1
UNITED
STATES
ENVIRONMENTAL
PROTECTION
AGENCY
WASHINGTON,
D.
C.
20460
OFFICE
OF
PREVENTION,
PESTICIDES
AND
TOXIC
SUBSTANCES
DATE:
October
10,
2001
MEMORANDUM
SUBJECT:
DIURON:
Cancer
Classification
and
Mechanism
of
Action
FROM:
Yung
G.
Yang,
Ph.
D.
Reregistration
Branch
2
Health
Effects
Division
(
7509C)

THROUGH:
Pauline
Wagner,
Branch
Chief
Reregistration
Branch
2
Health
Effects
Division
(
7509C)

TO:
Diana
Locke,
Ph.
D.,
Risk
Assessor
Reregistration
Branch
2
Health
Effects
Division
(
7509C)
And
Roberta
Farrell
/
Kathy
Monk
PM
52
Special
Review
and
Reregistration
Division
(
7508W)

DP
Barcode:
D278246
Submission:
S604292
Chemical:
Diuron
Case:
818790
PC
Code:
035505
CAS
No.:
330­
54­
1
Action:
Review
and
respond
to
Registrant's
submission
entitled
"
Cancer
Classification
and
Mechanism
of
Action"
(
MRID
45494501)
and
mutagenicity
studies
(
MRIDs
45494502­
05).

Response:
The
Reregistration
Branch
2
(
RRB2)
reviewed
the
submitted
data
and
presented
it
to
the
HED
Mechanism
of
Toxicity
Assessment
Review
Committee
(
MTARC).
A
pre­
screening
subgroup
of
the
MTARC
evaluated
the
proposed
mechanism
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.
After
consulting
with
the
Chair
of
the
Cancer
Assessment
Review
Committee
(
CARC),
the
RRB2
determined
that
there
is
insufficient
information
to
support
a
2
reclassification
of
cancer
category
for
diuron
at
this
time.
Diuron
3
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
1996,
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.

The
Registrant
argues
that
this
assessment
needs
reconsideration
for
the
following
reasons:
(
1)
There
is
no
history
of
human
carcinogenesis
as
the
result
of
diuron
exposure.
(
2)
There
is
a
plausible
mode
of
action
that
discounts
the
relevance
of
the
rat
bladder
carcinomas
to
humans.
(
3)
The
mouse
historical
data
was
not
considered
in
its
entirety
and
should
be
considered
`
spontaneous'.
(
4)
The
structure
activity
relationships
actually
decrease
the
weight­
of­
the­
evidence
of
diuron
carcinogenicity
rather
than
increase
the
weight,
and
(
5)
New
guidelines
are
in
place
that
separate
the
`
known'
from
`
likely'
category
(
extracted
from
pages
7­
8
of
Registrant's
submission,
MRID
45494501).
The
responses
of
the
RRB2
are
as
follows.

II.
The
Responses
of
RRB2
1.
There
is
no
history
of
human
carcinogenesis
as
the
result
of
diuron
exposure.

RRB2
Response:
The
Registrant
did
not
submit
any
data
or
information
to
support
its
claim;
in
addition,
it
cannot
be
used
to
rule
out
any
remote
possibility
of
human
carcinogenesis
as
the
result
of
diuron
exposure.

2.
There
is
a
plausible
mode
of
action
that
discounts
the
relevance
of
the
rat
bladder
carcinomas
to
humans.

RRB2
Response:
The
document
entitled
"
Diuron:
Cancer
Classification
and
mechanism
of
Action"
(
MRID
44302002,
resubmitted
as
MRID
45494501)
has
been
submitted
to
the
HED
MTARC
for
evaluation.
The
MTARC
concluded
that
the
submitted
information
is
insufficient
to
support
a
mode
of
action
on
bladder
carcinogenicity
for
diuron
based
on
the
following
reasons
(
extracted
from
the
HED
MTARC
Report):

(
1)
The
Registrant
claimed
that
a
mechanism
or
mode
of
action
document
has
been
submitted
to
the
Diuron
4
Agency
without
being
reviewed
by
the
CPRC.
The
pre­
screening
committee
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,
unpublished
data"
by
Schmidt
and
Karbe
(
1987)
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
pre­
screening
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)
The
CPRC
report
(
1997)
has
indicated
that
diuron
was
only
weakly
positive
(
considered
being
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
concern
on
mutagenic
activity
of
diuron.
Diuron
5
3.
The
mouse
historical
data
was
not
considered
in
its
entirety
and
should
be
considered
`
spontaneous'.

RRB2
Response:
The
mouse
historical
data
has
been
reviewed
and
included
in
the
updated
DER
(
MRIDs
42159501
and
43349301).
It
was
concluded
that
a
positive
oncogenic
response
was
seen
in
high­
dose
female
mice
compared
to
the
control
group.
The
following
conclusions
are
extracted
from
the
discussion
section
of
the
DER.

