UNITED
STATES
ENVIRONMENTAL
PROTECTION
AGENCY
WASHINGTON,
D.
C.
20460
OFFICE
OF
PREVENTION,
PESTICIDES
AND
TOXIC
SUBSTANCES
TXR:
0050570
Date:
March
6,
2002
MEMORANDUM
SUBJECT:
Diuron
­
Phase
2:
Revised
Toxicology
Disciplinary
Chapter
for
the
Reregistration
Eligibility
Decision
FROM:
Yung
G.
Yang,
Ph.
D.,
Toxicologist
Toxicology
Branch
Health
Effects
Division
(
7509C)

THROUGH:
Alan
Nielsen,
Branch
Senior
Scientist
Reregistration
Branch
II
Health
Effects
Division
(
7509C)

TO:
Carol
Christensen,
Risk
Assessor
Reregistration
Branch
II
Health
Effects
Division
(
7509C)

PC
Code:
035505
Chemicals:
Diuron
DP
BARCODE:
D281425
Submission:
S611595
Case:
818790
ACTION
REQUESTED:
Prepare
a
toxicology
chapter
for
diuron
to
reflect
comments
received
from
the
Registrant
in
Phase
1
of
the
public
participation
process.

RESPONSE:
The
toxicology
chapter
has
been
revised
to
reflect
comments
received
from
the
Registrant.
A
revised
toxicology
chapter
for
diuron
is
as
follows.
2
DIURON
PC
Codes:
035505
Toxicology
Disciplinary
Chapter
for
the
Reregistration
Eligibility
Decision
March
6,
2002
Prepared
by:
Yung
G.
Yang,
Ph.
D.
Toxicology
Branch
Health
Effects
Division
Mail
Code
7509C
Peer
Reviewed
by:
Alan
Nielsen
Branch
Senior
Scientist
Reregistration
Branch
II
Health
Effects
Division
Mail
Code
7509C
Yung
G.
Yang,
Toxicologist
Alan
Nielsen,
Branch
Senior
Scientist
3
TABLE
OF
CONTENTS
1.0
HAZARD
CHARACTERIZATION
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4
2.0
REQUIREMENTS
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6
3.0
DATA
GAP(
S)
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7
4.0
HAZARD
ASSESSMENT
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7
4.1
Acute
Toxicity
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7
4.2
Subchronic
Toxicity
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7
4.3
Prenatal
Developmental
Toxicity
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10
4.4
Reproductive
Toxicity
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12
4.5
Chronic
Toxicity
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14
4.6
Carcinogenicity
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17
4.7
Mutagenicity
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19
4.8
Neurotoxicity
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21
4.9
Metabolism
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21
5.0
TOXICITY
ENDPOINT
SELECTION
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22
5.1
See
Section
9.2
for
Endpoint
Selection
Table.
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22
5.2
Dermal
Absorption
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22
5.3
Classification
of
Carcinogenic
Potential
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23
6.0
FQPA
CONSIDERATIONS
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23
6.1
Special
Sensitivity
to
Infants
and
Children
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23
6.2
Recommendation
for
a
Developmental
Neurotoxicity
Study
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23
8.0
REFERENCES
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23
9.0
APPENDICES
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27
9.1
Toxicity
Profile
Summary
Tables
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28
9.1.1
Acute
Toxicity
Table
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28
9.1.2
Subchronic,
Chronic
and
Other
Toxicity
Tables
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28
9.2
Summary
of
Toxicological
Dose
and
Endpoints
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32
Diuron
RED
Toxicology
Chapter
4
1.0
HAZARD
CHARACTERIZATION
The
toxicity
database
for
diuron
is
adequate
to
assess
the
potential
hazard
to
humans,
including
special
sensitivity
of
infants
and
children.
The
database
will
support
a
reregistration
eligibility
decision
(
RED)
for
the
currently
registered
uses.
However,
a
new
28­
day
inhalation
toxicity
study
has
been
required
to
provide
better
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.
Diuron
has
a
low
acute
toxicity
(
Toxicity
Category
3
or
4)
by
oral,
dermal,
or
inhalation
route
exposure.
Diuron
is
not
an
eye
or
skin
irritant
and
not
a
skin
sensitizer.

The
primary
diuron
target
organs
are
hematopoietic
system
and
bladder
(
and
renal
pelvis).
Exposure
to
diuron
causes
erythrocyte
damage
resulting
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.

No
evidence
of
neurotoxicity
was
observed
in
the
rat,
rabbit,
or
dog
in
any
of
the
subchronic
or
chronic
studies.
Results
from
developmental
and
reproductive
toxicity
studies
indicated
that
there
was
no
evidence
(
qualitative
or
quantitative)
for
increased
susceptibility
following
in
utero
and/
or
pre­/
postnatal
exposure.

Administration
of
diuron
in
the
diet
to
rats
and
mice
resulted
in
increases
in
urinary
bladder
carcinomas
in
rats
of
both
sexes
at
the
highest
dose
and
mammary
gland
adenocarcinomas
in
female
mice.
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.
These
findings
provide
further
support
that
the
increase
of
bladder
tumors
is
compound
related.

Diuron
has
been
reviewed
by
the
HED
Carcinogenicity
Peer
Review
Committee
(
CPRC)
and
is
classified
as
a
"
known/
likely"
human
carcinogen
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
*
of
1.91x10­
2
(
mg/
kg/
day)­
1
be
applied
to
the
animal
data
for
the
quantification
of
human
risk,
based
on
the
urinary
bladder
carcinomas
in
the
rat.

A
proposed
mode
of
action
on
bladder
carcinogenicity
has
been
submitted
by
the
Registrant.
The
HED
Mechanism
of
Toxicity
Assessment
Review
Committee
(
MTARC)
reviewed
the
proposed
mode
of
Diuron
RED
Toxicology
Chapter
5
action
and
concluded
that
the
submitted
information
is
insufficient
to
support
a
mode
of
action
on
bladder
carcinogenicity
for
diuron.
Diuron
will
not
be
re­
classified
at
this
time.

A
rat
metabolism
study
indicated
that
diuron
is
rapidly
absorbed
and
metabolized
within
24
hours
postdose
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.
No
apparent
difference
was
observed
between
single
and
multiple
low
oral
doses.
There
was
no
apparent
sex­
related
difference
in
either
absorption
or
elimination.
Metabolism
of
diuron
involved
N­
oxidation,
ring
hydroxylation,
demethylation,
dechlorination,
and
conjugation
to
sulfate
and
glucuronic
acid.
The
major
urine
metabolite
was
IN­
R915
(
3,4­
dichlorophenylurea),
which
accounted
for
>
20%
of
the
total
administered
dose.
Other
metabolites
were
glucuronide
conjugates,
sulfate
conjugates
and
free
metabolites.
Diuron
RED
Toxicology
Chapter
6
2.0
REQUIREMENTS
The
requirements
(
CFR
158.340)
for
food
use
for
Diuron
are
in
Table
1.
Use
of
the
new
guideline
numbers
does
not
imply
that
the
new
(
1998)
guideline
protocols
were
used.
Table
1.

