Document ID: EPA-HQ-OPP-2002-0249-0024
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2002-10-01T04:00Z

March
13,
2002
MEMORANDUM:
Response
to
Comment
Document
­
Phase
2
DIURON:
The
HED
Chapter
of
the
Reregistration
Eligibility
Decision
PC
Code
(
035505).
Case
0046.
DP
Barcode
D281396
FROM:
Carol
Christensen,
Risk
Assessor
Reregistration
Branch
II
Health
Effects
Division
(
7509C)

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

TO:
Richard
Dumas
Team
Leader
Reregistration
Branch
II
Special
Review
and
Reregistration
Division
(
7508W)

The
attached
document
was
generated
in
response
to
the
comments
received
from
the
Diuron
registrant
Griffin
Chemical
on
February
12th,
2002.
This
document
was
generated
as
part
of
Phase
2
(
error­
only)
of
the
Interim
Public
Participation
Process.
The
comments
pertain
to
the
3­(
3,4­
dichlorophenyl)­
1,1­
dimethylurea
(
diuron)
RED
document
dated
December
13,
2002.
HED
has
acknowledged
these
comments
in
the
Response
to
Comment
document
as
well
as
in
an
updated
version
of
the
HED
Chapter
of
the
Diuron
RED
document
and
the
Diuron
Toxicology
Chapter.
The
responses
documented
here
reflect
the
Agency's
current
guidelines
and
policies
concerning
risk
assessment.
This
document
and
updated
HED
chapters
includes
replies
from
John
Punzi
on
residue
chemistry
and
dietary
risk
assessment,
Yung
Yang
concerning
toxicology
comments,
and
occupational
and
residential
exposure
responses
from
Renee
Sandvig
and
Christina
Jarvis,
as
well
as
risk
assessment
and
characterization
corrections
by
Carol
Christensen.

The
Environmental
Fate
and
Effects
Division
(
EFED)
revised
the
drinking
water
exposure
assessment
based
upon
Registrant
comments.
The
new
memorandum
entitled
"
Drinking
Water
Reassessment
for
Diuron
and
its
Degradates"
dated
March
11,
2002
has
been
incorporated
into
the
Revised
HED
Chapter
of
the
Reregistration
Eligibility
Decision
Document
(
RED)
as
appropriate.
Specific
comments
pertaining
to
the
Drinking
Water
Exposure
Assessment
for
Diuron
and
its
Degradates
2
are
completed
under
a
separate
memo.

HED's
Response
to
Registrant's
Phase
1
Error­
Only
Comments
I.
Toxicology
Disciplinary
Chapter
Page
4.
1.0
Hazard
Characterization:
Para
1,
Line
3.

However,
a
new
28­
day
inhalation
toxicity
study
has
been
required
to
provide
better
hazard
characterization.

Registrant's
Comment:
Although
inhalation
studies
are
preferred
for
the
assessment
of
inhalation
hazard,
there
is
no
triggering
for
a
28­
day
inhalation
as
outlined
in
the
40CFR
regulation.
The
acute
inhalation
study
shows
no
inhalation
toxicity.
The
limit
test
showed
no
inhalation
toxicity.
There
is
no
volatility
of
the
diuron
either
as
a
solid
formulation
or
as
a
liquid
formulation.
The
use
pattern
does
not
suggest
a
particular
inhalation
risk
to
mixers
or
applicators.
No
use
exceeds
the
short­
term
inhalation
designation
of
1­
30
days.
Based
on
the
regulations,
there
must
be
a
mistake
in
this
requirement.
It
was
not
triggered.

HED's
Response:
This
is
a
policy
issue
and
will
be
addressed
in
the
phase
4
period.

Page
4.
1.0
Hazard
Characterization:
Para
3,
Line
5.

Consistent
observations
of
erythrocyte
regeneration
are
seen
in
chronic
toxicity
studies
in
rats,
mice
and
dogs.

Registrant's
Comment:
This
implies
incorrectly
that
the
mice
and
dogs
responded
in
a
similar
manner.
The
dose
that
resulted
in
similar
effects
was
at
substantially
higher
dosages
of
diuron.
The
phrase
should
be
added
for
correctness,
"
 
chronic
toxicity
studies
in
rats,
mice
and
dogs
but
at
significantly
higher
dosages
of
diuron
than
seen
in
the
rat
chronic
study."

HED's
Response:
Hematological
effects
have
been
consistently
observed
in
the
rat,
dog,
and
mouse
chronic
toxicity
studies.
No
change
is
necessary.

Page
4.
1.0
Hazard
Characterization:
Para
6,
Line
2.

Classified
as
"
known/
likely"
human
carcinogen
by
all
routes,
based
on
urinary
bladder .

Registrant's
Comment:
Data
is
only
for
the
oral
route.
No
studies
were
done
to
demonstrate
that
tumors
resulted
by
other
routes.
The
mechanism
of
action
of
diuron
is
specific
for
the
oral
route.
Because
the
studies
using
other
routes
of
exposure
have
not
been
done,
other
routes
cannot
be
excluded
at
this
time.
However,
for
correctness
the
phase
"
by
oral
route
only"
needs
to
be
added
to
the
end
of
the
sentence.
It
should
read,
" 
in
the
female
NMRI
mouse
by
oral
routes
only."

HED's
Response:
The
sentence
is
revised
to
"
Classified
as
"
known/
likely"
human
carcinogen
based
on
urinary
bladder
......"

Page
5.
1.0
Hazard
Characterization:
Para
1
(
cont.),
Line
1.

There
is
no
additional
information
to
justify
a
reclassification
of
the
cancer
classification
for
diuron
at
this
time.
3
Registrant's
Comment:
This
statement
was
made
based
on
a
review
of
the
mechanistic
white
paper
that
the
MTARC
concluded
the
"
information
was
insufficient
to
support
a
mode
of
action
on
bladder
carcinogenicity."
However,
one
of
the
reasons
that
diuron
was
considered
as
a
`
known'
carcinogen
was
based
on
potential
genotoxicity.
Rereview
of
the
mouse
bone
marrow
chromosomal
aberration
study
changed
the
conclusion
of
the
study
from
positive
to
negative
based
on
a
review
of
the
historical
background
data
from
the
performing
laboratory.
This
was
the
only
positive
genotoxicity
result,
but
it
carried
much
weight
in
the
deliberation
of
the
cancer
classification
of
diuron.
The
change
in
the
classification
of
diuron
as
a
mutagen
to
a
non­
mutagen
is,
in
fact,
new
information
that
was
not
considered.
The
last
sentence
either
needs
to
be
deleted
or
should
simply
state
"
Diuron
will
not
be
reclassified
at
this
time."

HED's
Response:
The
sentence
is
revised
to
"
Diuron
will
not
be
re­
classified
at
this
time."

Page
6.
Requirement
870.3465:
90­
day
Inhalation.

The
HIARC
determined
that
a
28­
day
inhalation
toxicity
is
required.

Registrant's
Comment:
According
to
Section
158.340
of
the
40CFR,
a
90­
day
inhalation­
rat
study
is
conditionally
required.
Footnote
6
of
the
Toxicology
Data
Requirements
states,
"
Required
if
use
may
result
in
repeated
inhalation
exposure
at
a
concentration
likely
to
be
toxic.
A
test
with
duration
21
days
is
required
if
the
pesticide
is
used
on
tobacco."

The
following
agricultural
use
parameters
were
presented
at
the
SMART
meeting
held
on
May
3,
2001.

Table
1.
Diuron
Agricultural
Use
Parameters
Agricultural
Acreage
Treated
Per
Applicator
Unit
Application
Max
Acres/
Day
Max
Acre­
Apps/
Year
(
Season)

On­
Farm
Non­
Specialized
Ground
150
3000
On­
Farm
Specialized
Ground
800
6000
Custom
Ground
800
12000
Custom
Aerial
1200
30000
Even
in
the
worst
case
represented
by
aerial
application,
the
maximum
acre
application
per
year
averages
to
only
25
days
of
application.
Diuron
is
a
pre­
emergent
herbicide.
There
is
a
small
window
between
when
the
crop
is
planted
and
when
the
seed
emerges
in
which
the
field
is
treated
to
kill
weeds
that
emerge
before
the
crop.
The
Occupational
and
Residential
Exposure
Assessment
assumes
10
days
of
exposure
for
a
private
farmer
and
30
days
of
exposure
for
a
commercial
applicator
in
a
few
large
acreage
crops.
Therefore,
no
use
exceeds
the
short­
term
inhalation
designation
of
1­
30
days.
Diuron
is
not
a
volatile
chemical
either
as
a
TGAI
or
as
a
TEP.
Given
the
physical
characteristics
of
the
TEPs,
there
should
be
no
respirable
particles
generated
in
the
mixing,
loading
and
application
of
the
product.

Secondly,
based
on
the
inhalation
data
from
the
acute
study,
there
is
no
reason
to
believe
that
the
concentration
of
diuron
in
the
spray
mix
is
likely
to
be
toxic.
The
LD50
in
this
study
was
7.1
mg/
L.
There
is
no
trigger
to
require
this
study
for
this
type
of
product.
Therefore,
the
requirement
for
a
28­
day
inhalation
study
on
diuron
must
be
in
error.
4
HED's
Response:
This
is
a
policy
issue
and
will
be
addressed
in
the
phase
4
period.

Page
7.
4.2
Subchronic
Toxicity:
Para
1,
Line
3.

Registrant's
Comment:
The
28­
day
inhalation
study
requirement
should
be
conditional
according
to
the
40CFR.
Diuron
does
not
meet
the
triggers
for
such
a
study.
See
discussion
above.

HED's
Response:
This
is
a
policy
issue
and
will
be
addressed
in
the
phase
4
period.

Page
8.
Requirement
870.3100:
90­
Day
Oral
Toxicity
 
Rat,
Para
3.
General
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).

