Document ID: EPA-HQ-OPP-2002-0079-0015
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2002-06-19T04:00Z

UNITED
STATES
ENVIRONMENTAL
PROTECTION
AGENCY
WASHINGTON,
D.
C.
20460
OFFICE
OF
PREVENTION,
PESTICIDES
AND
TOXIC
SUBSTANCES
April
16,
2002
MEMORANDUM:
Response
to
Comment
Document
­
Phase
II
LINURON:
The
HED
Chapter
of
the
Tolerance
Reassessment
Eligibility
Decision
(TRED)
PC
Code
(035506).
Case
0047.
DP
Barcode
D281779
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:
Dirk
Helder
Chemical
Review
Manager
Reregistration
Branch
II
Special
Review
and
Reregistration
Division
(7508W)

The
attached
document
was
generated
in
response
to
the
comments
received
from
the
Linuron
registrant
Griffin
Chemical
on
March
11
th
,
2002.
This
document
was
generated
as
part
of
Phase
II
(error­
only)
of
the
Interim
Public
Participation
Process.
The
comments
pertain
to
the
3­(
3,4­
dichlorophenyl)­
1­
methoxy­
1­
methylurea
or
linuron
TRED
document
dated
January
30,
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
Linuron
TRED
document.
The
responses
documented
here
reflect
the
Agency's
current
guidelines
and
policies
concerning
risk
assessment.
This
document
and
the
updated
HED
chapter
includes
replies
from
John
Punzi
on
residue
chemistry
and
dietary
risk
assessment
and
Robert
Fricke
concerning
toxicology,
as
well
as
risk
assessment
and
characterization
corrections
by
Carol
Christensen.

Toxicological
Considerations:
2
Registrant
Comment
1:
The
first
discrepancy
is
the
statement
on
page
4
that
linuron
exhibits
developmental
concerns.
On
page
3
of
the
same
document
it
states:

Developmental
studies
in
the
rat
and
rabbit
showed
no
quantitative
or
qualitative
susceptibility
in
the
offspring.
…
These
findings
do
not
indicate
increased
susceptibility
because
increases
in
resorptions
were
marginal
and
there
was
no
change
in
the
number
of
live
fetuses
to
corroborate
the
increase
in
post­
implantation
losses.

This
is
in
direct
contradiction
with
the
statements
that
there
are
developmental
toxicity
concerns.
In
addition,
the
acute
dietary
endpoint
was
`derived
from
the
developmental
toxicity
study
in
the
rat
and
is
based
on
increases
in
post­
implantation
loss
and
litter/
fetal
resorptions."
(page
5)
Although
the
acute
dietary
endpoint
is
correctly
set
at
12.1
mg/
kg/
day,
it
should
be
based
on
the
NOEL
for
maternal
toxicity
seen
in
this
study
at
12.1
mg/
kg/
day.

Agency
Response
1:
The
following
statement
in
the
Hazard
Identification
and
Review
Committee
(HIARC)
report
and
the
HED
Chapter
of
the
TRED
and
is
correct.

"The
findings...
increases
in
resorptions
were
marginal
and
there
was
no
change
in
the
number
of
live
fetuses
to
corroborate
the
increase
in
post­
implantation
losses."

The
HIARC
felt
that
the
fetal
effects
were
not
severe
enough
to
be
indicative
of
qualitative
susceptibility.
If
the
fetal
effects
were
more
severe,
linuron
may
have
shown
qualitative
susceptibility,
even
if
there
was
no
evidence
of
quantitative
susceptibility
(fetal
and
maternal
effects
occurred
at
the
same
dose).
There
were
toxic
effects
seen
in
the
developmental
toxicity
study,
however,
these
effects
do
not
include
increased
susceptibility
of
fetuses.

For
determination
of
the
Acute
RfD,
the
HIARC
concluded
that
the
developmental
effects
were
presumed
to
occur
following
a
single
exposure
of
females
of
child­
bearing
age
and,
therefore,
are
appropriate
for
this
risk
assessment.
The
reduced
body
weights
and
food
consumption
observed
in
the
maternal
animals
were
not
a
result
of
a
single
exposure.
If
the
fetal
NOAEL
were
higher
than
the
maternal
NOAEL,
the
fetal
NOAEL
would
still
be
used
in
establishing
the
Acute
RfD.
Therefore,
this
study
and
endpoint
are
appropriate
to
the
acute
dietary
endpoint.