Test
Technical
Required
Satisfied
870.1100
Acute
Oral
Toxicity
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870.1200
Acute
Dermal
Toxicity
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870.1300
Acute
Inhalation
Toxicity
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870.2400
Primary
Eye
Irritation
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870.2500
Primary
Dermal
Irritation
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870.2600
Dermal
Sensitization
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yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
870.3100
Oral
Subchronic
(
rodent)
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870.3150
Oral
Subchronic
(
nonrodent)
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.
870.3200
21­
Day
Dermal
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.
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.
.
870.3250
90­
Day
Dermal
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.
870.3465
90­
Day
Inhalation
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.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
yes
yes
yes
no
yes2
yes1
yes1
yes
no
no2
870.3700a
Developmental
Toxicity
(
rodent)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.3700b
Developmental
Toxicity
(
nonrodent)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.3800
Reproduction
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
yes
yes
yes
yes3
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
yes4
yes
yes
yes
870.5100
Mutagenicity
 
Gene
Mutation
­
bacterial
.
.
.
.
.
.
.
.
.
.
.
870.5300
Mutagenicity
 
Gene
Mutation
­
mammalian
.
.
.
.
.
.
.
.
.
870.5375
Mutagenicity
 
Structural
Chromosomal
Aberrations
.
870.5550
Mutagenicity
 
Other
Genotoxic
Effects
.
.
.
.
.
.
.
.
.
.
.
.
yes
yes
yes
yes
yes
yes
yes
yes
870.6100a
Acute
Delayed
Neurotox.
(
hen)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.6100b
90­
Day
Neurotoxicity
(
hen)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.6200a
Acute
Neurotox.
Screening
Battery
(
rat)
.
.
.
.
.
.
.
.
.
.
.
.
870.6200b
90
Day
Neuro.
Screening
Battery
(
rat)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.6300
Develop.
Neuro
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
no
no
no
no
no
no
no
no
no
no
870.7485
General
Metabolism
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.7600
Dermal
Penetration
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
yes
no
yes
no
Special
Studies
for
Ocular
Effects
Acute
Oral
(
rat)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
Subchronic
Oral
(
rat)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
Six­
month
Oral
(
dog)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
no
no
no
no
no
no
1.
Requirements
are
satisfied
by
chronic
oral
toxicity
studies.
2.
The
HIARC
determined
that
a
28­
Day
inhalation
toxicity
study
is
required
(
5/
29/
2001).
3.
The
HIARC
determined
that
this
study
is
adequate
for
assessment
of
susceptibility
(
5/
29/
2001).
4.
The
HIARC
determined
that
a
repeated
chronic
dog
study
is
not
required
(
5/
29/
2001).
Diuron
RED
Toxicology
Chapter
7
3.0
DATA
GAP(
S)

28­
day
subchronic
inhalation
toxicity,
OPPTS
870.3465
4.0
HAZARD
ASSESSMENT
4.1
Acute
Toxicity
Adequacy
of
data
base
for
acute
toxicity:
The
data
base
for
acute
toxicity
is
considered
adequate.
No
additional
studies
are
required
at
this
time.
Diuron
has
low
acute
oral
and
dermal
toxicity
(
Category
III)
and
low
acute
inhalation
toxicity
(
Category
IV).
Diuron
is
not
an
eye
or
skin
irritant
and
not
a
skin
sensitizer.

Acute
Toxicity
of
Diuron
OPPTS
Guideline
No.
Study
Type
MRIDs
#
Results
Toxicity
Category
870.1100
Acute
Oral,
rat
00146144
LD50
=
4721
mg/
kg
(
M)
>
5000
mg/
kg
(
F)
III
870.1200
Acute
Dermal,
rat
00146146
LD50
>
2000
mg/
kg
III
870.1300
Acute
Inhalation,
rat
40228803
LD50
>
7.1
mg/
L
IV
870.2400
Primary
Eye
Irritation,
rabbit
00146147
At
48
hrs,
all
irritation
had
cleared.
III
870.2500
Primary
Skin
Irritation,
rabbit
00146148
All
irritation
had
cleared
by
72
hrs.
IV
870.2600
Dermal
Sensitization,
guinea
pig
00146149
Nonsensitizer
N/
A
N/
A:
Not
applicable.

4.2
Subchronic
Toxicity
Adequacy
of
database
for
subchronic
toxicity:
The
database
for
subchronic
toxicity
is
incomplete;
however,
chronic
studies
are
available
and
considered
adequate
for
risk
assessment
purposes.
A
28­
day
inhalation
toxicity
study
is
required
at
this
time
to
address
the
concern
for
inhalation
exposure
potential
based
on
the
use
pattern
(
HIARC,
5/
29/
2001).
Diuron
RED
Toxicology
Chapter
8
870.3100
90­
Day
Oral
Toxicity
­
Rat
EXECUTIVE
SUMMARY:
In
a
6­
month
oral
toxicity
study
(
MRID
40886502),
Diuron
(
98.8%
a.
i.,
Lot
No.
232114123)
was
administered
to
groups
of
10
male
and
10
female
BOR:
WISW
(
SPF
Cpb)
rats
in
the
diet
at
concentrations
of
0,
4,
10,
or
25
ppm.
Time­
weighted
average
doses
were
0,
0.3,
0.7,
and
1.6
mg/
kg/
day,
respectively,
for
males
and
0,
0.3,
0.8,
and
1.8
mg/
kg/
day,
respectively,
for
females.

Deaths
of
one
mid­
dose
male
and
one
mid­
dose
female
after
blood
collection
during
week
12
were
considered
incidental
to
treatment;
all
remaining
animals
survived
to
scheduled
sacrifice.
No
treatmentrelated
clinical
signs
of
toxicity
were
observed
in
any
animal.
Body
weights,
food
consumption,
differential
blood
counts,
erythrocyte
morphology,
and
organ
weights
were
unaffected
by
treatment.

Reticulocyte
counts
in
the
high­
dose
females
were
increased
at
all
intervals
with
statistical
significance
(
p
#
0.05)
attained
at
weeks
12
and
26
(
150­
165%
of
control
values).
Mean
hemoglobin
concentrations
in
the
high­
dose
females
were
slightly
(
n.
s.)
depressed
at
all
intervals
as
compared
to
the
controls
(
within
5%
of
control
levels).

Increased
incidences
of
gross
lesions
on
the
urinary
bladder
were
observed
in
all
treated
groups
of
males
and
females.
In
the
control,
low­,
mid­,
and
high­
dose
groups,
dilated
blood
vessels
were
observed
in
0/
10,
3/
10,
1/
10,
and
3/
10
males,
respectively,
and
in
1/
10,
3/
10,
3/
10,
and
5/
10
females,
respectively;
increased
firmness
was
observed
in
0/
10,
1/
10,
2/
10,
and
3/
10
males,
respectively,
and
in
0/
10,
5/
10,
2/
10,
and
3/
10
females,
respectively;
and
reduced
transparency
was
observed
in
0/
10,
1/
10,
1/
10,
and
2/
10
females,
respectively.

Microscopic
examinations
and
morphometric
measurements
of
the
urinary
bladder
were
done
in
an
attempt
to
characterize
the
gross
findings.
Hyperplasia
of
the
epithelium
was
observed
in
1
low­
dose
male,
1
control
female,
2
low­
dose
females,
and
2
high­
dose
females.
Thickening
of
the
epithelium
by
enlargement
of
the
epithelial
cells
(
hypertrophy)
was
seen
in
2
low­
dose
males
and
1
high­
dose
male.
In
females
from
the
control,
low­,
mid­,
and
high­
dose
groups,
the
thickness
of
the
urinary
bladder
wall
was
437,
492,
448,
and
486
µ
m,
respectively;
males
were
not
measured.
These
observations
are
judged
to
be
equivocal.

Pigment
deposition
(
iron)
in
the
spleen
was
observed
in
all
treated
and
control
animals,
however,
the
severity
and
extent
were
increased
in
the
high­
dose
groups.
In
the
control,
low­,
mid­,
and
high­
dose
groups,
severity
ratings
were
2.3,
2.3,
2.3,
and
3.0,
respectively
for
males,
and
2.5,
3.1,
2.9,
and
3.7,
respectively,
for
females
(
based
on
a
scale
of
increasing
severity
of
1­
5).
Morphometric
measurements
showed
the
percent
area
of
iron
deposits
to
be
8.4,
10.1,
9.8,
and
14.1,
respectively,
for
males,
and
14.7,
15.7,
15.1,
and
19.4,
respectively,
for
females.
Diuron
RED
Toxicology
Chapter
9
Under
the
study
condition,
the
NOAEL
can
not
be
determined
because
some
findings
were
judged
to
be
equivocal.

This
study
is
not
designed
for
a
guideline
study
and
is
classified
as
acceptable/
nonguideline
as
a
supplementary
subchronic
study
in
rats.

870.3100
90­
Day
Oral
Toxicity
­
Mouse
No
study
is
available.

870.3150
90­
Day
Oral
Toxicity
­
Dog
No
study
is
available.

870.3465
90­
Day
Inhalation
 
Rat
No
study
is
available.
The
HIARC
(
5/
29/
2001)
determined
that
a
28­
day
inhalation
study
is
required
to
address
the
concern
for
inhalation
exposure
potential
based
on
use
pattern.

