Document ID: EPA-HQ-OPP-2005-0265-0021
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2006-07-19T04:00Z

Page
1
of
84
OFFICE
OF
PREVENTION,
PESTICIDES
AND
TOXIC
SUBSTANCES
May
11,
2006
MEMORANDUM
SUBJECT:
Dicloran:
Revised
HED
Chapter
of
the
Reregistration
Eligibility
Decision
Document
(
RED).
PC
Code:
031301,
Case
#:
0113,
DP
Barcode:
D294460.

Regulatory
Action:
Reregistration
Risk
Assessment,
Phase
3
­
HED
Response
to
Public
Comments­
Revised
Risk
Assessment
Type:
Single
Chemical
Aggregate
FROM:
Toiya
Goodlow,
Risk
Assessor
Byong­
Han
Chin,
Ph.
D.,
Toxicologist
Christine
L.
Olinger,
Chemist
Matthew
G.
Lloyd,
M.
S.,
Industrial
Hygienist
Reregistration
Branch
1
Health
Effects
Division
(
7509P)

THROUGH:
Michael
S.
Metzger,
Branch
Chief
Whang
Phang,
Ph.
D.,
Branch
Senior
Scientist
Reregistration
Branch
1
Health
Effects
Division
(
7509P)

TO:
James
Parker,
Chemical
Review
Manager
Special
Review
and
Reregistration
Division
(
7508P)

This
document
is
a
revision
of
the
Human
Health
Risk
Assessment
for
the
Dicloran
Reregistration
Eligibility
Decision
Document
(
RED)
dated
February
28,
2006
(
T.
Goodlow).
The
HED
chapter
includes
the
Toxicology
and
Hazard
Assessment
from
Byong­
Han
(
Paul)
Chin,
Reregistration
Branch
I,
Residue
Chemistry
Assessments
and
Dietary
Exposure
Analysis
from
Christine
Olinger,
Reregistration
Branch
1,
and
the
Occupational
and
Residential
Exposure
Assessments
from
Matthew
Lloyd,
Reregistration
Branch
1.
Information
was
also
drawn
from
the
Environmental
Fate
and
UNITED
STATES
ENVIRONMENTAL
PROTECTION
AGENCY
WASHINGTON,
D.
C.
20460
2
of
84
Effects
Division
(
EFED)
Revised
Tier
1
Drinking
Water
Assessment
from
Cheryl
Sutton
and
the
Review
of
Dicloran
Incident
Reports
from
Jerry
Blondell,
HED,
Chemistry
and
Exposure
Branch.

This
risk
assessment
was
revised
in
response
to
public
comments.
The
corrections
were
reviewed
by
RRB1/
HED
and
revised
to
comply
with
Agency
policies.
See
DP
Barcode:
D325652,
dated
February
28,
2006
for
the
complete
HED
Response
to
Public
Comments.
3
of
84
Table
of
Contents
1.0
Executive
Summary
......................................................................................................
6
2.0
Ingredient
Profile
........................................................................................................
10
2.1
Summary
of
Registered/
Proposed
Uses..............................................................
10
2.2
Structure
and
Nomenclature...............................................................................
11
2.3
Physical
and
Chemical
Properties
......................................................................
14
3.0
Metabolism
Assessment
..............................................................................................
15
3.1
Rat
Metabolism
.................................................................................................
15
3.2
Nature
of
the
Residue
in
Foods
..........................................................................
15
3.2.1.
Description
of
Primary
Crop
Metabolism...............................................
15
3.2.2
Description
of
Livestock
Metabolism.....................................................
16
3.2.3
Description
of
Rotational
Crop
Metabolism,
including
identification
of
major
metabolites
and
specific
routes
of
biotransformation................................
16
3.3
Environmental
Degradation
...............................................................................
18
3.4
Toxicity
Profile
of
Major
Metabolites
and
Degradates
......................................
18
3.5
Summary
of
Residues
for
Tolerance
Expression
and
Risk
Assessment...............
19
3.5.1
Tabular
Summary...................................................................................
19
3.5.2
Rationale
for
Inclusion
of
Metabolites
and
Degradates
...........................
19
4.0
Hazard
Characterization/
Assessment
.............................................................................
20
4.1
Hazard
Characterization.....................................................................................
20
4.1.1
Database
Summary
                    ...
20
4.1.1.1.
Studies
Available
and
Considered
          
.20
4.1.1.2.
Mode
of
action,
metabolism,
toxicokinetic
data
     .
20
4.1.1.3.
Sufficiency
of
studies/
data
            ... 
20
4.1.2.
Toxicological
Effects
                   ....
20
4.1.3.
Dose­
response
                      ...
21
4.2
FQPA
Hazard
Considerations
............................................................................
27
4.2.1
Adequacy
of
the
Toxicity
Data
Base.......................................................
27
4.2.2
Evidence
of
Neurotoxicity......................................................................
27
4.2.3
Developmental
Toxicity
Studies.............................................................
27
4.2.4
Reproductive
Toxicity
Study..................................................................
29
4.2.5
Additional
Information
from
Literature
Sources
.....................................
31
4.2.6
Pre­
and/
or
Postnatal
Toxicity
...................................................................
31
4.2.6.1
Determination
of
Susceptibility...................................................
31
4.2.6.2
Degree
of
Concern
Analysis
and
Residual
Uncertainties
for
Pre
and/
or
Post­
natal
Susceptibility
..............................................................
31
4.3
Recommendation
for
a
Developmental
Neurotoxicity
Study
..............................
31
4
of
84
4.3.1
Evidence
that
supports
requiring
a
Developmental
Neurotoxicity
study
                     ...       .
31
4.3.2
Evidence
that
supports
not
requiring
for
a
Developmental
Neurotoxicity
study
 .................................................................................................
32
4.4
Hazard
Identification
and
Toxicity
Endpoint
Selection.......................................
32
4.4.1
Acute
Reference
Dose
(
aRfD)
­
Females
age
13­
49.................................
32
4.4.2
Acute
Reference
Dose
(
aRfD)
­
General
Population
...............................
34
4.4.3
Chronic
Reference
Dose
(
cRfD)
.............................................................
34
4.4.4
Incidental
Oral
Exposure
(
Short
and
Intermediate
Term)
........................
37
4.4.5
Dermal
Absorption.................................................................................
39
4.4.6
Dermal
Exposure
(
Short,
Intermediate
and
Long
Term)..........................
39
4.4.7
Inhalation
Exposure
(
Short,
Intermediate
and
Long
Term)
.....................
41
4.4.8
Margins
of
Exposure
..............................................................................
41
4.4.9
Recommendation
for
Aggregate
Exposure
Risk
Assessments.................
42
4.4.10
Classification
of
Carcinogenic
Potential
.................................................
42
4.4.10.1
Carcinogenicity
Study
in
Rats
             
42
4.4.10.2
Carcinogenicity
Study
in
Mice
            ...
44
4.4.11
Mutagenicity
                      
 .
45
4.5
Special
FQPA
Safety
Factor
                    
50
4.6
Endocrine
disruption..........................................................................................
50
5.0
Public
Health
Data
......................................................................................................
51
5.1
Incident
Reports.................................................................................................
51
6.0
Exposure
Characterization/
Assessment
.....................................................................
51
6.1
Dietary
Exposure/
Risk
Pathway.........................................................................
51
6.1.1
Residue
Profile.......................................................................................
51
6.1.2
Acute
and
Chronic
Dietary
Exposure
and
Risk
.......................................
55
6.2
Water
Exposure/
Risk
Pathway...........................................................................
57
6.3
Residential
(
Non­
Occupational)
Exposure/
Risk
Pathway
...................................
58
7.0
Aggregate
Risk
Assessments
and
Risk
Characterization...........................................
58
7.1
Acute
Aggregate
Risk
........................................................................................
59
7.2
Short­
Term
Aggregate
Risk
...............................................................................
59
7.3
Intermediate­
Term
Aggregate
Risk
....................................................................
59
7.4
Long­
Term
Aggregate
Risk
...............................................................................
59
7.5
Cancer
Risk
.......................................................................................................
60
8.0
Cumulative
Risk
Characterization/
Assessment
.........................................................
61
9.0
Occupational
Exposure/
Risk
Pathway
.......................................................................
62
9.1
Short/
Intermediate/
Long­
Term
Handler
Risk
.....................................................
62
9.2
Short/
Intermediate/
Long­
Term
Postapplication
Risk..........................................
67
10.0
Data
Needs
and
Label
Requirements
.........................................................................
72
5
of
84
10.1
Toxicology
........................................................................................................
72
10.2
Residue
Chemistry.............................................................................................
72
10.3
Occupational
and
Residential
Exposure
.............................................................
74
References:
..............................................................................................................................
75
Appendices
..............................................................................................................................
76
1.0
TOLERANCE
REASSESSMENT
RECOMMENDATIONS.............................
76
2.0
TOXICOLOGY
DATA
REQUIREMENTS.......................................................
79
3.0
NON­
CRITICAL
TOXICOLOGY
STUDIES....................................................
81
6
of
84
Executive
Summary
This
risk
assessment
was
performed
to
support
the
reregistration
eligibility
decision
for
dicloran
(
2,6­
dichloro­
4­
nitroaniline).
Dicloran,
also
referred
to
as
DCNA,
is
a
fungicide
used
control
pathogenic
species
such
as
Botrytis,
Monilinia,
Rhizopus,
Sclerotinia,
and
Sclerotium.
DCNA
is
registered
for
agriculture
and
horticulture
uses.
Its
registered
formulations
include
dusts
(
D),
wettable
powders
(
WP),
and
flowable
concentrates
(
FIC).
These
can
be
applied
using
aerial,
airblast,
groundboom,
chemigation,
and
hand
application
methods
such
as
handwands
and
backpack
sprayers.

The
submitted
toxicology
studies
provide
adequate
information
to
determine
whether
dicloran
poses
a
human
health
hazard.
The
Agency
is
confident
that
the
risk
estimates
presented
in
this
document
represent
conservative
approximations
of
human
health
risks
associated
with
the
use
of
DCNA.

The
available
toxicity
data
indicate
the
acute
oral,
dermal,
and
primary
eye
and
dermal
irritation
toxicity
of
dicloran
to
be
in
toxicity
categories
III
and
IV.
DCNA
has
been
shown
to
be
a
potential
skin
sensitizer.

Both
subchronic
and
chronic
toxicity
studies
in
rats
shows
that
dicloran
causes
reduced
body
weight,
reduced
body
weight
gain,
increased
liver
weights,
and
histopathologic
lesions
in
the
brain
and
spinal
cord
of
both
sexes,
optic
nerve
in
females
and
Leydig
cell
hyperplasia
in
the
testes
in
males.
The
developmental
toxicity
study
in
rats
showed
increased
incidences
of
supernumerary
rudimentary
ribs
and
also
decreased
fetal
weights
in
the
presence
of
maternal
toxicity.
The
data
from
the
developmental
toxicity
studies
in
rats
and
of
the
2­
generation
reproduction
study
indicated
no
increase
in
susceptibility
of
fetuses
and
pups
to
the
in
utero
and/
or
postnatal
exposure
to
DCNA.

There
are
no
neurotoxicity
studies
available.
However,
neuropathology
(
vacuolar
alterations
of
the
brain
and
spinal
cord)
was
seen
at
doses
of
25
mg/
kg
or
greater
in
the
chronic
rat
and
dog
studies.
The
available
data
did
not
demonstrate
neurotoxicity
with
subchronic
studies
in
rats,
dogs,
and
mice.
It
should
be
noted
that
the
chronic
reference
dose
was
established
at
0.0025
mg/
kg/
day.

The
mouse
carcinogenicity
study
showed
no
treatment­
related
increase
in
tumor
incidence.
The
carcinogenicity
study
in
rats
found
an
increase
in
Leydig
cell
tumor
and
a
marginal
increase
in
endometrial
adenocarcinoma
at
high
dose
groups.
The
committee
members
of
CARC
evaluated
the
carcinogenicity
studies
in
rats
and
mice
and
related
toxicity
data
on
dicloran
and
classified
this
chemical
as
having
"
Suggestive
Evidence
of
Carcinogenic
Potential."
The
CARC
recommended
no
quantification
of
cancer
risk.

HED
has
selected
acute
and
chronic
reference
doses
(
RfD)
for
the
dietary
risk
assessment,
and
calculated
the
Population
Adjusted
Dose
(
PAD),
which
is
the
RfD
divided
by
the
FQPA
safety
factor
7
of
84
(
SF).
Based
on
the
hazard
data,
HED
recommends
the
special
FQPA
SF
equal10X
due
to
data
gaps
present
within
the
toxicity
database.
The
developmental
rat
study,
the
one­
year
dog
study,
and
the
90­
day
oral
toxicity
study
in
dogs
were
the
primary
studies
used
for
selecting
toxicity
endpoints
for
risk
assessment.
The
developmental
rat
study
was
selected
for
acute
dietary
(
females
13­
49
years
of
age)
exposure
scenario.
The
reference
dose
for
acute
effects
is
equal
to
0.5
mg/
kg/
day,
and
the
PAD
is
equal
to
0.05
mg/
kg/
day.
Acute
dietary
endpoint
for
the
general
population,
including
infants
and
children,
was
not
selected
for
this
population
group
because
there
were
no
appropriate
effects
observed
that
are
attributable
to
a
single
exposure
(
dose).
The
one­
year
dog
study
was
chosen
for
the
chronic
RfD.
The
reference
dose
for
chronic
effects
(
general
population)
is
equal
to
0.025
mg/
kg/
day,
and
the
PAD
is
equal
to
0.0025
mg/
kg/
day.
The
21­
day
dermal
toxicity
study
in
rabbits
was
selected
for
the
short­
and
intermediate
term
dermal
exposure
scenarios.
The
90­
day
oral
toxicity
study
in
dogs
was
selected
for
both
the
short­
and
intermediate­
term
inhalation
and
incidental
oral
exposure
scenarios.
The
chronic
RfD
was
also
used
for
the
long
term
dermal
and
inhalation
exposure
assessments.

Dicloran
is
currently
registered
for
preharvest
and
postharvest
uses
on
various
raw
agricultural
commodities
under
40
CFR
§
180.200
for
residues
of
dicloran
per
se.
Preharvest
uses
include
apricots,
beans
(
snap),
celery,
cherries
(
sweet),
cucumbers,
endive
(
escarole),
fennel,
garlic,
grapes,
lettuce
(
head
and
leaf),
nectarines,
onions,
peaches,
plums
(
fresh
prunes),
potatoes,
rhubarb,
shallots,
and
tomatoes;
postharvest
uses
are
on
carrots
and
sweet
potatoes.
A
petition,
PP#
7F04879,
is
pending
for
the
establishment
of
permanent
tolerances
resulting
from
proposed
uses
on
peanuts
(
preharvest),
carrots
(
preharvest),
and
tomatoes
(
postharvest).
There
are
also
pending
pre­
harvest
uses
on
fennel,
shallot,
and
the
leafy
greens
subgroup
(
Subgroup
4a).

The
HED
Metabolism
Assessment
Review
Committee
(
MARC)
has
determined
the
residues
of
concern
for
both
risk
assessment
and
tolerance
purposes
(
D274726,
5/
8/
01,
T.
Bloem).
The
current
tolerance
expression
is
in
harmony
with
the
MARC's
determination
of
the
residues
of
concern
for
tolerance
purposes.
It
is
also
compatible
with
the
Codex
definition
of
residues
for
dicloran.
No
tolerances
have
been
established
for
livestock
commodities.

Acute
and
chronic
dietary
exposure
assessments
for
food
only
were
performed
using
DEEM­
FCID
 
.
No
acute
endpoint
was
identified
for
the
general
population;
therefore,
females
ages
13­
49
were
the
only
population
subgroup
included
in
the
acute
dietary
assessment.
Refined
assessments
were
required
for
both
acute
and
chronic
exposure
for
all
populations
exceeded
the
level
of
concern
assuming
100%
crop
treated
and
tolerance
values.
For
the
refined
assessments,
USDA
Pesticide
Data
Program
(
PDP)
monitoring
data
were
used
for
all
commodities,
except
rhubarb,
assuming
nondetectable
residues
were
at
the
limit
of
detection.
No
adjustments
for
percent
crop
treated
were
made.
Using
this
refinement,
the
exposures
for
food
only
was
9.9%
of
the
acute
Population
Adjusted
Dose
(
aPAD)
for
females
13­
39.
The
most
highly
exposed
subgroup
for
the
chronic
exposure
was
children
1­
2
years
old,
with
exposures
utilizing
13%
of
the
chronic
Population
Adjusted
Dose
(
cPAD).

EFED
provided
acute
and
chronic
surface
water
exposure
scenarios
and
one
ground
water
concentration
estimate
for
DCNA
using
two
EFED
Tier
1
screening­
level
models:
FIRST,
Version
1.0
and
SCI­
GROW,
Version
2.3.
Surface
water
(
acute
and
chronic)
and
groundwater
estimated
drinking
water
concentrations
(
EDWC's)
are
based
on
DCNA
use
on
apricots
at
4.0
lb
8
of
84
a.
i./
A/
application
applied
in
a
single
application.
All
EDWC's
were
incorporated
into
the
dicloran
aggregate
assessment.

There
are
no
residential
uses
for
DCNA.
Therefore,
residential
exposures
are
not
expected
and
associated
risks
were
not
calculated.

Since
there
are
no
residential
uses,
the
aggregate
exposure
assessment
for
dicloran
considered
exposures
from
food
and
drinking
water
only.
Refined
acute
and
chronic
dietary
exposure
assessments
for
food
and
water
were
performed
using
DEEM­
FCID
 
.
The
assessments
incorporated
PDP
monitoring
data
for
all
commodities
except
rhubarb,
assuming
non­
detectable
residues
were
at
the
limit
of
detection.
No
adjustments
for
percent
crop
treated
were
made.
Analyses
were
conducted
including
food
exposures
and
either
EDWCs
from
modeled
values
for
surface
water
sources
or
groundwater
sources
as
the
drinking
water
source.
At
the
99.9th
percentile
of
exposure,
the
estimated
food
and
water
exposure
for
females
13­
49
years
old
utilized
10%
and
52%
of
the
aPAD
for
ground
water
and
surface
water
sources,
respectively.
The
most
highly
exposed
subgroup
was
children
1­
2
years
old
for
the
chronic
assessment,
with
exposures
utilizing
14%
and
15%
of
the
cPAD
ground
water
and
surface
water
sources,
respectively.

Risk
calculations
have
been
completed
for
short/
intermediate
term
exposures
for
all
occupational
scenarios.
Long
term
risks
are
not
expected
and
associated
risks
were
not
calculated.

Current
dicloran
labels
typically
require
that
coveralls,
waterproof
gloves
and
shoes
plus
socks
be
used
for
agricultural
handler
for
both
the
wettable
powder
and
flowable
labels.
Non­
agricultural
applicators
and
other
handlers
are
required
by
the
wettable
powder
label
to
wear
long­
sleeved
shirt,
long
pants,
and
shoes
plus
socks.
In
addition,
applicators
and
other
handlers
are
required
by
the
liquid
flowable
label
to
wear
waterproof
gloves.
Most
labels
do
not
require
respiratory
protection.
For
the
loader
scenarios
involving
dust,
the
majority
of
aerial
application
exposures
are
of
concern
for
both
the
dermal
and
inhalation
route.
For
the
loader
scenarios
involving
ground
application
of
dust,
all
scenarios
are
of
concern
at
baseline
and
require
some
PPE
to
achieve
MOEs
of
100
or
greater.
For
all
of
the
mixer
loader
scenarios
involving
wettable
powder
formulations,
the
handler
risks
with
required
PPE
are
of
concern
and
in
some
cases
double
layer
dermal
PPE
are
required
to
be
achieve
acceptable
MOEs.
This
includes
all
aerial,
chemigation,
and
airblast
wettable
powder
scenarios.
Groundboom
wettable
powder
application
scenarios
are
of
concern
at
baseline
and
typically
achieve
acceptable
MOEs
with
single
layer
PPE.

The
short
and
intermediate
term
inhalation
risks
for
mixing
and
loading
dust
formulations
are
of
concern
at
baseline
up
through
the
use
of
a
PF10
respirator
for
aerial
application.
Engineering
controls
are
not
applicable
for
this
scenario
because
surrogate
data
for
mixing
and
loading
wettable
powder
is
being
used
for
the
unit
exposures.
The
short
and
intermediate
term
inhalation
risks
for
mixing
and
loading
wettable
powders
are
of
concern
at
baseline
and
require
PF5
respirator
to
achieve
MOEs
of
100
or
greater.

The
risks
for
mixing
and
loading
flowable
formulations
are
acceptable
at
baseline
and
do
not
require
mitigation.
The
risks
of
mixing/
loading/
applying
flowables
with
handheld
equipment
(
e.
g.
low
pressure
handwand)
are
not
of
concern
at
baseline
for
neither
the
dermal
or
inhalation
exposure
route.
9
of
84
Current
label
requirements
specify
12
hour
Restricted
Entry
Intervals
(
REIs)
while
Pre­
Harvest
Intervals
(
PHIs)
range
from
one
day
for
cherries
to
14
days
for
a
number
of
crops
including
head
lettuce
and
onions.
Postapplication
risk
calculations
based
on
the
current
label
maximum
rates
for
workers
entering
treated
fields
or
greenhouses
indicated
that
dicloran
risks
are
of
concern
at
the
current
REI
for
a
number
of
crop
groups.
The
time
for
the
MOEs
to
achieve
acceptable
levels
varies
considerably,
ranging
from
13
days
for
snap
beans
to
55
days
for
grapes
for
short/
intermediate
term
MOEs.
Postapplication
risk
calculations
for
those
scenarios
that
exceeded
HED's
level
of
concern
on
day
0
were
conducted
using
average
application
rate
data
provided
by
the
Special
Review
and
Reregistration
Division
(
SRRD).
Postapplication
risks
at
the
lower
application
rates
for
evergreen
fruit
trees,
onions,
garlic
and
shallots
are
no
longer
of
concern,
however
postapplication
risks
continue
to
be
of
concern
for
a
number
of
the
crop
groups.

In
conclusion,
DCNA
showed
both
low
acute
toxicity
(
toxicity
categories
III
and
IV)
and
low
dietary
risks.
Cancer
risk
quantification
was
not
recommended
by
the
CARC.
There
are
no
residential
uses
for
dicloran.
However,
occupational
handler
data
shows
that
many
of
the
scenarios
that
involve
the
mixing/
loading
of
wettable
powder
formulations
and
loader
scenarios
involving
dust
have
risks
of
concern
and
require
some
PPE
to
achieve
Agency
risk
targets.
In
most
of
the
scenarios,
the
MOEs
for
dicloran
do
not
exceed
100
at
the
REI;
and
are
therefore
of
concern
to
HED.

Data
gaps
include:

Toxicology
Guideline
870.6300
Developmental
Neurotoxicity
Study
­
rats
Guideline
870.3465
Inhalation
Toxicity
Study,
28­
day­
rats
Residue
Chemistry
Guideline
860.1200
Directions
for
Use
Guideline
860.1300
Nature
of
the
Residue,
livestock­
Storage
stability
data
is
required
for
the
livestock
metabolism
studies.
Guideline
860.1340
Residue
Analytical
Methods
Guideline
860.1380
Storage
Stability
Data,
plant
Guideline
860.1480
Meat/
Milk/
Poultry/
Eggs
(
Ruminant
feeding
study)
Guideline
860.1500
Crop
Field
Trials
Guideline
860.1520
Processed
Food/
Feed
Guideline
860.1900
Field
Accumulation
in
Rotational
Crops
Occupational
and
Residential
Exposure
The
Agency
is
requesting
process
descriptions
and
specific
application
rates
for
each
data
gap
listed
below.

°
The
risks
of
dipping
sweet
potato
seed
pieces
were
not
assessed
because
dipping
is
no
10
of
84
longer
used.
According
to
sweet
potato
researchers
at
the
Sweet
Potato
Research
Station
(
LSU),
sweet
potato
seed
pieces
are
treated
in
the
plant
bed
using
a
sprayer.

°
The
risks
of
postharvest
dip
treatment
of
sweet
potatoes
were
not
assessed
due
to
a
lack
of
exposure
data.
This
treatment
is
accomplished
by
using
automated
equipment;
however,
exposures
can
be
controlled
with
the
use
of
gloves.

°
There
are
no
data
available
to
evaluate
the
mix/
load/
apply
scenarios
for
backpack
sprayer
application
of
wettable
powders
and
flowables.
The
PHED
data
for
both
high
and
low
pressure
handwand
application
of
liquids
(
mix/
load/
apply
and
apply
only)
is
also
of
low
quality.
These
data
gaps
make
it
difficult
to
accurately
assess
the
risks
of
the
handwand
method
of
application,
which
is
commonly
used
in
horticulture.

°
The
risk
of
loading
the
dust
formulation
was
assessed
with
surrogate
unit
exposure
values
form
mixing
and
loading
wettable
powders.

°
The
risk
of
applying
dusts
was
not
assessed
due
to
lack
of
exposure
data
and
remains
as
a
data
gap.

°
The
risk
for
mixing/
loading/
applying
dust
with
handheld
power
duster.

°
Flagger
exposure
to
aerial
application
of
dust.

2.0
Ingredient
Profile
Dicloran
(
2,6­
dichloro­
4­
nitroaniline)
is
a
fungicide
used
control
pathogenic
species
such
as
Botrytis,
Monilinia,
Rhizopus,
Sclerotinia,
and
Sclerotium.
DCNA
is
registered
for
agriculture
and
horticulture
uses.
The
application
rates
in
agriculture
range
from
0.0172
 
122
lb
ai/
acre,
with
the
allowable
number
of
applications
ranging
from
four
times
per
season
to
once
a
week
for
the
majority
of
product
labels.
The
application
rates
in
horticulture
are
1
lb
ai/
acre
for
most
ornamentals
with
allowable
applications
up
to
once
weekly
with
no
annual
limit.
Current
label
requirements
specify
12
hour
REIs
while
preharvest
intervals
range
from
1­
14
days.
DCNA
registered
formulations
include
dusts
(
D),
wettable
powders
(
WP),
and
flowable
concentrates
(
FIC).
The
percentage
of
dicloran
used
in
each
formulation
type
ranges
from
4­
75%
active
ingredient
per
pound
formulated.
The
application
methods
for
DCNA
include
aerial,
airblast,
groundboom,
chemigation,
and
hand
application
methods
such
as
handwands
and
backpack
sprayers.

2.1
Summary
of
Registered/
Proposed
Uses
Table
2.1
provides
a
summary
of
registered
uses
for
DCNA.

Table
2.1
Active
Dicloran
End­
Use
Products
Registered
to
Gowan
Company,
Wilbur­
Ellis
Company,
and
Britz
Fertilizers,
Inc.
1
EPA
Reg.
No.
Formulation
Product
Name
11
of
84
Table
2.1
Active
Dicloran
End­
Use
Products
Registered
to
Gowan
Company,
Wilbur­
Ellis
Company,
and
Britz
Fertilizers,
Inc.
1
EPA
Reg.
No.
Formulation
Product
Name
Gowan
Company
10163­
187
8%
D
Botran
8%
Dust
10163­
188
6%
D
Botran
6%
Dust
10163­
189
75%
WP
Botran
75
W­
Fungicide
10163­
190
12%
D
Botran
12%
Dust
Fungicide
10163­
191
15%
D
Botran
15%
Dust
Fungicide
10163­
192
10%
D
Botran
10%
Dust
10163­
193
4%
D
Botran
4%
Dust
Fungicide
10163­
207
75%
WP
Botran
75WSB
Fungicide
10163­
221
4
lb/
gal
FlC
Botran
Flowable
Fungicide
10163­
226
3
5
lb/
gal
FlC
Botran
5F
Fungicide
Wilbur­
Ellis
Company
2935­
529
6%
D
Botran
6%
Dust
Britz
Fertilizers,
Inc.

10951­
13
6%
D
Britz
Botran
6%
Dust
10951­
14
6%
D
Britz
Botran
Sulfur
6­
25
Dust
1
Four
additional
SLNs
(
CA950011,
MT940003,
OR940017,
and
WA940017)
were
listed
in
the
OPPIN
Product
Listing
as
registered
products,
however,
the
study
reviewer
could
not
ascertain
the
parent
registration
and
if
the
SLN
products
contained
food
or
nonfood
uses.
2
Includes
SLNs
CA930023,
CA940007,
ID940006,
OR990056,
and
WA940009;
SLNs
were
listed
in
the
BEAD
Table
and
the
OPPIN
Product
Listing.
3
Includes
SLNs
ID970002,
OR990055,
and
WA960037;
SLNs
were
listed
in
the
BEAD
Table
and
the
OPPIN
Product
Listing.

2.2
Structure
and
Nomenclature
Tables
2.2a
and
2.2b
provide
structures
and
nomenclature
for
dicloran
and
its
metabolites.

