Document ID: EPA-HQ-OPP-2006-0481-0007
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2007-04-26T04:00Z

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 

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

3.1.1.2	Mode of action, metabolism, toxicokinetic data	  PAGEREF
_Toc160520967 \h  13 

3.1.1.3	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 

3.3.6.1	Determination of Susceptibility	  PAGEREF _Toc160520980 \h  23 

3.3.6.2	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. 

3.1.1.1	Studies available and considered (animal, human, general
literature)  tc  \l 4 "3.1.1.1	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)

3.1.1.2	Mode of action, metabolism, toxicokinetic data tc  \l 4 "3.1.1.2
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.

3.1.1.3	Sufficiency of studies/data tc  \l 4 "3.1.1.3	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 3.3.6.2 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.  

3.3.6.1	Determination of Susceptibility tc  \l 4 "3.3.6.1	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.  

3.3.6.2	Degree of Concern Analysis and Residual Uncertainties for Pre-
and/or Postnatal Susceptibility tc  \l 4 "3.3.6.2	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 3.5.11.1  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,
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.

A.3.4	Chronic Toxicity

	870.4100a (870.4300) Chronic Toxicity – Rat

A combined chronic toxicity/carcinogenicity study in rats is included in
section A.3.5 below.

	870.4100b Chronic Toxicity – Dog

In a chronic toxicity study (MRID 46474128) AE C638206 (95.9%, Lot No.
OP2050046) was administered to 5 beagle dogs/sex/dose by oral gavage at
concentrations of 0, 70, 300 and 1000 mg/kg/day for 52 weeks. 

There were no significant compound-related effects based on mortality,
clinical signs, food consumption, opthalmoscopic examinations,
urinalysis, hematology, clinical chemistry, organ weight, gross
pathology or histopathology.  Body weight gain was inhibited in males
treated with 1000 mg fluopicolide/kg/day.  Although increased
cholesterol concentrations at the end of the study were statistically
significant and slightly above the historical range in females treated
with 1000 mg/kg/day, there were no correlative changes indicating an
exposure-related effect on lipid metabolism in these animals.  One
female in the 300 mg/kg/day dosage group died during the study, however,
the death was not conclusively associated with exposure to fluopicolide.

The LOAEL for AE C638206 in male dogs was 1000 mg/kg/day based on
decreased body weight gain.  The NOAELs were 300 and 1000 mg/kg/day for
males and females, respectively.

This chronic study in the dog is Acceptable/Guideline and satisfies the
requirement for a chronic oral study [OPPTS 870.4100, OECD 452] in a
non-rodent.

A.3.5	Carcinogenicity

	870.4200a Carcinogenicity Study – rat

In a combined chronic toxicity/carcinogenicity study (MRID 46474139), AE
C638206 (Fluopicolide, 95.9%, a.i.; Batch No. OP2050046) was
administered to 60 Crl:CD (SD) IGS BR rats/sex/dose in the diet at
concentrations of 0 (controls), 50, 200, 750 or 2500 ppm (equivalent to
0, 2.1, 8.4, 31.5 or 109.4 mg/kg bw/day in males and 0, 2.8, 10.8, 41.0
or 142.2 mg/kg bw/day in females) for up to 104 weeks.  An additional 20
animals/sex/dose were administered the same concentration and sacrificed
after 52 weeks of treatment for a interim sacrifice.  A third set of 10
animals/sex/dose were fed the treated diet at the same concentrations
for 52 weeks followed by 13 weeks of being fed basal diet prior to
sacrifice in a recovery study.  A report, MRID 46474138, which consisted
of a summary of the study profile was provided as an additional source
of information.

Statistical analysis showed no increased incidence of mortality in any
of the treated groups 

compared to controls.  The only clinical signs observed were in the
females rats and consisted of 

yellow perigenital staining, brown staining of the pinna and brown
staining of the dorsum.  

Statistical significance was not evaluated for these clinical signs. 
Yellow perigenital staining and 

the brown staining of the pinna was observed primarily in the 2500 ppm
females in the main 

study with these signs beginning around week 13 and increasing to weeks
47-53 when they were 

observed in 21-31% of the females at 2500 ppm.  Both effects then
started to diminish and were 

seen in few animals (<5%) by the end of the second year.  Similar
results were observed in the 

52 week study.  Brown staining of the dorsum was observed but was not
seen in a concentration-

related increase, affecting controls as well as treated females.  These
clinical signs appear to be 

of low toxicological significance due to a lack of corresponding
urinalysis, clinical chemistry or 

histopathology effects identified, and they were transient with most
effects minimizing after the 

first year.  While palpable masses were observed and monitored, there
was not a treatment-

related increase in the incidence of these masses.

There was no statistically significant difference in body weight in any
of the treated groups.  A 

statistically significant (p< 0.05 or p<0.01) decrease in mean body
weight gain was observed in 

weeks 0-1 in both studies at the highest dose in males (33%) and females
(28%), compared to 

controls.  In the main study, a statistically significant (p<0.01)
decrease was also seen in the 

females at 200 (20%) and 750(32%) ppm groups.  The only significant
decrease in body weight 

gain in weeks 1-2 of the main study was in males at 2500 ppm and females
at 50 and 2500 ppm,

 and these gains were decreased 11% in the males and 15 and 42% in the
females, respectively, 

compared to controls.  After this time, body weight and body weight gain
remained lower than 

controls (n.s.) with the overall body weight gain of the 2500 ppm group
being 11% and 17% less 

than controls in the males and females, respectively.  In the animals
dosed for 52 weeks, the 

similar effect of decreased body weight gain in the highest dosed males
and females was 

observed with statistical significance in the first 2 weeks.  Both male
and female rats had 

comparable body weight gain by the end of the recovery period.  A
corresponding decrease in 

food consumption and food efficiency was observed in the highest dosed
group of males and 

females during the first two weeks of treatment; however, statistical
analysis was not included in 

the report.

Statistical differences in hematology and clinical chemistry were not
toxicologically significant.  

Those observed were minor, sporadic and did not have a clear
treatment-related association.

Statistically significant increases (p<0.01 or 0.05) in relative (to
body weight) and absolute 

kidney (122- 137%), thyroid (154-163%) and liver (122-134%) weights were
observed in the 

males at 2500 ppm in the main study.  These same increases were observed
in the males at 2500 

ppm in the 52 week study, except for absolute kidney weight.  Females at
2500 ppm in the 52 

week study had statistically significant increases in relative, but not
absolute, liver and kidney 

weights; this was associated with a significant decrease in terminal
body weight.

Males had a statistically significant increase in the incidence of and
severity of non-neoplastic 

microscopic lesions in the thyroid, kidney and liver in the main study. 
A corresponding increase 

(p< 0.05) in the incidence of enlarged kidneys and thyroids were present
in the males at 2500 

ppm compared to controls on gross observation.  On histopathological
examination, an increased 

incidence of thyroid cystic follicular hyperplasia was present in the
males and observed in 0/60, 

1/37, 0/37, 4/35 and 7/60 (p < 0.05) in the controls, 50, 200, 750 or
2500 ppm males.  Lesions in 

the kidney were those associated with the alpha -2u-globulin
accumulation normally present in 

male aged rats and are not considered adverse or applicable to human
risk assessment.  The liver 

effect, centrilobular hepatocyte hypertrophy, observed both at 52 and
104 weeks was considered 

to be an adaptive change due to treatment.  During the recovery period,
all lesions present were 

reversed except for a slight increase in the severity of the renal
cortical tubular basophilia in the 

males.  Females had no statistically significant differences in lesions
in any of the dose groups in 

either the toxicity or the main study.

The lowest-observed-adverse effect level (LOAEL) for AE C638206 in rats
is 2500 ppm 

(109.4 and 142.2 mg/kg/day for males and females, respectively) based on
decreases in body 

weight gain (M and F) and an increase in thyroid organ weight with
corresponding 

increases in the incidence of thyroid lesions (M only).  The
no-observed-adverse effect level 

(NOAEL) for AE C638206 is 750 ppm (31.5 and 41.0 in males and females,
respectively).

At the doses tested, there was not a treatment related increase in tumor
incidence of any type in 

animals dosed with up to 2500 ppm AE C638206 for up to 104 weeks. 
Dosing was considered 

adequate based on the decreased body weight gain in the male and female
rats at 2500 ppm, and 

the non-neoplastic lesions observed at 2500 ppm in males.  While effects
were minimal in the 

female, a reproductive study, MRID 46474124 (main study) and 46474125
(supplemental study 

histopathological evaluation of liver and kidneys) indicated kidney
toxicity (microscopic

lesions) in male and female rats in both parental generations and
decreased body weight 

gain in the F0 females treated with AC638206 for 16 weeks at 2000 ppm
indicating adequate dosing in this study at 2500 ppm.

This chronic/carcinogenicity study in the rat is Acceptable/Guideline
and satisfies the guideline 

requirement for a chronic/carcinogenicity study [(OPPTS 870.4300); OECD
453] in rats.

	870.4200b Carcinogenicity (feeding) – Mouse

In a carcinogenicity study (MRID 46474130) AE C638206 (Fluopicolide)
(95.9% a.i., batch #OP2050046) was administered to 50 C57BL/6
mice/sex/dose in the diet at dietary levels of 0, 50, 400, or 3200 ppm
(equivalent to 0, 7.9, 64.5, 551.0 mg/kg bw/day for males, and 0, 11.5,
91.9, and 772.3 mg/kg bw/day for females) for 18 months.  Satellite
groups of 10 C57BL/6 mice/sex/dose were similarly treated for 12 months.
 Historical control incidences of hepatocellular lesions were provided
(MRID 46474135).

2/10 for each lesion).

The LOAEL for AE C638206 in mice is 3200 ppm for both sexes (551.0
mg/kg/day for males, 772.3 mg/kg/day for females), based on severely
decreased body weights and body weight gains and liver lesions in both
sexes.  The NOAEL is 400 ppm in both sexes (64.5 mg/kg/day for males,
91.9 mg/kg/day for females).

At the doses tested, there was a treatment related increase in the
incidence of hepatocellular adenoma when compared to controls.  The 3200
ppm animals had statistically significant increases in hepatocellular
adenoma in both sexes after 78 weeks, and a small increase after 52
weeks.  The adenoma incidence after 78 weeks at 0, 50, 400 and 3200 ppm
was 5/50, 0/50, 5/50, and 11/50, respectively, for males, and 1/50,
2/50, 0/50, and 16/50, respectively, for females.  After 52 weeks,
hepatocellular adenoma was found in 3/10 high-dose females but no males.
   The adenomas were correlated with an increased incidence of liver
masses and nodules at necropsy.  Dosing was considered adequate based on
decreased body weight gains, decreased food efficiency, and liver
lesions seen in both sexes at the high dose.

This carcinogenicity study is Acceptable/Guideline and satisfies
guideline requirements for a carcinogenicity study [OPPTS 870.4200b;
OECD 451] in mice.

A.3.6	Mutagenicity

	Gene Mutation

Guideline 84-2, Reverse gene mutation

MRID 46474146

Unacceptable/guideline

	dose range:  1.6 to 5000 µg/plate

No increases in revertant colonies were found in either test series at
concentrations up to the limit dose, 5000 µg/plate. Therefore,
AEC638206 00 IC99 0005 is considered nonmutagenic in the conventional
battery of bacterial strains. 

This study was considered unacceptable/guideline because purity
information for the test material was not provided.

Guideline 84-2, Reverse gene mutation

MRID 46474202

acceptable/guideline

	dose range:  1.6 to 5000 µg/plate

No increases in revertant colonies were found in either test series at
concentrations up to the limit dose, 5000 µg/plate. Therefore,
AEC638206 00 IC99 0001 is considered nonmutagenic in the conventional
battery of bacterial strains. 

Guideline 84-2, Reverse gene mutation

MRID 46474148

acceptable/guideline

	dose range:  1.6 to 5000 µg/plate

No increases in revertant colonies were found in either test series at
concentrations up to the limit dose, 5000 µg/plate. Therefore,
AEC638206 00 IB99 0002 is considered nonmutagenic in the conventional
battery of bacterial strains.

Guideline 84-2, Reverse gene mutation

MRID 46474144

acceptable/guideline

	dose range:  1.6 to 5000 µg/plate

No increases in revertant colonies were found in either test series at
concentrations up to the limit dose, 5000 µg/plate. Therefore,
AEC638206 Technical is considered nonmutagenic in the conventional
battery of bacterial strains.

Guideline 84-2, Reverse gene mutation

MRID 46474142

acceptable/guideline

	dose range:  5 to 5000 µg/plate

AE C638206 (fluopicolide) is considered mutagenic at precipitating
concentrations in the conventional battery of bacterial strains.

	Cytogenetics

Guideline 84-2, in vitro mammalian cells in culture/gene mutation assay
in Chinese hamster lung cells

MRID 46474204

Acceptable/guideline

	1.2 to 3820 µg/mL,  0.4 to 120 µg/mL and 0.313 to 60 µg/mL with and
without activation

No concentration in any of the three experiments was a biologically
relevant, reproducible increase in mutant colonies found at
concentrations up to the highest subcytotoxic levels.  Both positive
controls showed marked increases. 

Guideline 84-2, in vivo mammalian chromosome
aber慲楴湯൳前䑉㐠㐶㐷〲സ捁散瑰扡敬术極敤楬敮܍⸱
㔲琠⁯㈶‵枵洯⁌楷桴畯⁴捡楴慶楴湯愠摮㐠㠮‸潴㘠
㔲딠⽧䱭眠瑩⁨捡楴慶楴湯

In the presence of  ≥50% reduction in the MI, no statistically
significant increases in the structural or numerical (polyploidy)
aberrant metaphases were found at any test concentration in either
trial, compared to marked (p≤0.001) increases in both positive
controls. 