Registrant's
Comment:
Although
the
high­
dose
females
show
increased
reticulocyte
counts,
all
except
for
the
3­
month
interval
are
within
the
control
values
for
the
study.
The
female
control
values
range
from
12
 
17.
Historically
in
the
conducting
laboratory,
the
1985
results
show
control
animals
to
range
between
0­
34
in
reticulocyte
counts
(
attached).
The
values
of
28
at
the
3­
month
interval
of
the
25
ppm
dosed
females
and
the
value
of
18
at
the
6­
month
interval
of
the
25
ppm
dosed
females
are
well
within
the
expected
values
observed
in
the
performing
laboratory
during
the
time
period
in
which
the
study
was
conducted.

Thus,
despite
statistical
significance,
there
is
little
biological
significance
to
the
increase
in
reticulocyte
counts
at
the
25
ppm
dose
level
in
the
female
rats.
The
same
is
true
of
the
nonstatistically
increased
(<
5%)
hemoglobin
concentration.
By
discussing
the
statistical
significance
apart
from
the
biological
significance,
it
would
appear
that
the
effects
as
delineated
by
the
statement
in
paragraph
3
have
relevance
to
the
assessment.

HED's
Response:
The
hematological
effects
are
consistently
observed
in
other
studies
and
are
considered
biologically
significant.
No
change
is
necessary.

Page
8.
Requirement
870.3100:
90­
Day
Oral
Toxicity
 
Rat,
Para
4,
5.
General
Increased
incidences
of
gross
lesions
on
the
urinary
bladder .

Microscopic
examination
and
morphometric
measurements
of
the
urinary
bladder
...
.

Registrant's
Comment:
The
discussion
in
these
two
paragraphs
misrepresents
the
conclusions
of
the
study
authors.
The
effects
as
described
were
noted
in
the
treated
groups
and
not
in
the
controls.
However,
a
closer
examination
of
the
incidences
in
both
males
and
females
demonstrate
little
dose
response
relationship.
On
page
15
of
the
study
report
the
authors
state:

"
The
following
alterations
were
noted
at
autopsy
at
the
end
of
study.
Part
of
the
animals'
urinary
bladder
walls
exhibited
dilation
of
blood
vessels,
increased
consistency
before
filling
with
the
fixative
or
reduced
transparency
after
filling
with
fixative.
These
findings
were
mostly
noted
only
in
the
treated
animals,
more
frequently
in
the
females
than
the
males."

Microscopic
examinations
were
also
made.
It
was
determined
that
2
low
dose
females
and
1
high
dose
female
showed
focal
hyperplasia.
The
degree
of
severity
was
1
(
slight)
5
on
a
scale
of
1
to
5.
One
low
dose
male
and
1
control
female
and
1
high
dose
female
showed
simple
hyperplasia
again
scored
as
1
or
slight
on
the
severity
scale.
One
low
dose
female
displayed
simple
hyperplasia
with
some
vascularization;
the
added
vascularization
pushed
the
severity
score
to
2
or
slight
to
moderate.
Two
low
dose
males
and
1
high
dose
male
showed
a
thickening
of
the
epithelial
cells
but
involved
less
than
three
cell
layers;
severity
score
of
1
or
slight.
There
is
no
dose
response
and
the
severity
of
the
lesions
are
slight
in
all
cases.
The
microscopic
observations
did
not
correlate
with
the
gross
findings.

On
the
basis
of
these
conflicting
qualitative
observations,
the
authors
decide
to
make
quantitative
measurements
of
the
bladder
wall
thickness.
They
measured
only
females
because
there
were
no
effects
that
differed
from
the
controls
in
the
males.
They
state
in
the
methods
section
on
page
7
of
the
report:

Gross
findings
made
in
particular
in
treated
females
indicated
possible
thickening
of
the
urinary
bladder
walls.
For
this
reason
the
thickness
of
all
the
females'
bladder
walls
was
quantitatively
measured
with
an
automatic
Omnicon
screen
unit
(
Bausch
&
Lomb
Co.).
Equally
long
paramedian
areas
of
the
two
wall
portions
of
each
bladder
half
were
measured,
that
is
four
measurements
per
animal.
The
area
contained
a
wall
portion
including
epithelium
and
peritoneal
tissue."

The
results
were
clear.
There
was
no
thickening
of
the
bladder
walls.
This
can
be
seen
in
Table
2
below
as
taken
from
the
study
report
on
page
17.

Table
2.
Females'
relative
bladder
wall
areas.
Mean
figures
per
group
on
measurement
of
4
area
portions
of
some
length
per
animal
(
area
=
paramedian
bladder
wall
section).

Dose
(
ppm)
0
4
10
25
Mean
437
492
448
486
Std
Deviation
58
80
50
51
Based
on
the
wide
variation
and
absence
of
dose
response
relationship,
no
differences
were
assessed
to
these
findings.
The
authors
conclude
on
page
17
of
the
study
report:

The
gross
findings
obtained
for
the
urinary
bladders
(
see
Section
5.7)
did
not
correlate
with
the
histopathological
results.
In
an
attempt
to
obtain
correlation
for
the
reduced
transparency
and
increased
consistency
of
the
bladder
walls,
automatic
measurements
of
the
bladder
wall
thickness
were
made.
The
results
of
these
measurements
are
compiled
in
Table
5
(
given
here
as
Table
2).
In
consideration
of
the
wide
variation
and
absence
of
dose
correlation,
no
major
differences
were
noted
between
the
figures
in
any
of
the
groups.
No
importance
is
therefore
attached
to
the
gross
findings.

These
observations
are
NOT
EQUIVOCAL.
There
are
no
effects
that
can
be
attributed
to
any
dose
level,
let
alone
the
low
dose
of
4
ppm.
The
NOEL
for
this
study
can
be
defined
by
the
blood
effects
for
which
the
study
was
designed.

HED's
Response:
This
nonguideline
study
was
conducted
in
1988
and
reviewed
by
the
HED
in
1990.
The
scope
of
the
study
was
primarily
restricted
to
parameters
associated
6
with
effects
on
erythrocytes.
However,
the
study
did
not
evaluate
the
status
of
the
bone
marrow.
Gross
macroscopic
observations
revealed
an
increase
of
urinary
bladder
incidences
related
to
blood
vessel
dilation,
and
reduced
transparency
and
increased
firmness
in
all
treated
groups
as
compared
to
the
control.
Quantitative
evaluation
of
the
urinary
bladder
wall
revealed
a
slight
increase
of
urinary
wall
thickening
in
all
treated
females
as
compared
to
the
controls.
Males
were
not
evaluated
in
this
study.
In
a
chronic
toxicity
study
(
MRID
40886501)
(
dose
levels
of
0,
25,
250,
or
2500
ppm),
a
treatment­
related
urinary
bladder
thickening
was
observed
in
the
25
ppm
males.
The
HED
reviewer
concluded
that
a
NOAEL
could
not
be
determined
because
many
parameters
were
not
evaluated
in
this
study.
No
change
is
necessary.

Page
8.
Requirement
870.3100:
90­
Day
Oral
Toxicity
 
Rat,
Para
3,
Line
2.
Specific
Mean
hemoglobin
concentrations
in
the
high­
dose
females
were
slightly
(
n.
s.)
depressed
at
all
intervals
as
compared
to
the
controls
(
within
5%
of
the
control
levels).

Registrant's
Comment:
This
sentence
either
needs
to
be
deleted
or
it
needs
to
be
made
clear
that
this
is
not
an
effect
as
there
is
neither
biological
nor
statistical
significance
in
this
finding.

HED's
Response:
By
the
weight
of
evidence,
these
hematological
effects
are
considered
biologically
significant.
No
change
is
necessary.

Page
8.
Requirement
870.3100:
90­
Day
Oral
Toxicity
 
Rat,
Para
5,
Line
2.
Specific
Hyperplasia
of
the
epithelium
was
observed
in
1
low
dose
male,
1
control
female,
2
low
dose
females
and
2
high
dose
females.

Registrant's
Comment:
When
the
focal
hyperplasia
is
separate
from
the
totals
as
given
in
the
EPA
document,
there
is
clearly
no
statistically
significant
hyperplasia
at
any
dose
level.
Focal
hyperplasia
is
given
as
2
females
at
the
low
and
1
female
at
the
high
dose.
Control
and
high
dose
females
(
one
each)
demonstrate
simple
hyperplasia
(
nonfocal
Secondly,
the
degree
of
hyperplasia
is
given
as
the
lowest
scored.
Severity
is
not
discussed.
It
needs
to
be
as
it
impacts
the
`
equivocal'
judgment
of
the
effect.

The
dose
response
needs
to
be
addressed.
The
lack
of
a
dose
correlation
is
omitted.
It
too
impacts
the
`
equivocal'
judgment
of
the
effect.

Also
omitted
is
the
lack
of
correlation
between
the
gross
examination
results
and
the
histopathological
results.
It
was
this
discordance
that
prompted
the
quantitative
measurements
of
the
female
bladders.

These
are
all
errors
of
omission
that
impact
the
assessment
of
the
effect.

HED's
Response:
See
above
HED's
response.

Page
8.
Requirement
870.3100:
90­
Day
Oral
Toxicity
 
Rat,
Para
5,
Line
7
(
last).

These
observations
are
judged
to
be
equivocal.

Registrant's
Comment:
The
effects
are
not
equivocal;
there
are
no
effects.
No
dose
response
was
observed,
no
thickening
of
the
bladder
as
demonstrated
by
either
quantitative
measurement
or
a
correlation
between
gross
observation
and
microscopic
observation.
This
constitutes
a
negative
effect
and
not
`
equivocal'.
7
The
results
of
the
2­
year
chronic
oncogenicity
study
in
rats
are
also
in
conflict
with
this
assessment.
The
females
displayed
bladder
carcinoma
only
at
the
high
dose
of
2500
ppm
in
contrast
to
the
males,
which
showed
effects
at
lower
dosages
of
diuron.
The
EPA
document
states
that
focal
hyperplasia
was
observed
in
the
female
only
at
the
mid
(
250
ppm)
and
high
(
2500
ppm)
dose
groups
at
12
and/
or
24
months.
There
were
effects
in
the
females
at
the
250
ppm
dosage,
but
only
at
24
months
and
not
at
12
months.
No
effects
at
the
25
ppm
dosage
in
the
females
were
seen
after
either
12
or
24
months
of
exposure.
These
results
should
cast
some
interpretative
light
on
the
nature
of
the
`
equivocal'
effects
in
the
6­
month
study.