Table
2.2a
Dicloran
(
DCNA)
Nomenclature
Chemical
structure
NH2
Cl
Cl
NO2
Common
name
Dicloran;
DCNA
12
of
84
Table
2.2a
Dicloran
(
DCNA)
Nomenclature
Molecular
Formula
C6H4Cl2
N2O2
Molecular
Weight
207.0
IUPAC
name
2,6­
dichloro­
4­
nitroaniline
CAS
name
2,6­
dichloro­
4­
nitrobenzenamine
CAS
#
99­
30­
9
Table
2.2a
DCNA
Metabolite
Nomenclature
Chemical
Name
Chemical
Structure
Identified
in
the
Following
DCAP
4­
amino­
2,6­
dichlorophenol
OH
Cl
Cl
NH2
Rotational
crops,
livestock
commodities
DCPD
4­
amino­
2,6­
dichloroaniline
NH2
Cl
Cl
NH2
Rotational
crops
3,5­
DCHA
3,5­
dichhloro­
4­
hydroxyacetanilide
OH
Cl
Cl
NH
C
CH
3
O
Rotational
crops
DCAA
4­
amino­
3,5­
dichloroacetanilide
NH2
Cl
Cl
NH
C
CH3
O
Rotational
crops,
livestock
commodities
13
of
84
DCHA
2,6­
dichloro­
4­
hydroxyaniline
NH2
Cl
Cl
OH
Primary
crops,
rotational
crops,
livestock
commodities
DCNP
2,6­
dichloro­
4­
nitrophenol
OH
Cl
Cl
NO2
Rotational
crops,
livestock
commodities
2,6­
DCP
2,6­
dichlorophenol
OH
Cl
Cl
Rotational
crops
2,6­
DCA
2,6­
dichloroaniline
NH2
Cl
Cl
Rotational
crops
Component
of
Unknown
1
Molecular
weight
=
182
NH2
OH
HO
NHCOCH3
Potatoes,
rotational
crops
Component
of
Unknown
1
Molecular
weight
=
218
NH2
SCH3
Cl
NO2
Potatoes,
rotational
crops
14
of
84
Component
of
Unknown
1
Molecular
weight
=
222
NH2
ONa
Cl
NHCOCH3
Potatoes,
rotational
crops
Component
of
Unknown
1
Molecular
weight
=
288
NH2
SCH2CH2
Cl
NHCOCH3
COOH
Potatoes,
rotational
crops
Component
of
Unknown
1
Molecular
weight
=
346
OH
SCH2CH
Cl
NHCOCH3
COOH
NHCOCH3
Potatoes,
rotational
crops
Component
of
Unknown
1
Molecular
weight
=
360
NH2
SCH2CH
Cl
NHCOCH3
CNHCH2COH
NH2
O
O
Potatoes,
rotational
crops
Component
of
Unknown
1
Molecular
weight
=
575
OH
SCH2CHCOOH
HCCH2S
NHCOCH3
NH2
HOOCCHCH2CH2OCHN
HOOCCH2NHOC
H2N
Potatoes,
rotational
crops
2.3
Physical
and
Chemical
Properties
Technical
dicloran
is
a
yellow
powder
with
a
melting
point
range
of
193.3­
194.8
°
C.
DCNA
is
practically
insoluble
in
water
and
other
compounds
with
a
water
solubility
of
6
x
10­
3
g/
L
at
20
°
C.
It
has
a
vapor
pressure
of
2.61
x
10­
4
Pa
at
25
°
C.
Dicloran
is
a
member
of
the
substituted
aromatics
group
of
fungicides.
Additional
physicochemical
properties
can
be
found
in
Table
2.3.
15
of
84
Table
2.3
Physicochemical
Properties
of
Dicloran
(
DCNA)

Parameter
Value
Reference
Melting
point
193.3­
194.8
°
C
RD
D223330,
5/
22/
96,
S.
Mathur
PH
6.16
(
±
0.03)
at
24.7
°
C
RD
D223330,
5/
22/
96,
S.
Mathur
Density,
bulk
density,
or
specific
gravity
0.277
(
±
0.002)
g/
mL
(
bulk
density)
RD
D223330,
5/
22/
96,
S.
Mathur
Water
solubility
Practically
insoluble;
6
x
10­
3
g/
L
at
20
°
C
DEB
#
5866,
1/
23/
90,
M.
Nelson
Solvent
solubility
At
20
EC:
ethanol
0.2%
chloroform
1.2%
ethyl
acetate
1.9%
ethanol,
2­
ethoxy
2.8%
2­
butanone
3.3%
acetone
4.3%
dioxane
4.0%
Product
Chemistry
Chapter
of
the
Reregistration
Standard,
8/
15/
83
Vapor
pressure
2.61
x
10­
4
Pa
at
25
°
C
DEB
#
5866,
1/
23/
90,
M.
Nelson
Dissociation
constant,
pKa
Not
applicable
due
to
low
water
solubility
Octanol/
water
partition
coefficient
572
at
25
°
C
DEB
#
5866,
1/
23/
90,
M.
Nelson
UV/
visible
absorption
spectrum
Not
available
3.0
Metabolism
Assessment
3.1
Rat
Metabolism
Oral
metabolism
studies
in
rats
showed
that
dicloran
is
rapidly
absorbed
and
metabolized
in
rats.
Approximately
96%
of
the
administered
dose
was
excreted
in
24
hours.
The
urine
was
the
major
route
of
excretion
(
86.3%
of
the
administered
dose),
and
smaller
amounts
in
feces
(
8.7%
of
the
administered
dose).
Dicloran
does
not
appear
to
accumulate
in
tissues.
The
major
urine
metabolites
were
DCHA­
sulfate,
and
DCHA­
glucuronide,
which
accounted
for
45.5%
to
79%
of
the
total
dose.
Other
metabolites
detected
were
DCHA
(
3.3
to
22.8%),
DCAP
(
0.3%
to
8.5%),
and
DCNAP
(<
0.1%
to
1.0%).
A
small
amount
of
dicloran
was
detected
in
feces.
The
metabolites
DCHA
and
DCAP
were
detected
in
plant
and
livestock
metabolism
studies.

3.2
Nature
of
the
Residue
in
Foods
3.2.1.
Description
of
Primary
Crop
Metabolism
The
nature
of
the
residue
in
plants
is
adequately
understood
based
on
acceptable
metabolism
studies
with
dicloran
on
peaches,
potatoes,
and
lettuce.
The
salient
features
of
these
plant
metabolism
studies
were
presented
to
the
HED
Metabolism
Assessment
Review
Committee
(
MARC)
on
May
8,
2001.
The
MARC
concluded
that
only
the
parent
compound
should
be
included
in
the
tolerance
expression
for
primary
crops.
The
Committee
also
recommended
that
one
major
metabolite,
2,6­
dichloro­
4­
16
of
84
hydroxyaniline
(
DCHA),
should
be
included
in
the
risk
assessments
for
all
presently
registered
crops
(
excluding
potato).
The
residues
of
concern
in
potatoes,
for
the
purpose
of
risk
assessment,
are
dicloran,
DCHA,
and
a
group
of
metabolites
designated
as
Unknown
1,
which
comprised
approximately
half
of
the
residues
characterized
in
the
potato
study.
The
registrant
tentatively
concluded
that
Unknown
1
was
most
likely
composed
of
glutathione­
conjugated
dicloran
metabolites
that
had
been
deaminated,
dechlorinated,
and/
or
hydroxylated,
and/
or
in
which
the
nitro
group
had
been
reduced
and
acetylated.

3.2.2
Description
of
Livestock
Metabolism
The
nature
of
the
residue
in
livestock
is
adequately
understood
provided
the
petitioner
could
provide
supporting
storage
stability
data
to
validate
the
integrity
of
samples
from
the
goat
and
hen
metabolism
studies
submitted
in
conjunction
with
PP#
7F04879.
The
salient
features
of
these
livestock
metabolism
studies
were
presented
to
the
HED
MARC
on
May
8,
2001.
The
MARC
concluded
that
the
terminal
residues
of
concern
(
or
residues
that
need
to
be
included
in
the
tolerance
expression
for
livestock
commodities)
will
include
dicloran
and
4­
amino­
2,6­
dichlorophenol
(
DCAP).
DCAP
is
included
since
dicloran
was
not
identified
in
the
liver
and
kidneys
of
ruminants.
For
risk
assessment
purposes,
the
HED
MARC
determined
that
the
residues
of
concern
in
livestock
commodities
are
dicloran,
DCAA,
DCHA,
DCAP,
DCNP,
and
the
A­
1
metabolite,
which
was
detected
in
milk
and
ruminant
liver
and
kidney.
Based
on
NMR
and
LC/
MS
analyses,
the
petitioner
proposed
that
A­
1
was
partially
comprised
of
2,6­
dichloro­
3­
glutathione­
4­
nitroaniline
and
4­
amino­
3­
chloro­
5­
glutathioneacetanilide.
Residues
of
A­
1
in
milk
will
be
estimated
based
on
the
ratio
of
A­
1
to
dicloran
in
the
metabolism
study
(
1.6x).
Residues
of
A­
1
in
ruminant
liver
and
ruminant
kidney
will
be
estimated
based
on
the
ratio
of
A­
1
to
DCAP
in
the
metabolism
study
(
liver
­
5.1x;
kidney
­
104x).
Because
the
MARC
concluded
that
the
metabolic
pathways
of
dicloran
in
livestock
and
rats
are
likely
to
be
qualitatively
similar,
a
swine
metabolism
study
need
not
be
conducted.

3.2.3
Description
of
Rotational
Crop
Metabolism,
including
identification
of
major
metabolites
and
specific
routes
of
biotransformation
Field
and
confined
accumulation
rotational
crop
studies
(
D270711,
5/
22/
01,
T.
Bloem
and
D246807,
3/
1/
05,
C.
Olinger)
were
submitted
for
dicloran.
The
limited
field
rotational
crops
study
only
included
analysis
for
the
parent
compound
and
did
not
include
the
aniline­
containing
metabolites.
The
study
was
conducted
at
0.9x
the
maximum
single
application
rate.
Current
product
labels
do
not
specify
a
maximum
number
of
applications
per
season,
so
these
residues
could
underestimate
the
actual
residues
in
rotational
crops.
For
these
reasons,
additional
limited
field
rotational
crop
studies
are
required
at
the
maximum
seasonal
application
rate
and
analyzing
for
the
total
dichloroanilinecontaining
residues.

For
the
confined
study,
uniformly
ring­
labeled
[
14C]
dicloran
was
mixed
with
nonlabeled
dicloran
and
dissolved
in
a
combination
of
water,
acetonitrile,
and
methanol
to
produce
a
test
substance.
The
prepared
test
substance
was
applied
as
a
broadcast
spray
(
without
any
further
incorporation)
to
the
soil
surface
of
sandy
loam
soil.
Application
of
the
test
substance
was
made
using
a
plastic
manual
trigger
sprayer
at
a
field­
equivalent
rate
of
13.2
lb
ai/
A
(
3.3x
the
maximum
single
application
rate).
Lettuce,
turnips,
and
wheat
were
planted
30,
120,
and
365
days
after
treatment
(
DAT).
All
samples
17
of
84
were
harvested
at
maturity
with
the
exception
of
the
wheat
crop.
Approximately
one­
half
of
the
wheat
was
sampled
at
the
immature
stage
to
yield
forage
samples.
Samples
were
analyzed
using
HPLC
and
TLC.
No
further
residue
characterization
and
identification
are
required
from
the
confined
rotational
crop
study.
See
Table
3.2.3
for
the
results
of
this
study.

The
MARC
concluded
that
dicloran
per
se
is
the
residue
of
concern
in/
on
rotational
crops
for
tolerance
expression.
For
risk
assessment,
the
residues
of
concern
are
dicloran
and
the
dichloroaniline­
containing
metabolites,
which
are
DCHA,
DCAA,
3,5­
DCHA,
DCPD,
DCAP,
DCNP,
2,6­
DCP,
2,6­
DCA,
Unknown
1.

Table
3.2.3
Major
Residues
Found
in
Confined
Rotational
Crop
Study
Analyte
Plantback
Interval
(
days)
Commodities
%
TRR
Found
30
Lettuce,
Turnip
Foliage,
Turnip
Root,
Wheat
Forage,
Wheat
Straw
12­
76
Dicloran
120
Lettuce,
Turnip
Foliage,
Turnip
Root,
Wheat
Forage
16­
23
DCAP
2
120
Wheat
Forage
11
DCPD
2
120
Wheat
Forage
11
30
Lettuce,
Turnip
Foliage,
Wheat
Forage,
Wheat
Grain
21­
29
Unknown
1
3
120
Turnip
Root,
Wheat
Forage,
Wheat
Grain
15­
20
120
Turnip
Foliage,
Turnip
Root,
Wheat
Grain
10­
17
Unknown
2
365
Lettuce,
Turnip
Foliage,
Turnip
Root,
Wheat
Forage
14­
42
Unknown
4
120
Wheat
Grain
30
Unknown
11
120
Wheat
Straw
12
Unknown
22
30
Wheat
Straw
12
30
Lettuce,
Turnip
Foliage,
Turnip
Root,
Wheat
Forage,
Wheat
Straw
20­
78
(
0.4
­
1.7
ppm)

120
Lettuce,
Turnip
Foliage,
Turnip
Root,
Wheat
Forage,
Wheat
Straw,
Wheat
Grain
8
­
66
(
0.2
­
0.9
ppm)
Total
Dicloran
plus
Unknown
1
360
Lettuce,
Turnip
Foliage,
Turnip
Root,
Wheat
Forage,
Wheat
Straw
3.1
­
12
(<
0.01
­
0.04
ppm)

30
Lettuce,
Turnip
Foliage,
Turnip
Root,
Wheat
Forage,
Wheat
Straw
47­
85
(
0.5
­
4.1
ppm)
Total
Known
Dichloranilinecontaining
Residues
4
120
Lettuce,
Turnip
Foliage,
Turnip
Root,
Wheat
Forage,
Wheat
Straw,
Wheat
Grain
15
­
66
(
0.2
­
1.8
ppm)
18
of
84
360
Lettuce,
Turnip
Foliage,
Turnip
Root,
Wheat
Forage,
Wheat
Straw
3.1
­
23
(<
0.01
­
0.04
ppm)

1
Major
residues
are
defined
as
those
comprising
greater
than
10%
of
the
TRR.
2
DCAP
=
4­
amino­
2,6­
dichlorophenol;
DCDP
=
4­
amino­
2,6­
dichloroaniline
3
Unknown
1
was
characterized
as
a
polar
multi­
component
species
derived
from
glutathione
conjugation
of
dicloran
at
one
or
both
of
the
chlorine
substitution
sites.
4
Includes
dicloran,
DCHA,
DCAA,
3,5­
DCHA,
DCPD,
DCAP,
DCNP,
2,6­
DCP,
2,6­
DCA
and
Unknown
1.

3.3
Environmental
Degradation
DCNA
is
a
low
volatility
compound
that
is
expected
to
be
persistent
and
to
have
low
or
almost
no
mobility
in
most
soils.
However,
dicloran
may
have
slightly
higher
mobility
in
coarser
(
sandy)
soils,
particularly
those
that
are
low
in
organic
matter.
DCNA
is
expected
to
undergo
faster
degradation
under
anaerobic
conditions
(
t1/
2'
s
of
0.5
­
10
days
in
anaerobic
aquatic
systems
and
t1/
2'
s
of
24­
38
days
in
anaerobic
soil)
than
under
aerobic
conditions
(
t1/
2'
s
of
approximately
6­
18
months
in
aerobic
soil),
with
much
of
the
apparent
loss
of
the
compound
attributed
to
the
formation
of
non­
extractable
residues.

In
the
field,
DCNA
is
expected
to
be
moderately
persistent
in
soil
based
on
a
first­
order
dissipation
half­
life
of
95
days.
The
compound
is
stable
to
hydrolysis,
but
does
undergo
both
aqueous
(
t1/
2
of
approximately
2
days)
and
soil
photodegradation
(
t1/
2
of
approximately
11
days).
However,
the
photolysis
rates
were
determined
under
optimal
conditions
in
the
laboratory
and
caution
must
be
used
in
extrapolating
laboratory
photolysis
data
to
the
environment.

There
is
a
potential
for
DCNA
to
reach
surface
water
through
spray
drift
when
applied
using
ground
spray
or
aerial
spray,
which
are
common
application
methods
for
many
of
the
DCNA
labeled
uses.
Since
DCNA
is
generally
persistent
under
field
conditions,
over
time
the
compound
may
be
present
in
field
runoff
and
could
thus
reach
surface
water
bodies.
The
slow
biodegradation
of
DCNA
in
most
soils
will
increase
the
potential
for
both
groundwater
and
surface
water
contamination.
However,
the
potential
for
groundwater
contamination
should
be
decreased
by
the
tendency
of
the
compound
to
adsorb
to
most
types
of
surface
soils.
While
DCNA
is
likely
to
adsorb
to
aquatic
sediments,
the
potential
for
the
compound
to
accumulate
in
such
environments
may
be
decreased
by
the
more
rapid
degradation
of
the
compound
in
anaerobic
conditions.

There
were
no
major
degradates
of
DCNA
in
the
laboratory
studies
(
i.
e.
none
accounted
for
as
much
as
10%
of
radioactivity
measured
at
any
point
in
the
studies),
with
the
exception
of
the
transformed
chemical
present
as
nonextractable
residues.
The
minor
degradates
of
DCNA
expected
in
the
environment
are:
DCPD,
DCAA,
DCHA,
and
3,5HA.
An
additional
degradate,
2,6­
dicholorbenzoic
acid,
was
identified
in
one
study
only
(
aerobic
aquatic
metabolism)
at
maximums
of
12.8%
(
day
7)
and
9.4%
(
day
7)
of
the
applied
in
the
two
water/
sediment
systems
studied,
with
the
majority
present
in
the
water
phase
of
each.
However,
that
study
was
classified
as
unacceptable
and
consequently
not
included
in
this
risk
assessment.

3.4
Toxicity
Profile
of
Major
Metabolites
and
Degradates
Plant
and
livestock
metabolites
of
DCNA
are
structurally
similar
to
the
parent
compound.
19
of
84
All
metabolites
belong
to
the
chemical
class
common
to
the
parent
of
substituted
aromatics.
There
is
no
specific
toxicity
data
available
for
any
metabolite;
therefore,
it
is
assumed
that
the
metabolites
and
the
parent
compound
share
similar
toxicity.

3.5
Summary
of
Residues
for
Tolerance
Expression
and
Risk
Assessment
3.5.1
Tabular
Summary
Table
3.5
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
All
Primary
Crops
except
Potatoes
Parent,
DCHA
Parent
Potatoes
Parent,
DCHA,
Unknown
1
Parent
Plants
Rotational
Crop
Parent,
DCHA,
DCAA,
3,5­
DCHA,
DCPD,
DCAP,
DCNP,
2,6­
DCP,
2,6­
DCA,
Unknown
1
Parent
Livestock
Ruminant
&
Poultry
Parent,
DCAP,
DCAA,
DCHA,
DCNP,
A­
1
metabolite
Parent,
DCAP
Drinking
Water
Parent
Not
Applicable
3.5.2
Rationale
for
Inclusion
of
Metabolites
and
Degradates
Metabolites
and
degradates
included
in
this
risk
assessment
are
based
on
recommendations
from
the
HED
Metabolism
Assessment
Review
Committee
and
the
Dicloran
Drinking
Water
Assessment
memo
provided
by
EFED.

Plant
and
livestock
metabolites
of
DCNA
are
structurally
similar
to
the
parent
compound.
All
metabolites
belong
to
the
chemical
class
common
to
the
parent
of
substituted
aromatics.
There
is
no
specific
toxicity
data
available
for
any
metabolite.
Therefore,
in
absence
of
evidence
to
the
contrary,
it
is
assumed
that
the
metabolites
and
the
parent
compound
share
similar
toxicity.

As
illustrated
in
the
above
table,
more
metabolites
are
included
in
the
risk
assessment
than
in
the
tolerance
expression.
However,
the
Metabolism
Committee
concluded
that
the
residues
of
the
parent
alone
are
sufficient
to
serve
as
a
measure
of
misuse
for
tolerance
purposes,
with
the
exception
of
livestock
commodities.
The
DCAP
metabolite
was
included
in
the
tolerance
expression
because
the
parent,
DCNA,
was
not
identified
in
the
liver
and
kidneys
of
ruminants.
20
of
84
4.0
Hazard
Characterization/
Assessment
4.1
Hazard
and
Dose­
Response
Characterization
4.1.1
Database
Summary
The
toxicological
database
on
dicloran
is
complete,
with
the
exception
of
a
developmental
neurotoxicity
study
in
rats
and
a
28­
day
inhalation
toxicity
study
in
rats.

4.1.1.1.
Studies
Available
and
Considered
°
Subchronic:
21­
day
dermal
toxicity,
21­
day
inhalation
toxicity,
90­
day
oral
toxicity
(
dog);
plus
others
°
Developmental:
rat
developmental
toxicity
study,
rabbit
developmental
toxicity
study
°
Reproduction:
2­
generation
reproduction
study
in
rats
°
Chronic:
combined
oral
chronic
toxicity/
carcinogenicity
(
rat);
carcinogenicity
(
mouse);
chronic
toxicity
(
dog)
°
Other:
mutagenicity
battery;
metabolism
study;

4.1.1.2.
Mode
of
action,
metabolism,
toxicokinetic
data
The
major
commercial
use
of
2,6­
dichloro­
4­
nitroaniline
is
as
a
fungicide
and
as
an
intermediate
in
the
manufacture
of
dye.
As
a
fungicide,
it
delays
germination
and
causes
a
severe
check
to
hyphal
growth.
It
is
suggested
that
dicloran
is
a
structurally
non­
specific
toxicant
exerting
its
effect
by
disorganizing
cell
growth
and
division
in
particular
plant
pathogens.
The
mode
of
action
in
test
animals
is
not
clear.

Oral
metabolism
studies
in
rats
showed
that
dicloran
is
rapidly
absorbed
and
metabolized
in
rats.
Approximately
96
%
of
the
administered
dose
was
excreted
in
24
hours.
The
urine
was
the
major
route
of
excretion
(
86.3%
of
the
administered
dose),
and
smaller
amounts
in
feces
(
8.7%
of
the
administered
dose).
Dicloran
does
not
appear
to
accumulate
in
tissues.
The
major
urine
metabolites
were
DCHA­
sulfate
and
DCHA­
glucuronide
which
accounted
for
45.5%
to
79%
of
the
total
dose.
Other
metabolites
detected
were
DCHA
(
3.3
to
22.8%),
DCAP
(
0.3%
to
8.5%),
and
DCNAP
(<
0.1%
to
1.0%).
A
small
amount
of
dicloran
was
detected
in
feces.

4.1.1.3.
Sufficiency
of
studies/
data
Data
are
sufficient
for
each
exposure
scenario,
FQPA
evaluation,
dose­
response
evaluation
and
endpoint
selection.

4.1.2.
Toxicological
Effects
°
Dicloran
has
low
acute
toxicity.
It
is
a
potential
skin
sensitizer.
The
toxicological
database
for
dicloran
is
adequate.
The
target
organs
include
the
liver,
kidney,
spleen
and
hematopoietic
21
of
84
system
(
anemia)
particularly
the
destruction
of
red
blood
cells.
It
is
positive
in
the
Ames
test
both
in
the
presence
and
the
absence
of
S9
activation
and
negative
in
both
the
in
vitro
chromosome
aberration
assay
in
human
lymphocytes
and
primary
rat
hepatocyte
unscheduled
DNA
synthesis
assay.
It
does
not
appear
to
be
a
reproductive
toxicant.
The
developmental
toxicity
study
in
rats
showed
increased
incidences
of
supernumerary
rudimentary
ribs
and
also
decreased
fetal
weights
in
the
presence
of
maternal
toxic
dose.
Although
no
neurotoxicity
studies
are
available,
the
available
data
did
not
demonstrate
neurotoxicity
with
subchronic
dosing
at
doses
lower
than
25
mg/
kg.
However,
neuropathology
was
seen
in
the
long
term
rat
study
(
NOAEL
=
11.3
mg/
kg/
day;
LOAEL
=
71
mg/
kg/
day)
with
chronic
dosing.
Neuropathology
was
seen
in
the
dogs
at
lower
levels
(
NOAEL
=
2.5
mg/
kg/
day;
LOAEL
=
25
mg/
kg/
day)
than
the
neuropathology
seen
in
the
long
term
rat
study.

°
The
chronic
toxicity
study
in
rats
showed
that
dicloran
caused
reduced
body
weight,
reduced
body
weight
gain,
and
histopathologic
lesions
in
the
brain
and
spinal
cord
of
both
sexes,
optic
nerve
in
females
and
Leydig
cell
hyperplasia
in
the
testes
in
males.
The
incidence
of
Leydig
cell
tumors
was
significantly
increased
in
high­
dose
male
rats
compared
with
the
control
incidence
and
the
incidence
of
endometrial
adenocarcinoma
was
marginally
increased
in
highdose
female
rats.
The
mouse
carcinogenicity
study
showed
no
treatment­
related
increase
in
tumor
incidence.
The
chronic
toxicity
study
in
dogs
showed
that
dicloran
caused
changes
in
clinical
chemistry,
increased
liver
weights,
hepatocyte
hypertrophy,
vacuolar
alterations
of
the
brain
and
spinal
cord,
prostate
atrophy,
degeneration
of
the
seminiferous
tubules,
and
hypospermia
in
the
epididymides.

°
The
committee
members
of
CARC
evaluated
the
carcinogenicity
studies
in
rats
and
mice
and
related
toxicity
data
on
dicloran
and
concluded
that
this
chemical
can
be
classified
as
"
Suggestive
Evidence
of
Carcinogenic
Potential"
and
recommended
no
quantification
of
cancer
risk
is
required.

4.1.3.
Dose­
response
The
developmental
rat
study,
one­
year
dog
study,
and
90­
day
oral
toxicity
study
in
dogs
were
the
primary
studies
used
for
the
dose­
response
assessment.
The
dog
is
the
most
sensitive
species
noted
from
testing
dicloran
with
the
effects
occurring
at
considerably
lower
doses
than
those
noted
for
the
rat
or
mouse.
The
developmental
rat
study
was
selected
for
the
acute
dietary
(
females
13­
49
years
of
age)
exposure
scenario
based
on
increased
incidences
of
supernumerary
rudimentary
ribs
and
decreased
fetal
weights.
An
acute
dietary
general
population,
including
infants
and
children,
endpoint
was
not
selected
for
this
population
group
because
there
were
no
effects
observed
in
oral
toxicology
studies
including
maternal
toxicity
in
the
developmental
toxicity
studies
in
rats
and
rabbits
that
are
attributable
to
a
single
exposure
(
dose).

For
short­
and
intermediate­
term
incidental
oral
exposures,
the
90­
day
oral
toxicity
study
in
dogs
was
selected
based
on
changes
in
hematological
(
decreased
hemoglobin
and
hematocrit
at
4,
8,
and
14
weeks)
and
clinical
biochemistry
parameters,
reduced
body
weight
gain,
increased
liver,
spleen
and
kidney
weights,
and
histopathological
changes
in
the
liver.
22
of
84
In
the
21­
day
dermal
toxicity
study
in
rabbits,
systemic
toxicity
[
increased
(
36%)
adrenal
weights
in
males
(
260
g
treated
vs
191
g
controls)]
was
noted
at
1200
mg/
kg/
day.
Therefore,
this
endpoint
was
selected
for
both
short­
and
intermediate­
term
dermal
risk
assessments.
For
short­
and
intermediateterm
inhalation
exposures,
the
90­
day
oral
toxicity
study
in
dogs
was
used.

Endpoints
and
dose
levels
for
chronic
dietary,
dermal
and
inhalation
exposures
were
based
on
the
chronic
oral
toxicity
study
in
dogs.
The
effects
observed
in
the
chronic
dog
study
were
changes
in
clinical
chemistry
(
increased
alkaline
phosphatase
in
both
sexes
and
increased
cholesterol
in
males),
increased
liver
weights,
hepatocyte
hypertrophy,
vacuolar
alterations
of
the
brain
and
spinal
cord,
prostate
atrophy,
degeneration
of
the
seminiferous
tubules,
and
hypospermia
in
the
epididymides.

The
committee
members
of
CARC
evaluated
the
carcinogenicity
studies
in
rats
and
mice
and
toxicity
data
on
dicloran
and
concluded
that
no
quantification
of
cancer
risk
is
required
based
on
the
"
Suggestive
Evidence
of
Carcinogenic
Potential"
classification.

The
uncertainty
factors
used
in
determining
the
acute
and
chronic
RfDs
(
aRfD
and
cRfD)
were
100
(
10x
for
intraspecies
variation;
10x
for
interspecies
extrapolation).

Acute
Toxicity
of
Technical
Dicloran
Guideline
No.
Study
Type
MRID
#(
S).
Results
Toxicity
Category
870.1100
Acute
Oral
00086879
LD50
=
1,000
mg/
kg
IV
870.1200
Acute
Dermal
00086894
LD50
=
>
2000
mg/
kg
mg/
kg
III
870.1300
Acute
Inhalation
Not
Available
LC50
=
m/
L
870.2400
Primary
Eye
Irritation
00086892
Mild
ocular
irritant
III
870.2500
Primary
Skin
Irritation
00086893
Not
a
dermal
irritant
IV
870.2600
Dermal
Sensitization
00082721
Potential
dermal
sensitizer
N/
A
23
of
84
SUBCHRONIC,
CHRONIC
AND
OTHER
TOXICITY
PROFILE
FOR
DICLORAN
Guideline
No./
STUDY
TYPE 
MRID
No.
(
year)/
Classification
/
Doses
NOAEL
(
mg/
kg/
day)
LOAEL
(
mg/
kg/
day)

870.4300
2­
year
combined
chronic/
carcino
genicity
 
rat
46360701
(
2004)

acceptable/
guideline
0,
60,
240
or
1200
ppm
for
the
first
105
days.
Dietary
concentration
was
raised
from
1200
ppm
to
1440
ppm
on
treatment
day
106
because
the
effects
on
body
weight
gains
in
animals,
especially
females
was
less
than
expected
from
the
90­
day
range
finding
study.
The
calculated
time­
weighted
average
dietary
concentration
for
the
high
dose
main
group
was
1405
ppm.
Males:
0,
2.8,
11.3,
and
71.0
mg/
kg/
day
Females:
0,
3.7,
15.0,
and
94.1
mg/
kg
/
day
M/
F:
11.3/
15.0
M/
F:
71.0/
94.1
based
on
reduced
body
weight,
reduced
body
weight
gain,
Histopathologic
lesions
in
the
brain
(
vacuolation
in
the
cerebral
cortex
including
the
optic
chiasma,
cerebellar
cortex,
and
medulla/
pons
regions
of
the
brain)
and
spinal
cord
of
both
sexes,
optic
nerve
in
females
and
Leydig
cell
hyperplasia
in
testes.
In
addition,
treatmentrelated
increase
in
the
relative
weights
in
the
liver,
brain
and
testes
in
males
and
relative
liver
weight
in
females
were
observed.

Suggestive
evidence
of
carcinogenic
potential.

Incidence
of
Benign
Leydig
cell
tumors
was
0/
50,
1/
50,
1/
50,
and
5/
50
(
p#
0.05)
in
control,
low­,
mid­
,
and
high­
dose
males
rats.
All
Leydig
tumors
were
found
in
animals
sacrificed
at
study
termination.

Incidence
of
malignant
endometrial
adenocarcinoma
was
3/
50,
7/
29,
7/
21,
and
9/
50
(
p=
0.061)
in
control,
low­,
mid­,
and
high­
dose
females
870.4200b
18
month
carcinogenicity
 
mouse
40977101
(
1989)

Acceptable/
guideline
0,
50,
175,
600
ppm
M/
F:
0/
0,
7.4/
10.1,
24.5/
35.4,
86.5/
118.8
mg/
kg/
day
24.5/
35.4
(
M/
F)
86.5/
118.8
(
M/
F)
histopathological
changes
in
liver
and
uterus:
microscopic
hepatic
lesions
in
males,
centrilobular
hepatocyte
vacuolation
in
females,
and
distended,
enlarged
uterus
with
cystic
endometrial
hyperplasia
increased
liver
weights
No
evidence
of
carcinogenicity
24
of
84
SUBCHRONIC,
CHRONIC
AND
OTHER
TOXICITY
PROFILE
FOR
DICLORAN
Guideline
No./
STUDY
TYPE 
MRID
No.
(
year)/
Classification
/
Doses
NOAEL
(
mg/
kg/
day)
LOAEL
(
mg/
kg/
day)

870.4100b
2­
year
chronic
study
in
dog
00029056,
00082718,
00026810
(
1962,
1964,
1979)

Acceptable/
guideline
0,
20,
100,
3000
ppm
0,
0.5,
2.5,
75
mg/
kg/
day
2.5
75
reduced
body
weight
gain,
increased
liver,
spleen
and
kidney
weights,
hematological
and
clinical
biochemistry
changes
and
histopathological
changes
in
the
liver.

