UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

                                        WASHINGTON, D.C.  20460

     OFFICE OF	

PREVENTION, PESTICIDES

AND TOXIC SUBSTANCES

Date: 11/21/07 

MEMORANDUM

SUBJECT:	2,6-Dichlorobenzamide (BAM ) as a Metabolite/Degradate of
Fluopicolide and Dichlobenil.  Human Health Risk Assessment for Proposed
Uses of Fluopicolide on Tuberous and Corm Vegetables, Leafy Vegetables
(except Brassica), Fruiting Vegetables, Cucurbit Vegetables, Grapes,
Turf, and Ornamentals, and for Indirect or Inadvertent Residues on the
Rotational Crop Wheat.  PC Codes: 027402 (BAM) and 027412
(Fluopicolide), Petition No: 5F7016, DP Number: 345918.

		

		Regulatory Action:  Section 3 Registration Action

Risk Assessment Type: Multiple Chemicals/Aggregate

FROM:	Nancy Dodd, Risk Assessor 

		Amelia Acierto, Chemist

		Kelly O’Rourke, Biologist

		Myron Ottley, Toxicologist

		Registration Action Branch 3

		Health Effects Division (7509P)

			AND

		Robert Mitkus, Toxicologist

		Registration  Action Branch 1

		Health Effects Division (7509P)

THROUGH:	Christine Olinger, Chemist

Mary Elissa Reaves, Ph.D., Toxicologist

Risk Assessment Review Committee

Health Effects Division (7509P)

			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)

This human health risk assessment is for 2,6-dichlorobenzamide (BAM)
which is the common metabolite/degradate of dichlobenil and
fluopicolide.  This assessment summarizes the human health risks from
exposure to BAM resulting from the use of dichlobenil and fluopicolide
on agricultural commodities, turf, and ornamentals.  The residue
chemistry assessment was provided by Amelia Acierto (RAB3), the
occupational and residential exposure assessment by Kelly O’Rourke
(RAB3), the hazard characterization by Myron Ottley (RAB3) and Robert
Mitkus (RAB1), and the dietary exposure assessment and risk assessment
by Nancy Dodd (RAB3).  



Table of Contents

  TOC \f  1.0	Executive Summary	  PAGEREF _Toc185228067 \h  5 

2.0	Ingredient Profile	  PAGEREF _Toc185228068 \h  11 

2.1	Summary of Registered/Proposed Uses	  PAGEREF _Toc185228069 \h  11 

2.2	Structure and Nomenclature	  PAGEREF _Toc185228070 \h  12 

2.3	Physical and Chemical Properties	  PAGEREF _Toc185228071 \h  12 

3.0	Hazard Characterization/Assessment	  PAGEREF _Toc185228072 \h  13 

3.1	Hazard and Dose-Response Characterization	  PAGEREF _Toc185228073 \h
 13 

3.1.1	Studies Considered in the Toxicity and Dose-Response Evaluation	 
PAGEREF _Toc185228074 \h  13 

3.1.2	Sufficiency of Studies/Data	  PAGEREF _Toc185228075 \h  13 

3.1.3 Mammalian Toxicology	  PAGEREF _Toc185228076 \h  13 

3.2	Absorption, Distribution, Metabolism, Excretion	  PAGEREF
_Toc185228077 \h  14 

3.3	FQPA Considerations	  PAGEREF _Toc185228078 \h  15 

3.3.1	Adequacy of the Toxicity Data Base	  PAGEREF _Toc185228079 \h  15 

3.3.2	Developmental Toxicity Study (Rabbit)	  PAGEREF _Toc185228080 \h 
15 

3.3.3	Evidence of Neurotoxicity	  PAGEREF _Toc185228081 \h  16 

3.3.4	Additional Information from Literature Sources	  PAGEREF
_Toc185228082 \h  16 

3.3.5	FQPA Safety Factor (SF) for Infants and Children	  PAGEREF
_Toc185228083 \h  17 

3.4	Hazard Identification and Toxicity Endpoint Selection	  PAGEREF
_Toc185228084 \h  17 

3.5	Classification of Carcinogenic Potential	  PAGEREF _Toc185228085 \h 
21 

3.6	Endocrine disruption	  PAGEREF _Toc185228086 \h  22 

4.0	Public Health and Pesticide Epidemiology Data	  PAGEREF
_Toc185228087 \h  22 

5.0	Dietary Exposure/Risk Characterization	  PAGEREF _Toc185228088 \h 
22 

5.1	Pesticide Metabolism and Environmental Degradation	  PAGEREF
_Toc185228089 \h  22 

5.1.1	Metabolism in Primary Crops	  PAGEREF _Toc185228090 \h  23 

5.1.2	Metabolism in Rotational Crops	  PAGEREF _Toc185228091 \h  24 

5.1.3	Metabolism in Livestock	  PAGEREF _Toc185228092 \h  24 

5.1.4	Analytical Methodology	  PAGEREF _Toc185228093 \h  25 

5.1.5	Environmental Degradation	  PAGEREF _Toc185228094 \h  26 

5.1.6	Comparative Metabolic Profile	  PAGEREF _Toc185228095 \h  26 

5.1.7	Toxicity Profile of BAM	  PAGEREF _Toc185228096 \h  27 

5.1.8	Pesticide Metabolites and Degradates of Concern	  PAGEREF
_Toc185228097 \h  28 

5.1.9	Drinking Water Residue Profile	  PAGEREF _Toc185228098 \h  28 

5.1.10	Food Residue Profile	  PAGEREF _Toc185228099 \h  32 

5.1.11	International Residue Limits	  PAGEREF _Toc185228100 \h  40 

5.2.	Dietary Exposure and Risk	  PAGEREF _Toc185228101 \h  40 

5.2.1	Acute Dietary Exposure/Risk	  PAGEREF _Toc185228102 \h  41 

5.2.2	Chronic Dietary Exposure/Risk	  PAGEREF _Toc185228103 \h  41 

5.2.3	Cancer Dietary Risk	  PAGEREF _Toc185228104 \h  41 

5.3.	Anticipated Residue and Percent Crop Treated (%CT) Information	 
PAGEREF _Toc185228105 \h  42 

6.0	Residential (Non-Occupational) Exposure/Risk Characterization	 
PAGEREF _Toc185228106 \h  43 

6.1.	Residential Handler Exposure	  PAGEREF _Toc185228107 \h  43 

6.2.	Residential Postapplication Exposure	  PAGEREF _Toc185228108 \h  43


6.3.	Other (Recreational Exposure; Spray Drift)	  PAGEREF _Toc185228109
\h  46 

7.0	Aggregate Risk Assessments and Risk Characterization	  PAGEREF
_Toc185228110 \h  47 

7.1	Acute Aggregate Risk	  PAGEREF _Toc185228111 \h  47 

7.2	Short-Term Aggregate Risk	  PAGEREF _Toc185228112 \h  47 

7.3	Intermediate-Term Aggregate Risk	  PAGEREF _Toc185228113 \h  49 

7.4	Long-Term Aggregate Risk	  PAGEREF _Toc185228114 \h  49 

8.0	Aggregate Risk Assessments and Risk Characterization	  PAGEREF
_Toc185228115 \h  49 

9.0	Occupational Exposure/Risk Pathway	  PAGEREF _Toc185228116 \h  50 

9.1	Short-/Intermediate-/Long-Term/Cancer (if needed) Handler Risk	 
PAGEREF _Toc185228117 \h  50 

9.2	Short-/Intermediate-/Long-Term/Cancer (if needed) Postapplication
Risk	  PAGEREF _Toc185228118 \h  50 

10.0	Data Needs and Label Recommendations	  PAGEREF _Toc185228119 \h  53


10.1	Toxicology	  PAGEREF _Toc185228120 \h  53 

10.2	Residue Chemistry	  PAGEREF _Toc185228121 \h  53 

10.3	Occupational and Residential Exposure	  PAGEREF _Toc185228122 \h 
53 

References:	  PAGEREF _Toc185228123 \h  53 

Appendix A:  Toxicity Profile Table and Executive Summaries/Published
Abstracts	  PAGEREF _Toc185228124 \h  54 

Appendix B:  Metabolism Assessment	  PAGEREF _Toc185228125 \h  64 

B.1	Metabolism Guidance and Considerations	  PAGEREF _Toc185228126 \h 
64 

B.2	Chemical Names and Structures	  PAGEREF _Toc185228127 \h  65 

Appendix C:  Tolerance Reassessment Summary and Table	  PAGEREF
_Toc185228128 \h  66 

Appendix D:  Review of Human Research	  PAGEREF _Toc185228129 \h  66 

 

1.0	Executive Summary  TC \l1 "1.0	Executive Summary 

2,6-Dichlorobenzamide (BAM) is a metabolite and/or environmental
degradate of both the fungicide fluopicolide and the herbicide
dichlobenil.  This human health risk assessment includes residues of BAM
from uses of both fluopicolide and dichlobenil; i.e., this human health
risk assessment assesses BAM as a metabolite/degradate resulting from
established/proposed uses of fluopicolide on tuberous and corm
vegetables (except potato), leafy vegetables (except Brassica), fruiting
vegetables, cucurbit vegetables, grapes, turf, and ornamentals and from
established/pending uses of dichlobenil.  This assessment includes only
BAM because there is no common toxicological effect for BAM and other
fluopicolide residues of concern.  A separate human health risk
assessment is being conducted concurrently for other fluopicolide
residues of concern (DP #325091, N. Dodd, 11/21/07).

This memo does not address the proposed use of fluopicolide on potato or
the proposed tolerances for the rotational crop wheat since the potato
use will not be registered at this time and some label restrictions will
be applied to rotational crops at this time.  Since tolerances on crops
with associated livestock feed items (potato and wheat) will not be
established at this time, livestock commodity tolerances are not needed
at this time and livestock issues are not discussed in this document. 
This risk assessment focused on the residues of BAM from both
fluopicolide and dichlobenil.  General information from the concurrent
risk assessment for fluopicolide and the latest risk assessment for
dichlobenil is mentioned below; however, for more details refer to the
specific risk assessment.

Use Profile:  2,6-Dichlorobenzamide (BAM; AE C653711) is a metabolite
and/or environmental degradate of both fluopicolide and dichlobenil.  As
discussed in the concurrent Fluopicolide Risk Assessment Document (DP
#325091, N. Dodd, 11/21/07), BAM is a residue of concern for the risk
assessment for drinking water and all plant and livestock matrices. 
Sources of BAM are tabulated below:

Table 1.0  Sources of BAM

Pesticide	Food	Water	Residential	Occupational

Fluopicolide	Ag Crop Uses	Ag Crop/Non-Crop Uses	Postapplication

Adult Dermal

Postapplication

Child Dermal + Incidental Oral	Postapplication Dermal

Dichlobenil	Ag Crop Uses + Tolerances with no Domestic Registrations	Ag
Crop/Non Crop Uses	No Significant Exposure	Not assessed because no
significant exposure was expected.



Fluopicolide:

Fluopicolide is a fungicide to be used on tuberous and corm vegetables
(except potato), leafy vegetables (except Brassica), fruiting
vegetables, cucurbit vegetables, grapes, turf, and ornamentals.  A
maximum of four foliar applications are to be made to agricultural crops
with a maximum seasonal application rate of 0.375 lb active
ingredient/acre (ai/A).  The fungicide can be sprayed on turf
(residential, commercial, golf course, and sod farms) with a maximum
seasonal application rate of 0.54 lb ai/A.  The maximum seasonal
application rates on ornamental plants (landscapes, commercial
greenhouses and nurseries) are 0.54 lb ai/A for overhead sprays and 27
lb ai/A for drench treatments.

 

HED is presently recommending for the following tolerances for
fluopicolide (parent):

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

N-[[3-chloro-5-(trifluoromethyl)-2-pyridinyl]methyl] benzamide] as an
indicator of combined residues of fluopicolide and its metabolite
2,6-dichlorobenamide, 

under “(a) General”:

	

Grape*		2.0 ppm

Grape, raisin*	6.0 ppm

Vegetable, cucurbit, group 9	0.50 ppm

Vegetable, fruiting, group 8	1.6 ppm

Vegetable, leafy, except Brassica, group 4	25 ppm

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

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

Tolerances have been established (40 CFR §180.627) for residues of
fluopicolide,
2,6-dichloro-N-[[3-chloro-5-(trifluoromethyl)-2-pyridinyl]methyl]
benzamide, on grape at 2.0 ppm and grape, raisin at 6.0 ppm for use on
imported crops.  No livestock tolerances have been established.  No
Codex, Canadian, or Mexican Maximum Residue Limits (MRLs) or tolerances
have been established for fluopicolide.

Dichlobenil:

Dichlobenil is registered as a granular (G) formulation (Casoron® 4G;
EPA Reg. No. 400-168; date of issuance: 5/18/05) for use on apple,
blueberry, cherry, filbert, grape, and pear at 6 lb ai/A/season and on
blackberry, cranberry, and raspberry at 4 lb ai/A/season.  Dichlobenil
is also used on roses and woody ornamentals (surrounding soil/mulch at
rates up to 8 lb ai/A and on nutsedge at 10 lb ai/A.  A registration for
Casoron® 4G for use on rhubarb at 2 lb ai/A/season is pending (DP
Number 315266, W. Cutchin, 2/22/06). 

Tolerances are established (40 CFR §180.231) for the herbicide
dichlobenil (2,6-dichlorobenzonitrile) and its metabolite
2,6-dichlorobenzamide as follows.  A tolerance for rhubarb is pending.

Tolerances established (40 CFR §180.231) for the combined residues of
the herbicide dichlobenil (2,6-dichlorobenzonitrile) and its metabolite
2,6-dichlorobenzamide

Apple	0.5 ppm

Blackberry	0.1 ppm

Blueberry	0.15 ppm

Cranberry	0.1 ppm

Filbert	0.1 ppm

Fruit, stone, group 12	0.15 ppm

Grape	0.15 ppm

Pear	0.5 ppm

Raspberry	0.1 ppm

Tolerance pending for the combined residues of the herbicide dichlobenil
(2,6-dichlorobenzonitrile) and its metabolite 2,6-dichlorobenzamide

 

Rhubarb	0.06 ppm 

The revised RED (7/31/96) recommended deletion of a stone fruit crop
group tolerance which was not being supported by the petitioner and
establishment of a separate tolerance on cherries.  However, as stated
in the previous RED, the stone fruit crop group was included in this
dietary exposure assessment since as long as the tolerance exists
commodities containing BAM residues could be imported (Kathryn Boyle,
07/31/96, DP Number D000000:  Dichlobenil: The Revised HED Chapter of
the Reregistration Eligibility Decision Document (RED), Case 0263,
Chemical 027401, 027402 (BAM).

Human Health Risk Assessment for BAM:

		Toxicity/Hazard:  Appropriate endpoints were identified for acute
dietary, chronic dietary, incidental oral, dermal, and inhalation
exposures:

	The acute dietary (females 13-49) NOAEL is 30 mg/kg/day.  The LOAEL is
90 mg/kg/day based on a developmental toxicity (rabbit) study. 

The acute dietary (general population, including infants and children)
LOAEL is 100 mg/kg/day from a single oral dose in the in vivo mouse
erythrocyte micronucleus assay.  A NOAEL was not established. 

The chronic dietary NOAEL is 4.5 mg/kg/day, based on a chronic toxicity
(dog) study.  

The inhalation (short-, intermediate-, and long-term) NOAEL is 3.1
mg/kg/day based on a 28-day inhalation study using dichlobenil.  

The estimated dermal short-/intermediate-term exposures were compared to
the NOAEL of 25 mg/kg/day from a dermal toxicity study in the mouse
(using dichlobenil) in which olfactory epithelial damage was observed at
the LOAEL of 50 mg/kg/day.  Because this endpoint is from a dermal
study, the estimated dermal exposures did not need to be adjusted for
dermal absorption.  