Guideline 84-2, in vitro mammalian chromosome aberrations

MRID 46474206

Acceptable/guideline

	3.2 to 100 µg/mL with and without activation; 0.1 to 6.3 µg/mL
without activation

This batch mixture of AE C638206 is considered a clastogen in the in
vitro Chinese hamster lung (V79) cell system in the absence of S9
activation. 

Guideline 84-2, in vivo mammalian cytogenetics

MRID 46474214

Acceptable/guideline

	IP injection of 150, 300 or 600 mg/kg/day

No dose up to the HDT was a significantly increased number of mPCEs
recorded, in the presence of a statistically increased ratio of PCEs to
NCEs (evidence of interference with erythropoiesis), either when
compared to vehicle controls, or to the laboratory’s 8-year historical
control data base. The positive control registered a marked increase in
mPCEs, in the absence of any alteration of erythropoietic effects. 

Guideline 84-2, in vivo mammalian cytogenetics

MRID 46474210

Acceptable/guideline

	Two oral doses of 200, 600, or 2000 mg/kg/day, 24 hours apart

No adverse clinical signs were observed during the main study. The ratio
of polychromatic to normochromatic erythrocytes was unaffected by
treatment. Additionally, at no dose level up to the limit dose, (2000
mg/kg/day), were increased numbers of mPCEs induced by the test article,
compared with the marked increases observed in CPA-treated cells.

	Other Genotoxicity

Guideline (no # given),  Unscheduled DNA synthesis in hepatocytes

MRID 46474216

acceptable/guideline	600 or 2000 mg/kg

There was no evidence (or a dose-related positive response) that
unscheduled DNA synthesis, as determined by radioactive tracer
procedures (nuclear silver grain counts) was induced at either timed
sacrifice in rats exposed to the test material up to the limit dose
(2000 mg/kg).

A.3.7	Neurotoxicity

	870.6100 Delayed Neurotoxicity Study – Hen

Not required for this chemical.

	870.6200 Acute Neurotoxicity Screening Battery

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/Guideline, and
satisfies the guideline 

requirement for an acute neurotoxicity study in rats (870.6200; OECD
424) provided positive 

control neuropathology data are submitted by the conducting laboratory.

	870.6200 Subchronic Neurotoxicity Screening Battery

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).

The study is classified as Acceptable/Guideline and does satisfy the
guideline requirement for a subchronic neurotoxicity study in rats
(870.6200b) provided positive control neuropathology data are submitted
by the conducting laboratory.

	870.6300 Developmental Neurotoxicity Study

Not required for this chemical. 

A.3.8	Metabolism

	870.7485	Metabolism - Rat

Five studies (MRIDs 46474226, 46474239, 46474241, 46474242, and
46474244) were conducted to examine the metabolism and disposition of AE
C638206 (fluopicolide) in male and female Sprague-Dawley CD rats
following single doses of [14C-2,6-pyridyl]-AE C638206 at 10 mg/kg bw or
[14C-2,6-pyridyl]-AE C538206 and [14C-U-phenyl]-AE C638206 at 10 and 100
mg/kg bw.  Rats were subjected to the dosing regimens above using
[14C-2,6-pyridyl]-AE C538206 (lot nos. 903AE-3 and GAR 2034-/4; >99% and
97% radiochemical purity) or [14C-U-phenyl]-AE C538206 (lot no. CFQ
12747; 99.1% radiochemical purity) and nonlabeled test article (batch
no. R001737, 99.3% chemical purity).  Excretion, tissue distribution,
pharmacokinetics (blood/plasma), and metabolite profiles were
determined.  In MRID 46474242, metabolite profiles were assessed in
urine and fecal extracts of male and female rats given a single oral 10
mg/kg bw dose of [14C-2,6-pyridyl]-AE C638206 and sacrificed at 48 hours
post-dosing. 

There were no biologically significant treatment-related effects noted
during the course of the study.  Overall recovery of administered
radioactivity was an acceptable 93.9-103.6%.  The data supported the
contention that AE C538206 is readily absorbed and rapidly excreted
within 72 hours following a single oral dose of 10 mg/kg.  Fecal
elimination accounted for 68.8-72.4% of the administered radioactivity
whereas urinary excretion accounted for only 18.8-21.4% of the
administered radioactivity.  In the bile excretion study (MRID
46474244), 51.7% of the administered radioactive dose in both sexes was
excreted by the cannulated bile duct indicating a significant portion of
the radioactivity recovered in feces is derived from hepatic metabolism
of AE C638206.  Time-course blood/plasma and tissue studies revealed
rapid absorption and distribution of administered radioactivity to all
organs and tissues followed by moderately rapid excretion with reduction
to background levels in most tissues and organs within 72 hours.  Tissue
concentrations peaked at 6-7 hours post-dosing and about 96% of the peak
tissue concentrations were dissipated between 6-7 hours and 168 hours
post-dose.  Absorption and excretory patterns did not exhibit
gender-related variability, but blood/plasma kinetic studies (MRID
46474226) suggest near-saturation of absorption at the high dose (100
mg/kg bw).  Based upon tissue burden data, neither AE C638206 nor its
metabolites appear to undergo any significant tissue sequestration. 
With the exception of transiently higher levels in the liver, kidneys,
and intestines during the elimination phase, radioactivity
concentrations in any given tissue consistently represented considerably
less than 1% of the administered dose within 24 hours of administration
of AE C638206. 

Both urinary and fecal metabolites were quantified by HPLC and most were
identified using HPLC or HPLC/MS in conjunction with known standards. 
The major metabolites identified appeared to be oxidative N-dealkylation
cleavage products.  Extraction efficiency appeared to be excellent and
most components in both of the matrices examined (urine and feces) were
adequately quantified and characterized.  The available data, based upon
studies using [14C-2,6-pyridyl]-AE C638206, affirmed the metabolism
pathway (Appendix, Figure 1) proposed by the investigators.

These metabolism studies (MRID 46474226, 46474239, 46474241, 46474242,
and 46474244) are, collectively, Acceptable/Guideline and satisfy the
requirements for a Metabolism and Pharmacokinetics Study
[OPPTS 870.7485 (§85-1)].  The studies were properly designed,
conducted and reported. 

	870.7600	Dermal Absorption – Rat

In a dermal penetration study (MRID 46708638), [14C-Phenyl]-AE C638206
(Fluopicolide; 99.8% radiochemical purity; Batch No. SEL/1200) in a
commercial concentrate (or aqueous dilution of a concentrate for the low
dose) was applied to the skin of 5 male Sprague-Dawley rats/time
point/dose. The dose (1.43 or 659 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.

A.3.9	Special/Other Studies

	None.

Appendix B:  Metabolism Assessment

  TC \l1 "Appendix B:  Metabolism Assessment 

Table B.	Tabular Summary of Fluopicolide and its Metabolites and
Degradates in Plants

Chemical Name (other names in parenthesis)	

Matrix	Percent TRR (PPM) 1	Structure

Matrices - Major Residue, >10%TRR	Matrices - Minor Residue, <10%TRR

	Parent fluopicolide

2,6-dichloro-N-[[3-chloro-5-(trifluoromethyl)-2-pyridinyl]methyl]-benzam
ide

(AE C638206)	Grapes (fruit)	91.2 %

(1.152 ppm)

(phenyl label)

87.4% 

(0.910 ppm)

(pyridinyl label)

Metabolite  1:

2,6-dichlorobenzamide

(BAM)

(AE C653711)	Grapes (fruit)

2.0%

(0.026 ppm)

(phenyl label only)	

Metabolite 2: 

3-chloro-5-trifluoromethylpyridine-2-carboxylic acid

(PCA)

(AE C657188)	Grapes (fruit)

2.3%

(0.024 ppm)

(pyridinyl label only)	

Metabolite 3: 

2,6-dichloro-N-[(3-chloro-5-trifluoromethylpyridin-2-yl)methyl]-3-hydrox
ybenzamide

(AE C643890)	Grapes (fruit)

0.2%

(0.002 ppm)

(phenyl label only)	

Grapes: MRID 46474025; three foliar applications for a total seasonal
rate of 0.357 lb ai/A (1x); 21-day PHI

Appendix C:  Tolerance Assessment Summary and Table  TC \l1 "Appendix
C:  Tolerance Assessment Summary and Table  

HED has determined that the terminal residue of concern in grape for the
tolerance expression is fluopicolide per se
[2,6-dichloro-N-[[3-chloro-5-(trifluoromethyl)-2-pyridinyl]methyl]benzam
ide].  The tolerance expression (fluopicolide) proposed in the petition
is appropriate.

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

Adequate field trial data for grapes are available.  The available field
trial data will support a tolerance for fluopicolide in/on grape of 2.0
ppm.

Adequate processing data for raisins are available pending submission of
the requested storage stability data/information.  The available data
indicate that residues of fluopicolide are not likely to concentrate in
juice but do concentrate in raisins.  The processing data indicate that
a tolerance of 6.0 ppm for grape, raisin is appropriate.  

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

Table C.   Tolerance Summary for Fluopicolide on Imported Grapes.

Commodity	Proposed Tolerance (ppm)	Recommended Tolerance (ppm)	Comments;
Correct Commodity Definition

Grape (imported)	2	2.0	Grape

Grape, raisin (imported)	6	6.0	Grape, raisin



Appendix D:  Review of Human Research TC \l1 "Appendix D:  Review of
Human Research  

None.

Appendix E: 	Sections 3.0, 4.0, 8.0, and 10.0 for BAM (from R. Mitkus,
RAB1, updated 7/27/06)  TC \l1 "Appendix E:  Sections 3.0, 4.0, 8.0, and
10.0 for BAM  

3.0	 	Hazard Characterization/Assessment

3.1	 	Hazard and Dose-Response Characterization

Studies Considered in the Toxicity and Dose-Response Evaluation 

Dichlobenil

Data from the following studies were used to evaluate the hazard
potential of dichlobenil:

Acute (for olfactory toxicity): one intraperitoneal (single dose)
toxicity study (mouse, rat) and one subcutaneous (single dose,
neonates)/intraperitoneal (single dose, adults) toxicity study (mouse)

Subchronic: Two oral (hamster, rat), one dermal (rabbit), one dermal
(mouse), and two inhalation (rat) toxicity studies

Chronic: Two oral toxicity (dog), two oral carcinogenicity (hamster),
and one combined oral toxicity/carcinogenicity (rat) studies

Reproduction/developmental: Two developmental (rat, rabbit) and one
two-generation reproduction (rat) studies

Other: Nine genotoxicity screens (in vivo/in vitro) and five
metabolism/toxicokinetics studies (rat)

BAM

Data from the following studies were used to evaluate the hazard
potential of dichlobenil:

Acute (for olfactory toxicity): one intraperitoneal (single dose)
olfactory toxicity study (mouse)

Subchronic: One oral (rat) toxicity study

Chronic: One oral toxicity (dog) study and one combined oral
toxicity/carcinogenicity (rat) study

Reproduction/developmental: One developmental (rabbit) toxicity study
and one three-generation reproduction (rat) study

Other: Three genotoxicity screens (in vivo/in vitro) 

3.1.2		Sufficiency of studies/data

Dichlobenil

The acute and chronic studies were sufficient to determine whether human
hazard 

could exist within the context of dose, duration, timing, and route of
exposure.  Data 

quality is acceptable.  There was no evidence that dichlobenil was
either 

mutagenic or clastogenic in either in vitro or in vivo assays. 
Dichlobenil was determined 

to be non-mutagenic in bacteria and mouse lymphoma cells, negative in an
in vivo 

chromosomal aberration assay, and did not cause unscheduled DNA
synthesis (repair of 

DNA damage) in or transformation of mammalian cells in vitro.  The HED
Cancer Peer 

Review Committee (1995) classified dichlobenil as a “Group C, possible
human 

carcinogen.”  An RfD approach was recommended for the quantification
of human 

cancer risk.

Based on olfactory toxicity observed following dermal (Deamer et al.
1994), inhalation 

(Guideline study), and intraperitoneal (i.p.) (Brandt et al. 1990;
Eriksson and 

Britebo 1995) exposures of adult animals and subcutaneous exposure
(s.c.) of neonatal 

mice (Eriksson and Brittebo 1995), the Agency requires a comparative
study of 

olfactory toxicity by the oral route in neonates and adults.  The
registrant is 

encouraged to consult with the Agency to discuss the protocol.

BAM

The acute and chronic studies were sufficient to evaluate human hazard
potential, and  

data quality is acceptable. There was no evidence that BAM was either
mutagenic or 

clastogenic in either in vitro or in vivo assays.  In addition, BAM did
not cause 

unscheduled DNA synthesis (repair of DNA damage) in mammalian cells in
vitro.  

The carcinogenic potential of BAM was evaluated in the rat.  An
increased incidence of hepatocellular adenomas was observed at the high
dose in females only in the study.  However, the statistical
significance of the effect was marginal (P=0.049), dosing was considered
adequate in the study, and the tumors were non-cancerous.  In the
absence of data for a second species, HED considers the carcinogenic
potential of BAM to be similar to that of the parent compound,
dichlobenil (possible human carcinogen).

BAM-mediated olfactory toxicity was observed in one study (i.p.)
collected from the open literature (Brittebo et al. 1991).  However,
olfactory epithelial necrosis was observed in adult animals at a dose
that was eight times higher than that which caused the same effect using
dichlobenil.  In the absence of studies via other routes of exposure,
potential BAM-mediated olfactory toxicity in offspring is considered by
HED to be similar to that of dichlobenil.