HED's
Response:
See
above
HED's
response.

Page
8.
Requirement
870.3100:
90­
Day
Oral
Toxicity
 
Rat,
Para
7,
Line
1.

The
NOEL
cannot
be
determined
because
some
findings
were
judged
to
be
equivocal.

A
NOEL
is
not
defined
by
this
study.
No
effects
were
biologically
relevant
including
the
reticulocyte
count.
The
study
authors
give
10
ppm
as
the
NOEL
without
an
evaluation
of
the
historical
blood
values.

HED's
Response:
See
above
HED's
response.

Page
9.
Requirement
870.3100:
90­
Day
Oral
Toxicity
 
Rat,
General
Registrant
Comment:
A
study
has
been
omitted
from
this
discussion.
It
is
the
"
Study
for
Toxicity
to
Wistar
Rats
with
Special
Attention
to
Urothelial
Alterations
(
Administration
in
Diet
for
2,4,12,
and
26
Weeks
with
Recovery)."
(
Reviewed
in
response
to
MRID
45494501).

Its
significance
is
that
it
allows
the
bladder
effects
that
EPA
judged
to
be
`
equivocal'
to
be
placed
into
perspective.

In
this
study,
male
Wistar
rats
were
administered
diuron
in
their
diet
at
a
concentration
of
2500
ppm
for
2,
4,
12,
or
26
weeks.
Further
animals
were
similarly
treated
for
4
or
26
weeks,
and
then
observed
for
4
or
8
weeks
(
recovery).
One
control
group
(
each
of
10
animals)
was
used
per
treatment
group
(
each
of
10
animals).

Histopathological
examination
of
the
urinary
bladders
revealed
a
treatment­
related
increased
incidence
of
hyperplasia
of
the
epithelium,
and
an
increase
in
the
degree
of
hyperplasia
from
treatment
duration
of
four
weeks
onwards.
Hyperplasia
with
exo­
and
endophytic
growth
(
within
4
weeks)
and
marked
squamous
epithelial
metaplasia
(
after
26
weeks)
were
found.
Morphometric
measurements
detected
in
addition
an
increase
in
the
sub­
epithelial
urinary
bladder
tissue
(
already
apparent
after
treatment
fro
two
weeks).
Examination
of
the
animals
in
the
recovery
groups
revealed
a
clear
trend
towards
reversibility
of
the
induced
alterations
after
cessation
of
treatment.

Bladder
thickening
is
measured
and
given
in
Table
3
below.
The
highest
value
of
492
seen
in
the
blood
study
documented
above
is
well
within
the
normal
values
as
shown
in
this
study
(
noting
differences
between
sexes).
Thickening
of
the
bladder
is
readily
observed
and
exceeds
the
error
as
expressed
by
the
standard
deviations.
This
is
quite
different
than
the
rather
small
changes
seen
in
the
blood
effect
study
above
for
which
no
dose
effect
exceeded
the
standard
deviations.

Table
3.
Areas
of
equally
long
wall
regions
from
paramedian
sections
of
the
urinary
bladder
8
(
relative
units,
mean
and
standard
deviation,
also
number
of
animals
examined
per
group).

Study
Length
Control
Groups
2500
ppm
Diuron
Weeks
Mean
Std
Dev
n
Mean
Std
Dev
n
2
418
45
10
510
110
10
4
439
94
9
635
123
9
8*
521
84
9
565
89
9
12
590
92
10
847
99
9
26
307
110
10
778
115
7
34**
580
90
8
716
84
4
*
4
weeks
diuron,
4
weeks
recovery
**
26
weeks
diuron,
8
weeks
recovery
This
study
is
important
in
that
it
demonstrates
a
marked
trend
towards
reversibility
and
should
be
included
with
the
similar
study
that
focuses
on
the
blood
effects.

HED
Response:
This
study
was
submitted
as
part
of
the
document
entitled
"
Cancer
Classification
and
Mechanism
of
Action
of
Diuron
(
MRID
45494501)"
for
a
proposed
mode
of
action
on
bladder
carcinogenicity.
The
HED's
Mechanism
of
Toxicity
Assessment
Committee
(
MTAC)
reviewed
the
study
and
concluded
that
this
study
suggested
a
reversibility
of
possible
precancerosis
but
did
not
present
or
propose
a
mode
of
action
for
assessment
of
mode
of
action
on
bladder
carcinogenicity
on
diuron.
No
change
necessary.

Page
9.
Requirement
870.3465:
90­
Day
Inhalation
 
Rat
The
HIARC
determined
that
a
28­
day
inhalation
study
is
required
to
address
the
concern
for
inhalation
exposure
potential
based
on
use
pattern.

Registrant
Comment:
There
is
no
need
for
a
28­
day
inhalation
study
based
either
on
the
use
pattern
or
the
inhalation
toxicity.
See
discussion
relating
to
this
issue
above.

HED
Response:
This
is
a
policy
issue
and
will
be
addressed
in
the
phase
4
period.

Page
9.
Requirement
870.3200:
21­
Day
Dermal
­
Rabbit,
Para
1,
Line
4.

Body
weight,
good
consumption,
clinical
signs .

Registrant
Comment:
Typographical
error:
`
Good'
consumption
should
be
`
food'.

HED
Response:
Changed
to
"
food".

Page
10.
Requirement
870.3700a:
Prenatal
Developmental
Toxicity
Study
 
Rat,
Para
3.
General
Registrant
Comment:
Paragraph
3
general
comment
on
omission.
Weight
of
both
males
and
females
rebounded
to
nearly
normal
in
all
dose
groups
after
removal
of
diuron
treatment.
This
should
be
noted.
9
HED
Response:
This
observation
confirmed
a
finding
that
the
body
weight
decrease
is
treatmentrelated
No
change
is
necessary.

Page
11.
Requirement
870.3700a:
Prenatal
Developmental
Toxicity
Study
 
Rat,
Para
2,
Line
2.

 
Skeletal
malformations/
variations
was
288
(
22),
305(
23),
 

Registrant
Comment:
Typographical
error:
`
305'
should
be
`
306'.

HED
Response:
Changed
to
"
306".

Page
13.
Requirement
870.3800:
Reproduction
and
Fertility
Effects
 
Rat,
Para
1,
Line
2.

Test
substance
intake
for
the
treated .

Registrant
Comment:
Test
substance
intake
should
read
`
Overall
test
substance
intake'.
The
dosing
reflects
the
entire
dosing
period.

HED
Response:
The
intakes
of
test
substance
are
estimated
for
F0
and
F1
parental
animals
respectively
by
the
reviewer.
No
change
is
necessary.

Page
13.
Requirement
870.3800:
Reproduction
and
Fertility
Effects
 
Rat,
Para
3,
Line
8.

Significant
reductions
in
food
consumption
were
observed .

Registrant
Comment:
This
is
in
error.
There
was
not
a
significant
difference
in
the
7­
14
day
interval
for
the
females.

HED
Response:
The
sentence
stated
that
"
.....
occasional
significant
differences
from
control
....
were
considered
incidental
to
treatment."
No
change
is
necessary.

Page
14.
Requirement
870.4300:
Combined
Chronic
Toxicity/
Carcinogenicity
 
Rat,
Para
1,
Line
5.

..
dietary
concentrations
of
0,
1.7,
17,
or
202
mg/
kg/
day 

Registrant
Comment:
Typographical
error:
Should
read
`
203
mg/
kg/
day'

HED
Response:
Changed
to
"
203."

Page
14.
Requirement
870.4300:
Combined
Chronic
Toxicity/
Carcinogenicity
 
Rat,
Para
2,
Line
2.

The
only
treatment
related
clinical
sign
was
reddish
discolored
or
bloody
urine
in
high­
dose
males.

Registrant
Comment:
This
implies
that
all
high­
dose
males
demonstrated
this
adverse
effect.
The
sentence
should
read,
" 
some
high­
dose
males".

HED
Response:
Changed
to
"
some
high­
dose
males".

Page
15.
Requirement
870.4300:
Combined
Chronic
Toxicity/
Carcinogenicity
 
Rat,
Para
2,
Line
2.
10
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...
.

Registrant's
Comment:
The
effects
first
outlined
are
for
the
24­
month
interval.
This
needs
to
be
noted.
Also,
in
line
5
of
the
same
sentence
the
parenthetical
phrase
that
states
(<
25%
change
for
most
parameters;
3­
fold
increase
for
reticulocytes)
applies
only
to
the
high­
dose
males
and
females.
The
mid­
dose
animals
do
not
show
this
degree
of
change.
The
low­
dose
females
show
a
very
small
increase
of
33%
in
the
erythrocyte
count
and
no
real
change
in
the
other
parameters.
(
Historical
control
data
from
the
conducting
laboratory
during
a
similar
time
period,
show
that
control
animals
can
have
the
same
33%
increase.
See
attached
historical
data.)

For
accuracy,
the
second
sentence
should
read,
"
Erythrocyte
damage
resulted
in
 .
in
mid
and
/
or
high­
dose
males
and
females,
and
in
low­
dose
females.
In
the
high­
dose
groups
there
was
<
25%
change
for
most
parameters
with
a
3­
fold
increase
for
reticulocytes.
For
the
low­
dose
females,
only
an
increase
of
33%
was
observed
in
erythrocyte
count
and
no
real
change
in
the
other
parameters."

