1
UNITED
STATES
ENVIRONMENTAL
PROTECTION
AGENCY
WASHINGTON,
D.
C.
20460
HED
DOC.
NO.
014596
OFFICE
OF
PREVENTION,
PESTICIDES
AND
TOXIC
SUBSTANCES
DATE:
June
20,
2001
MEMORANDUM
SUBJECT:
DIURON:
Report
of
the
Hazard
Identification
Assessment
Review
Committee
FROM:
Yung
G.
Yang,
Ph.
D.
Toxicology
Branch
Health
Effects
Division
(
7509C)

THROUGH:
Jess
Rowland,
Co­
Chair
and
Elizabeth
Doyle,
Co­
Chair
Hazard
Identification
Assessment
Review
Committee
Health
Effects
Division
(
7509C)

TO:
Diana
Locke,
Ph.
D.
Risk
Assessor,
RRB2
Health
Effects
Division
(
7509C)

PC
CODE:
035505
On
May
29,
2001,
the
Health
Effects
Division
(
HED)
Hazard
Identification
Assessment
Review
Committee
(
HIARC)
convened
to
review
the
toxicology
data
base
of
diuron
for
hazard
identification
and
to
select
doses
and
endpoints
for
acute
dietary,
chronic
dietary
(
RfD)
as
well
as
occupational
and
residential
exposure
assessments
and
to
address
the
sensitivity
of
infants
and
children
from
exposure
to
diuron
as
required
by
the
Food
Quality
Protection
Act
(
FQPA)
of
1996.
The
HIARC's
conclusions
are
presented
in
this
report.
2
Committee
Members
in
Attendance
Members
in
attendance:
Ayaad
Assaad,
Jonathan
Chen,
Pamela
Hurley,
Jess
Rowland
(
Chair),
David
Nixon,
Brenda
Tarplee,
and
Yung
Yang.

Members
in
absentia:
William
Burnam,
Elizabeth
Doyle,
and
Elizabeth
Mendez.

Also,
in
attendance:
Paula
Deschamp,
Diana
Locke,
Alberto
Protzel,
John
Punzi,
Renee
Sandvig,
and
Ibrahim
Abdel­
Saheb
(
EFED)

Data
evaluation
/
presentation:
Yung
G.
Yang
Toxicology
Branch.
Diuron
3
INTRODUCTION
Diuron
is
a
substituted
urea
herbicide
for
the
control
of
a
wide
variety
of
annual
and
perennial
broadleaves
and
grassy
weeds
on
both
crop
and
noncrop
sites.
Its
main
use
is
as
a
pre­
emergent,
soil
applied
herbicide,
but
it
can
also
be
used
to
control
emerged
weeds.
Diuron
is
available
as
a
technical
material,
at
95­
98%
active
ingredient
or
as
a
manufacturing
use
product
containing
80%
diuron
for
formulation
of
diuron
end­
use
formulations
or
as
manufacturing
use
products.
As
a
sole
active
ingredient,
diuron
is
available
in
wettable
powder,
granular,
flowables,
pelleted/
tableted,
liquid
suspensions,
and
soluble
concentrate
formulations.
The
exposure
duration
is
expected
to
be
short
term
for
residential
uses
and
short
and
intermediate
term
for
occupational
uses.

Empirical
formula:
C9H10Cl
2N2O
Molecular
weight:
233.1
CAS
Registry
No.:
330­
54­
1
PC
Code:
035505
NH
N
CH
3
CH3
O
Cl
Cl
The
toxicology
data
base
of
diuron
has
been
evaluated
by
the
Health
Effects
Division
RfD
Review
Committee
on
September
26,
1996
and
the
Carcinogenicity
Peer
Review
Committee
on
December
12,
1996.
A
Section
18
exemption
for
the
use
of
diuron
80W
in
catfish
ponds
in
Mississippi
has
been
issued
on
May
13,
1999
after
brief
reviews
by
the
HIARC
on
March
18,
1999
and
FQPA
Safety
Factor
Committee
on
March
22,
1999.
Since
then,
the
toxicology
data
base
of
diuron
has
been
rereviewed
and
updated
by
the
Toxicology
Branch
for
a
Reregistration
Eligibility
Decision
(
RED).

On
May
29,
2001
the
HIARC
reviewed
the
toxicology
data
base
of
diuron
for
hazard
identification
and
to
select
doses
and
endpoints
for
acute
dietary,
chronic
dietary
(
RfD)
as
well
as
occupational
and
residential
exposure
assessments
in
support
of
a
RED
and
to
address
the
sensitivity
of
infants
and
children
from
exposure
to
diuron
as
required
by
the
Food
Quality
Protection
Act
(
FQPA)
of
1996.
The
HIARC's
conclusions
are
as
follows.
Diuron
4
Acute
RfD
=
N/
A
1.
HAZARD
IDENTIFICATION
1.1
Acute
Reference
Dose
(
RfD)

Study
Selected:
None
MRID
No.:
N/
A
Executive
Summary:
N/
A
Dose
and
Endpoint
for
Establishing
RfD:
N/
A
Uncertainty
Factor
(
UF):
N/
A
Comments
about
Study/
Endpoint/
Uncertainty
Factor:
No
appropriate
effects
attributed
to
a
single
exposure
(
dose)
was
identified
including
in
the
rat
or
rabbit
developmental
toxicity
study.
It
should
be
noted
that
at
the
5/
13/
99
HIARC
meeting
for
Section
18
Exemption,
a
NOAEL
of
16
mg/
kg/
day
from
a
rat
developmental
study
with
an
uncertainty
factor
of
100
was
selected
for
the
acute
reference
dose
based
on
decreased
maternal
body
weight
(
beginning
at
gestation
day
9)
and
food
consumption
(
during
gestation
day
6­
10)
at
80
mg/
kg/
day
(
LOAEL).
This
dose/
endpoint
was
selected
to
provide
a
conservative
risk
assessment
for
that
action.
However,
at
this
meeting
(
5/
29/
01)
the
HIARC
determined
that
it
is
unlikely
that
one
dose
will
cause
body
weight
decrease.
In
addition,
there
was
no
developmental
or
neurotoxic
concern
for
diuron;
therefore,
no
hazard
was
identified
and
quantitative
risk
assessment
is
not
required.

1.2
Chronic
Reference
Dose
(
RfD)

Study
Selected:
Chronic
toxicity/
carcinogenicity
study­
rats
Guideline
#:
870.4300
MRID
No.:
40886501,
43871901,43804501,44302003
Executive
Summary:
In
a
chronic
toxicity/
oncogenicity
study
(
MRID
40886501;
supplementary
data
provided
in
MRIDs
43871901,
43804501,
and
44302003),
diuron
(
98.7%
a.
i.;
batch
no.
232114080)
was
administered
to
groups
of
60
male
and
60
female
Wistar
rats
at
dietary
concentrations
of
0,
25,
250,
or
2500
ppm
(
0,
1.0,
10,
or
111
mg/
kg/
day,
respectively,
for
males
Diuron
5
and
0,
1.7,
17,
or
202
mg/
kg/
day
for
females,
respectively)
for
up
to
24
months.
At
12
months,
10
animals/
sex/
group
were
sacrificed
for
interim
evaluation.

