R
UNITED
STATES
ENVIRONMENTAL
PROTECTION
AGENCY
WASHINGTON,
DC
20460
OFFICE
OF
PREVENTION,
PESTICIDES
AND
TOXIC
SUBSTANCES
MEMORANDUM
[
May
08,
1997]
[
TXR
#
0050671]
SUBJECT:
Carcinogenicity
Peer
Review
of
Diuron
FROM:
Linda
L.
Taylor,
Ph.
D.
Review
Section
II
Toxicology
Branch
II
Health
Effects
Division
(
7509C)
and
Esther
Rinde,
Ph.
D.
Manager,
Carcinogenicity
Peer
Review
Committee
Science
Analysis
Branch
Health
Effects
Division
(
7509C)

THROUGH:
Stephanie
R.
Irene,
Ph.
D.
Deputy
Director,
Health
Effects
Division
(
7509C)

TO:
Philip
Errico
Product
Manager
#
25
Fungicide­
Herbicide
Branch
Registration
Division
(
7505C)
and
Larry
Schnaubelt
Special
Review
and
Reregistration
Division
(
7508W)

The
Health
Effects
Division
Carcinogenicity
Peer
Review
Committee
(
CPRC)
met
on
December
18,
1996
to
discuss
and
evaluate
the
weightof
the­
evidence
on
Diuron
with
particular
reference
to
its
carcinogenic
potential.
In
accordance
with
the
EPA
proposed
Guidelines
for
Carcinogenic
Risk
Assessment
(
April
23,
1996)
Diuron
was
characterized
as
a
"
known/
likely"
human
carcinogen
by
all
routes,
based
on
urinary
bladder
carcinomas
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.
Information
from
structurally
related
analogs
provided
further
support.
Carcinogenicity
Peer
Review
of
Diuron
December
18,
1997
2
The
CPRC
recommended
that
for
the
purpose
of
risk
characterization,
a
low
dose
linear
extrapolation
model
be
applied
to
the
animal
data
for
the
quantification
of
human
risk,
based
on
the
urinary
bladder
carcinomas
in
the
male
rat.
Carcinogenicity
Peer
Review
of
Diuron
December
18,
1997
3
SUMMARY
Administration
of
Diuron
in
the
diet
to
NMRI
mice
resulted
in
increases
in
mammary
gland
adenocarcinomas
in
female
mice
which
had
statistically
significant
positive
trends;
there
were
no
pairwise
statistically
significant
increases.
The
incidence
of
tumors
at
the
highest
dose
(
2500
ppm)
exceeded
that
in
historical
controls
from
the
testing
facility.
There
were
no
apparent
significant
increases
in
tumors
in
male
mice.
The
CPRC
agreed
that
dosing
in
the
mouse
was
adequate,
and
not
excessive.

Administration
of
Diuron
in
the
diet
to
Wistar
rats
resulted
in
statistically
significant
increases
in
urinary
bladder
carcinomas
at
the
highest
dose
(
2500
ppm)
in
both
sexes;
there
were
also
statistically
significant
positive
trends
in
both
sexes.
The
incidences
at
the
highest
dose
was
73%
and
27%
(
vs
2%
in
concurrent
controls)
in
males
and
females,
respectively
and
were
well
in
excess
of
historical
controls
from
the
testing
facility.
In
male
rats
at
the
highest
dose,
there
were
also
increases
in
renal
epithelial
carcinomas
and
combined
papilloma/
carcinoma
which
had
a
statistically
significant
trend
for
the
combined
tumors
only.
There
were
no
pairwise
statistically
significant
increases
in
kidney
tumors;
however
the
numerical
increase
in
carcinomas
alone
(
4%
vs
O%
in
concurrent
controls)
was
considered
to
be
biologically
significant
because
of
the
rarity
of
this
tumor
type.
In
addition,
hyperplasia
of
the
urinary
bladder
at
lower
doses
noted
in
both
the
rat
and
mouse
studies
provided
further
support
that
the
kidney
tumors
(
as
well
as
the
bladder
tumors)
were
compound­
related.
The
CPRC
agreed
that
dosing
in
the
rat
was
adequate,
and
not
excessive.
There
were
no
data
provided
by
the
Registrant
to
attribute
a
mechanism
for
the
carcinogenic
response
in
mice
or
rats.

Diuron
is
structurally
related
to
Linuron,
Fluometuron
and
Monuron
which
all
have
demonstrated
carcinogenic
activity
at
various
sites
in
rodents.
Only
Monuron
is
associated
with
tumors
in
the
kidney;
however,
differences
in
metabolism
may
account
for
the
site
differences
of
the
other
analogs.
Diuron
was
only
weakly
positive
(
considered
to
be
equivocal)
in
an
in
vivo
cytogenetic
study;
other
submitted
mutagenicity
studies
were
negative
or
inadequate.
Information
from
structurally
related
analogs
provided
further
support.
Carcinogenicity
Peer
Review
of
Diuron
December
18,
1997
1Also
a
member
of
the
PRC
for
this
chemical;
signature
indicates
concurrence
with
the
peer
review
unless
otherwise
stated.

2Signature
indicates
concurrence
with
pathology
report.

4
A.
Individuals
in
Attendance
at
the
meeting:

1.
Peer
Review
Committee:
(
Signatures
indicate
concurrence
with
the
peer
review
unless
otherwise
stated.)

William
Burnam
Marion
Copley
Kerry
Dearfield
Elizabeth
Doyle
Yiannakis
Ioannou
Esther
Rinde
2.
Reviewers:
(
Non­
committee
members
responsible
for
data
presentation;
signatures
indicate
technical
accuracy
of
panel
report.)

Linda
Taylor1
Clark
Swentzel
Lori
Brunsman
Lucas
Brennecke2
(
PAI/
ORNL)

3.
Other
Attendees:
Albin
Kocialski
and
Bernice
Fisher
(
HED)
Carcinogenicity
Peer
Review
of
Diuron
December
18,
1997
5
Figure
2
Diuron
B.
Material
Reviewed
The
material
available
for
review
consisted
of
DER's,
oneliners
data
from
the
literature
and
other
data
summaries
prepared
and/
or
supplied
by
Dr.
Taylor,
and
tables
and
statistical
analysis
by
Lori
Brunsman.
The
material
reviewed
is
attached
to
the
file
copy
of
this
report.

