Document ID: EPA-HQ-OPP-2007-0604-0004
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2008-08-27T04:00Z

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460      

	OFFICE OF PREVENTION, PESTICIDE

                                                                        
                   AND TOXIC SUBSTANCES

	

  SEQ CHAPTER \h \r 1 MEMORANDUM

Date:  11/JUN/2008

SUBJECT:	Dichlobenil; Human Health Risk Assessment for Proposed Uses on
Rhubarb; Caneberry, Subgroup 13-07A; and Bushberry, Subgroup 13-07B.    

 

PC Code:  027401, 027402	DP Barcode:   341453

Decision No.: 380110	Registration No.: 400-168

Petition No.: 7E7230	Regulatory Action: Section 3 Registration

Risk Assessment Type:  Single                                           
                 Chemical/Aggregate	Case No.:  NA

TXR No.:  NA	CAS No.: 70852-53-8

MRID No.:  NA	40 CFR:  40 CFR §180.231

	         									

FROM:	Debra Rate, Ph.D., Biologist

		Mark Dow, Ph.D., Biologist

		Alternative Risk Integration and Assessment (ARIA) Team

		Risk Integration, Minor Use and Emergency Response Branch (RIMUERB)

		Registration Division (RD) (7505P)

			AND 

		Robert Mitkus, Ph.D., Toxicologist

		Registration Action Branch 1

		Health Effects Division (HED) (7509P)

		

THROUGH:	William Cutchin, Senior Acting Branch Scientist

		ARIA/RIMUERB/RD (7505P)

			George F. Kramer, Ph.D., Senior Chemist

			RAB1/HED(7509P)

			AND

Dana Vogel, Branch Chief

			RAB1/HED(7509P)

		

TO:	Susan Stanton, Environmental Specialist

	IR-4 Team/RIMUERB/RD (7505P)

This human health risk assessment is for dichlobenil (parent only). 
This assessment summarizes the human health risks from exposure to
dichlobenil on agricultural commodities, turf, and ornamentals.  The
human heath risks from exposure to 2,6-dichlorobenzamide (BAM) the
common metabolite/degradate of dichlobenil and fluopicolide is assessed
in separate Agency memorandums (DP Num: 345918, N. Dodd, 21/NOV/2007; DP
Num: 349864, F. Fort, 19/MAR/2008).  The residue chemistry assessment
was provided by W. Cutchin (ARIA) and D. Rate (ARIA), the occupational
and residential exposure assessment by M. Dow (ARIA), the hazard
characterization by R. Mitkus (RAB1), and the dietary exposure and risk
assessment by D. Rate (ARIA).  



Table of Contents

  TOC \o "1-3" \h \z \u  1.0	Executive Summary	5

2.0	Ingredient Profile	9

2.1	Summary of Registered/Proposed Uses	9

2.2	Structure and Nomenclature	9

2.3	Physical and Chemical Properties	10

3.0	Hazard Characterization/Assessment	11

3.1	  Hazard and Dose-Response Characterization	11

3.1.1	Studies Considered in the Toxicity and Dose-Response Evaluation	11

3.1.2	 Sufficiency of Studies/Data	11

3.1.3	 Mammalian Toxicology	11

3.2	Adsorption, Distribution, Metabolism, Excretion (ADME)	13

3.3	FQPA Considerations	14

3.3.1	  Adequacy of the Toxicity Data Base	14

3.3.2	 Developmental Toxicity Studies	14

3.3.3	 Reproductive Toxicity Study	16

3.3.4	 Evidence of Neurotoxicity	17

3.3.5	 Additional Information from DEREK Analysis	17

3.3.6	 FQPA Safety Factor (SF) for Infants and Children	18

3.4	  Hazard Identification and Toxicity Endpoint Selection	19

3.4.1	 aRfD - Females age 13-49	20

3.4.2	 aRfD - General Population	20

3.4.3	 cRfD	20

3.4.4	 Incidental Oral Exposure (Short- and Intermediate-Term)	21

3.4.5	 Dermal Absorption	21

3.4.6	Dermal Exposure (Short-, Intermediate-, and Long-Term)	21

3.4.7 	Inhalation Exposure (Short-, Intermediate-, and Long-Term)	21

3.4.8	Level of Concern for Margin of Exposure	21

3.4.9	  Recommendation for Aggregate Exposure Risk Assessments	22

3.5	Classification of Carcinogenic Potential	22

3.6	Endocrine disruption	22

4.0	Public Health and Pesticide Epidemiology Data	23

5.0	Dietary Exposure/Risk Characterization	23

            5.1       Pesticide Metabolism and Environmental Degradation
23

5.1.1	Metabolism in Primary Crops	23

5.1.2	Metabolism in Rotational Crops	23

5.1.3	Metabolism in Livestock	23

5.1.4	Analytical Methodology	24

5.1.5	Environmental Degradation	24

5.1.6	Comparative Metabolic Profile	24

5.1.7	Toxicity Profile of Major Metabolites and Degradates	25

5.1.8	Pesticide Metabolites and Degradates of Concern	25

5.1.9	Drinking Water Residue Profile	26

5.1.10	Food Residue Profile	26

5.1.11	International Residue Limits.	29

5.2	Dietary Exposure and Risk	29

5.2.1	Acute Dietary Exposure/Risk	29

5.2.2	Chronic Dietary Exposure/Risk	30

5.2.3	Cancer Dietary Risk	30

5.2.4	Anticipated Residue and Percent Crop Treated (%CT) Information	31

6.0	Residential (Non-Occupational) Exposure/Risk Characterization)	31

7.0	Aggregate Risk Assessments and Risk Characterization	31

7.1	Acute Aggregate Risk	31

7.2	Long-Term Aggregate Risk	31

8.0	Cumulative Risk Characterization/Assessment	32

9.0	Occupational Exposure/Risk Pathway	32

9.1	Handler Risk	32

9.2	Postapplication Risk	33

9.3	Restricted Entry Interval (REI)	34

10.0	 Data Needs and Label Requirements	34

10.1	Toxicology	34

10.2	Residue Chemistry	34

10.3	Occupational and Residential Exposure	34

References:	35

Appendix A:  Toxicity Profile Tables	37

Appendix B:  Tolerance Reassessment Summary and Table	42

Appendix C:  Review of Human Research	43

 

1.0	Executive Summary  XE "1.0	Executive Summary"  

Dichlobenil is a selective herbicide registered for use on cranberry
bogs, ornamentals, fruit orchards, vineyards, and right-of-ways to
control weeds, and in sewers to control roots.  Dichlobenil is a nitrile
herbicide that acts by inhibiting germination of actively dividing
meristems and acts primarily on growing points and root tips.  

A major metabolite of dichlobenil is 2,6-dichlorobenzamide (BAM).  BAM
appears to form slowly in plants and soil and is the major residue
detected in plants following dichlobenil use, and therefore, is a
residue of concern for dietary exposure.  BAM is also a major metabolite
of the active ingredient fluopicolide.  However, because BAM has a
toxicity profile that is different from dichlobenil, only exposure and
risk associated with dichlobenil is evaluated in this document, while
exposure and risk associated with BAM from both dichlobenil and
fluopicolide uses are assessed in separate memoranda (DP Num: 349864, F.
Fort, 19/MAR/2008; DP Num: 354590, D. Rate, in process; DP Num: 352656,
M. Manibusan, 12/MAY/2008).  The toxicological database for dichlobenil
includes studies performed with dichlobenil and studies performed with
BAM.  Since BAM is the major residue in plants and is consumed in the
food supply, it was necessary to perform toxicological studies on BAM,
as well as dichlobenil.  Although some uncertainty remains surrounding
olfactory toxicity following oral exposure of dichlobenil, the
toxicological database on dichlobenil is adequate for risk assessment.

This human health risk assessment addresses only the residues of
dichlobenil (parent only) due to current uses and proposed uses of
dichlobenil on rhubarb, caneberries, and bushberries.  General
information from the recent risk assessment for BAM from both
fluopicolide and dichlobenil uses may be mentioned below when
appropriate; however, for more details refer to the specific risk
assessment (DP Num: 354590, D. Rate, in process; DP Num: 352656, M.
Manibusan, 12/MAY/2008).

Use Profile:  Dichlobenil is registered as a granular (G) formulation
(Casoron® 4G; EPA Reg. No. 400-168; date of issuance: 18/MAY/2005) 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 uses on rhubarb at 2 lb
ai/A/season, caneberry, subgroup 13-07A at 4 lb ai/A/season, and
bushberry, subgroup 13-07B at 6 lb ai/A/season are pending (DP Num:
315266, W. Cutchin, 22/FEB/2006; DP Num: 349398, D. Rate, 12/MAR/2008). 

Tolerances are established (40 CFR §180.231) for the herbicide
dichlobenil (2,6-dichlorobenzonitrile) and BAM as follows.  Tolerances
for rhubarb, caneberry, subgroup 13-07A and bushberry, subgroup 13-07B
are 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 

Caneberry, Subgroup 13-07A	0.10 ppm 

Bushberry, Subgroup 13-07B	0.15 ppm 

Human Health Risk Assessment for Dichlobenil:

Toxicity/Hazard:  Appropriate endpoints were identified for acute
dietary, chronic dietary, incidental oral, dermal, and inhalation
exposures for both dichlobenil and BAM.  The endpoints for BAM are
discussed in detail in a previous Agency memo (DP Num: 349864, F. Fort,
19/MAR/2008; DP Num: 354590, D. Rate, in process; DP Num: 352656, M.
Manibusan, 12/MAY/2008).  The identified endpoints for dichlobenil are
as follows:

An endpoint of concern (effect) attributable to a single dose was not
identified in the database.  Therefore, quantification of acute risk to
general population, including infants and children, is not required.