Treatment
with
diuron
did
not
affect
the
survival
of
rats.
The
only
reported
treatment­
related
clinical
sign
was
reddish
discolored
or
bloody
urine
in
high­
dose
males.
A
significant
decrease
in
body
weight
was
seen
in
both
sexes
of
high­
dose
rats
(
12­
15%
for
males;
6­
14%
for
females,
p<
0.01)
throughout
the
study.
Body
weight
gains
were
similarly
depressed,
the
total
gains
for
high­
dose
males
and
females
were
82
and
79%
of
controls,
respectively.
The
slight
decreases
in
body
weights
and
weight
gains
of
mid­
dose
males
(
4­
6%;
p<
0.05
or
0.01)
were
not
biologically
significant.
Food
consumption
was
unaffected
but
overall
food
efficiency
was
lowered
for
high­
dose
males
and
females
(
86%
and
76%
of
controls,
respectively).

Diuron
affected
hematopoietic
system
resulting
in
hemolytic
anemia
and
compensatory
hematopoiesis,
which
were
manifested
as
significantly
decreased
(
p<
0.05
or
0.01)
erythrocyte
counts,
hemoglobin
levels,
and
hematocrit
and
increased
MCV,
MCH,
abnormal
erythrocyte
forms,
reticulocyte
counts,
and
leukocyte
counts
(
with
no
effect
on
differential
counts)
in
midand
or
high­
dose
males
and
females,
and
in
low­
dose
females
(
#
25%
change
for
most
parameters;
3­
fold
increase
for
reticulocytes).
Hemolysis
also
led
to
increased
(
39­
50%)
plasma
bilirubin
in
high­
dose
males
and
females.
Consistent
with
erythrocyte
damage,
postmortem
gross
examination
showed
a
dose­
related
increase
(
18­
220%)
in
spleen
weight
(
absolute
and
relative
to
body)
for
all
test
groups
at
12
and/
or
24
months,
and
an
increased
incidence
of
spleen
dark
discoloration
and/
or
swelling
in
mid
and
high­
dose
males
and
females
after
12
and/
or
24
months.
Morphometric
analysis
of
spleen
sections
to
determine
the
percentage
area
of
hemosiderin
revealed
an
increase
at
$
250
ppm
in
both
sexes
at
12
months
and
in
all
groups
at
24
months
(
p<
0.05
or
0.01),
with
the
females
being
affected
more
severely.
The
chronic
overburden
of
spleen
function
led
to
an
increased
incidence
of
spleen
fibrosis
in
2500
ppm
males
and
females
(
p<
0.01).
Bone
marrow
activation
occurred
in
both
sexes
at
all
test
doses
at
24
months
(
p<
0.05
or
0.01
for
all
but
low­
dose
females).
This
was
evident
morphometrically
as
an
increase
in
hematopoietic
(
red)
bone
marrow
for
mid­
and
high­
dose
rats
at
12
and/
or
24
months
(
possibly
in
low­
dose
males
at
12
months)
with
a
concomitant
decrease
in
fat
marrow
at
12
months
(
not
evaluated
at
24
months).

Gross
pathology
showed
that
the
incidence
of
urinary
bladder
wall
thickening
was
elevated
at
24
months
for
low­
and
high­
dose
males
and
high­
dose
females
(
p<
0.05
or
0.01).
Microscopic
evaluation
showed
that
epithelial
focal
hyperplasia
of
the
urinary
tract
and
renal
pelvis
increased
in
severity
in
both
sexes
at
12
and/
or
24
months,
and
increased
in
incidence
(
p<
0.01)
in
high­
dose
males
at
12
months
and
in
mid
and
high­
dose
females
at
12
and/
or
24
months.
Some
gross
and/
or
microscopic
changes
were
also
seen
in
the
liver
(
increased
weight,
swelling,
discoloration,
vacuolar
cell
degeneration,
round
cell
infiltration,
hyperemia)
although
Diuron
6
Chronic
RfD
=
1.0
(
LOAEL)
mg/
kg/
day
=
0.003
mg/
kg/
day
300
(
UF)
these
effects
were
not
clearly
primary
effects
of
treatment.

Based
on
evidence
of
hemolytic
anemia
and
compensatory
hematopoiesis
(
decreased
erythrocyte
count,
increased
reticulocyte
counts,
increased
spleen
weight
and
bone
marrow
activation),
the
LOAEL
is
25
ppm
for
both
sexes
of
rats
(
1.0
and
1.7
mg/
kg/
day
for
males
and
females,
respectively).
A
NOAEL
was
not
established.

This
chronic
toxicity
/
carcinogenicity
study
in
rats
is
classified
as
Acceptable/
Guideline.

Dose
and
Endpoint
for
Establishing
RfD:
1.0
mg/
kg/
day
(
LOAEL)
based
on
evidence
of
hemolytic
anemia
and
compensatory
hematopoiesis
(
decreased
erythrocyte
count,
increased
reticulocyte
counts,
increased
spleen
weight
and
bone
marrow
activation).
A
NOAEL
was
not
established.

Uncertainty
Factor(
s):
300
Comments
about
Study/
Endpoint/
Uncertainty
Factor:
An
uncertainty
factor
(
UF)
of
100
is
applied
to
account
for
both
interspecies
extrapolation
and
intra­
species
variability.
An
additional
UF
of
3
is
applied
for
the
use
of
a
LOAEL.

1.3
Occupational/
Residential
Exposure
1.3.1
Short­
Term
(
1­
7
days)
Incidental
Oral
Exposure
Study
Selected:
Developmental
toxicity
study­
rabbits
§
870.3700
MRID
No.:
40228802
Executive
Summary:
In
a
developmental
toxicity
study
(
MRID
40228802),
24­
25
artificially
inseminated
New
Zealand
white
rabbits
per
group
were
administered
0,
2,
10,
or
50
mg/
kg/
day
of
Diuron
(
99%
a.
i.;
Lot
No.
not
given)
by
gavage
on
gestation
days
(
GD)
7­
19,
inclusive.
On
GD
29,
all
surviving
does
were
sacrificed
and
examined
Diuron
7
grossly.

One
control
animal
died
on
GD
0
due
to
an
anaphylactic
shock
reaction
during
insemination
and
one
high­
dose
doe
aborted
and
was
killed
on
GD
26.
These
deaths
were
considered
unrelated
to
treatment.
All
remaining
animals
survived
to
scheduled
termination.
No
treatment­
related
clinical
signs
of
toxicity
were
observed
in
any
animal.
Maternal
liver
weights
were
comparable
between
the
treated
and
control
groups
and
gross
necropsy
was
unremarkable.