3.1.3 		Herbicidal Mode of Action

Dichlobenil is a systemic herbicide that inhibits cellulose biosynthesis
in plants, thereby leading to alteration of cell wall structure and
function (Sabba et al. 1999).  Dichlobenil is primarily converted to
2,6-dichlorobenzamide (BAM) in the soil by way of microbial degradation
and is then taken up by the roots of exposed plants (Verloop 1972).

3.1.4		Mammalian Toxicology

	

3.1.4.1		Dichlobenil 

Dichlobenil technical demonstrated moderate acute toxicity (Category II
or III) via the oral, dermal, and inhalation routes.  It is neither a
dermal irritant (Category IV), eye irritant (Category IV), nor a dermal
sensitizer (Table 3.1a).

A summary of the subchronic and chronic toxicity and genotoxicity
databases for dichlobenil is found in Table 3.1b.  In the subchronic and
chronic oral toxicity studies in hamsters, rats, and dogs, liver
toxicity was the adverse effect most often observed at the LOAEL.  For
example, in a 90-day oral toxicity study in rats, inflammation and
necrosis were observed in the liver of males, and increased liver weight
and liver histopathology (swelling and vacuolation of hepatocytes) were
observed in females.  In a 90-day oral toxicity study in hamsters,
increased liver weight, enlarged liver (with rough surface), and swollen
hepatocytes were observed in females.  In addition, decreased weight of
the prostate and mineralization of the prostate were reported in males. 
Increased liver weights and hepatic enzymes, as well as liver
histopathology, were observed at lower doses in both chronic dog
toxicity studies, as well as in the combined chronic
toxicity/carcinogenicity study in the rat.

In addition to the liver, the nose is considered a target organ for
dichlobenil.  Olfactory toxicity was observed in short-term dermal and
inhalation toxicity studies in mice and rats.  Because olfactory
toxicity was not assayed following acute or subchronic oral exposure to
dichlobenil, the absence of this information is considered a data gap. 
Olfactory toxicity was not observed in the chronic oral (capsule)
toxicity study in the dog.

In a high-dose carcinogenicity study in the hamster, decreased body
weight gain was observed in males and females, while liver
histopathology (finely vacuolated hepatocytes, hepatitis, and brown
pigment in the hepatocytes) was observed in males.  According to the
Health Effects Division 2nd Carcinogenicity Peer Review (1995), there
was a treatment-related increase in liver adenomas and combined
adenomas/carcinomas in males only at the highest dose tested, when
compared to controls.  However, dosing was considered excessive at this
dose in both sexes, based on decreased body weight gains and severe
hepatotoxicity.

In a second carcinogenicity study performed in hamsters at lower doses,
reduced secretion of the prostate and seminal vesicles was observed at
the LOAEL in males, whereas generalized systemic toxicity was observed
in females, as evidenced by decreased body weight gain, peritonitis, and
hyperplasia of the adrenal cortex, small intestine, and bone marrow
(sternum).  According to the Health Effects Division 2nd Carcinogenicity
Peer Review (1995), there was no treatment-related increase in the
incidence of any tumor type in this study.  Dosing was considered
adequate, based on decreased body weight gains and hyperplasia in
various tissues in both sexes.

In a combined chronic toxicity/carcinogenicity study in the rat, adverse
effects on clinical chemistry, gross pathology, and histopathology
confirmed dichlobenil hepatotoxicty. Nephrosis (kidney damage) was also
observed in males, followed by parathyroid hyperplasia, which was
considered a compensatory mechanism to maintain normal blood calcium
levels.  According to the Health Effects Division 2nd Carcinogenicity
Peer Review (1995), a treatment-related increase in the incidence of
hepatocellular adenomas and combined adenomas/carcinomas was observed in
females only at the highest dose tested.  Dosing was considered adequate
in females, but excessive in males, at this dose.  Based on the weight
of the evidence, the HED 2nd Carcinogenicity Peer Review (1995)
classified dichlobenil as a Group C, possible human carcinogen, and
recommended that an RfD approach should be used for quantification of
human cancer risk.

		

Olfactory toxicity was observed following dermal and inhalation
exposures in three

toxicity studies that were either published in the open literature (one
dermal) or submitted to the Agency (two inhalation).  In each study,
degeneration of the olfactory epithelium was observed.  Since the
olfactory epithelium is composed of olfactory sensory neurons, damage to
the olfactory epithelium is considered a neurotoxic effect that is
confined to this organ only.

  

HED concluded that there was no evidence of increased susceptibility to
offspring 

following pre-natal exposure to rats or rabbits in developmental
toxicity studies. 

Evidence of increased pre-/post-natal susceptibility was observed in the
two-generation 

reproduction study in rats.  However, the degree of concern for this
susceptibility is low,

since the NOAEL from this study is six times lower than the dose (LOAEL)
at which 

adverse effects (decreased pup body weight) were observed, and is
therefore protective.

Delayed maturity of the uterus was observed in all high-dose females
tested in the chronic oral (capsule) toxicity study in the dog.  A
marked decrease in mean uterine weight at the high dose confirmed this
finding.  Ovarian weights were also decreased in high-dose females, but
no alterations were observed microscopically.  These results are
suggestive of modulation of the female endocrine system in this study;
however, the dose utilized in this risk assessment for the chronic RfD
is almost forty times lower than that at which the effects were observed
and is considered protective of any potential endocrine modulation.



Table 3.1a.  Acute toxicity profile for dichlobenil technicala

Guideline No./Study Type	

MRID No.	

Results	Toxicity Category

870.1100/Acute oral toxicity (rat)	44866902	>2000 mg/kg	III

870.1200/Acute dermal toxicity (rabbit)	43250401	<2000 mg/kg	II

870.1300/Acute inhalation toxicity (rat)	40425401	

>0.250 mg/L	II

870.2400/Primary eye irritation (rabbit)	40425403	Not an eye irritant	IV

870.2500/Primary dermal irritation (rabbit)	40425402	

Not a dermal irritant	IV

870.2600/Dermal sensitization (guinea pig)	40548501	Not a skin
sensitizer	---

a Based on Memo, Dupuy JL, D257750, 11/12/1999

Table 3.1b.  SUBCHRONIC, CHRONIC, AND GENO- TOXICITY PROFILE FOR
DICHLOBENIL TECHNICAL

Guideline No./

Study Type	

MRID No. (Year)/Doses/ Classification	

Results

870.3100

90-day oral (hamster; dietary)	

40600701 (1987)

0, 41, 209, 1289, or 7500/4648 ppm (adjusted due to evaporation;
equivalent to 0, 3, 16, 79, or 395/263 mg/kg bw/day)

Acceptable/Non-guideline	

NOAEL = 3 (M) and 16 (F) mg/kg/day  

LOAEL = 16 mg/kg/day (M) based on decreased weight of the prostate and
mineralization of the prostate; and 79 mg/kg/day (F) based on increased
liver weight, enlarged liver (with rough surface), and swollen
hepatocytes

870.3100

90-day oral (rat; dietary)

	

00107106 (1961)

0, 100, 1000, 3000, or 10000 ppm (equivalent to 0, 4.5, 45, 135, or 453
mg/kg/day; adjusted for purity)

Acceptable/Non-guideline	

NOAEL = 4.5 (M) and 45 (F) mg/kg/day

LOAEL = 45 mg/kg/day (M) based on hepatocytic inflammation and necrosis;
and 135 mg/kg/day (F) based on increased liver weight and liver
histopathology (swelling and vacuolation of hepatocytes)

870.3200

21-day dermal

(rabbits)

	

43879301 (1995)

0, 100, 300, or 1000 mg/kg/day

Acceptable/Non-guideline	

NOAEL = 1000 mg/kg/day (HDT)

LOAEL was not observed.

Non-guideline (literature)

5-day dermal (mouse)	

Deamer et al. (1994); no MRID

0, 10, 25, 50, 100, 150, or 200 mg/kg/day

Acceptable/Non-guideline	

NOAEL = 25 mg/kg/day

LOAEL = 50 mg/kg/day based on olfactory epithelial damage following
single (1-day) and repeated (5-day) dosing

870.3465

90-day inhalation (rat)

	

46398701 (2002), 46653001 (2002)

0, 2.3, 5.1, or 12 mg/m3 (equivalent to 0, 0.03, 0.07, or 0.17
mg/kg/day, respectively) 

for 28 days (6 hrs/day; 5 days/week)

Unacceptable/Guideline due to inadequate dosing for 28 days	

NOAEL (28 days) = 12 mg/m3 (HDT) 

LOAEL (28 days) was not observed.

870.3465

90-day inhalation (rat)	46653001 (2002)

0, 21, 77, or 200 mg/m3 (equivalent to 0, 0.3, 1.1, or 2.9 mg/kg/day,
respectively  ) 

for 7 days (range finding; 6 hrs/day)

Acceptable/Non-guideline	

NOAEL (7 days, range finding) was not observed.

LOAEL (7 days, range finding) = 21 mg/m3 (0.3 mg/kg/day) based on an
increased incidence of nasal degeneration

870.4100

Chronic toxicity oral (dog; dietary)

	

00067649 (1969)

0, 20, 50, or 350 ppm (equal to 0, 0.5, 1.25, or 8.75 mg/kg/day) 

Acceptable/Non-guideline	

NOAEL = 1.25 mg/kg/day 

LOAEL = 8.75 mg/kg/day based on increased liver weight (M&F), serum
alkaline phosphatase (M&F), and serum alanine aminotransferase (F);
liver histopathology [leukocytic infiltration around the central veins
(M&F) and necrosis (M)]; and an increase in the number of erythrocytes
in the urine (F)

870.4100

Chronic toxicity oral (dog; capsule)

	

43969701 (1995)

0, 1, 6, or 36 mg/kg/day 

Acceptable/Guideline	

NOAEL = 1 mg/kg/day 

-GT and periportal hypertrophy of hepatocytes (M)

870.4200

Carcinogenicity oral (hamster; dietary)

	

41988301 (1991), 42015101 (1991), 42563601 (1992)

0, 5, 26, 132, or 675 ppm [equal to 0/0, 0.34/0.35, 1.69/1.78,
9.39/9.20, or 45.64/48.85 mg/kg/day (M/F)]

Acceptable/Non-guideline	

NOAEL = 1.69 (M) and 9.20 (F) mg/kg/day

LOAEL = 9.39 mg/kg/day (M) based on reduced secretion of the prostate
and seminal vesicles; and 48.85 mg/kg/day (F) based decreased body
weight gain, peritonitis, and hyperplasia of the adrenal cortex, small
intestine, and bone marrow (sternum)

No evidence of carcinogenicity.

870.4200

Carcinogenicity oral (hamster; dietary)

	

42221201 (1992), 42563601 (1992)

0, 675, 1500, or 3375 ppm [equal to 0/0, 51/55, 117/121, 277/277
mg/kg/day (M/F)]

Acceptable/Non-guideline	

NOAEL was not observed.

LOAEL = 51/55 mg/kg/day (M/F) based on decreased body weight gain (M&F),
and liver histopathology (finely vacuolated hepatocytes, hepatitis, and
brown pigment in the hepatocytes) (M)

Statistically significant increase in hepatocellular adenomas and
combined adenomas/carcinomas at 277 mg/kg/day (M); dosing considered
excessive in M&F

870.4300

Combined Chronic Toxicity/

Carcinogenicity oral (rat; dietary)	

00147438 (1983), 40401101 (1987), 40823801 (1988)

0, 50, 400, or 3200 ppm (equal to 0, 2.3, 18.9, or 173.1 mg/kg/day)

Acceptable/Non-guideline	

NOAEL = 2.3 mg/kg/day  

LOAEL = 18.9 mg/kg/day based on changes in clinical chemistry (increased
blood urea nitrogen, cholesterol), gross pathology (enlarged liver,
enlarged kidney), and histopathology (nephrosis, parathyroid
hyperplasia) in males; and increased liver weight, enlarged liver, and
cytologic alterations (polyploidy with hepatocytic swelling) in the
liver in females.

Statistically significant increase in hepatocellular adenomas and
combined adenomas/carcinomas in at 173.1 mg/kg/day (F); dosing
considered adequate in females

Statistically significant increasing trend for hepatocellular adenomas,
carcinomas, and combined adenomas/carcinomas at 173.1 mg/kg/day (M);
dosing considered excessive in males

870.3700

Developmental toxicity oral (rat; gavage)

	

00147437 (1984)

0, 20, 60, or 180 mg/kg/day

Acceptable/Non-guideline	

Maternal NOAEL = 20 mg/kg/day

Maternal LOAEL = 60 mg/kg/day based on decreased body weight gain, food
consumption, and food efficiency during dosing

Developmental  NOAEL = 180 mg/kg/day 

Developmental LOAEL was not identified.