The acute dietary no-observed adverse-effect level (NOAEL) is 45
mg/kg/day (females 13-49).  The lowest-observed adverse-effect level
(LOAEL) is 135 mg/kg/day based on a developmental toxicity (rabbit)
study. 

The chronic dietary NOAEL is 1 mg/kg/day.  The LOAEL is 6 mg/kg/day
based on a chronic toxicity (dog) study.  

The inhalation (short-, intermediate-, and long-term) NOAEL is 3.1
mg/kg/day.  The LOAEL is 5.5 mg/kg/day based on a 28-day inhalation
study in rat.  

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 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.  

The 10X Food Quality Protection Act (FQPA) safety factor (SF) has been
retained for prechronic oral exposure scenarios.  This is due to the
incompleteness of the database with regard to the potential of
dichlobenil to induce olfactory toxicity following prechronic oral
exposure.  For dermal and inhalation exposure scenarios, the FQPA SF for
dichlobenil toxicity has been reduced to 1X.  This is because the
endpoints for these exposure scenarios are based on a very sensitive
measure (olfactory histopathology), which is protective of any potential
adverse effect on the function of the sense of smell.  The endpoint is
therefore considered conservative.

Relating to the carcinogenic potential of dichlobenil, dichlobenil is
classified as a Group C chemical (possible human carcinogen).  The HIARC
determined that cancer dietary risk concerns due to long-term
consumption of dichlobenil residues are adequately addressed by the
chronic dietary exposure analysis using the reference dose; therefore, a
separate cancer dietary exposure analysis was not performed.

Dietary Exposure (Food and Drinking Water):  The dietary analyses were
performed on dichlobenil to support new Section 3 registration requests
for use of dichlobenil on rhubarb, caneberry, subgroup 13-07A, and
bushberry, subgroup 13-07B.  The dietary exposure assessment was
conducted for residues of dichlobenil (parent only) in food and drinking
water.  The estimated drinking water concentrations (EDWCs) for
dichlobenil residues used in the acute and the chronic dietary analyses
were 0.298 ppm and 0.0046 ppm, respectively.  The EDWCs were estimated
by the Pesticide Root Zone Mode/Exposure Analysis Modeling System
(PRZM/EXAMS) models.  These numbers were modeled from the use of
dichlobenil on turf in Florida.  

An acute endpoint was selected for only one population subgroup, females
13-49 years.  The acute dietary (food and drinking water) exposure to
dichlobenil is below the Agency’s level of concern for the population
subgroup, females 13-49 years.  The acute dietary exposure estimate for
this population subgroup at the 95th percentile of the exposure
distribution is 33% of the acute Population-Adjusted Dose (aPAD).  

The chronic dietary (food and drinking water) exposure to dichlobenil is
below the Agency’s level of concern for the general U.S. population
and all population subgroups.  The chronic dietary exposure estimates
are 5% chronic Population-Adjusted Dose (cPAD) for the general U.S.
population and 30% of the cPAD for the highest exposed population
subgroup (children 1-2 years).

Residential Exposure:  There are no residential use sites among the
proposed new uses.  There are several registered products which contain
dichlobenil that may be used around roses and other woody ornamentals in
established residential plantings.  However, dichlobenil may not be used
on residential lawns and turf.  Post-application exposure to residential
ornamental plantings is expected to be negligible and therefore was not
assessed.  Because these products are labeled for professional
applicator use only, post-application exposure is not expected.  

Aggregate Risk:  The acute aggregate risk for dichlobenil is composed of
exposures to dichlobenil residues in food and drinking water and is
equivalent to the acute dietary risk.  The acute dietary exposure
estimate at the 95th percentile of the exposure distribution is 33% of
the aPAD for females 13-49 years.  The acute risk estimates are well
below the level of concern.   

The chronic aggregate risk for dichlobenil is composed of chronic
exposures expected from dichlobenil residues in food and drinking water.
 Therefore, the chronic aggregate risk is equivalent to the chronic
dietary risk.  The chronic risk estimates are below the Agency’s level
of concern (<100% of the cPAD) for the general U.S. population and all
population subgroups.

With respect to cancer risk, HED classified dichlobenil as a Group C
chemical (possible human carcinogen).  The HIARC determined that cancer
dietary risk concerns due to long-term consumption of dichlobenil
residues are adequately addressed by the chronic dietary exposure
analysis using the reference dose; therefore, a separate cancer dietary
exposure analysis was not performed.

Occupational Exposure/Risk:  Based upon the proposed use patterns, the
most highly exposed occupational pesticide handlers are expected to be
loaders performing open-pour loading of granules and applicators using
open-cab tractors pulling broadcast granular spreaders.  Using the
proposed use patterns and label directed personal protective equipment
(PPE), the assessed margin of exposures (MOEs) for occupational
pesticide handlers is well below the level of concern (MOE>100).

Due to the recommended timing of application and to the method of
application, ARIA expects any occupational, post-application exposure to
be negligible.  Since it is a granular formulation applied essentially
during "dormant" times, foliar dislodgeable residue exposure is not
expected.  Therefore, a post-application exposure assessment was not
conducted herein.  

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.epa.gov/compliance/resources/policies/ej/exec_order_12898.pd
f" 
http://www.epa.gov/compliance/resources/policies/ej/exec_order_12898.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), ARIA and
HED estimate 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 C) 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.

Regulatory Recommendations and Data Deficiencies:  

Toxicology:  There are no toxicology data gaps that need to be
fulfilled.  

Residue Chemistry:  Provided an updated Section F, Section B and label
are received, ARIA recommends for the establishment of a tolerance for
dichlobenil residues in/on rhubarb at 0.06 ppm, caneberries at 0.10 ppm,
and bushberries at 0.15 ppm.  The revised Section F must be submitted to
account for tolerance and commodity definition recommendations.  The
label is adequate to allow evaluation of the residue data relative to
the proposed uses on rhubarb and caneberry, subgroup 13-07A; however,
the label should be revised for the bushberry, subgroup 13-07B from 4
lbs ai/A to 6 lbs ai/A to match the Section B proposed use and submitted
data for the bushberry, subgroup 13-07B commodities.  Also, the label
and Section B must be revised to correctly spell the commodities
containing “currant” in the name.  

Occupational/Residential:  The proposed label lists an REI of 12 hours. 
Due to the Acute Toxicity Category for dermal and inhalation toxicity,
the interim worker protection standard (WPS) REI should be 24 hours.  

2.0	Ingredient Profile  XE "2.0	Ingredient Profile"  

2.1	Summary of Registered/Proposed Uses  XE "2.1	Summary of
Registered/Proposed Uses"  

Dichlobenil is registered as a granular (G) formulation (Casoron® 4G;
EPA Reg. No. 400-168; date of issuance: 18/MAY/2005) 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 Num: 315266, W. Cutchin, 22/FEB/2006; DP Num: 349398, D.
Rate, 12/MAR/2008; DP Num: 353491, D. Rate, 10/JUN/2008).

2.2	Structure and Nomenclature  XE "2.2	Structure and Nomenclature"  

Table 2.2a.  Dichlobenil Nomenclature.

Compound	Chemical Structure

                                       

Common name	dichlobenil

Company experimental name	DCBN

IUPAC name	2,6-dichlorobenzonitrile

CAS name	2,6-dichlorobenzonitrile

CAS #	1194-65-6

End-use product/(EP)	Casoron® 4G (EPA Reg. No. 400-168)

Table 2.2b.  BAM Nomenclature.

Chemical Structure	

Empirical Formula	C7H5Cl2NO

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  XE "2.3	Physical and Chemical
Properties"  

Table 2.3a.  Physicochemical Properties of Dichlobenil.  

Parameter	Value	Reference

Melting point/range	145°C	RED Chapter, 6/29/95 

pH	NA

	Density	1.3 g/cm3	IPS Inchem, 4/05

Water solubility ( 25°C)	0.0021g/100mL	RED Chapter, 6/29/95

Solvent solubility (g/100mL at 25°C)	xylene 5.3 

ethanol 1.5 

cyclohexane 0.37   

	Vapor pressure at 20°C	5.5 x 10-4 mmHg	IPS Inchem, 4/05

Dissociation constant (pKa)	NA

	Octanol/water partition coefficient Log(KOW)	2.64	IPS Inchem, 4/05

UV/visible absorption spectrum	NA

	

Table 2.3b. Physiochemical Properties of BAM.

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

	

3.0	Hazard Characterization/Assessment  XE "3.0	 Hazard
Characterization/Assessment"   	 Hazard Characterization/Assessment" 
Error! Bookmark not defined. 

3.1		Hazard and Dose-Response Characterization  XE "3.1	 	Hazard and
Dose-Response Characterization"  

Studies Considered in the Toxicity and Dose-Response Evaluation  XE
"Studies Considered in the Toxicity and Dose-Response Evaluation"   

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

Acute (for olfactory toxicity): Two intraperitoneal (single dose)
toxicity studies (mouse, rat) and one subcutaneous (single dose)
toxicity study (mouse)

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

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

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

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

3.1.2		Sufficiency of Studies/Data  XE "3.1.2		Sufficiency of
Studies/Data"  

The available submitted acute, subchronic, and chronic studies were
sufficient to evaluate human hazard potential, and data quality is
acceptable.  Dichlobenil-mediated olfactory toxicity was observed
following dermal (Deamer et al. 1994), inhalation (Guideline study), and
intraperitoneal (i.p.) (Brandt et al. 1990; Eriksson and Britebo 1995)
animal exposures.