870.4100b
1­
year
chronic
study
in
dog
45610801
(
2002)

Acceptable/
guideline
0,
33,
100,
3000
ppm
3­
weeks
 
Fed
in
diet
at
0/
0,
1.1/
1.4,
4.5/
3.8,
and
54.8/
57.7
mg/
kg/
day.
Weeks
4
through
11 
Changed
to
capsule
at
doses
of
0,
0.75,
2.5,
or
50
mg/
kg/
day
in
capsules.
After
weeks
11
 
The
dosage
was
reduced
from
50
mg/
kg
to
25
mg/
kg/
day.
2.5
25
changes
in
clinical
chemistry
(
increased
alkaline
phosphatase
in
both
sexes
and
increased
cholesterol
in
males),
increased
liver
weights,
hepatocyte
hypertrophy,
vacuolar
alterations
of
the
brain
and
spinal
cord,
prostate
atrophy,
degeneration
of
the
seminiferous
tubules,
and
hypospermia
in
the
epididymides
870.3800
2­
generation
reproduction
study 
rat
44233803,
44414101
(
1996,
1997)

Acceptable/
guideline
0,
50,
250,
1250
ppm
M/
F:
0/
0,
3.4/
4.1,
16.9/
20.3,
87/
102
mg/
kg/
day
Parental
systemic:
16.9/
20.3
Offspring
systemic:
16.9/
20.3
Reproductive:
87/
102
Parental
systemic:
87/
102
[
M/
F],
reduced
body
weight
gain
of
P
females
prior
to
mating,
and
in
both
generations
during
gestation
and
lower
body
weights
during
lactation;
increased
liver
weights
(
both
sexes),
kidney
weights
of
males
and
decrease
in
ovary
weights
of
females
in
the
F1
generation
Offspring
systemic:
87/
102
[
M/
F],
reduced
mean
pup
weights
of
both
generations
Reproductive:
Not
established
870.3700a
Developmental
toxicity 
rat
46447501
(
2003)

acceptable/
guideline
0,
50,
100,
or
200
mg/
kg/
day
Maternal:
not
established
Developmental:
50
Maternal:
50
(
LDT)
decreased
body
weight
gains
and
food
consumption
Developmental:
100
decreased
fetal
weights
and
increased
incidences
of
supernumerary
rudimentary
ribs
25
of
84
SUBCHRONIC,
CHRONIC
AND
OTHER
TOXICITY
PROFILE
FOR
DICLORAN
Guideline
No./
STUDY
TYPE 
MRID
No.
(
year)/
Classification
/
Doses
NOAEL
(
mg/
kg/
day)
LOAEL
(
mg/
kg/
day)

870.3700b
Developmental
toxicity 
rabbit
43952101
(
1996)

Acceptable1
0,
8,
20,
50
mg/
kg/
day
Maternal:
50
(
HDT)

Developmental:
50
(
HDT)
Maternal:
not
established
Developmental:
not
established
870.3100
90­
day
oral
toxicity­
rat
00029056,
00082718
(
1962,
1964)

Acceptable/
guideline
0,
20,
100,
3000
ppm
0,
1,
5,
150
mg/
kg/
day
5
150
reduced
body
weight
gain,
increased
liver
and
kidney
weights,
and
histopathological
changes
in
the
liver
and
adrenals
870.3100
90­
day
oral
toxicity­
rat
46360702
(
2001)

Acceptable/
guideline
0,
300,
1000,
2000,
or
4000
ppm
M:
0,
19.4,
61.5,
121.2,
and
246.8
mg/
kg/
day
F:
0,
25.4,
72.4,
133.6,
and
264.6
mg/
kg/
day
61.5/
72.4
(
121.2/
133.6
mg/
kg/
day)
decreased
body
weight,
weight
gain,
and
food
consumption
Non­
guideline
Subchronic
(
146­
day
study)
toxicity­
rat
00082719
(
1963)

Acceptable/
non
guideline
0,
5,
20,
100
mg/
kg/
day
0,
20
mg/
kg/
day
in
diet
20
100
reduced
body
weight
gain
of
females
NO
Hematopoetic
Activity:
at
100
870.3150
Subchronic
toxicity­
dog
00029056,
00026810,
00082718
(
1962,
1964,
1979)

Acceptable/
guideline
0,
20,
100,
3000
ppm
0,
0.5,
2.5,
75
mg/
kg/
day
2.5
75
reduced
body
weight
gain,
increased
liver,
spleen
and
kidney
weights,
hematological
and
clinical
biochemistry,
and
histopathological
changes
in
the
liver
870.3200
21­
Day
Dermal
Toxicity
 
rabbit
40555101
(
1988)
Acceptable/
guideline
0,
12,
120,
1200
mg/
kg/
day
120
1200
increased
adrenal
weights
(
36%
over
controls)
in
males.
This
finding
was
corroborated
by
the
histopathological
changes
observed
in
the
adrenals
at
150
mg/
kg/
day
in
the
90­
day
feeding
study
in
rats
(
MRIDs
00029056
and
00082718).
26
of
84
SUBCHRONIC,
CHRONIC
AND
OTHER
TOXICITY
PROFILE
FOR
DICLORAN
Guideline
No./
STUDY
TYPE 
MRID
No.
(
year)/
Classification
/
Doses
NOAEL
(
mg/
kg/
day)
LOAEL
(
mg/
kg/
day)

Non­
guideline
Subchronic
(
21­
Day)
Inhalation
toxicity­
rats,
rabbits
and
dogs
00086896
(
1980)

Acceptable/
non
guideline
2
mg/
L
2
mg/
L
Not
established
This
study
indicative
that
the
LC50
of
dicloran
technical
is
greater
than
2
mg/
L.

870.7485
Metabolism
study 
rat
44061001
(
1995)
Acceptable/
Guideline
5
or
500
mg/
kg
Dicloran
was
rapidly
absorbed
and
metabolized.
urine
[
86.3%];
feces
[
8.7%]
highest
tissue
residue
levels
7
days
post
dose­­
in
liver
and
kidneys
Urine
metabolites
DCHA­
sulfate
[
DCHA
=
4­
amino­
3,5­
dichlorophenol]
and
DCHA­
glucuronide
(
45.5%
to
79.0%
of
the
total
dose
administered)
DCHA
[
4­
amino­
3,5­
dichlorophenol
(
3.3%
to
22.8%)]
DCAP
[
4­
amino­
2,6­
dichlorophenol
(
0.3%
to
8.5%)]
DCNAP
[
3,5­
dichloro­
4­
hydroxyacetanilide
(<
0.1%
to
1.0%)].

Fecal
Metabolite
[
3.0%
to
7.6%]­
glutathione
conjugate
The
metabolism
of
Dicloran
involved
reduction/
deamination/
hydroxylation
of
the
nitro
group
to
yield
the
DCHA
metabolite,
then
conjugation
occurred
to
form
the
major
metabolites
DCHA­
sulfate
and
DCHA­
glucuronide.
DCAP
was
produced
through
reduction/
deamination/
hydroxylation.
Following
Nacetylation
DCNAP
was
formed.

A
minor
metabolic
pathway
involved
dechlorination/
hydroxylation
of
Dicloran
to
form
2­
hydroxy­
4­
nitro­
6­
chloroaniline.

870.7485
Metabolism
study 
RAT
43255401
and
43255402
(
1991)
Acceptable/
Guideline
(
excretion
and
distribution
study
only)

5
or
500
mg/
kg/
day
432554­
01
>
97%
of
the
dose
excreted
via
both
urine
and
feces
within
first
24
hours
post
dose
Urine:
 
78%
 
/
 
73%
 
Feces:
>
13%
[
 
]
/>
14%
[
 
]

432554­
02
>
92
excreted
via
both
urine
and
feces
within
the
first
48
hours
post
dose
Urine:
 
68%
in
both
sexes
Feces:
 
22%
[
both
sexes]
27
of
84
SUBCHRONIC,
CHRONIC
AND
OTHER
TOXICITY
PROFILE
FOR
DICLORAN
Guideline
No./
STUDY
TYPE 
MRID
No.
(
year)/
Classification
/
Doses
NOAEL
(
mg/
kg/
day)
LOAEL
(
mg/
kg/
day)

870.5265
Reverse
gene
mutation
assay
40508801
(
1987)
Acceptable
50­
5000
:
g/
plate
(
±
S9)
Mutagenic
870.5265
Reverse
gene
mutation
assay
00046435,
00046436
and
00087018
(
1976­
1977)
Acceptable
16­
1000
:
g/
plate
(
±
S9)
Not
mutagenic
870.5375
Chromosome
aberration
assays
40508802
(
1988)
Acceptable
2­
20
:
g/
plate
(
±
S9)
Not
mutagenic
870.5550
in
vitro
Unscheduled
DNA
synthesis
(
UDS)
assays
40619001
(
1988)
Acceptable
3­
10
:
g/
mL
Not
mutagenic
1
No
maternal
or
developmental
toxicity
was
observed
at
the
highest
dose
(
50
mg/
kg/
day)
tested
in
this
study.
However,
this
study
is
considered
acceptable
based
on
the
results
of
range­
finding
study
(
MRID
No.
44282901)
where
doses
levels
of
100
mg/
kg/
day
and
greater
resulted
in
deaths
and
decreased
body
weight
gains.

4.2
FQPA
Hazard
Considerations
4.2.1
Adequacy
of
the
Toxicity
Database
The
database
for
evaluating
in
utero
or
postnatal
susceptibility
is
adequate
and
includes
developmental
toxicity
studies
in
both
rats
and
rabbits
and
a
two­
generation
reproduction
study
in
the
rat.

4.2.2
Evidence
of
Neurotoxicity
Although
the
available
data
base
indicated
that
this
chemical
does
not
induce
neurotoxicity
in
subchronic
toxicity
study
in
rats,
mice,
and
dogs,
with
chronic
toxicity
study
in
rats
and
dogs,
vacuolar
alterations
of
the
brain
and
spinal
cord
was
seen
at
doses
of
25
mg/
kg
or
greater.

4.2.3
Developmental
Toxicity
Studies
Prenatal
Developmental
Toxicity
Study
­
Rat;
OPPTS
870.3700a
[
§
83­
3a];
OECD
414.

EXECUTIVE
SUMMARY:

In
a
developmental
toxicity
study
(
MRID
46447501),
Dicloran
(
97.17%
a.
i.,
Batch
#
020327)
was
administered
daily
via
oral
gavage
to
25
presumed
pregnant
Wistar
rats/
group
at
dose
levels
of
0,
50,
28
of
84
100,
or
200
mg/
kg/
day
from
gestation
day
(
GD)
6
through
20.
All
dams
were
killed
on
GD
21;
their
fetuses
were
removed
by
cesarean
section
and
examined.

Ruffled
fur
was
observed
at
100
mg/
kg/
day
in
one
dam
from
GD
10­
13
and
18­
21
and
in
the
remaining
24
dams
at
this
dose
from
GD
18­
21.
Ruffled
fur
was
noted
in
all
25
dams
at
200
mg/
kg/
day
from
GD
13­
21.
Bloody
discharge
from
the
vagina
was
noted
between
GD
13
and
GD
15
in
one
dam
at
100
mg/
kg/
day
and
7
dams
at
200
mg/
kg/
day.
It
was
stated
that
this
was
a
normal
finding
unrelated
to
treatment,
marking
the
time
of
transition
from
yolk
sac
to
placental
nutrition.
However,
the
dose­
relatedness
of
this
finding
indicates
that
it
may
be
due
to
the
test
substance.

At
>=
100
mg/
kg/
day,
body
weights
were
decreased
(
p<=
0.05)
by
4­
9%
compared
to
controls
beginning
on
GD
8
and
continuing
through
the
remainder
of
the
study.
Body
weight
gains,
expressed
as
a
percentage
of
the
body
weight
on
GD
6,
were
decreased
(
p<=
0.05)
in
all
of
the
treated
groups
compared
to
controls
beginning
on
GD
7
and
continuing
through
the
remainder
of
the
study.
Body
weight
gains
were
dose­
dependently
decreased
by
39­
106%
in
all
treated
groups
during
GD
6­
11,
resulting
in
decreased
body
weight
gains
for
the
overall
treatment
period
(
GD
6­
21),
both
when
corrected
for
gravid
uterine
weights
(
decr.
53­
124%;
p<=
0.01)
and
uncorrected
for
gravid
uterine
weights
(
decr.
11­
34%;
statistics
not
performed).
Gravid
uterine
weights
were
comparable
to
controls.
Additionally
in
the
200
mg/
kg/
day
dams,
body
weight
gains
were
decreased
by
25%
during
GD
16­
21.

Throughout
the
treatment
period,
food
consumption
was
dose­
dependently
decreased
(
p<=
0.05
or
0.01)
by
9­
43%
at
>=
50
mg/
kg/
day.

The
maternal
LOAEL
was
50
mg/
kg/
day
based
on
decreased
body
weight
gains
and
food
consumption.
The
maternal
NOAEL
was
not
established.

At
200
mg/
kg/
day,
increases
were
noted
in
the
numbers
of
early,
late,
and
total
resorptions,
both
on
an
absolute
basis
and
on
a
per
dam
basis.
These
increases
in
resorptions
led
to
an
increased
(
p<=
0.05)
post­
implantation
loss
in
this
group
(
11.0%)
compared
to
controls
(
6.9%).

Fetal
body
weights
were
decreased
at
100
mg/
kg/
day
in
the
males
and
at
200
mg/
kg/
day
in
both
sexes.
Non­
ossification
of
the
talus
was
increased
in
fetal
(
p<=
0.01)
and
litter
(
NS)
incidences
in
all
treated
groups
(
89­
93%
fetuses;
100%
litters)
compared
to
concurrent
controls
(
77%
fetuses;
96%
litters).
Only
fetal
incidences
of
the
right
talus
exceeded
historical
controls
and
this
was
not
considered
a
dose­
related
effect.

Incidences
of
supernumerary
rudimentary
ribs,
a
variation,
were
increased
(
p<=
0.05)
at
>=
100
mg/
kg/
day
(
49­
58%
fetuses;
92­
100%
litters)
compared
to
concurrent
(
28­
33%
fetuses;
68­
72%
litters)
and
historical
(
31­
40%
fetuses;
63­
92%
litters)
controls.
Additionally
at
200
mg/
kg/
day,
increased
fetal
(
p<=
0.05)
and
litter
(
NS)
incidences
of
one
right
supernumerary
rib
were
observed
(
5%
fetuses;
21%
litters)
compared
to
concurrent
(
1%
fetuses;
4%
litters)
and
historical
(
1%
fetuses;
4­
8%
litters)
controls.
Also,
the
digits
of
forelimb
and
hindlimb
were
affected
at
200
mg/
kg/
day.

There
were
no
treatment­
related
external,
visceral,
or
skeletal
malformations.
29
of
84
The
developmental
LOAEL
is
100
mg/
kg/
day
based
on
decreased
fetal
weights
and
increased
incidences
of
supernumerary
rudimentary
ribs.
The
developmental
NOAEL
is
50
mg/
kg/
day.

This
study
is
classified
acceptable/
guideline
(
OPPTS
870.3700a)
and
satisfies
the
guideline
requirements
for
a
developmental
study
in
the
rat.

Prenatal
Developmental
Toxicity
Study
­
Rabbit;
OPPTS
870.3700b
[
§
83­
3b];
OECD
414
A
rabbit
developmental
toxicity
(
MRID
No.
43952101)
was
tested
up
to
50
mg/
kg/
day.
No
maternal
or
developmental
toxicity
was
seen.

4.2.4
Reproductive
Toxicity
Study
Reproduction
and
Fertility
Effects
Study
 
Rat
[
OPPTS
870.3800
(
§
83­
4)
OECD
416]

EXECUTIVE
SUMMARY:
In
a
2­
generation
reproduction
study
(
MRID
44414101,
44233803),
dicloran
(
99.2%
a.
i.,
lot
#
WJC1)
was
administered
in
the
diet
continuously
to
2
generations
of
Sprague­
Dawley
rats
(
28
rats/
sex/
dose)
at
dose
levels
of
0,
50,
250,
or
1250
ppm
(
equivalent
to
0,
3.4/
4.1,
16.9/
20.3,
or
87/
102
mg/
kg/
day
[
M/
F]
in
the
P
and
F1
animals).
The
P
and
F1
animals
were
exposed
to
the
test
substance
for
approximately
10
weeks
prior
to
mating.
The
F1
animals
were
mated
at
approximately
15
week
of
age.
The
F1
animals
and
their
F2
litters
were
sacrificed
at
the
same
time
of
weaning
of
these
litters.

There
was
no
evidence
of
treatment­
related
mortality
in
the
P
or
F1
adults.
All
animals
in
the
high
dose
(
P
or
F1)
exhibited
yellow
staining
of
the
traypaper.
Staining
may
have
been
due
to
the
test
material
and/
or
metabolite
since
the
test
material
is
yellow.
Other
clinical
signs
in
P
or
F1
were
observed
but
these
signs
were
considered
incidental
findings
since
they
did
not
occur
in
dose­
related
manner.
No
treatment
related
differences
in
mean
body
weights
were
observed
in
male
and
female
rats
of
P
or
F1
compared
to
corresponding
concurrent
controls.
During
the
pre­
mating
period,
there
was
a
decrease
in
body
weight
gain
of
Fo
females
(
88.4%
of
the
controls)
at
1250
ppm,
compared
with
control
values
(
130
grams
vs
147
grams
for
controls).
In
the
F1
generation,
weight
gains
of
both
sexes
at
1250
ppm
were
marginally
lower
than
the
control
and
does
not
appear
to
be
statistically
(
standard
deviations)
significant
different
from
the
control
values.
In
both
generations,
weight
gain
during
gestation
at
1250
ppm
was
lower
than
control
(
F0
animals
,90%
of
the
controls;
F1
animals,
93%
of
the
controls).
Overall
average
food
consumption,
as
calculated
by
the
reviewers,
did
not
appear
to
show
any
differences
of
toxicological
concern
for
any
generation
during
premating,
gestation
or
lactation.

There
were
no
adverse
effects
of
dicloran
on
mating
performance
or
on
litter
size
and
survival,
but
mean
pup
weights
of
both
generations
(
and
hence
litter
weights)
at
1250
ppm
were
lower
than
controls.
At
the
high
dose,
decrease
in
mean
litter
body
weight
gain
was
80.9%
for
the
F1
generation
and
86.6%
for
the
F2
generation
compared
to
corresponding
controls.
At
the
high
dose,
decrease
in
pup
body
weight
gain
was
85.6%
for
the
males
and
86.6%
for
the
females
in
F1
generation
and
90.3%
for
the
males
and
87.8%
for
the
females
in
F2
generation
compared
to
corresponding
controls.
No
30
of
84
statistical
analysis
except
standard
deviation
of
the
mean
was
provided
in
the
study
report.
Based
on
the
reported
standard
deviations
these
differences
do
not
appear
to
be
statistically
different
from
control
values.

The
number
of
seminiferous
tubules
at
different
stages
were
essentially
comparable
in
the
control
and
the
high
dose
groups
of
both
generation.
The
mean
values
for
Stage
VII
tubule
diameter
did
not
indicate
any
effect
of
treatment.
In
the
Fo
generation
at
the
high
dose,
the
mean
number
of
abnormal
sperm,
particularly
of
sperm
with
tail
defects,
was
greater
than
the
control
value,
this
increase
was
due
to
a
few
animals
with
a
large
number
of
abnormal
sperm
(
more
than
10
sperm
with
tail
acutely
folded/
tightly
coiled).
Based
on
the
historical
control
data
(
not
provided
in
the
study
report)
,
together
with
the
absence
of
a
similar
response
in
the
F1
generation,
the
study
authors
concluded
that
the
increase
observed
in
the
Fo
generation
were
unlikely
to
be
of
biological
significance.
Due
to
unavailability
of
the
historical
control
data
to
the
reviewer,
it
is
not
possible
to
agree
with
the
conclusion
made
by
the
study
authors.

No
organ
weight
data
were
reported
for
Fo
generation.
Liver
weights
(
absolute
and
adjusted
to
body
weights)
were
increased
(
p#
0.05,
0.01
or
0.001)
for
the
F1
males
and
females
in
the
high
dose
group.
Increases
in
absolute
and
adjusted
(
to
body
weight)
liver
weights
were
observed,
but
were
not
accompanied
by
abnormal
hepatic
histopathology.
Kidney
weights
were
increased
for
the
F1
males
compared
to
controls;
higher
absolute
kidney
weights
were
significant
at
p<
0.05
level
and
higher
kidney
weights
adjusted
to
body
weight
were
significant
at
p<
0.001
level.
The
mean
ovary
weights
(
absolute
and
adjusted
to
body
weights)
of
F1
females
at
the
high
dose
were
lower
than
controls.
At
the
1250
ppm
dose
level,
there
was
a
slightly
increased
incidence
of
pro­
oestrous
morphology
and
slightly
decreased
incidence
of
metoestrous.
This
observation
was
more
apparent
in
the
Fo
than
the
F1
generation,
and
was
considered
to
be
probably
incidental
by
the
study
authors.
This
reviewer
is
in
agreement
with
study
author's
conclusion.

The
LOAEL
for
systemic
parental
toxicity
is
1250
ppm
(
equivalent
to
87/
102
mg/
kg/
day
[
M/
F])
based
on
significantly
reduced
body
weight
gain
of
Fo
females
prior
to
mating,
and
in
both
generations
during
gestation
and
lower
body
weights
during
lactation;
increased
liver
weights
(
both
sexes),
kidney
weights
of
males
and
decrease
in
ovary
weights
of
females
in
the
F1
generation.
The
NOAEL
is
250
ppm
(
equivalent
to
16.9/
20.3
mg/
kg/
day
[
M/
F]).

The
LOAEL
for
systemic
offspring
toxicity
is
1250
ppm
(
equivalent
to
87/
102
mg/
kg/
day
[
M/
F])
based
on
significantly
reduced
mean
pup
weights
of
both
generations;
increased
liver
weights
(
both
sexes),
kidney
weights
of
males
and
decrease
in
ovary
weights
of
females
in
the
F1
generation.
The
NOAEL
is
250
ppm
(
equivalent
to
16.9/
20.3
mg/
kg/
day
[
M/
F]).

The
NOAEL
for
reproductive
toxicity
is
1250
ppm
(
equivalent
to
87/
102
mg/
kg/
day
[
M/
F]).
The
LOAEL
was
not
established.

The
reproductive
study
is
determined
to
be
acceptable/
guideline
(
§
83­
4[
a])
and
does
satisfy
the
guideline
requirement
for
a
multigenerational
reproductive
toxicity
study
in
rats.
31
of
84
4.2.5
Additional
Information
from
Literature
Sources
There
were
no
data
available
from
the
general
literature,
including
human
clinical
or
exposure
data
at
this
time.

4.2.6
Pre­
and/
or
Postnatal
Toxicity
4.2.6.1
Determination
of
Susceptibility
No
qualitative
or
quantitative
evidence
for
increased
susceptibility
was
seen
in
the
developmental
toxicity
study
in
rats.
In
this
study
increased
incidences
of
supernumerary
rudimentary
ribs
and
decreased
fetal
weights
were
observed
at
a
higher
dose
than
maternal
toxicity.

There
is
no
quantitative
and
qualitative
evidence
of
increased
susceptibility
of
rat
offspring
in
the
multi­
generation
reproduction
study.
In
this
study,
offspring
toxicity
observed
was
significantly
reduced
mean
pup
weights
of
both
generations.
This
offspring
toxicity
was
observed
at
a
dose
which
produced
also
maternal
toxicity
including
reduced
body
weight
gain
of
Fo
females
prior
to
mating,
and
in
both
generations
during
gestation
and
lower
body
weights
during
lactation;
increased
liver
weights
(
both
sexes),
kidney
weights
of
males
and
decrease
in
ovary
weights
of
females
in
the
F1
generation.

4.2.6.2
Degree
of
Concern
Analysis
and
Residual
Uncertainties
for
Pre­
and/
or
Postnatal
Susceptibility
There
are
no
concerns
or
residual
uncertainties
for
pre­
and/
or
post­
natal
toxicity
following
exposure
to
dicloran
from
the
available
data,
although
a
DNT
is
required
(
see
Section
4.3
below).

4.3
Recommendation
for
a
Developmental
Neurotoxicity
Study
No
acute
or
subchronic
neurotoxicity
studies
are
available
in
the
database.
In
a
rat
developmental
toxicity
study,
no
clinical
signs
of
neurotoxicity
were
reported.
Paralysis
and
depression
was
reported
in
an
acute
oral
toxicity
study
at
2500
mg/
kg.

A
DNT
study
is
recommended
and
evidence
that
supports
requiring
a
DNT
study
is
listed
below.

4.3.1
Evidence
in
favor
of
retaining
the
10X/
requiring
further
evaluation
of
neurobehavioral
development
°
Dicloran
appears
to
be
highly
neurotoxic
(
vacuolation
in
the
brain)
at
doses
of
25­
75
mg/
kg
following
exposures
greater
than
90
days.
Ninety­
eight
percent
of
animals
were
affected
so
this
is
a
true
effect.

°
Single
high
doses
of
aniline
produced
similar
neuropathology.
The
neuropathological
effects,
32
of
84
were
greater
in
four
week
old
rats
than
seven
week
old
rats,
indicating
that
age
could
be
an
important
variable
in
this
neurotoxicity.

4.3.2
Evidence
against
retaining
the
10X/
requiring
further
evaluation
of
neurobehavioral
development
°
No
neurotoxic
signs
were
seen
in
any
of
the
studies
with
dicloran,
including
studies
indicating
significant
neuropathology.

°
Neuropathology
was
reported
only
at
the
highest
doses
tested
in
chronic
dog
and
rat
studies.

°
There
was
no
dose­
response.

°
Regulatory
endpoints
are
based
on
the
NOAEL
(
2.5
mg/
kg)
for
the
dog
chronic
study,
the
more
sensitive
species,
is
10­
30
times
lower
than
doses
producing
neuropathology
(
25­
27
mg/
kg).

°
Neuropathology
appears
to
require
either
very
high
doses
or
exposures
greater
than
90
days.

°
There
was
no
susceptibility
evidence
in
developmental
and
reproductive
studies.

°
A
study
in
rats
is
unlikely
to
yield
a
lower
NOAEL,
as
the
dog
is
a
more
sensitive
species.

Although
a
DNT
study
is
unlikely
to
result
in
a
more
sensitive
endpoint
than
those
currently
being
used
for
risk
assessment,
the
study
is
necessary
to
fully
characterize
potential
fetal
neurotoxicity
and
neuropathology.
Therefore,
the
study
is
required
and
the
10X
FQPA
special
safety
factor
is
retained.

4.4
Hazard
Identification
and
Toxicity
Endpoint
Selection
4.4.1
Acute
Reference
Dose
(
aRfD)
­
Females
age
13­
49
Study
Selected:
Rat
developmental
toxicity
study
MRID
No.:
46447501
Executive
Summary:

In
a
developmental
toxicity
study
(
MRID
46447501),
Dicloran
(
97.17%
a.
i.,
Batch
#
020327)
was
administered
daily
via
oral
gavage
to
25
presumed
pregnant
Wistar
rats/
group
at
dose
levels
of
0,
50,
100,
or
200
mg/
kg/
day
from
gestation
day
(
GD)
6
through
20.
All
dams
were
killed
on
GD
21;
their
fetuses
were
removed
by
cesarean
section
and
examined.
33
of
84
Ruffled
fur
was
observed
at
100
mg/
kg/
day
in
one
dam
from
GD
10­
13
and
18­
21
and
in
the
remaining
24
dams
at
this
dose
from
GD
18­
21.
Ruffled
fur
was
noted
in
all
25
dams
at
200
mg/
kg/
day
from
GD
13­
21.
Bloody
discharge
from
the
vagina
was
noted
between
GD
13
and
GD
15
in
one
dam
at
100
mg/
kg/
day
and
7
dams
at
200
mg/
kg/
day.
It
was
stated
that
this
was
a
normal
finding
unrelated
to
treatment,
marking
the
time
of
transition
from
yolk
sac
to
placental
nutrition.
However,
the
dose­
relatedness
of
this
finding
indicates
that
it
may
be
due
to
the
test
substance.

At
>=
100
mg/
kg/
day,
body
weights
were
decreased
(
p<=
0.05)
by
4­
9%
compared
to
controls
beginning
on
GD
8
and
continuing
through
the
remainder
of
the
study.
Body
weight
gains,
expressed
as
a
percentage
of
the
body
weight
on
GD
6,
were
decreased
(
p<=
0.05)
in
all
of
the
treated
groups
compared
to
controls
beginning
on
GD
7
and
continuing
through
the
remainder
of
the
study.
Body
weight
gains
were
dose­
dependently
decreased
by
39­
106%
in
all
treated
groups
during
GD
6­
11,
resulting
in
decreased
body
weight
gains
for
the
overall
treatment
period
(
GD
6­
21),
both
when
corrected
for
gravid
uterine
weights
(
decr.
53­
124%;
p<=
0.01)
and
uncorrected
for
gravid
uterine
weights
(
decr.
11­
34%;
statistics
not
performed).
Gravid
uterine
weights
were
comparable
to
controls.
Additionally
in
the
200
mg/
kg/
day
dams,
body
weight
gains
were
decreased
by
25%
during
GD
16­
21.

Throughout
the
treatment
period,
food
consumption
was
dose­
dependently
decreased
(
p<=
0.05
or
0.01)
by
9­
43%
at
>=
50
mg/
kg/
day.

The
maternal
LOAEL
was
50
mg/
kg/
day
based
on
decreased
body
weight
gains
and
food
consumption.
The
maternal
NOAEL
was
not
established.

At
200
mg/
kg/
day,
increases
were
noted
in
the
numbers
of
early,
late,
and
total
resorptions,
both
on
an
absolute
basis
and
on
a
per
dam
basis.
These
increases
in
resorptions
led
to
an
increased
(
p<=
0.05)
post­
implantation
loss
in
this
group
(
11.0%)
compared
to
controls
(
6.9%).

Fetal
body
weights
were
decreased
at
100
mg/
kg/
day
in
the
males
and
at
200
mg/
kg/
day
in
both
sexes.
Non­
ossification
of
the
talus
was
increased
in
fetal
(
p<=
0.01)
and
litter
(
NS)
incidences
in
all
treated
groups
(
89­
93%
fetuses;
100%
litters)
compared
to
concurrent
controls
(
77%
fetuses;
96%
litters).
Only
fetal
incidences
of
the
right
talus
exceeded
historical
controls
and
this
was
not
considered
a
dose­
related
effect.

Incidences
of
supernumerary
rudimentary
ribs,
a
variation,
were
increased
(
p<=
0.05)
at
>=
100
mg/
kg/
day
(
49­
58%
fetuses;
92­
100%
litters)
compared
to
concurrent
(
28­
33%
fetuses;
68­
72%
litters)
and
historical
(
31­
40%
fetuses;
63­
92%
litters)
controls.
Additionally
at
200
mg/
kg/
day,
increased
fetal
(
p<=
0.05)
and
litter
(
NS)
incidences
of
one
right
supernumerary
rib
were
observed
(
5%
fetuses;
21%
litters)
compared
to
concurrent
(
1%
fetuses;
4%
litters)
and
historical
(
1%
fetuses;
4­
8%
litters)
controls.
Also,
the
digits
of
forelimb
and
hindlimb
were
affected
at
200
mg/
kg/
day.

There
were
no
treatment­
related
external,
visceral,
or
skeletal
malformations.
34
of
84
The
developmental
LOAEL
is
100
mg/
kg/
day
based
on
decreased
fetal
weights
and
increased
incidences
of
supernumerary
rudimentary
ribs.
The
developmental
NOAEL
is
50
mg/
kg/
day.
This
study
is
classified
acceptable/
guideline
(
OPPTS
870.3700a)
and
satisfies
the
guideline
requirements
for
a
developmental
study
in
the
rat.

Dose
and
Endpoint
for
Establishing
RfD:
NOAEL=
50
mg/
kg/
day
based
on
increased
incidences
of
supernumerary
rudimentary
ribs
and
also
decreased
fetal
weights
at
100
mg/
kg/
day
(
LOAEL).