C.
Background
Information
DIURON,
3­[
3,4­
dichlorophenyl]­
1,1­
dimethylurea
is
a
substituted
urea
herbicide
effective
against
emerging
and
young
broadleaf
and
grass
weeds
and
mosses.
Tolerances
for
residues
in
or
on
asparagus,
Bermuda
grass,
Bermuda
grass
hay;
alfalfa,
corn
fodder
or
forage
[
sweet
corn
field
corn,
popcorn],
grass
crops
[
other
than
Bermuda],
grass
hay
[
other
than
Bermuda],
hay,
forage
and
straw
of
barley,
oats,
rye,
and
wheat,
hay
and
forage
of
birdsfoot
trefoil,
clover,
peas,
and
vetch,
peppermint
hay,
sorghum
fodder
and
forage;
apples,
artichokes,
barley
grain,
blackberries,
blueberries,
boysenberries,
citrus
fruits,
corn
in
grain
and
ear
form
[
including
sweet,
field
and
popcorn],
cottonseed,
currants,
dewberries,
gooseberries,
grapes,
huckleberries,
loganberries,
oat
grain,
olives,
pears,
peas,
pineapple,
potatoes,
raspberries,
rye
grain,
sorghum
grain,
sugarcane,
vetch
(
seed),
wheat
grain;
meat,
fat
and
meat
byproducts
of
cattle,
goats,
hogs,
horses,
and
sheep;
bananas,
nuts,
and
peaches;
and
papayas
have
been
established.
The
CAS
Registry
Number
[
CAS
NO.]
is
150­
68­
5.
The
PC
Code
is
035505.
The
Tox.
Chemical
No.
is
410.

D.
Evaluation
of
Carcinogenicity
Evidence
1.
Carcinogenicity
Study
in
Mice
Reference:
DIURON:
Study
for
Chronic
Toxicity
and
Carcinogenicity
with
NMRI
Mice
(
Administration
in
Diet
for
24
Months).
[
Study
#
Bayer
AG
T
4010922,
DuPont
Report
#
DIUR/
TOX9,
dated
October,
1983
Carcinogenicity
Peer
Review
of
Diuron
December
18,
1997
6
[
translation
completed
January,
1991];
MRID
#
42159501;
Document
Nos.
009486
and
010902011030.
Addendum:
MRID
#
43349301
[
Supplemental
Data
and
Background
Tumor
Incidences].

a.
Experimental
Design
Groups
of
Bor
strain
NMRI
[
SPF
HAN]
mice
of
both
sexes
[
50
mice/
sex/
dose
(
carcinogenicity);
10
mice/
sex/
group
(
12­
month
interim
group)]
were
administered
Diuron
[
98.7%
pure]
via
the
diet
at
dose
levels
of
0,
25
ppm
[
%
%
5.5/
&
&
7.5
mg/
kg/
day],
250
ppm
[
%
%
50.8/
&
&
77.5
mg/
kg/
day],
or
2500
ppm
[
%
%
640.1/
&
&
869.0
mg/
kg/
day]
for
24
months.

b.
Discussion
of
Tumor
Data
MALES
­
There
were
no
statistically­
significant
tumors
observed
in
male
mice.

FEMALES
­
Female
mice
had
significant
increasing
trends
in
mammary
gland
adenocarcinomas
and
ovarian
luteomas,
both
at
p
<
0.05.
There
were
no
significant
differences
in
the
pair­
wise
comparisons
of
the
dosed
groups
with
the
controls.
[
Table
8
from
L.
Brunsman
memo
dated
11/
20/
96;
reproduced
here
as
Table
1].

TABLE
1.
DIURON
­
NMRI
Mouse
Study
Female
Mammary
Gland
and
Ovarian
Tumor
Rates+
and
Peto's
Prevalence
Test
Results
(
p
values)

Dose
(
ppm)

0
25
250
2500
Mammary
Gland
Adenocarcinomas
2/
34
1a/
29
1/
44
6/
37
(%)
(
6)
(
3)
(
2)
(
16)

p
=
0.016*
0.560
0.403
0.159
Ovarian
Luteomas
3/
34
1/
32
2/
46
7b/
41
(%)
(
9)
(
3)
(
4)
(
17)