3.1.3		Mammalian Toxicology  XE "3.1.3		Mammalian Toxicology"  

	

Dichlobenil is a systemic herbicide that inhibits cellulose biosynthesis
in plants, thereby leading to alteration of cell wall structure and
function (Sabba et al. 1999).  Dichlobenil is primarily converted to
2,6-dichlorobenzamide (BAM) in the soil by way of microbial degradation
and is then taken up by the roots of exposed plants (Verloop 1972). 
Dichlobenil technical demonstrated moderate acute toxicity (Category II
or III) via the oral, dermal, and inhalation routes.  It is neither a
dermal irritant (Category IV), eye irritant (Category IV), nor a dermal
sensitizer (Table A.1 in Appendix A).

A summary of the prechronic and chronic toxicity and genotoxicity
databases for dichlobenil is found in Table A.2 in Appendix A.  In the
subchronic and chronic oral toxicity studies in hamsters, rats, and
dogs, liver toxicity was the adverse effect most often observed at the
LOAEL.  For example, in a 90-day oral toxicity study in rats,
inflammation and necrosis were observed in the liver of males, and
increased liver weight and liver histopathology (swelling and
vacuolation of hepatocytes) were observed in females.  In a 90-day oral
toxicity study in hamsters, increased liver weight, enlarged liver (with
rough surface), and swollen hepatocytes were observed in females.  In
addition, decreased weight of the prostate and mineralization of the
prostate were reported in males.  Increased liver weights and hepatic
enzymes, as well as liver histopathology, were observed at lower doses
in both chronic dog toxicity studies, as well as in the combined chronic
toxicity/carcinogenicity study in the rat.  In addition to the liver,
the nose is considered a target organ for dichlobenil.  Olfactory
toxicity was observed following dermal and inhalation exposures in
toxicity studies that were either published in the open literature
(dermal) or submitted to the Agency (inhalation).  In each study,
degeneration of the olfactory epithelium was observed.  Olfactory
toxicity was not observed in the chronic oral (capsule) toxicity study
in the dog.

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

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

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

HED concluded that overall there was no evidence of increased
susceptibility to offspring following pre-natal exposure to rats or
rabbits in developmental toxicity studies.  Evidence of increased
pre-/post-natal susceptibility was observed in the two-generation
reproduction study in rats.  However, the degree of concern for this
susceptibility is low, since the NOAEL from this study is six times
lower than the dose (LOAEL) at which adverse effects (decreased pup body
weight) were observed, and is therefore protective.

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

3.2		Absorption, Distribution, Metabolism, Excretion (ADME)  XE "3.2	
Absorption, Distribution, Metabolism, Excretion (ADME)"    XE "3.2	
Absorption, Distribution, Metabolism, Excretion (ADME)"  

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

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

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

No metabolism or absorption studies are available for dichlobenil via
the dermal or inhalation routes.

3.3		FQPA Considerations  XE "3.3		FQPA Considerations"  

3.3.1	 	Adequacy of the Toxicity Data Base  XE "3.3.1	 	Adequacy of the
Toxicity Data Base"  

The toxicology database used to assess pre- and/or post-natal exposure
to dichlobenil is adequate.  The following acceptable studies are
available:

One developmental toxicity study in rats

One developmental toxicity study in rabbits

One two-generation reproduction study in rats

3.3.2		Developmental Toxicity Studies  XE "3.3.2		Developmental Toxicity
Studies"  

Rat

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

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

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

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

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

Rabbit

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

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

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

The developmental LOAEL is 135 mg/kg bw/day, based on increased number
of total resorptions/dam and post-implantation loss; and increased
incidences of external (cleft palate, adactyly, bilateral open eye),
visceral (abnormal cystic gallbladder, distended ureter with bilateral
severe hydronephrosis), and skeletal (malformed and malpositioned right
scapula, right radius absent with malpositioned ulna and humerus, fused
cervical vertebral arches, asymmetrically ossified and fused cervical
vertebra centra, abnormally shaped cranium with enlarged and misshapen
fontanelle, enlarged fontanelle, misshapen frontals, skull and frontals
foreshortened and nasal malpositioned, and major fusion of sternebrae)
anomalies.  The developmental NOAEL is 45 mg/kg bw/day.

3.3.3		Reproductive Toxicity Study  XE "3.3.3		Reproductive Toxicity
Study"  

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

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

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

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

3.3.4		Evidence of Neurotoxicity  XE "3.3.4		Evidence of Neurotoxicity" 

Olfactory toxicity was observed following dermal, inhalation, and i.p.
exposures to dichlobenil in five toxicity studies that were either
published in the open literature (one dermal, two i.p. studies) or
submitted to the Agency (two inhalation, including range-finding,
studies).  In each study, degeneration of the olfactory epithelium,
which is composed of olfactory sensory neurons, was observed.

3.3.5		Additional Information from DEREK Analysis  XE "3.3.5		Additional
Information from Literature and Derek Analysis"  

DP Num: 352656, M. Manibusan, 12/MAY/2008

Dichlobenil and fluopicolide are pesticides that share a common
metabolite and/or environmental degradate, BAM.  Based on rat metabolism
studies, BAM is not formed in vivo (<0.09% of the total administered
dose in rats); therefore, it has been assumed that neither toxicological
profiles for dichlobenil or fluopicolide would be reflective of the
toxicity specific for BAM.  Derek analysis focuses on structural
similarities of BAM and parent chemicals (dichlobenil and fluopicolide)
to determine whether relative toxicity predictions would be different
based on structural alerts.

Comparative Toxicity:

Overall, Derek is confirmatory of the animal data for fluopicolide and
dichlobenil, which forms the basis for the toxicity prediction for BAM. 
Based on the available animal data and Derek analyses, BAM does not
appear to cause different organ-specific toxicities compared to the
parent compounds, fluopicolide and dichlobenil.  The kidney and liver
toxicities are common to all three compounds.  With respect to relative
toxicity, conclusions from the evaluation of the animal studies appear
to confirm that both fluopicolide and dichlobenil appear to be more or
equally toxic to BAM.  Based on the Derek evaluation, Derek did not
appear to distinguish fluopicolide toxicity compared to BAM based on
alerts issued only for the benzamide (BAM) portion of the structure,
indicating that the remaining pyridine structure would not contribute
significant biological activity.  Derek also confirms the liver toxicity
profile and slight to minimal kidney effects evident in the empirical
data for all three compounds.

Olfactory Toxicity:

Olfactory toxicity has also been demonstrated after dermal, inhalation,
and i.p. exposure of dichlobenil to rodents and i.p administration of
BAM (Brandt et al. 1990; Brittebo et al. 1991; Eriksson and Brittebo
1995, Deamer et al. 1994).  There were no olfactory effects reported
following exposure to fluopicolide.

All three compounds are structurally similar based on sharing the
2,6-chlorinated benzene structure; the 2,6-positioning of chlorines in
combination with an electron-withdrawing group in the primary position
of the benzene ring is an arrangement that appears to facilitate
olfactory mucosal toxicity (Carlsson et al. 2004).  Based on this
structural rule, the nitrile group on the dichlobenil is a better
electron withdrawing group than the amide group on BAM, which is equal
or less than the pyridine group on fluopicolide.  This ranking is
reflective of the potency of olfactory toxicity exhibited in the animal
studies (dichlobenil>BAM>fluopicolide).

While the olfactory effects are relevant for i.p., inhalation and dermal
routes of exposure to dichlobenil and BAM, these effects may not be
directly relevant for the oral route.  No oral studies, to date, have
reported olfactory toxicity for these compounds.  However, olfactory
toxicity was assayed in only one study submitted to the Agency for
dichlobenil and none for BAM.  The chronic dietary dog study on
dichlobenil that assayed for olfactory histopathology did not observe
effects on the nasal epithelium from long term exposure.  Therefore,
based on the different routes of exposure and the negative long term
oral study in the dog, these data indicate that olfactory effects may
only occur when by-passing the liver metabolism.  

3.3.6		FQPA Safety Factor (SF) for Infants and Children  XE "3.3.6		FQPA
Safety Factor (SF) for Infants and Children"  

There was no evidence of increased prenatal susceptibility in the
developmental toxicity studies in rats or rabbits.  In the rat
developmental toxicity study, no developmental effects were observed at
the highest dose tested; maternal toxicity was observed at the mid dose.
 In the rabbit developmental toxicity study, an increase in total
resorptions/dam, post-implantation loss, as well as external, visceral,
and skeletal anomalies were observed at the high dose.  However,
maternal toxicity (decreased body weight gain and food consumption) was
also observed at the high dose.  Evidence of increased pre-/post-natal
susceptibility was observed in the two-generation reproduction study in
rats.  In this study, toxicologically significant decreases in body
weight gain (premating and gestation) and food consumption (premating)
were observed at the high dose in both parental and F1 generation
adults.  However, decreased body weight was observed during weaning in
both F1 (16-23%) and F2 (19-22%) generation pups at the next lower (mid)
dose.  HED considers the concern for increased susceptibility to
offspring following pre-/post-natal exposure to dichlobenil to be low. 
The Agency proposes to regulate potential incidental oral exposure by
using the NOAEL from the two-generation reproduction study in rats.  HED
is confident in this NOAEL, which is six times lower than the dose
(LOAEL) at which decreased pup body weight was observed in the
two-generation reproduction study in rats.

The risk assessment team recommends that the 10X FQPA SF be retained for
prechronic oral exposure scenarios.  This is due to the incompleteness
of the database with regard to the potential of dichlobenil to induce
olfactory toxicity following prechronic oral exposure.  For dermal and
inhalation exposure scenarios, the risk assessment team recommends that
the FQPA SF for dichlobenil toxicity be reduced to 1X.  This is because
the endpoints for these exposure scenarios are based on a very sensitive
measure (olfactory histopathology) and it is unknown whether olfactory
histopathology would have an adverse effect on the function of the sense
of smell.  The endpoint is therefore considered conservative.