HED's
Response:
The
DER
indicated
that
significant
hematological
effects
were
observed
in
the
mid­
and
high­
dose
males
and
females
as
early
as
6
months.
No
change
is
necessary.

Page
15.
Requirement
870.4300:
Combined
Chronic
Toxicity/
Carcinogenicity
 
Rat,
Para
3,
Line
2.

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<
0.05)
or
0.01)
in
high­
dose
males
at
12
months
and
in
mid
and
high­
dose
females
at
12
and/
or
24
months.

Registrant's
Comment:
The
mid­
dose
females
showed
an
increased
incidence
only
at
24
months.
The
sentence
should
read:

`
Microscopic
evaluation
showed
that
epithelial
focal
hyperplasia
of
the
urinary
tract
and
renal
pelvis
increased
in
severity
in
both
sexes
at
12
and/
or
24
months,
and
increased
in
incidence
(
p<
0.01)
in
high­
dose
males
at
12
months
and
in
high­
dose
females
at
12
and/
or
24
months
with
mid­
dose
females
showing
an
increased
incidence
at
24
months.'

HED's
Response:
Changed
as
Registrant's
comment.

Page
17.
4.6
Carcinogenicity:
Para
3.

There
is
no
additional
information
to
justify
a
re­
classification
of
the
cancer
classification
for
diuron
at
this
time.

Registrant's
comment:
The
change
in
classification
of
mutagenic
to
non­
mutagenic
is
enough
information
to
re­
classify
the
chemical
from
known/
likely
to
likely.
It
should
be
enough
to
just
indicate
that
diuron
will
not
be
re­
classified
until
the
new
guidelines
are
finalized.

HED'
Response:
The
sentence
is
revised
to
"
Diuron
will
not
be
re­
classified
at
this
time."

Page
19.
Requirement
870.4200b:
Carcinogenicity
(
feeding)
­
Mouse,
Para
3,
Line
1.

 
and
ovarian
luteomas
(
control,
6%;
2500
ppm,
14%)
in
female .
11
Registrant,'
Comment:
The
reference
to
luteomas
should
be
deleted.
The
CPRC
made
the
decision
(
May
8,
1997)
that
the
effect
was
inconsequential.
Combined
sex­
cord
stromal
tumors
are
a
better
reflection
of
the
system
than
`
luteomas'.
There
is
no
statistical
difference
between
control
and
treated
groups
for
ovarian
combined
sex
cord
stromal
tumors.

HED'
Response:
Additional
wording
is
added
to
the
document
to
address
this
issue.
"
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
cord­
stromal
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
cord­
stromal
tumors."

Page
19.
4.7
Mutagenicity:
Para
1,
Line
5.

 
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.

There
is
only
one
study
for
the
rat
bone
marrow
chromosomal
aberration
assay.
It
is
HLR
366­
85.
It
was
assigned
the
MRID
00146611.
This
study
was
revised
in
1995
to
include
the
historical
aberration
frequencies
that
changed
the
assessment
of
the
results.
The
revised
report
bears
the
same
laboratory
designation
HLR
366­
85
but
was
assigned
a
new
MRID
of
44350301.
All
references
to
the
first
study
designated
by
MRID
00146611
can
be
deleted.

The
reference
to
a
second
study
showing
statistically
significant
increases
in
structural
aberrations
was
only
at
the
48­
hour
post­
treatment
interval.
Nothing
was
observed
at
either
6
or
24
hours.

Suggested
wording:
"
There
were
marginal
statistically
significant
increases
in
cells
with
structural
aberrations
in
a
Sprague
Dawley
rat
in
vivo
bone
marrow
chromosomal
aberration
assay.
However,
the
levels
of
aberrations
were
within
the
historical
control
range
and
assessed
negative."

Note
the
type
in
the
word
evidence
in
the
last
sentence
of
the
paragraph.

Typographical
error:
The
word
`
does'
should
be
changed
to
`
dose.'

HED's
Response:
(
1)
Changed
to
"
dose".
(
2)
Deleted
the
study
(
MRID
00146611)
and
revised
wording
as
comment.

Page
20.
Requirement
870.5385:
Cytogenetics
­
Middle
Row
in
Table.

Registrant's
Comment:
Guideline
870.5385
..
MRID
#
00146611.
This
study
is
identical
to
the
one
above
and
should
be
deleted.

HED's
Response:
Deleted
the
study
(
MRID
00146611)
from
the
table.

Page
22.
5.3.1
Conclusions:
Line
1
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.

Registrant's
Comment:
The
way
this
sentence
is
phrased,
it
implies
that
the
incidences
of
kidney
carcinomas
were
also
significant.
There
was
no
statistical
significance
attached
to
the
incidences
of
renal
pelvis
tumors.
Reference
should
either
be
deleted
or
the
lack
of
statistical
significance
for
this
tumor
should
be
referenced.
12
HED's
Response:
This
is
the
conclusion
of
the
HED's
Carcinogenicity
Peer
Review
Committee
(
HED
Doc.
No.
012224).
No
change
is
necessary.

Page
28.
9.1.2
Subchronic,
Chronic
and
Other
Toxicity
Tables:
870.3100
Results
The
NOEL
cannot
be
determined
based
on
equivocal
findings
in
the
urinary
bladder
including
blood
vessel
dilation,
reduced
transparency,
and
increased
firmness.

Registrant's
Comment:
A
NOEL
can
be
established.
In
the
discussion
of
this
study
above,
there
was
more
than
adequate
evidence
that
the
gross
observations
did
not
match
either
the
histopathology
or
the
measurement
of
bladder
thickness.
The
pathologist
dismissed
the
gross
findings
as
not
relevant
to
the
assessment.
The
NOEL
should
be
set
based
on
the
blood
effects.

The
doses
should
read
"
0,
0.3,
0.8,
1.8",
not
"
0,
0,
0.3,
0.8,
1.8."

HED's
Response:
(
1)
See
above
HED's
response
on
the
NOAEL
issue.
(
2)
Corrected
the
doses
as
comment.

Page
29.
9.1.2
Subchronic,
Chronic
and
Other
Toxicity
Tables:
870.5100
Results
TA100
up
to
the
highest
does
tested 

Registrant's
Comment:
Typographical
error:
The
word
`
does'
should
be
changed
to
`
dose.'

HED's
Response:
Changed
to
"
dose".

Page
30.
9.1.2
Subchronic,
Chronic
and
Other
Toxicity
Tables:
870.5375
Results
Registrant's
Comment:
The
description
of
results
is
quite
long
and
inconsistent
with
the
brevity
of
the
rest
of
the
Table.
Would
suggest
deleting
much
of
the
material
and
matching
it
in
content
with
the
other
mutagenicity
experiments.

HED's
Response:
Revised
as
comment.

Page
31.
9.1.2
Subchronic,
Chronic
and
Other
Toxicity
Tables:
870.5375
Results
Registrant's
Comment:
This
first
item
on
page
31
of
the
Table
can
be
deleted.
The
study
was
revised
and
the
results
are
reflected
in
MRID#
44350301
on
the
last
page.

HED
Response:
Deleted
the
study
(
MRID
00146611).

II.
HED
Chapter
Page
1.
First
Para,
Line
15.

Application
rates
range
from
0.8
lbs
active
ingredient
(
ai)/
acre
for
corn
to
87.1
lbs
ai/
acre
for
non­
crop
areas.

Registrant's
Comment:
The
rate
of
87.1
lbs
ai/
acre
is
exaggerated.
We
can
find
no
label
to
back
these
claims.

HED's
Response:
Registration
769­
638
includes
a
label
rate
of
10
lbs
per
1000
ft2.
The
label
is
for
Granular
Dy­
Kil­
20
and
is
intended
for
use
in
irrigation
and
drainage
ditches.
It
is
manufactured
by
Southern
Mill
Creek
Product
Company.
Using
a
standard
conversion
of
43,560
ft2
per
acre
and
including
a
20%
a.
i.
concentration
from
the
end­
use
label
the
resulting
application
rate
is
87.12
lbs
13
a.
i.
per
acre.
No
change
necessary.

Page
29.
Last
Para,
Line
7.

Registrant's
Comment:
The
word
"
mile"
should
be
"
mile2".
Also,
this
use
rate
(>
1379
lb
ai/
mile2/
yr)
is
not
possible,
both
in
this
document
and
in
the
Drinking
Water
Assessment
from
which
it
is
quoted.
This
rate
is
equivalent
to
2.15
lb
ai/
acre,
a
rate
that
is
obtainable
as
an
average
only
if
every
acre
in
the
area
was
planted
to
cotton
and
100%
of
those
acres
received
the
maximum
annual
diuron
rate
for
clay
soils,
a
treatment
program
that
would
also
require
all
the
acres
to
receive
2
treatments
each
year.
In
the
subject
area,
soils
are
primarily
sandy
loam,
the
percentage
of
the
crop
treated
averages
about
50%
and
only
about
30%
of
the
acres
received
two
treatments.
These
parameters
would
produce
a
maximum
use
rate
of
1.2
lb
ai/
treated
acre/
yr
or
827.4
lb
ai/
mile
2/
yr
for
the
whole
area
if
it
were
100%
planted
to
cotton
and
50%
was
treated.

HED's
Response:
The
Environmental
Fate
and
Effects
Division
will
respond
to
this
comment
under
separate
cover
memo.

III.
Chronic
Dietary
Exposure
Assessment
Page
2.
Table,
Last
row,
2nd
column.

Registrant's
Comment:
The
Q1
*
should
be
"
1.91",
not
"
1.191."

HED's
Response:
This
typographical
error
is
noted.
It
is
also
noted
that
the
correct
value
was
included
in
the
dietary
exposure
and
risk
assessment,
1.91.