870.3700

Developmental toxicity oral (rabbit; gavage)

	

41257302 (1989)

0, 15, 45, or 135 mg/kg/day

Acceptable/Non-guideline	

Maternal NOAEL = 45 mg/kg/day

Maternal LOAEL = 135 mg/kg/day based on decreased body weight gain and
food consumption during dosing

Developmental  NOAEL = 45 mg/kg/day 

Developmental LOAEL = 135 mg/kg/day, based on increased 

number of total resorptions/dam and post-implantation loss; 

and increased incidences of fetal external (cleft palate, 

adactyly, bilateral open eye), visceral (abnormal cystic 

gallbladder, distended ureter with bilateral severe 

hydronephrosis), and skeletal (malformed and malpositioned 

right scapula, right radius absent with malpositioned ulna and 

humerus, fused cervical vertebral arches, asymmetrically 

ossified and fused cervical vertebra centra, abnormally 

shaped cranium with enlarged and misshapen fontanelle, 

enlarged fontanelle, misshapen frontals, skull and frontals 

foreshortened and nasal malpositioned, and major fusion of 

sternebrae) anomalies

870.3800

2-generation reproduction oral (rat; dietary)

	41257303 (1989), 42239101 (1992)

0, 60, 350, or 2000 ppm (equivalent to 0, 3, 17.5, or 100 mg/kg/day)

Acceptable/Non-guideline	Parental NOAEL = 17.5 mg/kg/day

Parental LOAEL = 100 mg/kg/day based on decreased body weight gains
during premating (M&F) and gestation (F) in both generations and
decreased food consumption during premating in both generations (M&F)

Reproductive NOAEL = 17.5 mg/kg/day

Reproductive LOAEL = 100 mg/kg/day based on decreased number of
implantations/dam in F1 (unreported for P)

Offspring NOAEL = 3 mg/kg/day

Offspring LOAEL = 17.5 mg/kg/day based on decreased body weight during
weaning in both generations

Non-guideline (literature)

Fetal and neonatal mouse olfactory study (single injections; s.c. in
neonates, i.p. in adults)	Eriksson and Brittebo (1995); no MRID

0, 12, or 25 mg/kg/day (s.c. in neonates, i.p. in adults)

Acceptable/Non-guideline	Parental NOAEL not observed.

Parental LOAEL (i.p.) = 12 mg/kg/day based on many vacuolated,
degenerated, or necrotic Bowman’s glands and no periodic acid-Schiff
(PAS) staining of contents of Bowman’s glands

Offspring NOAEL not observed.

Offspring LOAEL (PND 8; s.c.) = 12 mg/kg/day based on no periodic
acid-Schiff (PAS) staining of contents of Bowman’s glands (measure of
mucus production)

Non-guideline (literature)

Adult mouse olfactory study (single injection; i.p.)	Brandt et al.
(1990); no MRID

0, 6, 12, 25, or 50 mg/kg/day (i.p.)

Acceptable/Non-guideline	NOAEL (i.p.) = 6 mg/kg/day

LOAEL (i.p.) = 12 mg/kg/day based on necrosis in Bowman’s glands and
olfactory epithelium

870.5100

In vitro bacterial reverse mutation (Ames test)	

00153579 (1984)

g/plate (-/+ activation) in S. typhimurium

Acceptable/Guideline	

Negative with or without activation.

870.5100

In vitro bacterial reverse mutation (Ames test)	

00153586 (1981)

At concentrations up to 5000 g/plate (-/+ activation) in E. coli and
S. typhimurium; and 5000 g/disk (- activation) in B. subtilis

Acceptable/Guideline	

Negative with or without activation.

870.5300

In vitro mouse lymphoma (L5178Y) mutation 	

00153576 (1984)

At concentrations up to 280 g/ml (- activation) and 50 g/ml (+
activation)

Acceptable/Guideline	

Negative with or without activation.

870.5395

In vivo mouse erythrocyte micronucleus assay	

00153578 (1983)

0, 300, 600, or 1200 mg/kg 

Unacceptable/Guideline due to insufficient sampling times	

Negative.

870.5375

In vitro chromosomal aberrations (human lymphocytes)	

00153577 (1984)

g/ml (-/+ activation) (limit of solubility)

Acceptable/Guideline	

Negative with or without activation.

870.5375

In vitro chromosomal aberrations (CHO cells)	

43191501 (1990)

At concentrations up to 100 g/ml (-/+ activation)

Acceptable/Guideline	

Negative with or without activation.

870.5550

In vitro Unscheduled DNA synthesis (human HeLa epithelioid cells)	

00153580 (1984)

At concentrations up to 102.4 g/ml (-/+ activation) 

Acceptable/Guideline	

Negative with or without activation.

In vitro transformation assay (BALB/3T3 cells)	

00153581 (1984)

At concentrations up to 7500 g/ml (+ activation)

Acceptable/Guideline	

Negative.

In vitro recombination assay	

00153586 (1981)

At concentrations up to 5000 g/disk (- activation) in B. subtilis

Acceptable/Non-guideline	

Negative.

870.7485

Metabolism and toxicokinetics

(rats)	41227401-04 (1989), 41299401 (1987)

2.5 mg/kg (single dose; oral); 5 mg/kg (single dose; oral, i.v.); 3.75,
30, or 240 mg/kg (single and repeated dose; oral)

Acceptable/Guideline	After 7 days of i.v. exposure, 65-71% and 25-31% of
the dose was excreted in the urine and feces, resp., in M&F; similar
results were obtained for the oral route of exposure (therefore
efficient GI absorption).  79% and 20% oral dose was measured in bile
and urine, resp., 24 hrs. after exposure; 20-30% oral dose eliminated in
feces via bile (supports enterohepatic recirculation).  95% of urinary
metabolites were excreted 24 hrs. after dosing.  Recovery (96%) 7 days
after a single i.v. dose indicates low residence time in tissues;
slightly longer residence time following oral exposure is suggested by
84-86% recovery 7 days after a single oral dose. Tissue levels peaked
1-3 hrs. after oral dosing.  Dichlobenil is metabolized via
hydroxylation at the 3 or 4 position of the phenyl group followed by
sulfation or glucuronidation; or via displacement of a Cl atom followed
by glutathione conjugation. Glutathione conjugation appears to be
saturable during repeated dosing.

3.1.4.2		2,6-Dichlorobenzamide (BAM)

The dichlobenil soil metabolite, 2,6-dichlorobenzonitrile (BAM)
demonstrated moderate acute toxicity (Category III) via the oral route
of exposure (Table 3.1c).  Because the subchronic and chronic toxicity
of BAM is less than or equal to that of dichlobenil (parent compound),
the acute toxicity of BAM via the inhalation and dermal routes is
expected to be less than or equal to that of dichlobenil.

A summary of the subchronic and chronic toxicity and genotoxicity
databases for BAM is found in Table 3.1d.  In the subchronic and chronic
oral toxicity studies in the rat and dog, respectively, body weight
change was the toxicological effect most often observed at the LOAEL. 
In the combined chronic toxicity/carcinogenicity study in the rat,
toxicologically significant changes in body weight were also observed at
the LOAEL, as were eosinophilic foci in the liver.  In general, adverse
liver effects were observed in the submitted studies at doses of BAM
that were higher than those of dichlobenil (parent).

There was no evidence of carcinogenicity in the combined chronic
toxicity/carcinogenicity study of BAM in the rat.  An increased
incidence of hepatocellular adenomas was observed at the high dose in
females only in the study.  However, the statistical significance of the
effect was marginal (P=0.049), dosing was considered adequate in the
study, and the tumors were non-cancerous.  In addition, there was no
evidence that BAM was either mutagenic or clastogenic.  However, in the
absence of a second species, HED considers the carcinogenic potential of
BAM to be similar to that of dichlobenil (possible human carcinogen) and
that it is appropriate to use an RfD approach for quantification of
human cancer risk.

BAM-mediated olfactory toxicity was observed in one study collected from
the open literature (Brittebo et al. 1991).  Although olfactory
epithelial necrosis was observed after i.p. administration of BAM, the
dose was eight times higher than that which caused the same effect using
dichlobenil.  In the absence of studies via other routes of exposure,
BAM-mediated olfactory toxicity is considered by HED to be less than
that of dichlobenil (parent).

HED concluded that there was no evidence of increased susceptibility to
offspring following pre-natal exposure to rabbits in a developmental
toxicity study and pre-/post-natal exposure in the two-generation
reproduction study in the rat.  

BAM is considered neurotoxic.  Toxicity to the olfactory sensory neurons
was observed following single i.p. exposures of mice to BAM (Brittebo et
al. 1991).  In the 90-day oral toxicity study in rats, reduced muscle
tone was observed; however, the toxicological significance of this
finding is unclear, given the lack of reproducibility of the effect in
other studies, the age of the study itself (1967), and the fact that the
purity of the compound was not reported in the study.  Lethargy and
ataxia were observed in mice tested orally in a dose-range finding study
for the in vivo erythrocyte micronucleus assay.  The effects were
resolved after 24 hours.  In addition, in a two-week dietary study
recently submitted and not fully reviewed by the Agency (MRID 46892401),
clinical signs of toxicity (slightly decreased muscle tone, slight loss
of pinnae reflexes) were observed in mice at 2500 ppm (approximately
equal to 375 mg/kg/day).  Therefore, HED is requesting Guideline acute
and subchronic neurotoxicity screening batteries (OPPTS 870.6200) with
BAM.

Table 3.1c.  Acute toxicity profile for soil metabolite
2,6-dichlorobenzamide (BAM)a

Guideline No./Study Type	

MRID No.	

Results	Toxicity Category

870.1100/Acute oral toxicity (mouse)	42940201	

1538/1144 mg/kg (M/F)	III

a According to Reregistration Eligibility Decision (1998)

Table 3.1d.  SUBCHRONIC, CHRONIC, AND GENO- TOXICITY PROFILE FOR
METABOLITE, 2,6-DICHLOROBENZAMIDE (BAM)

Guideline No./

Study Type	

MRID No. (Year)/Doses/ Classification	

Results

870.3100

90-day oral (rat; dietary)

	

00067654 (1967)

0, 50, 180, 600, or 2300 ppm (equal to 0, 4, 14, 49, or 172 mg/kg/day)

Acceptable/Non-guideline	

NOAEL = 14 mg/kg/day  

LOAEL = 49 mg/kg/day based on decreased body weight gain (M) and reduced
skeletal muscle tone (day 4 only in males; days 91 and 92 only in
females)

870.3150

90-day oral (dog; dietary)

	

00067655 (1967)

0, 100, 300, or 2000 ppm (equal to 0, 7.5, 22.5, or 150 mg/kg/day)

Unacceptable/Guideline due to parasitic infections (ascariasis) in most
animals	

NOAEL = 22.5 mg/kg/day  

LOAEL = 150 mg/kg/day based on clinical signs (thin appearance, dull
coat, hair loss) and increased liver weight and serum alkaline
phosphatase concentrations (F) and clinical signs (thin appearance, dull
coat, hair loss) (M)

870.4700

Chronic toxicity oral (dogs; dietary)

	

42940203 (1971)

0, 60, 100, 180, or 500 ppm (equal to 0, 1.5, 2.5, 4.5, or 12.5
mg/kg/day) 

Acceptable/Non-guideline	

NOAEL = 4.5 mg/kg/day 

LOAEL = 12.5 mg/kg/day based on decreased body weight and body weight
gain

870.4300

Combined Chronic Toxicity/ Carcinogenicity oral (rat; dietary)

	

42940202 (1971), 44043601 (1996), 44052901 (1996)

0, 60, 100, 180, or 500 ppm [equal to 0, 2.2/2.8, 3.6/4.7, 6.5/8.5, or
19/25 mg/kg/day (M/F)]

Acceptable/Non-guideline	

NOAEL = 6.5 (M) and 4.7 mg/kg/day (F)

LOAEL = 19 mg/kg/day (M) and 8.5 mg/kg/day (F) based on decreased body
weight and body weight gain (≥ week 26) and an increased incidence of
hepatocellular alteration (eosinophilic foci)

Borderline statistically significant (P=0.049) increased incidence of
hepatocellular adenomas at 25 mg/kg/day (F only); dosing considered
adequate (M&F)

870.3700

Developmental toxicity oral (rabbit; gavage)

	

43003601 (1986), 43265201 (1994)

0, 10, 30, or 90 mg/kg/day

Acceptable/Guideline	

Maternal NOAEL= 30 mg/kg/day

Maternal LOAEL= 90 mg/kg/day based on increased incidences of clinical
signs (late abortion, thin appearance) and decreased (severe) body
weight gain and food consumption during dosing

Developmental NOAEL = 30 mg/kg/day 

Developmental LOAEL = 90 mg/kg/day based on increased 

incidences of late abortion and skeletal (bipartite interparietal 

bone) and visceral (postcaval lung lobe agenesis) anomalies

870.3800

3-generation reproduction oral (rat; dietary)

	42940204 (1971)

0, 60, 100, or 180 ppm (equivalent 0, 4.5, 7.5, or 13.5 mg/kg/day) 

Acceptable/Non-guideline	Parental NOAEL = 13.5 mg/kg/day

Parental LOAEL was not observed. 

Reproductive NOAEL = 13.5 mg/kg/day

Reproductive LOAEL was not observed.

Offspring NOAEL = 13.5 mg/kg/day

Offspring LOAEL was not observed.

Non-guideline (literature)

Adult mouse olfactory study (single injection; i.p.)	Brittebo et al.
(1991); no MRID

0, 25, 50, or 100 mg/kg/day (i.p.)

Acceptable/Non-guideline	NOAEL (i.p.) not observed.

LOAEL (i.p.) = 25 mg/kg/day based on decreased periodic acid-Schiff
(PAS) staining of contents of Bowman’s glands (measure of mucus
production)

Necrosis of Bowman’s glands and olfactory epithelium observed at 100
mg/kg/day only

870.5100

In vitro bacterial reverse mutation (Ames test)	

43003603 (1992)

g/plate (-/+ activation) in S. typhimurium

Acceptable/Guideline	

Negative with or without activation.