3.4	  Hazard Identification and Toxicity Endpoint Selection  XE "3.4	 
Hazard Identification and Toxicity Endpoint Selection"  

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

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

mg/kg/day	UFA = 10X

UFH = 10X

FQPA SF4 = 10X

(includes UFDB = 10X)

(UF = 1000)	aRfD = NOAEL

                  UF

aRfD = aPAD = 0.045 mg/kg/day

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

Chronic Dietary (All populations)	NOAEL = 1

mg/kg/day	UFA = 10X

UFH = 10X

FQPA SF = 1X

(UF = 100)	cRfD = NOAEL

                  UF

cRfD = cPAD = 0.01 mg/kg/day	Chronic toxicity (dog) LOAEL = 6 mg/kg/day
based on increased liver weights and increased serum cholesterol,
triglycerides, phospholipids, and alkaline phosphatase (M&F) and
increased serum γ-GT and periportal hypertrophy of hepatocytes (M);
olfactory histopathology was assayed and not observed in this study.

Incidental Oral

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

mg/kg/day	UFA = 10X

UFH = 10X

FQPA SF4 = 10X

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

Dermal

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

mg/kg/day	UFA = 10X

UFH = 10X

FQPA SF = 1X	Residential and Occupational LOC for MOE = 100	5-day dermal
(mouse; literature study 1) LOAEL = 50 mg/kg/day based on olfactory
epithelial damage.

Inhalation

Short-, Intermediate-, and Long-Term (1-30 days, 1-6 months, and >6
months)	NOAEL = 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 (rat) LOAEL = 5.5 mg/kg/day 3 based on nasal
degeneration.

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

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

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

2 Calculated as follows: [(NOAEL) x (m3 / 1000 L) x (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 10X FQPA SF has been retained in the form of a UFDB for the lack
of olfactory toxicity data following prechronic oral exposure to
dichlobenil.

3.4.1		aRfD - Females age 13-49  XE "3.4.1		aRfD - Females age 13-49"  

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

3.4.2		aRfD - General Population  XE "3.4.2		aRfD - General Population" 
  XE "3.4.2		aRfD - General Population"  

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

3.4.3		cRfD  XE "3.4.3		cRfD"  

-glutamyl transferase levels and periportal hypertrophy of
hepatocytes in males.  The NOAEL of 1 mg/kg is the lowest in the
database.  In addition, the study duration is appropriate for the
duration of exposure.  Because olfactory toxicity was assayed (and not
observed) in dogs in this study, the FQPA SF has been reduced to 1X.

3.4.4		Incidental Oral Exposure (Short- and Intermediate-Term)  XE
"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
observed during weaning in both generations at 17.5 mg/kg/day in the
two-generation reproduction study in rats.  The study length is
appropriate for the durations of exposure, namely, 1-30 days
(short-term) and 1-6 months (intermediate-term); and the NOAEL of 3
mg/kg/day is protective of the population of concern, namely, infants
and children.  The 10X FQPA SF has been retained in the form of a UFDB
for this exposure scenario to account for the lack of olfactory toxicity
data following subchronic oral exposure to dichlobenil.

3.4.5		Dermal Absorption  XE "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) is being used for
dermal risk assessment, estimation of dermal absorption is not
necessary.  

3.4.6	Dermal Exposure (Short-, Intermediate-, and Long-Term)  XE "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 mice
(Deamer et al. 1994).  The route of exposure of this study is ideal for
these dermal exposure scenarios.  The FQPA SF has been reduced to 1X
since a very sensitive dermal endpoint, olfactory toxicity, was measured
and observed in the study.

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

The 28-day inhalation toxicity study in the rat was chosen for the
short-, intermediate-, and long-term inhalation exposure scenarios.  The
effect of concern that is relevant to the selection of short-,
intermediate, and long-term inhalation endpoints is nasal degeneration
observed at 5.5 mg/kg/day (NOAEL = 3.1 mg/kg/day) in this study.  The
route of exposure of this study is ideal for these exposure scenarios. 
The FQPA SF has been reduced to 1X since a very sensitive endpoint,
olfactory toxicity, was measured and observed in the study.

3.4.8	Level of Concern for Margin of Exposure  XE "3.4.8	Level of
Concern for Margin of Exposure (Dichlobenil and BAM)"  

The target 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	NA

Dermal	100	100	100

Inhalation	100	100	100

3.4.9	  Recommendation for Aggregate Exposure Risk Assessments  XE
"3.4.9	  Recommendation for Aggregate Exposure Risk Assessments"  

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

3.5	Classification of Carcinogenic Potential  XE "3.5	Classification of
Carcinogenic Potential"  

Dichlobenil was determined to be non-mutagenic in bacteria and mammalian
cells, as well as non-clastogenic in several mammalian assays (in vitro
and in vivo).  The carcinogenic potential of dichlobenil was evaluated
for the second time by the HED Carcinogenicity Peer Review Committee
(CPRC) in 1995.  In a high- dose carcinogenicity study in the hamster, a
treatment-related increase in liver adenomas and combined
adenomas/carcinomas was observed in males only at the highest dose
tested.  However, dosing was considered excessive at this dose in both
sexes, based on decreased body weight gains and severe hepatotoxicity. 
In a second carcinogenicity study performed in hamsters at lower doses,
no treatment-related increases in the incidence of any tumor type were
observed.  Dosing was considered adequate, based on decreased body
weight gains and hyperplasia in various tissues in both sexes.  In a
combined chronic toxicity/carcinogenicity study in the rat, a
treatment-related increase in the incidence of hepatocellular adenomas
and combined adenomas/carcinomas was observed in females only at the
highest dose tested.  Dosing was considered adequate in females, but
excessive in males, at this dose.  Based on these data, the CPRC
classified dichlobenil as a “Group C, possible human carcinogen,”
and an RfD approach to quantification of cancer risk was recommended.

3.6	Endocrine disruption  XE "3.6	Endocrine disruption"  

EPA is required under the Federal Food, Drug, and Cosmetic Act (FFDCA),
as amended by FQPA, to develop a screening program to determine whether
certain substances (including all pesticide active and other
ingredients) “may have an effect in humans that is similar to an
effect produced by a naturally occurring estrogen, or other such
endocrine effects as the Administrator may designate.”  Following
recommendations of its Endocrine Disruptor and Testing Advisory
Committee (EDSTAC), EPA determined that there was a scientific basis for
including, as part of the program, the androgen and thyroid hormone
systems, in addition to the estrogen hormone system.  EPA also adopted
EDSTAC’s recommendation that the Program include evaluations of
potential effects in wildlife. For pesticide chemicals, EPA will use the
Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) and, to the
extent that effects in wildlife may help determine whether a substance
may have an effect in humans, FFDCA authority to require the wildlife
evaluations.  As the science develops and resources allow, screening of
additional hormone systems may be added to the Endocrine Disruptor
Screening Program (EDSP).  When additional appropriate screening and/or
testing protocols being considered under the Agency’s EDSP have been
developed, dichlobenil may be subjected to further screening and/or
testing to better characterize effects related to endocrine disruption. 

4.0	Public Health and Pesticide Epidemiology Data  XE "4.0	Public Health
and Pesticide Epidemiology Data"  

Based on the usage patterns and the lack of residential use sites, no
incident reports are expected at this time.

5.0	Dietary Exposure/Risk Characterization  XE "5.0	Dietary
Exposure/Risk Characterization"  

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

Metabolism in Primary Crops  XE "Metabolism in Primary Crops"  

The tolerance expression for dichlobenil includes the metabolite BAM
because it is the 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.”

5.1.2	Metabolism in Rotational Crops  XE "5.1.2	Metabolism in Rotational
Crops"  

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

 

5.1.3	Metabolism in Livestock  XE "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. 

5.1.4	Analytical Methodology  XE "5.1.4	Analytical Methodology"  

Plant Methods for Dichlobenil

The analytical methods SOP# Meth-83, Determination of Dichlobenil
Residues in Cherries and SOP# Meth-84, Determination of
2,6-dichlorobenzamide Residues in Cherries, developed by Morse
Laboratories were used with minor modifications for the analysis of
dichlobenil residues on rhubarb.  Dichlobenil residues were extracted
from the RAC by homogenizing the samples with ethyl acetate/hexane and
rotovaping the supernatant almost to dryness.  The residue is then
redissolved in hexane and cleaned up using a Florisil column.  The
dichlobenil residues are eluted with ethyl acetate/hexane, rotovaping
the eluant almost to dryness, and the sample redissolved in hexane for
analysis.  BAM residues were extracted from the RAC by homogenizing the
samples with ethyl acetate and taking the supernatant almost to dryness.
 The residue is then redissolved in hexane and cleaned up using a
Florisil column.  

Livestock Methods for Dichlobenil

Since there are no rhubarb animal feed items of regulatory concern, a
discussion of the livestock methods of the residue of dichlobenil is not
germane to this action.

5.1.5	Environmental Degradation  XE "5.1.5	Environmental Degradation"  

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  XE "5.1.6	Comparative Metabolic
Profile"   

In the rat, dichlobenil is readily absorbed from the gastro-intestinal
tract and is primarily excreted in the urine (65-70%).  Excretion was
95% complete in 24 hours.  Biliary excretion is responsible for 19-25%
of the dose.  Tissue residue levels were dose-dependent.  The highest
residue levels were in the liver in the rats receiving the highest dose
tested.  The results indicate that residue levels decreased with time
after dosing.  A total of nine metabolites were noted in the urine and 4
metabolites in the feces.  The major metabolites found in both urine and
feces were 2,6-dichloro-3-hydroxybenzonitrile and its sulfate conjugate;
6-chloro-3-hydroxy-2-cysteinyl-benzonitrile; and
6-chloro-2-cysteinyl-benzonitrile.  Based on the metabolites identified,
two metabolic pathways were proposed: (1) hydroxylation at the 3 or 4
position of the phenyl moiety followed by sulfation or glucoronidation
and (2) conjugation with glutathione through displacement of the
chlorine atom.  There were no significant sex-related differences.  