870.3200
21­
Day
Dermal
Toxicity
­
Rabbit
EXECUTIVE
SUMMARY:
In
a
21­
day
dermal
toxicity
study
(
MRID
42718301),
diuron
(
98.6%)
was
administered
dermally
at
0
(
deionized
water),
50,
500
and
1200
mg/
kg/
day
to
5
New
Zealand
White
rabbits/
sex/
dose
for
6
hours/
day.
Diuron
was
administered
on
the
backs
of
rabbits
whose
hair
was
clipped.
Body
weight,
food
consumption,
clinical
signs,
mortality,
clinical
chemistry,
hematology,
gross
pathology,
histopathology,
and
organ
weights
were
observed.
Erythema
and
edema
were
scored
using
the
Draize
scoring
system.

There
were
no
treatment
related
effects
on
clinical
signs,
body
weight,
body
weight
gain,
food
consumption,
hematology,
organ
weights,
or
histopathology
parameters
were
noted.

In
treatment
and
control
groups,
slight
to
mild
erythema
was
observed
by
days
10­
14
and
was
attributed
to
mechanical
skin
injury
from
experimental
treatment.
In
the
1200
mg/
kg/
day
group,
moderate
erythema
was
noted
at
1200
mg/
kg/
day
in
2
of
5
females.
Slight
or
mild
edema
was
noted
in
one
male
and
one
female,
respectively,
of
the
1200
mg/
kg/
day
group.

The
systemic
toxicity
NOAEL
for
21
day
dermal
toxicity
study
is
1200
mg/
kg/
day
(
HDT).

This
study
is
classified
acceptable/
guideline
and
satisfies
the
guideline
requirement
for
a
subchronic
dermal
study
in
rabbits.
Diuron
RED
Toxicology
Chapter
10
4.3
Prenatal
Developmental
Toxicity
Adequacy
of
database
for
Prenatal
Developmental
Toxicity:
The
database
for
prenatal
developmental
toxicity
is
considered
adequate.
No
additional
studies
are
required
at
this
time.
There
is
no
quantitative
or
qualitative
evidence
of
increased
susceptibility
of
rats
or
rabbit
fetuses
to
in
utero
exposure
in
available
developmental
toxicities.

870.3700a
Prenatal
Developmental
Toxicity
Study
­
Rat
EXECUTIVE
SUMMARY:
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
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
low­
dose
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
Diuron
RED
Toxicology
Chapter
11
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),
306(
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.

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)
highdose
litters
but
not
in
fetuses
from
the
other
treated
or
control
groups.

The
developmental
toxicity
LOAEL
is
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/
guideline
because
test
article
concentrations
in
the
mid­
and
high­
dose
solutions
were
highly
variable
and
well
outside
of
acceptable
ranges.
Also,
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.
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/
day,
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
(
HIARC
Report,
HED
DOC.
No.
014657)
.
Diuron
RED
Toxicology
Chapter
12
870.3700b
Prenatal
Developmental
Toxicity
Study
­
Rabbit
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.)
by
gavage
on
gestation
days
(
GD)
7­
19,
inclusive.
On
GD
29,
all
surviving
does
were
sacrificed
and
examined
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
highdose
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
50
mg/
kg/
day
based
on
decreased
body
weights
and
food
consumption
during
the
dosing
interval.
The
maternal
toxicity
NOAEL
is
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/
guideline
and
satisfy
the
guideline
requirements
for
a
developmental
toxicity
study
in
rabbits.

4.4
Reproductive
Toxicity
Adequacy
of
database
for
Reproductive
Toxicity:
The
database
for
reproductive
toxicity
is
Diuron
RED
Toxicology
Chapter
13
considered
adequate.
No
additional
studies
are
required
at
this
time.
There
is
no
reproductive
toxicity
observed.

870.3800
Reproduction
and
Fertility
Effects
­
Rat
EXECUTIVE
SUMMARY:
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.
Overall
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,
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,
postmating
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
Diuron
RED
Toxicology
Chapter
14
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.

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
(
132
mg/
kg/
day)
(
HDT).

This
study
is
classified
as
acceptable/
guideline
and
satisfies
the
guideline
requirements
for
a
reproductive
toxicity
study
in
rats.

4.5
Chronic
Toxicity
Adequacy
of
database
for
chronic
toxicity:
The
database
for
chronic
toxicity
is
considered
adequate.
No
additional
studies
are
required
at
this
time.
A
two­
year
chronic
toxicity
study
in
dogs
was
classified
as
unacceptable/
guideline
based
on
deficiences
in
analytical
data
for
dietary
analysis.
However,
the
HIARC
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
(
HIARC
Report,
HED
Doc.
No.
14657).

870.4300
Combined
Chronic
Toxicity/
Carcinogenicity
 
Rat
Diuron
RED
Toxicology
Chapter
15
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
and
0,
1.7,
17,
or
203
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
some
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).

The
hematopoietic
system
and
urinary
bladder
(
and
renal
pelvis)
were
the
primary
diuron
target
organs.
Erythrocyte
damage
resulted
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
mid­
and/
or
high­
dose
males
and
females,
and
in
lowdose
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,
post­
mortem
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
lowdose
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
Diuron
RED
Toxicology
Chapter
16
at
12
months
and
in
high­
dose
females
at
12
and/
or
24
months
with
mid­
dose
females
showing
an
increased
incidence
at
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
these
effects
were
not
clearly
primary
effects
of
treatment.

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

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.
Dosing
was
adequate
based
on
numerous
toxic
effects
(
hematological,
microscopic,
etc.)
observed
in
the
animals
at
all
tested
doses.

This
chronic
toxicity
/
carcinogenicity
study,
together
with
the
subsequently
submitted
supplementary
materials,
is
acceptable/
guideline
and
does
satisfy
the
guideline
requirement
for
a
chronic
toxicity/
oncogenicity
oral
study
in
the
rat.
There
were
some
noted
deficiencies
but
none
that
would
invalidate
the
study.

870.4100b
Chronic
Toxicity
­
Dog
EXECUTIVE
SUMMARY:
In
a
24­
month
dietary
toxicity
study
(
MRID
00091192),
groups
of
three
male
and
three
female
beagle
dogs
were
given
Diuron
(
80%
purity;
initial
lot
number
not
reported,
second
quantity
coded
T
7111
3D)
administered
in
feed
at
0,
25,
125,
250,
or
2500/
1250
ppm
(
0,
1.8,
9.4,
18.8,
or
93.8
mg/
kg/
day
by
conversion
factor
of
0.075).
The
high­
dose
group
received
a
diet
containing
2500
ppm
of
the
test
material
for
two
weeks,
then
received
only
the
basal
diet
for
a
three
week
reconditioning
period,
then
received
a
diet
containing
1250
ppm
of
the
test
material
for
the
remainder
of
the
two­
year
study.

There
were
no
treatment­
related
deaths
and
aside
from
occasional
partial
food
refusal
at
the
highest
dietary
concentration,
there
were
no
treatment­
related
clinical
signs.
Adverse
effects
of
treatment
on
body
weight
included
an
overall
day
0­
735
body
weight
losses
at
the
2500/
1250
ppm
dietary
concentration
by
both
males
(
18%
loss
of
the
pre­
treatment
weight
vs
a
15%
body
weight
gain
by
controls)
and
females
(
13%
loss
of
the
pretreatment
weight
vs
a
15%
body
weight
gain
by
controls)
and
decreased
day
0­
364
body
weight
gains
by
males
at
the
250
ppm
dietary
concentration
(
44%
of
Diuron
RED
Toxicology
Chapter
17
controls).
At
the
2500/
1250
ppm
dietary
concentration,
normocytic
to
macrocytic,
normochromic
anemia
was
noted
in
males
on
days
225­
720
and
in
females
at
all
time
points
starting
at
week
2,
and
the
observation
of
brown
pigment
(
likely
hemosiderin)
observed
in
Kupffer
cells
of
all
high­
dose
animals
is
suggestive
of
hemolysis.
At
the
highest
dietary
concentration,
increased
numbers
of
erythroid
precursors/
1000
bone
marrow
progenitor
cells
for
male
and
female
dogs
(
520
vs.
352
for
controls),
and
moderately
reduced
marrow
fat
[
implying
hypercellularity]
in
histopathological
preparations
are
consistent
with
attempts
at
erythrocytic
regeneration.
At
the
highest
dietary
concentration,
absolute
and
relative
liver
weights
were
increased
in
both
males
(
22
and
54%
greater
than
controls)
and
females
(
35
and
62%
greater
than
controls),
and
liver
to
brain
weight
ratios
were
increased
in
both
sexes
(
25
and
23%
for
males
and
females,
respectively).
There
were
no
other
gross
or
histopathological
hepatic
changes,
and
clinical
chemistry
parameters
were
not
evaluated.
Although
the
increased
liver
weights
may
be
associated
with
erythrocyte
sequestration,
a
hepatotoxic
treatment­
related
effect
cannot
be
definitely
ruled
out.

