1
UNITED
STATES
ENVIRONMENTAL
PROTECTION
AGENCY
WASHINGTON,
D.
C.
20460
OFFICE
OF
PREVENTION,
PESTICIDES
AND
TOXIC
SUBSTANCES
DATE:
September
20,
2001
MEMORANDUM
SUBJECT:
Diuron
(
PC
Code
035505):
Assessment
of
Mode
of
Action
on
Bladder
Carcinogenicity
FROM:
Yung
G.
Yang,
Ph.
D.
Reregistration
Branch
2
Health
Effects
Division
(
7509C)

THRU:
Pauline
Wagner,
Co­
Chair
Mechanism
of
Toxicity
Assessment
Review
Committee
(
MTARC)
Health
Effects
Division
(
7509C)
and
Karl
Baetcke,
Co­
Chair
Mechanism
of
Toxicity
Assessment
Review
Committee
(
MTARC)
Health
Effects
Division
(
7509C)

TO:
William
Burnham,
Senior
Science
Advisor
Chairman,
Cancer
Assessment
Review
Committee
(
CARC)
Immediate
Office
Health
Effects
Division
(
7509C)

cc:
Anna
Lowit,
Executive
Secretary,
MTARC
Diana
Locke,
Risk
Assessor,
RRB
2
Action:
The
Registrant
submitted
a
document
entitled
"
Cancer
Classification
and
Mechanism
of
Action
of
Diuron"
and
asked
the
Agency
to
reevaluate
the
cancer
classification
of
diuron
based
on
a
proposed
mode
of
action
on
bladder
carcinogenicity.
The
MTARC
is
asked
to
review
and
determine
the
relevance
of
the
proposed
mode
of
action
on
bladder
carcinogenicity
for
diuron.

Conclusion:
A
pre­
screening
subgroup
of
the
MTARC
has
evaluated
the
proposed
mode
of
action
with
the
data
submitted
by
the
Registrant
and
concluded
that
the
submitted
information
is
insufficient
to
support
a
mode
of
action
on
bladder
carcinogenicity
for
diuron.
Diuron
2
I.
Background
Diuron
[
3­(
3,4­
dichlorophenyl)­
1,1­
dimethylurea]
is
a
substituted
urea
herbicide
for
the
control
of
a
wide
variety
of
annual
and
perennial
broadleaves
and
grassy
weeds
on
both
crop
and
noncrop
sites.
In
1997,
the
HED
Carcinogenicity
Peer
Review
Committee
(
CPRC)
has
classified
diuron
as
a
"
known/
likely"
human
carcinogen
by
all
routes,
based
on
urinary
bladder
carcinoma
in
both
sexes
of
the
Wistar
rat,
kidney
carcinomas
in
the
male
rat
(
a
rare
tumor),
and
mammary
gland
carcinomas
in
the
female
NMRI
mouse.
The
CPRC
also
recommended
a
low
dose
linear
extrapolation
model
with
Q1
*
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.

Empirical
formula:
C9H10Cl
2N2O
Molecular
weight:
233.1
CAS
Registry
No.:
330­
54­
1
PC
Code:
035505
NH
N
CH
3
CH3
O
Cl
Cl
II.
A
Proposed
Mode
of
Action
on
Bladder
Carcinogenicity
for
Diuron
The
Registrant
stated
that
the
tumorigenesis
of
diuron
does
not
represent
an
expression
of
primary
carcinogenic
potential
by
diuron
or
its
metabolites,
it
represents
a
concurrence
of
factors
such
as
a
high
dose,
dietary
influence,
metabolism
and
urinary
pH.
The
Registrant
proposed
several
basic
elements
to
support
this
mode
of
action.
The
first
is
the
etiology
of
the
lesion,
the
second
is
the
role
of
diet
and
pH
of
the
rat
urine,
the
third
is
the
actual
metabolism
of
diuron
and
the
fourth
is
the
nongenotoxicity
of
diuron.
Documents
submitted
by
the
Registrant
to
support
this
mode
of
action
are
as
follows.