Registrant
Comment
2:
The
second
error
was
the
use
of
the
3­
generation
rat
study.
This
study
was
deemed
`supplemental'
because
it
was
a
non­
guideline
study.
Substantial
effort
was
expended
by
DuPont,
the
former
registrant,
to
upgrade
this
study
in
the
late
1980's.
The
Agency,
after
multiple
responses,
would
not
consider
this
study
as
acceptable
or
guideline
compliant
(CAS
#
004405,
Record
#
154,911,
CAS#
004819,
CAS#
005626,
CAS#
008113,
CAS#
008612).
After
a
meeting
held
on
July
22,
1987,
a
3
new
2­
generation
reproduction
study
in
rats
was
required.
No
records
of
additional
scientific
reviews
can
be
located
which
reverses
this
decision.
This
new
2­
generation
study
was
submitted
with
subsequent
studies
to
elucidate
questionable
effects.
This
study
with
the
amendments
was
accepted,
therefore,
this
study
should
be
used
for
regulatory
decision­
making
and
the
rejected
study
discounted.

The
report
states
on
page
4:

A
3­
generational
study
using
rats
showed
reduced
body
weights
and
fertility,
decreased
pup
survival,
and
decreased
weanling
body,
liver
and
kidney
weights,
as
well
as
liver
atrophy.
The
Hazard
Identification
Assessment
Review
Committee
(HIARC)
determined
that
these
results
illustrate
qualitative
susceptibility
in
the
rat
offspring.

In
the
discussion
of
the
3­
generational
study
in
the
HED
Toxicology
Disciplinary
Chapter
the
LOEL
for
systemic
toxicity
was
established
at
125
ppm
and
the
NOEL
was
set
at
25
ppm.
The
offspring
toxicity
LOEL
was
established
at
625
ppm
with
the
NOAEL
at
125
ppm.
This
was
based
on
decreased
pup
survival
and
lower
pup
body
weights.
It
is
clear
that
this
effect
was
at
maternally
toxic
levels.
This
is
NOT
evidence
of
a
qualitative
susceptibility
in
rat
offspring.

EPA's
position
was
very
clearly
stated
in
the
August
15,
1985
rebuttal
comments
from
James
N.
Rowe.
(Record
Number
154,911).
It
states:

"It
is
apparent
that
gross
and
histopathological
examinations
of
the
adult
rats
were
not
performed
by
the
registrant.
Therefore,
proper
interpretation
of
the
reproductive
effects
observed
in
the
study
cannot
be
performed."

In
addition,
meeting
minutes
from
a
discussion
between
DuPont
and
the
Agency's
scientists
held
on
July
22,
1987
(in
the
public
docket)
make
it
clear
that
in
addition
to
the
lack
of
histopathological
data,
fewer
than
20
animals
per
group
were
tested
which
were
fewer
than
guideline
specification.

Griffin
LLC
can
only
assume
an
error
was
made
in
reviewing
the
classification
of
the
acceptable/
guideline
designation
or
the
study
was
re­
evaluated
and
given
a
new
assessment.
If
there
is
a
new
review,
the
Agency
has
not
notified
the
registrant.
Regardless,
a
significant
discrepancy
exists.

Agency
Response
2:
The
HIARC
(TXR
No.
0050286,
November
20,
2001)
used
the
2­
generation
reproduction
study
in
the
rat
was
used
to
establish
the
endpoints
for
short­
term
oral,
dermal,
and
inhalation
exposure
scenarios.
In
the
2­
generation
reproduction
study,
the
NOAEL
was
established
at
5.8
mg/
kg/
day,
based
on
statistically
and
biologically
significant
increases
in
pre­
mating
body
weights
in
F0
and
F1
animals.
4
Further,
the
results
of
the
3­
generation
study,
in
conjunction
with
those
of
the
2­
generation
study,
were
examined
to
help
inform
the
Agency`
s
assessment
of
susceptibility.

Table
2
of
the
HED
Chapter
incorrectly
classified
the
3­
generation
reproduction
study
in
the
rat
(MRID
00146071,
00155168)
as
acceptable/
guideline.
The
Registrant
is
correct
in
stating
that
the
3­
generation
study
should
be
classified
as
unacceptable/
guideline.