Under
the
conditions
of
this
study,
the
LOAEL
for
Diuron
in
male
Beagle
dogs
is
250
ppm
(
18.8
mg/
kg/
day),
based
on
decreased
body
weight
gains,
and
the
LOAEL
in
female
Beagle
dogs
is
1250
ppm
(
93.8
mg/
kg/
day),
based
on
a
normocytic
to
macrocytic,
normochromic
anemia
and
body
weight
losses.
The
NOAEL
is
125
ppm
(
9.4
mg/
kg/
day)
in
males
and
250
ppm
(
18.8
mg/
kg/
day)
in
females.

This
study
is
classified
as
unacceptable/
guideline
and
does
not
satisfy
the
Subdivision
F
guideline
requirements.
The
exact
dietary
concentrations
administered
to
the
animals
is
unknown,
due
to
the
following
deficiencies:
1)
the
test
material
purity
was
80%
and
it
is
unknown
whether
the
amount
of
test
material
used
in
diet
preparation
was
adjusted
to
account
for
this;
2)
stability,
homogeneity,
and
concentration
of
the
test
material
in
food
were
not
determined
prior
to
study
initiation;
and
3)
the
physical
properties
(
including
stability)
of
the
test
substance
were
not
provided.
However,
after
reviewing
the
toxicity
database
of
diuron,
the
HIARC
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
(
HIARC
Report,
HED
DOC.
No.
014657).

4.6
Carcinogenicity
Adequacy
of
database
for
Carcinogenicity:
The
database
for
carcinogenicity
is
considered
adequate.
No
additional
studies
are
required
at
this
time.
The
HED
Carcinogenicity
Peer
Review
Committee
(
CPRC)
met
on
December
18,
1996
and
classified
diuron
as
a
"
known/
likely"
human
carcinogen
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
Diuron
RED
Toxicology
Chapter
18
also
recommended
a
low
dose
linear
extrapolation
model
with
Q1
*
of
1.91x10­
2
(
mg/
kg/
day)­
1
be
applied
to
the
animal
data
for
the
quantification
of
human
risk,
based
on
the
urinary
bladder
carcinomas
in
the
rat.

The
HED
Mechanism
of
Toxicity
Assessment
Review
Committee
(
MTARC)
has
evaluated
a
proposed
mode
of
action
submitted
by
the
Registrant
and
concluded
that
the
submitted
information
is
insufficient
to
support
a
mode
of
action
on
bladder
carcinogenicity
for
diuron.
Diuron
will
not
be
re­
classified
at
this
time.

870.4300
Combined
Chronic
Toxicity/
Carcinogenicity
 
Rat
See
executive
summary
above.

870.4200b
Carcinogenicity
(
feeding)
­
Mouse
EXECUTIVE
SUMMARY:
In
a
carcinogenicity
study
(
MRID
42159501),
Diuron
(
98.7%
a.
i.,
batch
no.
232114080)
was
administered
to
groups
of
60
male
and
60
female
NMRI
(
SPF
HAN)
mice
in
the
diet
at
concentrations
of
0,
25,
250,
or
2500
ppm.
The
test
diets
were
given
for
24
months
except
for
10
mice/
sex/
group
which
were
sacrificed
after
12
months
for
an
interim
study.
The
concentrations
of
25,
250,
and
2500
ppm
resulted
in
mean
daily
compound
intakes
for
males
of
5.4,
50.8,
or
640.13
mg/
kg/
day;
and
for
females
of
7.5,
77.5,
or
867.0
mg/
kg/
day,
respectively.
A
supplementary
document
(
MRID
43349301)
provided
additional
summary
data
from
the
original
study
on
body
weight
gain,
food
efficiency,
macroscopic
findings
at
12
months,
ovarian
and
mammary
gland
tumors;
and
also
provided
historical
control
tumor
frequencies.

No
significant
treatment­
related
effects
were
seen
in
clinical
signs
or
survival.
Body
weights
after
78
weeks
of
treatment
were
7%
(
p
#
0.01)
and
4%
(
NS)
less
than
the
controls
for
high­
dose
males
and
females,
respectively;
and
cumulative
body
weight
gains
were
21%
and
12%
less
than
the
controls
at
78
weeks.
The
overall
food
intake
was
about
17%
greater
for
high­
dose
males
and
12%
greater
for
high­
dose
females
than
the
controls.
Food
efficiency
for
the
2­
year
study
was
decreased
in
high­
dose
males
and
females
by
21­
22%
compared
to
the
controls.

Small,
but
statistically
significant
increases
of
4­
10%
in
group
mean
erythrocyte
cell
volume
and
mean
cell
hemoglobin
were
seen
in
males
and
females
at
various
times
during
the
study.
Reticulocyte
counts
were
increased
in
high­
dose
males
by
9­
62%
and
in
females
by
24­
63%
compared
to
the
controls.
These
hematology
changes
were
accompanied
by
increased
absolute
and
relative
(
to
body)
spleen
weights,
increased
serum
bilirubin,
and
increased
iron
deposits
(
hemosiderin)
in
the
spleens
of
highdose
males
and
females.
These
observations
are
consistent
with
a
treatment­
related
compensated
hemolytic
anemia
at
2500
ppm.
Total
leukocyte
counts
were
increased
by
48%
and
51%
(
p
#
0.01)
in
high­
dose
males
and
females,
respectively,
at
18
months
and
by
95%
(
p
#
0.01)
in
high­
dose
females
at
Diuron
RED
Toxicology
Chapter
19
24
months.
Differential
counts
were
within
normal
parameters
for
both
sexes
at
all
doses.

Serum
alanine
aminotransferase
activity
was
increased
by
95%
in
males
and
by
66%
in
females
at
2500
ppm
compared
to
the
controls
after
24
and
6
months
of
treatment,
respectively.
The
absolute
and
relative
(
to
body)
liver
weights
were
increased
by
9%
and
11
%,
respectively
in
high­
dose
males
at
24
months
compared
to
the
control.
Microscopic
evidence
of
liver
toxicity
at
2500
ppm
included
increased
incidences
of
increased
mitosis
in
both
sexes,
centrilobular
hypertrophy
in
males,
Kupffer
cell
clusters
in
males,
enlarged/
degenerative
liver
cells
in
females,
and
single
cell
necroses
in
females.

Increased
incidences
of
urinary
bladder
edema,
thickened
mucosa,
and
epithelia
hyperplasia
were
seen
in
high­
dose
females
after
24
months
of
treatment
compared
to
the
control.
The
epithelia
hyperplasia
incidence
was
increased
after
12
months
in
high­
dose
females.
There
was
also
an
increased
incidence
of
uterine
horn
diameters
measuring
greater
than
2
mm
in
females
at
2500
ppm,
but
no
adverse
microscopic
findings
were
noted.

The
LOAEL
is
2500
ppm
in
the
diet
for
males
(
640.13
mg/
kg/
day)
and
females
(
867.0
mg/
kg/
day),
based
on
hemolytic
anemia
and
liver
toxicity
in
both
sexes,
and
urinary
bladder
toxicity
in
females.
The
NOAEL
is
250
ppm
for
males
(
50.8
mg/
kg/
day)
and
females
(
77.5
mg/
kg/
day).

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.