p
=
0.024*
0.330n
0.358n
0.243
+
Number
of
tumor
bearing
mice/
Number
of
mice
examined,
excluding
those
that
died
before
week
54.
Also
excludes
week
53
interim
sacrifice
mice.
aFirst
mammary
gland
adenocarcinoma
observed
at
week
78,
dose
25
ppm.
bFirst
uterine
luteoma
observed
at
week
53,
dose
0
ppm,
in
an
interim
Carcinogenicity
Peer
Review
of
Diuron
December
18,
1997
7
sacrifice
mouse.
Second
uterine
luteoma
observed
at
week
72,
dose
2500
ppm,
in
a
mouse
that
died
on
study.
nNegative
change
from
control.
(
)
Percent
Note:
One
animal
in
the
control
group
of
the
interim
sacrifice
group
had
a
uterine
luteoma.
Interim
sacrifice
mice
are
not
included
in
this
analysis.
Significance
of
trend
denoted
at
control.
Significance
of
pair­
wise
comparison
with
control
denoted
at
dose
level.
If
*,
then
p
<
0.05.
If
**,
then
p
<
0.01.
Carcinogenicity
Peer
Review
of
Diuron
December
18,
1997
8
FEMALES:
When
compared
to
historical
control
data
from
published
papers
of
studies
on
NMRI
mice,
the
Registrant
stated
that
spontaneous
ovarian
tumors
are
usually
rare
in
mice
except
in
certain
strains,
which
include
Han:
NMRI
mice.
From
the
literature,
the
incidence
of
ovarian
tumors
in
these
mice
can
be
influenced
by
the
age
at
terminal
sacrifice,
husbandry
conditions,
source
of
stock,
and
the
nutritional
status
[
i.
e.,
obese
vs
lean],
and
variability
among
pathologists
in
classification
of
these
tumors
affects
the
reported
incidence.
The
Registrant
stated
that
primary
ovarian
tumors
are
classified
on
the
assumption
that
these
tumors
arise
from
one
of
three
ovarian
components:
epithelium
[
either
of
the
ovarian
surface
or
rete
ovarii],
germ
cells,
or
ovarian
stroma,
including
sex
cords,
which
probably
contribute
cells
to
ovarian
follicles
and
thus
to
the
endocrine
apparatus
of
the
ovary.
Tumors
of
the
latter
group
are
termed
sex
cord­
stromal
tumors
and
include
granulosa
cell
tumors,
luteomas,
thecomas,
Sertoli
cell
tumors
of
the
ovary,
Leydig
cell
tumors,
androblastoma,
arrhenoblastoma,
or
lipid
cell
tumors.
It
is
further
stated
that
NTP
recommends
combining
the
incidence
of
the
sex
cord­
stromal
tumors
for
statistical
assessment
of
tumor
data.
In
addition
to
the
similarity
in
the
histogenesis
of
the
granulosa/
theca
cell
tumors
and
luteomas,
any
one
of
these
tumors
may
have
components
of
the
other.
For
this
reason,
several
groups
of
pathologists
consider
luteoma
and
thecoma
as
morphologic
variants
of
granulosa
cell
tumors,
differing
only
in
their
degree
and
direction
of
differentiation.
Therefore,
the
Registrant
combined
the
sex
cord­
stromal
tumors
[
Table
2]
in
the
ovaries
and
analyzed
by
the
Cochran­
Armitage
test
for
trend
and
found
no
significant
increase
in
tumors
and
the
percent
incidence
falls
within
the
reported
range
for
spontaneous
occurrence
[
0­
35.5%].
Also
provided
were
historical
control
data
from
18
studies
performed
at
the
BAYER
testing
facility.
With
respect
to
ovarian
tumor
data,
9
of
the
18
studies
list
luteoma
[
0­
6.8%],
and
the
highest
number
is
3,
which
occurred
in
2
studies
[
3/
44
and
3/
45
mice].
Carcinogenicity
Peer
Review
of
Diuron
December
18,
1997
9
Table
2.
Ovarian
Tumor
Incidence
­
Registrant's
Analysis
Tumor/
Dose
0
ppm
25
ppm
250
ppm
2500
ppm
OVARIAN
TUMORS
n=
granulosa/
thec.
tumors
unilat.
benign
bilat.
benign
unilat.
malignant
luteoma
unilat.
benign
bilat.
benign
combined
sex
cord­
stromal
tumors
*
tubular
cystadenoma,
benign
leiomyoma,
unilat.
benign
teratoma,
unilat.
benign
50
7
[
14]
Ë
1
[
2]
0
3
[
6]
0
11
[
22]
2
[
4]

00
47
4
[
9]
1
[
2]
1
[
2]

0
1
[
2]
7
[
15]
1
[
2]
0
1
[
2]
49
11
[
22]
2
[
4]
0
2
[
4]
0
15
[
31]
1
[
2]

00
50
5
[
10]
2
[
4]
0
7
[
14]**
0
14
[
28]
0
1
[
2]
0
Ë
[%];
*
sum
of
all
sex
cord­
stromal
tumors,
including
all
granulosa/
theca
tumors
and
all
luteomas;
**
p<
0.01
At
the
Diuron
Carcinogenicity
Peer
Review
meeting
December
18,
1996,
it
was
decided
that
the
female
mouse
ovarian
tumor
rates
table
should
reflect
the
more
appropriate
"
combined
sex
chordstromal
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.
Since
only
the
luteoma
tumor
counts
have
been
verified,
the
counts
for
the
combined
sex
chord­
stromal
tumors
have
been
taken
from
Table
2,
page
3,
of
the
Diuron
data
package,
which
was
extracted
from
the
registrant's
analysis.

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
cord­
stromal
tumors
[
L.
Brunsman
memo
dated
12/
18/
96].
This
statistical
analysis
was
based
upon
the
Exact
trend
test
and
the
Fisher's
Exact
test
for
pair­
wise
comparisons.
See
Table
1a
for
female
mouse
ovarian
tumor
analysis
results.
Carcinogenicity
Peer
Review
of
Diuron
December
18,
1997
10
Table
1a.
Diuron
­
NMRI
(
SPF
HAN)
Mouse
Study
Female
Ovarian
Tumor
Rates+
and
Exact
Trend
Test
and
Fisher's
Exact
Test
Results
(
p
values)

Dose
(
ppm)

0
25
250
2500
Combined
Sex
Cord­
Stromal
Tumors
11/
34
7/
32
15/
46
14/
41
(%)
(
32)
(
22)
(
33)
(
34)

p
=
0.268
0.249n
0.588
0.534
+
Number
of
tumor
bearing
animals/
Number
of
animals
examined,
excluding
those
that
died
before
week
54.
Also
excludes
week
53
interim
sacrifice
animals.
nNegative
change
from
control.
Note:
Interim
sacrifice
animals
are
not
included
in
this
analysis.
Significance
of
trend
denoted
at
control.
Significance
of
pair­
wise
comparison
with
control
denoted
at
dose
level.
If
*,
then
p
<
0.05.
If
**,
then
p
<
0.01.