Registrant
Comment
3:
The
third
major
discrepancy
is
the
determination
of
a
`neurotoxicity'
concern.
There
has
never
been
an
Agency
concern
for
neurotoxicity
induced
by
linuron.
The
Agency
previously
recognized
this
in
that
no
acute
or
subchronic
neurotoxicity
studies
were
requested.
Linuron
has
been
shown
to
be
an
endocrine
disruptor.
This
has
never
been
in
question.
There
is,
however,
a
big
difference
between
the
weak
anti­
androgenic
activity
elicited
by
linuron
and
`neuroendocrine'
effects
referred
to
by
the
Agency
in
this
document.
No
data
have
been
presented
by
the
Agency
either
from
registrant
sponsored
studies
or
from
the
literature
which
would
be
a
basis
for
a
neurotoxicity
concern.
This
designation
of
"neuroendocrine
effects"
has
no
scientific
basis
and
should
be
either
deleted
from
the
document
or
supported
somewhere
in
the
scientific
documents.
The
request
for
a
developmental
neurotoxicity
test
is
not
supported
by
the
Agency's
own
assessment
of
the
science.
(see
discussion
above
as
it
relates
to
the
developmental
studies)

Agency
Response
3:
Linuron
causes
endocrine
disruption,
which
is
a
neuro­
endocrine
effect.
Classifying
linuron
as
neurotoxicant
is
too
broad
and
does
not
accurately
describe
the
neuro­
endocrine
effects–
endocrine
disruption­­
seen
with
linuron.
References
to
linuron
as
a
neurotoxicant
will
be
changed
to
the
more
accurate
term
neuro­
endocrine
or
endocrine
disruptor.

Registrant
Comment
4:
The
fourth
major
discrepancy
is
the
reference
with
Linuron
(and
subsequent
regulatory
action)
to
linuron
as
an
inhalation
concern.
There
is
essentially
no
toxicity
by
the
inhalation
route.
The
LD50
is
>218
mg/
L
or
21.8
g/
M
3
.
The
MOEs
calculated
in
the
Linuron
RED
of
March
1995
were
all
above
100
and
of
no
concern.
These
were
based
on
the
NOELs
(12.1
mg/
kg)
from
the
rat
developmental
study
for
the
short­
term
assessment
and
the
2­
generation
reproduction
study
(1.25
mg/
kg/
day)
for
the
intermediate
term
assessment.
Because
the
occupational
exposure
to
a
pre­
emergent
herbicide
used
once
per
season/
year
will
not
exceed
30
days
exposure,
there
is
not
a
great
inhalation
risk
concern
driven
by
the
use
patterns.
In
addition,
linuron
is
neither
volatile
as
an
active
ingredient
nor
contains
volatiles
nor
becomes
volatile
in
its
formulations.
Given
the
lack
of
inhalation
toxicity
and
potential
for
exposure,
the
request
for
a
28­
day
inhalation
study
is
not
supported.
This
is
either
in
error
or
requires
scientific
justification.

Agency
Response
4:
Beyond
the
scope
of
error­
only
comments
and
will
be
addressed
in
Phase
IV.
5
Residue
Chemistry
Considerations:

Registrant
Comment
5:
Page
46.
Miscellaneous
Commodities
"Cotton,
seed
and
gin
products
For
the
gin
byproducts
field
trials,
information
describing
the
type
of
equipment
used
for
harvesting
in
the
machine­
harvest
trials
must
be
submitted.
In
addition,
additional
cotton
gin
byproducts
field
trials
must
be
conducted,
such
that
the
requirements
of
GLN
860.1000
(Table
1)
for
gin
byproducts
field
trials
are
fulfilled,
or
a
justification
for
the
substitution
of
data
from
field
trials
reflecting
hand
harvesting
must
be
submitted."

A
response
to
the
issues
raised
above
was
submitted
to
Mr.
Tom
Myers,
Chemical
Review
Manager.
The
letter
of
transmittal
is
dated
January
14,
2002
and
was
sent
via
FedEx
on
this
date.
Our
records
indicate
that
this
response
was
received
on
January
16.

Agency
Response
5:
The
registrant
states
that
a
response
to
the
issues
raised
in
the
chapter
was
submitted
to
Mr.
Tom
Myers,
CRM,
on
January
14,
2002.
This
document
is
identified
as
additional
information
to
MRID
45302201
(d280653)
without
an
MRID.

The
registrant
has
submitted
justification
for
hand
harvesting
samples
of
cotton
gin
trash
and
has
supplied
the
requested
information
describing
the
machinery
used
in
harvesting.
Although
the
field
trial
data
are
not
consistent
with
current
guideline
for
geographic
distribution,
since
the
use
of
Linuron
is
limited
to
east
of
the
rocky
mountains
the
data
submitted
represent
nearly
90%
of
the
growing
regions.
The
data
requirement
for
a
tolerance
for
cotton
gin
trash
is
satisfied
and
a
tolerance
of
10
ppm
will
be
recommended.