Uncertainty
Factor
(
UF):
100X
[
10
interspecies;
10X
intraspecies]

Comments
about
Study/
Endpoint/
Uncertainty
Factor:
The
study
is
appropriate
for
a
single
dose
exposure
with
the
effects
of
concern
via
the
oral
route
and
length
of
exposure
for
an
acute
dietary
endpoint.
The
endpoints
for
risk
assessment
are
based
on
increased
incidences
of
supernumerary
rudimentary
ribs.
The
developmental
effects
are
presumed
to
occur
as
a
result
of
a
single
dose
at
a
critical
time
during
gestation.

4.4.2
Acute
Reference
Dose
(
aRfD)
­
General
Population
A
dose
and
endpoint
were
not
selected
for
this
population
group
because
there
were
no
effects
observed
in
oral
toxicology
studies
including
maternal
toxicity
in
the
developmental
toxicity
studies
in
rats
and
rabbits
that
could
be
attributable
to
a
single
exposure
(
dose).

4.4.3
Chronic
Reference
Dose
(
RfD)

TWO
CHRONIC
DOG
STUDIES
WERE
CONSIDERED
TO
SELECT
THE
ENDPOINT.

NEW
STUDY
(
2002) 
This
new
study
was
conducted
because
HIARC
recommended
new
chronic
toxicity
study
in
dog
since
the
existing
dog
study
appears
to
drive
the
risk
assessment
and
NOAEL
appears
to
be
artificially
low.

Study
Selected:
One
Year
Chronic
Toxicity
Study
­
dog,
OPPTS
Number:
870.4100
EXECUTIVE
SUMMARY
­
In
a
chronic
oral
toxicity
study
(
MRID
45610801),
Dicloran
(
94.6%
a.
i.,
Lot/
Batch
#
000313
or
98.3%
a.
i.,
Lot/
Batch#
QH­
1006)
was
administered
to
4
male
and
female
beagle
dogs/
group
in
the
diet
at
concentrations
of
0,
33,
100,
or
3000
ppm
(
equivalent
to
0/
0,
1.1/
1.4,
4.5/
3.8,
and
54.8/
57.7
mg/
kg/
day)
for
the
first
3
weeks.
Subsequently,
dosing
was
changed
from
dietary
to
capsule
at
doses
of
0,
0.75,
2.5,
or
50
mg/
kg/
day
in
capsules
for
Weeks
4
through
11.
Due
to
poor
health
conditions
in
the
high
doses
group,
the
dosage
of
this
group
was
reduced
from
50
mg/
kg
to
25
mg/
kg/
day
after
Weeks
11.
Acute
RfD
=
50
mg/
kg/
day
(
NOAEL)
=
0.5
mg/
kg/
day
100
(
UF)
35
of
84
No
adverse
treatment­
related
effects
were
noted
in
mortality,
ophthalmology,
hematology,
or
urinalysis.

Food
consumption
was
decreased
( 
43­
72%;
p<
0.05­
0.01)
in
both
sexes
at
3000
ppm
(
high
dose
group)
during
Weeks
1­
3.
Decreased
food
consumption
was
reflected
in
decreased
body
weights
( 
11­
27%;
p<
0.05­
0.01)
at
3000
ppm
in
males
at
Weeks
2­
6
and
in
females
at
Weeks
2­
3
and
in
decreased
body
weight
gains
(
p<
0.05)
in
males
at
Weeks
2­
6
and
in
females
at
Weeks
2­
3.
Slight
to
moderate
thinness
or
emaciation
was
observed
in
a
majority
of
animals
at
this
dose
(
high
dose
group)
during
Weeks
2­
5.
The
Sponsor
stated
that
these
effects
were
associated
with
the
lack
of
palatability
of
the
diet
and
subsequently
changed
the
administration
of
test
compound
to
capsules
after
Week
3.

Several
weeks
following
the
change
to
capsule
administration,
estimated
food
consumption
at
50
mg/
kg/
day
(
high
dose
group)
was
lower
in
males
(
Weeks
8­
11)
and
females
(
Weeks
10­
11).
At
this
dose,
decreased
body
weights
( 
11­
19%;
p<
0.05)
were
observed
in
males
during
Weeks
6­
13.
Additionally,
weekly
body
weight
gains
were
decreased
(
p<
0.05)
in
males
during
Weeks
6­
13.
Increased
incidences
of
slight
thinness
or
emaciation
were
observed
again
in
Weeks
10­
12
in
both
sexes
at
50
mg/
kg/
day.
As
a
result
of
these
effects,
the
high
dose
was
lowered
from
50
mg/
kg/
day
to
25
mg/
kg/
day.
No
further
treatment­
related
decreases
in
weekly
body
weight,
body
weight
gain,
food
consumption,
or
clinical
signs
were
observed.
However,
overall
(
Weeks
1­
13,
1­
26,
and
1­
53)
body
weight
gain
was
lower
in
the
high
dose
group
males
( 
12­
46%)
compared
to
controls.

In
high
dose
group,
alkaline
phosphatase
was
increased
( 
183­
384%;
p 
0.05­
0.01)
in
the
males
throughout
the
study.
In
females
at
this
dose,
alkaline
phosphatase
was
increased
at
3
months
( 
112%;
p 
0.05)
and
higher
than
controls
at
6,
9,
and
12
months
( 
55­
120%;
not
significant).
Serum
cholesterol
was
increased
in
males
at
6,
9,
and
12
months
( 
47­
55%;
p 
0.01).

Absolute
and
relative
(
body)
liver
weights
were
increased
( 
27­
48%;
p 
0.05­
0.01)
in
both
sexes
of
the
high
dose
group.
These
increases
were
consistent
with
increased
incidences
of
minimal
centrilobular
hepatocyte
hypertrophy
observed
in
all
animals
of
both
sexes
at
this
dose.

In
high
dose
group,
increased
incidences
of
extensive
vacuolation
of
the
white
matter
of
the
brain
and
all
three
levels
of
the
spinal
cord
were
observed
in
both
sexes.
In
males,
minimal
to
moderately
severe
atrophy
of
the
prostate
was
also
observed
in
all
males
in
this
group,
and
the
incidences
of
grossly
observed
small
prostate
were
higher
than
controls
(
2/
4
treated
vs
0/
4
controls).
Additionally,
slight/
mild
to
moderate
degeneration
of
the
seminiferous
tubules
and
moderate
to
moderately
severe
hypospermia
in
the
epididymides
were
observed
in
the
two
high
dose
group
males.

No
effects
were
observed
at
the
lower
doses.

The
LOAEL
was
25
mg/
kg/
day
based
on
clinical
chemistry
(
increased
alkaline
phosphatase
in
both
sexes
and
increased
cholesterol
in
males),
increased
liver
weights,
hepatocyte
hypertrophy,
36
of
84
vacuolar
alterations
of
the
brain
and
spinal
cord,
prostate
atrophy,
degeneration
of
the
seminiferous
tubules,
and
hypospermia
in
the
epididymides.
The
NOAEL
was
2.5
mg/
kg/
day.

This
study
is
classified
as
acceptable/
guideline
and
satisfies
the
guideline
requirements
(
OPPTS
870.4100b;
OECD
452)
for
a
non­
rodent
chronic
oral
toxicity
study.

OLD
STUDY
(
1962,
1964,
1979)
Study:
Two
Year
Chronic
Toxicity
­
dog,
OPPTS
Number:
870.4100
MRID
Nos.:
00029056,
00082718,
00026810
Executive
Summary:
In
this
chronic
(
104­
107
weeks)
oral
toxicity
study
(
MRID
00029056,
00082718),
dicloran
technical
grade
(
Lot
#
PS02451,
97.1%)
was
administered
in
the
diet
to
beagle
dogs
(
4/
sex/
group)
for
up
to
104
weeks
at
nominal
doses
of
0,
20,
100,
or
3000
ppm
(
equivalent
to
0,
0.5,
2.5
or
75
mg/
kg/
day).
Hematological,
clinical
chemistry
and
urinalysis
measurements
were
performed
on
all
dogs
at
0,
4,
8,
13,
26,
41,
52,
65,
78,
91,
and
104
weeks.
During
the
14
th
week,
1
male
and
1
female
dog
from
each
group
was
sacrificed
and
complete
autopsies
were
performed.
Selected
organs
were
weighed
and
histopathologic
examination
was
performed.
At
termination
(
104­
107
weeks),
all
surviving
dogs
were
sacrificed,
necropsied
and
selected
organs
were
weighed
and
histopathological
examination
was
performed.

No
mortality
was
observed
in
104
weeks
except
one
female
dog
from
the
high
dose
group
died
in
comatose
state
during
the
74th
week.
This
dog
and
one
dog
from
the
control
group
experienced
a
body
weight
loss.
Analysis
of
variance
indicated
that
there
was
no
difference
in
body
weights
between
treated
dogs
and
controls
at
104
week.
All
dogs
showed
normal
reflex
reactions
and
appeared
normal
with
the
exception
of
one
female
dog
in
the
high
dose
group
that
died.
At
the
high
dose,
watery
lacrimation
was
present
for
all
dogs
soon
after
the
start
of
the
study
and
persisted
throughout
the
study.
Mild
yellowing
of
the
sclera,
mucous
membranes,
and
abdominal
skin
was
noted
for
three
dogs
in
the
high
dose,
which
may
be
due
to
deposits
of
the
chemical
and/
or
its
metabolite
or
liver
toxicity
(
jaundice).

Hemoglobin
values
were
slightly
lower
for
the
high
dose
starting
at
week
4.
Similar
trends
were
observed
for
the
hematocrit
values.
Hemoglobin
and
hematocrit
values
were
similar
through
out
the
study
for
the
control,
20
ppm
and
100
ppm
dose
group.
Hematocrit
values
for
the
high­
dose
fluctuated.
The
erythrocytic
series
showed
immature
cells
and
numerous
polychromatophilic
macrocytes.
Actual
thrombocyte
(
platelets)
counts
were
not
conducted
after
13
week
because
no
differences
in
size
or
number
were
seen
at
the
later
intervals.

Clinical
chemistry
consisting
of
BUN
(
blood
urea
nitrogen),
methemoglobin,
fasting
blood
sugar
and
creatinine
remained
within
control
values
for
all
dogs.
Statistical
analysis
of
serum
chemistry
indicated
that
significant
elevation
in
serum
glutamic
pyruvic
transaminase
(
SGPT),
and
serum
alkaline
phosphatase
(
SAP)
values
occurred
in
the
high
dose
group
during
specific
intervals
of
the
study.
Increase
in
the
values
for
these
parameters
were
first
noted
at
week
8.
The
SGOT,
SGPT
and
SAP
values
were
similar
for
the
controls,
20
ppm
and
100
ppm
dose
group
dogs.
Results
of
bromsulphthalein
(
BSP)
indicated
elevated
levels
for
two
dogs
in
the
high
dose
group.
The
37
of
84
elevated
levels
were
not
sustained
indicating
that
this
was
probably
not
related
to
liver
dysfunction.

Urinalysis
indicated
highly
pigmented
urine
in
the
high­
dose
group.
No
remarkable
abnormalities
in
urinalysis
were
observed
between
the
controls
and
treated
groups.

Organ
weight
data
indicated
that
the
20
and
100
ppm
treatment
group
organ
weights
were
comparable
to
those
of
the
control.
However,
statistically
significant
increases
(
p
<
0.05)
of
kidney,
spleen,
and
liver
weights
were
evident
in
the
high
dose
group.

Histological
examination
revealed
liver
changes
at
the
high
dose
characterized
by
irregular
hepatic
cell
size,
hepatic
cell
hypertrophy,
increased
pigmentation
of
hepatic
cells
and
of
liver
macrophages.
Changes
in
gall
bladder
were
observed
for
the
two
dogs
in
the
high
dose
group
and
one
dog
in
the
20
ppm
group.

The
LOAEL
is
3000
ppm
(
equivalent
to
75
mg/
kg/
day)
based
on
reduced
body
weight
gain,
increased
liver,
spleen
and
kidney
weights,
hematological
and
clinical
biochemistry,
and
histopathological
changes
in
the
liver.
The
NOAEL
is
100
ppm
(
equivalent
to
2.5
mg/
kg/
day).

The
submitted
study
is
classified
as
acceptable/
guideline
(
§
83­
1[
b])
and
does
satisfy
the
requirements
for
a
chronic
toxicity
study
in
dogs.

Dose
and
Endpoint
for
Establishing
RfD:
2.5
mg/
kg/
day
(
NOAEL),
based
on
clinical
chemistry
(
increased
alkaline
phosphatase
in
both
sexes
and
increased
cholesterol
in
males),
increased
liver
weights,
hepatocyte
hypertrophy,
vacuolar
alterations
of
the
brain
and
spinal
cord,
prostate
atrophy,
degeneration
of
the
seminiferous
tubules,
and
hypospermia
in
the
epididymides
at
25
mg/
kg/
day.
The
older
study
(
MRID
00029056,
00082718,
00026810)
showed
reduced
body
weight
gain,
increased
liver,
spleen
and
kidney
weights,
hematological
and
clinical
biochemical
changes,
and
histopathological
changes
in
the
liver
at
3000
ppm
(
LOAEL=
75
mg/
kg/
day).

Uncertainty
Factor(
s):
100X
[
10
interspecies;
10X
intraspecies]

Comments
about
Study/
Endpoint/
Uncertainty
Factor(
s):
The
study
duration
and
route
of
exposure
is
appropriate
for
this
risk
assessment.
The
effects
of
concern
(
decreased
body
weight
gain,
liver
histopathology,
increased
liver
weights
and
hematological
changes)
seen
in
this
study
were
also
seen
in
other
subchronic
and
chronic
studies
in
dogs.

4.4.4
Incidental
Oral
Exposure
(
Short
and
Intermediate
Term)

Study
Selected:
90­
Day
feeding
study
in
dogs
Chronic
RfD
=
2.5
mg/
kg/
day
(
NOAEL)
=
0.025
mg/
kg/
day
100
(
UF)
38
of
84
MRID
No.:
MRIDs
00029056,
00026810,
00082718
Executive
Summary:
In
a
90­
day
toxicity
study
(
MRID
00029056,
00026810),
dicloran
technical
grade
(
Lot
#
PS02451,
97.1%)
was
administered
in
the
diet
to
beagles
dogs
(
4/
sex/
group)
for
up
to
104
weeks
at
nominal
doses
of
0,
20,
100,
or
3000
ppm
(
equivalent
to
0,
0.5,
2.5
or
75
mg/
kg/
day).
This
is
an
interim
report
(
13
Weeks)
of
a
104
week
study.
Hematological,
clinical
chemistry
and
urinalysis
measurements
were
performed
on
all
dogs
at
0,
4,
8,
and
13
weeks.
During
the
14th
week,
1
male
and
1
female
dog
from
each
group
was
sacrificed
and
complete
autopsies
were
performed.
Selected
organs
were
weighed
and
histopathologic
examination
was
performed.

No
mortality
was
observed
in
13
weeks.
With
the
exception
of
one
female
dog
receiving
100
ppm,
all
dogs
on
the
100
and
20
ppm
levels
gained
body
weight
comparable
with
control
dogs.
In
the
high
dose
group,
two
male
dogs
showed
significant
body
weight
loss(
28
and
18%
of
their
initial
body
weights)
and
one
female
showed
slight
weight
loss.
All
dogs
showed
normal
reflex
reactions
and
appeared
normal
with
the
exception
of
one
male
dog
in
the
high
dose
group
and
one
female
dog
in
the
100
ppm
dose
group.
The
female
dog
receiving
100
ppm
in
the
diet
showed
hair
loss
around
the
ears,
neck,
and
anal
regions
and
male
dog
in
the
high
dose
group
appeared
emaciated
and
icterit.

Clinical
chemistry
consisting
of
BUN
(
blood
urea
nitrogen),
methemoglobin,
fasting
blood
sugar
and
creatinine
remained
within
control
values
for
all
dogs.
Hematological
examination
revealed
that
the
dogs
receiving
20
and
100
ppm
of
dicloran
in
the
diet
could
not
be
distinguished
from
control
dogs.
However,
the
dogs
in
the
3000
ppm
dose
group
showed
evidence
of
anemia.
All
males
and
two
females
at
this
level
showed
a
decrease
in
hemoglobin
and
packed
cell
volume;
the
most
marked
reduction
being
in
one
male
dog
whose
initial
hemoglobin
was
14.3
and
at
13
week
was
8.1
grams.
Three
of
the
four
males
showed
leukocytosis.
Thrombocyte
counts
were
slightly
elevated
in
the
dogs
receiving
3000
ppm
than
in
the
control
dogs
at
9
and
13
week
measurements.
The
thrombocyte
counts
of
the
high
dose
level
dogs
ranged
from
342,500
to
575,000
whereas
the
control
dogs
ranged
from
241,500
to
315,000.
Urinalysis
indicated
highly
pigmented
urine
and
more
cast
in
the
high
dose
level
dogs
compared
to
urine
of
the
control
dogs.

Biochemical
values
likewise
on
the
dogs
receiving
100
and
20
ppm
levels
in
the
diet
could
not
be
distinguished
from
control
values.
Two
males
and
one
female
dog
in
the
high
dose
group
showed
increase
in
serum
alkaline
phosphatase,
serum
glutamic
pyruvic
transaminase
(
SGPT),
serum
glutamic
oxalacetic
transaminase
(
SGOT),
prothrombin
time
and
slight
reduction
in
serum
protein.

Gross
autopsy
did
not
show
any
changes
except
tissue
coloring
of
high
dose
dogs.
Organ
weights
expressed
relative
to
body
weight
suggest
slightly
enlarged
livers
and
kidneys
at
the
high
dose.
There
was
increase
in
spleen
weights
at
the
high
dose,
which
may
be
due
to
destruction
of
red
blood
cells
as
indicated
by
decreases
in
hemoglobin
and
hematocrit
values.
Statistically
analysis
(
MRID
00086902)
indicates
that
there
was
no
difference
in
hemoglobin
values,
hematocrit
values,
and
absolute
and
adjusted
(
to
body
weight)
liver
weights
at
100
ppm
dose
level.
39
of
84
Histological
examination
of
the
tissues
revealed
no
changes
related
to
compound
administration
other
than
some
moderate
degenerative
and
chronic­
inflamatory
hepatic
changes
in
the
3000
ppm
level.

The
LOAEL
is
3000
ppm
(
equivalent
to
75
mg/
kg/
day)
based
on
reduced
body
weight
gain,
increased
liver,
spleen
and
kidney
weights,
hematological
and
clinical
biochemistry,
and
histopathological
changes
in
the
liver.
The
NOAEL
is
100
(
equivalent
to
2.5
mg/
kg/
day).

The
submitted
study
is
classified
as
acceptable/
guideline
(
§
82­
2[
b])
and
does
satisfy
the
requirements
for
a
subchronic
toxicity
study
in
dogs.

Dose
and
Endpoint
for
Risk
Assessment:
LOAEL
=
75
mg/
kg/
day
based
on
changes
in
hematological
(
decreased
hemoglobin
and
hematocrit
at
4,
8,
and
14
weeks)
and
clinical
biochemistry
parameters,
reduced
body
weight
gain,
increased
liver,
spleen
and
kidney
weights,
and
histopathological
changes
in
the
liver.

Comments
about
Study/
Endpoint:
The
selected
dose/
endpoints
are
appropriate
for
the
route
and
duration
of
exposure
and
are
supported
by
the
1­
and
2­
year
chronic
toxicity
studies
in
dogs
with
a
NOAEL
of
2.5
mg/
kg/
day.

4.4.5
Dermal
Absorption
No
dermal
absorption
studies
are
available
on
dicloran.
Dermal
absorption
of
structurally
related
compounds
varied.
A
comparison
of
the
rabbit
21­
day
dermal
toxicity
NOAEL
[
120
mg/
kg/
day]
and
the
rabbit
developmental
toxicity
NOAEL
[
50
mg/
kg/
day]
provides
an
upper
bound
estimate
of
42%
dermal
absorption.

4.4.6
Dermal
Exposure
(
Short,
Intermediate
and
Long
Term)

Short
and
Intermediate
Term
Study
Selected:
21­
day
dermal
toxicity
study
MRID
No.:
40555101
Executive
Summary:
In
a
repeated­
dose
dermal
toxicity
study
(
MRID
40555101),
dicloran
(
96.2­
97.5%
purity,
Lot/
Batch
#:
CR
20642/
3)
was
applied
to
the
clipped
intact
skin
of
five
New
Zealand
White
albino
rabbits/
sex/
dose
at
nominal
doses
of
0
(
distilled
water),
12,
120,
or
1,200
mg/
kg/
day
for
6
hours/
day,
7
days/
week,
for
a
total
of
21
applications
during
a
21­
day
period.

No
rabbits
died
during
the
course
of
the
study
as
a
result
of
treatment
and
no
treatment­
related
clinical
signs
of
systemic
toxicity
were
observed.
No
differences
were
reported
for
either
body
weight
or
food
consumption.
Slight
transient
erythema
was
observed
in
2/
10
rabbits
at
low
dose.
All
of
the
mid­
dose
rabbits
displayed
slight
erythema
(
most
displaying
this
reaction
by
second
week),
and
slight
edema
was
observed
in
7/
10
animals
during
the
third
week.
At
the
high
dose,
40
of
84
slight
erythema
was
observed
during
the
second
week,
but
by
days
12
or
16,
yellow
staining
(
test
compound)
of
the
treated
skin
precluded
the
assessment
of
erythema.
Slight
edema
observed
on
day
8
in
one
high
dose
female,
and
two
high­
dose
males
and
all
high
dose
females
displayed
edema
from
days
13
to
17,
which
persisted
to
the
study
termination.
Statistically
significant
lower
methemoglobin
levels
were
recorded
for
all
treated
females,
but
the
increase
was
not
dose­
related.
In
male
rabbits,
statistically
significant
higher
adrenal
weights
(
260
g
treated
vs
191
g
controls)
were
recorded
for
high
dose
group.
For
female
rabbits
in
the
high
dose
group
adrenal
weights
were
higher
than
controls
(
211
g
treated
vs
190
g
controls)
but
they
were
not
statistically
significant.

The
LOAEL
can
be
set
at
1,200
mg/
kg/
day
based
on
increased
adrenal
weights
(
36%
over
controls)
in
males.
The
NOAEL
is
120
mg/
kg/
day.
Slight
dermal
irritation
at
the
site
of
application
was
observed
at
the
mid­
and
high­
dose
levels.

This
study
is
classified
acceptable
(
§
82­
2)/
Guideline
and
does
satisfy
the
requirement
for
a
repeated­
dose
dermal
toxicity
study.

Dose
and
Endpoint
for
Risk
Assessment:
NOAEL
=
120
mg/
kg/
day
based
on
increased
(
36%)
adrenal
weights
in
males
(
260
g
treated
vs.
191
g
controls)
at
1200
mg/
kg/
day.

Comments
about
Study/
Endpoint:
The
repeated
[
21­
day]
dermal
toxicity
study
in
rabbits
was
selected
for
the
exposure
scenario
because
the
route
of
exposure
is
appropriate.
The
effect
observed
was
increased
(
36%)
adrenal
weights
in
males
(
260
g
treated
vs.
191
g
controls).
This
finding
was
corroborated
by
the
histopathological
changes
observed
in
the
adrenals
at
150
mg/
kg/
day
in
the
90­
day
feeding
study
in
rats
(
MRIDs
00029056
and
00082718).

Long
Term
Study
Selected:
Same
as
Chronic
Reference
Dose
(
RfD)

MRID
No.:
Same
as
Chronic
Reference
Dose
(
RfD)

Executive
Summary:
Same
as
Chronic
Reference
Dose
(
RfD)

Dose
and
Endpoint
for
Risk
Assessment:
2.5
mg/
kg/
day
(
NOAEL),
based
on
reduced
body
weight
gain,
increased
liver,
spleen
and
kidney
weights,
hematological
and
clinical
biochemical
changes,
and
histopathological
changes
in
the
liver
at
3000
ppm
(
LOAEL=
75
mg/
kg/
day).

Comments
about
Study/
Endpoint:.
In
the
absence
of
dermal
toxicity
studies,
an
oral
study
is
selected
for
this
risk
assessment.
The
100%
default
value
should
be
used
in
route­
to­
route
extrapolation.
41
of
84
4.4.7
Inhalation
Exposure
(
Short,
Intermediate
and
Long
Term)

Short
and
Intermediate
Term
Study
Selected:
Same
as
short­
term
incidental
oral
MRID
No.:
Same
as
short­
term
incidental
oral
Executive
Summary:
Same
as
short­
term
incidental
oral
Dose
and
Endpoint
for
Risk
Assessment:
Same
as
short­
term
incidental
oral
Uncertainty
Factor(
s):
100X
[
10
interspecies;
10X
intraspecies]

Comments
about
Study/
Endpoint:
The
selected
dose/
endpoints
are
appropriate
for
the
duration
of
exposure.
In
the
absence
of
inhalation
toxicity
studies,
an
oral
study
is
selected
for
this
risk
assessment.
The
100%
default
value
should
be
used
in
route­
to­
route
extrapolation.

Long
Term
Study
Selected:
Same
as
Chronic
Reference
Dose
(
RfD)

MRID
No.:
Same
as
Chronic
Reference
Dose
(
RfD)

Executive
Summary:
Same
as
Chronic
Reference
Dose
(
RfD)

Dose
and
Endpoint
for
Risk
Assessment:
Same
as
Chronic
Reference
Dose
(
RfD)

Comments
about
Study/
Endpoint:
The
selected
dose/
endpoints
are
appropriate
for
the
route
and
duration
of
exposure.
In
the
absence
of
inhalation
toxicity
studies,
an
oral
study
is
selected
for
this
risk
assessment.
The
100%
default
value
should
be
used
in
route­
to­
route
extrapolation.

4.4.8
Margins
of
Exposure
Summary
of
Target
Margins
of
Exposure
(
MOEs)
for
Risk
Assessment
is
shown
below:

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
*
Since
DCNA
has
no
residential
uses,
only
the
target
MOEs
for
occupational
exposure
are
presented.
42
of
84
For
Occupational
exposure:
This
is
based
on
the
conventional
uncertainty
factor
of
100X
(
10X
for
intraspecies
variation
and
10X
for
interspecies
extrapolation).

4.4.9
Recommendation
for
Aggregate
Exposure
Risk
Assessments
4.4.10
Classification
of
Carcinogenic
Potential
The
committee
members
of
CARC
evaluated
the
carcinogenicity
studies
in
rats
and
mice
and
other
toxicity
data
on
dicloran
and
placed
DCNA
under
the
classification
of
"
Suggestive
Evidence
of
Carcinogenic
Potential."
No
quantification
of
cancer
was
recommended.
This
classification
is
based
on
the
following:

°
There
was
a
statistically
significant
pairwise
increase
in
benign
testicular
tumors
in
the
male
rats
the
high
dose.
This
dose
was
considered
adequate
and
not
excessive.

°
The
high
dose's
response
was
outside
of
the
laboratory's
historical
control
and
also
showed
an
increase
in
testicular
hyperplasia.

°
There
was
a
borderline
increase
(
p=
0.06)
in
endometrial
adenocarcinomas
in
the
female
rats
and
was
also
accompanied
by
some
increase
in
hyperplasia.

°
The
tumor
response
analysis
for
the
low
and
mid
dose
endometrial
adenocarcinomas
was
confounded
by
limited
numbers
of
tissue
examined
e.
g.
29
and
21
instead
of
50.

°
There
was
a
positive
Ames
test
that
was
repeated
as
positive.

°
There
was
some
evidence
that
a
plant
metabolite,
but
not
a
livestock
metabolite,
had
carcinogenic
activity.

°
The
mouse
study
was
negative
and
tested
at
adequate
doses.

4.4.10.1
Combined
Chronic
Toxicity/
Carcinogenicity
Study
in
Rats
MRID
No.:
46360701
Executive
Summary:
In
a
combined
chronic
toxicity/
carcinogenicity
study
(
MRID
46360701),
dicloran
(
94.9%
a.
i.;
batch/
lot
#
000313)
was
administered
in
the
diet
to
groups
of
50
male
and
50
female
Wistar
(
HsdCpb:
WU)
rats
at
concentrations
of
0,
60,
240
or
1200
ppm
for
the
first
105
days.
The
dietary
concentration
was
raised
from
1200
ppm
to
1440
ppm
on
treatment
day
106
because
the
effects
on
body
weight
gains
in
animals,
especially
females
was
less
than
expected
from
the
90­
day
range
finding
study.
Therefore,
the
calculated
time­
weighted
average
dietary
concentration
for
the
high
dose
main
group
was
1405
ppm.
The
dietary
concentrations
were
equivalent
to
0,
2.8,
11.3,
and
71.0
mg/
kg/
day,
respectively,
for
males
and
0,
3.7,
15.0,
and
94.1
mg/
kg
/
day,
respectively,
for
43
of
84
females.
Additional
groups
of
10
male
and
10
female
rats
were
administered
the
same
diets
for
12
months
for
interim
evaluations.

No
treatment­
related
signs
of
toxicity
were
observed
during
daily
observations,
weekly
physical
examinations,
or
monthly
examinations.
No
adverse
neurological
effects
were
observed
as
assessed
by
the
functional
observational
battery
(
FOB)
conducted
at
12
months.
Survival
was
not
affected
by
treatment
with
the
test
material,
and
no
eye
abnormalities
were
observed
during
ophthalmoscopic
examinations.
High­
dose
male
and
female
rats
gained
48%
and
31%
less
weight,
respectively,
than
controls
during
the
first
week
of
treatment
resulting
in
body
weights
16%
and
8%
(
both
p 
0.05)
less
than
that
of
controls.
Mean
body
weight
of
high­
dose
males
remained
8­
13%
(
p 
0.05)
less
than
that
of
controls
for
the
remainder
of
the
study,
and
mean
body
weight
of
high­
dose
females
was
10­
14%
(
p 
0.05)
less
than
that
of
controls
during
the
second
year
of
the
study.
High­
dose
males
and
females
gained
13%
(
p 
0.05)
and
20%
(
p 
0.05)
less
weight,
respectively,
than
controls
for
the
entire
study.
High­
dose
rats
consumed
significantly
less
food
than
controls
during
the
first
17
weeks
(
males)
and
73
weeks
(
females);
total
food
consumption
was
not
affected
and
food
efficiency
for
the
entire
study
was
similar
for
high­
dose
and
control
rats.
Body
weight,
weight
gain,
and
food
consumption
were
not
significantly
and
adversely
affected
in
low­
and
mid­
dose
rats
of
either
sex.

Analysis
of
hematologic
parameters
showed
very
mild
transient
changes
in
red
blood
cell
(
RBC)
count,
mean
cell
volume,
and
mean
cell
hemoglobin
in
high­
dose
male
and
female
rats
and
was
indicative
of
a
mild
hyperchromatic
macrocytic
anemia.
These
changes
are
not
considered
adverse.
Other
hematologic
changes
(
total
white
blood
cell
(
WBC),
neutrophil,
and
lymphocyte
counts
in
male
and
female
rats
and
prothrombin
time
and
platelet
count
in
females)
were
not
considered
treatment­
related.
Significant
changes
in
clinical
chemistry
parameters
in
high­
dose
rats
were
transient
and
were
not
correlated
with
histopathologic
findings.