Short-/intermediate-term incidental oral exposures (for toddlers) were
compared to the NOAEL of 14 mg/kg/day from a 90-day oral toxicity study
in the rat.  

The 10X FQPA Safety Factor has been retained for acute dietary, chronic
dietary, and incidental oral exposures.  This is due to the
incompleteness of the database with regard to the systemic neurotoxic
potential of BAM, including olfactory toxicity.  The 10X FQPA Safety
Factor is reduced to 1X for dermal and inhalation exposures because
higher doses of BAM are needed to induce levels of olfactory toxicity
that are similar to those caused by dichlobenil and olfactory toxicity
was the endpoint chosen for these exposure scenarios.  Since olfactory
toxicity was the most sensitive endpoint, further protection under FQPA
is not deemed necessary.

Relating to the carcinogenic potential of BAM, to be conservative, EPA
has assumed that BAM’s potential for carcinogenicity is similar to the
parent having the greatest carcinogenic potential, i.e., dichlobenil. 
(The parent fungicide fluopicolide is “not likely to be carcinogenic
to humans.”)  Dichlobenil is classified as “Group C, possible human
carcinogen” with the RfD approach utilized for quantification of human
risk.

Dietary Exposure (Food and Drinking Water):  The dietary analyses were
performed on BAM to support Section 3 requests for use of parent
fluopicolide on tuberous and corm vegetables (except potato), leafy
vegetables (except Brassica), fruiting vegetables, cucurbit vegetables,
grapes, turf, and ornamentals.  The dietary exposure assessment was
conducted for residues of BAM in food and drinking water from uses of
fluopicolide and dichlobenil since BAM is a metabolite/degradate of both
pesticides.  Considering uses of fluopicolide, dichlobenil, and both
pesticides (on grapes and rhubarb, the only crops on which both
pesticides will be registered), the highest drinking water residue
estimate (56.2 ppb) was from SciGrow modeling of BAM residues from
dichlobenil use on nutsedge at 10 lb ai/A.

The acute dietary (food and drinking water) exposure to BAM from
fluopicolide and dichlobenil uses is below HED’s level of concern for
the general U.S. population and all population subgroups.  The acute
dietary exposure estimates at the 99.9th percentile of the exposure
distribution are 11% of the acute Population Adjusted Dose (aPAD) for
the general U.S. population and 28% aPAD for all infants (<1 year old),
the most highly exposed group.

The chronic dietary (food and drinking water) exposure to BAM from
fluopicolide and dichlobenil uses is below HED’s level of concern for
the general U.S. population and all population subgroups.  The chronic
dietary exposure estimates are 29% chronic Population Adjusted Dose
(cPAD) for the general U.S. population and 93% cPAD for all infants (<1
year old), the most highly exposed group which is of concern to HED.

As noted above, EPA has assumed that BAM’s potential for
carcinogenicity is similar to that of  dichlobenil, which is classified
as “Group C, possible human carcinogen” with the RfD approach
utilized for quantification of human risk.  The quantification of cancer
risk using the RfD approach is identical to the assessment for chronic
effects; no separate carcinogenic risk assessment is necessary.

	Residential Exposure:  As mentioned previously, BAM is known to be a
metabolite of fluopicolide and dichlobenil.  While it is necessary to
evaluate residential exposure from all sources of BAM, the use pattern
for dichlobenil is not expected to result in scenarios with significant
residential/non-occupational exposure.  Therefore, BAM exposure
estimates are based on fluopicolide use only.

Residential handler exposure is not anticipated because the metabolite
BAM is believed to form slowly in plants and soil after the product
containing the parent (fluopicolide) has been applied.

Residential postapplication exposure via the dermal route is likely for
adults and children entering treated lawns.  Toddlers may also
experience exposure via incidental non-dietary ingestion [i.e.,
hand-to-mouth, object-to-mouth (turfgrass), and soil ingestion] during
postapplication activities on treated turf. 

Exposure and risk estimates for residential exposure scenarios are
typically assessed for the day of application (“Day 0”) because it
is assumed that adults and toddlers could contact the lawn immediately
after application.  However, BAM is a metabolite/degradate which forms
slowly; therefore, the scenarios were assessed assuming that BAM is
present at levels which reflect high-end measurements observed in the
longer-term metabolism studies in order to provide a protective
assessment.  The short-/intermediate-term dermal MOEs for adults and
children are 10,000 and 6,000, respectively, and the combined incidental
oral MOE for toddlers is 62,000.  These MOEs are greater than the LOC of
100 for dermal exposure and 1,000 for incidental oral exposure, on the
day of application, and therefore, are not of concern.

	Aggregate Risk:  In examining acute aggregate risk, HED has assumed
that the only pathway of exposure relevant to the acute time frame is
dietary exposure (i.e., any non-dietary exposures are short- and/or
intermediate-term in duration).  Therefore, the acute aggregate risk is
composed of exposures to BAM residues in food and drinking water from
uses of fluopicolide and dichlobenil and is equivalent to the acute
dietary risk.  The acute dietary exposure estimates at the 99.9th
percentile of the exposure distribution are 11% of the acute Population
Adjusted Dose (aPAD) for the general U.S. population and 28% of the aPAD
for all infants (<1 year old), the most highly exposed group.  The acute
risk estimates are well below HED’s level of concern for the general
U.S. population and all population subgroups.

The short-term aggregate risk combines dietary (food and drinking water)
exposures of BAM from both fluopicolide and dichlobenil uses and
incidental oral exposures of BAM from fluopicolide.  (Based on the
dichlobenil use pattern, no significant residential exposure is expected
to occur from dichlobenil.)   Short-term exposures (1 to 30 days of
continuous exposure) may occur as a result of activities on treated
turf.  Dermal exposures were not aggregated with oral exposures because
of different toxicity.  Incidental oral exposures related to turf
activities (Table 6.2.5) have been combined with chronic dietary
exposure estimates (as an estimate of background dietary exposure; Table
5.2.2) to assess short-term aggregate exposure. Since aggregate MOEs are
greater than 1000, they represent risk estimates that are below HED’s
level of concern.

The intermediate-term aggregate risk is the same as described above for
the short-term aggregate risk; the intermediate-term aggregate risk is
below HED’s level of concern for the U.S. population and all
population subgroups.  

In examining long-term aggregate risk, HED has assumed that the only
pathway of exposure relevant to that time frame is dietary exposure
(i.e., any non-dietary exposures are short- and/or intermediate-term in
duration).  Therefore, the long-term aggregate risk is composed of
exposures to BAM residues in food and drinking water from uses of
fluopicolide and dichlobenil  and is equivalent to the chronic dietary
risk.  The chronic risk estimates are below HED’s level of concern for
the general U.S. population and all population subgroups.

With respect to cancer risk, the quantification of cancer risk for BAM
using the RfD approach is identical to the assessment for chronic
effects; no separate carcinogenic risk assessment is necessary.

Occupational Exposure/Risk:  Occupational handler exposure was not
evaluated because the metabolite BAM is believed to form slowly in
plants and soil after the product containing the parent (fluopicolide)
has been applied. 

Occupational postapplication exposure to BAM may occur after application
of fluopicolide to agricultural crops as well as turf and ornamentals. 
(BAM which may occur after application of dichlobenil is not included
since no significant exposure to BAM from dichlobenil was  expected.) 
Postapplication inhalation exposure after application of fluopicolide
and dichlobenil is expected to be negligible; however, dermal exposure
to the metabolite BAM after application of fluopicolide is possible for
workers entering treated areas to tend or harvest crops, mow/maintain
turfgrass, or tend ornamentals in nurseries and greenhouses.

The results of the occupational postapplication exposure and risk
assessment indicate that for potential BAM exposure as a result of
fluopicolide use, MOEs for agricultural, turf, and ornamental uses are
greater than 100 on the day of application, and therefore, are not of
concern. 

The parent fluopicolide technical material has been classified in
Toxicity Category IV for acute dermal and primary skin irritation, and
in Category III for primary eye irritation.  Per the Worker Protection
Standard (WPS), a 12-hr restricted entry interval (REI) is required for
chemicals classified under Toxicity Category III/IV.  The proposed
fluopicolide labels indicate an REI of 12 hrs, which is in compliance
with the WPS for uses that reach an MOE of 100 on the day of
application.  Fluopicolide is also intended for non-agricultural use
sites (e.g., golf course) to which the WPS does not apply; the labels
appropriately contain language cautioning unprotected persons to keep
out of treated areas until sprays have dried.  

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

2.0	Ingredient Profile  TC \l1 "2.0	Ingredient Profile 

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

Fluopicolide is a fungicide to be used on tuberous and corm vegetables
(except potato), leafy vegetables (except Brassica), fruiting
vegetables, cucurbit vegetables, grapes, turf, and ornamentals.  Four
foliar applications are to be made to cucurbit vegetables (except
potato), fruiting vegetables, grapes, and leafy vegetables at the
maximum seasonal application rate of 0.34-0.375 lb active
ingredient/acre (ai/A).  For agricultural plants, minimum retreatment
intervals of 7-14 days and a preharvest interval of 2-21 days are to be
observed.  The proposed application rates on turf (residential,
commercial, golf course, and sod farms) range from 0.21 to 0.27 lb ai/A,
at 14-day intervals.  The proposed application rates on ornamental
plants (landscapes, commercial greenhouses and nurseries) range from
0.21 to 0.54 lb ai/A for overhead sprays and from 5.3 to 27 lb ai/A for
drench treatments, at 14-day intervals.  (Refer to the concurrent
Fluopicolide Risk Assessment Document (DP #325091, N. Dodd, 11/21/07)
for detailed used directions for fluopicolide).

Dichlobenil is registered as a granular (G) formulation (Casoron® 4G;
EPA Reg. No. 400-168; date of issuance: 5/18/05) for use on apple,
blueberry, cherry, filbert, grape, and pear at 6 lb ai/A/season and on
blackberry, cranberry, and raspberry at 4 lb ai/A/season.  A
registration for Casoron® 4G for use on rhubarb at 2 lb ai/A/season is
pending (DP Number 315266, W. Cutchin, 2/22/06).

There are no registered uses for BAM itself. 

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

Table 2.2.  BAM Nomenclature

Chemical Structure	



Empirical Formula	C7H5Cl2N1O1

Common Name	2,6-dichlorobenzamide

Company experimental name	AE C653711

IUPAC name	2,6-dichlorobenzamide

CAS Name	2,6-dichlorobenzamide

CAS Registry Number	70852-53-8

End-use product/EP	Not applicable

Chemical Class	amide; benzamide

Known Impurities of Concern	Not applicable



2.3	Physical and Chemical Properties  TC \l2 "2.3	Physical and Chemical
Properties 

Table 2.3.  Physiochemical Properties

Parameter	Value	References*

Molecular Weight	190.03 g/mol	Product Chemistry (HSDB, 2002)

Melting point/range	Not available

	pH	Not available

	Density	Not available

	Water solubility (pH 7, 20°C)	2700 mg/L 	Product Chemistry (HSDB,
2002)

Solvent solubility (20°C to 25°C)	Not available

	Vapor pressure	3.26 x 10-5 mm Hg	Product Chemistry (HSDB, 2002)

Dissociation constant, pKa	Not available

	Octanol/water partition coefficient, logPOW (25°C)	Kow = 30 mL/g**
HSDB, 2002

UV/visible absorption spectrum	Not available

	* DP #340773, J. Angier, Ph.D., 8/29/07 and DP #325804, J. Lin, 5/3/07

** The octanol/water partition coefficient (Kow) is defined as the ratio
of the molar concentrations of a chemical in n-octanol and water, in
dilute solution.

3.0	Hazard Characterization/Assessment  TC \l1 "3.0	Hazard
Characterization/Assessment  

3.1		Hazard and Dose-Response Characterization   TC \l2 "3.1	Hazard and
Dose-Response Characterization  

3.1.1	Studies Considered in the Toxicity and Dose-Response Evaluation 
TC \l3 "3.1.1	Studies Considered in the Toxicity and Dose-Response
Evaluation 

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

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

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

3.1.2		Sufficiency of Studies/Data  TC \l3 "3.1.2	Sufficiency of
Studies/Data 

The available submitted acute and chronic studies were sufficient to
evaluate human hazard potential, and data quality is acceptable.  

3.1.3		Mammalian Toxicology  TC \l3 "3.1.3 Mammalian Toxicology 

The major dichlobenil soil metabolite and minor fluopicolide foliar
metabolite, 2,6-dichlorobenzamide (BAM), demonstrated moderate acute
toxicity (Category III) via the oral route of exposure (Table 3.1a). 
Because the subchronic and chronic toxicity of BAM is considered less
than or equal to that of dichlobenil (parent herbicide) based on
submitted and published toxicity studies, the acute toxicity of BAM via
the inhalation and dermal routes is expected to be less than or equal to
that of dichlobenil.  The acute toxicity of BAM via the inhalation and
dermal routes is expected to be more than or equal to the toxicity of
fluopicolide.

A summary of the subchronic and chronic toxicity and genotoxicity
databases for BAM is found in Table 3.1b.  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).

While BAM is formally unclassified with respect to human cancer risk,
the available data do not suggest a cancer concern higher than that for
dichlobenil.  BAM is not mutagenic or clastogenic in submitted
genotoxicity studies and there is no evidence of carcinogenicity in the
2-year combined chronic toxicity/carcinogenicity study of BAM in rats. 
Although an increase in incidence of liver heptatocellular adenomas in
female rats was reported at the highest dose tested, the statistical
significance was considered marginal (p = 0.049) and there was no
progression to liver hepatocellular carcinomas.  BAM is not yet
classified for cancer risk because it was tested in only one species. 
Since the carcinogenic potential of BAM has been evaluated in only one
species, BAM is assumed to have the equivalent carcinogenic potential as
the parent compound dichlobenil, which is classified as a possible human
carcinogen.  An RfD approach was used to quantify the potential human
cancer risk.  The point of departure chosen for derivation of the RfD
for dichlobenil is also assumed to be protective of both liver toxicity
and the potential tumorigenicity for BAM, especially considering that
BAM is not genotoxic and the adverse liver effects observed in the
submitted toxicity studies for BAM were at higher doses than those
reported for dichlobenil.

There was no evidence of increased susceptibility to offspring following
pre-natal exposure to rabbits in a developmental toxicity study with
BAM.

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 (100 mg/kg) was eight times higher than that which caused the same
effect using dichlobenil in two other studies, i.e., 12 mg/kg i.p.
(Brandt et al. 1990; Eriksson and Brittebo 1995).  Based on this study
and 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 herbicide).

In addition to toxicity to the olfactory sensory neurons that was
observed following a single i.p. exposure of mice to BAM (Brittebo et
al. 1991), clinical signs of neurotoxicity were observed in several
submitted studies.  In the 90-day oral toxicity study in rats, reduced
muscle tone was observed with increasing dose.  Lethargy and ataxia were
observed in mice tested orally in a pilot (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, but 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).

3.2		Absorption, Distribution, Metabolism, Excretion (ADME)   TC \l2
"3.2	Absorption, Distribution, Metabolism, Excretion 

In a series of disposition studies (MRIDs 46708633, 46708634, and
46708635), radiolabeled BAM suspended in aqueous 0.75% methyl cellulose
was administered by oral gavage to three groups of Sprague Dawley
rats/sex.  Two groups of four rats/sex were given a single dose of
[14C]-AE C653711 at nominal dose levels of 10 or 150 mg/kg.  A third
group of five rats/sex was given 14 daily doses of [14C]-AE C653711 at a
nominal dose level of 10 mg/kg.  The recovery of radioactivity over six
days (seven days for the single high dose group) was determined, and the
concentrations of radioactivity in tissues and excreta were determined. 
Metabolites were identified and quantified in the urine and feces.