IV.
Drinking
Water
Assessment
Registrant's
Comment:
The
Agency
used
the
PRZM/
EXAMS
model
that
has
never
been
adequately
validated.
Nevertheless,
the
model
can
produce
results
that
predict
residue
levels
in
surface
water
reasonably
well
if
used
properly.
The
results
produced
by
this
model
are
very
sensitive
to
the
input
parameters
that
drive
the
computations.
When
inappropriate
input
parameters
are
selected,
as
is
the
case
in
this
assessment,
the
model
grossly
overestimates
residues
moving
into
surface
water.
Consequently,
the
results
from
the
model
are
incorrect
and
misrepresents
the
diuron
residues
likely
to
occur
in
drinking
water.
Some
of
the
incorrect
input
parameters
are
discussed
below.
A
more
thorough
assessment,
including
results
of
the
PRZM/
EXAMS
model
using
the
appropriate
input
parameters,
will
be
filed
during
the
public
comment
period.
Some
examples
of
inappropriate
input
parameters
EPA
used
in
the
model
are:

1.
The
Agency
chose
to
model
drinking
reservoirs
in
Osceola
County,
FL,
an
area
in
which
there
are
no
large
drinking
reservoirs.

2.
The
wrong
soil
type
was
used
for
the
area
being
modeled.
The
soil
in
the
Osceola
County,
FL,
area
is
loamy
sand
which
has
a
good
recharge
capacity.
In
their
use
of
the
model,
the
Agency
used
high
clay
soil
which
has
high
runoff
rates
and
little
recharge
capacity.

3.
The
Agency
assumed
that
all
of
the
chemical
was
deposited
on
the
top
of
the
soil.
Diuron
has
measurable,
but
limited
mobility
in
soil.
Changes
to
the
model
that
assume
the
chemical
applied
resides
in
the
top
4
cm
produce
runoff
estimates
10
to
40
fold
lower
than
the
levels
produced
when
the
chemical
is
assumed
to
reside
on
the
surface.

The
Agency
has
acknowledged
that
the
results
obtained
from
the
PRZM/
EXAMS
model
are
from
9
to
100
times
higher
than
the
data
obtained
from
the
various
monitoring
programs,
including
the
14
monitoring
data
from
the
US
Geological
Survey
(
USGS)
National
Water
Quality
Assessment
Program
(
NAWQA)
.
It
appears
that
the
large
difference
between
the
modeling
results
and
the
results
of
the
USGS
program
have
contributed
to
the
Agency's
concern
as
to
whether
the
USGS
data
are
reasonably
representative
of
residue
levels
of
diuron
in
surface
waters.
EPA
has
expressed
this
concern
in
spite
of
the
fact
that
the
USGS
results
come
from
over
1400
samples
from
62
streams
over
a
7­
year
period.
Griffin
fully
expects
that
when
appropriate
input
parameters
are
used,
the
PRZM/
EXAMS
model
will
produce
results
that
will
give
the
Agency
more
confidence
in
the
monitoring
data
from
the
US
Geological
Survey
(
USGS)
National
Water
Quality
Assessment
Program
(
NAWQA).

The
Agency
has
included
in
its
Drinking
Water
Assessment
the
results
of
a
monitoring
study
performed
in
the
playa
lakes
of
the
high
plains
of
western
Texas.
In
characterizing
the
results
of
this
study,
the
Agency
failed
to
recognize
that
the
playa
lakes
are
temporary
bodies
of
water
with
no
natural
outlets.
Water
from
these
"
lakes"
either
evaporates
or
infiltrates
into
the
soil.
The
area
that
becomes
a
playa
lake
may
be
planted
to
cotton
or
another
crop
in
a
previous
year
or
even
early
in
the
same
year
in
which
runoff
due
to
large
rainfall
events
create
the
playa
lake.
Consequently,
pesticide
residues
in
these
temporary
water
bodies
may
result,
not
only
from
surface
water
runoff
from
adjacent
fields
but
from
direct
application
to
the
area
of
the
lake
before
flooding
occurred.
Water
bodies
such
as
the
playa
lakes
are
never
used
as
sources
of
drinking
water.
Residue
levels
from
such
water
bodies,
while
of
academic
interest,
have
no
bearing
on
the
levels
of
pesticides
in
drinking
water.

In
their
lack
of
an
outlet
and
their
water
source
being
runoff
from
a
rather
large
area
of
heavily
cropped
land,
the
playa
lakes
bear
some
similarity
to
the
Index
Reservoir
scenario
EPA
utilized
in
its
use
of
the
PRZM/
EXAMS
model.
The
huge
differences
between
the
results
of
the
model
and
the
playa
lakes
results
should
have
led
the
Agency
to
re­
examine
the
input
parameters
it
used
in
the
model.

In
its
discussion
of
the
playa
lakes
study,
EPA
stated
that
diuron
usage
in
the
area
of
Texas
that
includes
the
playa
lakes
"
reached
and
average
of
>
1379
lb
ai/
mile
2/
yr.".
This
use
rate
is
simply
not
possible.
This
rate
is
equivalent
to
2.15
lb
ai/
acre,
a
rate
that
is
obtainable
as
an
average
only
if
every
acre
in
the
area
was
planted
to
cotton
and
100%
of
those
acres
received
the
maximum
annual
diuron
rate
for
clay
soils,
a
treatment
program
that
would
also
require
all
the
acres
to
receive
2
treatments
each
year.
In
the
subject
area,
soils
are
primarily
sandy
loam,
the
percentage
of
the
crop
treated
averages
about
50%,
and
only
about
30%
of
the
acres
receive
two
treatments.
These
parameters
would
produce
an
maximum
use
rate
of
1.2
lb
ai/
treated
acre/
yr
or
827.4
lb
ai/
mile
2/
yr
for
the
whole
area
if
it
were
100%
planted
to
cotton
and
50%
was
treated.

The
Agency
stated
that
there
is
no
aerobic
and
anaerobic
aquatic
studies
available;
however,
DuPont
has
submitted
both
studies,
MRID
#
s
42260501
and
42661901.
The
Agency
assumed
a
one
year
half­
life
in
water
which
is
contradictory
to
page
8,
paragraph
3
of
the
Diuron
Metabolism
Committee
Briefing
Memo
which
agrees
with
our
studies
estimating
a
half­
life
of
33
days
in
water
and
1.2
days
in
sediment.

The
Agency
used
a
soil
half­
life
of
372
days
and
our
data
show
half­
lives
ranging
from
20
to
372
days.
MRID
#
s
41709305,
44654001,
44738001
and
44865001.
The
choice
of
the
most
extreme
half­
life
is
just
not
a
conservative
choice
as
the
Agency
claims
but
is
a
worst­
case
choice
and
is
not
representative
of
major
diuron
use
areas.

HED's
Response:
The
Environmental
Fate
and
Effects
Division
will
respond
to
this
comment
under
separate
cover
memo.

Page
43.

Registrant's
Comment:
The
references
are
misnumbered,
appear
to
be
incomplete
and
may
be
15
misplaced.

HED's
Response:
No
error
noted.

V.
Report
of
the
HIARC
Page
16.
First
Para,
Line
5.

Registrant's
Comment:
The
value
"
0.8"
should
be
"
0.88."

HED's
Response:
This
typographical
error
is
noted.
However,
no
change
is
necessary
in
the
revised
HED
chapter.

VI.
RED,
Residue
Chemistry
Considerations
Registrant's
Comment:
The
Table
of
Contents
is
not
numbered
correctly.

HED's
Response:
The
error
will
be
corrected
in
the
next
version
of
the
Residue
Chemistry
Chapter.

Registrant's
Comment:
Studies
have
been
submitted
for
the
following
crops:
alfalfa
­
MRID
#
45508703;
lemons
­
MRID
#
45509702;
wheat
­
MRID
#
45509703;
and
alfalfa
­
MRID
#
45509704.

HED's
Response:
The
study
identified
as
MRID
45508703
is
not
a
submission
from
the
registrant
that
concerns
diuron
or
alfalfa
in
any
matter
related
to
this
assessment.
We
acknowledge
that
lemon­
MRID
45509702;
wheat­
MRID
45509703;
and
alfalfa­
MRID
45509704
were
inadvertently
not
included
in
the
Chemistry
Chapter
and
are
currently
in
the
Agency's
review
process.
HED
notes
the
MRID
numbers
quoted
by
the
registrant
for
wheat
and
alfalfa
are
incorrect.
The
correct
MRID
for
the
wheat
study
is
45509704
and
the
correct
MRID
for
the
alfalfa
study
is
45509703.

Registrant's
Comment:
Portions
of
the
residue
data
used
by
EPA
in
the
memorandum
entitled
Chronic
Dietary
Exposure
Assessment
differs
from
those
data
submitted
and
cited
in
the
Residue
Chemistry
Chapter,
but
apparently
were
not
used.
Below
is
a
summary
of
the
residue
data
in
which
we
differ
from
EPA,
along
with
an
explanation
for
that
difference,
MRID
numbers
and
references.
These
errors
lead
to
a
drastically
overstated
dietary
risk,
particularly
in
those
processed
commodities
where
the
Agency
has
ignored
the
available
data.
The
Agency
has
defaulted
to
their
percent
crop
treated
even
though
accurate
crop
treat
data
were
presented
by
Griffin
LLC.

HED's
Response:
The
residue
data
that
was
used
for
the
input
to
the
chronic
dietary
assessment
was
taken
from
field
trial
data
submitted
by
the
registrant
to
support
tolerances.
As
is
the
case
for
apple,
banana,
berries,
grapefruit,
grapes,
lemons,
limes,
oranges,
pineapples,
and
wheat
processed
commodities,
there
exists
more
than
one
field
trial
study.
If
the
application
rates
and
PHI's
are
appropriate
to
the
current
labeling
and
the
study
adheres
to
current
Agency
guidelines
for
geographic
distribution
and
analytical
methodology,
any
study
could
be
used
to
develop
the
residue
value(
s)
for
the
exposure
computation.