Studies indicate that the major residue of concern found in plants is
BAM; the parent compound (dichlobenil), was not detected.  However, BAM,
the major terminal residue in plants, was not found as a metabolite or
transitory intermediate in the ruminant or poultry studies.  Therefore,
additional animal metabolism studies in which ruminants and poultry are
dosed with [14C]BAM were conducted.  In the ruminant studies, the
primary residue found in milk, kidney, fat, and muscle was unchanged
BAM.  The major residue found in 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.  

5.1.7	Toxicity Profile of Major Metabolites and Degradates  XE "5.1.7
Toxicity Profile of Major Metabolites and Degradates"   

The metabolite/degradate of concern for dietary and exposure risk
assessments includes BAM.  BAM is a metabolite and/or environmental
degradate of both fluopicolide and dichlobenil.  The toxicity of BAM has
been recently reviewed (DP Num: 349864, F. Fort, 19/MAR/2008).  The
acute and chronic studies were sufficient to evaluate human hazard
potential.  BAM demonstrated moderate acute toxicity (Category III) via
the oral route of exposure.  Because the subchronic and chronic toxicity
of BAM is considered less than or equal to that of dichlobenil (parent
herbicide) based on submitted and published toxicity studies, the acute
toxicity of BAM via the inhalation and dermal routes is expected to be
less than or equal to that of dichlobenil.  In the case of fluopicolide,
the toxicity profile is different from that of BAM.  The cPAD (0.0045
mg/kg/day) for BAM is based on decreased body weight and decreased body
weight gain in the chronic oral toxicity study (dog).  There was no
evidence that BAM was either mutagenic or clastogenic in submitted
genotoxicity studies.  In the absence of carcinogenicity study data for
a second species, HED considers the carcinogenic potential of BAM to be
similar to that of dichlobenil, the parent compound having the greatest
carcinogenic potential.  BAM is considered to be neurotoxic.  No
evidence of endocrine modulation was observed in any study with BAM.  

5.1.8	Pesticide Metabolites and Degradates of Concern  XE "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.  

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

Matrix	Residues included in Risk Assessment	Residues included in
Tolerance Expression

Plants

	Primary Crop	Dichlobenil and BAM1	Dichlobenil and BAM

	Rotational Crop	Not Applicable	Not Applicable

Livestock

	Ruminant	Not Applicable	Not Applicable

	Poultry	Not Applicable	Not Applicable

Drinking Water

	Dicholobenil and BAM1	Not Applicable

1  Exposure and risk associated with residues of BAM have been assessed
in a separate Agency memorandum (DP Num: 349864, F. Fort, 19/MAR/2008).

5.1.9	Drinking Water Residue Profile  XE "5.1.9	Drinking Water Residue
Profile"   

Drinking Water Assessment for New Use of Dichlobenil on Rhubarb, DP Num:
322919; J. Angier; 01/NOV/2005.

Dichlobenil residues (parent only) predicted in water were incorporated
in the DEEM-FCID into the food categories “water, direct, all
sources” and “water, indirect, all sources.”  Dichlobenil is
predicted to volatilize from most surface waters; therefore, its
persistence in the surface water environment will depend primarily on
the environmental factors which control volatility rates (temperature,
wind speed, humidity, etc.).  The EDWCs for dichlobenil residues used in
the acute and the chronic dietary analyses were 0.298 ppm and 0.0046
ppm, respectively, the concentration estimated by PRZM/EXAMS models. 
PRZM/EXAMS is an empirical model for predicting pesticide levels in
surface water; the values from PRZM/EXAMS are considered conservative. 
Table 5.1.9 summarizes the drinking water concentrations of dichlbenil
(parent only) provided by EFED.  The model and its description are
available at the EPA internet site:   HYPERLINK
"http://www.epa.gov/oppefed1/models/water/" 
http://www.epa.gov/oppefed1/models/water/ .

Table 5.1.9.  EDWCs for Dichlobenil1 (parent only) in surface water.

Model Scenario	Peak (acute) Conc. in  Surface Water	1-in-10-Year Annual
Mean (Chronic) Conc. in Surface Water	30-Year Overall (Cancer) Conc. in
Surface Water

OR apple	108.75 ppb	3.724 ppb	1.953 ppb

FL turf	298.3 ppb	4.615 ppb	1.145 ppb

PA turf	78.5 ppb	2.907 ppb	1.159 ppb

1  EDWCs for BAM residues were reported and assessed in separate
documents (DP Num: 340773, J. Angier, 29/AUG/2007; DP Num: 349864, F.
Fort, 19/MAR/2008).

5.1.10	Food Residue Profile  XE "5.1.10	Food Residue Profile"   

Dichlobenil Acute and Chronic Aggregate Dietary (Food and Drinking
Water) Exposure and Risk Assessments for Section 3 Registration Action
For New Uses on Rhubarb, Caneberry, Subgroup 13-07A, and Bushberry,
Subgroup 13-07B, DP Num:346388, D. Rate, in process.

Dichlobenil.  Use on Rhubarb.  Summary of Analytical Chemistry and
Residue Data. Petition Number 2E6398, DP Num: 315266, W. Cutchin,
22/FEB/2006.

Dichlobenil.  Use on Caneberry (Subgroup 13-07) and Bushberry (Subgroup
13-07B).  Summary of Analytical Chemistry and Residue Data.  PP#7E7230,
DP Num: 349398, D. Rate, 12/MAR/2008.

Dichlobenil:  Amended: Use on Caneberry (Subgroup 13-07) and Bushberry
(Subgroup 13-07B).  Summary of Analytical Chemistry and Residue Data. 
PP#7E7230, DP Num: 349398, D. Rate, 10/JUN/2008.

2,6-Dichlobenzamide (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 and Root Vegetables (Subgroup 1A), Leaves of
Root and Tuber Vegetables (Group 2), Bulb Vegetables (Group 3), and Head
and Stem Brassica (Subgroup 5A) and Section 3 Registration Actions for
Dichlobenil on Rhubarb, Caneberries (Subgroup 13-07A), Bushberries
(Subgroup 13-07B) and Associated Berry Comodities; DP Num: 439722, S.
Piper, 19/MAR/2008.

Tolerances are currently established for residues of the herbicide
dichlobenil and BAM in/on various plant commodities, at levels ranging
from 0.1 to 0.5 ppm (as listed in 40CFR §180.231[a]).  Previously,
residue data from field trials conducted to support the existing
registrations show that, generally, residues of BAM are low, and no
dichlobenil residues were reported above the LLMV (<0.05 ppm) on the
RAC.  Assuming a dichlobenil contribution to tolerance (tolerance
residue minus maximum field trial residues of BAM) and the use of
default processing factors in the analysis is considered conservative
and will overestimate dietary exposure.  In conjunction with these new
uses, ARIA has recommended in favor of establishing tolerances on the
following commodities at the levels listed in Table 5.1.10a.  Table
5.1.10a lists the tolerance and the contribution to each tolerance from
dichlobenil and BAM, respectively. 

Table 5.1.10a.  Summary of Tolerances and Residue Contribution for
Dietary Analysis from Dichlobenil and BAM.

Commodity	Tolerance (Existing/ Recommentded)	Contribution from BAM1
(Dietary Risk)	Contribution from Dichlobenil2 (Dietary Risk)

Apples	0.5	 0.271	 0.229

Cranberry	0.1	0.03	0.07

Grapes	 0.15	0.09	0.06

Fruit, stone, Crop Group 12	 0.53	0.46	0.04

Filbert	0.1	0.02	0.08

Pear	0.5	 0.271	 0.229

Rhubarb	 0.06	0.01	0.05

Caneberry, Subgroup 13-07A	0.1	0.01	0.09

Bushberry, Subgroup 13-07B	 0.15	0.06	0.09

1  The BAM contribution to tolerance is based on maximum residues from
field trial data following the application of dichlobenil (DP Num:
340366, N. Dodd, 21/NOV/2007; DP Num: 439722, S. Piper, 19/AUG/2008).

2  Dichlobenil contribution to tolerance is calculated by subtracting
the BAM contribution from the existing or recommended tolerance.

3  Although the current established tolerance remains at 0.15 ppm, HED
recommended a tolerance of 0.5 ppm to cover stone fruit crop group based
on limited studies submitted on plums (July 31, 1996; K. Boyle; Dietary
Risk Evaluation System (DRES) )(MRID No. 42452804 and 42452801).

Magnitude of the Residue in Plants

45572201.der.doc, W. Cutchin, 22/FEB/2006

DP Num: 315266, W. Cutchin, 22/FEB/2006

DP Num: 179079, C. Olinger, 09/FEB/1993

DP Num:182600, C. Olinger, 05/MAR/1993

Rhubarb

Table 5.1.10b.  Summary of Residue Data from Crop Field Trials with
Dichlobenil.

Commodity	Total Applic. Rate

 (lb ai/A)

 (g ai/ha)	PHI (days)	Residue Levels

 (ppm)

	n	Min.	Max.	HAFT*	Median	Mean	Std. Dev.

Dichlobenil

Rhubarb	2.0

(2240)	64-83	3	<0.05	<0.05	<0.05	<0.05	<0.05	NA

BAM

Rhubarb	2.0

(2240)	64-83	3	<0.01	<0.01	<0.01	<0.01	<0.01	NA

* HAFT = Highest Average Field Trial.