The majority of the radioactivity was recovered in the urine. 
Absorption and excretion of the test compound was relatively rapid.  The
minimum levels of absorption were estimated from the total recovery of
radioactivity in urine, cage washes, and tissues to be at least
77.7-85.9% of the administered dose, indicating high oral
bioavailability.  Excretion of radioactivity in the urine and feces was
mostly complete by 48 (single low dose study) to 72 (single high dose
and repeat low dose studies) hours post-dosing.  The tissues (including
the residual carcass) accounted for <2.3% of the administered dose 144
or 168 h post-dosing.  In general, the highest concentrations of
radioactivity were detected in the kidneys, liver, Harderian gland, skin
(and fur), and adrenals.  Measurement of radioactivity in the nasal
tissues was not performed.

The test compound was extensively metabolized to at least 14 compounds. 
The majority of radioactivity in urine and fecal extract samples was
present as parent and a mercapturic acid conjugate of
hydroxyl-chlorobenzamide.  Metabolic profiles were qualitatively similar
across dose levels, multiple doses had no appreciable effect on
metabolism, and generally no differences were noted between sexes.  In
excreta, parent and identified compounds accounted for 50.3-78.6% of the
administered dose.  Unidentified metabolites accounted for 8.2-14.6% of
the administered dose, but each compound represented <5% of the
administered dose.  The total administered dose accounted for in the
analyzed excreta was 64.4-90.2%.

Parent compound accounted for 13.0-24.6% of the total radioactivity
eliminated, and was found in both urine and fecal extracts.  The
majority of the radioactivity was associated with a mercapturic acid
conjugate of hydroxyl-chlorobenzamide (15-5-26.2%) that was present in
the urine.  Other metabolites present at >5% of the administered dose
were identified and included the cysteine and O-glucuronide conjugates
of chlorobenzamide (3.4-6.6%), the cysteine conjugate of
hydroxyl-chlorobenzamide (1.9-12.4%), the O-sulfate conjugate of
dichlorobenzamide/thiomethyl-chlorobenzamide (5.4-13.8%), and
3-hydroxy-chlorobenzamide (2.7-7.3%; detected in the high dose study
only).

3.3		FQPA Considerations  TC \l2 "3.3	FQPA Considerations 

3.3.1	Adequacy of the Toxicity Data Base   TC \l3 "3.3.1	Adequacy of the
Toxicity Data Base 

The toxicology database used to assess pre- and/or post-natal exposure
to the soil metabolite, BAM, is incomplete; however, since BAM is a soil
metabolite of dichlobenil and a plant metabolite of fluopicolide,
additional studies are not required at this time.  The following
acceptable study is available:

One developmental toxicity study in rabbits

3.3.2	Developmental Toxicity Study (Rabbit)   TC \l3 "3.3.2
Developmental Toxicity Study (Rabbit) 

In an Acceptable/Guideline, prenatal developmental toxicity study (MRID
43003601, 43265201), 2,6-dichlorobenzamide (dichlobenil soil metabolite)
(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, respectively). The incidence of
abortion followed by sacrifice at 0, 10, and 30 mg/kg/day was 1/16,
1/16, and 0/16, respectively.  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,
respectively.  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, respectively.  

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.)  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.

3.3.3	Evidence of Neurotoxicity   TC \l3 "3.3.3	Evidence of
Neurotoxicity 

As mentioned in section 3.1.3, toxicity to the olfactory sensory neurons
was observed following single i.p. exposures of mice to BAM (Brittebo et
al. 1991), as were clinical signs of neurotoxicity following oral
exposure in several short-term assays.

3.3.4	Additional Information from Literature Sources   TC \l3 "3.3.4
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).

3.3.5	FQPA Safety Factor (SF) for Infants and Children   TC \l3 "3.3.5
FQPA Safety Factor (SF) for Infants and Children  

There was no evidence of increased prenatal susceptibility in the
developmental toxicity study in the rabbit.  In this 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 (severely decreased body weight gain and food consumption and
late abortion) was also observed at the same dose.

The risk assessment team recommends that the 10X FQPA SF be retained for
those exposure scenarios that do not rely on dichlobenil toxicity data. 
This is due to the incompleteness of the database with regard to the
systemic neurotoxic potential of BAM, including olfactory toxicity.  [A
subchronic neurotoxicity screening battery, modified to assess olfactory
toxicity, could fill this data gap.]  For those exposure scenarios that
do rely on dichlobenil toxicity data, the risk assessment team
recommends that the FQPA SF for BAM toxicity be reduced to 1X.  The
reasons for this are that, as stated previously, higher doses of BAM are
needed to induce levels of olfactory toxicity that are similar to those
caused by dichlobenil (Brandt et al. 1990; Brittebo et al. 1991;
Eriksson and Brittebo 1995) and olfactory toxicity was the endpoint
chosen for these exposure scenarios.  Since olfactory toxicity was the
most sensitive endpoint, further protection under FQPA is not deemed
necessary.

3.4		Hazard Identification and Toxicity Endpoint Selection  TC \l2 "3.4
Hazard Identification and Toxicity Endpoint Selection  

3.4.1		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 NOAEL is 30
mg/kg/day.  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.  While the increased
incidence of late abortion is not considered a single dose effect, the
increased incidence of skeletal and visceral effects can be considered
single-dose effects, enabling the use of this study in this risk
assessment.  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 database uncertainty factor (UFDB)
for this exposure scenario to account for the lack of guideline
neurotoxicity data, including olfactory toxicity data, following oral
exposure to BAM.

3.4.2	 	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 and to account
for the lack of guideline neurotoxicity data, including olfactory
toxicity data, following oral exposure to BAM, the 10X FQPA SF has been
retained in the form of a UFDB and an uncertainty factor for use of a
LOAEL to extrapolate to a NOAEL (UFL).

3.4.3	 	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 10X FQPA SF has been
retained in the form of a UFDB for this exposure scenario to account for
the lack of guideline neurotoxicity data, including olfactory toxicity
data, following oral exposure to BAM.

3.4.4	 	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
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 appropriate 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 retained in the form of a UFDB
for this exposure scenario to account for the lack of guideline
neurotoxicity data, including olfactory toxicity data, following oral
exposure to BAM.

3.4.5	 	Dermal Absorption

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

3.4.6		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) using the parent herbicide dichlobenil.  The route
of exposure of this study is ideal for these dermal exposure scenarios. 
While this study is of very short duration compared with intermediate-
and long-term exposure scenarios, it does nevertheless provide endpoints
that will be more protective than those provided by any other study
available for this risk assessment.  The FQPA SF has been reduced to 1X
for these exposure scenarios for the following reasons: 1) based on the
submitted data and published literature studies, BAM is considered less
toxic than dichlobenil; 2) the most sensitive endpoint, olfactory
toxicity, was measured and observed in the study.

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

The 28-day inhalation toxicity study using the parent herbicide
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 5.5 mg/kg/day
(NOAEL = 3.1 mg/kg/day) in this study using the parent herbicide
dichlobenil.  The route of exposure of this study is ideal for these
exposure scenarios.  The FQPA SF has been reduced to 1X for these
exposure scenarios for the following reasons: 1) based on the submitted
data and published literature studies, BAM is considered less toxic than
dichlobenil; 2) the most toxic endpoint, olfactory toxicity, was
measured and observed in the study.

A summary of the toxicological endpoints and doses chosen for the
relevant exposure scenarios for human risk assessment is found in Table
3.4.



Table 3.4.  Summary of Toxicological Doses and Endpoints for
2,6-Dichlorobenzamide (BAM) for Use in Dietary, Residential, and
Occupational Human Health Risk Assessments

Exposure Scenario	Point of Departure	Uncertainty/

FQPA Safety Factors	RfD, PAD, Level of Concern for Risk Assessment	Study
and Toxicological Effects

Acute Dietary (General population, including infants and children)	LOAEL
= 100 mg/kg/day 

	UFA = 10X

UFH = 10X

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

	aRfD = 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 SF4 = 10X

(includes UFDB)	aRfD = 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 SF4 = 10X

(includes UFDB)	cRfD = 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 SF4 = 10X

(includes UFDB)	Residential 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)	NOAEL = 25

mg/kg/day	UFA = 10X

UFH = 10X

FQPA SF = 1X (residential uses only)	Residential and Occupational LOC
for MOE = 100	5-day dermal using dichlobenil6 (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 = 3.1

mg/kg/day 2	UFA = 10X

UFH = 10X

FQPA SF = 1X (residential uses only)	Residential and Occupational LOC
for MOE = 100	28-day inhalation using dichlobenil6 (rat) LOAEL = 5.5
mg/kg/day3 based on nasal degeneration

Cancer	Classification: Formally unclassified; parent herbicide
dichlobenil classified as “Group C, possible human carcinogen” with
RfD approach utilized 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 (10.26 L / hr) x 6
hr/day x (1 / 0.236 kg)], where NOAEL= 12 mg/m3 from 28-day inhalation
toxicity study (Sprague Dawley rat)

3 Calculated as follows: [(LOAEL) x (m3 / 1000 L) x (10.26 L / hr) x 6
hr/day x (1 / 0.236 kg)], where LOAEL= 21 mg/m3 from 28-day inhalation
toxicity study (Sprague Dawley rat)

4 The FQPA SF has been retained in the form of a UFDB for the lack of
neurotoxicity data, including olfactory toxicity data.

5 The FQPA SF has been retained in the form of a UFL and UFDB for the
use of a LOAEL to extrapolate a NOAEL and for the lack of olfactory
toxicity data.

6 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].

3.4.8	 	Level of Concern for Margin of Exposure

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

Table 3.4.8.  Summary of Levels of Concern for Risk Assessment

Route

	Duration

	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

Residential (Non-Dietary) Exposure

Oral	1000	1000	1000

Dermal	100	100	100

Inhalation	100	100	100



3.4.9       Recommendation for Aggregate Exposure Risk Assessments

                

For occupational exposure, dermal and inhalation exposures can be
aggregated because the endpoint (adverse effects on the nose) is the
same even though the studies and routes are different.  However, for
residential exposure, exposures from the three different routes cannot
be aggregated because the endpoint for incidental oral (decreased body
weight gain and reduced skeletal muscle tone) are not the same as the
endpoint for dermal and inhalation (adverse nasal effects).

3.5     	    Classification of Carcinogenic Potential  TC \l2 "3.5
Classification of Carcinogenic Potential 

BAM was determined to be non-mutagenic in bacteria and non-clastogenic
in an in vivo mouse erythrocyte micronucleus assay.  BAM did not induce
unscheduled DNA synthesis in mammalian cells.  There was no evidence of
carcinogenicity in the combined chronic toxicity/carcinogenicity study
of BAM in the rat.  As stated previously, 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.  A mouse cancer study was not available. 

BAM is a metabolite of dichlobenil (Group C, possible human carcinogen
with the recommendation of an RfD approach to quantification of cancer
risk).  BAM is also a metabolite of fluopicolide (“not likely to be
carcinogenic in humans”). 

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 the parent herbicide dichlobenil (Group C, possible human
carcinogen).  As for dichlobenil, and RfD approach to quantification of
cancer risk is considered appropriate for BAM.

3.6	 	Endocrine disruption  TC \l2 "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, BAM may be subjected to further screening and/or testing to
better characterize effects related to endocrine disruption.  No
evidence of endocrine modulation was observed in any study with BAM.

4.0	Public Health and Pesticide Epidemiology Data  TC \l1 "4.0	Public
Health and Pesticide Epidemiology Data 

Because BAM is a metabolite and there are no registered uses for BAM
itself, HED does not expect any incident reporting data to be available.

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 

Refer to the concurrent Human Health Risk Assessment for fluopicolide
(DP #325091, N. Dodd, 11/21/07) for details regarding fluopicolide
metabolism. Refer to Appendix B for names and structures of dichlobenil,
fluopicolide, and metabolites/degradates.  Refer to the Dichlobenil
Reregistration Eligibility Decision (RED) (EPA-738-R-98-003, October
1998) for dichlobenil metabolism data.

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

BAM is a metabolite and/or environmental degradate of both fluopicolide
and dichlobenil.  

BAM is included in the tolerance expression for dichlobenil because it
is a major metabolite/degradate of dichlobenil in primary crops as shown
in grape and apple metabolism studies (Dichlobenil Reregistration
Eligibility Decision (RED), EPA-738-R-98-003, October 1998):  “In the
grape metabolism study, mature grape vines were treated with a single
soil application of uniformly benzene-ring labeled [14C]dichlobenil at a
rate equivalent to 1x.  HPLC analyses of the organosoluble and
acid-hydrolyzed aqueous extracts indicated that BAM was the major
residue, amounting to 82.1% of the total radioactive residues (TRR). 
4-Hydroxy-BAM was also identified as a residue at 1.9% of the TRR.  In
the apple metabolism study, an apple tree was treated with a single soil
application of uniformly benzene-ring labeled [14C]dichlobenil at a rate
equivalent to 1x.  HPLC analyses of the organosoluble extracts of the
apples indicated that BAM was the major residue, amounting to 57% of the
TRR.  The remaining TRR were insoluble or unidentified soluble
fractions, individually accounting for <0.01 ppm.”

BAM is a minor metabolite of fluopicolide.  The tolerance expression for
plants will include fluopicolide (parent) as an indicator of combined
residues of fluopicolide and BAM.  BAM is included in the risk
assessment for the proposed uses of fluopicolide on the primary domestic
plants (cucurbit vegetables, fruiting vegetables, grapes, leafy
vegetables, and tuberous and corm vegetables).  Metabolism of
fluopicolide in grapes, lettuce, and potato was found to be similar. 
Fluopicolide was the primary residue identified in grape fruit, lettuce
leaves, and potato tubers, accounting for ~51-98% TRR.  The metabolites
2,6-dichlorobenzamide (BAM;AE C653711) and
3-chloro-5-trifluoromethylpyridine-2-carboxylic acid (PCA; AE C657188)
were found in foliarly-treated grape fruit and lettuce leaves at <4% TRR
each.  In lettuce which had received soil drench application, BAM was
found (17-20% TRR), and both BAM and PCA were found in potato tubers
(12-26% TRR each).  One additional metabolite (AE C643890;
2,6-dichloro-N-[(3-chloro-5-trifluoromethylpyridin-2-yl)methyl]-3-hydrox
ybenzamide) was identified in grape, lettuce, and potato commodities at
<3% TRR. 

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

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

Metabolism of dichlobenil in rotational crops is not pertinent since
dichlobenil is registered on orchard crops, grapes, and cane and bush
berries, and proposed for use on rhubarb; these crops are not considered
to be rotated (OPPTS 860.1850). 

 

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

The tolerance expression for rotational crops will include fluopicolide
(parent) as an indicator of combined residues of fluopicolide and BAM. 
The residues of concern for the risk assessment are fluopicolide
(parent) and BAM for all rotational crops except the grain of cereal
grains used as human food.  The residues of concern for the risk
assessment for the grain portion of cereal grain rotational crops used
as human food are fluopicolide (parent), BAM, PCA, and
3-methylsulfinyl-5-fluoromethylpyridine-2-carboxylic acid (P1X; AE
1344122). 

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

Because dichlobenil is not a significant plant residue, metabolism
studies were conducted in which ruminants and poultry were dosed with
14C- BAM (Dichlobenil Reregistration Eligibility Decision (RED),
EPA-738-R-98-003, October 1998):  Lactating goats were dosed with
[U-phenyl]14C-BAM at a dose level of 10 ppm for five days.  The primary
residue found in milk, kidney, fat, and muscle of goats was unchanged
BAM.  The major residue found in goat liver was the glutathione
conjugate 6-chloro-3-hydroxy-2-mercaptobenzamide.  Laying hens were
dosed with [U-phenyl]14C-BAM at a dose level of 10 ppm for five days. 
The primary residue found in all poultry matrices collected was
unchanged BAM. 