Statistically
significant
changes
in
absolute
organ
weights
and
organ:
body
weight
ratios
were
due
to
decreased
terminal
body
weight.
Postmortem
examination
showed
no
treatment­
related
gross
findings
in
male
or
female
rats
receiving
any
dose
of
the
test
material.
The
primary
target
for
microscopic
lesions
appeared
to
be
the
brain
and
spinal
cord.
Vacuolation
was
observed
in
the
cerebral
cortex
including
the
optic
chiasma,
cerebellar
cortex,
and
medulla/
pons
regions
of
the
brain
and
in
the
cervical,
thoracic,
and
lumbar
segments
of
the
spinal
cord
of
high­
dose
males
and
females
at
12
and
24
months.
In
the
main
group,
vacuolation
was
observed
in
the
brain
of
62­
96%
of
males
and
84­
98%
of
females
and
in
the
spinal
cord
of
56­
86%
of
males
and
46­
86%
of
females
compared
with
0­
4%
of
male
controls
and
0­
2%
of
female
controls.
In
addition,
vacuolation
in
the
optic
chiasma
in
the
cerebral
cortex
occurred
in
28%
of
high­
dose
males
and
34%
of
high­
dose
females
compared
with
none
of
the
controls.
Vacuolar
changes
in
the
optic
nerve
were
observed
in
8%
(
p=
0.059)
of
high­
dose
females
compared
with
none
of
the
controls,
and
the
incidence
of
Leydig
cell
hyperplasia
in
the
testes
was
34%
(
p 
0.05)
in
high­
dose
males
compared
with
8%
of
controls.

The
lowest­
observed­
adverse­
effect
level
(
LOAEL)
for
dicloran
in
rats
is
1405
ppm
(
71.0
and
94.1
mg/
kg
bw/
day
for
males
and
females,
respectively)
based
on
reduced
body
weight,
reduced
body
weight
gain,
and
histopathologic
lesions
in
the
brain
and
spinal
cord
of
both
sexes,
optic
nerve
in
females
and
Leydig
cell
hyperplasia
in
the
testes
in
males.
In
addition,
treatment­
related
44
of
84
increase
in
the
relative
weights
in
the
liver,
brain
and
testes
in
males
and
relative
liver
weight
in
females
were
observed.

The
no­
observed­
adverse­
effect
level
(
NOAEL)
is
240
ppm
(
11.3
and
15.0
mg/
kg
bw/
day
for
males
and
females,
respectively).

At
the
doses
tested,
the
incidence
of
benign
Leydig
cell
tumors
was
0/
50,
1/
50,
1/
50,
and
5/
50
(
p 
0.05)
in
control,
low­,
mid­,
and
high­
dose
males
rats,
respectively.
All
Leydig
tumors
were
found
in
animals
sacrificed
at
study
termination.
The
incidence
of
malignant
endometrial
adenocarcinoma
was
3/
50,
7/
29,
7/
21,
and
9/
50
(
p=
0.061)
in
control,
low­,
mid­,
and
high­
dose
females,
respectively.
Both
tumor
types
occurred
in
hormone­
responsive
tissues,
but
there
was
no
other
evidence
suggesting
that
dicloran
is
an
endocrine
disruptor.
The
increased
incidences
of
Leydig
cell
tumors
and
endometrial
adenocarcinoma
is
considered
some
evidence
of
carcinogenicity
of
dicloran
in
rats.
Dosing
was
considered
to
be
sufficient
for
evaluating
the
carcinogenic
potential
for
this
pesticide
based
on
decreased
body
weight
and
weight
gain
in
male
and
female
rats
in
the
high
dose
groups.

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

Discussion
of
Tumor
Data
The
incidence
of
Leydig
cell
tumors
was
increased
in
high­
dose
male
rats
compared
with
the
control
incidence
and
the
incidence
of
endometrial
adenocarcinoma
was
marginally
increased
in
high­
dose
female
rats.

Adequacy
of
the
Dose
Levels
Tested
Dosing
was
considered
adequate
and
not
excessive
based
on
reduced
body
weight,
reduced
body
weight
gain,
and
histopathologic
lesions
in
the
brain
and
spinal
cord
of
both
sexes,
optic
nerve
in
females
and
Leydig
cell
hyperplasia
in
the
testes
in
males..

4.4.10.2
Carcinogenicity
Study
in
Mice
MRID
No.
40977101
Executive
Summary:

In
a
carcinogenicity
study
(
MRID#
40977101),
CD­
1
(
ICR)
BR
mice
(
50/
sex/
group)
were
administered
via
diets
for
80
weeks
with
dicloran
(
96.2
to
97.2%
a.
i.)
at
dose
levels
of
0,
50,
175
or
600
ppm
(
mean
compound
intake
0,
7.4,
24.5
or
86.5
mg/
kg/
day
for
males
and
0,
10.1,
35.4
or
118.8
mg/
kg/
day
for
females,
respectively).
In
addition
to
the
above,
groups
of
5
mice/
sex/
dose
were
used
for
microbiological
screening
and
baseline
histopathology.
45
of
84
Dicloran
was
not
oncogenic
in
male
or
female
CD­
1
mice
when
fed
at
dietary
levels
of
50,
175,
or
600
ppm
for
80
weeks.
No
adverse
effects
were
observed
on
mortality,
clinical
signs,
body
weight,
palpable
masses,
food
consumption
or
conversion,
hematology,
macroscopic
pathology,
or
tumor
incidence.
Correlation
of
gross
and
microscopic
findings
was
conducted
for
this
study.
Histopathologic
examination
showed
the
liver
to
be
the
principal
target
organ
with
changes
noted
at
the
high
dose.
Histopathologic
changes
in
the
liver,
which
were
noted
at
the
high
dietary
level
(
600
ppm),
included
centrilobular
hepatocyte
enlargement,
centrilobular
hemosiderosis,
focal
necrosis
(
males),
acute
inflammatory
cell
infiltration
(
males),
single­
cell
necrosis
(
males),
and
vacuolation
of
centrilobular
hepatocytes
(
females).
Other
organs,
in
which
histopathologic
changes
were
seen
in
animals
administered
the
high
dietary
level,
were
spleen
(
increased
incidence
of
erythropoiesis
in
males)
and
uterus
(
increase
in
severity
and
incidence
of
cystic
endometrial
hyperplasia).
Also,
liver
weight
in
females
and
kidney
weight
in
males
were
elevated
in
high­
dose
animals.
Since
no
treatment­
related
changes
were
evident
at
the
lower
dosages
(
50
or
175)
ppm,
the
No
Observed
Adverse
Effect
Level
(
NOAEL)
in
this
study
was
175
ppm
(
24.5
mg/
kg/
day).
The
Lowest
Observed
Effect
Level
(
LOAEL)
was
600
ppm
(
86.5
mg/
kg/
day)
based
on
histopathologic
changes
in
organs
(
liver,
spleen,
uterus)
and
increased
in
liver
and
kidney
weights.

This
study
is
classified
as
Acceptable/
Guideline
and
satisfies
the
guideline
requirement
for
a
carcinogenicity
study
(
83­
2(
b))
in
the
mice.

Discussion
of
Tumor
Data
The
administration
of
dicloran
to
mice
at
doses
up
to
600
ppm
(
86.5
mg/
kg/
day
for
males,
118.8
mg/
kg/
day
for
females)
in
the
diet
did
not
result
in
an
overall
treatment­
related
increase
in
incidence
of
tumor
formation.

Adequacy
of
the
Dose
Levels
Tested
Under
conditions
of
this
study,
dosing
is
considered
adequate
to
assess
the
carcinogenic
potential
of
dicloran
based
upon
histopathologic
changes
in
organs
(
liver,
spleen,
uterus)
and
increased
liver
and
kidney
weights
seen
at
600
ppm
(
86.5
mg/
kg/
day
for
males,
118.8
mg/
kg/
day
for
females).

4.4.11
Mutagenicity
REVERSE
GENE
MUTATION
ASSAY
In
independently
performed
microbial
reverse
gene
mutation
assays
(
MRID
No.
40508801),
Salmonella
typhimurium
strains
TA98,
TA100,
TA1535,
TA1537
and
TA1538
were
exposed
to
dicloran
(
97.5
%
ai)
at
concentrations
of
50­
5000
µ
g/
plate
with
and
without
S9
activation
in
both
trials.
The
S9
fraction
was
derived
from
Aroclor
1254­
induced
male
rat
(
strain
not
specified)
livers
and
the
test
material
was
delivered
to
the
test
system
in
dimethyl
sulfoxide
(
amount
not
specified).

Dicloran
induced
reverse
mutations
when
tested
at
5000
and
1500
µ
g/
plate
in
strains
TA1538
and
TA98
(
±
S9)
and
in
TA100
(­
S9).
Dicloran
did
not
induce
reverse
mutations
in
TA1535,
TA1537
46
of
84
(
±
S9)
or
in
TA100
(+
S9).
Positive
controls
confirmed
the
sensitivity
of
the
tester
strains.
A
repeat
assay
confirmed
the
results
of
the
first
study.
Therefore,
it
is
concluded
that
dicloran
is
genotoxic
in
the
strains
TA1538,
TA98
and
TA100.

This
study
is
classified
as
acceptable
and
satisfies
the
guideline
requirements
for
a
bacterial
gene
mutation
assay
(
84­
2).

In
a
second
study,
in
independently
performed
microbial
reverse
gene
mutation
assays
(
MRID
No.
00046435,
00046436
and
00087018),
Salmonella
typhimurium
strains
TA1535,
TA1537,
TA1538,
TA98
and
TA100
and
Escherichia
coli
WP2
uvrA
were
exposed
to
dicloran
(
99.9
%
ai)
at
concentrations
of
16­
1000
µ
g/
plate
with
and
without
S9
activation
in
both
trials
and
reversion
to
histidine
or
tryptophan
prototrophy
was
determined.
The
S9
fraction
was
derived
from
phenobarbitone
treated
male
Boots­
Wistar
rat
livers
and
the
test
material
was
delivered
to
the
test
system
in
dimethyl
sulfoxide.
It
was
also
tested
in
Bacillus
subtilis
strains
H17
Rec'
and
M45
Rec'
in
the
Rec
assay.

Dicloran
of
99.9%
purity
proved
to
be
without
mutagenic
activity
in
the
"
Ames
Test"
using
Salmonella
typhimurium
TA1535,
TA1537,
TA1538,
TA98
and
TA100
indicator
strains.
Semiquantitative
assays
with
Escherichia
coli
WP2
and
WP2
uvrA
also
gave
negative
results.
Dicloran
did
not
indicate
mutagenic
activity
in
the
Rec
assay
using
Bacillus
subtilis.
Therefore,
it
is
concluded
that
dicloran
(
purified)
is
not
genotoxic
in
the
bacterial
strains
utilized
in
this
study.

CHROMOSOME
ABERRATION
ASSAY
In
independently
conducted
in
vitro
mammalian
cell
cytogenetic
assays
(
MRID
No:
40508802),
human
lymphocytes
derived
from
a
unspecified
source
were
exposed
for
4
hours
to
dicloran
(
97.5
%
ai)
at
doses
of
2,
10
and
20
µ
g/
mL
with
or
without
S9
activation
using
a
22­
hour
cell
harvest.
Metaphases
were
collected
and
scored
for
structural
chromosome
aberrations.
The
S9
liver
homogenate
was
derived
from
Aroclor
1254
induced
Sprague­
Dawley
rat
livers
and
the
test
material
was
delivered
to
the
test
system
in
dimethylsulfoxide
(
DMSO).

Two
replications
were
used
at
each
dose
level
and
four
replications
for
controls.
Positive
controls
demonstrated
the
sensitivity
of
the
test
system.
In
cells
tested
without
metabolic
activation,
the
results
were
statistically
significant
increased
at
the
mid
and
high
doses
(
10
and
20
µ
g/
mL).
The
results
were
slightly
increased
over
the
low
dose.
In
cells
tested
with
metabolic
activation
the
study
was
negative
at
all
doses.
Therefore,
the
EPA
review
(
TXR
No.
006845)
concluded
that
dicloran
technical
induced
a
slight
increase
in
aberrations
in
human
lymphocytes
in
culture.
However,
a
subsequent
review
(
TXR
No.
007841)
concluded
that
dicloran
was
found
to
be
negative
in
this
in
vitro
test
system.
The
significantly
increased
percentage
of
cells
with
aberrations
in
treatment
groups
exposed
to
nonactivated
10
and
20
µ
g/
mL
dicloran
resulted
from
the
absence
of
aberrations
in
the
vehicle
control
group.
However,
the
percentage
of
aberrant
cells
(
1.5%
in
the
mid­
dose
group
and
2.5%
in
the
high­
dose
group)
were
well
within
the
historical
background
range
observed
by
the
contract
reviewers
in
evaluating
other
human
lymphocytes
cytogenetic
assays
(
0­
3.0%).
It
is
concluded
that
the
slight
increases
in
aberrant
cells
compared
to
concurrent
solvent
control
and
the
types
of
induced
aberrations
do
not
provide
sufficient
evidence
of
a
clastogenic
effects.
Therefore,
dicloran
did
not
induce
a
clastogenic
effect.
47
of
84
This
study
is
classified
as
acceptable
and
satisfies
the
guideline
requirement
for
an
in
vitro
cytogenetic
assay.

UNSCHEDULED
DNA
SYNTHESIS
ASSAY
In
independently
conducted
in
vitro
unscheduled
DNA
synthesis
(
UDS)
assays
(
MRID
No.
40619001),
primary
rat
hepatocytes
from
normal
adult
Fischer
344
males
were
exposed
to
eight
concentrations
of
dicloran
(
97.5
%
ai)
ranging
from
3.0­
10
µ
g/
mL
in
both
trials;
hepatocytes
treated
with
all
doses
#
10
µ
g/
mL
were
scored
for
net
nuclear
grains
to
determine
UDS.
The
test
material
was
delivered
to
the
test
system
in
dimethyl
sulfoxide.

The
results
from
both
assays
were
in
good
agreement,
and
showed
that
the
selected
doses
were
not
cytotoxic
or
genotoxic
in
the
target
cell.
The
presence
of
test
material
precipitation
at
the
highest
assayed
level
(
10
µ
g/
mL)
indicated
that
the
solubility
limit
of
dicloran
was
reached.
It
is
concluded
that
dicloran
was
adequately
tested,
and
there
was
no
evidence
of
a
genotoxic
effect.

The
study
is
classified
as
acceptable
and
satisfies
the
guideline
requirement
for
an
unscheduled
DNA
synthesis
(
genotoxicity)
assay
(
84­
2).

Summary
of
Toxicological
Endpoints
The
doses
and
toxicological
endpoints
selected
for
various
exposure
scenarios
are
summarized
below.

Exposure
Scenario
Dose
Used
in
Risk
Assessment,
UF
Special
FQPA
SF*
and
Level
of
Concern
for
Risk
Assessment
Study
and
Toxicological
Effects
Acute
Dietary
(
females
13­
49)
NOAEL
=
50
mg/
kg/
day
UF
=
100
Acute
RfD
=
0.5
mg/
kg/
day
FQPA
SF
=
10X
aPAD
=
acute
RfD
(
0.5)
FQPA
SF
(
10)

=
0.05
mg/
kg/
day
Developmental
toxicity
study
in
rats
LOAEL
=
100
mg/
kg/
day
based
on
increased
incidences
of
supernumerary
rudimentary
ribs
and
also
decreased
fetal
weights.

Acute
Dietary
(
general
population
including
infants
and
children)
NOT
APPLICABLE.
A
dose
and
endpoint
were
not
selected
for
this
population
group
because
there
were
no
effects
observed
in
oral
toxicology
studies
including
maternal
toxicity
in
the
developmental
toxicity
studies
in
rats
and
rabbits
that
are
attributable
to
a
single
exposure
(
dose).
48
of
84
Exposure
Scenario
Dose
Used
in
Risk
Assessment,
UF
Special
FQPA
SF*
and
Level
of
Concern
for
Risk
Assessment
Study
and
Toxicological
Effects
Chronic
Dietary
(
All
populations)
NOAEL=
2.5
mg/
kg/
day
UF
=
100
Chronic
RfD
=
0.025
mg/
kg/
day
FQPA
SF
=
10X
cPAD
=
chronic
RfD
FQPA
SF
(
10)

=
0.0025
mg/
kg/
day
One
Year
Chronic
Toxicity
Study
in
Dogs
LOAEL
=
25
mg/
kg/
day
based
on
clinical
chemistry
(
increased
alkaline
phosphatase
in
both
sexes
and
increased
cholesterol
in
males),
increased
liver
weights,
hepatocyte
hypertrophy,
vacuolar
alterations
of
the
brain
and
spinal
cord,
prostate
atrophy,
degeneration
of
the
seminiferous
tubules,
and
hypospermia
in
the
epididymides
Short­
Term
Incidental
Oral
(
1­
30
days)
NOAEL=
2.5
mg/
kg/
day
Occupational
=
NA
90­
Day
feeding
­
Dog
LOAEL
=
75
mg/
kg/
day
based
on
changes
in
hematological
(
decreased
hemoglobin
and
hematocrit
at
4,
8,
and
14
weeks)
and
clinical
biochemistry
parameters,
reduced
body
weight
gain,
increased
liver,
spleen
and
kidney
weights,
and
histopathological
changes
in
the
liver
Intermediate­
Term
Incidental
Oral
(
1­
6
months)
NOAEL
=
2.5
mg/
kg/
day
Occupational
=
NA
Same
as
for
Short­
Term
Incidental
Oral
Short­
Term
Dermal
(
1
to
30
days)
NOAEL=
120
mg/
kg/
day
Occupational
LOC
for
MOE
=
100
rabbit
21­
day
dermal
toxicity
study
LOAEL
=
1200
mg/
kg/
day
based
on
increased
(
36%)
adrenal
weights
in
males.
This
finding
was
corroborated
by
the
histopathological
changes
observed
in
the
adrenals
at
150
mg/
kg/
day
in
the
90­
day
feeding
study
in
rats
(
MRIDs
00029056
and
00082718).
49
of
84
Exposure
Scenario
Dose
Used
in
Risk
Assessment,
UF
Special
FQPA
SF*
and
Level
of
Concern
for
Risk
Assessment
Study
and
Toxicological
Effects
Intermediate­
Term
Dermal
(
1
to
6
months)
NOAEL
=
120
mg/
kg/
day
(
a)
Occupational
LOC
for
MOE
=
100
Same
as
for
Short­
Term
Dermal
Long­
Term
Dermal
(>
6
months)
Oral
NOAEL=
2.5
mg/
kg/
day
(
dermal
absorption
rate
=
100%)
Occupational
LOC
for
MOE
=
100
Same
as
for
Chronic
RfD
Short­
Term
Inhalation
(
1
to
30
days)
oral
NOAEL=
2.5
mg/
kg/
day
(
inhalation
absorption
rate
=
100%)
(
a)
Occupational
LOC
for
MOE
=
100
Same
as
for
Short­
Term
Incidental
Oral
Intermediate­
Term
Inhalation
(
1
to
6
months)
oral
NOAEL
=
2.5
mg/
kg/
day
(
inhalation
absorption
rate
=
100%)
(
a)
Occupational
LOC
for
MOE
=
100
Same
as
for
Short­
Term
Incidental
Oral
Long­
Term
Inhalation
(>
6
months)
oral
NOAEL=
2.5
mg/
kg/
day
(
inhalation
absorption
rate
=
100%)(
a)
Occupational
LOC
for
MOE
=
100
Same
as
for
Chronic
RfD
Cancer
(
oral,
dermal,
inhalation)
"
Suggestive
Evidence
of
Carcinogenic
Potential"

UF
=
uncertainty
factor,
FQPA
SF
=
Special
FQPA
safety
factor,
NOAEL
=
no
observed
adverse
effect
level,
LOAEL
=
lowest
observed
adverse
effect
level,
PAD
=
population
adjusted
dose
(
a
=
acute,
c
=
chronic),
RfD
=
reference
dose,
MOE
=
margin
of
exposure,
LOC
=
level
of
concern,
NA
=
Not
Applicable
NOTE:
The
Special
FQPA
Safety
Factor
assumes
exposure
databases
(
dietary
food,
drinking
water,
and
residential)
are
complete
and
risk
assessment
for
each
potential
exposure
scenario
includes
all
metabolites
and/
or
degradates
of
concern
and
does
not
underestimate
the
potential
risk
for
infants
and
children.

a:
The
inhalation
exposure
limits
for
all
durations
were
based
on
the
NOAELs
from
oral
studies
for
each
exposure
scenario
since
no
route­
specific
study
was
available.
Since
no
inhalation
absorption
data
are
available,
toxicity
by
the
inhalation
route
was
considered
to
be
equivalent
to
toxicity
by
the
oral
route
of
exposure.
b:
Dicloran
does
not
have
any
residential
uses;
therefore,
the
residential
LOC
was
not
included.
50
of
84
4.5
Special
FQPA
Safety
Factor
FQPA
directs
EPA,
in
setting
pesticide
tolerances,
to
use
an
additional
tenfold
margin
of
safety
to
protect
infants
and
children,
taking
into
account
the
potential
for
pre­
and
post­
natal
toxicity
and
the
completeness
of
the
toxicology
and
exposure
databases.
The
statute
authorizes
EPA
to
modify
this
tenfold
FQPA
safety
factor
only
if
reliable
data
demonstrate
that
the
resulting
level
of
exposure
will
be
safe
for
infants
and
children.

The
toxicity
database
for
DCNA
includes
acceptable
developmental
and
reproductive
toxicity
studies,
and
these
studies
showed
no
increase
in
susceptibility
in
fetuses
and
pups
with
in
utero
and
postnatal
exposure.
However,
EPA
has
determined
that
all
of
the
FQPA
safety
factor(
10X)
must
be
retained
to
account
for
database
uncertainties.

DCNA
appears
to
elicit
neuropathology
(
vacuolation
in
the
brain)
at
doses
of
25­
75
mg/
kg
following
exposures
greater
than
90
days.
The
neuropathological
effects
were
greater
in
fourweek
old
rats
than
seven­
week
old
rats,
indicating
that
age
could
be
a
variable
in
this
neurotoxicity.
The
study
is
necessary
to
fully
characterize
potential
fetal
neuropathology.
Since
the
DCNA
database
does
not
include
a
DNT
study,
and
a
DNT
study
is
required,
an
FQPA
safety
factor
must
be
retained
for
exposure
scenarios
through
which
exposure
to
children
or
pregnant
women
is
expected.

4.6
Endocrine
disruption
EPA
is
required
under
the
FFDCA,
as
amended
by
FQPA,
to
develop
a
screening
program
to
determine
whether
certain
substances
(
including
all
pesticide
active
and
other
ingredients)
"
may
have
an
effect
in
humans
that
is
similar
to
an
effect
produced
by
a
naturally
occurring
estrogen,
or
other
such
endocrine
effects
as
the
Administrator
may
designate."
Following
the
recommendations
of
its
Endocrine
Disruptor
Screening
and
Testing
Advisory
Committee
(
EDSTAC),
EPA
determined
that
there
was
scientific
bases
for
including,
as
part
of
the
program,
the
androgen
and
thyroid
hormone
systems,
in
addition
to
the
estrogen
hormone
system.
EPA
also
adopted
EDSTAC's
recommendation
that
the
Program
include
evaluations
of
potential
effects
in
wildlife.
For
pesticide
chemicals,
EPA
will
use
FIFRA
and,
to
the
extent
that
effects
in
wildlife
may
help
determine
whether
a
substance
may
have
an
effect
in
humans,
FFDCA
authority
to
require
the
wildlife
evaluations.
As
the
science
develops
and
resources
allow,
screening
of
additional
hormone
systems
may
be
added
to
the
Endocrine
Disruptor
Screening
Program
(
EDSP).

When
the
appropriate
screening
and/
or
testing
protocols
being
considered
under
the
Agency's
EDSP
have
been
developed,
dicloran
may
be
subjected
to
additional
screening
and/
or
testing
to
better
characterize
effects
related
to
possible
endocrine
disruption.

It
is
noted
that
the
results
of
the
chronic
dietary
feeding
study
in
dogs
showed
that
dicloran
produced
prostate
atrophy,
degeneration
of
the
seminiferous
tubules,
and
hypospermia
in
the
epididymides.
In
addition,
dicloran
produced
increased
incidences
of
Leydig
cell
tumors
and
endometrial
adenocarcinoma
in
the
chronic
dietary
feeding
study
in
rats.
No
data
indicates
that
these
findings
are
related
to
hormonal
effects.
51
of
84
5.0
Public
Health
Data
5.1
Incident
Reports
The
following
databases
have
been
consulted
for
the
poisoning
incident
data
on
the
active
ingredient
dicloran:
OPP
Incident
Data
System
(
IDS),
Poison
Control
Centers,
California
Department
of
Pesticide
Regulation,
National
Pesticide
Information
Center
(
NPIC),
and
the
National
Institute
of
Occupational
Safety
and
Health's
Sentinel
Event
Notification
System
for
Occupational
Risks
(
NIOSH
SENSOR).

A
total
of
seven
cases
were
located
in
the
Poison
Control
Center
records
from
1993
through
2001.
Two
involved
children
under
age
six,
one
was
exposed
in
an
occupational
setting,
and
the
remaining
four
were
adults
exposed
in
a
non­
occupational
setting.
Only
one
case
has
medical
outcome
determined
with
dermal
symptoms
characterized
as
minor.
There
was
a
potentially
toxic
case
that
did
not
receive
follow­
up
treatment.
Nothing
can
be
concluded
from
such
a
small
number
of
cases,
except
that
there
is
no
positive
evidence
of
significant
harm
in
the
small
number
of
cases
examined.
There
were
no
poisoning
reports
due
to
DCNA
exposure
according
to
the
OPP
IDS,
California
Department
of
Pesticide
Regulation
(
1982­
2002),
NPIC
(
1984­
1991),
and
NIOSH
SENSOR
(
1998­
2002).
Additionally,
there
were
no
incidents
of
poisoning
or
other
human
health
effects
related
to
DCNA
found
in
scientific
literature.
Very
few
incidents
of
illness
have
been
reported
due
to
DCNA;
as
a
result,
no
recommendations
are
warranted.

6.0
Exposure
Characterization/
Assessment
6.1
Dietary
Exposure/
Risk
Pathway
6.1.1
Residue
Profile
Dicloran
is
currently
registered
for
preharvest
and
postharvest
uses
on
various
raw
agricultural
commodities.
Tolerances
are
established
under
40
CFR
§
180.200
for
residues
of
dicloran
per
se
in/
on
the
following
commodities:
apricots,
beans
(
snap),
celery,
cherries
(
sweet),
cucumbers,
endive
(
escarole),
fennel,
garlic,
grapes,
lettuce
(
head
and
leaf),
nectarines,
onions,
peaches,
plums
(
fresh
prunes),
potatoes,
rhubarb,
shallots,
and
tomatoes.
It
is
also
registered
for
postharvest
uses
on
carrots
and
sweet
potatoes.

The
current
tolerance
expression
is
in
harmony
with
the
MARC's
determination
that
only
the
parent
compound
should
be
included
in
the
tolerance
expression
for
primary
crops.
It
is
also
compatible
with
the
Codex
definition
of
residues
for
dicloran.
No
tolerances
have
been
established
for
livestock
commodities.

The
registrant
has
expressed
interest
in
supporting
postharvest
uses
on
stone
fruit
that
were
previously
registered.
A
petition,
PP#
7F04879,
is
pending
for
the
establishment
of
permanent
tolerances
resulting
from
proposed
uses
on
peanuts
(
preharvest),
carrots
(
preharvest),
and
tomatoes
(
postharvest).
Preharvest
treatments
are
typically
made
with
either
aerial
or
ground
52
of
84
equipment,
whereas
postharvest
treatments
are
made
as
sprays
and
dips.
An
IR­
4
petition,
PP#
5E04557,
is
pending
for
uses
on
leafy
vegetables
subgroup
4a,
except
spinach.

The
nature
of
the
residue
in
plants
is
adequately
understood
based
on
acceptable
metabolism
studies
with
dicloran
on
peaches,
potatoes,
and
lettuce.
The
residues
of
concern
for
all
primary
crops
are
the
parent
only,
DCNA,
for
the
tolerance
expression
and
for
risk
assessment
purposed
the
residues
of
concern
are
the
parent
plus
2,6­
dichloro­
4­
hydroxyaniline
(
DCHA)
for
all
primary
crops
excluding
potatoes.
The
residues
of
concern
in
potatoes,
for
the
purpose
of
risk
assessment,
are
dicloran,
DCHA,
and
the
group
of
metabolites
designated
as
Unknown
1.

The
nature
of
the
residue
in
livestock
is
adequately
understood
provided
the
petitioner
could
provide
supporting
storage
stability
data
to
validate
the
integrity
of
samples
from
the
goat
and
hen
metabolism
studies
submitted
in
conjunction
with
PP#
7F04879.
The
residues
that
need
to
be
included
in
the
tolerance
expression
for
livestock
commodities
includes
dicloran
and
4­
amino­
2,6­
dichlorophenol
(
DCAP).
For
risk
assessment
purposes,
the
residues
of
concern
in
livestock
commodities
are
dicloran,
DCAA,
DCHA,
DCAP,
DCNP,
and
the
A­
1
metabolite.
Since
the
MARC
concluded
that
the
metabolic
pathways
of
dicloran
in
livestock
and
rats
are
likely
to
be
qualitatively
similar,
a
swine
metabolism
study
need
not
be
conducted.

The
nature
of
the
residue
in
rotational
crops
is
adequately
understood.
Dicloran
per
se
is
the
residue
of
concern
in/
on
rotational
crops
for
tolerance
expression.
For
risk
assessment,
the
residues
of
concern
are
dicloran
and
the
dichloroaniline­
containing
metabolites.
A
limited
field
rotational
crop
study
is
available,
however
additional
data
from
limited
field
rotational
crop
trials
are
required.
The
requested
trials
should
be
conducted
at
the
maximum
seasonal
application
rate,
and
samples
should
be
analyzed
for
the
total
dichloroaniline­
containing
residues.
Extensive
rotational
crop
studies
may
be
required
if
residues
are
detected
at
the
desired
plantback
interval.
The
required
trials
will
need
supporting
storage
stability
data
for
total
dichloroaniline­
containing
residues
if
samples
are
stored
for
more
than
30
days
prior
to
sample
analysis.

The
HED
MARC's
decisions
and
recommendations
for
the
residues
of
concern
for
tolerance
and
risk
assessment
purposes
are
triggering
new
sets
of
data
requirements
for
residue
analytical
methods,
storage
stability,
magnitude
of
the
residue
in
plants
and
livestock,
and
rotational
crops.
These
new
requirements
are
incorporated
in
this
risk
assessment.

There
are
plant
enforcement
methods
listed
in
the
Pesticide
Analytical
Manual
(
PAM)
Volume
II
for
the
determination
of
dicloran
per
se.
The
PAM
Volume
II
methods
include
a
colorimetric
method
(
Method
I
(
a))
and
a
microcoulometric
gas
chromatography
method
(
Method
A).
The
sensitivity
of
both
methods
is
reported
at
0.1
ppm.
The
8/
15/
83
Dicloran
Guidance
Document
has
determined
that
the
colorimetric
method
is
adequate
for
residue
data
collection
but
is
not
acceptable
for
regulatory
purposes.
It
was
also
stated
in
the
Dicloran
Update,
issued
8/
2/
91
that
the
microcoulometric
gas
chromatography
method
is
not
recommended
for
enforcement
purposes
because
of
potential
interference
with
sulfur­
containing
compounds.