Interregional Research Project No. 4 (IR-4) has submitted field trial
data for dichlobenil on rhubarb.  Three field trials were conducted in
the United States encompassing Regions XI (WA) and XII (OR [2]) during
the 1999 growing season.  No specific Regions are indicated in OPPTS
860.1500 guidelines for rhubarb.  Since Region XII accounts for 72% of
the domestic rhubarb production, the location and number of field trials
are adequate.

In each trial, dichlobenil was applied to rhubarb with a granular
applicator as a single soil surface broadcast application at 2.0 lb
ai/A.  Applications were made at pre-emergence or when the crop was just
breaking ground.  In each trial, marketable rhubarb was harvested at 64
to 83 days PHI.  The analytical methods SOP# Meth-83, Determination of
Dichlobenil Residues in Cherries and SOP# Meth-84, Determination of
2,6-dichlorobenzamide Residues in Cherries, developed by Morse
Laboratories were used with minor modifications for the analysis of
dichlobenil residues on rhubarb.  Dichlobenil residues were extracted by
homogenizing the samples with ethyl acetate/hexane and cleaned up using
a Florisil column.  The BAM residues were extracted by homogenizing the
samples with ethyl acetate and cleaned up using a Florisil column.  A
gas chromatograph with a Hall detector (electrolytic conductivity
detector) in halogen mode was used for the analysis.  Method recoveries
were 63-96% dichlobenil and 76-110% for BAM.  The lowest-level method
validation (LLMV) was reported for dichlobenil and BAM as 0.05 ppm and
0.01 ppm, respectively.  The limit of detection (LOD) was 0.006 ppm for
both dichlobenil and BAM.  No residues above the LLMV of 0.05 ppm for
dichlobenil or 0.01 ppm for BAM were found in any rhubarb sample.

Conclusions.  The crop field trials were conducted according to the
proposed use pattern.  The studies were supported by adequate storage
stability data and analytical methods suitable for data gathering
purposes.  No residues above the LLMV of 0.05 ppm for dichlobenil or
0.01 ppm for BAM were found in any rhubarb sample.  The proposed
tolerance of 0.15 ppm for dichlobenil residues is too high.  The
expected residues of dichlobenil on rhubarb when treated according to
the proposed use pattern will not exceed the combined LLMV of 0.06 ppm
for rhubarb; therefore, a tolerance at that level would be appropriate. 
ARIA recommends for the establishment of a tolerance for dichlobenil
residues on rhubarb at 0.06 ppm.  A revised Section F is required.

Because there were so few samples submitted and no residues were found
above the LLMV, no maximum residue limit (MRL) spreadsheet analysis was
conducted for this proposed use.  

Caneberry, Subgroup 13-07A and Bushberry, Subgroup 13-07B

No additional field trial data has been submitted.  The petitioner has
requested that current tolerances and previously submitted studies be
translated to include tolerances on caneberry, subgroup 13-07A, and
bushberry, subgroup 13-07B.  Previously reviewed studies indicate that
dichlobenil was not quantifiable (<0.05 ppm) in/on blueberry and
blackberry matrices.

Conclusions.  Adequate data is available to support the requested
tolerances.  ARIA recommends for the establishment of tolerances for
dichlobenil residues in/on caneberry, subgroup 13-07A at 0.10 ppm, and
bushberry, subgroup 13-07B at 0.15 ppm.  A revised Section F is
required.

5.1.11	International Residue Limits.  XE "5.1.11	International Residue
Limits."  

Dichlobenil residues of concern are parent dichlobenil and the
metabolite BAM (2,6-dichlorobenzamide) as stated in 40 CFR §180.231. 
There are no international harmonization issues associated with this
action.

5.2	Dietary Exposure and Risk  XE "5.2	Dietary Exposure and Risk"   

Dichlobenil Acute and Chronic Aggregate Dietary (Food and Drinking
Water) Exposure and Risk Assessments for Section 3 Registration Action
For New Uses on Caneberry, Subgroup 13-07A and Bushberry, Subgroup
13-07B, DP Num:346388, D. Rate, in process.

Acute and chronic dietary (food and drinking water) exposure and risk
assessments were conducted using the Dietary Exposure Evaluation Model
software with the Food Commodity Intake Database (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
dichlobenil (parent only) to support current uses and Section 3 requests
for use on rhubarb, caneberry, subgroup 13-07A, and bushberry, subgroup
13-07B.  

Dichlobenil is classified as Group C chemical (possible human
carcinogen).  The HIARC determined that cancer dietary risk concerns due
to long-term consumption of tebuconazole residues are adequately
addressed by the chronic dietary exposure analysis using the reference
dose; therefore, a separate cancer dietary exposure analysis was not
performed.

5.2.1	Acute Dietary Exposure/Risk  XE "5.2.1	Acute Dietary
Exposure/Risk"   

The acute exposure analysis was based on the following assumptions.  As
no dichlobenil residues were reported above the LLMV on raw agricultural
commodities (RACs) in the submitted studies, these assumptions will
result in conservative estimates of dietary exposure and risk: 

Dichlobenil contributions to the established or recommended tolerance
(tolerance-level residues minus maximum BAM residues) were used in the
dietary analysis for all existing and proposed RACs (see Table 5.1.10a);

DEEM 7.81 default processing factors for all processed commodities;

100% crop treated (CT); and

0.298 ppm for the dichlobenil acute EDWC (DP Num: 322919; J. Angier;
01/NOV/2005).

An acute endpoint was selected for only one population subgroup, females
13-49 years.  Typically, the Agency has concerns regarding dietary risk
when the estimates exceed 100% of the aPAD.  This subgroup had a risk
estimate below the level of concern, utilizing 33% of the aPAD at the
95th percentile of exposure.  

5.2.2	Chronic Dietary Exposure/Risk  XE "5.2.2	Chronic Dietary
Exposure/Risk"   

The chronic exposure analysis was based on the following assumptions
which result in conservative estimates of dietary exposure and risk:

Dichlobenil contributions to the established or recommended tolerance
(tolerance level residues minus maximum BAM residues) were used in the
dietary analysis for all existing and proposed RACs (see Table 5.1.10a);

DEEM 7.81 default processing factors for all processed commodities;

100% crop treated (CT); and

0.0046 ppm for the dichlobenil chronic EDWC (DP Num: 322919; J. Angier;
01/NOV/2005).

Typically, the Agency has concerns regarding dietary risk when the
estimates exceed 100% of the cPAD.  The general US population and all
population subgroups had risk estimates below the level of concern.  The
most highly exposed population subgroup (children 1-2 years) utilizes
30% of the cPAD, while the general US population utilizes 5% of the
cPAD. 

5.2.3	Cancer Dietary Risk  XE "5.2.3	Cancer Dietary Risk"  

The HED Cancer Peer Review Committee classified dichlobenil as a Group C
chemical (possible human carcinogen).  The HIARC determined that cancer
dietary risk concerns due to long-term consumption of dichlobenil
residues are adequately addressed by the chronic dietary exposure
analysis using the reference dose; therefore, a separate cancer dietary
exposure analysis was not performed.

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

Population Subgroup 1

[Years of Age]	

DEEM Acute Dietary Analysis,

95th Percentile	

DEEM Chronic Dietary Analysis

	

aPAD (mg/kg)	

Exposure (mg/kg/day)	

% aPAD	

cPAD (mg/kg/day)	

Exposure (mg/kg/day)	

% cPAD

General US Population	

NA 2 	

0.01	

0.000484	

5

All Infants [<1]

0.01	

0.002425	

24

Children [1-2]

0.01	

0.003000	

30

Children [3-5]

0.01	

0.001815	

18

Children [6-12]

0.01	

0.000657	

7

Youths [13-19]

0.01	

0.000270	

3

Adults [20-49]

0.01	

0.000235	

2

Adults [50+]

0.01	

0.000270	

3

Females [13-49]	

0.045	

0.014744	

33	

0.01	

0.000258	

3

1 Values for the population with the highest risk for each type of risk
assessment are bolded.  

2 NA = Not Applicable; no acute dietary endpoint was identified for
these population subgroups.  

5.2.4	Anticipated Residue and Percent Crop Treated (%CT) Information  XE
"5.2.4	Anticipated Residue and Percent Crop Treated (%CT) Information"  

No anticipated residues and 100% CT were utilized in the analyses of
dichlobenil.  

6.0	Residential (Non-Occupational) Exposure/Risk Characterization)  XE
"6.0	Residential (Non-Occupational) Exposure/Risk Characterization)"  

There are no residential use sites among the proposed new uses.  There
are several products which contain dichlobenil that may be used around
roses and other woody ornamentals in established residential plantings. 
However, dichlobenil may not be used on residential lawns and turf, and
these products are labeled for professional applicator use only. 
Post-application exposure to residential ornamental plantings is
expected to be negligible and therefore was not assessed.  

7.0	Aggregate Risk Assessments and Risk Characterization  XE "7.0
Aggregate Risk Assessments and Risk Characterization"  

The use pattern for dichlobenil is not expected to result in significant
residential exposure.  

7.1	Acute Aggregate Risk  XE "7.1	Acute Aggregate Risk"  

In the case of dichlobenil, the acute aggregate risk is composed of
exposures to Dichlobenil 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 the level of
concern for the population subgroup, females 13-49 years.

7.2	Long-Term Aggregate Risk  XE "7.2	Long-Term Aggregate Risk"    

In the case of dichlobenil, the chronic aggregate risk is composed of
exposures to dichlobenil 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 the level of
concern for the general U.S. population and all population subgroups.

As noted above, dichlobenil 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 and was not assessed.

8.0	Cumulative Risk Characterization/Assessment  XE "8.0	Cumulative Risk
Characterization/Assessment"  

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 dichlobenil, though, dichlobenil
does produce a metabolite (BAM) common to another active ingredient,
fluopicolide.  However, for the purposes of this tolerance action, EPA
has not assumed that dichlobenil 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/. 