On
December
18,
1996
the
Carcinogenicity
Peer
review
Committee
(
CPRC)
determined
that
the
female
mouse
ovarian
tumor
rates
table
should
reflect
the
more
appropriate
'
combined
sex
cordstromal
tumors'
nomenclature
in
lieu
of
the
"
luteoma"
terminology
used
in
the
qualitative
risk
assessment
(
Lori
L.
Brunsman
to
Linda
L.
Taylor,
11/
20/
96).
Dr.
Lucas
Brennecke,
EPA's
consulting
pathologist,
confirmed
that
the
combined
tumor
counts
are
more
appropriate
than
the
individual
counts
for
ovarian
tumors,
as
it
is
difficult
to
distinguish
between
the
different
types
of
ovarian
tumors.
The
CPRC
concluded
that
female
mice
do
not
have
a
significant
increasing
trend,
or
any
significant
differences
in
the
pair­
wise
comparisons
of
the
dosed
groups
with
the
controls,
for
ovarian
combined
sex
cordstromal
tumors.

This
carcinogenicity
study
in
the
mouse
is
acceptable/
guideline
and
does
satisfy
the
guideline
requirement
for
an
oncogenicity
study
in
mice.
Diuron
RED
Toxicology
Chapter
20
4.7
Mutagenicity
Adequacy
of
database
for
Mutagenicity:
The
database
for
mutagenicity
is
considered
adequate.
Diuron
was
not
mutagenic
in
bacteria
or
in
cultured
mammalian
cells
and
no
indication
of
DNA
damage
in
primary
rat
hepatocytes
was
observed.
There
were
marginal
statistically
increases
in
cells
with
structural
aberrations
in
Sprague
Dawley
rats
in
vivo
bone
marrow
chromosomal
aberration
assay.
However,
the
levels
of
aberrations
were
within
the
historical
control
range
and
assessed
negative.
In
addition,
there
is
no
eveidence
of
a
clastogenic
effect
of
diuron
in
an
in
vivo
mouse
micronucleus
test.

Gene
Mutation
Guideline
870.5100
Gene
mutation:
Salmonella
typhimurium
reverse
gene
mutation
MRID
00146608/
40228805
Acceptable/
Guideline
Independent
trials
were
negative
in
S.
typhimurium
strains
TA1535,
TA97,
TA98
and
TA100
up
to
the
highest
dose
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.

Guideline
870.5300
Gene
mutation
Chinese
Hamster
Ovary
(
CHO)/
HGPRT
cell
forward
gene
mutation
assay
MRID
00146609
Acceptable/
Guideline
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).

Cytogenetics
Guideline
870.5385
Chromosomal
aberration
In
vivo
bone
marrow
cytogenetic
assay
MRID
00146611
MRID
44350301
(
revised)
Acceptable/
Guideline
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
%
(
&
)
].

Guideline
870.5385
Chromosomal
aberration
In
vivo
bone
marrow
cytogenetic
assay
MRID
45494505
Acceptable/
Guideline
The
test
was
negative
in
male
and
female
Hsd/
Win:
NMRI
mice
administered
0
or
700
mg/
kg
by
a
single
intraperitoneal
injection.
Signs
of
overt
toxicity
(
apathy,
roughened
flur,
staggering
gait,
sternal
recumbency,
spasm,
twitching,
difficulty
in
breathing
and
eyelids
stuck
together)
were
seen
at
700
mg/
kg.
No
compound­
related
mortality
was
seen.
There
is
no
evidence
of
clastogenic
effect
of
diuron.

Other
Genotoxicity
Diuron
RED
Toxicology
Chapter
21
Guideline
870.5550
Unscheduled
DNA
Synthesis
MRID
00146610
Acceptable/
Guideline
The
test
was
negative
up
to
cytotoxic
doses
(
$
0.33
mM,
equivalent
to
.
76
F
g/
mL).

4.8
Neurotoxicity
Adequacy
of
database
for
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.

870.6100
Delayed
Neurotoxicity
Study
­
Hen
Not
available
and
not
required
for
diuron
at
this
time.

870.6200
Acute
Neurotoxicity
Screening
Battery
Not
available
and
not
required
at
this
time.

870.6200
Subchronic
Neurotoxicity
Screening
Battery
Not
available
and
not
required
at
this
time.

870.6300
Developmental
Neurotoxicity
Study
Not
available
and
not
required
for
diuron
at
this
time.

4.9
Metabolism
Adequacy
of
database
for
metabolism:
The
database
for
metabolism
is
considered
adequate.
No
additional
studies
are
required
at
this
time.

870.7485
Metabolism
­
Rat
EXECUTIVE
SUMMARY:
In
a
metabolism
study
(
MRID
44019601)
in
rats,
14C­
Diuron
[
radiolabel
>
98.3%;
>
95%
a.
i.]
was
administered
to
5
Sprague­
Dawley
rats/
sex/
dose
as
(
1)
a
single
oral
high
[
400
mg/
kg]
dose,
(
2)
a
single
oral
low
[
10
mg/
kg]
dose,
or
(
3)
a
multiple
oral
low
dose
[
10
mg/
kg/
day]
of
unlabeled
Diuron
for
15
consecutive
days
followed
by
a
single
oral
low
[
10
mg/
kg]
dose
[
14C­
Diuron].
The
objectives
of
this
study
were
to
determine
(
1)
the
Diuron
RED
Toxicology
Chapter
22
absorption/
distribution/
metabolism/
excretion
of
14C­
Diuron
in
rats
following
single
or
multiple
dose
exposure,
(
2)
to
identify/
characterize,
and
to
the
extent
possible,
quantify
products
of
excreta,
and
(
3)
to
determine
any
possible
bioaccumulation
and/
or
bioretention
of
Diuron
and
its
metabolites.
Diuron
was
rapidly
absorbed
and
metabolized
following
all
dosing
regimens.
The
total
recovery
of
radioactivity
following
all
exposure
was
>
95%.
Greater
than
90%
of
the
administered
radiolabel
was
recovered
in
excreta
and
cage
wash
of
the
low­
dose
groups
within
24
hours
postdose
and
within
48
hours
postdose
in
the
high­
dose
group.
The
urine
was
the
major
route
of
excretion
for
all
groups
in
both
sexes.
A
slightly
higher
percent
of
the
dose
was
excreted
in
the
feces
following
the
single
high
dose
[
%
%
.
15%/
&
&
.
13%]
than
was
found
following
both
low­
dose
exposures
[
%
%
9%­
10%/
&
&
8%­
9%].
The
highest
tissue
residue
levels
were
found
in
the
liver
and
kidneys
4
days
post
14C­
Diuron
dose,
at
which
time
the
blood
levels
were
0.04%­
0.08%
of
the
administered
dose.
The
major
urine
metabolite
in
both
sexes
following
all
dosing
regimens
was
IN­
R915,
which
accounted
for
>
20%
of
the
total
administered
radiolabel.
Other
metabolites
were
glucuronide
conjugates
of
IN­
U1232,
HO­
Me­
IND0432
IN­
D0230,
IN­
T1035,
and
sulfate
conjugate
of
IN­
U1232
[
only
found
in
low­
dose
groups],
and
free
metabolites
IN­
U1232,
IN­
JT680,
IN­
T1035,
and
IN­
KH289.
A
small
amount
of
Diuron
was
detected
in
the
feces
following
all
dosing
regimens.

Metabolism
of
Diuron
involved
N­
oxidation,
ring
hydroxylation,
demethylation,
dechlorination,
and
conjugation
to
sulfate
and
glucuronic
acid.
Diuron
was
well
absorbed
following
all
exposure
regimens,
and
the
majority
of
the
radioactivity
was
eliminated
via
the
urine.
No
apparent
difference
was
observed
between
single
and
multiple
low
oral
doses.
There
was
no
apparent
sex­
related
difference
in
either
absorption
or
elimination,
and
minimal
tissue
accumulation
was
observed.

This
metabolism
study
in
the
rat
is
classified
Acceptable/
guideline
and
does
satisfy
the
guideline
requirement
for
a
metabolism
study.