The residues of concern from fluopicolide in livestock commodities are
tentative since additional information is needed to support the ruminant
and poultry metabolism studies.  Pending submission of the required
additional data, HED has tentatively determined that the residue of
concern in livestock commodities for a tolerance expression is BAM.  The
residues of concern in livestock commodities for the risk assessment
have been tentatively determined to be parent fluopicolide and BAM.  BAM
as a metabolite of fluopicolide is found in the ruminant metabolism
study in milk (3.9%) and in the poultry metabolism study in liver (37%).

5.1.4	Analytical Methodology  TC \l3 "5.1.4	Analytical Methodology 

Plant Methods for BAM

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

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

Livestock Methods for BAM

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

Multiresidue Methods for Fluopicolide and BAM

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

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

5.1.5	Environmental Degradation TC \l3 "5.1.5	Environmental Degradation 

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

 “The major routes of degradation for fluopicolide and its degradates
in laboratory studies are photodegradation in water and on soil and
aerobic microbial degradation. Laboratory studies predict that
fluopicolide should persist in soil and aquatic environments.
Degradation in soil was slow with a mean half-life of 413 days. In an
aerobic aquatic system, fluopicolide slowly partitioned into the
sediment and degraded from the water-sediment system with half-lives of
699 to 866 days. In an anaerobic aquatic system, fluopicolide partitions
from water into sediment (water dissipation half-lives of 21.6 to 24.7
days), then slowly degrades with system half-lives of 967 to 1553 days.
A mean KOC value of 340 suggests that fluopicolide could leach in soil
but this leaching potential should abate due to a time dependent
increase in KOC. Field studies support the conclusion that fluopicolide
will not leach. In the soil environment, fluopicolide degradation was
faster with half-lives of 72 to 315 days (mean 181 days) in terrestrial
field studies with no significant leaching of parent, AE C653711.”

As stated in the Dichlobenil Registration Eligibility Decision
(EPA-738-R-98-003, October 1998):  “Dichlobenil dissipates in the
environment (on soil and in surface water) principally by
volatilization.  However, it is persistent under field conditions that
reduce the potential for volatilization (i.e., cooler climates).  When
degradation proceeds through aerobic soil metabolism,
2,6-dichlorobenzamide (BAM) is generated (13.1% at 50 weeks).  Under
conditions where dichlobenil does not volatilize, there is potential for
both dichlobenil and BAM to move to ground water in coarse-textured
soils low in organic matter.”

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.

Because crops with associated livestock feed items (potato and the
rotational crop wheat) will not be registered at this time, residues are
not expected to occur in livestock commodities (ruminants and poultry)
as a result of use of fluopicolide.  In the livestock metabolism
studies, the major residues (> 10% TRR) in ruminants were fluopicolide
(parent) and the dihydroxy glucuronide of fluopicolide; the major
residues in poultry were fluopicolide (parent), BAM, AE 0712556
(2,6-dichloro-N-[(3-chloro-5-trifluoromethyl-2-pyridyl)methyl]-4-hydroxy
benzamide), Metabolite 1
(2,6-dichloro-N-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]methyl}-3-(me
thylsulfonyl)benzamide), and the dihydroxy sulfate of fluopicolide.

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

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

5.1.7	Toxicity Profile of BAM TC \l3 "5.1.7	Toxicity Profile of BAM 

BAM (2,6-dichlorobenzamide; AE C653711) is a metabolite and/or
environmental degradate of both fluopicolide and dichlobenil.  The acute
and chronic studies were sufficient to evaluate human hazard potential. 
BAM demonstrated moderate acute toxicity (Category III) via the oral
route of exposure.  Because the subchronic and chronic toxicity of BAM
is considered less than or equal to that of dichlobenil (parent
herbicide) based on submitted and published toxicity studies, the acute
toxicity of BAM via the inhalation and dermal routes is expected to be
less than or equal to that of dichlobenil.  The 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
either mutagenic or clastogenic in submitted genotoxicity studies.  In
the absence of carcinogenicity study data for a second species, HED has
assumed, to be conservative, that BAM’s carcinogenic potential is
similar to that of dichlobenil, the parent compound having the greatest
carcinogenicity potential.  Dichlobenil is classified as “Group C,
possible human carcinogen” with the RfD approach used for
quantification of human cancer risk.  BAM is considered to be
neurotoxic.  No evidence of endocrine mediated toxicity was observed. 
An FQPA SF of 10X for database uncertainty is applied to acute and
chronic dietary and incidental oral exposure scenarios for
incompleteness of the database with regard to the systemic neurotoxic
potential of BAM, including olfactory toxicity) and also, in the case of
acute dietary exposure, use of a LOAEL to extrapolate to a NOAEL.  

The soil metabolite BAM has a different toxicity profile than parent
fluopicolide.  The parent has no acute dietary endpoint and a cPAD of
0.32 mg/kg/day.  BAM has aPADs of 0.1 mg/kg/day for the general
population and 0.03 mg/kg/day for females 13-49 years old, and a cPAD of
0.0045 mg/kg/day for the general population.

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

For dichlobenil, the residues which are regulated in plant commodities
are dichlobenil (parent) and BAM (40 CFR §180.231).  No livestock
tolerances have been established.  In drinking water, residues of
concern from use of dichlobenil are dichlobenil and BAM.  

For fluopicolide, the residues of concern are shown in the table below. 
HED notes that tolerances on rotational crops and livestock will not be
established at this time.

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

Matrix	Residues included in Risk Assessment1	Residues included in
Tolerance Expression

Plants

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

Grapes)	Primary Crops

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

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



Rotational Crops

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



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



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

	Livestock	Ruminant	fluopicolide (parent) and BAM 	BAM

	Poultry



Drinking Water	fluopicolide (parent) and BAM	Not applicable

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

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

Drinking Water Assessment for the BAM (2,6-Dichlorobenzamide) Degradate
of Dichlobenil, DP #340773, J. Angier, Ph.D., 8/29/07

Drinking Water Exposure Assessment for Fluopicolide Uses on Grapes,
Vegetables, Potatoes, Sugar Beet, Onion, and Turf – Exposure of
2,6-Dichlorobenzamide (BAM), DP #325804, J. Lin, 5/3/07.

Considering residues of BAM in drinking water from uses of fluopicolide,
uses of dichlobenil, and uses of both pesticides as described below, the
highest drinking water residue estimate (56.2 ppb) was from SciGrow
modeling of BAM residues from dichlobenil use on nutsedge at 10 lb ai/A.
 Therefore, 56.2 ppb was used as the value of BAM residues in drinking
water in the dietary assessment for both the acute and chronic
assessments.

BAM in Drinking Water from Dichlobenil Uses 

No monitoring data were available for BAM.  Drinking water residues of
BAM were modeled for exposures resulting from currently approved uses of
the parent herbicide, dichlobenil.  The toxic degradate of concern, BAM,
is formed as a result of accepted usage of the parent dichlobenil.  This
assessment utilizes known physical/chemical characteristics of BAM,
combined with estimated rates of formation of the degradate following
dichlobenil application.  The OPP/EFED Tier 2 surface water model
PRZM-EXAMS was used in this assessment.  Percent Cropped Area (PCA)
corrections were applied for appropriate crops as well.  Dichlobenil use
is currently registered for: control of weeds in fruit and nut orchards
(6 lbs a.i./acre), non-crop areas (12 lbs a.i./acre), and, control of
nutsedge (10 lbs a.i./acre).  Note that this memorandum replaces an
earlier version where nutsedge usage was evaluated at 20 lbs a.i./acre;
current label restricts this use to a maximum application rate of 10 lbs
a.i./acre.  New use on rhubarb (2 lbs a.i./acre) is also pending.  A
screening assessment for the impact of BAM on potential groundwater
drinking water sources, using the Tier 1 groundwater model SciGrow, has
also been conducted.  Results and conclusions are contained herein.  

Below are the model results for predicted surface water concentrations
(using the PRZM-EXAMS model) and groundwater concentrations (using
SciGrow).  There were no specific PRZM scenarios for some uses (e.g.,
nutsedge control, rhubarb), so the closest surrogates were used instead.
 For rhubarb, the nearest surrogates for which scenarios were available
(in terms of crop type, agricultural practices, and setting) were:
lettuce, cabbage, and sugar beet, in the states of California, Florida,
and Minnesota.  The most protective surrogate, lettuce grown in
California, was used in this assessment.  For other cases, the Oregon
Apple PRZM scenario was used for orchard crops, Florida Turf was used as
a proxy for nutsedge control in non-crop areas, and Florida Turf used
for weed control in non-crop areas.  However, since the weed control in
non-crop areas is typically applied beneath a semi-protective layer such
as concrete, vinyl liner, etc., it is not expected to contribute
substantially to runoff or infiltration (as the covering will restrict
contact with water). 

Each run was performed using fate and mobility parameters for BAM only. 
To determine the equivalent amount of BAM degradate applied as a result
of dichlobenil usage, the ‘applied’ BAM amounts were calculated by
multiplying the maximum amount of BAM expected to form as a result of
registered dichlobenil use (13.1%) by the (maximum allowed for each
scenario) amounts of dichlobenil applied.  However, since BAM has a
different molecular weight (190.3 g/mol) than parent dichlobenil (172
g/L), a further correction was applied.  Thus, in terms of total mass,
BAM represents 14.5% of parent dichlobenil.  Results are listed below;
rhubarb and orchard values have had Percent Cropped Area (PCA)
adjustments of 87% applied, while the nutsedge control and other
non-crop uses have no PCA applied.



SURFACE WATER DRINKING WATER CONCENTRATIONS (ppb) FOR THE DEGRADATE BAM
(RESULTING FROM DICHLOBENIL USE), MODELED USING PRZM-EXAMS

Scenario	Peak (acute)	1 in 10 Year Annual Mean		30 Year Overall Mean

FL turf (Nutsedge control):

20.9				8.61					3.97

CA lettuce (surrogate for Rhubarb):	

		12.9				6.59					3.69

OR apple (Orchards):

		6.13				3.63					0.896

Results for estimated (high-end) groundwater BAM concentrations from
SciGrow were obtained using the maximum proposed application rates
(adjusted to reflect 14.5% of applied dichlobenil) and the available
fate parameters for BAM.  

GROUND WATER DRINKING WATER CONCENTRATIONS FOR BAM, RESULTING FROM
PARENT DICHLOBENIL USE – MODELED USING SCIGROW

SciGrow output for Nutsedge control use = 56.2 ppb

SciGrow output for Orchard use = 33.7 ppb

SciGrow output for Rhubarb use = 11.2 ppb

Based on modeling results, the estimated ground water drinking water
concentration for BAM from use of dichlobenil is 56.2 ppb (based on
SciGrow modeling of dichlobenil use on nutsedge).  (The use for non-crop
weed control is not expected to exceed the use for nutsedge control on
an actual per acre basis.)  This BAM residue level is higher than
estimated residues in surface water.  



Table 5.1.9a	Summary of Estimated Surface Water and Groundwater
Concentrations for BAM from Dichlobenil Uses.

	BAM

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

Acute	20.9	56.2

Chronic (non-cancer)	8.61	56.2

a From the Tier II PRZM-EXAMS - Index Reservoir model.  Input parameters
are based on FL turf (nutsedge control with an application rate of 10
lbs fluopicolide ai/acre.  

b From the SCI-GROW model assuming a maximum seasonal application rate
of 0.054 lb BAM/acre (based on a maximum seasonal application rate for
nutsedge of 10 lb ai/A, a Koc of 30 mL/g, and an aerobic soil metabolism
half-life of 365 days. 



BAM in Drinking Water from Fluopicolide Uses 

No monitoring data were available for BAM.  Drinking water residues of
BAM were modeled for exposures through ingestion of drinking water from
uses of the parent fungicide, fluopicolide, on grapes, vegetables, sugar
beet, onion, and turf.  Surface water concentrations were estimated
using the Tier II model PRZM version 3.12 and EXAMS version 2.98. 
Ground water concentrations were estimated using the Tier I SCI-GROW
model. 

Based on modeling results, the estimated surface water drinking water
concentrations for 2,6-dichlorobenzamide (BAM) – a major degradate of
fluopicolide are:  

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

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

The 1 in 10 year annual peak (acute) was derived from modeling on
Florida peppers.  The 1 in 10 year annual mean (non-cancer chronic) was
derived from modeling on California lettuce.  These values were highest
among all modeling scenarios examined.  

 μg/L, which was based on 2 applications of 0.054 lb ai/acre per
application.



Table 5.1.9b	Summary of Estimated Surface Water and Groundwater
Concentrations for BAM from Fluopicolide Uses.

	BAM

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

Acute	4.26	4.19

Chronic (non-cancer)	1.53	4.19

a From the Tier II PRZM-EXAMS - Index Reservoir model.  Input parameters
are based on ...

b From the SCI-GROW model assuming a maximum seasonal application rate
of 0.054 lb BAM/acre, a Koc of 30 mL/g, and an aerobic soil metabolism
half-life of 365 days.  



BAM in Drinking Water from both Dichlobenil and Fluopicolide Uses 

Grapes and rhubarb (a leafy vegetable) are the only crops on which both
dichlobenil and fluopicolide are to be used.  The rates on grapes are 2
lb ai/A for dichlobenil and 0.375 lb ai/A for fluopicolide.  The rates
on rhubarb are also 2 lb ai/A for dichlobenil and 0.375 lb ai/A for
fluopicolide.  The rate for dichlobenil on nutsedge is much higher (10
lb ai/A); the use of dichlobenil on nutsedge will result in the highest
residues in drinking water. 

Considering residues of BAM in drinking water from uses of fluopicolide,
uses of dichlobenil, and uses of both pesticides (on grapes and rhubarb,
the only crops on which both pesticides will be registered), the highest
drinking water residue estimate (56.2 ppb) was from SciGrow modeling of
BAM residues from dichlobenil use on nutsedge at 10 lb ai/A.  Therefore,
this assessment will use the highest estimate of 56.2 ppb (from SciGrow
modeling of BAM residues from dichlobenil use on nutsedge) for the
drinking water estimate for both the acute and chronic exposures:  

56.2 ppb for the 1 in 10 year annual peak concentration (acute)  

56.2 ppb for the 1 in 10 year annual mean concentration (non-cancer
chronic).

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

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

2,6-Dichlorobenzamide (BAM) as a Metabolite of Fluopicolide and
Dichlobenil.  Acute and Chronic Aggregate Dietary (Food and Drinking
Water) Exposure and Risk Assessments for the Section 3 Registration
Actions for Fluopicolide on Tuberous and Corm Vegetables, Leafy
Vegetables (except Brassica), Fruiting Vegetables, Cucurbit Vegetables,
and Grapes, and for Indirect or Inadvertent Residues on the Rotational
Crop Wheat, DP Number 340366, N. Dodd, 11/21/07.

BAM as a Metabolite/Degradate from Established/Proposed Uses of
Fluopicolide on Tuberous and Corm Vegetables, Leafy Vegetables (except
Brassica), Fruiting Vegetables, Cucurbit Vegetables, and Grapes and from
Established/Pending Uses of Dichlobenil:

BAM is a metabolite and/or environmental degradate of both fluopicolide
and dichlobenil.  This risk assessment includes residues of BAM in food
and drinking water from uses of both fluopicolide and dichlobenil.  A
separate risk assessment is being conducted concurrently for
fluopicolide (parent).  

Fluopicolide:

HED is presently recommending for the following tolerances for
fluopicolide (parent) based on the submitted residue data:

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

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

under “(a) General”:

	

Grape*	2.0 ppm

Grape, raisin*	6.0 ppm

Vegetable, cucurbit, group 9	.0.50 ppm

Vegetable, fruiting, group 8	1.6 ppm

Vegetable, leafy, except Brassica, group 4	25 ppm

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

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

Tolerances have been established (40 CFR §180.627) for residues of
fluopicolide,
2,6-dichloro-N-[[3-chloro-5-(trifluoromethyl)-2-pyridinyl]methyl]
benzamide, on grape at 2.0 ppm and grape, raisin at 6.0 ppm for use on
imported crops.  No livestock tolerances have been established.  No
Codex, Canadian, or Mexican Maximum Residue Limits (MRLs) or tolerances
have been established for fluopicolide.