Maternal
body
weights,
body
weight
gains,
and
food
consumption
for
the
low­
and
mid­
dose
groups
were
similar
to
the
control
levels
throughout
the
study.
Absolute
body
weights
of
the
high­
dose
does
were
significantly
(
p
#
0.01)
less
than
the
controls
on
GD
20.
Mean
body
weight
gains
by
the
high­
dose
group
were
significantly
(
p
#
0.05
or
0.01)
reduced
as
compared
with
the
controls
during
the
intervals
of
GD
10­
13,
13­
16,
and
7­
20
(
weight
loss).
Weight
gain
by
the
high­
dose
group
was
significantly
(
p
#
0.05
or
0.01)
greater
than
the
controls
during
the
post­
dosing
interval.
Food
consumption
by
the
high­
dose
group
was
significantly
(
p
#
0.01)
less
than
the
controls
during
the
GD
13­
16,
16­
20
and
7­
20
intervals.

The
maternal
toxicity
LOAEL
is
established
at
50
mg/
kg/
day
based
on
decreased
body
weights
and
food
consumption
during
the
dosing
interval.
The
maternal
toxicity
NOAEL
is
established
at
10
mg/
kg/
day.

At
cesarean
section,
the
pregnancy
rates,
numbers
of
corpora
lutea,
implantation
sites,
resorptions,
and
live
fetuses,
and
fetal
body
weights
were
similar
between
the
treated
and
control
groups.
No
dose­
or
treatment­
related
external,
visceral,
or
skeletal
malformations/
variations
were
observed
in
any
fetus.

The
developmental
toxicity
NOAEL
is
$
50
mg/
kg/
day
and
the
developmental
toxicity
LOAEL
is
not
identified.

This
study
is
classified
as
Acceptable
and
satisfy
the
guideline
requirements
for
a
developmental
toxicity
study
[
OPPTS
870.3700
(
83­
3b)]
in
rabbits.

Dose
and
Endpoint
for
Risk
Assessment:
10
mg/
kg/
day
(
NOAEL)
based
on
maternal
toxicity
(
decreased
body
weights
and
food
consumption
during
the
dosing
interval)
at
50
mg/
kg/
day
(
LOAEL).

Comments
about
Study/
Endpoint:
This
study
was
previously
classified
as
Diuron
8
unacceptable/
upgradable
based
on
deficiencies
in
analytical
data
of
sample
analysis.
However,
the
HIARC
determined
that
this
study
is
acceptable
because
the
low
nominal
level
of
sample
concentration
was
observed
at
the
low
dose
only
and
the
NOAEL
was
established
at
the
mid­
dose
with
the
LOAEL
at
the
high­
dose.
Therefore,
the
deficiencies
in
the
analytical
data
did
not
affect
the
results
of
the
study.
The
systemic
toxicity
(
expressed
as
maternal
toxicity)
is
relevant
for
the
populations
(
infants
and
children)
and
duration
(
1­
7
days)
of
concern.

1.3.2
Intermediate­
Term
(
7
Days
to
Several
Months)
Incidental
Oral
Exposure
Study
Selected:
Chronic
toxicity/
carcinogenicity
study­
rats
§
MRID
No.:
40886501,
43871901,
43804501,
44302003
Executive
Summary:
See
Chronic
RfD.

Dose
and
Endpoint
for
Risk
Assessment:
A
NOAEL
of
1.0
mg/
kg/
day
based
on
hematological
effects
observed
at
10
mg/
kg/
day
(
LOAEL)
at
the
6th
month
observations.

Comments
about
Study/
Endpoint:
The
HIARC
established
a
NOAEL
of
1.0
mg/
kg/
day
for
this
time
period
based
on
hematological
effects
observed
at
10
mg/
kg/
day
at
the
6th
month
observation.
It
is
noted
that
this
NOAEL/
LOAEL
is
different
from
the
24th
month
observation
where
the
NOAEL
is
not
established
(
LOAEL=
1.0
mg/
kg/
day).
The
endpoint
observed
at
the
6th
month
observation
period
is
appropriate
for
this
exposure
scenario
and
is
relevant
for
the
population
of
concern.

1.3.3
Dermal
Absorption
No
dermal
absorption
study
is
available.

Dermal
Absorption
Factor:
An
upper­
bound
estimation
of
dermal
absorption
factor
of
4%
is
extrapolated
using
the
maternal
LOAEL
of
50
mg/
kg/
day
from
the
developmental
study
in
the
rabbit
and
the
NOAEL
of
1200
mg/
kg/
day
(
HDT)
from
the
21­
day
dermal
toxicity
study
in
the
rabbit:
the
ratio
is
50/
1200
or
4%.

1.3.4
Short­
Term
Dermal
(
1­
7
days)
Exposure
Diuron
9
Study
Selected:
None
MRID
No.:
N/
A
Executive
Summary:
N/
A
Dose
and
Endpoint
for
Risk
Assessment:
N/
A
Comments
about
Study/
Endpoint:.
No
systemic
toxicity
following
repeated
dermal
dosing
at
1200
mg/
kg/
day
was
seen
in
the
rabbit
dermal
toxicity
study.
Also,
there
is
no
developmental
concern.
No
hazard
was
identified
and
no
quantitative
assessment
is
required.

1.3.5
Intermediate­
Term
Dermal
(
7
Days
to
Several
Months)
Exposure
Study
Selected:
None
MRID
No.:
N/
A
Executive
Summary:
N/
A
Dose/
Endpoint
for
Risk
Assessment:
N/
A
Comments
about
Study/
Endpoint:
No
systemic
toxicity
following
repeated
dermal
dosing
at
1200
mg/
kg/
day
was
seen
in
the
rabbit
dermal
toxicity
study.
Also,
there
is
no
developmental
concern.
No
hazard
was
identified
and
no
quantitative
assessment
is
required.

1.3.6
Long­
Term
Dermal
(
Several
Months
to
Life­
Time)
Exposure
Study
Selected:
Chronic
toxicity/
carcinogenicity
study­
rats
MRID
No.:
40886501,
43871901,
43804501,
44302003
Executive
Summary:
See
chronic
RfD.

Dose
and
Endpoint
for
Risk
Assessment:
1.0
mg/
kg/
day
(
LOAEL)
based
on
evidence
of
hemolytic
anemia
and
compensatory
hematopoiesis
(
decreased
erythrocyte
count,
Diuron
10
increased
reticulocyte
counts,
increased
spleen
weight
and
bone
marrow
activation).
A
NOAEL
was
not
established.

Comments
about
Study/
Endpoint:
An
additional
UF
of
3
is
applied
to
account
for
the
lack
of
a
NOAEL
in
this
study.
A
MOE
of
300
is
required
for
this
risk
assessment
with
a
dermal
absorption
factor
of
4%.