5.0
TOXICITY
ENDPOINT
SELECTION
5.1
See
Section
9.2
for
Endpoint
Selection
Table.

5.2
Dermal
Absorption
Dermal
Absorption
Factor:
4%

No
dermal
absorption
study
is
available
for
diuron
at
the
time
of
this
assessment.
A
dermal
absorption
factor
of
4%
for
diuron
was
extrapolated
using
the
maternal
toxicity
LOAEL
of
50
mg/
kg/
day
from
a
developmental
toxicity
study
in
the
rabbit
and
the
NOAEL
of
1200
mg/
kg/
day
from
a
21­
day
dermal
toxicity
study
in
the
rabbit:
the
ratio
is
50/
1200
or
4%
(
HIARC
Report,
HED
DOC.
No.
014657).
Diuron
RED
Toxicology
Chapter
23
5.3
Classification
of
Carcinogenic
Potential
5.3.1
Conclusions
Treatment
of
diuron
resulted
in
a
significant
increase
in
the
incidences
of
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.
There
are
no
acceptable
modes
of
action
on
mechanism
of
carcinogenicity
for
diuron.

5.3.2
Classification
of
Carcinogenic
Potential
The
HED
Carcinogenicity
Peer
Review
Committee
(
CPRC)
classified
diuron
as
"
known/
likely"
human
carcinogen.

5.3.3
Quantification
of
Carcinogenic
Potential
The
CPRC
recommended
a
low
dose
linear
extrapolation
model
with
Q1
*
of
1.91x10­
2
(
mg/
kg/
day)­
1
be
applied
to
the
animal
data
for
the
quantification
of
human
risk,
based
on
the
urinary
bladder
carcinomas
in
the
male
rat.

6.0
FQPA
CONSIDERATIONS
6.1
Special
Sensitivity
to
Infants
and
Children
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.

6.2
Recommendation
for
a
Developmental
Neurotoxicity
Study
There
is
no
evidence
to
suggest
requiring
a
developmental
neurotoxicity
study.
The
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.

7.0
OTHER
ISSUES
None.

8.0
REFERENCES
Diuron
RED
Toxicology
Chapter
24
00091192
Hodge,
H.
C.;
Downs,
W.
L.;
Maynard,
E.
A.;
et
al.
(
1964)
Chronic
Feeding
Studies
of
Diuron
in
Dogs.
(
Unpublished
study
received
Aug
8,
1964
under
5F0432;
prepared
by
Univ.
of
Rochester,
Dept.
of
Pharmacology,
submitted
by
E.
I.
du
Pont
de
Nemours
&
Co.,
Inc.,
Wilmington,
Del.;
CDL:
090468­
B)
00146144
Rosenfeld,
G.
(
1985)
Acute
Oral
Toxicity
Study
in
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Diurex
Tech
(
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Study
#
1222A.
Unpublished
study
prepared
by
Cosmopolitan
Safety
Evaluation,
Inc.
28
p.
00146146
Rosenfeld,
G.
(
1985)
Acute
Dermal
Toxicity
Study
in
Rabbits.
Diurex
Tech
(
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Study
#
1222B.
Unpublished
study
prepared
by
Cosmopolitan
Safety
Evaluation,
Inc.
18
p.
00146147
Rosenfeld,
G.
(
1985)
Primary
Eye
Irritation
Study
in
Rabbits.
Diurex
Technical
(
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Study
#
1222D.
Unpublished
study
prepared
by
Cosmopolitan
Safety
Evaluation,
Inc.
17
p.
00146148
Rosenfeld,
G.
(
1985)
Primary
Dermal
Irritation
Study
in
Rabbits
Diurex
Tech
(
Diuron):
Study
#
1222E.
Unpublished
study
prepared
by
Cosmopolitan
Safety
Evaluation,
Inc.
14
p.
00146149
Rosenfeld,
G.
(
1985)
Guinea
Pig
Sensitization
Study
(
Buehler).
Diurex
Tech
(
Diuron):
Study
#
1222F.
Unpublished
study
prepared
by
Cosmopolitan
Safety
Evaluation,
Inc.
16
p.
00146611
Ullman,
D.
(
1985)
In
vivo
Assay
of
Diuron
for
Chromosome
Aberrations
in
Rat
Bone
Marrow
Cells:
Report
No.
366­
85.
Unpublished
study
prepared
by
E.
I.
du
Pont
de
Nemours
&
Co.,
Inc.
22
p.
00146608
Poet,
L.
(
1985)
Mutagenicity
Evaluation
in
Salmonella
typhimurium:
Diuron:
Report
No.
471­
84.
Unpublished
study
prepared
by
E.
I.
du
Pont
de
Nemours
&
Co.,
Inc.
17
p.
00146609
Rickard,
L.
(
1985)
Mutagenicity
Evaluation
of
Diuron
in
the
CHO/
HGPRT
Assay:
Chinese
Hamster
Ovary
(
CHO)
Cells:
Report
No.
282­
85.
Unpublished
study
prepared
by
E.
I.
du
Pont
de
Nemours
&
Co.,
Inc.
17
p.
00146610
Arce,
G.
(
1985)
Assessment
of
Diuron
in
the
in
vitro
Unscheduled
DNA
Synthesis
Assay
in
Primary
Rat
Hepatocytes:
Report
No.
349­
85.
Unpublished
study
prepared
by
E.
I.
du
Pont
de
Nemours
&
Co.,
Inc.
18
p.
40228801
Dearlove,
G.
(
1986)
Developmental
Toxicity
Study
of
H­
16035
(
Diuron)
Administered
by
Gavage
to
Rats:
Haskell
Laboratory
Report
No.
HLO
410­
86.
Unpublished
study
prepared
by
Argus
Research
Laboratories,
Inc.
240
p.
40228802
Dearlove,
G.
(
1986)
Developmental
Toxicity
Study
of
H­
16035
(
Diuron)
Administered
by
Gavage
to
New
Zealand
White
Rabbits:
Haskell
Laboratory
Report
No.
HLO
332­
86.
Unpublished
study
prepared
by
Argus
Research
Laboratories,
Inc.
242
p.
41957301
Cook,
J.
(
1990)
40228803
Kinney,
L.
(
1987)
Acute
Inhalation
Toxicity
Study
with
Diuron
in
Rats:
Haskell
Laboratory
Report
No.
101­
87:
Medical
Research
No.
4581­
432.
Unpublished
study
prepared
by
E.
I.
du
Pont
de
Nemours
&
Co.,
Inc.,
Haskell
Laboratory
for
Toxicology
Diuron
RED
Toxicology
Chapter
25
and
Industrial
Medicine.
22
p.
40228805
Arce,
G.
(
1984)
Mutagenicity
Evaluation
(
of
Diuron)
in
Salmonella
Typhimurium:
Haskell
Laboratory
Report
No.
HLR
471­
84.
Unpublished
study
prepared
by
E.
I.
du
Pont
de
Nemours
&
Co.,
Inc.,
Haskell
Laboratory
for
Toxicology
and
Industrial
Medicine.
22
40886501
Schmidt,
W.
(
1985)
Diuron:
Study
for
Chronic
Toxicity
and
Carcinogenicity
with
Wistar
Rats
(
Administration
in
Diet
for
Up
to
Two
Years:
Project
ID:
T/
8010647;
Du
Pont
Report
No.
D/
TOX
17.
Unpublished
study
prepared
by
Bayer
AG.
1473
p.
40886502
Schmidt,
W.;
Karbe,
E.
(
1986)
Diuron:
Toxicological
Study
with
Wistar
Rats
Paying
Special
Attention
to
Effects
on
the
Blood
(
Administration
in
Diet
for
Six
Months):
Project
ID:
T7018927;
Du
Pont
Report
No.
D/
TOX
18.
Unpublished
study
prepared
by
Bayer
AG.
135
p.
41957301
Cook,
J.
(
1990)
Reproductive
and
Fertility
Effects
with
Diuron
(
IN
14740):
Multigeneration
Reproductive
Study
in
Rats:
Lab
Project
Number:
8670­
001:
560­
90.
Unpublished
study
prepared
by
E.
I.
du
Pont
de
Nemours
and
Co.
1080
p.
42159501
Eiben,
R.
(
1983)
Diuron:
Study
for
Chronic
Toxicity
and
Carcinogencity
with
NMRI
Mice
(
Administration
in
Diet
for
24
Months):
(
Trans.)
Lab
Project
Number:
T4010922:
DIUR/
TOX
9.
Unpublished
study
prepared
by
Bayer
Ag.
(
Wuppertal).
1532
p.
42718301
MacKenzie,
S.
(
1992)
Repeated
Dose
Dermal
Toxicity:
21­
Day
Study
with
DPX­
14740­
166
(
Diuron)
in
Rabbits:
Lab
Project
Number:
9122­
001:
484­
92.
Unpublished
study
prepared
by
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I.
du
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Haskell
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198
p.
43349301
Hardesty,
P.;
van
Pelt,
C.
(
1994)
Volume
I
of
Supplementary
Data
Supporting
the
Diuron
2­
Year
Feeding
Study
in
NMRI
Mice:
Lab
Project
Number:
MFS­
1:
21534.
Unpublished
study
prepared
by
E.
I.
du
Pont
de
Nemours
and
Co.,
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131
p.
43804501
Rossberg,
W.
(
1995)
Volume
1
of
Supplementary
Data
Supporting
the
Diuron
2­
Year
Feeding
Study
in
Rats:
Lab
Project
Number:
D/
TOX
17:
T8010647.
Unpublished
study
prepared
by
Bayer
Ag
Institute
of
Toxicology.
46
p.
43871901
Rossberg,
W.;
Wirnitzer,
U.
(
1995)
Addendum
1
Supporting
the
Diuron
2­
Year
Feeding
Study
in
Rats:
Lab
Project
Number:
13962A:
T8010647.
Unpublished
study
prepared
by
Bayer
AG
Institute
of
Toxicology.
42
p.
44019601
Wu,
D.
(
1996)
Absorption,
Distribution,
Metabolism,
and
Elimination
of
(
carbon
14)­
Diuron
in
Rats:
Lab
Project
Number:
AMR
3145­
94:
XBL94161:
RPT00247.
Unpublished
study
prepared
by
XenoBiotic
Labs,
Inc.
and
E.
I.
du
Pont
de
Nemours
and
Co.
303
44302003
Malek,
D.
(
1997)
Volume
2
of
Supplementary
Data
Supporting
the
Diuron
Two­
Year
Feeding
Study
in
Rats:
Lab
Project
Number:
D/
TOX
17:
T8010647:
13962
B.
Unpublished
study
prepared
by
DuPont
Agricultural
Products.
25
p.
44350301
Cox,
L.
(
1997)
In
vivo
Assay
of
Diuron
for
Chromosome
Aberrations
in
Rat
Bone
Marrow
Cells:
Revision
No.
2:
Lab
Project
Number:
7372­
001:
HLR
#
366­
85.
Unpublished
study
prepared
by
E.
I.
DuPont
Haskell
Laboratory
for
Toxicology
and
Diuron
RED
Toxicology
Chapter
26
Industrial
Medicine.
40
p.
45494501
Arce,
G
(
2001)
Diuron:
Cancer
Classification
and
mechanism
of
Action.
Report
No.
GRIFFDIUR052901.
Prepared
by
Griffin
LLC.
Valdosta,
GA.
781
p.
45494505
Herbold,
B.
(
1998)
Diuron:
Micronucleus
Test
on
the
Mouse.
Lab.
Project
Number:
PH­
27204.
Unpublished
study
prepared
by
Bayer
Ag,
Toxicology.
U.
S.
EPA
Carcinogenicity
Peer
Review
of
Diuron.
December
18,
1996.
HED
Doc.
No.
012224.
Office
of
Pesticides
Program,
Health
Effects
Division,
U.
S.
EPA,
Washington,
DC.
U.
S.
EPA
Diuron:
Report
of
the
Hazard
Identification
Assessment
Review
Committee.
May
29,
2001.
HED
Doc.
No.
014596.
Office
of
Pesticides
Program,
Health
Effects
Division,
U.
S.
EPA,
Washington,
DC.
U.
S.
EPA
Diuron:
2nd
Report
of
the
Hazard
Identification
Assessment
Review
Committee.
August
28,
2001.
HED
Doc.
No.
014657.
Office
of
Pesticides
Program,
Health
Effects
Division,
U.
S.
EPA,
Washington,
DC.
U.
S.
EPA
Diuron:
Report
of
the
FQPA
Safety
Factor
Committee.
June
18,
2001.
HED
Doc.
No.
014635.
Office
of
Pesticides
Program,
Health
Effects
Division,
U.
S.
EPA,
Washington,
DC.
U.
S.
EPA
Diuron:
Assessment
of
Mode
of
Action
on
Bladder
Carcinogenicity.
September
20,
2001.
Office
of
Pesticides
Program,
Health
Effects
Division,
U.
S.
EPA,
Washington,
DC.
Diuron
RED
Toxicology
Chapter
27
9.0
APPENDICES
Tables
for
Use
in
Risk
Assessment
Diuron
RED
Toxicology
Chapter
28
9.1
Toxicity
Profile
Summary
Tables
9.1.1
Acute
Toxicity
Table
­
See
Section
4.1
9.1.2
Subchronic,
Chronic
and
Other
Toxicity
Tables
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification/
Doses
Results
870.3100
90­
Day
oral
toxicity
in
rats
MRID
40886502
(
1988)
Acceptable/
Nonguideline
0,
4,
10,
or
25
ppm
(
0,
0.3,
0.7,
or
1.6
mg/
kg/
day
for
males
and
0,
0.3,
0.8,
1.8
mg/
kg/
day
for
females)
The
NOAEL
can
not
be
determined
based
on
equivocal
findings
in
the
urinary
bladder
including
blood
vessel
dilation,
reduced
transparency,
and
increased
firmness.