(
1)
Diuron
Risk
Assessment:
Evaluation
of
Dietary
Exposure
(
MRID#
44302002).
Bogdanffy,
M.
S.,
1997.
Haskell
Lab.
No.
HL­
1997­
00613.
E.
I.
Du
Pont
de
Nemours
and
Company.
(
2)
Oral
Toxicity
and
Metabolism
of
Diuron
in
Rats
and
Dogs.
Hodge
et
al.,
1967.
Fd.
Cosmet.
Toxicol.
5:
513­
531.
(
3)
Study
for
Toxicity
to
Wistar
Rats
with
Special
Attention
to
Urothelial
Alterations
(
Administration
in
Diet
for
2,
4,
12,
and
26
Weeks
with
Recovery).
Schmidt
and
Karbe,
1987.
unpublished
data.
(
4)
Risk
Assessment
Based
on
High­
Dose
Animal
Exposure
Experiments.
Cohen
and
Ellwen,
1992.
Chem.
Res.
Toxicol.
5:
742­
748.
(
5)
Induction
of
Hyperplasia
in
the
Bladder
Epithelium
of
Rats
by
a
Dietary
Excess
of
Acid
or
Base:
Diuron
3
Implications
for
Toxicity/
Carcinogenicity
Testing.
Groot
et
al.,
1988.
Fd.
Chem.
Toxicol.
5:
425­
434.
(
6)
Lack
of
Bladder
Tumor
Promoting
Activity
in
Rats
Fed
Sodium
Saccharin
in
AIN­
76A
Diet.
Okamura
et
al.,
1991.
Cancer
Research
51:
1778­
1782.
(
7)
Mitogenic
Effects
of
Propoxur
on
Male
Rat
Bladder
Urothelium.
Cohen
et
al.,
1994.
Carcinogenesis
15:
2593­
2597.
(
8)
Rapid
Induction
of
Hyperplasia
in
Vitro
in
Rat
Bladder
Explants
by
Elevated
Sodium
Ion
Concentrations
and
Alkaline
pH.
Storer
et
al.,
1996.
Toxicol.
Appl.
Pharm.
138:
219­
230.
(
9)
Tributyl
Phosphate
Effects
on
Urine
and
Bladder
Epithelium
in
Male
Sprague­
Dawley
Rats.
Arnold
et
al.,
1997.
Fund.
Appl.
Toxicol.
40:
247­
255.
(
10)
Species­
Specific
Mechanisms
of
Carcinogenesis.
Swenberg
et
al.
(
Eds.),
1992.
Mechanism
of
Carcinogenesis
in
Risk
Identification.
pp.
477­
500.
(
11)
Tumors
of
the
Kidney,
Renal
Pelvis
and
Ureter.
Hard,
G.
C.
(
source
not
provided).
(
12)
Influence
of
Food
Restriction
and
Body
Fat
on
Life
Span
and
Tumor
Incidence
in
Female
Outbred
Han:
NMRI
Mice
and
Two
Sublines.
Rehm
et
al.,
1985.
Z.
Versuchtierk
27:
249­
283.
(
13)
The
Interpretation
of
Equivocal
or
Marginal
Animal
Carcinogenicity
Tests.
Squire,
R.
A.
1989.
Cell
Biol.
Toxicol.
5:
371­
376.
(
14)
Micronucleus
Induction
by
Diuron
in
Mouse
Bone
Marrow.
Agrawal
et
al.
1996.
Toxicol.
Lett.
89:
1­
4.
(
15)
Diuron:
Micronucleus
Test
on
the
Mouse
to
Evaluate
for
Mutagenic
Effect.
Herbold,
B.
1983.
Report
No.
11915,
Bayer
AG,
Inst.
of
Toxicology.
(
16)
Diuron:
Micronucleus
Test
on
the
Mouse.
Herbold,
B.
1998.
Report
no.
PH­
27204.
Bayer
AG
Toxicology.
(
17)
Mouse
Bone
Marrow
Micronucleus
Assay
of
DPX­
14740­
194
(
Karmex
®
DF).
Biegel,
L.
B.
1995.
Haskell
Lab
No.
682­
95.
E.
I.
Du
pont
de
Nemours
and
Company.
(
18)
Mouse
Bone
Marrow
Micronucleus
Assay
of
DPX­
14740­
200
(
Karmex
®
500
SC).
Biegel,
L.
B.
1995.
Haskell
Lab
No.
683­
95.
E.
I.
Du
pont
de
Nemours
and
Company.
(
19)
Mouse
Bone
Marrow
Micronucleus
Assay
of
DPX­
14740­
205
(
Karmex
®
800
WP).
Cox
L.
R.
1996.
Haskell
Lab
No.
688­
95.
E.
I.
Du
pont
de
Nemours
and
Company.