With
regard
to
the
mammary
gland,
the
Registrant
states
that
mouse
mammary
gland
tumors
are
classified
as
1)
adenocarcinoma
type
A
[
synonyms:
adenoma
simple,
acinar
carcinoma,
adenocarcinoma
simple],
2)
adenocarcinoma
type
B
[
synonyms:
irregular
tubular
adenocarcinoma,
solid
polygonal­
cell
carcinoma,
intratubular
carcinoma,
papillary
cystic
adenocarcinoma,
intracanalicular
adenocarcinoma],
3)
adenocarcinoma
type
C
[
synonyms:
fibroadenoma,
adenofibroma],
4)
adenocanthoma
[
synonyms:
keratinizing
tumors,
mammary
tumor
with
keratinization,
squamous
carcinoma,
metaplastic
carcinoma,
adenocarcinoma,
variable,
type
IV],
5)
carcinosarcoma
[
synonyms:
spindle­
cell
carcinoma,
sarcomatoid
carcinoma],
6)
sarcoma,
and
7)
miscellaneous
tumors.
It
is
stated
that
the
mammary
tumors
observed
in
the
Diuron
study
in
mice
are
synonymous
with
adenocarcinoma
types
A
and
B.
Their
analysis
shows
a
statistically
significant
increase
in
the
incidence
of
malignant
[
12%]
mammary
adenocarcinomas
in
the
high­
dose
females.
The
spontaneous
incidence
of
malignant
mammary
gland
tumors
[
carcinoma,
Types
A/
B
combined]
in
Han:
NMRI
female
mice
is
stated
to
be
9­
14%
in
ad
libitum
fed
mice
and
2­
9%
in
food
restricted
fed
mice.
There
is
no
age­
specific
appearance
of
carcinomas.
The
Registrant
concludes
that
because
the
incidence
is
within
the
published
historical
control
range,
Diuron
is
not
carcinogenic
for
the
mammary
gland
[
Table
3].
In
the
historical
control
data
from
Carcinogenicity
Peer
Review
of
Diuron
December
18,
1997
11
the
testing
facility
[
16
studies],
the
highest
number
of
mice
observed
with
a
malignant
mammary
gland
tumor
was
3,
which
occurred
in
3
studies
[
3/
48,
3/
48,
3/
49
mice;
range
0­
6.3%].

Table
3.
Mammary
Tumor
Incidence
­
Registrant's
Analysis
Tumor/
Dose
[
ppm]
0
25
250
2500
MAMMARY
GLAND
TUMORS
n=
mammary
adenocarcinoma,
malignant
mammary
carcinoma,
anaplastic,
malignant
mammary
gland
tumors,
combined
50
2
[
4]
Ë
02
[
4]
47
1
[
2]
1
[
2]
2
[
4]
49
1
[
2]

01
[
2]
50
6*
[
12]
0
6*
[
12]

Ë
[%];
*
p<
0.05
c.
Non­
Neoplastic
Lesions
MALES:
The
incidence
of
several
non­
neoplastic
liver
lesions
was
significantly
increased
at
the
high
dose
compared
to
the
concurrent
control
[
Table
4].
There
were
no
adverse
findings
in
the
urinary
bladder.

Tissue/
Lesion/
Dose
(
ppm)
MALES
Table
4.
Microscopic
Findings
­
Non­
Neoplastic
[
%
%
/
&
&
]

0
25
250
2500
Liver
N=
enlarged
degenerative
hepatopathy
increased
mitosis
single
cell
necrosis
8
accumulation
of
Kupffer
Cells
45/
46
0/
0
1/
0
1/
0
3/
12
6/
9
48/
38
0/
1
0/
0
2/
3
2/
7
6/
9
46/
48
0/
3
0/
0
0/
0
5/
10
8/
9
46/
46
0/
10**
15**/
0
8**/
4*
7*/
19**
11*/
9
*
p<
0.05;
**
p<
0.01;

FEMALES:
The
incidence
of
non­
neoplastic
lesions
in
the
mammary
gland
and
ovaries
were
comparable
among
the
groups.
At
the
highdose
level,
there
was
an
increased
incidence
of
epithelial
hyperplasia,
edema,
and
thickened
mucosa
in
the
urinary
bladder
[
Table
5].
Carcinogenicity
Peer
Review
of
Diuron
December
18,
1997
12
Tissue/
Lesion/
Dose
(
ppm)
FEMALES
Table
5.
Microscopic
Findings
­
Non­
Neoplastic
0
25
250
2500
Urinary
Bladder
N=
epithelial
hyperplasia
edema
mucosa
thickened
46
500
36
500
45
300
44
23**
17**
5**

*
p<
0.05;
**
p<
0.01;
data
from
page
62
of
report.
d.
Adequacy
of
the
Dosing
for
Assessment
of
Carcinogenicity
The
statistical
evaluation
of
mortality
indicated
no
significant
incremental
change
with
increasing
doses
of
Diuron
in
either
male
or
female
mice.
The
highest
dose
tested
[
2500
ppm]
was
considered
adequate.
Signs
of
toxicity
at
this
dose
level
include
(
1)
decreased
body
weight
gain
for
both
sexes
[
%
%
90%/
&
&
87%
of
control
overall],
(
2)
increased
spleen
and
liver
weights
in
males,
(
3)
increased
leucocyte
and
reticulocyte
counts,
mean
corpuscular
volume,
mean
corpuscular
hemoglobin,
and
bilirubin
values
in
both
sexes,
(
4)
increased
incidence
of
intracellular
pigments
in
the
renal
tubules
in
females
and
in
the
spleen
of
both
sexes,
(
5)
increased
incidence
of
hemosiderin
deposits
in
liver
cells
in
males,
(
6)
increased
incidence
of
liver
single
cell
necrosis
and
cell
mitosis
in
both
sexes,
(
7)
increased
incidence
of
enlarged
degenerative
cells
in
the
liver
in
females
and
of
hepatopathy
and
accumulation
of
Kupffer
cells
in
males,
and
(
8)
increased
incidence
of
urinary
bladder
edema
and
epithelial
hyperplasia,
thickened
mucosa,
and
enlarged
uterine
horn
in
females.
The
HED
RfD
Committee
discussed
Diuron
at
the
9/
26/
96
meeting
and
concluded
that
the
study
was
acceptable;
i.
e.,
the
dose
levels
were
considered
adequate.
The
NOEL
is
250
ppm
[
%
%
50.5/
&
&
77.5
mg/
kg/
day],
and
the
LOEL
is
2500
ppm
[
%
%
640.1/
&
&
869.0
mg/
kg/
day],
based
on
the
effects
listed
above.
The
CPRC
agreed
that
dosing
in
the
mouse
study
was
adequate
(
not
excessive)
for
assessing
the
carcinogenicity
potential
of
Diuron
in
mice.