1.3.7
Inhalation
Exposure
Except
for
an
acute
inhalation
study,
for
which
diuron
was
placed
in
Toxicity
Category
IV
(
LC
50>
7.1
mg/
L),
no
other
studies
are
available
via
this
route.
Therefore,
the
HIARC
selected
the
NOAELs
from
oral
studies
for
risk
assessment.
Since
the
doses
identified
for
inhalation
risk
assessment
are
from
oral
studies,
route­
to­
route
extrapolation
should
be
as
follows:

The
inhalation
exposure
component
(
i.
e.,
F
g
a.
i./
day)
using
a
100%
(
default)
absorption
rate
and
application
rate
should
be
converted
to
an
equivalent
oral
dose
(
mg/
kg/
day).

Then,
the
oral
equivalent
doses
should
be
compared
to
the
following
NOAELs/
LOAEL
to
calculate
the
MOEs.

Short­
term
NOAEL=
10
mg/
kg/
day
(
developmental
rabbit
study)
Intermediated­
term
NOAEL=
1.0
mg/
kg/
day
(
chronic
rat
study
at
6
month)
Long­
term
LOAEL=
1.0
mg/
kg/
day
(
chronic
rat
study)

1.3.8
Margins
of
Exposure
for
Occupational/
Residential
Risk
Assessments
A
MOE
of
100
is
adequate
for
short
and
intermediate­
term
occupational
inhalation
exposure.
However,
a
MOE
of
300
is
required
for
long­
term
occupational
dermal
and
inhalation
exposure
due
to
the
use
of
LOAEL.
The
acceptable
MOEs
for
residential
exposure
will
be
determined
by
the
FQPA
SF
committee.

1.4
Recommendation
for
Aggregate
Exposure
Risk
Assessments
A
toxicological
endpoint
was
not
identified
for
acute
dietary
risk
assessment;
therefore,
the
acute
aggregate
is
not
required.

A
common
toxicological
endpoint
(
decreased
body
weight
and
food
consumption)
was
Diuron
11
selected
for
assessment
of
short­
term
exposure
by
oral
and
inhalation
routes.
These
routes
can
be
aggregated
for
this
scenario.

A
common
toxicological
endpoint
(
altered
hematological
parameters)
was
selected
for
intermediated­
term
exposure
by
oral
and
inhalation
routes.
These
routes
can
be
aggregated
for
this
scenario.

A
common
toxicological
endpoint
(
evidence
of
hemolytic
anemia
and
compensatory
hematopoiesis)
was
selected
for
long­
term
exposure
by
oral,
dermal,
and
inhalation
routes.
These
routes
can
be
aggregated
for
this
scenario.

2
CLASSIFICATION
OF
CARCINOGENIC
POTENTIAL
2.1
Combined
Chronic
Toxicity/
Carcinogenicity
Study
in
Rats
MRID
No.
40886501,
43871901,
43804501,
44302003
Discussion
of
Tumor
Data:
This
study
showed
conclusive
evidence
for
the
carcinogenicity
of
diuron
in
male
and
female
rats.
The
incidence
of
urinary
bladder
carcinoma
was
increased
at
2500
ppm
in
both
sexes
(
males:
33/
49
vs.
1/
50
for
controls;
females:
11/
50
vs.
0/
48
for
controls;
p<
0.01).
The
malignancies
were
usually
characterized
as
transitional
epithelial
carcinomas.
The
slight
increase
(
NS)
in
the
incidence
of
urinary
bladder
papilloma
and
the
3
neoplasms
in
the
renal
pelvis
in
high­
dose
males
(
one
papilloma
and
two
carcinomas)
were
also
considered
treatment­
related.

Adequacy
of
the
Dose
Levels
Tested:
Dosing
was
adequate
based
on
numerous
toxic
effects
(
hematological,
microscopic,
etc.)
observed
in
the
animals
at
all
tested
doses.

2.2
Carcinogenicity
Study
in
Mice
MRID
No.
:
42159501,
43349301
Discussion
of
Tumor
Data:
Treatment
of
up
to
102
weeks
with
2500
ppm
diuron
resulted
in
a
significant
increase
in
the
incidences
of
mammary
adenocarcinomas
(
control,
4%;
2500
ppm,
12%,
p
#
0.05)
and
ovarian
luteomas
(
control,
6%;
2500
ppm,
14%,
p
#
0.01)
in
female
NMRI
(
SPF
HAN)
mice
under
the
conditions
of
this
study.
However,
the
incidence
of
mammary
adenocarcinoma
in
high­
dose
females
was
at
or
near
the
high
range
of
incidences
seen
in
historic
controls.
Diuron
12
Adequacy
of
the
Dose
Levels
Tested:
Dosing
was
adequate
based
on
observations
at
the
highest
dose
tested
including
decreased
body
weight
of
both
sexes,
increased
spleen
and
liver
weights
in
males
and
increased
incidence
of
urinary
bladder
edema
and
epithelial
hyperplasia,
thickened
mucosa
and
enlarged
uterine
horn
in
females.

2.3
Classification
of
Carcinogenic
Potential
The
HED
Carcinogenicity
Peer
Review
Committee
(
CPRC)
met
on
December
18,
1996
and
classified
diuron
as
a
"
known/
likely"
human
carcinogen
by
all
routes,
based
on
urinary
bladder
carcinoma
in
both
sexes
of
the
Wistar
rat,
kidney
carcinomas
in
the
male
rat
(
a
rare
tumor),
and
mammary
gland
carcinomas
in
the
female
NMRI
mouse.
The
CPRC
also
recommended
a
low
dose
linear
extrapolation
model
with
Q1
*
(
mg/
kg/
day)­
1
of
1.91x10­
2
be
applied
to
the
animal
data
for
the
quantification
of
human
risk,
based
on
the
urinary
bladder
carcinomas
in
the
rat.
The
HIARC
acknowledged
that
this
classification
may
be
re­
evaluated
by
the
CARC
pending
Registrant's
submissions
of
mechanistic
study
for
cancer.

3
MUTAGENICITY
Five
acceptable
genetic
toxicology
studies
with
Diuron
have
been
submitted
to
the
Agency.
Findings
from
these
studies
indicated
the
following:

GENE
MUTATIONS
1)
Salmonella
typhimurium
reverse
gene
mutation
assay
(
MRID
No.
00146608/
40228805):
Independent
trials
were
negative
in
S.
typhimurium
strains
TA1535,
TA97,
TA98
and
TA100
up
to
the
highest
does
tested
(
10
µ
g/
plate
­
S9;
250
µ
g/
plate
+
S9);
higher
concentrations
(
$
50
µ
g/
plate
­
S9;
500
µ
g/
plate
+
S9)
were
cytotoxic.
The
assay
is
Acceptable
and
satisfies
the
guideline
requirement
for
gene
mutation
in
microbial
test
systems.