Dichlobenil:

Dichlobenil is registered as a granular (G) formulation (Casoron® 4G;
EPA Reg. No. 400-168; date of issuance: 5/18/05) for use on apple,
blueberry, cherry, filbert, grape, and pear at 6 lb ai/A/season and on
blackberry, cranberry, and raspberry at 4 lb ai/A/season.  A
registration for Casoron® 4G for use on rhubarb at 2 lb ai/A/season is
pending (DP Number 315266, W. Cutchin, 2/22/06). 

Tolerances are established (40 CFR §180.231) for the herbicide
dichlobenil (2,6-dichlorobenzonitrile) and its metabolite
2,6-dichlorobenzamide as follows.  A tolerance for rhubarb is pending.

Tolerances established (40 CFR §180.231) for the combined residues of
the herbicide dichlobenil (2,6-dichlorobenzonitrile) and its metabolite
2,6-dichlorobenzamide

Apple	0.5 ppm

Blackberry	0.1 ppm

Blueberry	0.15 ppm

Cranberry	0.1 ppm

Filbert	0.1 ppm

Fruit, stone, group 12	0.15 ppm

Grape	0.15 ppm

Pear	0.5 ppm

Raspberry	0.1 ppm

Tolerance pending for the combined residues of the herbicide dichlobenil
(2,6-dichlorobenzonitrile) and its metabolite 2,6-dichlorobenzamide

 

Rhubarb	0.06 ppm 

The revised RED (7/31/96) recommended deletion of stone fruit crop group
tolerance which was not being supported by the petitioner and
establishment of a separate tolerance on cherries.  However, as stated
in the previous RED, the stone fruit crop group was included in this
dietary exposure assessment since as long as the tolerance exists
commodities containing BAM residues could be imported (Kathryn Boyle,
07/31/96, DP Number D000000:  Dichlobenil: The Revised HED Chapter of
the Reregistration Eligibility Decision Document (RED), Case 0263,
Chemical 027401, 027402 (BAM).

  

Residue Data used for Acute and Chronic Assessments:

Maximum residues of BAM from fluopicolide field trials on tuberous and
corm vegetables (except potato), leafy vegetables (except Brassica),
fruiting vegetables, cucurbit vegetables, and grapes (domestic and
imported) and from dichlobenil field trials on food commodities with
established/pending dichlobenil tolerances (40 CFR §180.231) were
included in the assessment.  The assessments assumed 100% crop treated
for fluopicolide and dichlobenil, except for the following
dichlobenil-treated crops:  1) for the acute assessment: apples (2.5%),
blueberries (2.5%), cherries (2.5%), peaches (2.5%), pears (2.5%), and
raspberries (5%); and 2) for the chronic assessment: apples (1%),
blueberries (1%), cherries (1%), cranberries (45%), peaches (1%), pears
(1%), and raspberries (5%).

No livestock tolerances are established or proposed for either
fluopicolide or dichlobenil.  Since the potato use will not be
registered at this time and some restrictions will be applied to
rotational crops, no livestock feed items are associated with this
fluopicolide petition.  DEEM default processing factors were used in the
calculation.

Magnitude of BAM Residues in Plants from Use of Fluopicolide 

Table 5.1.10.1.  BAM Residues in Tuberous and Corm Vegetables (except
Potato), Leafy Vegetables (except Brassica), Fruiting Vegetables,
Cucurbit Vegetables, and Grapes from Field Trials with Fluopicolide.

Commodity

(MRID)

(Formulation)	Total Applic.

Rate

(lb ai/A)	PHI

(days)	Residue Levels (ppm)



	n	Min.	Max.	HAFT*	Median

(STMdR)	Mean (STMR)	Std. Dev

Celery

(46708539)	0.354-0.365	2	12	<0.041	0.041	0.039	NA**	NA	NA

Cantaloupe

(46708531)	0.352-0.362	2	18	<0.01	<0.01	NA	NA	NA	NA

Cucumber

(46708532)	0.349-0.361	2	12	<0.01	<0.01	NA	NA	NA	NA

Grape

(46708541)	0.346-0.401	20-21	32	<0.01	<0.01	NA	NA	NA	NA

Lettuce, head

(46708533)	0.350-0.368	2	14	<0.01	0.0132	0.012	<0.01	<0.01	NA

Lettuce, leaf

(46708534)	0.349-0.364	2	14	<0.01	0.038	0.031	<0.01	0.012	0.010

Pepper, bell

(46708530)	0.349-0.358	2	14	<0.01	<0.01	NA	NA	NA	NA

Pepper, chile 

(46708535)	0.355-0.363	2	6	<0.01	<0.01	NA	NA	NA	NA

Spinach

(46708540)	0.357-0.365	2	14	0.022	0.188	0.170	0.065	0.072	0.047

Squash, summer

(46708538)	0.354-0.367	2	12	<0.01	<0.01	NA	NA	NA	NA

Tomato

(46708536)	0.356-0.368	2	24	<0.01	<0.01	NA	NA	NA	NA

* HAFT = Highest Average Field Trial.

** NA = Not Applicable.

HED’s memo entitled “Guidance for Translation of Field Trial Data
from Representative Commodities in the Crop Group Regulation to Other
Commodities in Each Crop Group/Subgroup, HED Standard Operating
Procedure 2000.1 (9/12/2000) was used to translate residue data from
celery, head lettuce, leaf lettuce, or spinach to other Group 4
commodities. 

Magnitude of BAM Residues in Plants from Use of Dichlobenil

Residues of BAM in crops from dichlobenil field trials are reported in
the tables below.  (The maximum residues are bolded.) 

Table 5.1.10.2a.  BAM Residues in Apples and Grapes from Field Trials
with Dichlobenil.

Commodity

(MRID)	Formulation	Total Applic.

Rate

(lb ai/A)	PHI

(days)	Residue Levels (ppm)





n	Min.	Max.

Apples1,2

(42177102)	4%G	6 (1x)	85	3	0.064	0.271



	154-167	12	0.011	0.048

Grapes1

(42117101)	4%G	6 (1x)	119-158	12	0.027	0.064

1 DP #174526, CBRS 9390, D. McNeilly, 7/2/92.

2 Data for apples in MRID 42177102 will translate to pears.



Table 5.1.10.2b.   BAM Residues in Apples, Blackberries, Cranberries,
and Plums from Field Trials with Dichlobenil

Commodity

(MRID)	Formulation	Total 

Applic

Rate

(lb ai/A)	PHI

(days)	n	Residue Levels (ppm)

Apples 1

(42452802)	4%G	6 (1x)	80-179	15	<0.01

Blueberries2

(42304201)	4%G	6 (1x)	94	3	0.04-0.06

Blackberries1

(42452803)	4%G	4 (1x)	94	3	<0.01

Cherries



	No BAM data on cherries.  Use plum data until data are available. 

Cranberries1

(42452801)	4%G	4 (1x)	158, 166	6	0.02-0.03

Filberts3

(42476101)	4%G	6 (1x)	160	3	<0.01  (Use 0.02 ppm because of approx. 50%
degradation in storage.)

Grapes3

(42476103)	4%G	6 (1x)	124-173	12	0.01-0.09*

Peaches3

(42476102)	4%G	6 (1x)	63-68	6	0.02-0.04

Plums1

(42452804)

Or

(42452801)	4%G	6 (1x)	154

Or

158-166	2	0.43, 0.46

Pear



	No BAM data have been submitted on pear.  Use apple data.

Raspberries



	No BAM data were submitted on raspberries.  Use blackberry data.

Rhubarb4

(45572201)	4%G	2 (1x)	64-83	3	<0.01**

1 DP #182600, C. Olinger, 3/5/93.

2 DP #179079, C. Olinger, 2/9/93.

3 DP #183209, C. Olinger, 3/24/94.

4  DP #315266, C. Olinger, 2/22/06.

* The value 0.09 ppm is the highest BAM residue in/on grapes from use of
dichlobenil.  The value of 0.10 ppm for grapes (the sum of 0.09 for BAM
from dichlobenil  + 0.01 for BAM from fluopicolide) was used in the
DEEM.

** The value <0.01 ppm is the highest BAM residue in/on rhubarb from use
of dichlobenil.  The value of 0.05 ppm (sum of <0.01 ppm for BAM from
dichlobenil + 0.041 ppm (translated from celery) for BAM from
fluopicolide) was used in the DEEM.

For the stone fruit crop group, residue data on the representative crops
peach and plum were translated to the individual crops in the crop group
without data  (HED SOP 200.1:  Guidance for Translation of Field Trial
Data from Representative Commodities in the Crop Group Regulation to
Other Commodities in Each Crop Group/Subgroup, HED Standard Operating
Procedure (9/12/2000).  The peach residue of 0.04 ppm was translated to
apricot and nectarine; the plum residue of 0.46 ppm was translated to
various plums and plumcot.

For filberts, the highest reported residue was doubled to 0.02 because
of approximately 50% degradation on storage. 

Magnitude of BAM Residues in Plants from Use of both Fluopicolide and
Dichlobenil

Considering the registered and proposed crops, grapes and rhubarb (a
member of the Leafy Vegetables, except Brassica, Crop Group, Crop Group
4) are the only commodities which may be treated with both dichlobenil
and fluopicolide.

The maximum residue of BAM from use of fluopicolide on imported grapes
is 0.047 ppm (DP Number 321209, A. Acierto, 11/29/06).  The maximum
residue level of BAM from use of fluopicolide on domestic grapes is
<0.01 ppm (Table 5.1.10.1 above).  The maximum residue of BAM from use
of dichlobenil on domestic grapes is 0.09 ppm (Table 5.1.10.2b above).  
A total of 0.10 ppm for BAM in grapes was used in this assessment, the
result of summing the highest residues from domestic uses of
fluopicolide and dichlobenil.

A total of 0.05 ppm was used for residues of BAM in rhubarb in this
assessment.  The value of 0.05 ppm for rhubarb is the sum of residues of
0.041 ppm from use of fluopicolide (translated from celery field trial
data as directed by SOP 2000.1) and <0.01 ppm from use of dichlobenil.

BAM Processing Studies

Dichlobenil

Although an adequate processing study is not available for apples, the
available data indicate that residues of BAM do not significantly
concentrate in apple juice and wet pomace processed from apples
individually spiked with BAM at approx 0.1 ppm  (DP Number 203324, Paula
Deschamp, 7/1/94.)  Residues concentrate in dry apple pomace (DP Number
203324, Paula Deschamp, 7/1/94).  Adequate processing studies are not
available for dichlobenil on grapes (D182033, C. Olinger, 3/8/93) and
plums ((MRID 42679001; DP Number 188926, C. Olinger, 3/16/04). 

Fluopicolide

Processing studies were conducted for BAM on grape and tomato.

  SEQ CHAPTER \h \r 1 Table 5.1.10.3.  Summary of Processing Factors for
BAM 

RAC	Processed Commodity	Average Processing Factor 1



BAM

Grape

(DP#321209)	Juice	1x

	Raisin	4x2

Tomato	Paste	NC

	Puree	NC

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

2 The dietary assessment uses the tolerance of 6.0 ppm for raisin,
instead of the grape tolerance (2.0 ppm) and a processing factor.

In this assessment, DEEM default processing factors were used.  The
following processing factors were used:

BAM Processing Factors Used (DEEM Default Processing Factors 

Table 5.1.10.4  SEQ CHAPTER \h \r 1 .  Summary of Processing Factors for
BAM 

RAC	Processed Commodity	Processing Factor Used

Apple	dried apple	8.0x

	Juice	1.3x

Apricot	dried apricot	6.0x

Beef	dried meat	1.92x

Cherry	Juice	1.5x

Cranberry	Juice	1.1x

Grape

	juice 	1.2x

	Raisin	4.3x

	wine & sherry	1.2x

 (based on grape juice)

Peach

	dried peach	7.0x

	Juice	1.5x

Pear	dried pear	6.25x

Plum

	dried prune	5.0x

	prune juice	1.4x

Tomato	dried tomato	14.3x

	Juice	1.5x

	Paste	5.4x

	Puree	3.3x



Percent Crop Treated

Percent crop treated data (below) were used for apples, blueberries,
cherries, cranberries, peaches, pears, and raspberries as provided by
the Biological and Economic Analysis Division (DP #342741, Jihad
Alsadek, 8/22/07).  “Percent of Crop Treated” values were used for
the chronic assessment; “Maximum Percent of Crop Treated” values
were used for the acute assessment. 

Table 5.1.10.5.  Screening Level Estimates of Agricultural Uses of
Dichlobenil 

Crop	Pounds of Active Ingredient	Percent of Crop Treated	Maximum Percent
of Crop Treated

Apples	6,000	<1	<2.5

Blueberries	<500	<1	<2.5

Cherries	2,000	<1	<2.5

Cranberries	30,000	45	--

Grapes	3,000	<1	<2.5

Peaches	1,000	<1	<2.5

Pears	<500	<1	<2.5

Raspberries	1,000	  5	  5

Strawberries*	<500	<1	<2.5

*No tolerance is established on strawberries.  Percent crop treated data
on grapes were not used because BAM on grapes comes from two sources
(dichlobenil and fluopicolide).

Meat, Milk, Poultry, Eggs

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

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

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

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

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

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

Wheat, hay	R	88	15	0.102	0.017

Potato, processed waste	CC	15	30	 0.054	0.10

Wheat, milled byproducts	CC	88	40	0.0185	0.0082

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

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

TOTAL BURDEN	--	--	100

0.13

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

Wheat, hay	R	88	40	0.102	0.046

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

Wet apple pomace	CC	40	10	0.271	0.068

Wheat, milled byproducts	CC	88	35	0.0185	0.0072

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

TOTAL BURDEN	--	--	100

0.12

Poultry  CC: 75 %;  PC: 25%

Wheat, milled byproducts	CC	88	50	0.0185	0.009

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

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

TOTAL BURDEN	--	--	100

0.009

Swine CC: 85 %;  PC: 15%

Wheat, milled byproducts	CC	88	50	0.0185	0.009

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

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

TOTAL BURDEN	--	--	100

0.009

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

2  OPPTS 860.1000 Table 1 Feedstuffs (October 2006).  

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

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

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

6  N/A:  Not applicable.  

No livestock tolerances are established for dichlobenil and no livestock
tolerances have been proposed for fluopicolide.  Since the potato use
will not be registered at this time and some restrictions will be
applied to rotational crops so that tolerances on the rotational crop
wheat will not be established at this time, no livestock feed items are
associated with this fluopicolide petition.  

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

This topic is not applicable since there is no registration for BAM
itself.

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

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

2,6-Dichlorobenzamide (BAM) as a Metabolite of Fluopicolide and
Dichlobenil.  Acute and Chronic Aggregate Dietary (Food and Drinking
Water) Exposure and Risk Assessments for the Section 3 Registration
Actions for Fluopicolide on Tuberous and Corm Vegetables, Leafy
Vegetables (except Brassica), Fruiting Vegetables, Cucurbit Vegetables,
and Grapes, and for Indirect or Inadvertent Residues on the Rotational
Crop Wheat, DP #340366, N. Dodd, 11/21/07. 

isk assessments were conducted using the Dietary Exposure Evaluation
Model DEEM-FCID™, Version 2.03, which use 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 analyses
were performed on BAM to support Section 3 requests for use of parent
fluopicolide on tuberous and corm vegetables (except potato), leafy
vegetables (except Brassica), fruiting vegetables, cucurbit vegetables,
and grapes..

BAM is formally unclassified with respect to cancer; the parent
herbicide dichlobenil is classified as “Group C, possible human
carcinogen” with the RfD approach utilized for quantification of human
risk.  The parent fungicide fluopicolide is classified as not likely to
be carcinogenic to humans.