2.
Combined
Chronic
Toxicity/
Carcinogenicity
Study
in
Rats
Reference:
Diuron:
Study
for
Chronic
Toxicity
and
Carcinogenicity
with
Wistar
Rats
(
Administration
in
Diet
for
up
to
Two
Years)
[
BAYER
AG
T
8010647;
DuPont
Report
No.
D/
Tox
17,
dated
11/
29/
85;
MRID
#
40886501;
Document
No.
008160].

a.
Experimental
Design
Carcinogenicity
Peer
Review
of
Diuron
December
18,
1997
13
Wistar
rats
[
50/
sex/
group
for
104
weeks;
10/
sex/
group
for
interim
52­
week
sacrifice]
were
fed
Diuron
at
dose
levels
of
0,
25
ppm
[
%
%
1.02/
&
&
1.69
mg/
kg/
day],
250
ppm
[
%
%
10.46/
&
&
16.88
mg/
kg/
day],
or
2500
ppm
[
%
%
111.17/
&
&
202.22
mg/
kg/
day].

b.
Discussion
of
Tumor
Data
MALES:
Male
rats
had
significant
increasing
trends,
and
significant
differences
in
the
pair­
wise
comparisons
of
the
2500
ppm
dose
group
with
the
controls,
for
urinary
bladder
epithelial
carcinomas,
and
papillomas
and/
or
carcinomas
combined,
all
at
p
<
0.01.
Male
rats
also
had
a
significant
increasing
trend
in
kidney
renal
pelvis
epithelial
papillomas
and/
or
carcinomas
combined
at
p
<
0.05.
[
Tables
3
and
4
of
L.
Brunsman
memo,
reproduced
here
as
Tables
6
and
7].

FEMALES:
Female
rats
had
significant
increasing
trends,
and
significant
differences
in
the
pair­
wise
comparisons
of
the
2500
ppm
dose
group
with
the
controls,
for
urinary
bladder
epithelial
carcinomas,
and
papillomas
and/
or
carcinomas
combined,
all
at
p
<
0.01.
[
Table
5
of
L.
Brunsman
memo,
reproduced
here
as
Table
8].

Table
6.
DIURON
­
Wistar
Rat
Study
Male
Urinary
Bladder
Epithelial
Tumor
Rates+
and
Exact
Trend
Test
and
Fisher's
Exact
Test
Results
(
p
values)

Dose
(
ppm)

0
25
250
2500
Papillomas
0/
49
0/
50
0/
49
1a/
48
(%)
(
0)
(
0)
(
0)
(
2)

p
=
0.245
1.000
1.000
0.495
Carcinomas
1/
49
0/
50
1/
49
35b/
48
(%)
(
2)
(
0)
(
2)
(
73)

p
=
0.000**
0.495n
0.753
0.000**

Combined
1/
49
0/
50
1/
49
35c/
48
(%)
(
2)
(
0)
(
2)
(
73)

p
=
0.000**
0.495n
0.753
0.000**

+
Number
of
tumor
bearing
rats/
Number
of
rats
examined,
excluding
those
that
died
or
were
sacrificed
before
week
53.
Also
excludes
week
52
interim
sacrifice
animals.
aFirst
papilloma
observed
at
week
104,
dose
2500
ppm.
Carcinogenicity
Peer
Review
of
Diuron
December
18,
1997
14
bFirst
carcinoma
observed
at
week
81,
dose
2500
ppm.
cOne
rat
in
the
2500
ppm
dose
group
had
both
a
papilloma
and
a
carcinoma.
nNegative
change
from
control.
(
)
Percent
Note:
Interim
sacrifice
rats
are
not
included
in
this
analysis.
Significance
of
trend
denoted
at
control.
Significance
of
pair­
wise
comparison
with
control
denoted
at
dose
level.
If
*,
then
p
<
0.05.
If
**,
then
p
<
0.01.
Carcinogenicity
Peer
Review
of
Diuron
December
18,
1997
15
Table
7.
DIURON
­
Wistar
Rat
Study
Male
Kidney
Renal
Epithelial
Tumor
Rates+
and
Exact
Trend
Test
and
Fisher's
Exact
Test
Results
(
p
values)

Dose
(
ppm)

0
25
250
2500
Papillomas
0/
49
0/
50
0/
50
1a/
48
(%)
(
0)
(
0)
(
0)
(
2)

p
=
0.244
1.000
1.000
0.495
Carcinomas
0/
49
0/
50
0/
50
2b/
48
(%)
(
0)
(
0)
(
0)
(
4)

p
=
0.058
1.000
1.000
0.242
Combined
0/
49
0/
50
0/
50
3/
48
(%)
(
0)
(
0)
(
0)
(
6)

p
=
0.014*
1.000
1.000
0.117
+
Number
of
tumor
bearing
rats/
Number
of
rats
examined,
excluding
those
that
died
or
were
sacrificed
before
week
53.
Also
excludes
week
52
interim
sacrifice
rats.
aFirst
papilloma
observed
at
week
104,
dose
2500
ppm.
bFirst
carcinoma
observed
at
week
104,
dose
2500
ppm.
Note:
Interim
sacrifice
rats
are
not
included
in
this
analysis.
Significance
of
trend
denoted
at
control.
Significance
of
pair­
wise
comparison
with
control
denoted
at
dose
level.
If
*,
then
p
<
0.05.
If
**,
then
p
<
0.01.
Carcinogenicity
Peer
Review
of
Diuron
December
18,
1997
16
Table
8.
DIURON
­
Wistar
Rat
Study
Female
Urinary
Bladder
Epithelial
Tumor
Rates+
and
Exact
Trend
Test
and
Fisher's
Exact
Test
Results
(
p
values)

Dose
(
ppm)