With
the
exception
of
wheat
and
berries,
the
residue
values
are
essentially
non­
detectable
and
the
difference
between
the
studies
are
essentially
in
the
limits
of
detection
of
the
method.
The
studies
referred
to
by
the
registrants
will
be
examined
to
determination
if
the
processing
factors
reported
16
therein
are
more
appropriate
than
those
presently
used.

It
is
presently
HED
policy
to
use
the
percent
crop
treated
data
provided
by
BEAD.

Registrant's
Comment:
MRID
#
43434301
­
Apples
=
0.007
ppm
=
Mean
of
Field
Trial
data
(
All
samples
were
less
than
LOD
(
0.0145
ppm)
so
½
LOD
was
used)
Residue
Factor
of
2.
In
a
processing
study,
all
residues
in
pomace
and
juice
were
less
than
0.013
at
a
3X
treatment
rate.

Food
Name
Anticipated
Residues
from
Residue
Studies
Anticipated
Residues
from
EPA
Adj
#
1
Adj
#
1
EPA
Adj
#
2
Adj
#
2
EPA
Concentration
Factor
%
Crop
Treated
Apples
0.007
0.016
1
1
0.11
0.13
Apples
Dried
0.007
0.016
8
8
0.11
0.13
Apples
Juice
0.007
0.016
1
1.3
0.11
0.13
Apple
Juice
Conc
0.007
0.016
3
3.9
0.11
0.13
HED's
Response:
The
percent
of
crop
treated
are
weighted
averages
provided
by
the
Biological
and
Economic
Analysis
Division
(
BEAD)
in
a
Quantitative
Usage
Analysis
issued
3­
20­
01
and
supplemented
for
miscellaneous
usage
sites
on
04­
27­
2001.

Registrant's
Comment:
MRID
#
44583001
­
Bananas
=
0.005
ppm
=
Mean
of
Field
Trial
data.
All
values
were
less
than
LOQ,
but
were
reported
as
actual
values.
The
two
reported
values
above
LOQ
(
i.
e.
0.005
ppm)
were
used
while
the
values
reported
below
0.005
ppm
were
replaced
with
0.005
ppm.
This
led
to
a
mean
value
of
0.005
ppm.

Food
Name
Anticipated
Residues
from
Residue
Studies
Anticipated
Residues
from
EPA
Adj
#
1
Adj
#
1
EPA
Adj
#
2
Adj
#
2
EPA
Concentration
Factor
%
Crop
Treated
Bananas
0.005
0.025
1
1
0.05
0.14
Bananas
Dried
0.005
0.025
3.9
3.9
0.05
0.14
Bananas
Juice
0.005
0.025
1
1
0.05
0.14
HED's
Response:
The
percent
of
crop
treated
are
weighted
averages
provided
by
the
Biological
and
Economic
Analysis
Division
(
BEAD)
in
a
Quantitative
Usage
Analysis
issued
3­
20­
01
and
supplemented
for
miscellaneous
usage
sites
on
04­
27­
2001.

Registrant's
Comment:
MRID
#
44797701
­
Blackberries
=
0.02
ppm
=
Mean
of
Field
Trial
data.
The
LOQ
was
0.04
ppm
and
all
values
were
reported
as
either
0
or
0.017
ppm.
We
used
½
LOQ
(
i.
e.
0.02
ppm)
for
all
the
samples,
which
gives
an
average
residue
of
0.02
ppm.
MRID
#
44544101
­
Blueberries
=
0.02
ppm
=
Mean
of
Field
Trial
data.
The
LOQ
was
0.04
ppm
and
all
values
were
reported
as
zero,
therefore
½
LOQ
was
used.
Boysenberries,
Currants,
Dewberries,
Huckleberries
and
Loganberries
=
0.02
ppm
=
Mean
of
field
trial
data.
Value
taken
from
blackberry/
blueberry
study.

Food
Name
Anticipated
Residues
from
Residue
Studies
Anticipated
Residues
from
EPA
Adj
#
1
Adj
#
1
EPA
Adj
#
2
Adj
#
2
EPA
Concentration
Factor
%
Crop
Treated
Blackberries
0.02
0.1
1
1
0.53
0.53
17
Blackberries
Juice
0.02
0.1
1
1
0.53
0.53
Blueberries
0.02
0.1
1
1
0.29
0.29
Boysenberries
0.02
0.1
1
1
0.53
0.07
Currants
0.02
0.1
1
1
0.29
0.31
Dewberries
0.02
0.1
1
1
0.53
0.53
Huckleberries
0.02
0.1
1
1
0.29
0.29
Loganberries
0.02
0.1
1
1
0.53
0.33
HED's
Response:
The
percent
of
crop
treated
are
weighted
averages
provided
by
the
Biological
and
Economic
Analysis
Division
(
BEAD)
in
a
Quantitative
Usage
Analysis
issued
3­
20­
01
and
supplemented
for
miscellaneous
usage
sites
on
04­
27­
2001.

Registrant's
Comment:
MRID
#
43339201
­
Grapefruit
=
0.006
ppm
=
All
Field
Trial
values
are
less
than
LOD
of
0.0110
ppm,
therefore
½
of
the
LOD
was
used.
A
processed
commodity
study
accepted
by
the
Agency
which
demonstrated
no
concentration
in
juice
was
ignored.

Food
Name
Anticipated
Residues
from
Residue
Studies
Anticipated
Residues
from
EPA
Adj
#
1
Adj
#
1
EPA
Adj
#
2
Adj
#
2
EPA
Concentration
Factor
%
Crop
Treated
Grapefruit
Juice
0.006
0.012
1
2.1
0.36
0.47
Grapefruit
Juice
Concentrate
0.006
0.012
1
8.26
0.36
0.47
Grapefruit
Peeled
Fruit
0.006
0.012
1
1
0.36
0.47
HED's
Response:
The
percent
of
crop
treated
are
weighted
averages
provided
by
the
Biological
and
Economic
Analysis
Division
(
BEAD)
in
a
Quantitative
Usage
Analysis
issued
3­
20­
01
and
supplemented
for
miscellaneous
usage
sites
on
04­
27­
2001.

Registrant's
Comment:
MRID
#
43421501
­
Grapes
=
0.008
ppm.
All
Field
Trial
values
are
less
than
the
LOD
of
0.0160
ppm,
therefore
½
LOD
was
used.
A
processing
study
which
demonstrates
no
concentration
in
raisins
has
been
ignored.

Food
Name
Anticipated
Residues
from
Residue
Studies
Anticipated
Residues
from
EPA
Adj
#
1
Adj
#
1
EPA
Adj
#
2
Adj
#
2
EPA
Concentration
Factor
%
Crop
Treated
Grapes
0.008
0.021
1
1
0.1
0.1
Grapes
Juice
0.008
0.021
1
1.2
0.1
0.1
Grapes
Juice
Concentrate
0.008
0.021
1
3.6
0.1
0.1
Grapes
Leaves
0.008
0.021
1
1
0.1
0.1
Grapes
Raisins
0.008
0.021
1
4.3
0.1
0.1
Grapes
Wine
0.008
0.021
1
1
0.1
0.1
HED's
Response:
The
percent
of
crop
treated
are
weighted
averages
provided
by
the
18
Biological
and
Economic
Analysis
Division
(
BEAD)
in
a
Quantitative
Usage
Analysis
issued
3­
20­
01
and
supplemented
for
miscellaneous
usage
sites
on
04­
27­
2001.

Registrant's
Comment:
MRID
#
45509702
­
Lemons
=
0.09
ppm
=
Mean
of
Field
Trial
data.
Four
of
6
samples
were
less
than
LOQ,
so
½
LOQ
(
i.
e.
0.005
ppm)
was
used
for
those
samples.
The
other
two
samples
were
at
0.2
ppm
and
0.32
ppm.
When
taken
all
together,
this
gives
a
mean
of
0.09
ppm.

Food
Name
Anticipated
Residues
from
Residue
Studies
Anticipated
Residues
from
EPA
Adj
#
1
Adj
#
1
EPA
Adj
#
2
Adj
#
2
EPA
Concentration
Factor
%
Crop
Treated
Lemons
Juice
0.09
0.05
2
2
0.2
0.26
Lemons
Juice
Concentrate
0.09
0.05
11.4
11.4
0.2
0.26
Lemons
Peeled
Fruit
0.09
0.05
1
1
0.2
0.26
HED's
Response:
The
percent
of
crop
treated
are
weighted
averages
provided
by
the
Biological
and
Economic
Analysis
Division
(
BEAD)
in
a
Quantitative
Usage
Analysis
issued
3­
20­
01
and
supplemented
for
miscellaneous
usage
sites
on
04­
27­
2001.

Registrant's
Comment:
MRID
#
45509702
­
Limes
=
0.09
ppm
=
Lemon
Field
Trial
data
used
for
lime.
A
processed
commodity
study
accepted
by
the
Agency
which
demonstrated
no
concentration
in
juice
was
ignored.

Food
Name
Anticipated
Residues
from
Residue
Studies
Anticipated
Residues
from
EPA
Adj
#
1
Adj
#
1
EPA
Adj
#
2
Adj
#
2
EPA
Concentration
Factor
%
Crop
Treated
Limes
Juice
0.09
0.05
1
2
0.2
0.33
Limes
Juice
Concentrate
0.09
0.05
1
6
0.2
0.33
Limes
Peel
0.09
0.05
1
1
0.2
0.33
Limes
Peeled
Fruit
0.09
0.05
1
1
0.2
0.33
HED's
Response:
The
percent
of
crop
treated
are
weighted
averages
provided
by
the
Biological
and
Economic
Analysis
Division
(
BEAD)
in
a
Quantitative
Usage
Analysis
issued
3­
20­
01
and
supplemented
for
miscellaneous
usage
sites
on
04­
27­
2001.