2)
Chinese
Hamster
Ovary
(
CHO)/
HGPRT
cell
forward
gene
mutation
assay
(
MRID
No.
00146609):
Independent
tests
were
negative
up
to
cytotoxic
doses
without
S9
activation
(
1.250
mM,
.
291
µ
g/
mL)
and
with
S9
activation
(
0.5
mM
,
.
117
µ
g/
mL).
The
assay
is
Acceptable
and
satisfies
the
guideline
requirement
for
gene
mutation
in
cultured
mammalian
cells.

CHROMOSOME
ABERRATIONS
Diuron
13
3)
In
vivo
bone
marrow
cytogenetic
assay
(
MRID
No.
00146611):
The
test
was
weakly
positive
in
male
Sprague
Dawley
rats
administered
0,
50,
500
or
5000
mg/
kg/
day
by
single
oral
gavage.
Signs
of
overt
toxicity
(
mortality,
body
weight
loss,
ocular
discharge,
depression,
labored
respiration,
diarrhea,
and
tremors)
and
cytotoxicity
to
the
target
organ
(
significantly
decreased
mitotic
index)
were
seen
at
5000
mg/
kg
in
conjunction
with
a
significant
(
p<
0.05)
increase
in
the
percentage
of
abnormal
cells
when
the
data
for
both
sexes
were
combined
(
0.11
versus
0.00
in
controls).
A
significant
positive
linear
trend
(
p<
0.01)
was
also
recorded
for
the
percentage
abnormal
cells
combined.
A
total
of
4/
10
animals
in
the
high­
dose
group
were
affected:
single
chromatid
breaks
were
seen
in
two
males
and
one
female
and
a
chromatid
fragment
was
seen
in
one
male.
This
study
is
classified
as
Acceptable
and
satisfies
the
guideline
requirement
for
in
vivo
cytogenetic
mutagenicity
data.

4)
In
vivo
bone
marrow
cytogenetic
assay
(
MRID
No.
44350301):
The
test
was
negative
in
male
Sprague
Dawley
rats
administered
0,
50,
500
or
5000
mg/
kg/
day
by
single
oral
gavage.
Signs
of
overt
toxicity
(
mortality,
body
weight
loss,
ocular
discharge,
depression,
labored
respiration,
diarrhea,
and
tremors)
were
noted
at
5000
mg/
kg.
Cytotoxicity
to
the
target
organ
as
indicated
by
the
significantly
decreased
(
p
#
0.01)
mitotic
indices
at
24
and
48
hours
for
high­
dose
males;
data
combined
for
both
sexes
were
also
significantly
decreased
at
24
hours.
A
significant
(
p<
0.05)
increase
in
the
percentage
of
abnormal
cells
and
the
average
number
of
aberrations
per
cell
was
seen
but
only
when
the
data
were
combined
for
the
high­
and
mid­
dose
males
and
females
at
the
48­
hour
sampling
time.
Values
were
0.6
and
0.9
%
(
combined
percentage
abnormal
cells)
at
500
and
5000
mg/
kg,
respectively
and
0.008
and
0.009
(
combined
number
of
aberrations/
cell)
at
500
and
5000
mg/
kg,
respectively.
A
significant
positive
linear
trend
was
also
recorded
for
the
combined
(
by
sex)
aberrations
per
cell
and
percentage
abnormal
cells.
Nevertheless,
the
values
fell
well
within
the
range
of
historical
control
[
percent
abnormal
cells/
group:
0­
2.6%
(
%
)
and
0­
2.0%
(
&
)
;
average
number
of
aberrations/
cell:
0­
0.023%
(
%
)
and
0­
0.060
%
(
&
)
].
This
study
is
classified
as
Acceptable
and
satisfies
the
guideline
requirement
for
in
vivo
cytogenetic
mutagenicity
data.

OTHER
MUTAGENIC
MECHANISMS
4)
Unscheduled
DNA
synthesis
(
UDS)
in
primary
rat
hepatocytes
assay
(
MRID
No.
00146610):
The
test
was
negative
up
to
cytotoxic
doses
(
$
0.33
mM,
equivalent
to
.
76
F
g/
mL).
The
assay
is
Acceptable
and
satisfies
the
guideline
requirement
for
a
UDS
assay.

Conclusions:
Diuron
was
not
mutagenic
in
bacteria
or
in
cultured
mammalian
cells
and
no
indication
of
DNA
damage
in
primary
rat
hepatocytes
was
observed.
There
was
weak
evidence
of
an
in
vivo
clastogenic
response
in
Sprague
Dawley
rats
in
one
study
and
statistically
significant
increases
in
cells
with
structural
aberrations
in
a
second
study
conducted
with
the
same
rat
strain.
The
data
from
the
latter
study,
however,
were
shown
to
fall
within
the
historical
control
range.
Diuron
14
4
FQPA
CONSIDERATIONS
4.1
Adequacy
of
the
Data
Base
The
data
base
is
adequate
for
FQPA
assessment.

­­
Acute
delayed
neurotoxicity
study
in
hen:
Not
required.
­­
Acute
and
subchronic
neurotoxicity
studies:
Not
available.
­­
Developmental
toxicity
studies
in
Rats:
Study
was
Unacceptable.
­­
Developmental
toxicity
studies
in
Rabbits:
Acceptable
study
available.
­­
Two­
Generation
Reproduction
Study
in
rats:
Acceptable
study
available.
­­
Developmental
neurotoxicity
study:
Not
available.

4.2
Neurotoxicity
No
acute
or
subchronic
neurotoxicity
study
is
available.
There
are
no
neurotoxic
signs
in
any
of
the
subchronic
or
chronic
studies.
Literature
search
did
not
reveal
studies
relevant
for
assessing
the
potential
neurotoxicity.

4.3
Developmental
Toxicity
Developmental
toxicity
study
in
rabbits
See
short­
term
incidental
oral
exposure.

Developmental
toxicity
study
in
rats
In
a
developmental
toxicity
study
(
MRID
40228801),
25
presumed
pregnant
Crl:
COBS
®
CD
®
(
SD)
BR
rats
per
group
were
administered
H­
16035
(
99%;
Lot
No.
not
given)
by
gavage
in
0.5%
aqueous
hydroxypropyl
methylcellulose
at
doses
of
0,
16,
80,
or
400
mg/
kg/
day
on
gestation
days
(
GD)
6­
15,
inclusive.
On
GD
20,
dams
were
sacrificed,
subjected
to
gross
necropsy,
and
all
fetuses
were
examined
externally.
Approximately
one­
half
of
all
fetuses
were
examined
viscerally
by
the
Staples
technique;
these
fetuses
were
decapitated,
and
the
heads
fixed
in
Bouin's
solution
for
subsequent
free­
hand
sectioning.
The
remaining
one­
half
of
the
fetuses
were
eviscerated
and
all
carcasses
were
processed
for
Diuron
15
skeletal
examination.