A
new
plant
method,
GC/
ECD
(
Method
R­
450.2),
was
submitted
as
part
of
PP#
7F04879.
Method
R­
450.2,
which
appears
to
be
an
improvement
to
the
existing
PAM
Volume
II
methods,
was
forwarded
to
the
Analytical
Chemistry
Branch
(
ACB)
for
a
petition
method
validation.
ACB
53
of
84
tested
this
method
for
determination
of
dicloran
residues
in/
on
peanuts,
potatoes,
lettuce,
and
peaches
and
recommended
that
the
method
along
with
the
EPA
addendum
be
forwarded
to
the
FDA
for
publication
in
PAM
Volume
II
with
a
Roman
numeral
designation;
the
method
was
forwarded
by
HED
to
FDA
on
5/
22/
01.
HED
has
identified
a
few
data
gaps,
which
must
be
fulfilled
before
Method
R­
450.2
can
be
considered
suitable
for
tolerance
enforcement.
The
petitioner
is
required
to
submit
an
interference
study
demonstrating
the
specificity
of
the
proposed
method
in
the
presence
of
pesticides
with
established
tolerances
in/
on
carrot,
tomato,
and
peanut
commodities.
Alternately,
the
petitioner
could
propose
a
confirmatory
method
that
employs
a
mass
spectrum
detector.
Radiovalidation
of
the
method
is
also
required.

A
residue
analytical
method
for
the
metabolite
DCHA,
which
is
a
residue
of
concern
for
the
purpose
of
risk
assessment,
is
not
available.
A
validated
DCHA
method
is
required
for
data
collection.

The
need
for
analytical
methods
for
milk
and
meat
is
reserved
pending
the
outcome
of
the
requested
ruminant
feeding
study.
If
the
requested
study
shows
that
milk
and
meat
tolerances
are
quantifiable
as
a
result
of
the
currently
registered
and
proposed
uses,
then
the
registrant
will
be
required
to
develop
an
analytical
enforcement
method
for
the
analysis
of
all
residues
of
concern
in
meat
and
milk.
The
registrant
will
be
required
to
submit
all
ancillary
data
for
any
proposed
method
(
confirmatory
method,
interference
study,
radiovalidation,
and
independent
laboratory
validation)

A
validated
data­
collection
method
is
required
for
the
analysis
of
dichloroaniline­
containing
metabolites
in
rotational
crops.

Information
concerning
the
behavior
of
dicloran
through
FDA
Multiresidue
Protocols
A
through
E
has
been
submitted
and
reviewed
by
HED,
and
the
data
have
been
forwarded
to
the
FDA
on
2/
7/
95.
If
in
the
future
HED
determines
that
tolerances
for
livestock
commodities
are
necessary,
then
the
petitioner
will
be
required
to
submit
information
concerning
the
behavior
of
the
DCAP
metabolite
through
FDA
Multiresidue
Protocols
A
through
F.

Several
studies,
which
investigated
the
storage
stability
of
dicloran
per
se
in/
on
various
crop
commodities,
have
been
reviewed
and
deemed
adequate
to
validate
the
storage
intervals
of
crop
commodities
analyzed
for
dicloran
per
se.
These
data
indicate
that
dicloran
is
stable
under
freezer
storage
conditions
in/
on
cherries,
peaches,
strawberries,
apricots,
apples,
nectarines,
grapes,
snap
beans,
and
onions
for
11
months.
More
recent
data
indicate
that
following
storage
at
<­
15
EC,
fortified
residues
of
dicloran
declined
by
­
20%
in/
on
carrots
after
18
months
and
by
16­
18%
in/
on
lettuce
after
9
months.
Following
storage
at
­
15
to
­
5
EC,
fortified
residues
of
dicloran
were
found
to
be
relatively
stable
in/
on
lettuce
but
declined
by
13%
in/
on
carrots
after
3
months.
The
total
storage
intervals
between
harvest
and
analysis
of
samples
from
submitted
field
trials
for
grapes,
peaches,
plums,
potatoes,
and
tomatoes
and
their
processed
commodities
were
approximately1­
2
months.
Supporting
storage
stability
data
for
grapes,
grape
juice,
peaches,
plums,
dried
prunes,
potatoes,
tomatoes,
tomato
puree
and
paste
are
not
required
due
to
short
storage
intervals
of
collected
samples
prior
to
residue
analysis.
54
of
84
Storage
stability
data
for
the
metabolite
DCHA
are
not
available.
These
data
are
now
required
since
the
Agency
is
requesting
field
trial
and
processing
data
for
DCHA
to
perform
dietary
risk
assessment.
The
storage
stability
data
should
be
generated
as
described
in
OPPTS
860.1380.

The
limited
storage
stability
data
for
livestock
commodities
are
inadequate
to
satisfy
reregistration
requirements.
These
data
indicate
that
dicloran
is
stable
in
poultry
eggs
for
18
months
and
in
cow
fat
for
25
months.
In
addition,
residues
of
dicloran,
DCNP,
and
DCAA
are
stable
in
cow
muscle,
egg
white,
and
egg
yolk
stored
frozen
for
up
to
16
months.
It
was
also
found
that
dicloran
is
not
stable
in
liver,
and
that
the
stability
of
DCNA
in
muscle
could
not
be
reliably
determined
due
to
an
unacceptably
low
procedural
recovery.
Since
the
Agency
is
now
requiring
a
ruminant
feeding
study,
supporting
storage
stability
data
are
required
for
all
dicloran
residues
of
concern.
The
requirement
for
storage
stability
on
milk
and
meat
data
may
be
waived
if
samples
to
be
collected
from
the
requested
ruminant
feeding
study
are
analyzed
within
30
days
of
collection.

A
new
ruminant
feeding
study
is
required
to
determine
whether
tolerances
are
needed
(
and
if
so
the
appropriate
tolerance
levels)
for
milk
and
meat.
The
feeding
study
should:
(
i)
reflect
feeding
levels
of
1x,
3x,
and
10x
the
estimated
maximum
theoretical
dietary
burden
(
MTDB),
and
(
ii)
analyze
for
residues
of
dicloran,
DCAA,
DCHA,
DCAP,
and
DCNP.
The
estimated
MTDB
of
dicloran
to
beef
cattle
and
dairy
cattle
has
been
calculated
at
59
and
55
ppm,
respectively.
A
poultry
feeding
study
is
not
required
because
there
are
no
poultry
feedstuffs
associated
with
the
currently
registered
uses.

Adequate
data
depicting
the
magnitude
of
the
residues
of
dicloran
per
se
have
been
submitted
to
reassess
the
tolerances
for
the
following
raw
agricultural
commodities:
bean,
snap,
succulent;
carrot;
celery;
cucumber;
grape;
lettuce;
and
potato
(
pending
label
revision
to
specify
a
20­
day
PHI).
The
available
data
for
lettuce
may
be
translated
to
leafy
vegetables
subgroup
4a
(
except
spinach)
provided
labels
are
amended
to
specify
a
maximum
seasonal
rate
of
4
lb
ai/
A.
Additional
data
are
required
for
the
reassessment
or
establishment
of
tolerances
for:
apricot;
cherry
(
sweet);
fennel;
garlic;
onion;
peach;
plum;
rhubarb;
shallot;
sweet
potato;
and
tomato.
The
requested
data
for
peaches
will
be
translated
to
nectarines
since
uses
are
identical.

None
of
the
samples
collected
from
the
submitted
field
trials
were
analyzed
for
the
metabolite
DCHA.
HED
is
now
requiring
the
registrant
to
conduct
limited
magnitude
of
the
residue
studies
for
all
registered
crops
wherein
residues
of
dicloran
and
the
metabolite
DCHA
are
monitored.
In
addition,
potato
field
trials
must
also
monitor
residues
of
Unknown
1.

There
are
presently
no
registered
uses
of
dicloran
on
blackberry,
boysenberry,
cotton,
kiwifruit,
peanut
(
seed
treatment),
and
raspberry.
Therefore,
the
previously
requested
residue
data
for
these
crops
are
no
longer
required.

Adequate
processing
studies,
which
depict
the
magnitude
the
residues
of
dicloran
per
se
in
the
processed
commodities
of
grapes,
plums,
potatoes,
and
tomatoes,
are
available.
Overall,
no
concentration
of
dicloran
residues
was
observed
except
for
the
minimal
concentration
that
occurred
in
grape
juice
(­
1.3x),
dried
prunes
(
1.8­
1.9x),
tomato
puree
(
1.1­
1.2x),
and
tomato
paste
(
1.9­
2.0x).
At
this
time,
HED
is
unable
to
determine
whether
tolerances
will
be
needed
for
the
above
processed
commodities
because
the
highest
average
field
trial
(
HAFT)
residues
in/
on
the
55
of
84
raw
agricultural
commodities
have
not
been
determined
since
additional
field
trial
data
are
required.

Because
the
available
processing
studies
did
not
analyze
for
the
metabolite
DCHA,
HED
is
now
requiring
the
registrant
to
conduct
additional
grape,
plum,
potato,
and
tomato
processing
studies
with
analysis
for
both
the
parent
and
DCHA
metabolite.
In
addition,
the
potato
processing
study
must
also
monitor
residues
of
Unknown
1.

6.1.2
Acute
and
Chronic
Dietary
Exposure
and
Risk
Please
see
DP
Barcode:
D294456,
Dicloran
(
DCNA)
Revised
Acute
and
Chronic
Dietary
Exposure
Assessment[
s]
for
the
Reregistration
Eligibility
Decision
(
Phase
3),
March
2006
by
Christine
Olinger
for
the
complete
dicloran
dietary
assessment.

Acute
and
chronic
dietary
risk
assessments
were
conducted
using
the
Dietary
Exposure
Evaluation
Model
(
DEEM­
FCID
 
,
Version
2.03)
which
uses
food
consumption
data
from
the
USDA's
Continuing
Surveys
of
Food
Intakes
by
Individuals
(
CSFII)
from
1994­
1996
and
1998.

As
previously
stated,
the
MARC
concluded
the
residues
of
concern
for
risk
assessment
purposes
are
DCNA
and
DCHA
for
all
plant
commodities
excluding
potatoes,
and
DCNA,
DCHA,
and
the
Unknown
1
group
of
metabolites
for
potatoes.
Since
no
magnitude
of
residue
data
are
available
for
DCHA
or
the
Unknown
metabolite
1,
adjustment
factors
have
been
developed
based
on
the
metabolism
studies
to
account
for
potential
exposure
to
these
metabolites
of
concern.
A
summary
of
these
factors
is
presented
in
Table
6.1a,
along
with
the
metabolism
data
on
which
they
are
based
and
the
crops
to
which
they
will
be
applied.
No
factors
will
be
applied
to
the
postharvest
uses,
as
there
is
minimal
opportunity
for
degradation
of
these
uses
to
the
metabolite.
56
of
84
Table
6.1a
Summary
of
Adjustment
Factors
to
Account
for
DCNA
Metabolites
Study
Peaches
14­
day
PHI
Potato
Tubers
14­
day
PHI
Potato
Vines
14­
day
PHI
Lettuce
20­
day
PHI
Dicloran
32%
TRR
10
39
74%

DCHA
11%
TRR
15
<
1
<
1
Unknown
1
<
1
50%
30
<
1
Factor
used
to
approximate
total
ROC
1
for
Risk
Assessment
Multiply
dicloran
per
se
residues
by
1.3
Multiply
dicloran
per
se
residues
by
7.5
Multiply
dicloran
per
se
residues
by
1.8
No
adjustment
needed
Applied
to:
Grapes
(
1­
day
PHI)
Garlic,
onion,
potato,
shallot
Snap
beans,
Cucumber,
tomato
Pre­
harvest
treatments:
celery,
endive,
fennel,
lettuce,
rhubarb,
radicchio.
Postharvest
treatments:
carrot,
sweet
potato,
stone
fruit
Acute
Dietary
Exposure
Results
and
Characterization
A
refined
chronic
exposure
assessment
was
required
as
the
exposures
for
Females
ages
13­
49
exceeded
the
level
of
concern
assuming
100%
crop
treated
and
tolerance
values.
No
endpoints
were
identified
for
the
general
population.
USDA
Pesticide
Data
Program
(
PDP)
monitoring
data
were
used
for
all
commodities,
except
rhubarb,
assuming
non­
detectable
residues
were
at
the
limit
of
detection.
No
adjustments
for
percent
crop
treated
were
made.
At
the
99.9th
percentile
of
exposure,
the
estimated
exposure
for
food
only
was
at
9.9%
of
the
acute
Population
Adjusted
Dose
for
females
aged
13­
49.

Chronic
Dietary
Exposure
Results
and
Characterization
A
refined
chronic
exposure
assessment
was
required
as
the
exposures
for
all
populations
exceeded
the
level
of
concern
assuming
100%
crop
treated
and
tolerance
values.
USDA
Pesticide
Data
Program
(
PDP)
monitoring
data
were
used
for
all
commodities,
except
rhubarb,
assuming
nondetectable
residues
were
at
the
limit
of
detection.
No
adjustments
for
percent
crop
treated
were
made.
Using
these
refinements,
the
most
highly
exposed
subgroup
was
children
1­
2
years
old
with
the
exposure
at
13%
of
the
cPAD
for
food
only.
57
of
84
Table
6.1b
Summary
of
Dietary
Exposure
and
Risk
for
DCNA
Using
DEEM
FCIDTM
Food
Only.
Acute
Dietary
Chronic
Dietary
Tier
1
Assessment
95th
Percentile
Refined
Assessment
99.9th
Percentile
Tier
1
Assessment
Refined
Assessment
Population
Subgroup
Dietary
Exposure
(
mg/
kg/
day)
%
aPAD
Dietary
Exposure
(
mg/
kg/
day)
%
aPAD
Dietary
Exposure
(
mg/
kg/
day)
%
cPAD
Dietary
Exposure
(
mg/
kg/
day)
%
cPAD
General
U.
S.
Population
0.048
1900
0.00015
6.0
All
Infants
(<
1
year
old)
0.094
3700
0.00024
9.4
Children
1­
2
years
old
0.14
5500
0.00032
13
Children
3­
5
years
old
0.097
3900
0.00026
10
Children
6­
12
years
old
0.058
2300
0.00017
6.8
Youth
13­
19
years
old
0.037
1500
0.00012
4.8
Adults
20­
49
years
old
0.040
1600
0.00012
4.8
Adults
50+
years
old
NA1
0.040
1600
0.00016
6.3
Females
13­
49
years
old
0.13
260
0.0049
9.9
4.8
1600
0.00012
4.8
The
population
subgroups
with
the
highest
exposure
are
bolded.
1
No
appropriate
endpoint
has
been
identified
for
this
population
subgroup.

6.2
Water
Exposure/
Risk
Pathway
Please
see
DP
Barcode:
D294452,
DCNA
(
Dicloran):
Revised
Tier
I
Drinking
Water
EDWC's
(
Estimated
Drinking
Water
Concentrations)
for
Use
in
the
Human
Health
Risk
Assessment,
January
24,
2006
by
Cheryl
Sutton
for
the
complete
dicloran
drinking
water
assessment.

The
MARC
was
unable
to
make
a
decision
on
the
water
degradates
of
concern,
as
the
environmental
fate
data
are
limited.
However
a
new
aerobic
aquatic
metabolism
study
was
submitted,
which
identified
an
additional
dicloran
degradate:
2,6­
dicholorbenzoic
acid
(
DCBA).
DCBA
was
found
at
maximum
concentrations
of
9.2­
9.3%
of
the
applied
in
the
water
phase
(
7
days)
and
3.3­
5.8%
of
the
applied
in
the
sediment
phase
(
14
days).
By
study
termination,
DCBA
had
decreased
to
1.0­
1.7%
of
the
applied
in
the
water
phase.
There
were
no
major
degradates
of
DCNA
detected
in
the
previously
reviewed
laboratory
studies
(
i.
e.
none
accounted
for
as
much
as
10%
of
radioactivity
measured
at
any
point
in
the
studies),
with
the
exception
of
the
transformed
58
of
84
chemical
present
as
nonextractable
residues.
The
minor
degradates
of
DCNA
expected
in
the
environment
are
DCPD,
DCAA,
DCHA
and
3,5
DCHA.
For
the
above
reasons,
the
Revised
Tier
1
Drinking
Water
Assessment
for
DCNA
included
the
parent
compound
only.

EFED
provided
both
acute
and
chronic
surface
water
exposure
scenarios
and
one
ground
water
concentration
estimate
for
DCNA
using
two
EFED
Tier
1
screening­
level
models:
FIRST,
Version
1.0
and
SCI­
GROW,
Version
2.3.
Surface
water
(
acute
and
chronic)
and
groundwater
EDWC's
are
based
on
DCNA
use
on
apricots
at
4.0
lb
a.
i./
A/
application
applied
in
a
single
application.
A
summary
of
all
three
exposure
scenarios
can
be
found
in
Tables
6.2.
All
estimated
drinking
water
concentrations
were
incorporated
into
the
dicloran
aggregate
assessment.

Table
6.2.
Summary
of
Estimated
Surface
and
Ground
Water
Concentrations
for
Dicloran.

Exposure
Duration
Surface
Water
Conc.
(
ppb
or
µ
g/
L)
1
Ground
Water
Conc.
(
ppb
or
µ
g/
L)
2
Acute
172.8
1.3
Chronic
(
non­
cancer)
1.8
1.3
1
From
the
FIRST
model
(
FQPA
Index
Reservoir
Screening
Tool).
2
From
the
SCI­
GROW
model
assuming
a
maximum
seasonal
use
rate
of
4.0
lb
ai/
A.

6.3
Residential
(
Non­
Occupational)
Exposure/
Risk
Pathway
There
are
no
residential
uses
for
DCNA.
It
is
only
registered
for
agricultural
use
as
a
fungicide
to
control
pathogenic
species
in
various
food/
feed
crops.
Therefore,
residential
exposures
are
not
expected
and
associated
risks
were
not
calculated.

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

7.0
Aggregate
Risk
Assessments
and
Risk
Characterization
In
accordance
with
the
FQPA,
HED
must
consider
and
aggregate
pesticide
exposures
and
risks
from
three
major
sources:
food,
drinking
water,
and
residential
exposures.
Since
there
are
no
residential
uses,
an
aggregate
exposure
assessment
for
dicloran
includes
consideration
of
59
of
84
exposures
from
food
and
drinking
water
only.
In
an
aggregate
assessment,
exposures
from
relevant
sources
are
added
together
and
compared
to
quantitative
estimates
of
hazard
(
e.
g.,
a
NOAEL
or
PAD),
or
the
risks
themselves
can
be
aggregated.
When
aggregating
exposures
and
risks
from
various
sources,
HED
considers
both
the
route
and
duration
of
exposure.
Acute
and
chronic
dietary
risk
assessments
(
D294459,
3/
06,
C.
Olinger)
were
conducted
using
the
Dietary
Exposure
Evaluation
Model
(
DEEM­
FCID
 
,
Version
2.03),
which
uses
food
consumption
data
from
the
USDA's
Continuing
Surveys
of
Food
Intakes
by
Individuals
(
CSFII)
from
1994­
1996
and
1998.

7.1
Acute
Aggregate
Risk
An
acute
dietary
exposure
assessment
was
conducted
assuming
tolerance
level
residues
and
100%
crop
treated
for
the
females
13­
49
years
of
age
population
subgroup.
No
endpoints
were
identified
for
the
general
population.
However,
since
acute
exposures
exceeded
HED's
level
of
concern
for
food
and
water,
refined
acute
analyses
were
necessary.
Acute
dietary
exposure
assessments
were
performed
using
DEEM­
FCID
 
.
Food
exposures
and
either
EDWCs
from
modeled
values
for
surface
water
sources
or
groundwater
sources
as
the
drinking
water
source
were
included.
The
assessments
incorporated
PDP
monitoring
data
for
all
commodities
except
rhubarb,
assuming
nondetectable
residues
were
at
the
limit
of
detection.
No
adjustments
for
percent
crop
treated
were
made.
At
the
99.9th
percentile
of
exposure,
the
estimated
food
and
water
exposure
for
females
13­
49
years
old
utilized
10%
and
52%
of
the
aPAD
for
ground
water
and
surface
water
sources,
respectively.
See
Tables
7.0a
and
7.0b
for
acute
aggregate
risks.

7.2
Short­
Term
Aggregate
Risk
A
short­
term
aggregate
assessment
is
not
required
at
this
time
for
DCNA.

7.3
Intermediate­
Term
Aggregate
Risk
An
intermediate­
term
aggregate
assessment
is
not
required
at
this
time
for
DCNA.

7.4
Long­
Term
Aggregate
Risk
Chronic
dietary
exposure
analyses
were
conducted
including
both
food
and
drinking
water
estimates
from
surface
and
ground
water
sources.
A
Tier
1
assessment
assuming
tolerance
level
residues
and
100%
crop
treated
was
performed,
and
risks
exceeded
the
level
of
concern
for
all
population
subgroups.
The
most
highly
exposed
subgroup
was
Children,
1­
2
years
old,
with
an
exposure
estimate
at
5500%
of
the
cPAD.
Thus,
a
refined
exposure
assessment
was
required.
The
refined
assessment
incorporated
USDA
Pesticide
Data
Program
(
PDP)
monitoring
data
for
all
commodities
except
rhubarb,
assuming
non­
detectable
residues
were
at
the
limit
of
detection.
No
adjustments
for
percent
crop
treated
were
made.
Using
these
refinements,
the
exposure
for
combined
food
and
water
were
below
<
1%
of
the
cPAD
for
most
population
subgroups.
The
most
highly
exposed
subgroup
was
children
1­
2
years
old,
with
exposures
utilizing
14%
and
15%
of
the
cPAD
for
ground
water
and
surface
water
sources,
respectively.
See
Tables
7.0a
and
7.0b
for
long­
term
aggregate
risks.
60
of
84
7.5
Cancer
Risk
Toxicological
studies
did
not
warrant
a
quantification
of
cancer
risk
for
DCNA,
thus
a
cancer
assessment
was
not
performed.

Table
7.0
a.
Summary
of
Dietary
Exposure
and
Risk
for
Dicloran
(
DCNA)
Incorporating
Surface
Water
as
a
Drinking
Water
Source
Acute
Dietary
Chronic
Dietary
Tier
1
Assessment
95th
Percentile
Refined
Assessment
99.9th
Percentile
Tier
1
Assessment
Refined
Assessment
Population
Subgroup
Dietary
Exposure
(
mg/
kg/
day)
%
aPAD
Dietary
Exposure
(
mg/
kg/
day)
%
aPAD
Dietary
Exposure
(
mg/
kg/
day)
%
cPAD
Dietary
Exposure
(
mg/
kg/
day)
%
cPAD
General
U.
S.
Population
0.048
1900
0.00019
7.5
All
Infants
(<
1
year
old)
0.094
3800
0.00036
14
Children
1­
2
years
old
0.14
5500
0.00038
15
Children
3­
5
years
old
0.10
3900
0.00031
12
Children
6­
12
years
old
0.058
2300
0.00021
8.2
Youth
13­
19
years
old
0.037
1500
0.00015
5.9
Adults
20­
49
years
old
0.040
1600
0.00016
6.3
Adults
50+
years
old
NA1
0.040
1600
0.00019
7.7
Females
13­
49
years
old
0.13
270
0.026
52
6.2
1600
0.00016
6.2
The
values
for
the
population
with
the
highest
risk
for
each
type
of
risk
assessment
are
bolded.
1
No
appropriate
endpoint
has
been
identified
for
this
population
subgroup.
61
of
84
Table
7.0b
Summary
of
Dietary
Exposure
and
Risk
for
Dicloran
(
DCNA)
Incorporating
Ground
Water
as
a
Drinking
Water
Source
Acute
Dietary
Chronic
Dietary
Tier
1
Assessment
95th
Percentile
Refined
Assessment
99.9th
Percentile
Tier
1
Assessment
Refined
Assessment
Population
Subgroup
Dietary
Exposure
(
mg/
kg/
day)
%
aPAD
Dietary
Exposure
(
mg/
kg/
day)
%
aPAD
Dietary
Exposure
(
mg/
kg/
day)
%
cPAD
Dietary
Exposure
(
mg/
kg/
day)
%
cPAD
General
U.
S.
Population
0.048
1900
0.00018
7.1
All
Infants
(<
1
year
old)
0.094
3800
0.00033
13
Children
1­
2
years
old
0.14
5500
0.00036
14
Children
3­
5
years
old
0.097
3900
0.00030
12
Children
6­
12
years
old
0.058
2300
0.00020
7.8
Youth
13­
19
years
old
0.037
1500
0.00014
5.6
Adults
20­
49
years
old
0.040
1600
0.00015
5.9
Adults
50+
years
old
NA1
0.040
1600
0.00018
7.3
Females
13­
49
years
old
0.13
260
0.0050
10
5.8
1600
0.00015
5.8
The
values
for
the
population
with
the
highest
risk
for
each
type
of
risk
assessment
are
bolded.
1
No
appropriate
endpoint
has
been
identified
for
this
population
subgroup.

8.0
Cumulative
Risk
Characterization/
Assessment
Unlike
other
pesticides
for
which
EPA
has
followed
a
cumulative
risk
approach
based
on
a
common
mechanism
of
toxicity,
EPA
has
not
made
a
common
mechanism
of
toxicity
finding
as
to
dicloran
and
any
other
substances
and
dicloran
does
not
appear
to
produce
a
toxic
metabolite
produced
by
other
substances.
For
the
purposes
of
this
tolerance
action,
therefore,
EPA
has
not
assumed
that
DCNA
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
http://
www.
epa.
gov/
pesticides/
cumulative/.
62
of
84
9.0
Occupational
Exposure/
Risk
Pathway
This
section
of
the
risk
assessment
addresses
exposures
to
individuals
who
are
exposed
as
part
of
their
employment.
These
exposures
can
occur
because
people
have
contact
with
DCNA
residues
while
using
commercial
products
containing
DCNA
(
i.
e.,
handlers)
or
by
being
in
areas
that
have
been
previously
treated
(
postapplication
workers).

Please
see
DP
Barcode:
D325650,
Dicloran:
Revised
Occupational
and
Residential
Exposure
and
Risk
Assessment
for
the
Reregistration
Eligibility
Decision
Document,
February
28,
2006,
by
Matthew
Lloyd
for
the
complete
dicloran
occupational
and
residential
exposure
assessment.

9.1
Occupational
Handler
Risk
For
dicloran
uses,
the
Agency
identified
several
major
occupational
exposure
scenarios
based
on
the
types
of
equipment
and
techniques
that
can
potentially
be
used
for
DCNA
applications.
These
scenarios
are
listed
below:

Agricultural
Crop
Treatment
Scenarios
°
Mix/
Load
wettable
powder,
dusts,
or
liquids
°
Apply
using
aerial,
groundboom,
airblast,
turfgun
or
HP
handwand
°
Mix/
Load/
Apply
wettable
powder
with
a
LP
handwand,
backpack
sprayer
or
turfgun;
°
Mix/
Load/
Apply
liquids
with
a
LP
handwand,
backpack
sprayer
or
turfgun;
°
Mix/
Load/
Apply
dusts
with
a
handheld
power
duster;
°
Flag
aerial
application
liquids
or
dust
Data
and
Assumptions
A
series
of
assumptions
and
exposure
factors
served
as
the
basis
for
completing
the
occupational
handler
risk
assessments.
The
assumptions
and
factors
are
detailed
below.

°
It
is
anticipated
that
most
of
the
occupational
dicloran
exposures
will
generally
occur
in
a
short­
and
intermediate­
term
pattern,
given
that
most
uses
in
agriculture
and
other
settings
are
for
controlling
disease
outbreaks
during
the
growing
season.

°
No
PHED
data
were
available
for
applying
dusts
for
aerial
or
ground
equipment.
Applicator
exposures
from
these
scenarios
remain
as
a
data
gap.

°
No
PHED
data
were
available
for
mix/
load/
apply
dust
scenarios
with
a
handheld
power
duster.
This
scenario
remains
as
a
data
gap.

°
The
Agency
always
considers
the
maximum
application
rates
allowed
by
labels
in
its
short­
and
intermediate­
term
risk
assessments
in
order
to
consider
what
is
legally
possible
based
on
the
label.

°
The
acres
treated
per
day
values
were
taken
from
Health
Effects
Division
Science
63
of
84
Advisory
Committee
on
Exposure
Policy
9.1:
Standard
Values
for
Daily
Acres
Treated
in
Agriculture
of
September
25,
2001.
These
factors
are
listed
below:

­
Aerial
applications:
350
acres
­
Chemigation:
350
acres
for
most
crops
­
Groundbloom:
80
acres
treated
­
Groundboom
(
sweet
potatoes):
3
acres/
day
for
plant
bed
spray
based
on
the
assumption
­
that
one
acre
of
bedded
seed
will
produce
enough
transplants
for
100
acres
of
potatoes
(
USDA
crop
profile
for
sweet
potatoes
in
Texas,
June
2003).
­
Airblast:
40
acres
treated
­
High
Pressure
Handwand:
10
acres
for
ornamental
applications
based
on
the
assumption
that
at
least
100
gallons
are
applied
per
acre
and
1000
gallons
are
applied
per
day
­
Backpack
Sprayer:
0.40
acres
per
day
based
on
the
assumption
that
at
100
gallons
are
applied
per
acre
and
40
gallons
are
applied
per
day
­
Low
Pressure
Handwand
Sprayer:
0.4
acres
acre
per
day
based
on
the
assumption
that
100
gallons
are
applied
per
acre
and
40
gallons
are
applied
per
day
Occupational
Handler
Risks
The
MOEs
for
short/
intermediate
term
dermal
and
inhalation
exposures
were
calculated
separately
because
the
endpoints
are
based
upon
different
effects.
These
MOEs
are
summarized
below
in
Tables
9.1a
and
9.1b.

Current
dicloran
labels
typically
require
that
coveralls,
waterproof
gloves
and
shoes
plus
socks
be
used
for
agricultural
handler
for
both
wettable
powder,
and
flowable
labels.
Non­
agricultural
applicators
and
other
handlers
are
required
by
the
WP
label
to
wear
long­
sleeved
shirt,
long
pants,
and
shoes
plus
socks.
In
addition,
applicators
and
other
handlers
are
required
by
the
liquid
flowable
labels
to
wear
waterproof
gloves.
Most
labels
do
not
require
respiratory
protection.
For
the
loader
scenarios
involving
dust,
the
majority
of
aerial
application
exposures
are
of
concern
for
both
the
dermal
and
inhalation
route.
For
the
loader
scenarios
involving
ground
application
of
dust,
all
scenarios
are
of
concern
at
baseline
and
require
some
PPE
to
achieve
MOEs
of
100
or
greater.
For
all
of
the
mixer
loader
scenarios
involving
wettable
powder
formulations,
the
handler
risks
for
label
required
PPE
are
of
concern
and
in
some
cases
double
layer
dermal
PPE
is
required
to
achieve
acceptable
MOEs.
This
includes
all
aerial,
chemigation,
and
airblast
wettable
powder
scenarios.
Groundboom
wettable
powder
application
scenarios
are
of
concern
at
baseline
and
typically
achieve
acceptable
MOEs
with
single
layer
PPE.