Registrant's
Comment:
MRID
#
43339201­
Oranges
=
0.007
ppm
=
Mean
orange
Field
Trial
residue
was
used.
Orange
juice
processing
factor
of
0.96
was
calculated
from
MRID
#
43260101.
To
get
orange
juice
concentrate,
the
ratio
of
the
orange
juice
concentrate
and
orange
juice
default
processing
factors
(
6.7/
1.8)
were
multiplied
by
0.96,
which
equals
3.6.
The
default
processing
factors
was
used
by
EPA.
A
processed
commodity
study
accepted
by
the
Agency
which
demonstrated
no
concentration
in
juice
was
ignored.

Food
Name
Anticipated
Residues
from
Residue
Studies
Anticipated
Residues
from
EPA
Adj
#
1
Adj
#
1
EPA
Adj
#
2
Adj
#
2
EPA
Concentration
Factor
%
Crop
Treated
19
Oranges
Juice
0.007
0.03
0.96
1.8
0.46
0.51
Oranges
Juice
Concentrate
0.007
0.03
1
6.7
0.46
0.51
Oranges
Peel
0.007
0.03
1
1
0.46
0.51
Oranges
Peeled
Fruit
0.007
0.03
1
1
0.46
0.51
HED's
Response:
The
percent
of
crop
treated
are
weighted
averages
provided
by
the
Biological
and
Economic
Analysis
Division
(
BEAD)
in
a
Quantitative
Usage
Analysis
issued
3­
20­
01
and
supplemented
for
miscellaneous
usage
sites
on
04­
27­
2001.

Registrant's
Comment:
MRID
#
42798501
­
Pineapples
=
0.004
ppm
=
Average
residue
data
from
RAC
portion
of
Processing
study.
These
were
used
because
they
were
from
a
4­
5X
application
rate.
0.25
is
juice
processing
factor
from
processing
study.
0.93
=
0.25
x
the
ratio
of
the
juice
concentrate
to
juice
default
processing
factors
(
6.3/
1.7),
which
=
0.93.
Five
is
the
default
processing
factor
for
dried
pineapples.

Food
Name
Anticipated
Residues
from
Residue
Studies
Anticipated
Residues
from
EPA
Adj
#
1
Adj
#
1
EPA
Adj
#
2
Adj
#
2
EPA
Concentration
Factor
%
Crop
Treated
Pineapples
dried
0.04
0.1
5
5
0.8
0.13
Pineapples
juice
0.04
0.07
0.25
1.7
0.8
0.13
Pineapples
juice
Concentrate
0.04
0.07
0.93
6.3
0.8
0.13
Pineapples
peeled
fruit
0.04
0.1
1
1
0.8
0.13
HED's
Response:
The
percent
of
crop
treated
are
weighted
averages
provided
by
the
Biological
and
Economic
Analysis
Division
(
BEAD)
in
a
Quantitative
Usage
Analysis
issued
3­
20­
01
and
supplemented
for
miscellaneous
usage
sites
on
04­
27­
2001.

Registrant's
Comment:
MRID
#
42740401
­
Wheat
=
0.025
ppm
=
Mean
Field
Trial
residue
(
All
residues
less
than
LOQ
of
0.05
ppm,
so
0.025
ppm
was
used).
Wheat
bran
and
wheat
flour
processing
factors
calculated
from
wheat
processing
study.

Food
Name
Anticipated
Residues
from
Residue
Studies
Anticipated
Residues
from
EPA
Adj
#
1
Adj
#
1
EPA
Adj
#
2
Adj
#
2
EPA
Concentration
Factor
%
Crop
Treated
Wheat
Bran
0.025
0.3
2
1
0.01
0.01
Wheat
Flour
0.025
0.019
0.33
1
0.01
0.01
Wheat
Germ
0.025
0.3
1
1
0.01
0.01
Wheat
Germ
Oil
0.025
0.3
1
1
0.01
0.01
Wheat
Rough
0.025
0.136
1
1
0.01
0.01
HED's
Response:
The
percent
of
crop
treated
are
weighted
averages
provided
by
the
20
Biological
and
Economic
Analysis
Division
(
BEAD)
in
a
Quantitative
Usage
Analysis
issued
3­
20­
01
and
supplemented
for
miscellaneous
usage
sites
on
04­
27­
2001.

In
addition
to
this
review
of
the
Human
Health
Risk
Assessment
for
diuron,
several
discrepancies
were
noted
in
the
previous
review
of
the
RED
for
diuron.
These
comments
are
reiterated
below:

Diuron:
2nd
Report
of
the
Hazard
Identification
Assessment
Review
Committee
1.1
Acute
Reference
Dose
(
RfD)
­
No
errors
noted.

1.2
Chronic
Reference
Dose
(
RfD)

Registrant's
Comment:
Paragraph
1,
Line
5,
of
Executive
Summary.
The
high
dose
female
group,
according
to
the
text
of
the
study
report,
is
listed
as
"
203
mg/
kg/
day"
rather
than
"
202
mg/
kg/
day."

Paragraph
2,
Lines
1­
2,
of
Executive
Summary.
The
sentence,
"
The
only
reported
related
clinical
sign
was
reddish
discolored
or
bloody
urine
in
high­
dose
males."
This
implies
all
high­
dose
males
showed
this
effect
which
was
not
the
case.
This
sentence
should
read,
" 
in
some
high­
dose
males."

Paragraph
3,
Line
1,
of
Executive
Summary.
The
first
sentence
should
be
prefaced
with,
"
At
24
months,"
to
be
correct.
Also
in
line
5
of
the
same
sentence,
the
parenthetical
phrase
that
states
(<
25%
change
for
most
parameters;
3­
fold
increase
for
reticulocytes)
applies
only
to
the
high
dose
males
and
females.
The
mid­
dose
animals
do
not
show
this
degree
of
change.
The
low
dose
females
show
a
very
small
increase
of
33%
in
the
erythrocyte
count
and
no
real
change
in
the
other
parameters.

For
accuracy,
the
first
sentence
of
the
second
paragraph
should
read:

At
24
months,
diuron
affected
hematopoietic
system
resulting
in
hemolytic
anemia
and
compensatory
hematopoiesis,
which
were
manifested
as
significantly
decreased
(
P<
0.05
or
0.01)
erythrocyte
counts,
hemoglobin
levels,
and
hematocrit
and
increased
MCV,
MCH,
abnormal
erythrocyte
forms,
reticulocyte
counts,
and
leukocyte
counts
(
with
no
effects
on
differential
counts)
in
mid­
and/
or
high­
dose
males
and
females,
and
in
low­
dose
females.
In
the
high­
dose
groups
there
was
<
25%
change
for
most
parameters
with
a
3­
fold
increase
for
reticulocytes.
For
the
low­
dose
females
only
an
increase
of
33%
was
observed
in
erythrocyte
count
and
no
real
change
in
the
other
parameters.

Paragraph
4,
Second
Sentence,
of
the
Executive
Summary
states,
"
Microscopic
evaluation
showed
that
epithelial
focal
hyperplasia
of
the
urinary
tract
and
renal
pelvis
increased
in
severity
in
both
sexes
at
12
and/
or
24
months,
and
increased
in
incidence
(
p<
0.01)
in
high­
dose
males
at
12
months
and
in
mid­
and
high­
dose
females
at
12
and/
or
24
months."
The
mid­
dose
females
showed
an
increased
incidence
only
at
24
months.
The
sentence
should
read:

Microscopic
evaluation
showed
that
epithelial
focal
hyperplasia
of
the
urinary
tract
and
renal
pelvis
increased
in
severity
in
both
sexes
at
12
and/
or
24
months,
and
increased
in
incidence
(
p<
0.01)
in
high­
dose
males
at
12
months
and
in
high­
dose
females
at
12
and/
or
24
months
with
mid­
dose
females
showing
an
increased
incidence
at
24
months.

HED's
Response:
See
above
HED's
response
in
the
toxicology
chapter
section.

Dose
and
Endpoint
for
Establishing
RfD
Registrant's
Comment:
This
analysis
provides
a
1.0
mg/
kg/
day
LOAEL
and
no
NOAEL.
The
dose
of
1.0
mg/
kg/
day
represents
a
LOEL
and
not
a
LOAEL
because
of
the
compensatory
response
to
the
minor
changes
seen
in
the
females
at
the
low
dose
(
only
33%
increase
in
erythrocytes).
In
fact,
a
NOAEL
could
be
established
as
distinct
from
a
NOEL
or
LOEL.
Because
the
anemia
is
compensated
21
by
an
increase
in
erythrocytes,
the
end
effect
is
not
adverse.
We
would
suggest
that
the
Agency
consider
the
LOAEL
as
a
NOAEL.

HED's
Response:
The
LOAEL
was
established
based
on
evidence
of
hemolytic
anemia
and
compensatory
hematopoiesis.
No
change
is
necessary.

1.3
Occupational/
Residential
Exposure
1.3.1
Registrant's
Comment:
Paragraph
3,
Line
3,
of
the
Executive
Summary
states
the
absolute
body
weight
of
the
high­
dose
does
were
significantly
less
than
the
controls
on
GD
20.
Although
this
is
accurate,
it
is
worth
noting
that
the
weight
rebounded
on
GD20­
24
and
GD
24­
29.

HED's
Response:
This
observation
also
support
the
finding
that
body
weight
decrease
is
treatment­
related.
No
change
is
necessary.

1.3.2
Comments
about
Study/
Endpoint:
A
note
in
passing.
There
were
no
effects
observed
at
6
months
for
the
NOEL
of
1.0
mg/
kg/
d.
There
were
also
no
effects
for
this
dose
at
the
12
month
interval
as
well.

1.3.3
No
errors
noted.

1.3.4
No
errors
noted.

1.3.5
No
errors
noted.

1.3.6
Long­
Term
Dermal
(
Longer
than
6
Months)
Exposure
Registrant's
Comment:
Dose
and
Endpoint
for
Risk
Assessment.
There
were
also
no
effects
at
the
1.0
mg/
kg/
d
females
at
12
months
exposure.
The
effects
seen
at
24
months
at
this
dose
in
the
female
group
were
compensatory
and
should
be
classified
as
a
NOAEL
rather
than
a
LOAEL.