Dichlobenil and fluopicolide can form the common metabolite BAM.  To
establish new tolerances for dichlobenil, EPA conducted a human health
risk assessment for exposure to BAM resulting from the use of current
and proposed uses of dichlobenil and the fungicide fluopicolide.  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. 

Occupational Exposure/Risk Pathway  XE "Occupational Exposure/Risk
Pathway"  

DICHLOBENIL – Occupational Exposure/Risk Assessment for the Proposed
Uses of Dichlobenil on Rhubarb, Caneberries (Crop SubGroup 13A) and
Bushberries (Crop SubGroup 13B), DP Num: 343142, M. Dow, 27/AUG/2007.

9.1	Handler Risk  XE "9.1	Handler Risk"  

Based upon the proposed use patterns, i.e., the rates of formulation per
acre, ARIA believes the only method of application will be as a granular
broadcast application to the soil using ground equipment.  As such, the
most highly exposed occupational pesticide handlers are expected to be
loaders performing open-pour loading of granules and applicators using
open-cab tractors pulling broadcast granular spreaders.  

For such ground applications, private (i.e., grower) applicators may
perform all functions, that is, mix, load and apply the material.  The
HED Exposure Science Advisory Council (ExpoSAC) Standard Operating
Procedure (SOP) Number 12 (29 March 2000) directs that although the same
individual may perform all those tasks, they shall be assessed
separately.  The available exposure data for combined
mixer/loader/applicator scenarios are limited in comparison to the
monitoring of these two activities separately.  These exposure scenarios
are outlined in the Pesticide Handler Exposure Database (PHED) Surrogate
Exposure Guide (August 1998).  HED has adopted a methodology to present
the exposure and risk estimates separately for the job functions in some
scenarios and to present them as combined in other cases.  Most exposure
scenarios for hand-held equipment (such as hand wands, backpack
sprayers, and push-type granular spreaders) are assessed as a combined
job function.  With these types of hand-held operations, all handling
activities are assumed to be conducted by the same individual.  The
available monitoring data support this and HED presents them in this
way.  Conversely, for equipment types such as fixed-wing aircraft,
groundboom tractors, or air-blast sprayers, the applicator exposures are
assessed and presented separately from those of the mixers and loaders. 
By separating the job functions, HED determines the most appropriate
levels of personal protective equipment (PPE) for each aspect of the job
without requiring an applicator to wear unnecessary PPE that might be
required for a mixer/loader (e.g., chemical-resistant gloves may only be
necessary during the pouring of a liquid formulation).  

No chemical-specific data were available with which to assess potential
exposure to pesticide handlers.  The estimates of exposure to pesticide
handlers are based upon surrogate study data available in the PHED (v.
1.1, 1998).  For pesticide handlers, it is HED standard practice to
present estimates of dermal exposure for “baseline;” that is, for
workers wearing a single layer of work clothing consisting of a
long-sleeved shirt, long pants, shoes plus socks and no protective
gloves as well as for baseline and the use of protective gloves or other
PPE as might be necessary.  The label directs applicators and other
handlers to wear PPE consisting of long-sleeved shirt, long pants,
chemical-resistant gloves made of any waterproof material such as butyl
rubber, natural rubber, neoprene rubber or nitrile rubber and shoes plus
socks.  

Table 9.1.  Summary of Exposure & Risk for Occupational Handlers
Applying Dichlobenil.  The dermal NOAEL is 25 mg/kg/day; the inhalation
NOAEL is 3.1 mg/kg/day.

Unit Exposure1

mg ai/lb handled	Applic. Rate2

lb ai/unit	Units Treated3	Avg. Daily Exposure4

mg ai/kg bw/day	MOE5	Combined

MOE6

Loader Using Open-pour Loading of Granules

Dermal:

SLNoGlove      0.0084 LC

SLWithGlove   0.0069 MC

Inhal.                0.0017 HC	6.0 lb ai/A	40 A/day	Dermal:

SLNoGlove    0.0288

SLWithGlove 0.024

Inhal.              0.00583	

870

1040

531	

330

352

Applicator Using Open-cab Broadcast Application of Granules

Dermal:

SLNoGlove       0.0099 LC

SLWithGlove    0.0069 LC

Inhal.                 0.0012 LC	6.0 lb ai/A	40 A/day	Dermal:

SLNoGlove     0.034

SLWithGlove  0.024

Inhal.               0.00411	

735

1040

754	

371

436

1.  Unit Exposures are taken from “PHED SURROGATE EXPOSURE GUIDE”,
Estimates of Worker Exposure from The Pesticide Handler Exposure
Database Version 1.1, August 1998.   Inhal. = Inhalation.  Units = mg
ai/pound of active ingredient handled.  Data Confidence: LC = Low
Confidence, MC = Medium Confidence, HC = High Confidence.

2.  Applic. Rate. = Taken from the  IR4 Submission, Section B

3.  Units Treated are taken from “Standard Values for Daily Acres
Treated in Agriculture”; SOP  No. 9.1.   Science Advisory Council for
Exposure;  Revised 5 July 2000; 

4.  Average Daily Dose (ADD) = Unit Exposure * Applic. Rate * Units
Treated ( Body Weight (70 kg)  

5.  MOE = Margin of Exposure = No-Observed Adverse-Effect Level (NOAEL) 
( ADD.    

Effect Level (25 mg ai/kg bw/day for  dermal and 3.1 mg ai/kg bw/day for
inhalation)

6.  Combined MOE = 1/(1/MOEDermal ) + (1/MOEInhalation)

9.2	Postapplication Risk  XE "9.2	Postapplication Risk"  

Application of dichlobenil to control perennial weeds is recommended as
a late fall soil treatment, from 15 November to 15 February.  For
control of annual weeds, applications are recommended in early spring,
before 1 May.  Applications are either followed by shallow mechanical
incorporation or via "watering-in."  

Due to the recommended timing of application and to the method of
application, ARIA expects any occupational, post-application exposure to
be negligible.  Since it is a granular formulation applied essentially
during "dormant" times, foliar dislodgeable residue exposure is not
expected.  Therefore, a post-application exposure assessment was not
conducted herein.  

9.3	Restricted Entry Interval (REI)  XE "9.3	Restricted Entry Interval
(REI)"  

Dichlobenil is classified in Acute Toxicity Category II for acute dermal
toxicity and acute inhalation toxicity.  It is classified in Toxicity
Category IV for primary eye irritation and primary dermal irritation. 
It is not a dermal sensitizer.  

According to Title 40, Code of Federal Regulations, § 156.208 (c) (2)
(ii), “If the product contains only one active ingredient and it is in
toxicity category II by the criteria in paragraph (c)(1) of this
section, the restrictive entry interval shall be 24 hours” (bold
added).

The proposed label lists a REI of 12 hours.  Due to the Acute Toxicity
Category for dermal and inhalation toxicity, the interim WPS REI should
be 24 hours.  

10.0		Data Needs and Label Requirements  XE "10.0		Data Needs and Label
Requirements"  

	

Toxicology  XE "Toxicology"  

None

10.2	Residue Chemistry  XE "10.2	Residue Chemistry"  

Revised Section F:  ARIA recommended for the establishment of a
tolerance for dichlobenil residues on rhubarb at 0.06 ppm.  ARIA
recommended for the establishment of tolerances for dichlobenil residues
in/on caneberry, subgroup 13-07A at 0.10 ppm, and bushberry, subgroup
13-07B at 0.15 ppm.  A revised Section F must be submitted to account
for these tolerance and commodity definition recommendations.

Revised Label/Section B:  The label is adequate to allow evaluation of
the residue data relative to the proposed uses on rhubarb and caneberry,
subgroup 13-07A.  However, the label should be revised for the
bushberry, subgroup 13-07B from 4 lbs ai/A to 6 lbs ai/A to match the
propose Section B use pattern and submitted data for the bushberry,
subgroup 13-07B commodities.  Also, the label and Section B must be
revised to correctly spell the commodities containing “currant” in
the name.  

10.3	Occupational and Residential Exposure  XE "10.3	Occupational and
Residential Exposure"   

The proposed label lists a REI of 12 hours.  Due to the Acute Toxicity
Category for dermal and inhalation toxicity, the interim WPS REI should
be 24 hours.  

References:  XE "References\:"  

Drinking Water Assessment for New Use of Dichlobenil on Rhubarb, DP Num:
322919; J. Angier; 01/NOV/2005

Dichlobenil Acute and Chronic Aggregate Dietary (Food and Drinking
Water) Exposure and Risk Assessments for Section 3 Registration Action
For New Uses on Caneberry, Subgroup 13-07A and Bushberry, Subgroup
13-07B, DP Num:346388, D. Rate, 14/MAY/2008.

Dichlobenil.  Use on Caneberry (Subgroup 13-07) and Bushberry (Subgroup
13-07B).  Summary of Analytical Chemistry and Residue Data.  PP#7E7230,
DP Num: 349398, D. Rate, 12/MAR/2008.

Dichlobenil. Amended:  Use on Caneberry (Subgroup 13-07) and Bushberry
(Subgroup 13-07B).  Summary of Analytical Chemistry and Residue Data. 
PP#7E7230, DP Num: 353491, D. Rate, 10/JUN/2008.

Dichlobenil.  Use on Rhubarb.  Summary of Analytical Chemistry and
Residue Data. Petition Number 2E6398.DP Num: 315266, W. Cutchin,
22/FEB/2006.

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 Num: 340366, N. Dodd, 21/NOV/2007.