870.3200
21/
28­
Day
dermal
toxicity
in
rabbits
MRID
42718301
(
1992)
Acceptable/
Guideline
0,
50,
500,
or
1200
mg/
kg/
day
Systemic
toxicity
NOAEL
=
1200
mg/
kg/
day
(
HDT)

870.3465
90­
Day
inhalation
toxicity
Not
available
Not
available
870.3700a
Prenatal
developmental
toxicity
in
rats
MRID
40228801
(
1986)
Unacceptable/
Guideline
0,
16,
80,
or
400
mg/
kg/
day
Maternal
toxicity
NOAEL
=
16
mg/
kg/
day.
Maternal
toxicity
LOAEL
=
80
mg/
kg/
day,
based
on
decreased
body
weight
gain
and
food
consumption.

Developmental
toxicity
NOAEL=
80
mg/
kg/
day.
Developmental
toxicity
LOAEL
=
400
mg/
kg/
day,
based
on
whole
litter
resorption,
reduced
fetal
body
weights,
and
delayed
ossification
of
the
vertebrae
and
sternebrae.

870.3700b
Prenatal
developmental
toxicity
in
rabbits
MRID
40228802
(
1986)
Acceptable/
Guideline
0,
2,
10,
or
50
mg/
kg/
day
Maternal
toxicity
NOAEL
=
10
mg/
kg/
day.
Maternal
toxicity
LOAEL
=
50
mg/
kg/
day,
based
on
decreased
body
weight
and
food
consumption.

Developmental
toxicity
NOAEL
=
50
mg/
kg/
day
(
HDT).
Diuron
RED
Toxicology
Chapter
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification/
Doses
Results
29
870.3800
Reproduction
and
fertility
effects
in
rats
MRID
41957301
(
1990)
Acceptable/
Guideline
0,
10,
250,
or
1750
ppm.
(
0,
0.58,
14.8,
or
101
mg/
kg/
day
for
males
and
0,
0.71,
18.5,
or
131
mg/
kg/
day
for
females,
respectively.
Parental
NOAEL
=
250
ppm
(
18.6
mg/
kg/
day).
Parental
LOAEL
=
1750
ppm
(
132
mg/
kg/
day)
based
on
decreased
body
weight,
body
weight
gain,
food
consumption
and
food
efficiency
in
both
generations.

Reproductive
NOAEL
=
1750
ppm
(
HDT).

Offspring
NOAEL
=
250
ppm
(
18.6
mg/
kg/
day).
Offspring
LOAEL
=
1750
ppm
(
132
mg/
kg/
day)
based
on
decreased
body
weight
of
the
F1
and
F2
pups
during
lactation.