This risk assessments includes only BAM because there is no common
toxicological effect for BAM and other fluopicolide residues of concern.
 A separate human health risk assessment is being conducted concurrently
for other fluopicolide residues of concern [i.e., fluopicolide (parent);
also including P1X and/or PCA in some crops].  This assessment includes
residues of BAM from uses of both fluopicolide and dichlobenil since BAM
is a metabolite and/or environmental degradate of both fluopicolide and
dichlobenil.

5.2.1	Acute Dietary Exposure/Risk   TC \l3 "5.2.1	Acute Dietary
Exposure/Risk  

A conservative acute exposure assessment was conducted.  Maximum
residues of BAM from fluopicolide field trials on tuberous and corm
vegetables (except potato), leafy vegetables (except Brassica), fruiting
vegetables, cucurbit vegetables, and grapes (domestic and imported)  and
from dichlobenil field trials on food commodities with
established/pending tolerances (40 CFR 180.231) were included in the
assessments.  The assessments assumed 100% crop treated for fluopicolide
and dichlobenil, except for the following dichlobenil-treated crops:  1)
for the acute assessment: apples (2.5%), blueberries (2.5%), cherries
(2.5%), peaches (2.5%), pears (2.5%), and raspberries (5%); and 2) for
the chronic assessment: apples (1%), blueberries (1%), cherries (1%),
cranberries (45%), peaches (1%), pears (1%), and raspberries (5%).  No
livestock tolerances are established or proposed for either fluopicolide
or dichlobenil.  DEEM default processing factors were used. 

The acute dietary (food and drinking water) exposure to BAM from
fluopicolide and dichlobenil uses is below HED’s level of concern for
the general U.S. population and all population subgroups.  The acute
dietary exposure estimates at the 99.9th percentile of the exposure
distribution are 11% of the acute Population Adjusted Dose (aPAD) for
the general U.S. population and 28% of the aPAD for all infants (<1 year
old), the most highly exposed group.

5.2.2	Chronic Dietary Exposure/Risk   TC \l3 "5.2.2	Chronic Dietary
Exposure/Risk  

A conservative chronic exposure assessment was conducted as described
above.

The chronic dietary (food and drinking water) exposure to BAM from
fluopicolide and dichlobenil uses is below HED’s level of concern for
the general U.S. population and all population subgroups.  The chronic
dietary exposure estimates are 29% of the chronic Population Adjusted
Dose (cPAD) for the general U.S. population and 93% of the cPAD for all
infants (<1 year old), the most highly exposed group which is of concern
to HED.  Residues in drinking water contribute the most to exposure.

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

As noted above, EPA has assumed that BAM’s potential for
carcinogenicity is similar to that of  dichlobenil, which is classified
as “Group C, possible human carcinogen” with the RfD approach
utilized for quantification of human risk.  The quantification of cancer
risk using the RfD approach is identical to the assessment for chronic
effects; no separate carcinogenic risk assessment is necessary.



Table 5.2. Results of Acute and Chronic Dietary (Food + Water) Exposure
and Risk Estimates for BAM.

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



Exposure, mg/kg/day	% PAD

Acute Dietary Estimates (99.9th) Percentile of Exposure)

U.S. Population	0.1	0.011430	11

All infants (< 1 yr)	0.1	0.028239	28

Children 1-2 yrs	0.1	0.016758	17

Children 3-5 yrs	0.1	0.012291	12

Children 6-12 yrs	0.1	0.007340	7

Youth 13-19 yrs	0.1	0.007223	7

Adults 20-49 yrs	0.1	0.008377	8

Adults 50+ yrs	0.1	0.006619	7

Females 13-49 yrs	0.03	0.008426	28

Chronic Dietary Estimates

U.S. Population	0.0045	0.001312	29

All infants (< 1 yr)	0.0045	0.004167	93

Children 1-2 yrs	0.0045	0.002276	51

Children 3-5 yrs	0.0045	0.001979	44

Children 6-12 yrs	0.0045	0.001292	29

Youth 13-19 yrs	0.0045	0.000926	21

Adults 20-49 yrs	0.0045	0.001191	26

Adults 50+ yrs	0.0045	0.001283	28

Females 13-49 yrs	0.0045	0.001191	26

Cancer Dietary Estimate

U.S. Population	*	*	*

* Classification:  BAM is formally unclassified; the parent herbicide
dichlobenil is classified as “Group C, possible human carcinogen,”
with the RfD approach utilized for quantification of human risk.  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, the parent having the greatest carcinogenic potential. 
Therefore, as for dichlobenil, an RfD approach to quantification of
cancer risk is considered appropriate for BAM.  The quantification of
cancer risk using the RfD approach is identical to the assessment for
chronic effects; no separate carcinogenic risk assessment is necessary.

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

Maximum residues of BAM from fluopicolide field trials on tuberous and
corm vegetables (except potato), leafy vegetables (except Brassica),
fruiting vegetables, cucurbit vegetables, and grapes (domestic and
imported), and from dichlobenil field trials on food commodities with
established/pending tolerances (40 CFR 180.231) were included in the
assessments.    

As discussed in Section 5.1.10, the assessments used 100% crop treated
except for apples, blueberries, cherries, cranberries, peaches, pears,
and raspberries.

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

Occupational and Residential Risk Assessment of Metabolite BAM (to
Support Request for Registration of Fluopicolide on a Variety of Crops,
Residential Turf and Ornamentals), DP #345920, K. O’Rourke, 10/9/07

As mentioned previously, BAM is known to be a metabolite of both
fluopicolide and dichlobenil.  While it is necessary to evaluate
residential exposure from all sources of BAM, the use pattern for
dichlobenil is not expected to result in scenarios with significant
residential exposure.  Dichlobenil products are not intended for use by
residential handlers.  They may be applied by professional pest control
operators (PCOs) to soil/mulch around roses and other woody ornamentals
in established residential plantings, but not to residential lawns or
turf.  Dermal and incidental oral exposures are expected to be
negligible from these sources.  Therefore, BAM exposure estimates are
based on fluopicolide use only.

Two products containing fluopicolide (i.e., V-10161 VPP Fungicide and
V-10162 VPP Fungicide) are proposed for application to residential
turfgrass and recreational sites.  Although the label does not prohibit
homeowners using these products, residential handler exposure was not
evaluated because the metabolite BAM is believed to form slowly in
plants and soil after the product containing the parent fluopicolide or
dichlobenil) has been applied.  However, residential postapplication
exposure via the dermal route is likely for adults and children entering
treated lawns.  Toddlers may also experience exposure via incidental
non-dietary ingestion (i.e., hand-to-mouth, object-to-mouth (turfgrass),
and soil ingestion) during postapplication activities on treated turf.

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

Residential handler exposure was not evaluated because the metabolite
BAM is believed to form slowly in plants and soil after the product
containing the parent (fluopicolide) has been applied.

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

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

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

In order to adjust the TTR estimates to reflect BAM residues, data from
plant metabolism studies were considered.  Grape, lettuce, and potato
metabolism data indicate that the majority of total radioactive residue
(TRR) was located on the surface of foliage and fruit samples (DP
#327026, A. Acierto, 8/20/07).  The parent fluopicolide was the primary
residue identified in grape fruit, lettuce leaves, and potato foliage
and tubers, accounting for 51-98% TRR.  The metabolite BAM was found in
foliarly-treated grapes (fruit), lettuce leaves and potato foliage at
<4% TRR.  Although BAM was found at higher percentages in lettuce which
had received soil drench application (17-20% TRR) and potato tubers
(12-26% TRR), the actual concentration was lower than BAM occurring on
grapes (fruit), lettuce leaves, and potato foliage.  For the purposes of
this postapplication exposure assessment, it was conservatively assumed
that the surface residues of BAM are transferable, and that they are
present at 4% of the initial amount of parent fluopicolide.  In
addition, the drinking water assessment (D340773, J. Angier, 8/29/07)
indicates that, based on aerobic soil metabolism data, BAM may be
present at up to 40% of application rate; this value was used to
estimate residues for the incidental soil ingestion scenario.

Exposure and risk estimates for residential exposure scenarios are
typically assessed for the day of application (“Day “0”) because
it is assumed that adults and toddlers could contact the lawn
immediately after application.  However, BAM is a metabolite/degradate
which forms slowly; therefore, these scenarios were assessed with the
assumption that BAM is present at the percentages described above (which
were actually measured on days 21 and 369 after application, for plants
and soil, respectively) for “Day 0” in order to provide a protective
assessment.  The equations used for the exposure calculations and the
results are presented in Tables 6.2.1 through 6.2.4.

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

The short-/intermediate-term dermal MOEs are above the LOC of 100, and
the MOEs for each incidental oral scenario are above the LOC of 1,000;
they are not of concern.  Although dermal and incidental oral exposure
may co-occur for toddlers, the toxic effects from these two routes are
different.  Therefore, only the incidental oral exposures were combined.
 As shown in Table 6.2.5, the Total incidental oral MOE for children is
62,000, which is greater than the LOC of 1,000 on the day of
application, and not of concern.



Table 6.2.1.  Postapplication Dermal Exposure and Risk from Treated
Lawns



Subgroup Exposed	

Application Rate

 (lb ai/A)	

Post-application day (t)	

Fraction of ai Transferable from the Foliage	

Turf Transferable Residue 1

(µg/cm2)	

Dermal Transfer Coefficient

(cm2/hr)	

 Body Weight

(kg)	

 Daily Dermal Dose 2

(mg/kg/day)

	

Dermal MOE 3









Short-/

Intermediate-term

Adults	0.27	0	0.05	0.0060	14,500	

70	0.0025	10,000

Children



	5,200	

15	0.0042	6,000

1 Turf Transferable Residue Postapplication day (µg/cm2)= Application
rate of fluopicolide (lb ai/A) x Fraction of ai Transferable from the
Foliage x (1- Fraction of Residue

 That Dissipates Daily, 0.1) Postapplication day x  4.54E+8  µg/lb x
2.47E-8 A/cm2 x  0.04 (to adjust for amount of BAM, based on plant
metabolism data)

2 Daily Dermal Dose = (Turf transferable Residue (µg/cm2) x Absorption
Factor (1) x Dermal Transfer Coefficient (cm2/hr) x Exposure Time (2
hrs/day) x 0.001 mg/µg] / [Body Weight (kg)]

3 Dermal MOE = Dermal NOAEL / Daily Dermal Dose; where
Short-/Intermediate-term NOAEL = 25 mg/kg/day.

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



Application Rate

 (lb ai/A)	

Post-application day (t)	

Fraction of ai Transferable from the Foliage	

Turf Transferable Residue 1

(µg/cm2)	

Hand Surface Area 

(cm2/event)	

Saliva Extraction Factor 	

 Frequency

(events/ hr)	

Body Weight

(kg)	

 Daily Dose2

(mg/kg/day)

	

Oral MOE3









	Short-/ 

Int-term



0.27	

0	

0.05	

0.0060	

20	

50%	

20	

15	0.00016	87,000

1 Turf Transferable Residue Postapplication day (µg/cm2)= Application
rate of fluopicolide (lb ai/A) x Fraction of ai Transferable from the
Foliage x (1- Fraction of Residue That Dissipates Daily, 0.1)
Postapplication day x  4.54E+8  µg/lb x 2.47E-8 A/cm2 x  0.04 (to
adjust for amount of BAM, based on plant metabolism data)

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

3 Oral MOE = Oral NOAEL/Daily Dose; where Short-/Intermediate-term NOAEL
= 14 mg/kg/day.

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



Application Rate

 (lb ai/A)	

Post-

application day 

(t)	

Fraction of ai Transferable from the Foliage	

Grass/Object

Residue 1

(µg/cm2)	

Ingestion Rate

(cm2/day)	

Body 

Weight

(kg)	

 Daily Dose2

(mg/kg/day)	

Oral MOE3







	Short-/

Int-term



0.27	

0	

0.29	

0.035	

25	

15	0.000058	240,000

1Grass/Object residue Postapplication day (µg/cm2) = Application rate
of fluopicolide (lb ai/A) x Fraction of ai Transferable from the Foliage
(from MRID#: 46708641) x (1- Fraction of Residue That Dissipates Daily)
Postapplication day x  4.54E+8  µg/lb x 2.47E-8 A/cm2 x  0.04 (to
adjust for amount of BAM, based on plant metabolism data)

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

3Oral MOE = Oral NOAEL / Daily Dose; where Short-/Intermediate-term
NOAEL = 14 mg/kg/day.



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

Application Rate

 (lb ai/A)	

Fraction of ai Retained in the Soil	

Soil

Residue 1

(µg/g)	

Ingestion Rate

(mg/day)	

Body 

Weight

(kg)	

 Daily Dose2

(mg/kg/day)	

Oral MOE3







Short-/ Intermediate-term



0.27	1	

0.81	

100	15	0.0000054	2,600,000

1 Soil residue Postapplication day zero (µg/cm2) = Application rate of
fluopicolide (lb ai/A) x Fraction of ai Retained on the Soil x (4.54E+8
µg/lb x 2.47E-8 A/cm2 x 0.67 cm3/g soil x  0.4 (to adjust for amount of
BAM, based on soil metabolism data)

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

3 Oral MOE = Oral NOAEL/Daily Dose; where Short-/Intermediate-term NOAEL
= 14 mg/kg/day.

Table 6.2.5.  Aggregate Exposure and Risk Estimates from Residential
Lawns



Scenario 

and 

Pathway	

TTR/GR/SR0 (µg/cm2 or g) 1	

PDR0-norm

(mg/kg/day) 2	

Short-/ Int-Term

 MOE 3	

Total MOE 4





Short-/

Int-Term

Adult’s Scenarios



(1) Dermal Postapplication	0.0060	0.0025	10,000	N/A

Children’s Scenarios – All Postapplication



(1) Dermal 	0.0060	0.0042	6,000	N/A



(2) Hand-to-Mouth	0.0060	0.00016	87,000	62,000



(3) Mouthing Grass/Object	0.035	0.000058	240,000

	

(4) Soil Ingestion	0.81	0.0000054	2,600,000

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

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

3 MOE = NOAEL/PDR; 

	where Short-/Intermediate-term Dermal NOAEL = 25 mg/kg/day, and
Incidental Oral NOAEL = 14 mg/kg/day.

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

N/A = not applicable.

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

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

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

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

7.0	Aggregate Risk Assessments and Risk Characterization  TC \l1 "7.0
Aggregate Risk Assessments and Risk Characterization 

Two products containing fluopicolide (i.e., V-10161 VPP Fungicide and
V-10162 VPP Fungicide) are proposed for application to residential
turfgrass and recreational sites.  The use pattern for dichlobenil is
not expected to result in significant residential exposure.  Therefore,
the non-dietary BAM exposure estimates are based on fluopicolide use
only. 

There is a potential for short-/intermediate-term non-occupational
exposure to BAM during postapplication activities.  Chronic exposure is
not expected for the proposed use patterns associated with fluopicolide.


7.1	Acute Aggregate Risk TC \l2 "7.1	Acute Aggregate Risk 

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

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

Short-term exposures (1 to 30 days of continuous exposure) may occur as
a result of activities on treated turf.  Incidental oral exposures
related to turf activities (Table 6.2.5) have been combined with chronic
dietary exposure estimates (as an estimated of background dietary
exposure; Table 5.2.2) to assess short-term aggregate exposure. Since
aggregate MOEs in Table 7.2 are greater than 1000, they represent risk
estimates that are below HED’s level of concern.