All
dams
survived
to
terminal
sacrifice.
One
high­
dose
animal
appeared
thin
on
GD
13­
18
as
a
result
of
marked
weight
loss.
No
other
treatment­
related
clinical
signs
of
toxicity
were
observed
in
any
group.
Body
weights,
body
weight
gains,
and
food
consumption
by
the
lowdose
group
were
similar
to
the
controls
throughout
the
study.
No
treatment­
related
lesions
were
observed
in
any
dam
at
necropsy.

Absolute
body
weights
of
the
mid­
and
high­
dose
groups
were
significantly
(
p
#
0.01)
less
than
the
controls
during
the
dosing
interval
and
ranged
from
92­
94%
and
84­
88%,
respectively,
of
the
control
levels.
Body
weight
gains
by
the
mid­
and
high­
dose
dams
were
significantly
(
p
#
0.05
or
0.01)
less
than
that
of
the
controls
during
the
dosing
period
with
the
exception
of
GD
12­
16.
The
most
pronounced
effect
on
body
weight
gain
occurred
immediately
after
the
initiation
of
dosing
(
GD
6­
9)
when
the
mid­
and
high­
dose
groups
had
a
net
weight
loss
compared
to
a
gain
by
the
controls.
The
high­
dose
group
also
had
a
weight
loss
for
GD
9­
12.
Weight
change
during
the
entire
dosing
interval
was
37%
of
the
control
level
for
the
mid­
dose
group
and
a
weight
loss
of
12.2
g
by
the
high­
dose
group.
Food
consumption
by
the
mid­
and
high­
dose
groups
was
significantly
(
73
and
47%,
respectively,
of
controls;
p
#
0.01)
less
than
the
controls
during
the
dosing
interval.
Weight
gain
and
food
consumption
by
the
mid­
and
high­
dose
dams
during
the
post­
dosing
period
was
significantly
(
p
#
0.01)
greater
than
the
controls.

The
maternal
toxicity
LOAEL
is
established
at
80
mg/
kg/
day
based
on
decreased
body
weights,
body
weight
gains,
and
food
consumption.
The
maternal
toxicity
NOAEL
is
16
mg/
kg/
day.

No
differences
were
observed
between
the
treated
and
control
groups
for
pregnancy
rate,
number
of
corpora
lutea,
number
of
implantation
sites,
number
of
fetuses/
litter,
or
fetal
sex
ratios.
No
dead
fetuses
or
late
resorptions
were
observed.
Two
high­
dose
dams
had
total
litter
resorption
and
the
number
of
early
resorptions/
dam
in
the
high­
dose
group
(
3.2)
was
slightly
greater
than
that
of
the
controls
(
1.2).
Mean
fetal
body
weight
in
the
high­
dose
group
was
significantly
(
p
#
0.01;
91%
of
controls)
less
than
that
of
the
controls.

In
the
0,
16,
80,
and
400
mg/
kg/
day
groups,
the
total
number
of
fetuses(
litters)
examined
for
external
and
skeletal
malformations/
variations
was
288(
22),
305(
23),
297(
22),
and
279(
20),
respectively,
and
for
visceral
malformations/
variations
was
138(
22),
149(
23),
144(
22),
and
134(
20),
respectively.
No
treatment­
related
external
or
visceral
malformations/
variations
were
observed
in
any
group.
Diuron
16
Delayed
ossification
of
the
vertebrae
and
sternebrae
was
observed
in
fetuses
of
the
high­
dose
group.
In
the
0,
16,
80,
and
400
mg/
kg/
day
groups
the
incidence
rates
for
litters
containing
fetuses
with
bifid
thoracic
vertebral
centra
was
1/
22,
1/
23,
2/
22,
and
7/
20
(
p
#
0.05),
respectively.
Incomplete
ossification
of
the
sternebrae
was
observed
in
fetuses
from
3/
22,
3/
23,
1/
22,
and
9/
20
(
p
#
0.05),
litters
respectively.
Unossified
thoracic
vertebral
centra
was
observed
in
fetuses
from
3/
20
(
p
#
0.05)
high­
dose
litters
but
not
in
fetuses
from
the
other
treated
or
control
groups.

The
developmental
toxicity
LOAEL
is
established
at
400
mg/
kg/
day
based
on
whole
litter
resorption,
reduced
fetal
body
weights,
and
delayed
ossification
of
the
vertebrae
and
sternebrae.
The
developmental
toxicity
NOAEL
is
80
mg/
kg/
day.

This
study
is
classified
as
Unacceptable
and
does
not
satisfy
the
requirements
for
a
developmental
toxicity
study
[
870.3700
(
§
83­
3a)]
in
rats.
Test
article
concentrations
in
the
mid­
and
high­
dose
solutions
were
highly
variable
and
well
outside
of
acceptable
ranges.
Based
upon
available
analytical
data,
it
appears
that
target
doses
may
not
have
been
representative
of
the
actual
doses
to
the
animals.
In
addition,
the
lot
number
and
corresponding
analyses
were
not
provided.
It
is
unlikely
that
this
study
may
be
upgraded.

However,
the
HIARC
determined
that
this
study
is
adequate
for
the
assessment
of
susceptibility
in
rats.
This
decision
was
made
based
on
the
fact
that
maternal
toxicity
was
seen
at
a
lower
dose
(
80
mg/
kg/
day)
compared
to
developmental
toxicity
(
400
mg/
kg/
day).
At
400
mg/
kg/
say,
developmental
effects
(
increased
incidence
of
early
resorption
and
decreased
fetal
body
weight)
were
seen
in
the
presence
of
maternal
toxicity
(
significantly
decreased
body
weight
gain
and
food
consumption).
The
HIARC
also
determined
that
a
repeat
of
this
study
is
not
required
since
the
effects
of
the
range­
finding
study
showed
maternal
toxicity
(
decreased
body
weight
gain
and
food
consumption)
at
100,
200,
and
400
mg/
kg/
day
and
developmental
toxicity
(
increased
incidence
of
early
resorption
and
decreased
fetal
body
weight)
at
400
mg/
kg/
day.
Also,
the
rabbit
was
shown
to
be
the
more
susceptible
species
for
developmental
toxicity
study.
A
repeat
rat
study
would
not
provide
additional
data
for
risk
assessment/
risk
characterization.

4.4
Reproductive
Toxicity
In
a
two­
generation
reproduction
study
Diuron
(
97.1%
a.
i.,
Lot
No.
8805540)
was
administered
to
groups
of
30
male
and
30
female
Crl:
CD
®
BR
rats
in
the
diet
at
concentrations
of
0,
10,
250,
or
1750
ppm
(
MRID
41957301).
One
litter
was
produced
by
each
generation.
Test
substance
intake
for
the
treated
F0
groups
was
0.58,
14.8,
and
101
mg/
kg/
day,
respectively,
for
males
and
0.71,
18.5,
and
131
mg/
kg/
day,
respectively,
for
females.
Test
substance
intake
for
the
treated
F1
groups
was
0.77,
18.9,
and
139
mg/
kg/
day,
respectively,
Diuron
17
for
males
and
0.8,
22.1,
and
157
mg/
kg/
day,
respectively,
for
females.
F0
and
F1
parental
animals
were
administered
test
or
control
diet
for
73
or
105
days,
respectively,
prior
to
mating
and
throughout
mating,
gestation,
and
lactation,
and
until
necropsy.