HED's
Response:
The
LOAEL
was
based
on
evidence
of
hemolytic
anemia
and
compensatory
hematopoiesis
(
decreased
erythrocyte
counts,
increased
reticulocyte
counts,
increased
spleen
weight
and
bone
marrow
activation).
No
change
is
necessary.

1.3.7
No
errors
noted.

1.3.8
Registrant's
Comment:
If
the
LOAEL
were
corrected
to
a
NOAEL,
then
an
MOE
of
100
would
be
appropriate.

HED's
Response:
The
LOAEL
will
not
be
changed
to
a
NOAEL.

2.
Classification
of
Carcinogenic
Potential
2.1
Combined
Chronic
Toxicity/
Carcinogenicity
Study
in
Rats
No
errors.
Although
these
tumors
are
dose­
related,
they
are
due
to
a
secondary
mechanism
that
is
not
relevant
to
humans.

2.2
Carcinogenicity
Study
in
Mice
Registrant's
Comment:
Line
1,
Paragraph
1,
of
Discussion
of
Tumor
Data:
Treatment
was
for
104
weeks.
Animals
were
treated
and
sacrificed
after
104
weeks
(
excluding
early
mortality).
Some
confusion
may
have
resulted
since
mortality
tables
were
developed
at
102
weeks,
body
weights
and
clinical
parameters
were
recorded
at
103
weeks.
22
Line
3,
Paragraph
1,
of
Discussion
of
Tumor
Data:
The
reference
to
ovarian
luteomas
should
be
deleted.
This
effect
was
determined
to
be
inconsequential
by
the
CPRC
report
(
May
8,
1997)
which
states:

The
female
mouse
ovarian
tumor
rates
table
should
reflect
the
more
appropriate
'
combined
sex
cord­
stromal
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
cord­
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.
(
from
page7).

Therefore,
Sentence
1
should
read:

"
Treatment
of
up
to
104
weeks
with
2500
ppm
diuron
resulted
in
a
significant
increase
in
the
incidences
of
mammary
adenocarcinomas
(
control,
4%;
2500
ppm,
12%,
p
#
0.05)
in
female
NMRI
(
SPF
HAN)
mice
under
the
conditions
of
this
study."

HED's
Response:
Additional
wording
has
been
added
to
the
document.
See
above
HED's
response
in
the
"
Requirement
870.4200b:
Carcinogenicity
(
feeding)­
mouse".

2.3
Classification
of
Carcinogenic
Potential
Registrant's
Comment:
When
the
HED
CPRC
met
on
December
18,
1996,
they
classified
diuron
as
a
`
known/
likely'
carcinogen.
Since
then,
mechanistic
studies
and
additional
genotoxicity
studies
have
been
submitted.
These
need
to
be
evaluated
in
light
of
the
cancer
assessment.
In
addition,
the
classification
`
known/
likely'
is
no
longer
used.
We
would
encourage
the
CARC
to
re­
evaluate
the
cancer
classification
of
diuron.
We
believe
the
classification
of
`
known/
likely'
to
be
incorrect.

HED's
Response:
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.

3.
Mutagenicity
Registrant's
Comment:

In
addition
to
the
five
studies
previously
submitted
to
the
Agency,
Griffin
LLC
has
supplied
seven
additional
studies
on
June
4,
2001:

1)
Salmonella
typhimurium:
Line
3.
Typographical
error:
Highest
`
does'
should
be
`
dose'.

2)
Chinese
Hamster
Ovary.
No
errors
3)
Chromosome
Aberrations:
Paragraph
1.
This
study
is
the
same
as
the
study
given
as
4)
In
vivo
Bone
Marrow
Cytogenetics
Assay
(
MRID
#
44350301).
This
study
(
MRID#
00146611)
was
revised
with
additional
information
on
historical
background
frequencies.
This
study
can
be
removed
completely.

4)
In
Vivo
Bone
Marrow
Cytogenetics
Assay
(
MRID
#
44350301),
Line
6.
A
sentence
should
be
23
inserted
after
the
sentence
beginning
Cytotoxicity
to
the
target
organ
...
and
ending
...
decreased
at
24
hours.
It
should
read:

There
were
no
statistical
significant
dose­
related
increases
observed
in
the
diuron­
treated
groups
at
either
6
or
24
hours.

Numerical
designation
of
4)
will
become
3)
after
deletion
of
the
replicate/
revised
study.

5)
Unscheduled
DNA
Synthesis.
No
errors
noted.

Conclusions:
Line
2­
6.
Because
these
`
two'
studies
are
actually
the
same
study,
this
sentence
needs
to
be
corrected.
It
should
read:

Diuron
was
not
clastogenic
when
evaluated
by
the
in
vivo
chromosomal
assay
in
Sprague
Dawley
rats.

The
additional
studies
submitted
in
June
further
document
the
negative
genotoxic
response
of
diuron.
These
studies
evaluated
in
vivo
mouse
bone
marrow
micronucleus
formation,
mouse
dominant
lethal
response
and
mouse
spermatogonial
chromosomal
aberrations.
All
were
negative.
(
MRID
#
s
45494501,
45494502,
45494503,
45494504,
and
45494505)

HED's
Response:
All
studies
have
been
reviewed
and
put
into
consideration
for
evaluation
of
mutagenicity.

4.3
Developmental
Toxicity
Registrant's
comment:
Paragraph
3,
General
Comment:
Weight
of
both
males
and
females
rebounded
to
nearly
normal
in
all
dose
groups
after
removal
of
diuron
treatment.
This
should
be
mentioned.

Line
2,
Paragraph
6:
The
number
of
fetuses
examined
in
the
low
dose
was
306
and
not
305.
This
should
read
288(
22),
306(
23),
297(
22)
and
279(
20).

HED's
Response:
See
above
HED's
response
in
the
toxicology
chapter.

4.4
Reproductive
Toxicity
Registrant's
Comment:
Line
3,
Paragraph
1:
Test
substance
intake
should
read
"
Overall
test
substance
intake".
The
dosing
reflects
the
entire
dosing
period.

Line
9,
Paragraph
4:
There
was
not
a
significant
difference
in
the
7­
14
day
interval
for
the
females.

HED's
Response:
See
above
HED's
response
in
the
toxicology
chapter.

4.5
Additional
Information
­
No
errors
noted.

4.6
Determination
of
Susceptibility
­
No
errors
noted.

4.7
Recommendation
for
a
Developmental
Neurotoxicity
Study
­
No
errors
noted.

5.
Hazard
Characterization
Registrant's
Comment:
Line
3,
Paragraph
3:
The
NOAELS
for
the
maternal/
parental
toxicity
were
less
than
the
NOAELS
for
fetal
or
reproductive
toxicity.
The
reference
to
equal
can
be
deleted.

HED's
Response:
No
error
noted.
24
Registrant's
Comment:
Paragraph
4,
General
Comment:
There
needs
to
be
a
reassessment
of
the
cancer
classification
of
diuron.
It
is
inconsistent
with
the
care
that
was
taken
by
the
HIARC
to
evaluate
this
chemical
using
current
classifications
of
risk
and
exposure.
The
cancer
classification
of
"
known/
likely"
no
longer
exists.
This
assessment
was
also
performed
without
consideration
of
the
mechanism
of
action
of
diuron.
The
urinary
bladder
and
renal
tumor
(
not
statistically
significant)
carcinoma
is
induced
by
irritation
of
the
urinary
system.
The
mouse
mammary
tumors
observed
are
consistent
with
the
historical
background
incidences.
The
use
of
the
low
dose
linear
extrapolation
model
under
these
circumstances
is
not
warranted.
A
threshold
approach
with
benchmark
reference
doses
is
more
appropriate
given
the
scientific
data.

HED's
Response:
See
above
HED's
response
in
the
toxicology
chapter.

6.
Data
Gaps
­
No
errors
noted.

7.
Acute
Toxicity
­
No
errors
noted.

8.
Summary
of
Toxicological
Endpoint
Selection
Registrant's
Comment:

Acute
dietary:
No
errors
noted.

Chronic
Dietary:
The
LOAEL
=
1.0
should
read
LOEL.
There
was
an
absolute
effect.
The
effect
of
anemia
was
compensated
for
by
increased
hematopoiesis.
This
dose
should
be
considered
an
NOAEL
and
not
an
LOAEL.
With
the
establishment
of
an
NOAEL,
a
UF
of
100
could
be
set.

Cancer:
As
indicated
in
discussions
above,
the
classification
of
"
known/
likely"
is
incorrect.
Based
on
the
new
guidelines,
diuron
should
be
classified
as
either
`
unlikely'
or
`
suggestive'.
The
guidelines
properly
assert
that
application
of
a
descriptor
is
a
matter
of
judgement
and
subject
to
gray
areas
and
borderline
cases.
The
final
classification
depends
on
the
weight
that
is
given
to
the
mode
of
action
and
its
human
relevance.
A
new
assessment
needs
to
be
made
that
considers
the
mechanism
of
action.

The
reference
to
the
kidney
carcinoma
needs
to
indicate
that
the
incidence
observed
was
not
statistically
significant.

The
reference
to
the
mammary
gland
carcinoma
in
female
NMRI
mice
should
be
deleted.
The
incidence
is
within
the
historical
range.

Dermal,
Long­
term:
As
indicated
in
the
Chronic
Dietary
exposure
scenario,
the
LOAEL
should
be
a
NOAEL.

Inhalation,
Long­
term:
As
indicated
in
the
Chronic
Dietary
exposure
scenario,
the
LOAEL
should
be
a
NOAEL.

HED'S
Response:
These
issues
will
be
addressed
in
the
Phase
4
period.