870.5395

In vivo mouse erythrocyte micronucleus assay	

43003602 (1993), 43747101 (1995)

0, 250 mg/kg 

Acceptable/Guideline	

Negative.  

Lethargy observed in dose-range finding (pilot) study at 100 mg/kg/day
(=LOAEL; NOAEL not observed)

870.5550

In vitro Unscheduled DNA synthesis (rat hepatocytes)	

43003604 (1993)

At concentrations up to 1000 g/ml

Acceptable/Guideline	

Negative.

3.2		Absorption, Distribution, Metabolism, Excretion (ADME)

The metabolism of [phenyl-U14C]dichlobenil was studied in male and
female Sprague-Dawley rats.  Following oral administration of
dichlobenil at 2.5 or 5 mg/kg, approximately 65-75% of the dose was
eliminated in the urine and 20-30% in the feces (via biliary excretion)
after seven days.  There were no apparent differences between the sexes.
 Results from oral, intravenous, and biliary excretion studies indicated
that the compound is readily absorbed from the gastrointestinal tract
and eliminated in the bile.  However, as a result of enterohepatic
recirculation, the compound is reabsorbed and then eliminated primarily
in the urine.  Based on elimination patterns, it was concluded that
animals dosed at 3.75, 30, or 240 mg/kg exhibited reduced absorption at
the high dose (i.e., saturation).  Specifically, the relative rate of
urinary excretion varied inversely with dose level, and increased
amounts of unchanged parent compound were excreted in the feces at high
doses.  No apparent sex-related differences were seen.  Similar
elimination patterns were noted following the administration of
[phenyl-U14C]dichlobenil on days 1 and 11 and of unlabeled compound on
days 2-10, in an 11-day daily dosing experiment.  No major differences
in metabolic patterns between sexes were observed. 

Dichlobenil is metabolized via hydroxylation at the 3 or 4 position of
the phenyl group followed by sulfation or glucuronidation; or via
displacement of a chlorine atom followed by glutathione conjugation. 
Glutathione conjugation appears to be saturable during repeated dosing. 
The soil metabolite 2,6-dichlorobenzamide (BAM) was not identified as a
metabolite in the rat.  

Radioactive residue levels were assayed in the liver, kidney, whole
blood, and plasma.  High residues were detected in the liver.  In a
time-course study of residue levels in various tissues from rats
receiving 2.5 mg/kg, the highest levels were found in the liver, kidney,
and some samples of kidney fat.  The highest radioactive levels were
found during 1-3 hours post dosing.  Thereafter, residue levels
decreased.  Recovery (96%) seven days after a single i.v. dose indicates
low residence time in tissues; slightly longer residence time following
oral exposure is suggested by 84-86% recovery 7 days after a single oral
dose.  No major sex-related differences were noted in tissue
distribution.

No metabolism or absorption studies are available for dichlobenil via
the dermal or inhalation routes.  The Agency is currently reviewing
metabolism studies for BAM.

3.3		FQPA Considerations

3.3.1	 	Adequacy of the Toxicity Data Base

The toxicology database used to assess pre- and/or post-natal exposure
to dichlobenil is adequate.  However, the toxicology database used to
assess pre- and/or post-natal exposure to the soil metabolite, BAM, is
incomplete.  Data from a 2-week oral toxicity study has been requested
to evaluate potential neurotoxic effects of BAM in mice.  The following
acceptable studies are available:

Dichlobenil

One developmental toxicity study in rats

One developmental toxicity study in rabbits

One two-generation reproduction study in rats

2,6-Dichlorobenzamide (BAM)

One developmental toxicity study in rabbits

One three-generation reproduction study in rats

3.3.2		Evidence of Neurotoxicity (Dichlobenil and BAM)

Olfactory toxicity was observed following dermal, inhalation, and
intraperitoneal (i.p.) 

exposures to dichlobenil in five toxicity studies that were either
published in the open 

literature (one dermal, two i.p. studies) or submitted to the Agency
(two inhalation 

studies).  In each study, degeneration of the olfactory epithelium was
observed.  Since the 

olfactory epithelium is composed of olfactory sensory neurons, damage to
the olfactory 

epithelium is considered a neurotoxic effect.

BAM is considered neurotoxic.  Toxicity to the olfactory sensory neurons
was observed following single i.p. exposures of mice to BAM (Brittebo et
al. 1991).  In the 90-day oral toxicity study in rats, reduced muscle
tone was observed; however, the toxicological significance of this
finding is unclear, given the lack of reproducibility of the effect in
other studies, the age of the study itself (1967), and the fact that the
purity of the compound was not reported in the study.  Lethargy and
ataxia were observed in mice tested orally in a dose-range finding study
for the in vivo erythrocyte micronucleus assay.  The effects were
resolved after 24 hours.  In addition, in a two-week dietary study
recently submitted and not fully reviewed by the Agency (MRID 46892401),
clinical signs of toxicity (slightly decreased muscle tone, slight loss
of pinnae reflexes) were observed in mice at 2500 ppm (approximately
equal to 375 mg/kg/day).  Therefore, HED is requesting Guideline acute
and subchronic neurotoxicity screening batteries (OPPTS 870.6200) with
BAM.

3.3.3.1		Developmental Toxicity Studies (Dichlobenil)

Rat

In an Acceptable/Non-guideline, prenatal developmental toxicity study
(MRID 00147437), dichlobenil technical (purity not reported; batch# 
FUN82B07A/FUX003000) was administered by gavage in 1% gum tragacanth to
25 pregnant Wistar Cpb:WU rats/sex/dose from gestation day (GD) 6-15
inclusive at daily dose levels of 0, 20, 60, or 180 mg/kg/day.  No
treatment-related mortality or clinical signs of toxicity were observed
in pregnant does in the study.  

A 29% (P<0.01) and 36% (P<0.01) decrease in mean body weight gain was
observed during the dosing period in does treated at 60 and 180
mg/kg/day, resp.  This effect was accompanied by a 15% (P<0.01) and 21%
(P<0.01) decrease in food consumption at 60 and 180 mg/kg/day,
respectively, as well as a respective 19% (P<0.05) and 24% (P<0.01)
decrease in food efficiency.  During the post-dosing period (GD 16-21),
body weight gain, food consumption, and food efficiency values in mid-
and high-dose animals rebounded to levels that were similar to or
greater than those of controls.  The maternal LOAEL is 60 mg/kg bw/day,
based on decreased body weight gain, food consumption, and food
efficiency during dosing.  The maternal NOAEL is 20 mg/kg bw/day.

No treatment-related changes were observed in cesarean section
parameters (death, altered growth) for either embryos or fetuses.  It is
unclear from the study report whether statistical analysis was performed
for litter incidences of external, skeletal, or visceral observations. 
With regard to external anomalies, a shallow dose-dependent increase in
the incidence of small subcutaneous hemorrhage or petechia was observed
(0/23, 1/22, 2/22, and 3/21 litters at 0, 20, 60, and 180 mg/kg/day);
however, the increase in the number of fetuses affected (0-3) was only
slightly increased across dose and not statistically significant. 
Historical control incidences for this specific observation were not
reported.  However, the percentage of litters affected at all doses was
within the historical control range (0-20%) of litter incidences of
externally visible alterations.

An increased litter (13.6-14.3%) and fetal (3.1-3.5%) incidence of
unilateral supernumerary rib (14th) was observed at ≥ 60 mg/kg/day. 
The fetal incidences were not statistically significantly different from
concurrent controls.  The litter incidence (19%) of bilateral
supernumerary rib (14th) was also increased at 180 mg/kg/day, as was the
fetal incidence (4.7%; P<0.05).  However, both the litter and fetal
incidences of supernumerary (14th) rib were below the historical control
incidences (32.26% and 10.86%, resp.).  An increase (P<0.01) in the
“degree” of absence of ossification of the sternebrae (expressed as
transformed ossification values per litter) was also observed at 180
mg/kg/day (7.03 vs. 0.59 in controls).  The increase was outside the
historical control range (0-0.31).  However, given that the concurrent
control value (0.59) was above the upper limit of the historical control
range and dose-response was lacking in the effect, the calculated value
is not considered toxicologically significant.

With respect to visceral anomalies, a very slight increase in the
malformations, unilateral microphthalmia and intestinal alteration of
the situs viscerum (combined with focal fibrosis of the peritoneum and
mesentery) was observed at the high dose in one animal in 1/21 litters
only.  The malformation, soft consistency of the lens/unilateral folded
retina, was observed in a different animal in 1/21 litters only.  The
incidence of each effect was above that of the historical controls
(1/2691 fetuses; 1/401 litters); however, fetal incidences were not
statistically significant and a dose-response was lacking at the doses
tested.  The developmental LOAEL was not identified.  The developmental
NOAEL is 180 mg/kg bw/day.

Rabbit

In an Acceptable/Non-guideline, prenatal developmental toxicity study
(MRID 41257302), dichlobenil technical (98.5% a.i.; lot#s 3 and 6;
batch# FUX010000) was administered by gavage in 1% gum tragacanth to 18
pregnant New Zealand white rabbits/sex/dose from gestation day (GD) 7-19
inclusive at daily dose levels of 0, 15, 45, or 135 mg/kg/day.  No
treatment-related mortality, clinical signs of toxicity (including
abortions), or gross pathology were observed in the study.

A decrease (129%; P<0.05) in body weight gain was observed during the
dosing period only (GD 7-19) in does treated at 135 mg/kg/day.  This
effect was accompanied by a 30% (P<0.01) decrease in food consumption at
the high dose during the dosing period only.  Body weight gain and food
consumption in high-dose animals rebounded during the post-dosing period
(GD 19-29).  The maternal LOAEL is 135 mg/kg bw/day, based on decreased
body weight gain and food consumption during dosing.  The maternal NOAEL
is 45 mg/kg bw/day.

Increases in total resorptions/dam (1.3) and post-implantation loss
(17.9%) were observed at 135 mg/kg/day.  Although the effects were not
dose-dependent, the incidences were outside the historical control range
and considered treatment-related.  Although generally occurring at very
low incidences (1-3 fetuses), several external, visceral, and skeletal
defects anomalies were reported at 135 mg/kg/day. These effects were not
observed in either concurrent or historical controls or were observed at
incidences outside historical control ranges and were therefore
considered toxicologically significant.  External anomalies included
bilateral open eye (3/115 fetuses; 3/14 litters), cleft palate, and
adactyly.  High-dose visceral anomalies included abnormal cystic
gallbladder and distended ureter with bilateral severe hydronephrosis. 
Skeletal defects at 135 mg/kg/day were composed of malformed and
malpositioned right scapula, right radius absent with malpositioned ulna
and humerus, fused cervical vertebral arches, asymmetrically ossified
and fused cervical vertebra centra, abnormally shaped cranium with
enlarged and misshapen fontanelle, enlarged fontanelle (19/115 fetuses;
13/14 litters), misshapen frontals (2/115 fetuses; 2/14 litters), skull
and frontals foreshortened and nasal malpositioned, and major fusion of
sternebrae (3/115 fetuses; 3/14 litters).

The developmental LOAEL is 135 mg/kg bw/day, based on increased number
of total 

resorptions/dam and post-implantation loss; and increased incidences of
external (cleft 

palate, adactyly, bilateral open eye), visceral (abnormal cystic
gallbladder, distended 

ureter with bilateral severe hydronephrosis), and skeletal (malformed
and malpositioned 

right scapula, right radius absent with malpositioned ulna and humerus,
fused cervical 

vertebral arches, asymmetrically ossified and fused cervical vertebra
centra, abnormally 

shaped cranium with enlarged and misshapen fontanelle, enlarged
fontanelle, misshapen 

frontals, skull and frontals foreshortened and nasal malpositioned, and
major fusion of 

sternebrae) anomalies.  The developmental NOAEL is 45 mg/kg bw/day.

3.3.3.2		Reproductive Toxicity Study (Dichlobenil)

In an Acceptable/Non-guideline, two-generation reproduction study (MRIDs
41257303 and 42239101), dichlobenil technical (99.4% a.i.; lot#s 4 and
5; batch# F6N87EO8A/FUX011000) was administered in the diet to
Crl:CD(SD)BR rats (30/sex/dose in the P generation; 25/sex/dose in the
F1 generation) at daily dose levels of 0, 60, 350, or 2000 ppm
(equivalent to 0, 3, 17.5, or 100 mg/kg/day) for 2 consecutive
generations.  One (of 30) high-dose P males was found dead during week
14 of the study.  The cause of death was liver necrosis and hemorrhage
(MRID 42239101).  One (of 25) F1 high-dose males was sacrificed in
extremis during week 12 of the study due after an accidental injury to
the snout.  Both deaths were considered incidental to treatment.  There
were no treatment-related clinical signs of toxicity in the study.  

During the 10-week premating period for P animals, mean cumulative body
weight gains were decreased by 25-26% (P<0.05) at 2000 ppm in both males
and females.  Similarly, mean overall body weight gains for F1 males
were decreased by 25% during the 10-week premating period and by 18% for
F1 females at 2000 ppm.  During gestation, mean body weight gains were
decreased by 13-14% in both P and F1 females at 2000 ppm.  Decrements in
body weight gains were not observed in adult females of either
generation during lactation.  Mean food consumption at 2000 ppm was
decreased by 11-33% (P<0.001) in P males and by 17-28% (P<0.001) in P
females during premating.  In F1 males, mean food consumption during
premating was decreased by 16-21% (P<0.001) and by 16-20% (P<0.001) in
F1 females at 2000 ppm.  Mean food consumption for P and F1 females
during gestation and lactation was not reported.