Deaths
or
premature
sacrifices
of
several
F0
and
F1
parental
animals
were
considered
incidental
to
treatment.
No
treatment­
related
clinical
signs
of
toxicity
were
observed
in
the
adult
animals
of
either
generation.
Gross
necropsy
was
unremarkable
and
testes
weights
were
not
affected
by
treatment.

For
the
low­
and
mid­
dose
groups
of
both
generations,
occasional
significant
differences
from
the
control
group
for
body
weights,
body
weight
gains,
food
consumption,
and
food
efficiencies
were
considered
incidental
to
treatment.

Body
weights
of
the
high­
dose
F0
males
and
females
were
significantly
(
p
#
0.05)
decreased
by
an
average
of
7%
beginning
on
day
7.
Body
weight
gains
by
the
high­
dose
F0
males
were
significantly
(
p
#
0.05)
less
than
the
control
group
on
days
0­
14,
21­
28,
42­
49,
77­
84,
and
91­
98.
Premating,
post­
mating,
and
overall
(
entire
study)
body
weight
gains
by
the
F0
males
were
significantly
(
p
#
0.05)
decreased
by
16%,
28%,
and
18%,
respectively,
compared
with
the
controls.
Body
weight
gains
by
the
high­
dose
F0
females
were
significantly
(
p
#
0.05)
less
than
the
control
group
on
days
0­
14
and
21­
28
with
overall
premating
body
weight
gains
significantly
(
p
#
0.05)
decreased
by
28%
compared
with
the
controls.
Significant
(
p
#
0.05)
reductions
in
food
consumption
were
observed
in
the
high­
dose
F0
males
and
females
on
days
0­
14,
21­
28,
35­
49
(
females),
42­
56
(
males),
and
0­
70.
Food
efficiencies
for
the
F0
males
and
females
were
significantly
(
p
#
0.05)
reduced
at
similar
intervals
to
food
consumption
with
overall
premating
food
efficiency
reduced
by
8.3%
and
22.7%,
respectively.

Body
weights
of
the
high­
dose
F1
males
and
females
were
significantly
(
p
#
0.05)
decreased
by
an
average
of
16%
beginning
on
day
0
of
premating.
Body
weight
gains
by
the
high­
dose
F1
males
were
significantly
(
p
#
0.05)
less
than
the
control
group
on
days
0­
28,
42­
49,
63­
70,
91­
98,
and
147­
154.
Premating,
post­
mating,
and
overall
(
entire
study)
body
weight
gains
by
the
F1
males
were
significantly
(
p
#
0.05)
decreased
by
15%,
41%,
and
17%,
respectively,
compared
with
the
controls.
Body
weight
gains
by
the
high­
dose
F1
females
were
significantly
(
p
#
0.05)
less
than
the
control
group
on
days
0­
14
with
overall
premating
body
weight
gains
significantly
(
p
#
0.05)
decreased
by
14%
compared
with
the
controls.
Significant
(
p
#
0.05)
reductions
in
food
consumption
were
observed
in
the
high­
dose
F0
males
and
females
throughout
premating
with
the
exception
of
days
77­
84
for
males.
Food
efficiencies
were
significantly
(
p
#
0.05)
reduced
for
the
high­
dose
F1
males
on
days
91­
98
and
for
the
high­
dose
F1
females
on
days
0­
7,
21­
28,
and
0­
70.
Diuron
18
The
systemic
toxicity
LOAEL
is
1750
ppm
(
approximately
132
mg/
kg/
day)
based
on
reduced
body
weight,
body
weight
gain,
food
consumption,
and
food
efficiency
during
both
generations.
The
systemic
toxicity
NOAEL
is
250
ppm
(
approximately
18.6
mg/
kg/
day).

For
the
F0
and
F1
females,
reduced
body
weights
and
food
consumption
during
gestation
were
considered
a
continuation
of
premating
effects.

No
treatment­
related
effects
were
noted
in
either
generation
on
fertility
indices,
gestation
length,
pup
survival,
pup
clinical
observations,
and
pup
anomalies.
Pup
body
weights
for
sexes
combined
or
separate
were
significantly
(
p
#
0.05)
reduced
in
high­
dose
litters
as
compared
with
the
controls
throughout
lactation
for
the
F1
pups
and
beginning
on
lactation
day
7
for
the
F2
pups.

The
offspring
toxicity
LOAEL
is
1750
ppm
(
approximately
132
mg/
kg/
day)
based
on
decreased
body
weights
of
the
F1
and
F2
pups
during
lactation.
The
offspring
toxicity
NOAEL
is
250
ppm
(
18.6
mg/
kg/
day).

The
reproductive
toxicity
NOAEL
is
1750
ppm
(
HDT).

This
study
is
classified
as
Acceptable/
Guideline
and
satisfies
the
guideline
requirements
for
a
reproductive
toxicity
study
[
OPPTS
870.3800
(
§
83­
4)]
in
rats.

4.5
Additional
Information
from
Literature
Sources
Literature
searches
have
been
conducted
and
no
additional
neurotoxicity,
developmental
or
reproductive
toxicity
was
found.

4.6
Determination
of
Susceptibility
Base
on
the
developmental
and
reproductive
toxicity
studies,
there
was
no
evidence
(
qualitative
or
quantitative)
for
increased
susceptibility
following
in
utero
and/
or
pre­/
post­
natal
exposure.

4.7
Recommendation
for
a
Developmental
Neurotoxicity
Study
There
are
no
evidence
that
suggest
requiring
a
developmental
neurotoxicity
study.
The
Diuron
19
developmental
toxicity
studies
in
rats
and
rabbits
as
well
as
the
reproductive
toxicity
study
in
rats
did
not
show
any
adverse
effects
below
maternal
or
parental
doses.

5
HAZARD
CHARACTERIZATION
Diuron
is
a
substituted
urea
herbicide
for
the
control
of
a
wide
variety
of
annual
and
perennial
broadleaved
and
grassy
weeds
on
both
crop
and
noncrop
sites.
The
mechanism
of
action
is
the
inhibition
of
photosynthesis.
Diuron
has
a
low
acute
toxicity
(
Tox.
Cat.
3
or
4)
by
oral,
dermal,
or
inhalation
route
exposure.
Diuron
is
not
an
eye
or
skin
irritant
and
not
a
skin
sensitizer.
A
rat
metabolism
study
indicated
that
diuron
is
rapidly
absorbed
and
metabolized
within
24
hours
post­
dose
at
low
dose
and
within
48
hours
post­
dose
at
high
dose.
The
urine
is
the
major
route
of
excretion
in
both
sexes.
A
small
amount
of
diuron
is
detected
in
the
feces.
The
highest
tissue
residue
levels
were
found
in
the
liver
and
kidneys
4
days
post
14C­
diuron
dose.
Metabolism
of
diuron
involved
N­
oxidation,
ring
hydroxylation,
demethylation,
dechlorination,
and
conjugation
to
sulfate
and
glucuronic
acid.