The
risks
of
mixing/
loading/
applying
flowables
with
handheld
equipment
(
e.
g.
low
pressure
handwand)
are
not
of
concern
at
baseline
for
the
dermal
exposure
route.
64
of
84
Table
9.1a
Dicloran
Short/
Intermediate
Term
Dermal
MOEs
for
Agricultural
Handlers
(
Note
­
The
labels
typically
require
single
layer
PPE
without
respirator)

Exposure
Scenario
Typical
Crops
lb
ai/
acre
Acres
per
Day
Baseline
SL
PPE
DL
PPE
EC
Mixer/
Loader
(
M/
L)

M/
L
Dust
for
Aerial
Crop
Dusting
grapes
tree/
vine
crops,
field/
row
crops
1.8
3.0­
4.0
350
4
2
78
47­
35
100
62­
46
N/
A
M/
L
Dust
with
Ground
Equipment
tree/
vine
crops,
grapes,
field/
row
crops
1.8
3.0­
4.0
40
32
19­
14
690
410­
310
900
540­
400
N/
A
M/
L
Wettable
Powder
(
WP)
for
Aerial
Application
or
Chemigation
field/
row
crops,
tree/
vine
crops
conifers/
christmas
trees
3.0­
4.5
2.0
350
2­
1
3
47­
31
71
62­
41
93
>
610
>
1000
M/
L
WP
for
Ground­
boom
sweet
potatoes
field/
row
crops
120
2.0­
4.5
3
80
6
14­
6
140
310­
140
180
400­
180
>
1000
>
1000
M/
L
WP
for
Airblast
tree
and
vine
crops
conifers/
christmas
trees
3.5­
4.0
2.0
40
16­
14
28
350­
310
620
460­
400
810
>
1000
M/
L
WP
for
HP
Handwand
ornamentals,
greenhouse
vegetables/
potatoes
0.75­
2.5
10
300­
94
>
1000
>
1000
>
1000
M/
L
Liquids
for
Aerial
Application
or
Chemigation
field/
row
crops
4.0
350
2
260
350
700
M/
L
Liquids
for
Groundboom
field/
row
crops
1.5­
4.0
80
24­
9
>
1000
>
1000
>
1000
M/
L
Liquids
for
Airblast
tree
and
vine
crops
conifers/
christmas
trees
4.0
2.0
40
18
36
>
1000
>
1000
>
1000
Applicator
(
APP)

Aerial
Application
field/
row
crops,
tree
and
vine
crops
conifers/
christmas
trees
3.0­
4.5
2.0
350
N/
A
­
It
was
assumed
that
only
engineering
controls
are
used
>
1000
Groundboom
Application
field/
row
crops
sweet
potatoes
2.0­
4.5
120.0
80
3
>
1000
>
1000
>
1000
>
1000
Airblast
Application
tree
and
vine
crops
conifers/
christmas
trees
3.5­
4.0
2.0
40
170­
150
290
250­
220
440
270­
240
480
>
1000
HP
Handwand
Application
ornamentals,
greenhouse
vegetables/
potatoes
0.8­
2.5
10
860­
260
>
1000
>
1000
ND
65
of
84
Mixer/
Loader/
Applicator
(
M/
L/
A)

M/
L/
A
WP
with
LP
Handwand
No
Data
>
490
>
680
No
Data
M/
L/
A
WP
with
Backpack
Sprayer
No
Data
M/
L/
A
Liquids
with
LP
Handwand
ornamentals,
greenhouse
vegetables/
potatoes
0.75­
2.5
0.4
280­
84
>
1000
>
1000
No
Data
M/
L/
A
Liquids
with
Backpack
Sprayer
field/
row
crops
4.0
0.4
No
Data
>
1000
>
1000
No
Data
Flagger
Flag
Aerial
Applications
field/
row
crops,
tree
and
vine
crops
conifers/
christmas
trees
3.0­
4.5
2.0
350
730­
480
>
1000
No
Data
800­
530
>
1000
>
1000
>
1000
*
MOEs
in
bold
are
less
than
100
and
are
of
concern.

N/
A
 
The
engineering
controls
specified
for
the
surrogate
dust
data
(
water
soluble
bags
for
wettable
powder)
are
not
possible
for
dust.

Crop
Groups
field/
row
crops
­
includes
celery,
florence,
fennel,
endive,
lettuce,
onion,
shallots,
garlic,
potatoes,
snap
beans,
etc.
tree
and
vine
crops
 
includes
apricots,
grapes,
peaches,
nectarines,
plums,
prunes,
sweet
cherries
ornamentals
 
includes
chrysanthemums,
geraniums,
roses,
gladiolus,
roses,
hydrangeas
greenhouse
vegetables
­
includes
cucumbers,
lettuce,
rhubarb,
tomatoes
PPE
Levels
Baseline
­
includes
long
pants
and
long
sleeve
shirts
without
gloves.
Single
Layer
(
SL)
­
includes
baseline
PPE
with
chemical
resistant
gloves
Double
Layer
(
DL)
­
includes
coveralls
over
baseline
PPE
and
chemical
resistant
gloves
­
typically
required
by
the
labels
EC
­
Engineering
control
­
includes
water
soluble
bags
,
closed
loading
systems
and
enclosed
cabs.

Table
9.1b
­
DCNA
Short/
Intermediate
Term
Inhalation
MOEs
for
Agricultural
Handlers
(
Note
­
The
labels
typically
require
single
layer
PPE
without
respirator)

Exposure
Scenario
Typical
Crops
(
See
Notes)
lb
ai/
acre
Acres
per
Day
Baseline
PF5
PF10
EC
Mixer/
Loader
(
M/
L)

M/
L
Dust
for
Aerial
Crop
Dusting
grapes
tree/
vine
crops,
field/
row
crops
1.8
3.0­
4.0
350
7
4­
3
32
19­
15
65
39­
29
N/
A
M/
L
Dust
with
Ground
Equipment
grapes,

tree/
vine
crops,
field/
row
crops
1.8
3.0­
4.0
40
57
34­
25
280
170­
130
570
340­
250
N/
A
M/
L
Wettable
Powder
(
WP)
for
Aerial
Application
or
Chemigation
field/
row
crops,
tree
and
vine
crops
conifers/
christmas
trees
3.0­
4.5
2.0
350
4­
3
6
19­
13
29
39­
26
58
>
460
1000
M/
L
WP
for
Groundboom
sweet
potatoes
field/
row
crops
120
2.0­
4.5
3
80
11
25­
11
57
130­
57
110
250­
110
>
1000
>
1000
66
of
84
Table
9.1b
­
DCNA
Short/
Intermediate
Term
Inhalation
MOEs
for
Agricultural
Handlers
(
Note
­
The
labels
typically
require
single
layer
PPE
without
respirator)

Exposure
Scenario
Typical
Crops
(
See
Notes)
lb
ai/
acre
Acres
per
Day
Baseline
PF5
PF10
EC
M/
L
WP
for
Airblast
tree
and
vine
crops
conifers/
christmas
trees
3.5­
4.0
2.0
40
29­
25
51
150­
130
250
290­
250
510
>
1000
>
1000
M/
L
WP
for
HP
Handwand
ornamentals,
greenhouse
vegetables/
potatoes
0.75­
2.5
10
540­
160
>
1000
>
1000
>
1000
M/
L
Liquids
for
Aerial
Application
or
Chemigation
field/
row
crops
4.0
350
100
520
1000
>
1000
M/
L
Liquids
for
Groundboom
field/
row
crops
4.0­
4.5
80
460­
410
>
1000
>
1000
>
1000
M/
L
Liquids
for
Airblast
tree
and
vine
crops
conifers/
christmas
trees
4.0
2.0
40
910
1800
>
1000
>
1000
>
1000
Applicator
(
APP)

Aerial
Application
field/
row
crops,
tree
and
vine
crops
conifers/
christmas
trees
3.0­
4.5
2.0
350
N/
A
­
It
was
assumed
that
only
engineering
controls
are
used
>
1000
Groundboom
Application
field/
row
crops
sweet
potatoes
2.0­
4.5
120.0
80
3
>
660
660
>
1000
>
1000
>
1000
Airblast
Application
tree
and
vine
crops
conifers/
christmas
trees
3.5­
4.0
2.0
40
280­
240
490
>
1000
>
1000
>
1000
HP
Handwand
Application
ornamentals,
greenhouse
vegetables/
potatoes
0.8­
2.5
10
>
1000
>
1000
>
1000
ND
Mixer/
Loader/
Applicator
(
M/
L/
A)

M/
L/
A
WP
with
LP
Handwand
530­
160
>
1000
>
1000
No
Data
M/
L/
A
WP
with
Backpack
Sprayer
No
Data
M/
L/
A
Liquids
with
LP
Handwand
ornamentals,
greenhouse
vegetables/
potatoes
0.75­
2.5
0.4
>
1000
>
1000
>
1000
No
Data
M/
L/
A
Liquids
with
Backpack
Sprayer
field/
row
crops
4.0
0.4
>
1000
>
1000
>
1000
No
Data
Flagger
Flag
Aerial
Applications
field/
row
crops,
tree
and
vine
crops
conifers/
christmas
trees
3.0­
4.5
2.0
350
480­
320
>
720
>
1000
>
1000
>
1000
67
of
84
Table
9.1b
­
DCNA
Short/
Intermediate
Term
Inhalation
MOEs
for
Agricultural
Handlers
(
Note
­
The
labels
typically
require
single
layer
PPE
without
respirator)

Exposure
Scenario
Typical
Crops
(
See
Notes)
lb
ai/
acre
Acres
per
Day
Baseline
PF5
PF10
EC
*
MOEs
in
bold
are
less
than
100
and
are
of
concern.

N/
A
 
The
engineering
controls
specified
for
the
surrogate
dust
data
(
water
soluble
bags
for
wettable
powder)
are
not
possible
for
dust.

Crop
Groups
field/
row
crops
­
includes
celery,
florence,
fennel,
endive,
lettuce,
onion,
shallots,
garlic,
potatoes,
snap
beans,
etc.
tree
and
vine
crops
 
includes
apricots,
grapes,
peaches,
nectarines,
plums,
prunes,
sweet
cherries
ornamentals
 
includes
chrysanthemums,
geraniums,
roses,
gladiolus,
roses,
hydrangeas
greenhouse
vegetables
­
includes
cucumbers,
lettuce,
rhubarb,
tomatoes
PPE
Levels
Baseline
­
no
respirator
is
worn
PF5
­
Filtering
facepiece
respirator
(
i.
e.
a
dustmask)
with
a
protection
factor
of
5
PF10
­
Half
face
cartridge
respirator
with
a
protection
factor
of
10
EC
­
Engineering
control
­
includes
water
soluble
bags
,
closed
loading
systems
and
enclosed
cabs.

Occupational
Risk
Characterization
The
Gowan
SMART
memo
of
August
14,
2003
8(
10)
notes
that
"
The
label
allows
multiple
applications,
although
the
season
maximum
of
4
lb/
A
is
intended
to
be
maintained
in
all
cases.
However,
typically
one
application
is
made."
The
majority
of
product
labels
do
not
indicate
a
4
lb/
A
maximum
seasonal
application
rate.
If
this
seasonal
maximum
rate
was
mandated
on
the
product
labels,
chronic
exposures
would
be
eliminated
for
handler
scenarios.
The
available
NASS
data
indicate
that
very
little
(<
50
lbs.)
dicloran
is
used
in
floriculture.

9.2
Occupational
Postapplication
Risk
Post
application
dicloran
exposures
can
occur
in
the
agricultural
environment
when
workers
enter
fields
recently
treated
with
DCNA
to
conduct
tasks
such
as
hand
harvesting.
Dicloran
use
sites
include
field/
row
crops,
tree
crops,
vineyards,
greenhouse
crops
and
ornamentals.
Applications
are
typically
begun
in
the
spring
or
when
disease
conditions
occur
and
can
typically
be
repeated
at
5
to
14
day
intervals
for
the
seasonal
applications.
In
some
instances,
such
as
ornamental
crops,
it
can
be
used
more
frequently.

Data
and
Assumptions
One
recent
dislodgeable
foliar
residue
(
DFR)
study
(
2000)
was
submitted
by
Gowan
Company.
The
studies
involved
the
application
of
Botran
75WP
wettable
powder
to
snap
beans,
DFR
samples
were
collected
using
the
standard
methodology
and
were
analyzed
for
dicloran
the
using
electron
gas
chromatography
analysis.
Complete
descriptions
of
the
analytical
methods
and
method
validation
data
were
included
in
the
study
reports.
These
studies
were
reviewed
by
the
68
of
84
Agency
and
they
generally
complied
with
series
875
guidelines
and
were
adequate
for
exposure
and
risk
assessment
purposes.

The
following
assumptions,
factors
and
transfer
coefficients
were
used
for
assessing
the
occupational
post­
application
risks:

°
The
body
weights,
dermal
absorption
factors
and
toxicological
endpoints
are
the
same
as
those
used
for
the
occupational
handler
assessments.
With
the
exception
of
greenhouse
ornamentals
and
vegetables,
only
short
and
intermediate
term
exposures
were
assessed
for
handler
risks.

°
Only
maximum
application
rates
were
used
for
most
of
the
post­
application
assessments
because
of
the
complexity
of
the
calculations,
which
involved
short
term,
intermediate
term,
and
long
term
for
several
agronomic
groups.

°
When
the
Agency
extrapolated
the
available
DFR
data
to
other
crops,
it
adjusted
the
data
for
differences
in
application
rate
using
a
simple
proportional
approach.
This
approach
seems
to
be
the
most
appropriate
given
the
data
that
are
available.
This
approach
is
commonly
used
in
Agency
post­
application
risk
assessments.

°
Risks
were
calculated
using
generic
transfer
coefficients
that
represent
many
different
types
of
cultural
practices.
A
listing
of
the
transfer
coefficients
used
in
this
assessment
is
given
below
in
Table
9.2a.
Most
of
these
transfer
coefficients
were
taken
from
the
Agency's
revised
Policy
003.1
Science
Advisory
Council
for
Exposure
Policy
Regarding
Agricultural
Transfer
Coefficients
(
August
7,
2000).
The
transfer
coefficients
for
ornamentals
excluding
cut
flowers
was
taken
from
studies
(
ARTF­
039
and
ARTF­
043)
recently
submitted
by
the
ARTF.
The
transfer
coefficients
for
ornamentals
including
cut
flowers
was
taken
from
the
ARTF­
055
study.

°
The
use
of
personal
protective
equipment
or
other
types
of
equipment
to
reduce
exposures
for
post­
application
workers
is
not
considered
a
viable
alternative
for
the
regulatory
process
except
in
specialized
situations
(
e.
g.,
a
rice
scout
will
wear
rubber
boots
in
flooded
paddies).
This
is
described
in
some
detail
in
the
Agency's
Worker
Protection
Standard
(
40
CFR
170).

Table
9.2a
Post­
Application
Exposure
Scenarios
and
Transfer
Coefficients
Crop
Type
(
Specific
Crops)
Post­
application
Exposure
Scenarios
Transfer
Coefficient
(
cm
2
/
hr)

Field/
Row
Crops,
Low/
Medium
(
Snap
Beans)
Low
­
Irrigation,
handweeding,
scouting
immature/
low
foliage
plants
Medium
­
Irrigation
and
scouting
mature/
high
foliage
plants
High
­
Hand
harvesting
100
1500
2500
69
of
84
Table
9.2a
Post­
Application
Exposure
Scenarios
and
Transfer
Coefficients
Crop
Type
(
Specific
Crops)
Post­
application
Exposure
Scenarios
Transfer
Coefficient
(
cm
2
/
hr)

Cut
Flowers
(
gladiolas,
roses,
hydrangeas)
Hand
harvesting
 
short
term
exposures
Hand
harvesting
 
Intermediate
term/
long
term
exposures
51001
27002
Ornamentals,
Potted
Plants
Low
­
Irrigation,
scouting,
thinning
weeding
immature
low
foliage
plants
Medium
­
Irrigation,
scouting
mature/
high
foliage
plants
High
­
Hand
harvesting,
pruning,
thinning,
pinching
110
175
400
Vegetable,
Curcurbit
(
cucumber
and
rhubarb)
Low
­
Irrigation,
scouting,
thinning
weeding
immature
plants
Medium
­
Irrigation,
scouting,
weeding
mature
plants
High
­
Hand
harvesting,
pulling,
leaf
thinning,
thinning,
turning
500
1500
2500
Vegetable,
Fruiting
Low
­
Irrigation,
scouting,
thinning
weeding
immature
plants
Medium
­
Irrigation,
scouting,
weeding
mature
plants
High
­
Hand
harvesting,
pruning,
staking,
tying
500
700
1000
Tree,
Fruit,
Deciduous
(
apricots,
peaches,
nectarines,
plums,
prunes,
and
sweet
cherries)
Low
­
Irrigation,
scouting,
weeding
High
 
Pruning,
training,
tying,
harvesting
Very
High
 
Thinning
100
1500
3000
Tree,
Fruit,
Evergreen
(
christmas
trees/
conifers)
Low
­
Irrigation,
scouting,
hand
weeding
Medium
­
Pruning,
harvesting
Medium*
­
thinning
1000
1500
3000
Vegetable,
Leafy,
Outdoors
(
lettuce,
celery,
florence,
fennel)
Low
­
Irrigation,
scouting,
thinning
weeding
immature
plants
Medium
­
Irrigation,
scouting,
weeding
mature
plants
High
­
Hand
harvesting,
pruning,
thinning
500
1500
2500
Vegetable,
Leafy,
Greenhouse
(
lettuce)
Low
­
Irrigation,
scouting,
thinning
weeding
immature
plants
Medium
­
Irrigation,
scouting,
weeding
mature
plants
High
­
Hand
harvesting,
pruning,
thinning
500
1500
2500
Vegetable,
Leafy,
Endive
(
escarole)
Low
­
Irrigation,
scouting,
thinning
weeding
immature
plants
Medium
­
Irrigation,
scouting,
weeding
mature
plants
High
­
Hand
harvesting,
pruning,
thinning
500
1500
2500
Vegetable,
Root
(
onions,
garlic,
shallots)
Low
­
Irrigation,
scouting,
thinning,
weeding
immature
plants
Medium
 
Irrigation
and
scouting
mature
plants
300
1500
Vegetable,
Root
(
potatoes)
Low
­
Irrigation,
scouting,
thinning,
weeding
immature
plants
Medium
 
Irrigation
and
scouting
mature
plants
300
1500
Vegetable,
Root
(
sweet
potatoes)
Low
­
Irrigation,
scouting,
thinning,
weeding
immature
plants
300
70
of
84
Table
9.2a
Post­
Application
Exposure
Scenarios
and
Transfer
Coefficients
Crop
Type
(
Specific
Crops)
Post­
application
Exposure
Scenarios
Transfer
Coefficient
(
cm
2
/
hr)

Vine/
Trellis
(
Grape)
Low
­
Hedging,
irrigation,
scouting,
hand
weeding
Medium
­
Scouting,
training,
tying
High
 
Leaf
pulling,
thinning,
pruning,
training/
tying
Very
High
 
Cane
Turning
and
Tabling
Grapes
500
1000
5000
10000
1
Maximum
mean
value
from
ARTF­
055
2
Mean
of
means
from
ARTF­
055
Post­
application
Risks
The
post
application
risks
for
dicloran
are
summarized
in
Tables
9.2b
and
9.2c.
Within
each
crop
group,
differing
transfer
coefficients
were
used
to
represent
different
types
of
cultural
practices
which
were
applicable
to
each
crop
group.
Most
of
the
MOEs
for
dicloran
are
of
concern
(
i.
e.
are
less
than
100)
at
the
currently
labeled
REI
of
12
hours
for
short
and
intermediate
term
risks.
The
time
needed
to
achieve
MOEs
of
100
for
short/
intermediate
term
risks
ranges
from
2
to
55
days
with
the
longest
time
needed
for
cane
turning
and
girdling
grapes.

Table
9.2b
Dicloran
Post­
application
Short/
Intermediate
Term
Risks
MOE
on
Day
0
(
Days
when
MOE
>
100)
Crop
Group
Application
Rate
(
lb
a.
i/
acre)
Low
Medium
High
Very
High
Field/
Row
Crops,
Low/
Medium
3
1590
110
64
(
13)
1
N/
A
Cut
Flowers
0.75
1
N/
A
N/
A
N/
A
N/
A
130
94
(
2)
N/
A
N/
A
Ornamentals,
Potted
Plants
0.75
5780
3630
1590
N/
A
Vegetable,
Curcurbit
1
950
320
190
N/
A
Vegetable,
Fruiting
0.75
1270
910
640
N/
A
Tree,
Fruit,
Deciduous
4
120
N/
A
80
(
7)
40
(
26)

Tree,
Fruit,
Evergreen
2
240
80
(
7)
N/
A
N/
A
Vegetable,
Leafy,
Greenhouse
2
480
160
95
(
3)
N/
A
Vegetable,
Leafy,
Outdoors
(
celery,
lettuce)
(
endive)
4
2
240
480
80
(
7)

160
50
(
30)

95
(
2)
N/
A
N/
A
Vegetable,
Root
(
onions,
garlic
shallots)

(
potatoes)

(
sweet
potatoes)
4
3
2.8
400
530
570
80
(
7)

110
N/
A
N/
A
N/
A
N/
A
N/
A
N/
A
N/
A
Vine/
Trellis
(
grapes)
3.5
270
140
30
(
36)
14
(
55)
71
of
84
At
the
request
of
SRRD,
for
those
scenarios,
above,
where
risks
exceeded
HED's
level
of
concern
(
MOE
<
100)
at
Day
0,
an
additional
risk
assessment
was
conducted
using
the
lower
application
rates
provided
by
SRRD.
Results
of
the
analysis
are
shown
below
in
Table
9.2c.
For
evergreen
fruit
trees,
onions,
garlic
and
shallots
the
lower
application
rate
resulted
in
MOEs,
which
were
no
longer
of
concern
at
day
0.
However,
for
the
remainder
of
the
scenarios
identified
of
concern
in
Table
9.2c,
concern
remains
for
MOEs
significantly
less
than
100
at
day
0.
The
time
needed
to
achieve
MOEs
of
100
for
short/
intermediate
term
risks
ranges
from
2
to
32
days
with
the
longest
time
needed
for
cane
turning
and
girdling
grapes.

Table
9.2c
Dicloran
Postapplication
Short/
Intermediate
Term
Risks
(
Reflecting
Revised
Rates
Provided
by
SRRD)

MOE
on
Day
0
(
Days
when
MOE
>
100)
Crop
Group
Application
Rate
(
lb
a.
i/
acre)
Low
Medium
High
Very
High
Field/
Row
Crops,
Low/
Medium
2
2400
160
95
(
2)
1
N/
A
Tree,
Fruit,
Deciduous
2
240
N/
A
160
80
(
7)

Tree,
Fruit,
Evergreen
1.5
320
110
N/
A
N/
A
Vegetable,
Leafy,
Outdoors
(
celery,
lettuce)
2
480
160
95
(
2)
N/
A
N/
A
Vegetable,
Root
(
onions,
garlic
shallots)
2
800
160
N/
A
N/
A
Vine/
Trellis
(
grapes)
1.5
640
320
64
(
13)
32
(
32)

A
summary
of
all
the
occupational
postapplication
risks
of
concern
for
dicloran
is
included
in
Table
9.2d,
below.
Current
label
requirements
specify
12
hour
REI's.
In
most
of
the
scenarios,
the
MOEs
for
dicloran
do
not
exceed
100
at
the
REI;
and
are
therefore
of
concern
to
HED.

Table
9.2d
Summary
of
Dicloran
Postapplication
Risks
of
Concern
Short­/
Intermediate­
Term
Risks
of
Concern
on
Day
0
(
12
hr
REI)
1
Crop
Group
Maximum
Application
Rate
Lowered
Application
Rates
Cut
flowers
N/
A
N/
A
Ornamentals,
potted
plants
N/
A
N/
A
Field/
row
crops
Short/
Intermediate
Term
­
irrigation,
scouting,
weeding
mature/
high
foliage
plants,
hand
harvesting
(
high
exposure
tasks)
Short/
Intermediate
Term
­
irrigation,
scouting,
weeding
mature/
high
foliage
plants,
hand
harvesting
(
high
exposure
tasks)

Deciduous
Fruit
Trees
(
Apricots,
peaches,
nectarines,
plums,
prunes,
sweet
cherries
)
Short/
Intermediate
Term
­
harvesting,
pruning,
training,
tying,
thinning
(
medium
and
high
exposure
tasks)
Short/
Intermediate
Term
 
thinning
(
very
high
exposure
task)
72
of
84
Table
9.2d
Summary
of
Dicloran
Postapplication
Risks
of
Concern
Short­/
Intermediate­
Term
Risks
of
Concern
on
Day
0
(
12
hr
REI)
1
Crop
Group
Maximum
Application
Rate
Lowered
Application
Rates
Evergreen
Fruit
Trees
(
conifers/
christmas
trees)
Short/
Intermediate
Term
­
shearing,
harvesting
(
medium
exposure
task)
N/
A
Leafy
Vegetables
(
lettuce,
celery,
florence,
fennel,
endive,
greenhouse
lettuce)
Short/
Intermediate
Term
 
Irrigation
and
scouting
mature
plants,
hand
harvesting,
pruning
(
medium
&
high
exposure
tasks)
Short/
Intermediate
Term
 
hand
harvesting,
pruning
and
thinning
mature
plants
(
high
exposure
tasks)

Root
Vegetables
(
onions,
garlic,
shallots,
potatoes)
Short/
Intermediate
Term
 
Irrigation
and
scouting
mature
plants
(
medium
exposure
tasks)
N/
A
Vine/
trellis
(
grapes)
Short/
Intermediate
Term
 
hand
harvest,
leaf
pulling,
thinning,
pruning,
cane
turning
and
girdling
table
grapes
(
high
&
very
high
exposures)
Short/
Intermediate
Term
 
hand
harvest,
leaf
pulling,
thinning,
pruning,
cane
turning
and
girdling
table
grapes
(
high
&
very
high
exposures)

Post
Application
Risk
Characterization
As
previously
mentioned,
the
Gowan
SMART
memo
of
August
14,
2003
8(
10)
notes
that
"
The
label
allows
multiple
applications,
although
the
season
maximum
of
4
lb/
A
is
intended
to
be
maintained
in
all
cases.
However,
typically
one
application
is
made."
The
majority
of
product
labels
do
not
indicate
a
4
lb/
A
maximum
seasonal
application
rate.
If
this
seasonal
maximum
rate
was
mandated
on
the
product
labels,
chronic
exposures
would
be
eliminated
for
post­
application
scenarios.

Since
the
DFR
data
was
extrapolated
from
dry
California
conditions,
dissipation
of
dicloran
may
be
faster
in
greenhouse
settings.

The
2003
NASS
Floriculture
Survey
indicates
very
low
overall
national
use
rates
for
dicloran
on
greenhouse
grown
plants
and
flowers;
therefore
the
dicloran
long­
term
post­
application
exposure
scenarios
are
not
likely
to
occur.

10.0
Data
Needs
and
Label
Requirements
10.1
Toxicology
Guideline
870.6300
Developmental
Neurotoxicity
Study
­
rats
Guideline
870.3465
Inhalation
Toxicity
Study,
28­
day­
rats
10.2
Residue
Chemistry
Guideline
860.1200
Directions
for
Use
73
of
84
°
Label
revisions
are
required
for
consistency
of
use
directions
with
the
available
residue
data.
Details
of
the
required
label
revisions
are
specified
in
the
respective
crop
section
under
OPPTS
860.1500.

Guideline
860.1300
Nature
of
the
Residue,
livestock
°
The
petitioner
is
required
to
provide
supporting
storage
stability
data
in
order
to
validate
the
integrity
of
samples
from
the
submitted
goat
and
hen
metabolism
studies.
The
petitioner
should
determine
if
the
metabolic
profile
for
dicloran
and
metabolites
is
stable
in:
(
i)
hen
tissue
and
eggs
for
20
months,
and
(
ii)
goat
milk
and
tissue
for
24
months.
Chromatograms
and
quantitative
data
should
be
submitted.

Guideline
860.1340
Residue
Analytical
Methods,
plant
and
livestock
°
Before
Method
R­
450.2
can
be
considered
adequate
for
tolerance
enforcement,
the
petitioner
or
registrant
should
submit
an
interference
study
demonstrating
the
specificity
of
the
proposed
method
in
the
presence
of
pesticides
with
established
tolerances
in/
on
carrot,
tomato,
and
peanut
commodities.
Alternately,
the
petitioner
could
propose
a
confirmatory
method
that
employs
a
mass
spectrum
detector.
Fortified
carrot,
tomato,
and
peanut
samples
should
be
analyzed;
structurally
significant
ions
should
be
chosen
with
a
m/
z
>
91
and
intensity
>
3x
noise
at
the
LOQ
for
the
primary
method.
Radiovalidation
of
the
method
is
also
required.

°
A
residue
analytical
method
should
be
developed
and
validated
for
the
determination
of
DCHA
in/
on
the
commodities
of
registered
crops.
In
addition,
a
validated
data­
collection
method
is
required
for
the
analysis
of
dichloroaniline­
containing
metabolites
in
rotational
crops.

°
The
need
for
residue
analytical
method(
s)
for
milk
and
livestock
meat
is
reserved
pending
the
outcome
of
the
requested
ruminant
feeding
study.
If
the
requested
study
shows
that
milk
and
meat
tolerances
are
needed
to
support
currently
registered
and
proposed
uses,
then
the
registrant
will
be
required
to
develop
and
validate
an
analytical
enforcement
method
for
the
analysis
of
all
dicloran
residues
of
concern
in
meat
and
milk.
The
registrant
will
be
required
to
submit
all
ancillary
data
(
confirmatory
method,
interference
study,
radiovalidation,
and
independent
laboratory
validation)
for
any
proposed
livestock
method.

Guideline
860.1360
Multiresidue
Method
°
If
in
the
future
HED
determines
that
tolerances
for
livestock
commodities
are
necessary,
then
the
petitioner
should
submit
information
concerning
the
behavior
of
the
DCAP
metabolite
through
FDA
Multiresidue
Protocols
A
through
F.

Guideline
860.1380
Storage
Stability
Data,
plant
°
Storage
stability
data
for
plant
commodities
are
now
required
for
the
metabolite
74
of
84
DCHA.

Guideline
860.1480
Meat/
Milk/
Poultry/
Eggs
(
Ruminant
feeding
study)

°
A
new
ruminant
feeding
study
is
required
to
determine
whether
tolerances
are
needed
(
and
if
so
the
appropriate
tolerance
levels)
for
milk
and
meat.
The
requested
ruminant
feeding
study
will
need
supporting
storage
stability
data
for
all
dicloran
residues
of
concern
(
dicloran,
DCAA,
DCHA,
DCAP,
DCNP,
and
the
A­
1
metabolite).
The
requirement
for
storage
stability
on
milk
and
meat
data
may
be
waived
if
samples
to
be
collected
from
the
ruminant
feeding
study
are
analyzed
within
30
days
of
collection.

Guideline
860.1500
Crop
Field
Trials
°
Additional
data
are
required
for
the
reassessment
or
establishment
of
tolerances
for:
apricot;
cherry
(
sweet);
fennel;
garlic;
onion;
peach;
plum;
rhubarb;
shallot;
sweet
potato;
and
tomato.
In
addition,
HED
is
now
requiring
the
registrant
to
conduct
limited
magnitude
of
the
residue
studies
for
all
registered
crops
to
allow
HED
to
perform
dietary
risk
assessment.
The
required
trials
should
monitor
for
residues
of
dicloran
and
DCHA
metabolite.
In
addition,
the
potato
field
trials
must
also
monitor
residues
of
Unknown
1.

Guideline
860.1520
Processed
Food/
Feed
°
The
registrant
is
required
to
conduct
additional
grape,
plum,
potato,
and
tomato
processing
studies
with
analysis
for
both
the
parent
and
DCHA
metabolite.
In
addition,
the
potato
processing
study
must
also
monitor
residues
of
Unknown
1.