No treatment-related effects were observed on fertility index, fecundity
index, gestation index, or mean gestation length in either P or F1
females.  The mean number of implantations/dam was unreported for P
females and decreased at 2000 ppm in F1 females (12.3 vs. 14.6 in
controls).  The parental systemic LOAEL is 2000 ppm (100 mg/kg bw/day),
based on decreased body weight gains during premating (males and
females) and gestation (females) in both generations, decreased food
consumption during premating in both generations (males and females),
and decreased number of implantations/dam in F1 females.  The parental
systemic NOAEL is 350 ppm (17.5 mg/kg bw/day).  The reproductive LOAEL
is 2000 ppm (100 mg/kg bw/day), based on decreased number of
implantations/dam in F1 females.  The reproductive NOAEL is 350 ppm
(17.5 mg/kg bw/day).

 dam at 2000 ppm.  At ≥ 350 ppm, the mean pup body weight of F1
offspring was decreased by 16-23% (P<0.05) from postnatal day (PND) 4
(precull)-21.  The effect was dose-dependent.  In F2 offspring, mean pup
body weight was also dose-dependently decreased by 19-22% (P<0.05) from
PND 14-21.  An increased incidence of pelvic cavitation of the kidney at
2000 ppm (3% vs. 0%) was observed during necropsy in weanling F2
offspring; however, the incidence was similar to the sporadic incidence
observed in P and F1 animals and was not considered toxicologically
significant.  The offspring LOAEL is 350 ppm (17.5 mg/kg bw/day), based
on decreased body weight during weaning in both generations.  The
offspring NOAEL is 60 ppm (3 mg/kg bw/day).

3.3.4.1		Developmental Toxicity Study (BAM)

Rabbit

In an Acceptable/Non-guideline, prenatal developmental toxicity study
(MRID 43003601), 2,6-dichlorobenzamide (99.4% a.i.; batch# FUX001000)
was administered by gavage in 1% gum tragacanth to 16 pregnant New
Zealand white rabbits/sex/dose from gestation day (GD) 7-19 inclusive at
daily dose levels of 0, 10, 30, or 90 mg/kg/day.  Five (of 16) females
treated at 90 mg/kg/day were sacrificed in extremis.  Three of the 5
sacrificed high-dose dams had late abortions (GD 19, 21, and 22, resp.).
The incidence of abortion followed by sacrifice at 0, 10, and 30
mg/kg/day was 1/16, 1/16, and 0/16, resp.  The other 2/5 high-dose
animals were sacrificed moribund.  Moribund condition followed by
sacrifice was observed in 1/16, 0/16, and 2/16 animals at 0, 10, and 30
mg/kg/day, resp.  The incidence of thin appearance was increased at 90
mg/kg/day (10/16), whereas the incidences at 0, 10, and 30 mg/kg/day
were 1/16, 0/16, and 2/16, resp.  

A decrease (129%) in mean body weight gain, relative to controls, was
observed during the dosing period (GD 7-19) in does treated at 90
mg/kg/day.  Similarly, food consumption at 90 mg/kg/day was decreased
during the dosing period by 49%, relative to controls.  Body weight gain
and food consumption in high-dose animals rebounded above control levels
during the post-dosing period (GD 20-28).  No treatment-related gross
pathology was observed.  The maternal LOAEL is 90 mg/kg bw/day, based on
increased incidences of clinical signs (late abortion, thin appearance)
and decreased (severe) body weight gain and food consumption during
dosing.  The maternal NOAEL is 30 mg/kg bw/day.

No treatment-related effects were observed on several developmental
endpoints, including the number of resorptions, post-implantation loss,
litter size, and sex ratio.  Mean fetal body weight at 90 mg/kg bw/day
(33.9 g) was decreased by 6%, relative to controls; however, the change
was not statistically significant and the mean value fell within the
historical control range (27.7 g-39.4 g).  No treatment-related changes
were observed on the incidences of external defects.  

An increase in the incidence of bipartite interparietal bone was
observed at 90 mg/kg bw/day.  Litter incidences were 1/14, 1/15, 2/14,
and 3/11 litters at 0, 10, 30, and 90 mg/kg/day.  Bipartite
interparietal bone is considered a malformation in rats (Solecki et al.
2001).  Historical control data were not provided for the litter
incidences of bipartite interparietal bone, and fetal incidences only
were reported for the current study.  However, the fetal incidences were
not statistically significant different from concurrent controls, and
the concurrent control fetal incidence (0.8%) exceeded that of the
historical controls (0.3%).  An increase in the incidence of postcaval
lung lobe agenesis was also observed at 90 mg/kg bw/day.  Litter
incidences were 0/14, 0/15, 1/14, and 3/11 at 0, 10, 30, and 90
mg/kg/day.  The fetal incidence of postcaval lung lobe agenesis at 90
mg/kg bw/day (3.2%) exceeded that of the historical controls (1.2%),
whereas that at 30 mg/kg bw/day (0.9%) did not.  The developmental LOAEL
is 90 mg/kg bw/day, based on increased incidences of late abortion and
skeletal (bipartite interparietal bone) and visceral (postcaval lung
lobe agenesis) anomalies.  The developmental NOAEL is 30 mg/kg bw/day.

3.3.4.2		Reproductive Toxicity Study (BAM)

In an Acceptable/Non-guideline, 3-generation reproduction study (MRID
42940204), 2,6-dichlorobenzamide (99.5% a.i.; batch # 195) was
administered in the diet to Long-Evans rats (10 males/dose and 20
females/dose in the P, F1, and F2 generations) at daily dose levels of
0, 60, 100, or 180 ppm (equivalent to 0, 4.5, 7.5, or 13.5 mg/kg/day)
for 3 consecutive generations.  Two litters were produced in each
generation.  The number of pups per litter was counted on postnatal days
(PNDs) 1, 5, and 21 (also weighed).  Litters were culled to ten animals
each on PND 5.  P, F1, and F2 generation parental animals were weighed
and examined for gross pathology on the day of termination
(unspecified).  Organ weights were measured, and histopathology was
performed on select F3b weanlings only.

No treatment-related mortality was observed in the P, F1b, or F2b
parental generations.  A 6% (P<0.05) decrease in mean parental terminal
body weight was observed at 180 ppm in the F2b generation; however, the
decrease was not biologically significant and not observed in P or F1b
parental animals.  No treatment-related gross pathology was observed in
P, F1b, or F2b parental animals.  Fertility and gestation indices were
similar across treatment groups in P, F1, and F2 generation dams.  The
parental systemic LOAEL was not observed.  The parental systemic NOAEL
is 180 ppm (13.5 mg/kg bw/day).  The reproductive LOAEL was not
observed.  The reproductive NOAEL is 180 ppm (13.5 mg/kg bw/day).

No treatment-related differences were observed in the mean number of
pups per litter on PNDs 1, 5 (pre-cull), or 21 in the F1, F2 or F3
generations.  Viability and lactation indices were similar across the
treatment groups in F1, F2, and F3 generation pups.  Mean survival from
birth to PND 5 (viability index) was slightly reduced (86.2%, P<0.01;
vs. 95.7% in controls) at 180 ppm in the F3b generation; however this
decrease was not observed in any other generation.  In addition, mean
survival from birth to weaning was similar across dose for each of the
three generations of offspring.  Hyperexcitability was observed in pups
(number not reported) from four litters in the F1b generation only.

 ≥100 ppm in females was observed in this same generation. Changes in
F3b generation weanling mean organ weights were not considered
toxicologically significant, however, due to a lack of histopathological
correlates in the liver and kidney.  The offspring LOAEL was not
observed.  The offspring NOAEL is 180 ppm (13.5 mg/kg bw/day).

3.3.5		Additional Information from Literature Sources

Dichlobenil and its soil metabolite, BAM, have both been shown to be
olfactory toxicants 

in adult animals following intraperitoneal (i.p.) exposure (Brandt et
al. 1990; Brittebo et 

al. 1991; Eriksson and Brittebo 1995).  Dichlobenil alone also causes
olfactory toxicity in 

neonatal animals following subcutaneous (s.c.) exposure (Eriksson and
Brittebo 1995).  

Olfactory toxicity has also been demonstrated after dermal exposure of
dichlobenil 

(Deamer at al. 1994) to adult animals.  

Experimental evidence suggests that dichlobenil and BAM are activated to
the ultimate 

olfactory toxicant (currently unknown) by cytochrome P (CYP) 450 enzymes
located in 

Bowman’s glands of the nasal mucosa (Brandt et al. 1990; Brittebo
1997).  It is suggested 

that damage to the olfactory epithelium is a secondary effect of damage
to the Bowman’s 

glands (primary lesion), which are located in the lamina propria of the
olfactory mucosa 

(Brandt et al. 1990; Brittebo et al. 1991).  Since CYP 450s are abundant
in both the 

olfactory epithelium and Bowman’s glands, both areas may be sites of
bioactivation of 

dichlobenil and BAM (Harkema et al. 2006).  Further, it has been
hypothesized that 

damage to the olfactory epithelium, as well as the liver, may be
mediated by 

hydroxylated metabolites of dichlobenil or BAM, the metabolites of which
have been 

shown in vitro to be uncouplers of oxidative phosphorylation in rat
liver mitochondria 

(Brittebo et al. 1991).

3.3.6	 	Pre-and/or Postnatal Toxicity (Dichlobenil and BAM)

	

Determination of Susceptibility

Dichlobenil

There was no evidence of increased prenatal susceptibility in the
developmental toxicity 

studies in rats or rabbits.  In the rat developmental toxicity study, no
developmental 

effects were observed at the highest dose tested; maternal toxicity was
observed at 

the mid dose.  In the rabbit developmental toxicity study, an increase
in total  

resorptions/dam, post-implantation loss, as well as external, visceral,
and skeletal 

anomalies were observed at the high dose.  However, maternal toxicity
(decreased body 

weight gain and food consumption) was also observed at the high dose.  

Evidence of increased pre-/post-natal susceptibility was observed in
the two-generation 

reproduction study in rats.  In this study, toxicologically significant
decreases in body 

weight gain (premating and gestation) and food consumption (premating)
were observed 

at the high dose in both parental and F1 generation adults.  However,
decreased body 

weight was observed during weaning  in both F1 (16-23%) and F2 (19-22%)
generation 

pups at the next lower (mid) dose.

Overall, HED concluded that there is evidence of increased
susceptibility to offspring 

following pre-/post-natal exposure to rats in the two-generation
reproduction study in 

rats.

BAM

There was no evidence of increased prenatal susceptibility in the
developmental toxicity 

study in the rabbit or in the three-generation reproduction study in the
rat.  In the rabbit 

developmental toxicity study, an increase in the incidences of late
abortion, as well as 

visceral and skeletal anomalies were observed at the high dose. 
However, severe 

maternal toxicity [decreased body weight gain (>15%) and food
consumption (49%) and 

late abortion] was observed at the same dose.  In the rat
three-generation reproduction 

study, no adverse effects were observed up to the highest dose tested in
either generation.

  

Degree of Concern Analysis 

Dichlobenil

HED considers the concern for increased susceptibility to offspring
following pre-/post-

natal exposure to dichlobenil to be low.  The Agency proposes to
regulate potential 

incidental oral exposure by using the NOAEL from the two-generation
reproduction 

study in rats.  HED is confident in this NOAEL, which is six times lower
than the dose 

(LOAEL) at which decreased pup body weight was observed in the
two-generation 

reproduction study in rats.

BAM

Since there is no evidence of increased pre-/post-natal susceptibility
in the developmental 

toxicity study in the rabbit or in the three-generation reproduction
study in the rat, there is 

no concern.

Recommendation for a Developmental Neurotoxicity Study (Dichlobenil   

                and BAM)

Abnormal offspring behavior, CNS malformations or neuropathology in
offspring, effects 

on offspring brain weights, and effects on offspring sexual maturation
were not observed 

in any study for dichlobenil..  However, neuropathology (olfactory
sensory neuron  

toxicity) was observed in both adult and neonatal animals following i.p.
and s.c. 

exposure, respectively, to dichlobenil (Eriksson and Brittebo 1995). 
Toxicity to olfactory 

sensory neurons was also observed in adult animals following a single
i.p. dose of BAM 

(Brittebo et al. 1991).

Clinical signs of neurotoxicity were observed in three studies for BAM. 
In the subchronic oral toxicity study in the rat, decreased skeletal
muscle tone was observed with increasing severity at the mid-high and
high doses.  However, the toxicological significance of this finding is
unclear, given the lack of reproducibility of the effect in other
studies, the age of the study itself (1967), and the fact that the
purity of the compound was not reported in the study.  

Lethargy and ataxia were observed after a single dose in mice in an oral
dose-range finding study for the in vivo erythrocyte micronucleus assay
for BAM.  The effects were transient (resolved within 24 hours).  In
addition, in a two-week dietary study recently submitted and not fully
reviewed by the Agency (MRID 46892401), clinical signs of toxicity
(slightly decreased muscle tone, slight loss of pinnae reflexes) were
observed in mice at 2500 ppm (approximately equal to 375 mg/kg/day). 
Until acute and subchronic neurotoxicity batteries are received and
evaluated by the Agency, their absence is considered a data gap.  A
developmental neurotoxicity study is pending, based on receipt and
review of the requested acute and subchronic neurotoxicity screening
batteries.