The
primary
diuron
target
organs
are
hematopoietic
system
and
bladder
(
and
renal
pelvis).
Erythrocyte
damage
resulted
in
hemolytic
anemia
and
compensatory
hematopoiesis,
which
are
manifested
as
significantly
decreased
erythrocyte
counts,
hemoglobin
levels,
and
hematocrit,
and
increased
MCV,
MCH,
abnormal
erythrocyte
forms,
reticulocyte
counts,
and
leukocyte
count.
Consistent
observations
of
erythocytic
regeneration
are
seen
in
chronic
toxicity
studies
in
rats,
mice
and
dogs.
Gross
pathology
findings
in
chronic
rat
and
mouse
studies
showed
increased
incidences
of
urinary
bladder
edema
and
wall
thickening
at
high
doses.
Microscopic
evaluation
showed
dose­
related
increases
in
the
severity
of
epithelial
focal
hyperplasia
of
the
urinary
bladder
and
renal
pelvis
in
both
sexes.

Although
the
developmental
toxicity
studies
in
rats
is
classified
unacceptable,
the
data
base
on
diuron
are
adequate
for
pre­
and
post­
natal
toxicity
evaluation
and
did
not
reveal
developmental
or
reproductive
toxicity.
The
NOAELs
for
maternal/
parental
toxicity
were
either
less
than
or
equal
to
the
NOAELs
for
fetal
or
reproductive
toxicity
The
HED
Carcinogenicity
Peer
Review
Committee
(
CPRC)
characterized
diuron
as
a
"
known/
likely"
human
carcinogen
by
all
routes,
based
on
urinary
bladder
carcinoma
in
both
sexes
of
the
Wistar
rat,
kidney
carcinomas
in
the
male
rat
(
a
rare
tumor),
and
mammary
gland
carcinomas
in
the
female
NMRI
mouse.
The
CPRC
also
recommended
a
low
dose
linear
extrapolation
model
with
Q1
*
(
mg/
kg/
day)­
1
of
1.91x10­
2
be
applied
to
the
animal
data
for
the
quantification
of
human
risk,
based
on
the
urinary
bladder
carcinomas
in
the
rat.
Diuron
20
6
DATA
GAPS
The
HIARC
determined
that
a
28
day
inhalation
study
is
required
to
address
the
concern
for
inhalation
exposure
potential
based
on
the
use
pattern.
The
Registrant
can
follow
the
90­
day
inhalation
study
protocol
but
cease
exposure
at
28
days.
The
HIARC
also
determined
that
a
repeated
chronic
dog
study
is
not
required
because
a
new
study
would
not
provide
additional
data
since
the
observed
effects
are
similar
in
the
rat
and
the
rat
is
the
more
sensitive
species
for
this
chemical.
Diuron
21
7
ACUTE
TOXICITY
Acute
Toxicity
of
Diuron
Guideline
No.
Study
Type
MRIDs
#
Results
Toxicity
Category
81­
1
Acute
Oral
00146144
LD50
=
4721
mg/
kg
(
M)
>
5000
mg/
kg
(
F)
III
81­
2
Acute
Dermal
00146146
LD50
>
2000
mg/
kg
III
81­
3
Acute
Inhalation
40228803
LC50
>
7.1
mg/
L
IV
81­
4
Primary
Eye
Irritation
00146147
At
48
hrs,
all
irritation
had
cleared.
III
81­
5
Primary
Skin
Irritation
00146148
All
irritation
had
cleared
by
72
hrs.
IV
81­
6
Dermal
Sensitization
00146149
Nonsensitizer
N/
A
81­
8
Acute
Neurotoxicity
N/
A
Not
available
N/
A
Diuron
22
8.
SUMMARY
OF
TOXICOLOGY
ENDPOINT
SELECTION
The
doses
and
toxicological
endpoints
selected
for
various
exposure
scenarios
are
summarized
below.

EXPOSURE
SCENARIO
DOSE
(
mg/
kg/
day)
ENDPOINT
STUDY
Acute
Dietary
There
is
no
appropriate
endpoint
attributed
to
a
single
dose
was
identified.
Therefore,
an
acute
RfD
was
not
established.

Chronic
Dietary
LOAEL
=
1.0
UF
=
300
Evidence
of
hemolytic
anemia
and
compensatory
hematopoiesis.
Chronic
toxicity/
carcinogenicity
study
in
rats
Chronic
RfD
=
0.003
mg/
kg/
day
Cancer
Known/
likely
human
carcinogen
Q1*
=
1.91
x
10­
2
Urinary
bladder
carcinoma
in
both
sexes
of
the
Wistar
rat,
kidney
carcinomas
in
the
male
rat
(
a
rare
tumor),
and
mammary
gland
carcinomas
in
the
female
NMRI
mouse
Carcinogenicity
study
in
rats
and
mice
Incidental
Oral,
short­
Term
NOAEL=
10
Decreased
body
weight
and
food
consumption
Developmental
toxicity
study
in
rabbits
Incidental
Oral,
Intermediate­
Term
NOAEL
=
1.0
Altered
hematological
parameters
observed
at
6
months.
Chronic
toxicity/
carcinogenicity
study
in
rats
Dermal,
Short­
Intermediate­
Term
No
systemic
toxicity
following
repeated
dermal
dosing
at
1200
mg/
kg/
day
was
seen
in
the
dermal
toxicity
study.
Also,
there
is
no
developmental
concern.
No
hazard
was
identified
and
no
quantitative
assessment
is
required.

Dermal,
Long­
Terma
LOAEL
=
1.0
Evidence
of
hemolytic
anemia
and
compensatory
hematopoiesis.
Chronic
toxicity/
carcinogenicity
study
in
rats
Inhalation,
Short­
Termb
NOAEL
=
10
Decreased
body
weight
and
food
consumption
Developmental
toxicity
study
in
rabbits
Inhalation,
Intermediate­
Termb
NOAEL
=
1.0
Altered
hematological
parameters
observed
at
6
months.
Chronic
toxicity/
carcinogenicity
study
in
rats
Inhalation,
Long­
Termb
LOAEL
=
1.0
Evidence
of
hemolytic
anemia
and
compensatory
hematopoiesis.
Chronic
toxicity/
carcinogenicity
study
in
rats
a
An
oral
endpoint
was
used
for
dermal
exposure:
dermal
absorption
factor
of
4%
of
oral
exposure
shall
be
used.
b
An
oral
endpoint
was
used
for
inhalation
exposure:
inhalation
exposure
assumed
equivalent
to
oral
exposure.