0
25
250
2500
Papillomas
0/
47
0/
49
2a/
50
0/
49
(%)
(
0)
(
0)
(
4)
(
0)

p
=
0.560
1.000
0.263
1.000
Carcinomas
1/
47
0/
49
1/
50
13b/
49
(%)
(
2)
(
0)
(
2)
(
27)

p
=
0.000**
0.490n
0.737
0.001**

Combined
1/
47
0/
49
3/
50
13c/
49
(%)
(
2)
(
0)
(
6)
(
27)

p
=
0.000**
0.490n
0.332
0.001**

+
Number
of
tumor
bearing
rats/
Number
of
rats
examined,
excluding
those
that
died
before
week
44.
Also
excludes
week
52
interim
sacrifice
rats.
aFirst
papilloma
observed
at
week
104,
dose
250
ppm.
bFirst
carcinoma
observed
at
week
44,
dose
2500
ppm.
cOne
rat
in
the
2500
ppm
dose
group
had
both
a
papilloma
and
a
carcinoma.
nNegative
change
from
control.
Note:
Interim
sacrifice
rats
are
not
included
in
this
analysis.
Significance
of
trend
denoted
at
control.
Significance
of
pair­
wise
comparison
with
control
denoted
at
dose
level.
If
*,
then
p
<
0.05.
If
**,
then
p
<
0.01.
Carcinogenicity
Peer
Review
of
Diuron
December
18,
1997
17
When
compared
to
historical
controls
of
the
testing
facility,
the
incidence
of
transitional
epithelial
carcinomas
[
malignant
tumors
of
the
bladder
epithelium]
at
the
high­
dose
level
exceeds
the
historical
control
incidence
[
range
not
provided],
and
the
maximum
[
2%]
incidence
at
the
low­
and
mid­
dose
levels
was
said
to
be
within
the
spontaneous
rate.
With
regard
to
the
uterus,
the
slight
increase
in
the
number
of
adenocarcinomas
and
total
malignant
neoplasias
observed
at
the
high­
dose
level
was
not
statistically
significant
either
on
a
pairwise
comparison
or
trend
basis
[
personnel
communication
from
L.
Brunsman].
The
spontaneous
incidence
of
adenocarcinomas
was
listed
as
2%­
20%,
with
a
mean
of
8%.

Table
9.
Uterine
Tumor
Incidence
Tumor/
Dose
[
ppm]
0
25
250
2500
UTERUS
n=
adenocarcinoma,
malignant
endometrial
sarcoma,
malignant
squamous
cell
carcinoma,
malignant
48
500
50
500
50
501
50
921
c.
Non­
Neoplastic
Lesions
MALES
There
was
an
increased
incidence
of
hyperplasia
in
the
renal
pelvis
and
urinary
bladder
with
dose,
and
the
severity
of
the
lesion
was
also
increased
[
Table
10].
In
the
kidney,
round
cell
infiltration
was
increased
at
the
high­
dose
level
compared
to
the
control
and
lower
dose
levels.
Carcinogenicity
Peer
Review
of
Diuron
December
18,
1997
18
Table
10.
Non­
neoplastic
Lesions
in
the
Male
Rat
Lesion/
Dose
0
ppm
25
ppm
250
ppm
2500
ppm
Renal
Pelvis
#
examined
focal
hyperplasia/
epithelium
total
Grade
1
Grade
2
Grade
3
50
37
31
51
50
37
30
70
50
45
18
25
2
47
43
3
23
17
Urinary
Bladder
#
examined
urothelial
hyperplasia
total
Grade
1
Grade
2
Grade
3
50
13
11
20
50
5500
50
16
15
10
49
14
13
10
Kidney
#
examined
round
cell
infiltration
50
3
50
12
50
9
49
31
Spleen
#
examined
hyperemia/
blood
congestion
fibrosis
50
0
0
50
0
0
50
1
3
49
15
16
Thyroids
#
examined
C
cell
hyperplasia
50
29
48
27
50
37
49
39
Bone
Marrow
#
examined
activated
50
0
50
5
50
7
49
42
FEMALES
There
was
an
increased
incidence
of
hyperplasia
in
the
renal
pelvis
and
urinary
bladder
with
dose,
and
the
severity
of
the
lesion
was
also
increased
[
Table
11].
Glandular­
cystic
hyperplasia
was
increased
slightly
at
the
high­
dose
level,
and
the
high­
dose
displayed
increased
fibrosis
in
the
spleen.
Increased
incidences
of
lesions
also
occurred
in
the
liver,
thyroid,
and
bone
marrow.
Carcinogenicity
Peer
Review
of
Diuron
December
18,
1997
19
Table
11.
Non­
neoplastic
Lesions
in
the
Female
Rat
Lesion/
Dose
0
ppm
25
ppm
250
ppm
2500
ppm
Renal
Pelvis
#
examined
focal
hyperplasia/
epithelium
total
Grade
1
Grade
2
Grade
3
48
23
20
3
0
50
25
22
3
0
50
46
12
30
4
47
42
5
33
4
Urinary
Bladder
#
examined
urothelial
hyperplasia
total
Grade
1
Grade
2
Grade
3
48
11
10
10
49
7700
50
17
935
50
30
4
17
9
Kidney
#
examined
round
cell
infiltration
48
7
49
9
50
12
50
3
Uterus
#
examined
glandular­
cystic
hyperplasia
48
3
50
5
50
2
50
7
Spleen
#
examined
hemosiderin
storage
fibrosis
48
44
0
50
46
0
50
50
0
50
49
17
Liver
#
examined
fatty
degeneration
round
cell
infiltration
hyperemia
bile
duct
infiltration
vacuolar
degeneration
of
liver
cells
48
04
19
16
0
50
09
32
10
1
50
1
10
33
15
3
50
3
13
36
25
11
Thyroids
#
examined
C
cell
hyperplasia
47
17
49
23
50
30
48
28
Bone
Marrow
#
examined
activated
48
5
50
12
50
22
50
42
d.
Adequacy
of
Dosing
for
Assessment
of
Carcinogenicity
The
statistical
evaluation
of
mortality
indicated
no
significant
incremental
changes
with
increasing
doses
of
Diuron
in
either
male
or
female
rats.
The
HED
RfD
Committee
discussed
Diuron
at
the
9/
26/
96
meeting
and
concluded
that
the
rat
study
was
Acceptable
as
supplementary
data
due
to
deficiencies
with
respect
to
the
Carcinogenicity
Peer
Review
of
Diuron
December
18,
1997
20
examination
of
organs.
Specific
concern
was
expressed
that
the
mammary
gland
was
not
examined
in
the
rat
study,
given
the
fact
that
mammary
gland
tumors
were
observed
to
be
increased
in
the
mouse
study.
There
was
no
NOEL
determined
in
the
rat
study,
and
the
LOEL
was
considered
to
be
25
ppm,
the
lowest
dose
tested,
based
on
decreased
erythrocyte
count
in
females,
increased
hemosiderin
in
the
spleen,
increased
spleen
weight,
bone
marrow
activation,
increased
hematopoietic
marrow,
decreased
fat
marrow,
and
thickened
urinary
bladder
wall
in
males.
The
RfD
Committee
recommended
that
the
chronic
toxicity/
carcinogenicity
study
in
rats
be
repeated.
The
CPRC
concluded
that
the
dosing
in
the
rat
study
was
adequate
(
not
excessive)
for
assessing
the
carcinogenic
potential
of
Diuron
in
rats.