III.
MTARC
Response
A
pre­
screening
MTARC
(
Karl
Baetcke,
Mike
Ioannou,
Anna
Lowit,
Pauline
Wagner,
and
Yung
Yang)
reviewed
the
available
information
and
concluded
that
the
submitted
information
is
insufficient
to
support
a
mode
of
action
on
bladder
carcinogenicity
for
diuron
based
on
the
following
reasons:

(
1)
The
Registrant
claimed
that
a
mechanism
or
mode
of
action
document
(
MRID#
44302002)
has
been
submitted
to
the
Agency
without
being
reviewed
by
the
CPRC.
The
pre­
screening
committee
Diuron
4
reviewed
the
document
and
found
that
the
document
is
only
a
report
of
an
analysis
using
two
models
(
quantal
polynomial
multistage
and
Weibull
models)
to
evaluate
carcinogenic
risk
to
human
of
dietary
exposure
to
diuron.
This
study
was
not
designed
to
nor
was
it
intended
to
address
a
mode
of
action
on
bladder
carcinogenicity
of
diuron.

(
2)
A
study
entitled
"
Study
for
toxicity
to
Wistar
rats
with
special
attention
to
urothelial
alterations
by
Schmidt
and
Karbe
(
1987),
unpublished
data"
indicated
that
male
Wistar
rats
were
fed
diuron
in
their
diet
at
a
concentration
of
2500
ppm
for
2,
4,
12,
or
26
weeks.
Recovery
groups
were
similarly
treated
for
4
or
26
weeks
and
then
observed
for
4­
8
weeks.
Histopathological
examination
of
urinary
bladders
revealed
a
treatment­
related
increased
incidence
of
hyperplasia
of
the
epithelium
and
an
increase
in
the
degree
of
hyperplasia
from
a
treatment
duration
of
four
weeks
onwards.
Examination
of
animals
in
the
recovery
groups
revealed
a
clear
trend
toward
reversibility
of
the
induced
alterations
after
cessation
of
treatment.
The
pre­
screening
committee
concluded
that
this
study
suggested
a
reversibility
of
possible
precancerosis
but
did
not
present
or
propose
a
mode
of
action
on
bladder
carcinogenicity
for
diuron.

(
3)
The
Registrant
submitted
published
literature
in
an
attempt
to
address
the
role
of
diet
and
pH
of
the
rat
urine
for
supporting
the
mode
of
action
on
bladder
carcinogenicity
of
diuron.
The
prescreening
committee
reviewed
these
literature
reports
and
determined
that
these
reports
were
either
non­
diuron
specific
or
irrelevant
to
diuron.
The
Registrant
did
not
provide
direct
evidence
to
support
a
mode
of
action
on
dietary
influence
and
high
pH
value
as
the
mechanism
on
bladder
carcinogenicity
for
diuron.

(
4)
The
Registrant
cited
a
rat
metabolism
study
on
diuron
(
HED
Doc.
No.
012408)
and
stated
that
there
are
no
common
mechanisms
among
diuron,
linuron,
and
propanil
with
regard
to
cancer
endpoints.
No
further
information
was
presented.
The
pre­
screening
committee
determined
that
the
Registrant
did
not
demonstrate
a
relevance
of
the
metabolism
of
diuron
to
mode
of
action
on
bladder
carcinogenicity.

(
5)
In
1997,
the
CPRC
report
has
indicated
that
diuron
was
only
weakly
positive
(
considered
to
be
equivocal)
in
an
in
vitro
cytogenetic
study.
The
Registrant
submitted
several
reports
on
mouse
bone
marrow
micronucleus
study
to
show
that
diuron
is
non­
genotoxic.
The
pre­
screening
committee
referred
its
decision
to
latest
HIARC
Report
on
mutagenicity
(
HED
Doc.
No.
014657,
dated
August
28,
2001).
The
HIARC
report
stated
that
"
diuron
was
not
mutagenic
in
bacteria
or
in
cultured
mammalian
cells
and
no
indication
of
DNA
damage
in
primary
rat
hepatocytes
was
observed.
There
was
weak
evidence
of
an
in
vivo
clastogenic
response
in
Sprague
Dawley
rats
in
one
study
and
statistically
significant
increases
in
cells
with
structural
aberrations
in
a
second
study
conducted
with
the
same
rat
strain.
The
data
from
the
latter
study,
however,
were
shown
to
fall
within
the
historical
control
range."
The
pre­
screening
committee
concurred
with
the
Registrant
that
there
is
little
or
no
Diuron
5
concern
on
mutagenic
activity
of
diuron.

IV.
MTARC
Conclusion
The
pre­
screening
MTARC
concluded
that
the
submitted
information
is
insufficient
to
support
the
proposed
mode
of
action
on
bladder
carcinogenicity
for
diuron
at
this
time.