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


(1/MOE Approach – All LOCs Identical)



Population	Short- or Intermediate-Term Scenario

	NOAEL

mg/kg/day	LOC1 

	Max Allowable

Exposure2

mg/kg/day	Average

Food & Water

Exposure

mg/kg/day	Residential Exposure3

mg/kg/day	Aggregate MOE

(food and

residential)4

General U.S. Population	14	1000	0.014	0.001351	NA	NA

All Infants (<1 year old)	14	1000	0.014	0.004193	0.0002234	3200

Children 1-2 years old	14	1000	0.014	0.002379	0.0002234	5400

Children 3-5 years old	14	1000	0.014	0.002075	0.0002234	6100

Children 6-12 years old	14	1000	0.014	0.001356	0.0002234	8900

Youth 13-19 years old	14	1000	0.014	0.000965	NA	NA

Adults 20-49 years old	14	1000	0.014	0.001221	NA	NA

Adults 50+ years old	14	1000	0.014	0.001309	NA	NA

Females 13-49 years old	14	1000	0.014	0.001220	NA	NA

1 UFA  = 10x (extrapolation from animal to human (interspecies); UFH =
10x potential variation in sensitivity among members of the human
population (intraspecies); FQPA SF = 10x.  10 x 10 x 10 = 1000.

2 Maximum Allowable Exposure (mg/kg/day) = NOAEL/LOC = 14 mg/kg/day ÷
1000 = 0.014 mg/kg/day.

3 Residential Exposure = Incidental oral exposure, calculated by adding
PDR values (for hand-to-mouth, mouthing grass/object, and soil
ingestion) as shown in Table 6.2.5 above.  Residential exposures were
calculated for children only (15 mg bw).

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

7.3	Intermediate-Term Aggregate Risk  TC \l2 "7.3	Intermediate-Term
Aggregate Risk  

The intermediate-term aggregate risk is the same as described above for
the short-term aggregate risk; the intermediate-term aggregate risk is
below HED’s level of concern for the U.S. population and all
population subgroups.  

 

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

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

As noted above, EPA has assumed that BAM’s potential for
carcinogenicity is similar to that of  dichlobenil, which is classified
as “Group C, possible human carcinogen” with the RfD approach
utilized for quantification of human risk.  The quantification of cancer
risk using the RfD approach is identical to the assessment for chronic
effects; no separate carcinogenic risk assessment is necessary.

8.0	Cumulative Risk Assessments and Risk Characterization  TC \l1 "8.0
Aggregate Risk Assessments and Risk Characterization 

Unlike 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 BAM and any other substances and BAM
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 BAM 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/. 

Fluopicolide and dichlobenil can form the common metabolite BAM.  To
establish new tolerances for fluopicolide, EPA conducted this human
health risk assessment for exposure to BAM resulting from the use of
current and proposed uses of fluopicolide and the herbicide dichlobenil.
 The risk assessment is conservative in terms of potential dietary and
non-dietary exposures.  In addition, the Agency retained the additional
10X FQPA safety factor for the protection of infants and children.  The
assessment includes evaluations of risks for various subgroups,
including those composed of infants and children. 

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

Occupational and Residential Risk Assessment of Metabolite BAM (to
Support Request for Registration of Fluopicolide on a Variety of Crops,
Residential Turf and Ornamentals), DP #345920, K. O’Rourke, 10/9/07

9.1	Short-/Intermediate-/Long-Term/Cancer (if needed) Handler Risk  TC
\l2 "9.1	Short-/Intermediate-/Long-Term/Cancer (if needed) Handler Risk 

Occupational handler exposure was not evaluated because the metabolite
BAM is believed to form slowly in plants and soil after the product
containing the parent (fluopicolide) has been applied. 

9.2	Short-/Intermediate-/Long-Term/Cancer (if needed) Postapplication
Risk  TC \l2 "9.2	Short-/Intermediate-/Long-Term/Cancer (if needed)
Postapplication Risk 

The registration action for fluopicolide involves application to
agricultural crops as well as turf and ornamentals.  Postapplication
inhalation exposure is expected to be negligible, however, dermal
exposure to the metabolite BAM is possible for workers: entering treated
areas to tend or harvest crops, mow/maintain turfgrass, or tend
ornamentals in nurseries and greenhouses.  A dislodgeable foliar residue
(DFR) study on fluopicolide was submitted by the registrant (MRID#:
46708641) for use in assessing postapplication activities.  As discussed
in the fluopicolide assessment (K. O’Rourke, DP #326082, 10/9/07),
this study is considered to be acceptable, and the results indicate that
the initial dislodgeable residue of fluopicolide is 29% of the
application rate.  The data were considered applicable to residue
estimation for agricultural crops and ornamentals.  A turf transferable
residue (TTR) study was not available.  Therefore, turf scenario
calculations were based on the standard turf residue assumption of 5% of
the application rate for the initial transferable residue for
fluopicolide.

In order to adjust these estimates to reflect BAM residues, which were
not measured in the DFR study, data from plant metabolism studies were
considered.  Grape, lettuce, and potato metabolism data indicate that
the majority of total radioactive residue (TRR) was located on the
surface of foliage and fruit samples (DP #327026, A. Acierto, 8/20/07). 
The parent fluopicolide was the primary residue identified in grape
fruit, lettuce leaves, and potato foliage and tubers, accounting for
51-98% TRR.  The metabolite BAM was found in foliarly-treated grapes
(fruit),  lettuce leaves, and potato foliage at <4% TRR.  Although BAM
was found at higher percentages in lettuce which had received soil
drench application (17-20% TRR) and potato tubers (12-26% TRR), the
actual concentration was lower than BAM occurring on grapes (fruit),
lettuce leaves, and potato foliage.  For the purposes of this
postapplication exposure assessment, it was conservatively assumed that
the surface residues of BAM are dislodgeable/transferable, and that they
are present at 4% of the initial amount of parent fluopicolide.  

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

Postapplication MOEs are typically estimated for “Day 0" exposure
(i.e., the day of application).  As shown in Table 9.2, the
short-/intermediate-term MOEs for BAM are greater than the LOC of 100 on
the day of application for all agricultural, turf and ornamental uses of
fluopicolide, and are not of concern.  

The fluopicolide technical material has been classified in Toxicity
Categories III-IV for acute dermal and primary skin irritation, and
Category III for primary eye irritation.  Per the Worker Protection
Standard (WPS), a 12-hr restricted entry interval (REI) is required for
chemicals classified under Toxicity Category III/IV.  The proposed
fluopicolide labels indicate an REI of 12 hrs, which is in compliance
with the WPS for uses that reach an MOE of 100 on the day of
application.  Fluopicolide is also intended for non-agricultural use
sites (e.g., golf course) to which the WPS does not apply; the labels
appropriately contain language cautioning unprotected persons to keep
out of treated areas until sprays have dried.  

Table 9.2.  Summary of Estimated Post-application MOEs for Agricultural
Crops

Crop	Application Rate

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

(μg/cm2)	TC 4

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

Term MOE 5

Agricultural Crops

Fruiting Vegetables	0.13	0	0.017	500	Irrigation, scouting, thinning,
weeding immature plants	26,000





700	Irrigation and scouting mature plants	18,000





1,000	Hand harvesting, pruning, staking, tying	13,000

Cucurbit & Leafy Vegetables

0	0.017	500	Irrigation, scouting, thinning, weeding immature plants
26,000





1,500	Irrigation, scouting, weeding mature plants	8,600





2,500	Hand harvesting, pulling, pruning, and thinning mature plants
5,200

Grapes

0	0.017	500	Hedging, irrigation, scouting, hand weeding	26,000





1,000	Scouting	13,000





5,000	Hand harvest, leaf pulling, thinning, pruning, training/tying
2,600





10,000	Girdling and cane turning	1,300

Sweet Potatoes

0	0.017	300	Irrigation, scouting, thinning, weeding immature plants
43,000





1,500	Irrigation and scouting mature plants	8,600





2,500	Hand harvesting	5,200

Turf

Turf	0.27	0	0.0060	

3,400	Mowing and other maintenance activities	11,000







6,800	Sod harvesting and transplanting	5,300

Ornamentals – Nursery Stock

Nursery Stock	0.54	0	0.070	100	Hand pruning containerized ornamentals
31,000





400	Harvesting, ball/burlap containerized ornamentals	7,800

Ornamentals – Cut Flowers

Cut Flowers	0.54	0	0.070	500	Pinching	6,200





5,100	Hand harvesting, pruning, thinning, pinching	610

1 Maximum application rate from proposed fluopicolide labels.

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

3 DFR or TTR (µg/cm2) = dislodgeable foliar residues (for agricultural
crops and ornamentals) corresponding to DAT, based on results from a
fluopicolide-specific DFR study (MRID 46708641) or turf transferable
residue based on the standard assumption for turf.  Plant metabolism
data were used to adjust residues for amount of BAM.

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

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

   Daily Dose = [(TTR or DFR x  TC x 100% Dermal absorption  x  8-hr
Exposure Time)] / [(CF: 1000 µg/mg) x (70-kg Body Weight)]

   Short-/intermediate-term NOAEL = 25 mg/kg/day.  The LOC is 100.10.0
Data Needs and Label Recommendations  TC \l1 "10.0	Data Needs and Label
Recommendations 

10.1	Toxicology  TC \l2 "10.1	Toxicology 

None.

10.2	Residue Chemistry  TC \l2 "10.2	Residue Chemistry 

Refer to the Fluopicolide Risk Assessment Document, DP #325091 (N. Dodd,
11/21/07).

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

None.

References:  TC \l1 "References: 

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

2,6-Dichlorobenzamide (BAM) as a Metabolite of Fluopicolide and
Dichlobenil.  Acute and Chronic Aggregate Dietary (Food and Drinking
Water) Exposure and Risk Assessments for the Section 3 Registration
Actions for Fluopicolide on Tuberous and Corm Vegetables, Leafy
Vegetables (except Brassica), Fruiting Vegetables, Cucurbit Vegetables,
and Grapes, and for Indirect or Inadvertent Residues on the Rotational
Crop Wheat, DP Number 340366, N. Dodd, 11/21/07.

Occupational and Residential Risk Assessment of Metabolite BAM (to
Support Request for Registration of Fluopicolide on a Variety of Crops,
Residential Turf and Ornamentals), DP #345920, K. O’Rourke, 10/9/07.

Drinking Water Assessment for the BAM (2,6-Dichlorobenzamide) Degradate
of Dichlobenil, DP #340773, J. Angier, Ph.D., 8/29/07.

Drinking Water Exposure Assessment for Fluopicolide Uses on Grapes,
Vegetables, Potatoes, Sugar Beet, Onion, and Turf – Exposure of
2,6-Dichlorobenzamide (BAM), DP #325804, J. Lin, 5/3/07.

Appendix A:  Toxicity Profile Table and Executive Summaries/Published
Abstracts   TC \l1 " Appendix A:  Toxicity Profile Table and Executive
Summaries/Published Abstracts  

Table 3.1a.  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	LD50 ≥ 1538/1144 mg/kg
(M/F)	III

870.1100/Acute oral toxicity (rat)	46708602	LD50 ≥ 2000  mg/kg (M) and
 LD50 ≥300 mg/kg (F)	II

a According to Reregistration Eligibility Decision (1998)

Table 3.1b.  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/Guideline	

NOAEL = 14 mg/kg/day  

LOAEL = 49 mg/kg/day based on decreased body weight gain (M) and reduced
skeletal muscle tone (M&F)



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/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/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) 

Unacceptable/Guideline due to lack of individual animal data	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.)

cus production) observed at ≥25 mg/kg/day (reversible); degeneration
of olfactory epithelium and necrosis of Bowman’s glands observed at
100 mg/kg/day (sustained)

870.5100

In vitro bacterial reverse mutation (Ames test)	

43003603 (1992)

At concentrations up to 5000 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); clinical signs worsened with increasing
dose



870.5550

In vitro Unscheduled DNA synthesis (rat hepatocytes)	

43003604 (1993)

g/ml

Acceptable/Guideline	

Negative.



BAM

90-day rat

In a 13-week oral toxicity study (MRID 00067654), 2,6-dichlorobenzamide
technical (dichlobenil soil metabolite) (batch # 133/2/4/104; purity not
reported) was administered to 10 Wistar rats/sex/dose in the diet at
dose levels of 0, 50, 180, 600, or 2300 ppm (equal to 0, 4, 14, 49, or
172 mg/kg bw/day).

There were no treatment-related effects on survival.  Increased
relaxation scores (muscle hypotonus; P<0.05) were observed at 600 ppm on
day 4 only in males and on days 91 and 92 only in females (Table 1).  At
2300 ppm, increases in relaxation scores (P<0.05) were observed at each
measurement in both sexes.  Mean terminal body weights were decreased in
both males (18%) and females (11%) at 2300 ppm, relative to controls. 
Mean body weight gain in males treated at 2300 ppm was decreased by 30%
(P=0.01) during weeks 2-11, while food consumption in the same group was
decreased by 16% (P=0.01).  In females, mean body weight gain was
decreased by 18% (P=0.01) after 11 weeks at 600 ppm and by 30% (P=0.01)
at 2300 ppm.  Food consumption was decreased by 17% (P=0.01) at 2300 ppm
only.  

No treatment-related changes were observed in hematological or
urinalysis parameters.  A 19% (P=0.02) decrease in mean blood
coagulation time in males at 2300 ppm was not considered clinically
significant and was also not dose-dependent.  Mean serum urea
concentration in males was increased by 55% (P<0.001) after 6 weeks at
2300 ppm.  After 12 weeks in males, mean serum urea concentration was
increased by 53% (P=0.04) at 600 ppm and by 69% (P=0.04) at 2300 ppm. 
In the absence of histopathological correlates in the kidney or liver,
increased urea concentrations were not considered toxicologically
significant.  No biologically significant changes in clinical chemistry
were observed in females.  There was also no difference in
bromosulphthalein serum retention (measure of liver function) between
control and high-dose animals.

Mean absolute thymus, heart, and brain weights were decreased in males
by 28% (P=0.01), 21% (P=0.01), and 7% (P=0.01), resp., while mean
absolute spleen, thymus, and heart weights were decreased in females by
13% (P=0.05), 23% (P=0.01), and 9% (P=0.01), resp.  However, there was
no difference in mean relative weights for these organs in either sex,
and the differences from control are likely related to the observed
decreases in body weight.  For these reasons and because
histopathological correlates were lacking in these organs, the changes
in organ weights were not considered toxicologically significant.

The LOAEL for males is 600 ppm (49 mg/kg/day), based on reduced skeletal
muscle tone (males and females) and decreased body weight gain
(females).  The NOAEL is 180 ppm (14 mg/kg/day).

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

Chronic Toxicity/Carcinogenicity (Rat)

In a combined chronic toxicity/carcinogenicity study (MRID 42940202,
44052901), 2,6-dichlorobenzamide (dichlobenil soil metabolite) (99.5%;
batch# 195) was administered in the diet for 106 weeks to Crl:CD®BR
rats (35/sex/dose) at daily dose levels of 0, 60, 100, 180, or 500 ppm
(equal to 0, 2.2, 3.6, 6.5, or 19 mg/kg/day in males and 0, 2.8, 4.7,
8.5, or 25 mg/kg/day in females).  No treatment-related mortality or
clinical signs of toxicity were observed.

Body weight, relative to controls, at 500 ppm was decreased by 13%
(P<0.05) in males at termination and by 10-21% in females from week 13
until the end of the study.  At 180 ppm, body weight in females was
decreased by 13% at termination only.  At 500 ppm, mean body weight gain
was decreased by 10-16% in males and by 16-26% in females from on or
after week 26.  Body weight gain in females treated at 180 ppm was also
decreased by 10-17% during the second half of the study.  No
treatment-related differences in food consumption or food efficiency
were observed during the study.  Ophthalmological findings were similar
between the control and high-dose groups.