E.
Additional
Toxicology
Data
on
Diuron
1.
Metabolism
Reference:
Although
the
HED
Metabolism
Peer
Review
Committee
expressed
concern
about
the
lack
of
metabolism
data
for
Diuron
in
the
rat,
and
TB
II
informed
SRRD
that
the
Registrant
should
be
requested
to
submit
a
rat
metabolism
study
[
memo
dated
11/
18/
93],
no
study
was
located
in
the
files.

2.
Mutagenicity
References:
(
a)
Rickard,
L.
B.,
et
al.
[
1985].
Mutagenicity
Evaluation
of
Diuron
in
the
CHO/
HGPRT
Assay
MRID#
00146609;
Document
No.
005039]
(
b)
Sarrif,
A.
[
1985].
Assessment
of
Diuron
in
the
In
Vivo
Cytogenetic
Study
in
Rats
MRID#
00146611,
Document
No.
005039]
(
c)
Arce,
G.
T.
and
Sarrif,
A.
M.
[
1985].
Assessment
of
Diuron
in
the
In
Vitro
Unscheduled
DNA
Synthesis
Assay
in
Primary
Rat
Hepatocytes
MRID#
00146610;
Document
No.
005039]
(
d)
Arce,
G.
T.
[
1987]
Mutagenicity
Evaluation
(
of
Diuron)
in
Salmonella
typhimurium
MRID#
s
00146608
and
40228805;
Document
Nos.
005039
and
008751].

a.
CHO/
HGPRT
assay.
Negative.
Under
the
conditions
of
the
experiment,
Diuron
up
to
cytotoxic
levels
with
and
without
metabolic
activation
was
negative.

b.
In
vivo
cytogenetic
study
in
rats.
Positive
Under
the
conditions
of
the
assay,
Diuron
was
weakly
clastogenic
at
5000
mg/
kg,
the
highest
dose
tested
[
HDT].
Carcinogenicity
Peer
Review
of
Diuron
December
18,
1997
21
c.
In
vitro
unscheduled
DNA
synthesis
[
UDS]
assay.
Negative.
Under
the
conditions
of
the
assay,
doses
of
Diuron
up
to
20
mM
[
HDT]
were
negative,
but
the
RfD
Committee
recommended
reevaluation
of
the
study.

d.
Salmonella
typhimurium
reverse
gene
mutation
assay.
Negative.
Under
the
conditions
of
the
study,
the
results
were
negative.
Carcinogenicity
Peer
Review
of
Diuron
December
18,
1997
22
Figure
3
Linuron
3.
Structure­
Activity
Relationship
Diuron
is
a
substituted
urea
herbicide.
(
1)
Linuron
is
classified
a
Group
C
carcinogen
without
quantitation
[
hepatocellular
adenomas
in
female
CD­
1
mice
at
HDT
[
1500
ppm]
and
testicular
adenoma/
hyperplasia
in
male
Crl:
CD(
SD)
BR
Sprague­
Dawley
rats.
Linuron
was
negative
in
the
Ames
assay
at
dose
levels
up
to
5
g/
plate,
with
and
without
activation;
did
not
produce
gene
mutations
in
an
in
vitro
assay
using
CHO
cells
both
with
and
without
activation;
did
not
induce
bone
marrow
chromosome
aberrations
in
vivo;
did
not
induce
unscheduled
DNA
synthesis
in
rat
hepatocytes.
(
2)
Fluometuron
classified
a
Group
C
carcinogen
with
both
a
low­
dose
extrapolation
model
(
Q*
1)
applied
to
the
animal
data
[
lung
tumors
in
male
CD­
1
mice]
and
the
Reference
Dose
[
RfD]
approach
[
combined
adenomas/
carcinomas
of
the
lungs
in
male
mice
and
malignant
lymphocytic
lymphomas
in
female
mice
[
dose
levels
considered
inadequate­
too
low].
Fluometuron
did
not
induce
UDS
in
primary
rat
hepatocytes
at
dose
levels
that
were
sufficiently
high;
was
negative
for
inducing
micronuclei
at
a
toxic
dose
level;
and
was
negative
in
the
Ames
assay
when
tested
up
to
the
limit
dose
[
5000
µ
g/
plate].
(
3)
Monuron
has
not
been
reviewed
by
HED
CPRC.
Kidney
and
liver
tumors
have
been
reported
in
F344/
N
rats;
malignant
gastric
adenoma,
microcellular
cancer
of
lung,
seminoma
in
testes
in
rats
and
benign
hepatoma,
alveolocellular
cancer
and
cancer
of
the
kidney
have
been
reported
in
old
Russian
studies.
(
4)
Siduron
was
not
reviewed
by
CPRC
and
data
has
not
been
reviewed.
During
the
Phase
II
review,
mutagenicity
studies
were
identified
and
assessed
as
adequate
for
review,
and
a
2­
year
rat
study
was
to
be
submitted;
there
is
no
evidence
that
the
studies
were
forwarded
to
HED
for
review.
Carcinogenicity
Peer
Review
of
Diuron
December
18,
1997
23
Figure
4
Fluometuron
Figure
6
Siduron
Figure
5
Monuron
Carcinogenicity
Peer
Review
of
Diuron
December
18,
1997
24
F.
Weight
of
Evidence
Considerations
The
Committee
was
asked
to
consider
the
following
facts
regarding
the
toxicology
data
on
Diuron
in
the
Weight­
of­
the­
Evidence
determination
of
its
carcinogenic
potential:

1.
Male
and
female
NMRI
(
SPF
Han)
mice
were
fed
0,
25,
250,
or
2500
ppm
of
Diuron
for
104
weeks.
There
was
no
adverse
effect
on
survival
of
either
sex.
Neoplastic
findings
were
observed
only
at
the
high
dose
in
females
compared
with
the
controls.

Female
mice
had
a
significant
increasing
trend
in
mammary
gland
adenocarcinomas
at
p
<
0.05.
There
were
no
significant
differences
in
the
pair­
wise
comparisons
of
the
dosed
groups
with
the
controls.

The
incidence
of
this
tumor
appears
to
be
outside
the
testing
facility's
historical
control.

2.
Wistar
rats
were
fed
Diuron
at
dose
levels
of
0,
25
ppm
[
%
%
1.02/
&
&
1.69
mg/
kg/
day],
250
ppm
[
%
%
10.46/
&
&
16.88
mg/
kg/
day],
or
2500
ppm
[
%
%
111.17/
&
&
202.22
mg/
kg/
day].
There
was
no
adverse
effect
on
survival
of
either
sex.
Neoplastic
findings
were
observed
in
the
urinary
bladder
of
both
sexes
and
in
the
renal
pelvis
of
the
males
compared
with
the
controls.

Male
rats
had
significant
increasing
trends,
and
significant
differences
in
the
pair­
wise
comparisons
of
the
2500
ppm
dose
group
with
the
controls,
for
urinary
bladder
epithelial
carcinomas,
and
papillomas
and/
or
carcinomas
combined.
Male
rats
also
had
a
significant
increasing
trend
in
kidney
renal
pelvis
epithelial
papillomas
and/
or
carcinomas
combined.

Female
rats
had
significant
increasing
trends,
and
significant
differences
in
the
pair­
wise
comparisons
of
the
2500
ppm
dose
group
with
the
controls,
for
urinary
bladder
epithelial
carcinomas,
and
papillomas
and/
or
carcinomas
combined.

The
incidence
of
these
tumors
is
greater
than
the
historical
control
incidence.

3.
From
the
submitted
studies,
Diuron
was
very
weakly
positive
in
the
rat
in
vivo
cytogenetic
assay
at
5000
mg/
kg,
negative
in
the
CHO/
HGPRT
assay,
negative
in
the
in
vitro
UDS
assay
and
negative
Carcinogenicity
Peer
Review
of
Diuron
December
18,
1997
25
in
the
reverse
gene
mutation
assay
in
Salmonella
typhimurium.
There
is
little
identified
mutagenic
concern
with
respect
to
Diuron.

4.
Structure­
Activity.
Linuron
is
a
Group
C
carcinogen
without
quantitation
[
hepatocellular
adenomas
in
female
CD­
1
mice
at
HDT
[
1500
ppm]
and
testicular
adenoma/
hyperplasia
in
male
Crl:
CD(
SD)
BR
Sprague­
Dawley
rats.
Fluometuron
is
a
Group
C
carcinogen
with
both
a
low­
dose
extrapolation
model
(
Q*
1)
applied
to
the
animal
data
[
lung
tumors
in
male
CD­
1
mice]
and
the
Reference
Dose
[
RfD]
approach
[
combined
adenomas/
carcinomas
of
the
lungs
in
male
mice
and
malignant
lymphocytic
lymphomas
in
female
mice
[
dose
levels
considered
inadequate­
too
low].
Carcinogenicity
Peer
Review
of
Diuron
December
18,
1997
26
G.
Classification
of
Carcinogenic
Potential:

The
Peer
Review
Committee
considered
the
EPA
proposed
Guidelines
for
Carcinogenic
Risk
Assessment
(
April
10,
1996)
for
classifying
the
weight
of
evidence
for
Diuron.

In
accordance
with
these
proposed
Guidelines,
the
CPRC
unanimously
agreed
to
characterize
the
weight
of
the
evidence
for
Diuron
as
"
known/
likely"
to
be
carcinogenic
to
humans
by
all
routes
of
exposure
based
on:
the
robust
tumor
response
of
carcinomas
in
the
urinary
bladder
in
both
sexes
of
the
Wistar
rat;
kidney
carcinomas
(
a
rare
tumor)
in
the
male
Wistar
rat;
and
mammary
gland
carcinomas
in
the
female
NMRI
mouse.
There
is
no
known
data
on
human
exposure
to
Diuron.

Diuron
is
a
member
of
a
chemical
class
(
substituted
ureas)
of
which
Linuron,
Fluometuron
and
Monuron
have
demonstrated
carcinogenic
activity
at
various
sites
in
rodents.
Diuron
was
only
weakly
positive
in
an
in
vivo
cytogenicity
study,
which
was
considered
to
be
equivocal
and
other
submitted
mutagenicity
studies
were
either
negative
or
inadequate.

No
mechanistic
or
mode
of
action
data
were
presented
to
justify
the
quantification
of
human
risk
by
a
method
other
than
the
low­
dose
linear
extrapolation
default.
The
CPRC
recommended
that
for
the
purpose
of
risk
characterization,
a
low
dose
linear
extrapolation
model
be
applied
to
the
animal
data
for
the
quantification
of
human
risk,
based
on
the
urinary
bladder
carcinomas
in
the
male
rat.

The
CPRC
recommended
that
the
in
vivo
cytogenicity
study
be
repeated.