Registrant
Comment
6:
Page
47.
Magnitude
of
the
Residue
in
Processed
Food/
Feed
"The
2/
94
RED
and
2/
95
RED
Addendum
concluded
that
additional
data
were
required
to
upgrade
an
existing
potato
processing
study
(S.
Knizner,
9/
2/
92);
these
data
remain
outstanding."

A
response
to
the
memorandum
from
Steven
A.
Knizer
to
Lois
Rossi
was
submitted
to
the
Agency
on
February
14,
2000.
Our
records
show
that
the
response
was
received
by
the
Agency
on
February
18,
2000.
The
information
requested
for
upgrading
this
study
was
included
in
the
submittal.

Agency's
Response
6:
The
registrant
claims
to
have
submitted
a
response
on
February
14,
2000
to
the
memorandum
from
Steven
Knizer
to
Lois
Rossi
(09/
02/
1992)
upgrading
the
potato
processing
study.
The
registrant
has
identified
the
response
only
by
date.
The
document
in
question
cannot
be
located
without
a
MRID
number.
If
the
registrant
can
provide
the
Agency
with
a
copy
of
the
original
February
14,
2000
document
or
an
MRID
number
it
will
be
reviewed.
6
Drinking
Water
Considerations
Registrant
Comment
7:
The
Agency
used
the
IR­
PCA
PRZM/
EXAM
model
that
has
never
been
validated
and
has
been
proven
to
grossly
overestimate
residues
in
drinking
water.
It
is
stated
in
the
document
that
"Modeling
results
are
higher
than
those
from
existing
surface
water
monitoring
data
for
linuron
targeted
to
the
pesticide
use
area".
Percent
Crop
Area
(PCA)
was
used
in
the
modeling
of
linuron
on
carrots.
PCA
is
only
applicable
to
major
crops
and
carrots
in
the
San
Joaquin
–Tulare
Basins
is
not
considered
a
major
crop.
Data
from
the
1992
Census
of
Agriculture
were
used
to
generate
the
PCA's
and
recent
changes
in
the
agriculture
sector
has
significantly
impacted
the
distribution
of
crops
throughout
the
US.
We
feel
that
the
IR­
PCA
PRZM/
EXAM
model
is
not
a
valid
modeling
system
for
estimating
residues
in
drinking
water
and
that
the
inputs
into
the
model
are
not
valid.
The
results
from
this
model
misrepresent
the
actual
residues
that
occur
in
drinking
water.
Monitoring
data
cited
by
the
Agency
much
more
accurately
reflects
linuron
residues
in
drinking
water.

Agency
Response
7:
These
comments
are
beyond
the
scope
of
error­
only
comments
and
will
be
addressed
in
the
Public
Comment
Phase
(Phase
III)
of
the
public
participation
process.

Registrant
Comment
8:
The
Agency
recommended
that
5
ppb
of
linuron
be
used
in
the
drinking
water
assessment
based
on
monitoring
data
cited.

It
is
recommended
in
this
document
that
5
ppb
be
used
in
the
drinking
water
assessment
in
ground
water.
Data
cited
in
the
review
show
that
the
highest
residue
in
drinking
water
was
5
ppb.
We
recommend
that
the
Agency
use
in
their
drinking
water
assessment
an
average
residue
from
the
water
monitoring
data.
Data
cited
by
the
Agency
from
a
USGS
NAWQA
monitoring
study
show
linuron
residues
were
detected
in
only
0.11%
of
the
924
samples
analyzed.
The
maximum
concentration
was
0.029
ppb.
In
another
study
cited,
linuron
residues
were
present
in
29%
of
the
377
analyses.
The
highest
residue
from
this
monitoring
study
was
5
ppb.
Again,
the
Agency
is
using
a
value
that
grossly
overestimates
linuron
residues
in
drinking
water.
If
an
average
residue
value
is
used,
then
the
estimated
exposure
would
be
<1
ppb.

Additional
monitoring
data
can
be
found
at
the
following
website:
http://
water.
wr.
usgs.
gov/
pnsp/
pestgw/

In
this
monitoring
program,
water
samples
were
collected
from
1243
wells
and
1849
aquifers
located
in
agricultural
areas.
Linuron
residues
were
detected
in
0.16%
of
the
wells
and
0.05%
of
the
aquifers.
The
maximum
linuron
residue
detected
in
these
water
samples
was
0.03
ppb.
Water
samples
were
also
collected
from
643
wells
in
urban
areas
and
no
residues
were
detected
in
any
of
the
water
samples
analyzed.

Agency
Response
8:
These
comments
are
beyond
the
scope
of
error­
only
comments
and
7
will
be
addressed
in
the
Public
Comment
Phase
(Phase
III)
of
the
public
participation
process.