FQPA Safety Factor (SF) for Infants and Children (Dichlobenil and 

                BAM)

Dichlobenil

Data from the published literature (Eriksson and Brittebo 1995) indicate
that 

olfactory toxicity following s.c. (neonates) or i.p. (adults) exposure
is similar in both 

subpopulations of mice.  However, a comparative assessment of the tissue
dose of 

dichlobenil following s.c. or i.p. administration cannot be made based
on the existing 

data.  Therefore, the risk assessment team recommends that the 10X FQPA
SF, in the 

form of a UFDB be retained until the potential of dichlobenil to induce
olfactory toxicity 

in neonates relative to adults via the oral route is assessed.  

BAM

The risk assessment team recommends that the 10X FQPA SF, in the form of
two UFDBs, 

be retained for most exposure scenarios.  The first UFDB of 3X
corresponds to the lack of 

data assessing the potential of dichlobenil (parent) to induce olfactory
toxicity in neonates 

relative to adults via the oral route is assessed.  HED believes that a
value of 3X (rather 

than 10X) for the first UFDB is warranted based on the observation that
approximately 3-

fold higher doses of BAM are needed to induce levels of olfactory
toxicity that are 

similar to those caused by dichlobenil, following a single i.p.
injection of either 

compound to adult mice (Brandt et al. 1990; Brittebo et al. 1991).  The
second UFDB of 

3X corresponds to the incompleteness of the database with regard to the
systemic 

neurotoxic potential of BAM.

The risk assessment team also recommends that the FQPA SF be retained,
but reduced to 

3X for the acute dietary exposure scenario (general population) only,
since a LOAEL 

based on clinical signs of neurotoxicity was utilized to extrapolate a
NOAEL for this 

scenario.  HED believes this reduction is warranted based on the
decrease in severity of 

effects that was observed with decreasing dose in the pilot study for
the in vivo mouse 

micronucleus assay.

Hazard Identification and Toxicity Endpoint Selection

Dichlobenil

A summary of the toxicological endpoints and doses chosen for the
relevant exposure scenarios for human risk assessment is found in Table
3.2.

Table 3.2.  Summary of Toxicological Doses and Endpoints for Dichlobenil
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 (General population, including infants and children)	N/A
N/A	N/A	An endpoint of concern (effect) attributable to a single dose
was not identified in the database. Quantification of acute risk to
general population, including infants and children, is not required.

Acute Dietary (Females 13-49 years of age)	NOAEL = 45

mg/kg/day	UFA = 10X

UFH = 10X

FQPA SF4 = 10X

(includes UFDB = 10X)	aRfD = 0.45 mg/kg/day

aPAD = 0.045 mg/kg/day	Developmental toxicity (rabbit) Offspring LOAEL =
135 mg/kg/day based on increased incidences of total resorptions/dam,
post-implantation loss, and fetal external, visceral, and skeletal
anomalies (see tox table)

Chronic Dietary (All populations)	NOAEL = 1

mg/kg/day	UFA = 10X

UFH = 10X

FQPA SF4 = 10X

(includes UFDB = 10X)	cRfD = 0.01 mg/kg/day

-GT and periportal hypertrophy of hepatocytes (M); olfactory toxicity
was assayed and not observed in this study

Incidental Oral

Short- and Intermediate-Term (1-30 days and 1-6 months)	NOAEL = 3

mg/kg/day	UFA = 10X

UFH = 10X

FQPA SF4 = 10X

(includes UFDB = 10X)	Residential LOC for MOE = 1000	2-generation
reproduction (rat) Offspring LOAEL = 17.5 mg/kg/day based on decreased
body weight during weaning in both generations

Dermal

Short-, Intermediate-, and Long-Term (1-30 days, 1-6 months, and > 6
months)	NOAEL = 25

mg/kg/day	UFA = 10X

UFH = 10X

FQPA SF4 = 10X

(includes UFDB = 10X)	Residential LOC for MOE = 1000

OccupationalLOC for MOE = 100	5-day dermal (mouse; literature study 1)
LOAEL = 50 mg/kg/day based on olfactory epithelial damage

Inhalation

Short-, Intermediate-, and Long-Term (1-30 days, 1-6 months, and >6
months)	NOAEL = 0.17

mg/kg/day 2	UFA = 10X

UFH = 10X

FQPA SF4 = 10X

(includes UFDB = 10X)	Residential LOC for MOE = 1000

OccupationalLOC for MOE = 100	7-day inhalation (rat; dose-range finding)
LOAEL = 0.30 mg/kg/day 3 based on nasal degeneration

Cancer	Classification: Group C, possible human carcinogen; RfD approach
should be used for quantification of human risk (2nd Carcinogenicity
Peer Review, 1995)

Abbreviations: UF = uncertainty factor, UFA = extrapolation from animal
to human (interspecies), UFH = potential variation in sensitivity among
members of the human population (intraspecies), FQPA SF = FQPA Safety
Factor, UFDB = to account for the absence of key data, NOAEL = no
observed adverse effect level, LOAEL = lowest observed adverse effect
level, RfD = reference dose (a = acute, c = chronic), PAD = population
adjusted dose, MOE = margin of exposure, LOC = level of concern, N/A =
Not Applicable

1   HYPERLINK
"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itoo
l=pubmed_Abstract&term=%22Deamer+NJ%22%5BAuthor%5D"  Deamer NJ ,  
HYPERLINK
"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itoo
l=pubmed_Abstract&term=%22O%27Callaghan+JP%22%5BAuthor%5D"  O'Callaghan
JP ,   HYPERLINK
"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itoo
l=pubmed_Abstract&term=%22Genter+MB%22%5BAuthor%5D"  Genter MB . (1994).
Olfactory toxicity resulting from dermal application of
2,6-dichlorobenzonitrile (dichlobenil) in the C57Bl mouse.
Neurotoxicology 15(2):287-93

2 Calculated as follows: [(NOAEL) x (m3 / 1000 L) x (24,550 / MW) x
(0.100 mg/kg/day / ppm for a young rat)], where NOAEL= 12 mg/m3 from
28-day inhalation toxicity study (rat) and MW=172

3 Calculated as follows: [(LOAEL) x (m3 / 1000 L) x (24,550 / MW) x
(0.100 mg/kg/day / ppm for a young rat)], where LOAEL= 21 mg/m3 from
7-day inhalation range finding study (rat) and MW=172

4 The 10X FQPA SF has been retained in the form of a UFDB for the lack
of olfactory toxicity data in neonates and/or adults following oral
exposure to dichlobenil

3.5.1 		aRfD - Females age 13-49

The aRfD for females 13-49 years of age was established based on the
NOAEL (100 mg/kg/day) from the developmental toxicity study in rabbits. 
The LOAEL of 135 mg/kg/day is based on increased incidences of total
resorptions/dam, post-implantation loss, and fetal external, visceral,
and skeletal anomalies.  This study and endpoint are the most
appropriate for the population of concern, namely, women of childbearing
age.  The FQPA SF has been retained in the form of a UFDB for this
exposure scenario to account for the lack of olfactory toxicity data in
adults and neonates following oral exposure to dichlobenil.

3.5.2	 	aRfD - General Population

An acute dietary endpoint for all populations, including infants and
children, was not established since an endpoint of concern attributable
to a single dose was not identified in the database.

3.5.3	 	cRfD

The cRfD was established based on the NOAEL (1 mg/kg/day) from the
chronic toxicity 

study in the dog.  The LOAEL of 6 mg/kg/day is based on increased liver
weights and 

increased serum cholesterol, triglyceride, phospholipid, and alkaline
phosphatase levels

-glutamyl transferase levels and periportal hypertrophy of
hepatocytes in males.  The NOAEL of 1 mg/kg is the lowest in the
database.  In addition, the study duration is appropriate for the
duration of exposure.  Although olfactory toxicity was assayed and not
observed in adult dogs in this study, the 10X FQPA SF has been retained
in the form of a UFDB for this exposure scenario to account for the lack
of olfactory toxicity data in neonates following oral exposure to
dichlobenil.

3.5.4	 	Incidental Oral Exposure (Short- and Intermediate-Term)

The effects of concern that are relevant to the selection of the short-
and 

intermediate-term incidental oral doses are decreased body weight
observed during 

weaning in both generations at 17.5 mg/kg/day in the two-generation
reproduction study 

in rats.  The study length is appropriate for the durations of exposure,
namely, 1-30 days 

(short-term) and 1-6 months (intermediate-term); and the NOAEL of 3
mg/kg/day is 

protective of the population of concern, namely, infants and children. 
However, the 10X FQPA SF has been retained in the form of a UFDB for
this exposure scenario to account for the lack of olfactory toxicity
data in neonates following oral exposure to dichlobenil.

3.5.5	 	Dermal Absorption

No dermal absorption study is available in the database.  Since a
route-specific toxicity study (5-day dermal in mouse) is being used for
dermal risk assessment, estimation of dermal absorption is not
necessary.  

3.5.6 		Dermal Exposure (Short-, Intermediate-, and Long-Term)

The effects of concern that are relevant to the selection of the short-,
intermediate-, and 

long-term dermal doses are olfactory epithelial damage observed in a
published 5-day 

dermal toxicity study in rats (Deamer et al. 1994).  The route of
exposure of this study is 

ideal for these dermal exposure scenarios.  However, the 10X FQPA SF has
been retained 

in the form of a UFDB for this exposure scenario to account for the lack
of olfactory toxicity data in neonates following exposure to
dichlobenil.

3.5.7 		Inhalation Exposure (Short-, Intermediate-, and Long-Term)

The 7-day dose-range finding inhalation toxicity study in the rat was
chosen for the 

short-, intermediate-, and long-term inhalation exposure scenarios.  The
effect of concern 

that is relevant to the selection of  short-, intermediate, and
long-term inhalation 

endpoints is nasal degeneration observed at 0.3 mg/kg/day (NOAEL = 0.17
mg/kg/day) 

in this study.  Although the route of exposure of this study is ideal
for these exposure 

scenarios, the 10X FQPA SF has been retained in the form of a UFDB to
account for the 

lack of olfactory toxicity data in neonates following exposure to
dichlobenil.

BAM

A summary of the toxicological endpoints and doses chosen for the
relevant exposure scenarios for human risk assessment is found in Table
3.3.

Table 3.3.  Summary of Toxicological Doses and Endpoints for
2,6-Dichlorobenzamide (BAM) 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 (General population, including infants and children)	LOAEL
= 100 mg/kg/day 

	UFA = 10X

UFH = 10X

FQPA SF4,5 = 10X (includes UFL = 3X and UFDB = 3X)

	aRfD = 1 mg/kg/day

aPAD = 0.1 mg/kg/day	Dose-range finding assay for in vivo mouse
erythrocyte micronucleus assay LOAEL = 100 mg/kg/day based on lethargy
after a single oral dose

Acute Dietary (Females 13-49 years of age)	NOAEL = 30 mg/kg/day	UFA =
10X

UFH = 10X

FQPA SF5,6 = 10X

(includes UFDB = 10X)	aRfD = 0.30 mg/kg/day

aPAD = 0.03 mg/kg/day	Developmental toxicity (rabbit) Offspring LOAEL =
90 mg/kg/day based on increased incidences of  late abortion and
skeletal (bipartite interparietal bone) and visceral (postcaval lung
lobe agenesis) anomalies

Chronic Dietary (All populations)	NOAEL = 4.5

mg/kg/day	UFA = 10X

UFH = 10X

FQPA SF5,6 = 10X

(includes UFDB = 10X)	cRfD = 0.045 mg/kg/day

cPAD = 0.0045 mg/kg/day	Chronic toxicity (dog) LOAEL = 12.5 mg/kg/day
based on decreased body weight and body weight gain

Incidental Oral

Short- and Intermediate-Term (1-30 days and 1-6 months)	NOAEL = 14

mg/kg/day	UFA = 10X

UFH = 10X

FQPA SF5,6 = 10X

(includes UFDB = 10X)	Residential and Occupational LOC for MOE = 1000
90-day oral (rat) LOAEL = 49 mg/kg/day based on decreased body weight
gain (M) and reduced skeletal muscle tone (day 4 only in males; days 91
and 92 only in females)

Dermal

Short-, Intermediate-, and Long-Term (1-30 days, 1-6 months, and >6
months) 7	NOAEL = 25

mg/kg/day	UFA = 10X

UFH = 10X

FQPA SF5,6 = 10X

(includes UFDB = 10X)	Residential and Occupational LOC for MOE = 1000
5-day dermal using dichlobenil (mouse; literature study 1) LOAEL = 50
mg/kg/day based on olfactory epithelial damage

Inhalation

Short-, Intermediate-, and Long-Term (1-30 days, 1-6 months, and >6
months) 7	NOAEL = 0.17

mg/kg/day 2	UFA = 10X

UFH = 10X

FQPA SF5,6 = 10X

(includes UFDB = 10X)	Residential and Occupational LOC for MOE = 1000
7-day inhalation using dichlobenil (rat; dose-range finding) LOAEL =
0.30 mg/kg/day 3 based on nasal degeneration

Cancer	Classification: Formally unclassified; however, NOAEL in
carcinogenicity study similar to that for parent (dichlobenil);
therefore “Group C, possible human carcinogen” (former system); RfD
approach appropriate for quantification of human risk

Abbreviations: UF = uncertainty factor, UFA = extrapolation from animal
to human (interspecies), UFH = potential variation in sensitivity among
members of the human population (intraspecies), FQPA SF = FQPA Safety
Factor, UFL = use of a LOAEL to extrapolate a NOAEL, UFDB = to account
for the absence of key data, NOAEL = no observed adverse effect level,
LOAEL = lowest observed adverse effect level, RfD = reference dose (a =
acute, c = chronic), PAD = population adjusted dose, MOE = margin of
exposure, LOC = level of concern, N/A = Not Applicable