870.4200b
Chronic
toxicity
in
dogs
MRID
00091192
(
1964)
Unacceptable/
Guideline
0,
25,
125,
250,
or
2500/
1250
ppm
(
0,
1.8,
9.4,
18.8,
or
93.8
mg/
kg/
day
by
conversion
factor
of
0.075)
for
24
months.
NOAEL
=
125
ppm
(
9.4
mg/
kg/
day)
in
males
and
250
ppm
(
18.8
mg/
kg/
day)
for
females.
LOAEL
=
250
ppm
(
18.8
mg/
kg/
day)
for
males
and
1250
ppm
(
93.8
mg/
kg/
day)
for
females
based
on
anemia
and
body
weight
losses.

870.4300
Combined
Chronic/
Carcinogenicity
in
rats
MRID
40886501,43871901,
43804501,
44302003
(
1986)
Acceptable/
Guideline
0,
25,
250,
2500
ppm
(
0,
1.0,
10,
or
111
mg/
kg/
day
for
males
and
0,
1.7,
17,
or
202
mg/
kg/
day
for
females)
for
24
months.
NOAEL
=
Not
established.
LOAEL
=
25
ppm
(
1.0
mg/
kg/
day
for
males
and
1.7
mg/
kg/
day
for
females)
based
on
evidence
of
hemolysis
and
compensatory
hematopoiesis
(
decreased
erythrocyte
counts,
increased
reticylocyte
counts,
increased
spleen
weight
and
bone
marrow
activation).

Dosing
was
considered
adequate.

870.4300
Carcinogenicity
in
mice
MRID
42159501
(
1983)
Acceptable/
Guideline
0,
25,
250,
or
2500
ppm
(
0,
5.4,
50.8,
or
640.13
mg/
kg/
day
for
males
and
0,
7.5,
77.5,
or
867.0
mg/
kg/
day
for
females)
for
24
months
NOAEL
=
250
ppm
(
50.8
and
77.5
mg/
kg/
day)
for
males
and
females.
LOAEL
=
2500
ppm
(
640.1
and
867.0
mg/
kg/
day)
for
males
and
females
based
on
hemolytic
anemia
and
liver
toxicity
in
both
sexes
and
urinary
bladder
toxicity
in
females.

Dosing
was
considered
adequate.

870.5100
Gene
mutation
Salmonella
typhimurium
reverse
gene
mutation
MRID
00146608
(
1985),
40228805
(
1991)
Acceptable/
Guideline
Independent
trials
were
negative
in
S.
typhimurium
strains
TA1535,
TA97,
TA98
and
TA100
up
to
the
highest
dose
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.
Diuron
RED
Toxicology
Chapter
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification/
Doses
Results
30
870.5300
Gene
mutation
Chinese
hamster
ovary
(
CHO)/
HGPRT
cell
forward
gene
mutation
assay
MRID
00146609
(
1985)
Acceptable/
Guideline
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).

870.5375
Chromosomal
aberration
in
vivo
rat
bone
marrow
cytogenetic
assay
MRID
00146611
(
1985)
MRID
44350301
(
1997)(
Revised)
Acceptable/
Guideline
The
test
was
negative
in
Sprague
Dawley
rats
up
to
cytotoxic
doses.
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.
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
ranges.

870.5550
Unscheduled
DNA
Synthesis
MRID
00146610
(
1985)
Acceptable/
Guideline
The
test
was
negative
up
to
cytotoxic
doses
(
$
0.33
mM,
equivalent
to
.
76
F
g/
mL).

870.7485
Metabolism
and
pharmacokinetics
MRID
42010501
(
1996)
Acceptable/
Guideline
Diuron
was
rapidly
absorbed,
metabolized
and
excreted.
Urine
was
the
major
route
of
excretion.
Metabolism
of
diuron
involved
N­
oxidation,
ring
hydroxylation,
demethylation,
dechlorination,
and
conjugation
to
sulfate
and
glucuronic
acid.

870.7600
Dermal
penetration
Not
available
for
diuron.
Not
available.
Diuron
RED
Toxicology
Chapter
31
9.2
Summary
of
Toxicological
Dose
and
Endpoints
for
Diuron
for
Use
in
Human
Risk
Assessment1
Exposure
Scenario
Dose
Used
in
Risk
Assessment,
UF
FQPA
SF
and
Endpoint
for
Risk
Assessment
Study
and
Toxicological
Effects
Acute
Dietary
general
population
including
infants
and
children
There
is
no
appropriate
endpoint
attributed
to
a
single
exposure
(
dose)
was
identified
including
in
the
rat
or
rabbit
developmental
toxicity
study.
Therefore,
an
acute
RfD
was
not
established.

Chronic
Dietary
all
populations
LOAEL=
1.0
mg/
kg/
day
UF
=
300
Chronic
RfD
=
0.003
mg/
kg/
day
FQPA
SF
=
1x
cPAD
=
0.003
mg/
kg/
day
Combined
chronic/
carcinogenicity
study
in
rats.
LOAEL=
1.0
mg/
kg/
day
based
on
evidence
of
hemolytic
anemia
and
compensatory
hematopoiesis.
A
NOAEL
was
not
established.

Short­
Term
Oral
(
1­
30
days)

(
Residential)
NOAEL=
10
mg/
kg/
day
LOC
for
MOE
=
100
(
Residential,
includes
the
FQPA
SF)
Developmental
toxicity
study
in
rabbits.
LOAEL=
50
mg/
kg/
day
based
on
maternal
toxicity
(
decreased
body
weight
and
food
consumption).

Intermediate­
Term
Oral
(
1­
6
months)

(
Residential)
oral
study
NOAEL=
1.0
mg/
kg/
day
LOC
for
MOE
=
100
(
Residential,
includes
the
FQPA
SF)
Combined
chronic/
carcinogenicity
in
rats.
LOAEL
=
10
mg/
kg/
day
based
on
altered
hematological
parameters
observed
at
6
months.

Short­
Term
Dermal
(
1­
30
days)
Intermediate­
Term
Dermal
(
1­
6
months)
(
Occupational/
Residential)
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.

Long­
Term
Dermal
(
Longer
than
6
months)

(
Occupational/
Residential)
oral
study
LOAEL=
1.0
mg/
kg/
day
(
dermal
absorption
factor
=
4%)
LOC
for
MOE
=
300
(
Occupational)

LOC
for
MOE
=
300
(
Residential,
includes
the
FQPA
SF)
Combined
chronic/
carcinogenicity
in
rats.
Evidence
of
hemolytic
anemia
and
compensatory
hematopoiesis.
NOAEL
was
not
established.
Diuron
RED
Toxicology
Chapter
Exposure
Scenario
Dose
Used
in
Risk
Assessment,
UF
FQPA
SF
and
Endpoint
for
Risk
Assessment
Study
and
Toxicological
Effects
32
Short­
Term
Inhalation
(
1­
30
days)

(
Occupational/
Residential)
oral
study
NOAEL=
10
mg/
kg/
day
LOC
for
MOE
=
100
(
Occupational)

LOC
for
MOE
=
100
(
Residential,
includes
the
FQPA
SF)
Developmental
toxicity
study
in
rabbits.
LOAEL=
50
mg/
kg/
day
based
on
decreased
body
weight
and
food
consumption.

Intermediate­
Term
Inhalation
(
1­
6
months)

(
Occupational/
Residential)
oral
study
NOAEL=
1.0
mg/
kg/
day
LOC
for
MOE
=
100
(
Occupational)

LOC
for
MOE
=
100
(
Residential,
includes
the
FQPA
SF)
Combined
chronic/
carcinogenicity
in
rats.
LOAEL
=
10
mg/
kg/
day
based
on
altered
hematological
parameters
observed
at
6
months.

Long­
Term
Inhalation
(
longer
than
6
months)

(
Occupational/
Residential)
oral
study
LOAEL=
1.0
mg/
kg/
day
LOC
for
MOE
=
300
(
Occupational)

LOC
for
MOE
=
300
(
Residential,
includes
the
FQPA
SF)
Combined
chronic/
carcinogenicity
in
rats.
Evidence
of
hemolytic
anemia
and
compensatory
hematopoiesis.
NOAEL
was
not
established.

Cancer
(
oral,
dermal,
inhalation)
Known/
likely
human
carcinogen
Q1*
=
1.91
x
10­
2
(
mg/
kg/
day)­
1
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.

1
UF
=
uncertainty
factor,
FQPA
SF
=
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,
LOC
=
level
of
concern,
MOE
=
margin
of
exposure