Mean hematocrit levels were decreased in males at 500 ppm by 4% (week
39) and 11% (week 103).  Decreases were also observed in females at 180
ppm (9%, week 26) and at 500 ppm (7%, week 52).  Mean hemoglobin
concentration (Hb) was decreased by 3% (week 26), 8% (week 39), 7% (week
52), and 9% (week 103) at 500 ppm.  A decrease (6%) in females was
observed at 180 ppm during week 26 only.  Mean erythrocyte counts were
decreased in males at 180 ppm (6%, week 40) and at 500 ppm (9%, week 26;
7%, week 39).  In females, the same parameter was decreased at 500 ppm
by 5% (week 26).  Last, mean corpuscular hemoglobin concentration was
also decreased by 3% at 500 ppm in females at week 103.  Although
statistically significant, the magnitude of change in the hematological
parameters was not biologically significant.  No treatment-related
changes were observed in clinical chemistry or urinalysis measurements. 

A 25% increases in mean relative liver weight was observed at 500 ppm in
females, as was a 48% increase in mean relative adrenal weight.  The
increase in liver weight was considered toxicologically significant due
to the presence of liver histopathology at 500 ppm.  No
treatment-related changes were observed at necropsy.

Non-neoplastic histopathological observations in the liver are
summarized in Tables 1 and 2.  Dose-dependence was lacking for several
parameters measured in the liver (Table 1).  An increase in
“moderate” fat deposition was observed at 500 ppm in females (14/35
vs. 6/26); however, the incidence of “marked” fat deposition (more
severe) was higher at 60 ppm than at 500 ppm.  In addition, the reported
incidences of fat deposition are unreliable, because the sum of the
number of animals with and without fat deposition at each dose is less
than the number of animals examined per dose.  Upon reanalysis of
non-neoplastic liver findings (MRID 44043601), increases in the
incidences of eosinophilic (focal) hepatocytes (21/34 vs. 5/26; P<0.01)
and centrilobular hepatocytic vacuolation (16/34 vs. 5/26; P<0.05) were
observed in males at 500 ppm (Table 2).  The increase in eosinophilic
(focal) staining hepatocytes at 100 ppm (P<0.01) was not considered
toxicologically significant, since the incidence at the next highest
dose (180 ppm) was not statistically significant.  In females, an
increase in the incidence of eosinophilic hepatocytes (focal) was
observed at 180 ppm (16/32 vs. 5/25; P<0.05) and 500 ppm (23/35 vs.
5/25; P<0.01).  Increases were also observed at 500 ppm in the
incidences of focal basophilic hepatocytes (23/35 vs. 9/25; P<0.05) and
eosinophilic (diffuse) hepatocytes (18/35 vs. 2/25; P<0.01).  No
treatment-related histopathological effects were observed in any other
examined organ.

The LOAEL is 500 ppm (19 mg/kg/day) in males, based on decreased body
weight and body weight gain and an increased incidence of hepatocellular
alteration (eosinophilic foci); and 180 ppm (8.5 mg/kg/day) in females,
based on decreased body weight and body weight gain and an increased
incidence of hepatocellular alteration (eosinophilic foci).  The NOAEL
is 180 ppm (6.5 mg/kg/day) in males and 100 ppm (4.7 mg/kg/day) in
females.

Upon re-analysis of the tumor data (MRID 44043601), a marginally
significant increase (P=0.049) in the incidence of hepatocellular
adenomas was observed in females at 500 ppm (Table 3).  No
hepatocellular carcinomas were observed in female rats, and neither
adenomas nor carcinomas were observed in males.  Dosing was considered
adequate at 500 ppm, based on decreased body weight and body weight gain
and increased incidence of hepatocellular alteration in both sexes.

This combined chronic toxicity/carcinogenicity study in the rat is
Acceptable/Guideline and does satisfy the guideline requirement for a
combined chronic toxicity/carcinogenicity study in mammals [OPPTS
870.4300; OECD 453].

2-year dog

In a 2-year toxicity study (MRID 42940203), 2, 6-dichlorobenzamide
(dichlobenil soil metabolite) (97% a.i.; batch # 133-2-4-104) was
administered in the diet to Beagle dogs (4/sex/dose) at daily dose
levels of 0, 60, 100, 180, or 500 ppm (equal to 0, 1.5, 2.5, 4.5, or
12.5 mg/kg/day).  No animals died during the study, and it was reported
that there were no treatment-related clinical signs of toxicity.  Mean
body weight in males treated at 500 ppm was decreased (non-stat. sig.)
at weeks 54 (14%) and 103 (12%), while in females mean body weight was
decreased (P<0.01) at weeks 14 (12%), 54 (21%), and 103 (23%) at 500
ppm, relative to controls.  Mean cumulative body weight gains (week
0-103) in males were 19% and 38% lower than control values at 180 and
500 ppm, resp.  However, neither was statistically significantly
different from controls (Table 1).  Similarly, in females, mean
cumulative body weight gains at 100, 180, and 500 ppm were 27%, 32%, and
69% lower than control values, respectively, without statistical
significance.  Changes in body weight or body weight gain at ≤180 ppm
were not considered toxicologically significant based on the wide
variation in these measured parameters (Tables 1 and 2).  No adverse
effects were observed on hematological or clinical chemistry parameters,
at necropsy, or on organ weights.  Microscopic pathology was not
observed as a function of dose.

The LOAEL is 500 ppm (12.5 mg/kg/day), based on decreased body weight
and body weight gain.  The NOAEL is 180 ppm (4.5 mg/kg/day).

This chronic toxicity study in the dog is Acceptable/Guideline and does
satisfy the guideline requirement for a chronic toxicity study in
non-rodents (OPPTS 870.4100; OECD 452).

3-gen. repro. (rat)

The following executive summary provides an overview of the submitted
results of a 3-generation reproduction study (MRID 42940204), but for
which individual animal data were not submitted.  BAM
(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.

Mean weanling weights (calculated as entire litter weight divided by
number of pups per litter) at 180 ppm were decreased by 15% (P<0.05),
12% (P<0.05), and 14% (P<0.01) in the F1b, F3a, and F3b generations,
respectively (Table 1); however, the decreases were not dose-dependent,
not observed in the F2 generation, and not calculated from individual
pup body weights.  No treatment-related differences were observed in
mean absolute brain weights or mean brain-to-body weight ratios in F3b
generation weanling rats of either sex.  A 12% increase in mean absolute
kidney weights and mean kidney-to-body weight ratios (P<0.01) was
observed in F3b generation female weanlings at 180 ppm.  A 10% increase
in mean absolute liver weights and mean liver-to-body weight ratios
(P<0.05) in males at 180 ppm and at ≥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).

This study in the rat is Unacceptable/Guideline and does not satisfy the
guideline requirement for a 2-generation reproduction study in mammals
(OPPTS 870.3800; OECD 416).  Individual animal data necessary to verify
summary results were not 

submitted.

Developmental tox (rabbit)

In a prenatal developmental toxicity study (MRID 43003601, 43265201),
2,6-dichlorobenzamide  (dichlobenil soil metabolite) (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, respectively.  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, respectively.  

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.  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.

This study in the rabbit is Acceptable/Guideline and does satisfy the
guideline requirement for a prenatal developmental toxicity study in
non-rodents (OPPTS 870.3700; OECD  414).

Acute (i.p.) (mouse)

The toxic effects of the herbicide chlorthiamid
(2,6-dichlorothiobenzamide) and its major environmental metabolite
2,6-dichlorobenzamide (DCBA) were examined in the nasal passages of
C57Bl mice following single ip injections. Chlorthiamid (12.25, and 50
mg/kg) induced an extensive destruction of the olfactory region, similar
to that previously observed with the analogue dichlobenil
(2,6-dichlorobenzonitrile). Necrosis of Bowman's glands was evident
first, whereas degeneration and necrosis of the olfactory
neuroepithelium developed less rapidly. The lesions were most severe in
the dorsomedial region of the nasal cavity. At longer post-treatment
intervals, the olfactory epithelium was replaced by a respiratory-like
epithelium, and there was fibrosis of the lamina propria. DCBA was also
toxic to the olfactory region (100 mg/kg), inducing necrosis of the
Bowman's glands and the neuroepithelium in the dorsomedial region of the
nasal cavity. No lesions were observed in other parts of the nasal
cavity or in the liver after administration of chlorthiamid or DCBA.
Chlorthiamid (IC50 = 51 microM), but not DCBA, inhibited the covalent
binding of 14C-labeled dichlobenil in the olfactory mucosa in vitro. It
is proposed that the toxic effects of chlorthiamid and dichlobenil in
the olfactory mucosa are mediated by common or closely related
metabolites.

Genotoxicity

870.5100

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.



Dichlobenil

5-day dermal (mouse)

2,6-Dichlorobenzonitrile (dichlobenil) is an herbicide which has
previously been reported by other investigators to be toxic to the
olfactory mucosa following intraperitoneal administration. The objective
of this study was to determine whether a more occupationally-relevant
route of pesticide exposure, namely dermal exposure to dichlobenil, also
resulted in olfactory system damage. Male C57Bl mice were clipped and
administered 0-200 mg/kg dichlobenil dermally in acetone either as a
single dose or for five consecutive days. In addition, olfactory bulb
glial fibrillary acidic protein (GFAP) analysis was performed in order
to determine whether the damage in the olfactory mucosa translated into
damage which could be measured as an astroglial increase in GFAP
concentration in the olfactory bulb, a marker of central nervous system
neuronal loss. Olfactory mucosal histology revealed that single or
multiple exposures to 50, 100, 150 and 200 mg/kg dichlobenil dermally
caused olfactory epithelial damage (primarily sensory cell loss) in the
epithelium lining the dorsal medial meatus of the nasal cavity. While
the olfactory epithelial lesions were much less severe than those caused
by i.p. administration of dichlobenil, GFAP was significantly elevated
in both the 150 and 200 mg/kg treatment groups, demonstrating that
relatively minor damage to a portion of the olfactory mucosa in the
nasal cavity can be detected in the central nervous system.

7/28-day inhalation (rat)

In a subchronic inhalation toxicity study (MRID 46398701),
Sprague-Dawley rats (10/sex/concentration) were exposed by nose-only
inhalation to Dichlobenil technical (98.1% a.i., Lot/Batch #: BFI-4138)
as a dust aerosol at concentrations of 0, 2.3, 5.1, or 12 mg/m3
(equivalent to 0, 0.0023, 0.0051, and 0.012 mg/L, respectively) for 6
hours/day, 5 days/week for 4 weeks.

There were no treatment-related effects on survival, clinical
observations, FOB, motor activity, body weights, body weight gains, food
consumption, ophthalmoscopy, hematology, clinical chemistry, organ
weights, gross pathology, or histopathology in either sex at any
concentration.

The LOAEL was not observed in this study, and the investigators did not
test to the limit concentration (2 mg/L).  However, the 7-day
range-finding study (MRID 46653001) indicated that toxicity occurred at
21 mg/m3 based on trace to mild nasal degeneration in males and females.
The nasal effects are considered adverse rather than adaptive since the
nasal tissue has been determined to be a target by routes of exposure
other than inhalation.

 

The LOAEL is 21 mg/m3 (equivalent to 5.5 mg/kg/day) based on increased
incidence of nasal degeneration (from the 7 day study).  The NOAEL is 12
mg/m3 (equivalent to 3.1 mg/kg/day), the highest concentration tested.

At the request of the Agency, this study was conducted for a duration of
28 days, instead of the 90 days required by Guideline OPPTS 870.3465. 
Aside from the different study duration, this study was conducted in
accordance with Guideline OPPTS 870.3465.

This 28-day study is classified as Acceptable/Guideline and does satisfy
the guideline requirement (OPPTS 870.3465; OECD 413) for a subchronic
inhalation study in the rat.

Appendix B:  Metabolism Assessment  TC \l1 "Appendix B:  Metabolism
Assessment 

B.1	Metabolism Guidance and Considerations TC \l2 "B.1	Metabolism
Guidance and Considerations 

BAM is a metabolite and/or environmental degradate of both fluopicolide
and dichlobenil.  

BAM is included in the tolerance expression for dichlobenil because it
is a major metabolite/degradate of dichlobenil.

BAM is a minor metabolite of fluopicolide.  The tolerance expression for
plants will include fluopicolide (parent) as an indicator of combined
residues of fluopicolide and BAM.  HED determined that BAM should be
included as a residue of concern for the risk assessment for the
proposed uses of fluopicolide on the primary domestic plants [cucurbit
vegetables, fruiting vegetables, grapes, leafy vegetables, and tuberous
and corm vegetables (except potato)].  

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



B.2	Chemical Names and Structures  TC \l2 "B.2	Chemical Names and
Structures 

Appendix I.  Chemical Names and Structures 

Common name/code	Chemical name	Chemical structure

Dichlobenil	2,6-dichlorobenzonitrile	



Fluopicolide

AE C638206
2,6-dichloro-N-[[3-chloro-5-(trifluoromethyl-2-pyridinyl]methyl]benzamid
e 	

AE C653711

BAM	2,6-dichlorobenzamide	

AE C657188

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

AE 1344122

P1X	3-methylsulfinyl-5-trifluoromethylpyridine-2-carboxylic acid	

 

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on data from studies in which adult human subjects were intentionally
exposed to a pesticide or other chemical.  These studies, listed below,
have been determined to require a review of their ethical conduct.  They
are also subject to review by the Human Studies Review Board.  The
listed studies have received the appropriate review.

The PHED Task Force, 1995.  The Pesticide Handlers Exposure Database,
Version 1.1.  Task Force members Health Canada, U.S. Environmental
Protection Agency, and the National Agricultural Chemicals Association,
released February, 1995.

   HYPERLINK
"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itoo
l=pubmed_Abstract&term=%22Solecki+R%22%5BAuthor%5D" \o "Click to search
for citations by this author."  Solecki R ,   HYPERLINK
"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itoo
l=pubmed_Abstract&term=%22Burgin+H%22%5BAuthor%5D" \o "Click to search
for citations by this author."  Burgin H ,   HYPERLINK
"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itoo
l=pubmed_Abstract&term=%22Buschmann+J%22%5BAuthor%5D" \o "Click to
search for citations by this author."  Buschmann J  et al. 2001.
Harmonisation of rat fetal skeletal terminology and classification.
Report of the Third Workshop on the Terminology in Developmental
Toxicology. Berlin, 14-16 September 2000.   HYPERLINK
"javascript:AL_get(this,%20'jour',%20'Reprod%20Toxicol.');"  Reprod
Toxicol  15(6):713-21.

 Calculated as follows: Dose (mg/kg bw/day) = (Concentration of a.i. in
ppm) x (1 ppm ÷ 0.075 mg/kg bw/day)

   HYPERLINK
"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itoo
l=pubmed_Abstract&term=%22Solecki+R%22%5BAuthor%5D" \o "Click to search
for citations by this author."  Solecki R ,   HYPERLINK
"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itoo
l=pubmed_Abstract&term=%22Burgin+H%22%5BAuthor%5D" \o "Click to search
for citations by this author."  Burgin H ,   HYPERLINK
"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itoo
l=pubmed_Abstract&term=%22Buschmann+J%22%5BAuthor%5D" \o "Click to
search for citations by this author."  Buschmann J  et al. 2001.
Harmonisation of rat fetal skeletal terminology and classification.
Report of the Third Workshop on the Terminology in Developmental
Toxicology. Berlin, 14-16 September 2000.   HYPERLINK
"javascript:AL_get(this,%20'jour',%20'Reprod%20Toxicol.');"  Reprod
Toxicol  15(6):713-21.

   HYPERLINK
"http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&T
ermToSearch=1916084&ordinalpos=2&itool=EntrezSystem2.PEntrez.Pubmed.Pubm
ed_ResultsPanel.Pubmed_RVDocSum"  Brittebo EB, Eriksson C, Feil V, Bakke
J, Brandt I.  (1991). Toxicity of 2,6-dichlorothiobenzamide
(chlorthiamid) and 2,6-dichlorobenzamide in the olfactory nasal mucosa
of mice. Fundam Appl Toxicol 17(1):92-102.

   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.

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