1   HYPERLINK
"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itoo
l=pubmed_Abstract&term=%22Deamer+NJ%22%5BAuthor%5D"  Deamer NJ ,  
HYPERLINK
"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itoo
l=pubmed_Abstract&term=%22O%27Callaghan+JP%22%5BAuthor%5D"  O'Callaghan
JP ,   HYPERLINK
"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itoo
l=pubmed_Abstract&term=%22Genter+MB%22%5BAuthor%5D"  Genter MB . (1994).
Olfactory toxicity resulting from dermal application of
2,6-dichlorobenzonitrile (dichlobenil) in the C57Bl mouse.
Neurotoxicology 15(2):287-93

2 Calculated as follows: [(NOAEL) x (m3 / 1000 L) x (24,550 / MW) x
(0.100 mg/kg/day / ppm for a young rat)], where NOAEL= 12 mg/m3 from
28-day inhalation toxicity study (rat) and MW=172

3 Calculated as follows: [(LOAEL) x (m3 / 1000 L) x (24,550 / MW) x
(0.100 mg/kg/day / ppm for a young rat)], where LOAEL= 21 mg/m3 from
7-day inhalation range finding study (rat) and MW=172

4 The FQPA SF has been retained in the form of a UFL, because a LOAEL
was used to extrapolate a 

NOAEL

5 The FQPA SF has been retained in the form of a UFDB for the lack of
acute and subchronic olfactory toxicity data in neonates following oral
exposure to dichlobenil

6 The FQPA SF has been retained in the form of a UFDB for the lack of
neurotoxicity data

7 In the absence of route-specific data, endpoints for all dermal and
inhalation exposure scenarios were identical to those for dichlobenil
(parent), since olfactory toxicity has been observed following i.p.
administration of BAM in mice [  HYPERLINK
"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itoo
l=pubmed_Abstract&term=%22Brittebo+EB%22%5BAuthor%5D"  Brittebo EB ,  
HYPERLINK
"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itoo
l=pubmed_Abstract&term=%22Eriksson+C%22%5BAuthor%5D"  Eriksson C ,  
HYPERLINK
"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itoo
l=pubmed_Abstract&term=%22Feil+V%22%5BAuthor%5D"  Feil V ,   HYPERLINK
"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itoo
l=pubmed_Abstract&term=%22Bakke+J%22%5BAuthor%5D"  Bakke J ,   HYPERLINK
"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itoo
l=pubmed_Abstract&term=%22Brandt+I%22%5BAuthor%5D"  Brandt I . (1991).
Toxicity of 2,6-dichlorothiobenzamide (chlorthiamid) and
2,6-dichlorobenzamide in the olfactory nasal mucosa of mice.   HYPERLINK
"javascript:AL_get(this,%20'jour',%20'Fundam%20Appl%20Toxicol.');" 
Fundam Appl Toxicol  17(1):92-102].

3.5.8		aRfD - Females age 13-49

The aRfD for females 13-49 years of age was established based on the
LOAEL from the 

developmental toxicity study in rabbits.  The LOAEL of 90 mg/kg/day is
based on 

increased incidences of  late abortion and skeletal (bipartite
interparietal bone) and 

visceral (postcaval lung lobe agenesis) anomalies.  This study and
endpoint are the most 

appropriate for the population of concern, namely, women of childbearing
age.  The 10X

FQPA SF has been retained in the form of a UFDB for this exposure
scenario to account 

for the lack of olfactory toxicity data in adults and neonates following
oral exposure to 

dichlobenil or BAM, as well as for the lack of systemic neurotoxicity
data for BAM.  It is noted 

that approximately 3-fold higher doses of BAM are needed to induce
levels of olfactory 

toxicity that are similar to those caused by dichlobenil, following a
single i.p. injection of 

either compound to adult mice (Brandt et al. 1990; Brittebo et al.
1991).

3.5.9	 	aRfD - General Population

The aRfD for the general population, including infants and children, was
established based on the LOAEL from the dose-range finding assay for the
in vivo mouse erythrocyte micronucleus assay.  The LOAEL of 100
mg/kg/day is based on lethargy following a single oral dose of BAM.  A
NOAEL was not identified in this study.  Since a LOAEL was used to
estimate a point of departure for this exposure scenario, the FQPA SF
has been retained in the form of a 3X UFL.  The 10X FQPA SF is also
composed of 3X UFDB to account for the lack of olfactory toxicity data
in adults and neonates following oral exposure to BAM or dichlobenil.

3.5.10	 	cRfD

The cRfD was established based on the NOAEL (4.5 mg/kg/day) from the
chronic 

toxicity study in the dog.  The LOAEL of 12.5 mg/kg/day is based on
decreased body weight and body weight gain.  The NOAEL of 4.5 mg/kg is
the lowest in the BAM database.  In addition, the study duration is
appropriate for the duration of exposure.  The FQPA SF has been retained
in the form of a 10X UFDB for this exposure scenario to  account for the
lack of olfactory toxicity data in neonates following oral exposure to
BAM or dichlobenil, as well as the lack of systemic neurotoxicity data
for BAM.

3.5.11	 	Incidental Oral Exposure (Short- and Intermediate-Term)

The effects of concern that are relevant to the selection of the short-
and 

intermediate-term incidental oral doses are decreased body weight gain
observed in males 

and reduced skeletal muscle tone (observed on day 4 only in males and on
days 91 and 92 

only in females) at  49 mg/kg/day in the 90-day oral toxicity study in
rats.  The study 

length and effects are ideal for the durations of exposure, namely, 1-30
days (short-term) 

and 1-6 months (intermediate-term).  The NOAEL of 14 mg/kg/day is
protective of the 

population of concern, namely, infants and children.  The 10X FQPA SF
has been 

 

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 in the form of a UFDB for this exposure scenario to account for the
lack of 

olfactory toxicity data in adults and neonates following oral exposure
to dichlobenil or 

BAM, as well as for the lack of systemic neurotoxicity data for BAM.  .

3.5.12	 	Dermal Absorption

No dermal absorption study is available in the database.  Since a
route-specific toxicity study (5-day dermal in mouse using dichlobenil)
is being used for dermal risk assessment, calculation of dermal
absorption is not necessary.  

3.5.13		Dermal Exposure (Short-, Intermediate-, and Long-Term)

The effects of concern that are relevant to the selection of the short-,
intermediate-, and 

long-term dermal doses are olfactory epithelial damage observed in a
published 5-day 

dermal toxicity study in rats (Deamer et al. 1994) using dichlobenil. 
The route of 

exposure of this study is ideal for these dermal exposure scenarios. 
However, the 

FQPA SF has been retained in the form of a 10X UFDB for this exposure
scenario to 

account for the lack of olfactory toxicity data in neonates following
oral exposure to 

dichlobenil or BAM, as well as for the lack of systemic neurotoxicity
data for BAM.  

Based on the results from two published literature studies of BAM via
the intraperitoneal 

route, BAM is expected to cause olfactory toxicity at doses 3X higher
than dichlobenil.

3.5.14		Inhalation Exposure (Short-, Intermediate-, and Long-Term)

The 7-day dose-range finding inhalation toxicity study using dichlobenil
in the rat was 

chosen for the short-, intermediate-, and long-term inhalation exposure
scenarios.  The 

effect of concern that is relevant to the selection of  short-,
intermediate, and long-term 

inhalation endpoints is nasal degeneration observed at 0.3 mg/kg/day
(NOAEL = 0.17 

mg/kg/day) in this study.  Although the route of exposure of this study
is ideal for these 

exposure scenarios, the FQPA SF has been retained in the form of a 10X
UFDB to account 

for the lack of olfactory toxicity data in neonates following oral
exposure to dichlobenil 

or BAM, as well as for the lack of systemic neurotoxicity data for BAM. 
Based on the 

results from two published literature studies of BAM via the
intraperitoneal route, BAM 

is expected to cause olfactory toxicity at doses 3X higher than
dichlobenil.

3.5.15	 	Level of Concern for Margin of Exposure (Dichlobenil and BAM)

The target MOEs for occupational and residential exposure risk
assessments are as follows:

Route

	Duration

	Short-Term

(1-30 days)	Intermediate-Term

(1-6 Months)	Long-Term

(> 6 Months)

Occupational (Worker) Exposure

Dermal	100/1000a	100/1000	100/1000

Inhalation	100/1000	100/1000	100/1000

Residential (Non-Dietary) Exposure

Oral	1000/1000	1000/1000	1000/1000

Dermal	1000/1000	1000/1000	1000/1000

Inhalation	1000/1000	1000/1000	1000/1000

a MOEs expressed for dichlobenil/BAM

3.5.16	       Recommendation for Aggregate Exposure Risk Assessments

                

Estimation of aggregate risk is currently not required, because a common
toxicological effect across oral, dermal, and inhalation exposure
scenarios was not observed for either dichlobenil or BAM.

     Classification of Carcinogenic Potential

Dichlobenil was determined to be non-mutagenic in bacteria and mammalian
cells, as 

well as non-clastogenic in several mammalian assays (in vitro and in
vivo).  The 

carcinogenic potential of dichlobenil was evaluated for the second time
by the Health 

Effects Division Carcinogenicity Peer Review Committee (CPRC) in 1995. 
In a high-

dose carcinogenicity study in the hamster, a treatment-related increase
in liver adenomas 

and combined adenomas/carcinomas was observed in males only at the
highest dose 

tested.  However, dosing was considered excessive at this dose in both
sexes, based on 

decreased body weight gains and severe hepatotoxicity.  In a second
carcinogenicity 

study performed in hamsters at lower doses, no treatment-related
increases in the 

incidence of any tumor type were observed.  Dosing was considered
adequate, based on 

decreased body weight gains and hyperplasia in various tissues in both
sexes.  In a 

combined chronic toxicity/carcinogenicity study in the rat, a
treatment-related increase in 

the incidence of hepatocellular adenomas and combined
adenomas/carcinomas was 

observed in females only at the highest dose tested.  Dosing was
considered adequate in 

females, but excessive in males, at this dose.  Based on these data, the
CPRC classified 

dichlobenil as a “Group C, possible human carcinogen” (former
system), and an RfD 

approach to quantification of cancer risk was recommended.

BAM was determined to be non-mutagenic in bacteria and non-clastogenic
in an in vivo 

mouse erythrocyte micronucleus assay.  Like dichlobenil, BAM also did
not induce 

unscheduled DNA synthesis in mammalian cells.  The Agency is currently
reviewing 

additional genotoxicity studies for BAM.  There was no evidence of
carcinogenicity in 

the combined chronic toxicity/carcinogenicity study of BAM in the rat. 
An increased 

incidence of hepatocellular adenomas was observed at the high dose in
females only in 

the study.  However, the statistical significance of the effect was
marginal (P=0.049), 

dosing was considered adequate in the study, and the tumors were
non-cancerous.  

However, since the carcinogenic potential of BAM was evaluated in only
one species, 

HED considers the carcinogenic potential of BAM to be similar to that of
dichlobenil 

(possible human carcinogen).  Therefore, an RfD approach to
quantification of cancer 

risk is also warranted for BAM.  

3.6	 	Endocrine disruption

EPA is required under the Federal Food, Drug, and Cosmetic Act (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 the Federal Insecticide,
Fungicide, and 

Rodenticide Act (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).  When additional appropriate screening and/or testing protocols
being  

considered under the Agency’s EDSP have been developed, dichlobenil or
its soil 

metabolite, BAM, may be subjected to further screening and/or testing to
better 

characterize effects related to endocrine disruption.  It is noted that
in the chronic dog 

toxicity study with dichlobenil, delayed maturity of the uterus was
observed in all high-dose females.  A marked decrease in mean uterine
weight at the high dose confirmed this finding.  Ovarian weights were
also decreased in high-dose females, but no alterations were observed
microscopically.  These results are suggestive of modulation of the
female endocrine system; however, the dose at which these effects were
observed was forty times higher than that utilized for risk assessment,
i.e., the NOAEL.  The NOAEL utilized for risk assessment is therefore
considered protective of any potential endocrine modulation by
dichlobenil.  In addition, no other reproductive parameters were
affected in this or any other study in the database.  No evidence of
endocrine modulation was observed in any study with BAM.

4.0		Public Health and Pesticide Epidemiology Data

This is the function of the ORE assessor.  It would be interesting to
know if adverse nasal effects have been reported in human Ag workers
exposed to dichlobenil.

8.0		Cumulative Risk Characterization/Assessment

Dichlobenil produces a toxic metabolite (BAM) that is also produced by
chlorthiamid (2,6-dichlorothiobenzamide), and this should be considered.
 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
http://www.epa.gov/pesticides/cumulative/.

10.0		Data Needs and Label Requirements

		

Toxicology

Guideline acute neurotoxicity screening battery (OPPTS 870.6200) with
2,6-dichlorobenzamide (BAM)

Guideline subchronic neurotoxicity screening battery (OPPTS 870.6200)
with 2,6-dichlorobenzamide (BAM)

A comparative study of olfactory toxicity by the oral route in neonates
and adults.  The registrant is encouraged to consult with the Agency to
discuss the protocol.

A DNT is reserved pending receipt and review of the acute and subchronic
neurotoxicity screening batteries

1 Calculated as follows: [(Concentration in mg/m3) x (m3 / 1000 L) x
(24,550 / MW) x (0.100 mg/kg/day / ppm for a young rat)], where MW=172.

 Calculated as follows: [(Concentration in mg/m3) x (m3 / 1000 L) x
(24,550 / MW) x (0.100 mg/kg/day / ppm for a young rat)], where MW=172.

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