2,6-Dichlobenzamide (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 and Root Vegetables (Subgroup 1A), Leaves of
Root and Tuber Vegetables (Group 2), Bulb Vegetables (Group 3), and Head
and Stem Brassica (Subgroup 5A) and Section 3 Registration Actions for
Dichlobenil on Rhubarb, Caneberries (Subgroup 13-07A), Bushberries
(Subgroup 13-07B) and Associated Berry Comodities; DP Num: 439722, S.
Piper, 19/MAR/2008.

2,6-Dichlorobenzamide (BAM ) as a Metabolite/Degradate of Fluopicolide
and Dichlobenil.  Human Health Risk Assessment for Proposed Uses of
Fluopicolide on Root Vegetables (Subgroup 1A), Leaves of Root and Tuber
Vegetables (Group 2), Bulb Vegetables (Group 3), and Head and Stem
Brassica (Subgroup 5A), DP Number: 349864, F. Forte, 19/MAR/2008.

DICHLOBENIL – Occupational Exposure/Risk Assessment for the Proposed
Uses of Dichlobenil on Rhubarb, Caneberries (Crop SubGroup 13A) and
Bushberries (Crop SubGroup 13B), DP Num: 343142, M. Dow, 27/AUG/2007.

2,6-Dichlorobenzamide (BAM ) as a Metabolite/Degradate of Fluopicolide
and Dichlobenil.  Human Health Risk Assessment for Proposed Uses of
Rhubarb, Dichlobenil on Caneberries (Subgroup 13-07A), and Bushberries
(Subgroup 13-07B), DP Number: 354590, D. Rate, 15/MAR/2008.

Comparative Toxicity using Derek analysis for Dichlobenil, Fluopicolide
and BAM, DP Num: 352656, M. Manibusan, 12/MAY/2008.

Appendix A:  Toxicity Profile Tables 

Table A.1.  Acute toxicity profile for dichlobenil technicala.

Guideline No./Study Type	

MRID No.	

Results	Toxicity Category

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

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

870.1300/Acute inhalation toxicity (rat)	40425401	

>0.250 mg/L	II

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

870.2500/Primary dermal irritation (rabbit)	40425402	

Not a dermal irritant	IV

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

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

Table A.2.  Subchronic, Chronic, and Geno- Toxicity Profile for
Dichlobenil Technical.

Guideline No./

Study Type	

MRID No. (Year)/Doses/ Classification	

Results

870.3100

90-day oral (hamster; dietary)	

40600701 (1987)

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

Acceptable/Guideline	

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

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

870.3100

90-day oral (rat; dietary)

	

00107106 (1961)

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

Acceptable/Guideline	

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

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

870.3200

21-day dermal

(rabbits)

	

43879301 (1995)

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

Acceptable/Guideline	

NOAEL = 1000 mg/kg/day (HDT).

LOAEL was not observed.

Non-guideline (literature)

5-day dermal (mouse)	

Deamer et al. (1994) ; no MRID

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

Acceptable/Non-guideline	

NOAEL = 25 mg/kg/day.

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

870.3465

90-day inhalation (rat)

	

46398701 (2002), 46653001 (2002)

Main study: 0, 2.3, 5.1, or 12 mg/m3 (equivalent to 0, 0.0023, 0.0051,
and 0.012 mg/L, respectively) 

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

Range finding (7 days): 0, 21, 77, or 200 mg/m3 (equivalent to 0, 0.021,
0.077, or 0.2 mg/L, respectively) 

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

Acceptable/Guideline	

NOAEL = 12 mg/m3 (3.1 mg/kg/day  ). 

LOAEL = 21 mg/m3 (5.5 mg/kg/day 2 ) based on an increased incidence of
nasal degeneration.

870.4100

Chronic toxicity oral (dog; dietary)

	

00067649 (1969)

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

Acceptable/Non-guideline	

NOAEL = 1.25 mg/kg/day. 

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

870.4100

Chronic toxicity oral (dog; capsule)

	

43969701 (1995)

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

Acceptable/Guideline	

NOAEL = 1 mg/kg/day. 

LOAEL = 6 mg/kg/day based on increased liver weights and increased serum
cholesterol, triglycerides, phospholipids, and alkaline phosphatase
(M&F) and increased serum γ-GT and periportal hypertrophy of
hepatocytes (M).

870.4200

Carcinogenicity oral (hamster; dietary)

	

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

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

Acceptable/Non-guideline	

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

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

No evidence of carcinogenicity.

870.4200

Carcinogenicity oral (hamster; dietary)

	

42221201 (1992), 42563601 (1992)

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

Acceptable/Non-guideline	

NOAEL was not observed.

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

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

870.4300

Combined Chronic Toxicity/

Carcinogenicity oral (rat; dietary)	

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

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

Acceptable/Non-guideline	

NOAEL = 2.3 mg/kg/day.  

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

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

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

870.3700

Developmental toxicity oral (rat; gavage)

	

00147437 (1984)

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

Acceptable/Non-guideline	

Maternal NOAEL = 20 mg/kg/day.

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

Developmental  NOAEL = 180 mg/kg/day.

Developmental LOAEL was not identified.

870.3700

Developmental toxicity oral (rabbit; gavage)

	

41257302 (1989)

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

Acceptable/Non-guideline	

Maternal NOAEL = 45 mg/kg/day.

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

Developmental NOAEL = 45 mg/kg/day. 

Developmental LOAEL = 135 mg/kg/day, based on increased number of total
resorptions/dam and post-implantation loss; and increased incidences of
fetal external (cleft palate, adactyly, bilateral open eye), visceral
(abnormal cystic gallbladder, distended ureter with bilateral severe
hydronephrosis), and skeletal (malformed and malpositioned right
scapula, right radius absent with malpositioned ulna and humerus, fused
cervical vertebral arches, asymmetrically ossified and fused cervical
vertebra centra, abnormally shaped cranium with enlarged and misshapen
fontanelle, enlarged fontanelle, misshapen frontals, skull and frontals
foreshortened and nasal malpositioned, and major fusion of sternebrae)
anomalies.

870.3800

2-generation reproduction oral (rat; dietary)

	41257303 (1989), 42239101 (1992)

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

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

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

Reproductive NOAEL = 17.5 mg/kg/day.

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

Offspring NOAEL = 3 mg/kg/day.

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

Non-guideline (literature)

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

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

Acceptable/Non-guideline	Parental NOAEL not observed.

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

Offspring NOAEL not observed.

Offspring LOAEL (PND 8; s.c.) ≥ 12 mg/kg/day based on no periodic
acid-Schiff (PAS) staining of contents of Bowman’s glands (measure of
mucus production); the adversity of this effect in itself is unclear.

Non-guideline (literature)

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

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

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

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

870.5100

In vitro bacterial reverse mutation (Ames test)	

00153579 (1984)

μg/plate (-/+ activation) in S. typhimurium

Acceptable/Guideline	

Negative with or without activation.

870.5100

In vitro bacterial reverse mutation (Ames test)	

00153586 (1981)

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

Acceptable/Guideline	

Negative with or without activation.

870.5300

In vitro mouse lymphoma (L5178Y) mutation 	

00153576 (1984)

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

Acceptable/Guideline	

Negative with or without activation.

870.5395

In vivo mouse erythrocyte micronucleus assay	

00153578 (1983)

0, 300, 600, or 1200 mg/kg 

Unacceptable/Guideline due to insufficient sampling times	

Negative.

870.5375

In vitro chromosomal aberrations (human lymphocytes)	

00153577 (1984)

μg/ml (-/+ activation) (limit of solubility)

Acceptable/Guideline	

Negative with or without activation.

870.5375

In vitro chromosomal aberrations (CHO cells)	

43191501 (1990)

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

Acceptable/Guideline	

Negative with or without activation.

870.5550

In vitro Unscheduled DNA synthesis (human HeLa epithelioid cells)	

00153580 (1984)

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

Acceptable/Guideline	

Negative with or without activation.

In vitro transformation assay (BALB/3T3 cells)	

00153581 (1984)

At concentrations up to 7500 μg/ml (+ activation)

Acceptable/Guideline	

Negative.

In vitro recombination assay	

00153586 (1981)

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

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Metabolism and toxicokinetics

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

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

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

Appendix B:  Tolerance Reassessment Summary and Table  XE "Appendix B\: 
Tolerance Reassessment Summary and Table"  

No Codex, Canadian, or Mexican MRLs have been established for
dichlobenil.  

Table B.1.  Tolerance Summary for Dichlobenil.

Commodity	

Established/Proposed Tolerance (ppm)	

Recommended Tolerance (ppm)	

Comments (correct commodity definition)

Rhubarb	0.15	0.06

	Caneberry, Subgroup 13A	0.1	0.1	Caneberry, Subgroup 13-07A

Wild raspberry	0.1	NA	Member of new Caneberry, Subgroup 13-07A.

Bushberry, Subgroup 13B	0.15	0.15	Bushberry, Subgroup 13-07B.

Aronia berry	0.15	NA	Member of new Bushberry, Subgroup 13-07B.

Blueberry, lowbush	0.15	NA 	

Member of new Bushberry, Subgroup 13-07B.

Buffalo currant	0.15	NA

	Chilian guava	0.15	NA

	European barberry	0.15	NA

	Highbush cranberry	0.15	NA

	Honeysuckle	0.15	NA

	Jostaberry	0.15	NA

	Juneberry	0.15	NA

	Lingonberry	0.15	NA

	Native currant	0.15	NA

	Salal	0.15	NA

	Sea buckthorn	0.15	NA

	

Appendix C:  Review of Human Research  XE "Appendix C\:  Review of
Human Research"  

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.

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 [(mg/m3) x (m3 / 1000 L) x (10.26 L / hr) x 6 hr/day x (1 / 0.236
kg)], using estimated ventilation rate of Sprague Dawley rat

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