The
study
authors
presented
data
from
historic
controls
performed
from
1981
to
1988
using
mice
of
the
same
strain
from
the
same
source
that
showed
mammary
gland
adenocarcinoma
incidences
that
ranged
from
0%
to
13%
with
the
average
frequency
being
3.2%.
This
same
source
showed
ovarian
luteoma
frequencies
ranging
from
0%
to
7%
[
Bomhard,
E.
(
1992)
Historical
control
data
showing
the
frequency
of
tumors
in
NMRI­
mice
taken
from
18
long­
term
studies
over
21
months,
Bayer
Report
No.
21534].
An
additional
reference
provided
historic
control
data
collected
from
studies
done
from
1974
through
1981
[
Bomhard,
E.
and
Mohr,
U.
(
1989)
Spontaneous
tumors
in
NMRI
mice
from
carcinogenicity
studies.
Exp.
Pathol.
36:
129­
145].
In
the
latter
reference,
the
mammary
adenocarcinoma
average
incidence
was
3.9%
with
a
range
of
0%
to
10.8%
and
the
ovarian
granulosa
cell
tumor
average
frequency
was
19.1%
with
a
range
of
5.0%
to
35.5%.
Ovarian
luteomas
develop
from
granulosa
cells,
but
were
not
specifically
identified
in
the
reference.
Compared
to
the
historic
data,
the
mammary
adenocarcinoma
incidences
seen
in
the
control
group
in
the
current
study
agree
well,
but
the
incidences
in
the
high­
dose
group
are
at,
or
slightly
above,
the
upper
limit
of
that
seen
in
control
animals.
The
ovarian
luteoma
instances
seen
in
the
current
study
are
slightly
high
in
the
control
group
and
well
above
the
normal
range
at
2500
ppm
compared
to
the
historic
control
animals;
however,
the
luteoma
incidences
are
not
outside
the
upper
range
for
all
granulosa
cells
derived
tumors
according
to
the
historic
data.
The
statistical
significance
of
the
increased
incidences
in
this
study
depends
on
a
test
for
trend;
the
differences
are
not
statistically
significant
according
to
the
Fisher's
exact
test
performed
by
the
reviewer.
The
study
authors
concluded
that
the
increased
incidences
of
mammary
and
ovarian
neoplasms
in
high­
dose
female
mice
compared
to
the
control
group
were
not
treatment­
related.
This
conclusion
is
questionable
because
the
incidences
of
spontaneous
tumors
in
normal
control
populations
of
this
strain
of
mice
vary
considerably,
and
the
best
control
is
usually
thought
to
be
the
one
that
was
performed
during
the
current
study.
Under
the
conditions
of
this
study,
a
positive
oncogenic
response
was
seen
in
high­
dose
female
mice
compared
to
the
control
group.

4.
The
structure
activity
relationships
actually
decrease
the
weight­
of­
the­
evidence
of
diuron
carcinogenicity
rather
than
increase
the
weight.

RRB2
Response:
This
issue
has
been
reviewed
and
addressed
by
the
MTARC.
Please
see
above
RRB2
response
#
2.

5.
New
guidelines
are
in
place
that
separate
the
`
known'
from
`
likely'
category.
Diuron
6
RRB2
Response:
The
1999
Guidelines
for
Carcinogen
Risk
Assessment
is
a
preliminary
draft
and
should
not
be
used
as
a
justification
for
cancer
reclassification.
The
document
has
a
notice
in
the
front
page
stated
that
"
THIS
DOCUMENT
IS
A
PRELIMINARY
DRAFT.
It
has
not
been
formally
released
by
the
U.
S.
Environmental
protection
Agency
and
should
not
at
this
stage
be
construed
to
represent
Agency
policy."

Additional
information
6.
Mouse
bone
marrow
micronucleus
assays
(
MRIDs
45494502­
05).

RRB2
Response:
Preliminary
reviews
have
been
conducted
on
these
in
vivo
cytogenetic
mutagenicity
studies.
No
evidence
of
cytogenetic
effect
is
seen
in
mice
administered
either
technical
grade
or
formulated
diuron.
However,
these
studies
provide
little
additional
information
since
the
CARC
has
already
concluded
that
there
is
little
or
no
concern
on
mutagenic
activity
of
diuron.

III.
Conclusion
The
RRB2
evaluated
the
submitted
data
with
MTARC
report
and
concluded,
after
consulting
with
the
Chair
of
the
HED
CARC,
that
there
is
insufficient
information
to
support
a
reclassification
of
cancer
category
for
diuron
at
this
time.
Therefore,
the
cancer
classification
for
diuron
remains
the
same
as
"
known/
likely
human
carcinogen
with
a
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.
Diuron
7
SignOff
Date:
10/
10/
01
DP
Barcode:
D278246
HED
DOC
Number:
014696
Toxicology
Branch:
RRB2