Guideline
860.1900
Field
Accumulation
in
Rotational
Crops
°
Additional
data
from
limited
field
rotational
crop
trials
are
required.
The
requested
trials
should
be
conducted
at
the
maximum
seasonal
application
rate,
and
samples
should
be
analyzed
for
the
total
dichloroaniline­
containing
residues.
Extensive
rotational
crop
studies
may
be
required
if
residues
are
detected
at
the
desired
plantback
interval.
The
required
trials
will
need
supporting
storage
stability
data
for
total
dichloroanilinecontaining
residues
if
samples
are
stored
for
more
than
30
days
prior
to
sample
analysis.

10.3
Occupational
and
Residential
Exposure
The
Agency
is
requesting
process
descriptions
and
specific
application
rates
for
each
data
gap
listed
below.

°
The
risks
of
dipping
sweet
potato
seed
pieces
were
not
assessed
because
dipping
is
no
longer
used.
According
to
sweet
potato
experts
at
Sweet
Potato
Research
Station
(
LSU),
sweet
potato
seed
pieces
are
treated
in
the
plant
bed
using
a
sprayer.

°
The
risks
of
postharvest
dip
treatment
of
sweet
potatoes
were
not
assessed
due
to
a
75
of
84
lack
of
exposure
data.
This
treatment
is
accomplished
by
using
automated
equipment
however,
exposures
can
be
controlled
with
the
use
of
gloves.

°
There
are
no
data
available
to
evaluate
the
mix/
load/
apply
scenarios
for
backpack
sprayer
application
of
wettable
powders
and
dry
flowables.
The
PHED
data
for
both
high
and
low
pressure
handwand
application
of
liquids
(
mix/
load/
apply
and
apply
only)
is
also
of
low
quality.
These
data
gaps
make
it
difficult
to
accurately
assess
the
risks
of
the
handwand
method
of
application,
which
is
commonly
used
in
horticulture.

°
The
risk
of
applying
dusts
was
not
assessed
due
to
lack
of
exposure
data.

°
The
risk
for
mixing/
loading/
applying
dust
with
handheld
power
duster.

°
Flagger
exposure
to
aerial
application
of
dust.

References:

Bloem,
Tom.
DP
Barcodes:
D270711
and
D270712.
May
22,
2001.
PP#
7F04879
(
Peanut
and
Carrot)
and
010163­
00189
(
Tomato)
­
Dicloran
(
DCNA).
Application
to
Peanuts
(
pre­
harvest);
Carrots
(
postharvest);
and
Tomatoes
(
postharvest):
Evaluation
of
Residue
Chemistry
Data
and
Analytical
Methods.

Bloem,
Tom.
DP
Barcode:
D274421.
May
2,
2001.
HED
Metabolism
Assessment
Review
Committee
(
MARC)
Briefing
Document
for
Determination
of
Residues
of
Concern
in
Plants,
Livestock,
and
Drinking
Water.

Bloem,
Tom.
DP
Barcode:
D274726.
May
8,
2001.
Health
Effects
Division
(
HED)
Metabolism
Assessment
Review
Committee
(
MARC)
Decision
Document.

Goodlow,
Toiya.
DP
Barcode:
D325652.
February
28,
2006.
Dicloran:
HED
Response
to
Public
Comments­
Phase
4.

Goodlow,
Toiya.
DP
Barcode:
D325653.
February
28,
2006.
Dicloran:
Revised
HED
Chapter
of
the
Reregistration
Eligibility
Decision
Document
(
RED),
Phase
3
Public
Comments.

Lloyd,
Matthew
G.
DP
Barcode:
D325650.
February
28,
2006.
Dicloran:
Revised
Occupational
and
Residential
Exposure
and
Risk
Assessment
for
the
Reregistration
Eligibility
Decision
Document.

Olinger,
Christine.
DP
Barcodes:
D234923
and
D235035.
March
1,
2005.
Reregistration
of
Dicloran
(
DCNA):
Lettuce
and
Potato
Metabolism
Studies;
Discussion
on
Residues
of
Concern
in
Primary
Crops.

Olinger,
Christine.
DP
Barcode:
D246807.
March
1,
2005.
Reregistration
of
Dicloran
(
DCNA):
Confined
Rotational
Crop
Study.
76
of
84
Olinger,
Christine.
DP
Barcode:
D318895.
June
17,
2005.
Dicloran
(
DCNA).
Residue
Chemistry
Considerations
for
the
Reregistration
Eligibility
Decision
(
RED)
Document.
Summary
of
Analytical
Chemistry
and
Residue
Data.

Olinger,
Christine.
June
24,
2005.
Dicloran
(
DCNA)
RED
­
Reregistration
Eligibility
Decision.
Product
Chemistry
Considerations.

Olinger,
Christine.
DP
Barcode:
D294456.
March,
2006.
Dicloran
(
DCNA)
Revised
Acute
and
Chronic
Dietary
Exposure
Assessment[
s]
for
the
Reregistration
Eligibility
Decision
(
Phase
3).

Sutton,
Cheryl
A.
DP
Barcode:
D294452.
January
26,
2006.
DCNA
(
Dicloran):
Revised
Tier
I
Drinking
Water
EDWC's
for
Use
in
the
Human
Health
Risk
Assessment.
77
of
84
Appendices
1.0
TOLERANCE
REASSESSMENT
SUMMARY
Tolerances
Established
Under
CFR
§
180.200(
a)

Adequate
data
depicting
the
magnitude
of
the
residues
of
dicloran
per
se
have
been
submitted
to
reassess
the
tolerances
for
the
following
raw
agricultural
commodities:
bean,
snap,
succulent;
carrot;
celery;
cucumber;
grape;
lettuce;
and
potato
(
pending
label
revision
to
specify
a
20­
day
PHI).
The
available
and
requested
data
for
some
commodities
may
be
translated
(
i.
e.,
lettuce
to
leafy
vegetables
and
peach
to
nectarine)
pending
label
revisions.
Whenever
possible,
the
tolerances
were
reassessed
to
harmonize
with
existing
Codex
or
Canadian
MRLs.

Additional
data
are
required
for
the
reassessment
of
tolerances
established
for:
apricot;
cherry
(
sweet);
garlic;
nectarine;
onion;
peach;
plum;
rhubarb;
sweet
potato;
and
tomato.

Tolerances
to
be
Proposed
Under
40
CFR
§
180.200(
a)

Tolerances
must
be
proposed
for
fennel
and
shallot.
Typically,
the
Agency
allows
translation
of
data
from
celery
to
Florence
fennel
(
sweet
anise,
sweet
fennel,
finocchio)
and
dry
bulb
onions
to
shallots
as
per
40
CFR
§
180.1(
h)
if
the
registered
uses
for
the
two
crops
are
identical.
Because
the
current
use
patterns
for
fennel
differ
from
celery
and
shallots
differ
from
onions,
translation
of
data
is
not
an
option.

Residues
of
dicloran
were
found
to
concentrated
in
grape
juice
(­
1.3x),
dried
prunes
(
1.8­
1.9x),
tomato
puree
(
1.1­
1.2x),
and
tomato
paste
(
1.9­
2.0x).
At
this
time,
HED
is
unable
to
determine
whether
tolerances
will
be
needed
for
the
above
processed
commodities
because
the
highest
average
field
trial
(
HAFT)
residues
in/
on
the
raw
agricultural
commodities
have
not
been
determined
since
additional
field
trial
data
are
required.

Pending
Tolerance
Petitions:

PP#
5E04557
IR­
4
requested
a
tolerance
on
leafy
greens
(
except
spinach)
(
G.
Kramer,
D217939,
11/
18/
96).
Sufficient
lettuce
residue
data
are
available
to
support
this
use,
however,
the
appropriate
current
commodity
definition
is
Leafy
Vegetables,
except
Brassica,
Subgroup
4a
(
excluding
spinach).

PP#
7F04879:
Gowan
Company
is
requesting
a
Section
3
registration
for
application
of
the
fungicide
dicloran
to
peanut
(
preharvest),
carrots
(
preharvest),
and
tomatoes
(
postharvest)
and
proposed
the
establishment
of
permanent
tolerances
for
residues
of
dicloran
(
2,6­
dicloran­
4­
nitroaniline)
in/
on
tomatoes
(
pre­
and
postharvest)
at
5
ppm,
carrots
(
pre­
and
postharvest)
at
10
ppm,
peanuts
at
3
ppm,
and
peanut
oil
at
6
ppm.
HED
has
recommended
against
the
establishment
of
the
proposed
tolerances
(
DP
Barcodes
D270711
and
D270712,
5/
22/
01,
T.
Bloem).

A
summary
of
dicloran
tolerances
are
presented
below
in
Table
1.
78
of
84
Table
1.
Tolerance
Reassessment
Summary
for
Dicloran
(
DCNA).

Commodity
Current
Tolerance
(
ppm)
Tolerance
Reassessment
(
ppm)
Comment/
[
Correct
Commodity
Definition]

Tolerances
Listed
Under
40
CFR
§
180.200(
a)

Apricot,
postharvest
20
TBD1
[
Apricot]

Bean,
snap,
succulent
20
20
The
maximum
residues
of
dicloran
in/
on
snap
and
succulent
beans
from
trials
approximating
the
registered
label
rate
is
<
18.30
ppm.
The
reassessed
tolerance
is
harmonized
with
the
Canadian
MRL;
no
Codex
MRL
is
established
for
dicloran
on
snap
beans.

Carrot,
roots,
postharvest
10
10
The
calculated
residues
of
dicloran
from
trials
reflecting
the
registered
postharvest
rate
at
1x
ranged
from
2.66
to
9.24
ppm.
The
reassessed
tolerance
is
harmonized
with
Codex
MRL.

Celery
15
TBD1
[
Celery]

Cherry,
sweet,
postharvest
20
TBD1
[
Cherry,
sweet]

Cucumber
5
2
The
maximum
residue
of
dicloran
in/
on
cucumbers
from
trials
approximating
current
label
use
pattern
is
<
1.92
ppm.
The
reassessed
U.
S.
tolerance
level
is
not
in
harmony
with
the
Canadian
MRL
of
0.5
ppm
presumably
due
to
differences
in
registered
uses
and
good
agricultural
practices;
no
Codex
MRL
has
been
established
for
dicloran
on
cucumber.

Endive
(
escarole)
10
Revoke
A
leafy
vegetable
subgroup
tolerance
will
be
established.

Garlic
5
TBD1
Grape
10
10
The
maximum
residues
of
dicloran
in/
on
grapes
from
trials
approximating
the
registered
label
rate
is
<
3.86
ppm.
These
data
suggest
that
the
established
grape
tolerance
of
10
ppm
could
be
lowered.
HED,
however,
is
reassessing
the
grape
tolerance
at
10
ppm
to
remain
harmonized
with
Codex.

Lettuce
10
Revoke
A
leafy
vegetable
subgroup
tolerance
will
be
established.

Nectarine,
postharvest
20
TBD1
The
requested
data
for
peach
may
be
translated
to
nectarine.
When
the
requested
data
for
peaches
have
been
submitted
and
reviewed,
HED
will
examine
whether
the
nectarine
tolerance
could
be
revoked
as
per
40
CFR
§
180.1(
h).
[
Nectarine]

Onion
10
TBD1
Peach,
postharvest
20
TBD1
[
Peach]

Plum,
prune,
fresh,
postharvest
15
TBD1
[
Plum]
79
of
84
Table
1.
Tolerance
Reassessment
Summary
for
Dicloran
(
DCNA).

Commodity
Current
Tolerance
(
ppm)
Tolerance
Reassessment
(
ppm)
Comment/
[
Correct
Commodity
Definition]

Potato
0.25
0.25
The
maximum
residues
of
dicloran
in/
on
potatoes
from
trials
reflecting
a
20­
day
PHI
and
label
rate
is
0.22
ppm.
The
potato
tolerance
is
reassessed
at
the
same
level
pending
label
revision
to
specify
a
20­
day
PHI.

Rhubarb
10
TBD1
Sweet
potato,
postharvest
10
TBD1
[
Sweet
potato]

Tomato
5
TBD1
Tolerances
to
be
Established
Under
CFR
§
180.200(
a)

Fennel
None
TBD1
Vegetable,
Leafy
(
except
Brassica
and
spincach),
Subgroup
4a
none
10
The
maximum
residues
of
dicloran
in/
on
lettuce
from
trials
reflecting
current
label
use
pattern
is
<
4.89
ppm.
These
data
suggest
that
the
established
lettuce
tolerance
of
10
ppm
could
be
lowered.
HED,
however,
is
reassessing
the
lettuce
tolerance
at
10
ppm
to
remain
harmonized
with
Codex.

Shallot
None
TBD1
1
TBD
=
To
be
determined.
Additional
data
are
required
for
tolerance
reassessment.
80
of
84
2.0
TOXICOLOGY
DATA
REQUIREMENTS
The
requirements
(
CFR
158.340)
for
food
and
non­
food
uses
for
Dicloran
are
in
Table
2.
Use
of
the
new
guideline
numbers
does
not
imply
that
the
new
(
1998)
guideline
protocols
were
used.

Technical
Test
Required
Satisfied
870.1100
Acute
Oral
Toxicity......................................................
870.1200
Acute
Dermal
Toxicity.................................................
870.1300
Acute
Inhalation
Toxicity.............................................
870.2400
Primary
Eye
Irritation...................................................
870.2500
Primary
Dermal
Irritation
.............................................
870.2600
Dermal
Sensitization
....................................................
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
870.3100
Oral
Subchronic
(
rodent)
..............................................
870.3150
Oral
Subchronic
(
nonrodent).........................................
870.3200
21­
Day
Dermal.............................................................
870.3250
90­
Day
Dermal.............................................................
870.3465
90­
Day
Inhalation.........................................................
yes
yes
yes
no
yes
yes
yes
yes
­
no
a
870.3700a
Developmental
Toxicity
(
rodent)
..................................
870.3700b
Developmental
Toxicity
(
nonrodent).............................
870.3800
Reproduction................................................................
yes
yes
yes
yes
yes
yes
870.4100a
Chronic
Toxicity
(
rodent)
.............................................
870.4100b
Chronic
Toxicity
(
nonrodent)
.......................................
870.4200a
Oncogenicity
(
rat)
........................................................
870.4200b
Oncogenicity
(
mouse)...................................................
870.4300
Chronic/
Oncogenicity...................................................
yes
yes
yes
yes
yes
yes
1
yes
yes
yes
yes
870.5100
Mutagenicity 
Gene
Mutation
­
bacterial
.....................
870.5300
Mutagenicity 
Gene
Mutation
­
mammalian
................
870.5xxx
Mutagenicity 
Structural
Chromosomal
Aberrations
....
870.5xxx
Mutagenicity 
Other
Genotoxic
Effects
.......................
yes
yes
yes
yes
yes
yes
2
yes
yes
870.6100a
Acute
Delayed
Neurotox.
(
hen).....................................
870.6100b
90­
Day
Neurotoxicity
(
hen)
..........................................
870.6200a
Acute
Neurotox.
Screening
Battery
(
rat)
.......................
870.6200b
90
Day
Neuro.
Screening
Battery
(
rat)
..........................
870.6300
Develop.
Neuro............................................................
no
no
no
no
yes
­
­
­
­
no
870.7485
General
Metabolism.....................................................
870.7600
Dermal
Penetration.......................................................
yes
no
yes
­

Special
Studies
for
Ocular
Effects
Acute
Oral
(
rat)
............................................................
Subchronic
Oral
(
rat)....................................................
Six­
month
Oral
(
dog)
...................................................
no
no
no
­
­
­

a
Twenty
eight
(
28)­
day
inhalation
study
in
rats
(
abbreviated
90­
day
protocol).
The
registrant
is
recommended
to
follow
all
the
procedures
stipulated
in
the
Subdivision
F
Guidelines
for
the
90­
day
inhalation
toxicity
study
(
870.3465)
except
that
the
exposure
duration
can
be
reduced
to
28
days.
We
request
this
study
due
to
the
potential
occupational/
residential
exposure
via
this
route
and
there
are
no
studies
available
at
the
present
time.

1
Either
870.4300
or
870.4100
can
fulfil
this
requirement.
2
The
data
base
for
mutagenicity
is
considered
adequate
based
on
1991
mutagenicity
guidelines
and
no
further
testing
is
required
at
this
time.
81
of
84
3.0
NON­
CRITICAL
TOXICOLOGY
STUDIES
Executive
summaries
for
studies
not
used
for
toxicity
endpoint
selection
or
FQPA
assessment
are
as
follows.

A­
2.1
Subchronic
Oral
Toxicity
­
Rat
(
870.3100)

In
a
90­
day
toxicity
study
(
MRID
00029056),
dicloran
technical
(
Lot
#
PS02451,
97.1%)
was
administered
in
the
diet
to
albino
rats
(
35/
sex/
group)
for
up
to
104
weeks
at
nominal
doses
of
0,
20,
100,
or
3000
ppm
(
equivalent
to
0,
1,
5
and
150
mg/
kg/
day).
This
is
an
interim
report
(
13
Weeks)
of
a
104
week
study.
For
the
first
four
weeks,
the
feeding
levels
were
one
half
the
desired
dosage
in
an
attempt
to
maintain
the
drug
intake
per
kilogram
of
body
weight
at
a
constant
level.
Hematological
measurements
were
performed
on
five
males
and
five
females
of
the
control
and
high
dose
level
rats
at
4
and
8
weeks
and
in
addition,
on
five
female
rats
on
the
100
ppm
level
at
8
weeks.
Hematological
measurements
were
also
performed
on
five
males
and
five
females
from
each
dose
group
at
13
week
prior
to
sacrifice
of
these
rats.
At
13
weeks,
5
males
and
5
females
from
each
group
were
sacrificed,
selected
organs
weighed
and
histopathologic
examination
was
performed.

No
mortality
(
except
one
female
in
100
ppm
group)
was
observed
in
13
weeks.
Body
weights,
body
weight
gain
and
food
consumption
of
male
and
female
rats
in
20
ppm
and
100
ppm
dose
group
were
comparable
to
control
rats.
Body
weight
gain
and
food
consumption
was
slightly
depressed
in
the
high
dose
rats.
Decreased
in
body
weight
gain
of
the
male
rats
in
high
dose
were
93.2%,
89.6%,
and
89.0%
of
the
control
values
at
4
week,
8
week
and
14
week,
respectively.
Decreased
in
body
weight
gain
of
the
female
rats
in
high
dose
were
83.8%,
77.8%,
and
76.1%
of
the
control
values
at
4
week,
8
week
and
14
week,
respectively.
No
treatment
related
effects
were
observed
on
the
hematological
parameters
measured.

Increase
in
liver
and
kidney
weights
were
observed
in
the
high
dose
rats.
Histopathological
examination
of
the
tissues
from
the
13­
week
autopsy
revealed
all
within
normal
limits
or
comparable
to
controls
with
the
exception
of
the
livers
and
adrenals
of
the
high
dose
rats.
Mild
hepatic
cell
changes
were
observed
in
some
of
the
livers
and
slight
adrenal
cortical
atrophy
of
the
high
dose
rats.

The
LOAEL
is
3000
ppm
(
equivalent
to
150
mg/
kg/
day)
based
on
reduced
body
weight
gain,
increased
liver
and
kidney
weights,
and
histopathological
changes
in
the
liver
and
adrenals.
The
NOAEL
is
100
(
equivalent
to
5
mg/
kg/
day).

The
submitted
study
is
classified
as
acceptable/
guideline
(
§
82­
2[
a])
and
does
satisfy
the
requirements
for
a
subchronic
toxicity
study
in
rats.

Note:
This
study
does
not
conform
to
the
current
guideline
requirements.
Homogeneity
and
stability
of
the
diet
was
not
measured.
The
actual
concentration
of
dicloran
in
the
prepared
diet
was
not
determined.
Clinical
chemistry,
urinalysis
and
ophthalmoscopic
examination
was
not
performed.
Achieved
mean
doses
were
not
calculated.
Only,
five
rats
/
sex/
group
were
evaluated
at
the
13
week
treatment
duration.
No
statistical
analysis
was
performed
82
of
84
A­
2.2
Subchronic
Oral
Toxicity­
Rat
(
870.3100)

In
a
90­
day
ranging­
finding
study
(
MRID
46360702),
dicloran
(
94.6%
a.
i.;
batch/
lot
#
000313)
was
administered
in
the
diet
to
groups
of
10
male
and
10
female
Wistar
(
HsdCpb:
WU)
rats
at
concentrations
of
0,
300,
1000,
2000,
or
4000
ppm
for
90
days.
The
dietary
concentrations
were
equivalent
to
0,
19.4,
61.5,
121.2,
and
246.8
mg/
kg/
day,
respectively,
for
males
and
0,
25.4,
72.4,
133.6,
and
264.6
mg/
kg/
day,
respectively,
for
females.
The
following
parameters
were
examined:
clinical
signs,
body
weight,
food
consumption,
clinical
pathology
(
hematologic
and
clinical
chemistry
parameters),
gross
lesions,
selected
organ
weights,
and
histopathology
of
selected
tissues
and
organs.

All
animals
survived
to
study
termination
and
no
treatment­
related
clinical
signs
of
toxicity
were
observed
at
any
time
during
treatment.
Body
weight,
weight
gain,
and
food
consumption
were
significantly
(
p#
0.05)
decreased
throughout
the
study
in
males
and
females
at
2000
and
4000
ppm.
At
2000
and
4000
ppm,
males
weighed
10­
14%
and
19­
29%
less
than
controls,
respectively,
and
females
weighed
6­
13%
and
8­
19%
less
than
controls,
respectively.
Males
and
females
in
the
2000­
and
4000­
ppm
groups
lost
weight
during
the
first
week
of
the
study.
The
males
gained
29%
and
56%
less
weight,
respectively,
and
the
females
gained
29%
and
44%
less
weight,
respectively,
over
the
entire
study.

Male
rats
in
the
1000
ppm
group
weighed
5%
(
p#
0.05)
less
and
gained
55%
less
weight
than
controls
after
the
first
week.
However,
over
the
entire
study,
the
1000
ppm
group
gained
11%
(
N.
S.)
less
weight
than
controls.
Females
in
the
1000­
ppm
group
weighed
up
to
7%
(
p#
0.05)
less
than
controls
from
weeks
9­
13
and
gained
24%
(
p#
0.05)
less
weight
over
the
entire
study.
Females
in
the
1000­
ppm
group
had
weekly
weight
gains
similar
to
the
controls
after
week
1;
therefore,
the
cumulative
weight
gain
is
not
indicative
of
an
adverse
effect.
Body
weight
and
weight
gain
were
not
affected
at
300
ppm.
Weekly
food
consumption
was
markedly
reduced
by
42%
and
71%
in
2000­
and
4000­
ppm
male
groups,
respectively,
during
week
1
and
was
reduced
by
10­
19%
and
15­
36%
(
p#
0.05)
less
food
than
controls
for
the
remaining
weeks.
Males
in
the
1000­
ppm
group
consumed
7­
16%
(
p#
0.05)
less
food
than
controls.
Females
in
the
1000­,
2000­,
and
4000­
ppm
groups
consumed
24%,
54%,
and
66%
less
food
than
controls
during
week
1
and
16­
21%,
20­
28%,
and
21­
37%
(
p#
0.05)
less
food
than
controls
for
the
remaining
weeks
of
the
study.

In
male
and
female
rats
at
2000
and
4000
ppm,
the
RBC
counts
were
lower
and
MCV
and
MCH
were
higher
than
controls.
Blood
urea
nitrogen
(
BUN)
was
elevated
in
males
and
females
at
2000
and
4000
ppm,
total
protein
and
albumin
levels
were
elevated
in
males
at
4000
ppm,
and
total
cholesterol
was
elevated
in
females
at
2000
and
4000
ppm.
Except
for
hepatocyte
hypertrophy
(
see
below),
which
may
be
associated
with
increased
protein
and
BUN,
clinical
chemistry
findings
were
not
associated
with
pathologic
findings.

At
necropsy,
terminal
body
weight
was
significantly
decreased
in
males
at
2000
and
4000
ppm
and
absolute
epididymis
weight
was
significantly
decreased
at
4000
ppm.
Organ:
body
weight
ratios
of
the
adrenals,
testes,
kidneys,
liver,
brain,
and
spleen
were
increased
at
4000
ppm,
kidney,
liver
and
brain
at
2000
ppm,
and
liver
at
1000
ppm.
Terminal
body
weight
and
absolute
adrenal
83
of
84
weight
were
significantly
decreased
and
liver
weight
was
significantly
increased
in
females
at
2000
and
4000
ppm;
spleen
weight
was
significantly
increased
in
females
at
4000
ppm.
Organ:
body
weight
ratios
of
liver
and
kidneys
were
significantly
increased
at
1000­
4000
ppm,
and
the
ratios
of
brain
and
spleen
weights
were
significantly
increased
in
females
at
4000
ppm.
Except
for
increased
liver
weight,
changes
in
absolute
organ
weights
and
organ:
body
weight
ratios
were
due
primarily
to
decreases
in
terminal
body
weight.
No
treatment­
related
gross
lesions
were
observed
in
male
or
female
rats.
Microscopic
examination
showed
significantly
increased
incidences
of
hepatocellular
hypertrophy
in
males
at
2000
and
males
and
females
at
4000
ppm,
increased
hemosiderosis
in
the
spleen
of
males
at
2000
and
4000
ppm
and
in
females
at
all
doses,
and
hyaline
droplets
in
the
renal
tubular
epithelium
of
males
at
2000
and
4000
ppm.
Hepatocellular
hypertrophy
and
hemosiderosis
in
the
spleen
are
not
considered
adverse
effects
and
hyaline
droplet
formation
in
the
kidney
tubules
is
not
relevant
to
humans.

Based
on
the
range­
finding
study,
the
high
dose
selected
for
the
24­
month
study
was
1200
ppm.

The
LOAEL
for
dicloran
in
the
90­
day
feeding
study
in
the
rat
is
2000
ppm
(
121.2
mg/
kg
bw/
day
for
males
and
133.6
mg/
kg/
day
for
females)
based
on
decreased
body
weight,
weight
gain,
and
food
consumption.
The
corresponding
NOAEL
is
1000
ppm
(
61.5
mg/
kg
bw/
day
for
males
and
72.4
mg/
kg
bw/
day
for
females).

This
study
is
classified
as
acceptable/
guideline
and
satisfies
the
guideline
requirements
(
OPPTS
870.3100a;
OECD
408)
for
a
subchronic
oral
toxicity
study
in
the
rat.

A­
2.3
Metabolism
­
Rat
(
870.7485)

In
a
metabolism
study
(
MRID
44061001)
in
rats,
14C­
Dicloran
(
BOTRAN
TECHNICAL)
[
radiolabel
>
99%;
97%
a.
i.]
was
administered
to
5
Sprague­
Dawley
rats/
sex/
dose
either
as
a
single
high
[
500
mg/
kg]
dose
or
as
15
consecutive
low
doses
[
5
mg/
kg/
day].
The
objectives
of
this
study
were
to
determine
(
1)
the
absorption/
distribution/
elimination/
biotransformation
of
14C­
Dicloran
in
rats
following
multiple
low
oral
dose
exposure,
(
2)
the
metabolism
of
14C­
Dicloran
in
rats
receiving
a
single
high
oral
dose
exposure,
and
(
3)
to
provide
samples
for
characterization/
identification
of
metabolites
of
14C­
Dicloran
in
the
rat
to
define
its
metabolic
pathway.
Dicloran
was
rapidly
absorbed
and
metabolized
following
both
dosing
regimens.
The
total
recovery
of
radioactivity
following
repeat
exposure
was
98.3%.
Approximately
96%
of
the
administered
radiolabel
was
recovered
in
excreta
and
cage
wash
within
24
hours
postdose.
The
urine
was
the
major
route
of
excretion
[
86.3%
of
total
radiolabel],
and
smaller
amounts
of
radiolabel
were
excreted
in
the
feces
[
8.7%
of
total
radiolabel]
following
repeat
exposure.
The
highest
tissue
residue
levels
were
found
in
the
liver
and
kidneys
7
days
post
14C­
Dicloran
dose,
at
which
time
the
blood
levels
were
0.01%
of
the
administered
dose.
The
major
urine
metabolites
were
DCHAsulfate
[
DCHA
=
4­
amino­
3,5­
dichlorophenol]
and
DCHA­
glucuronide,
which
accounted
for
45.5%
to
79.0%
of
the
total
administered
radiolabel.
Other
metabolites
detected
were
DCHA
[
4­
amino­
3,5­
dichlorophenol
(
3.3%
to
22.8%)],
DCAP
[
4­
amino­
2,6­
dichlorophenol
(
0.3%
to
8.5%)],
and
DCNAP
[
3,5­
dichloro­
4­
hydroxyacetanilide
(<
0.1%
to
1.0%)].
A
small
amount
of
Dicloran
was
detected
in
the
feces
from
the
high­
dose
sample.
Many
minor
metabolites
were
detected,
with
total
radioactivity
ranging
from
<
0.1%
to
6.2%
for
each
region.
Amounts
of
3.0%
to
7.6%
of
radioactivity
were
retained
in
the
feces
PES
[
post­
extraction
solids]
sample.
84
of
84
Radioactivity
was
released
by
acid
hydrolysis
and
considered
to
be
components
formed
by
glutathione
conjugation.
The
metabolism
of
Dicloran
involved
reduction/
deamination/
hydroxylation
of
the
nitro
group
to
yield
the
DCHA
metabolite,
then
conjugation
occurred
to
form
the
major
metabolites
DCHA­
sulfate
and
DCHA­
glucuronide.
DCAP
was
produced
through
reduction/
deamination/
hydroxylation.
Following
N­
acetylation,
DCNAP
was
formed.
A
minor
metabolic
pathway
involved
dechlorination/
hydroxylation
of
Dicloran
to
form
2­
hydroxy­
4­
nitro­
6­
chloroaniline.

This
metabolism
study
in
the
rat
is
classified
ACCEPTABLE,
and
it
satisfies
the
guideline
requirement
for
a
metabolism
study
(
§
85­
1)
in
rats
when
considered
with
MRIDs
43255401
and
43255502
(
see
summaries
below).

Under
the
conditions
of
the
study
[
MRID
43255401;
single
oral
dose
of
5
mg/
kg],
elimination
of
radiolabeled
Dicloran
was
rapid
in
both
sexes.
The
majority
[>
97%]
of
the
radiolabel
excreted
via
both
urine
and
feces
occurred
within
the
first
24
hours
post
dose,
and
the
majority
of
the
dose
[.
78%
%%/.
73%
&&]
was
excreted
via
the
urine.
Fecal
excretion
accounted
for
>
13%
[%%]/>
14%
[&&]
of
the
radiolabel.
The
mean
recovery
of
radiolabel
was
>
98%
for
both
sexes.
Tissue
levels
were
low,
with
the
majority
of
the
tissues
having
levels
below
the
limit
of
detection.

Under
the
conditions
of
the
study
[
MRID
43255402;
single
oral
dose
of
500
mg/
kg],
elimination
of
radiolabeled
Dicloran
was
rapid
in
both
sexes.
The
majority
[>
92%]
of
the
radiolabel
excreted
via
both
urine
and
feces
occurred
within
the
first
48
hours
post
dose,
and
the
majority
of
the
dose
[.
68%
in
both
sexes]
was
excreted
via
the
urine.
Fecal
excretion
accounted
for
.22%
[
both
sexes]
of
the
radiolabel.
The
mean
recovery
of
radiolabel
was
>
94%
for
both
sexes.
Tissue
levels
were
low,
but
detectable
at
4
days
post
dose.