on
pregnancy rates, number of

corpora lutea, pre- or post implantation losses, resorptions/dam,
fetuses/litter, or fetal sex ratio

were observed in the treated groups compared with the controls.  No dams
had complete litter

resorption.  No treatment-related malformations or external or visceral
variations were observed

in any group.

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

Therefore, the developmental toxicity LOAEL for AE C638206 in rats is
700 mg/kg bw/day

based on delays in fetal growth (decreased fetal weight, crown/rump
length, delays in

ossification) and skeletal defects of the thoracic vertebra, and ribs
and the developmental

 toxicity NOAEL is 60 mg/kg bw/day.

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

	870.3700b Prenatal Developmental Toxicity Study – Rabbit

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

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

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

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

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

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

A.3.3	Reproductive Toxicity

	870.3800 Reproduction and Fertility Effects – Rat

In a two-generation reproduction study (MRID 46474124 and 46474125), AE
C638206 (95.9% a.i., batch/lot # OP2050046) was administered to 28 F0
generation and 24 F1 generation male and female Crl:CD®(SD)IGS BR rats
at concentrations of 0, 100, 500, or 2000 ppm.  The dietary levels
corresponded to doses of 0, 7.4, 36.4, and 144.6 mg/kg bw/day,
respectively, for F0 males; 0, 8.8, 43.7, and 179.9 mg/kg bw/day for F1
males; 0, 8.1, 41.0, and 159.7 mg/kg bw/day for F0 females; and 0, 9.4,