Document ID: EPA-HQ-OPP-2002-0188-0026
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2002-09-16T04:00Z

UNITED
STATES
ENVIRONMENTAL
PROTECTION
AGENCY
WASHINGTON,
D.
C.
20460
OFFICE
OF
PREVENTION,
PESTICIDES
AND
TOXIC
SUBSTANCES
MEMORANDUM
DATE:
August
22,
2002
SUBJECT:
Response
to
DuPont's
Comments
Concerning
the
HED
Chapter
for
the
Hexazinone
Tolerance
Reassessment
Eligibility
Decision.
PC
Code
107201.
Case
0026.
DP
Barcode
D284193.

FROM:
Carol
Christensen,
MPH
Reregistration
Branch
II
Health
Effects
Division
(7509C)

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

TO:
Dirk
Helder,
Chemical
Review
Manager
Special
Review
and
Reregistration
Division
(7508C)

This
document
acknowledges
the
comments
received
from
the
registrant,
DuPont,
citing
errors
in
the
HED
Chapter
for
the
Hexazinone
Tolerance
Reassessment
Eligibility
Decision
(TRED)
and
related
materials.
The
Agency
has
provided
its
response
to
these
comments
herein.
The
comments
are
also
directly
reflected
in
the
Revised
HED
Chapter
for
the
Hexazinone
TRED
(D275621,
August
22,
2002)
and
accompanying
disciplinary
chapters
and
memoranda,
where
appropriate.
The
comments
consisted
primarily
of
editorial
suggestions,
an
objection
to
the
28­
day
inhalation
study
requirement,
and
a
statement
that
because
the
Agency
has
received
a
new
developmental
toxicity
study
in
rabbits
the
10X
database
uncertainty
factor
previously
assigned
for
risk
assessment
be
removed.
Most
of
the
editorial
comments
have
been
included.
The
comment
objecting
to
the
28­
day
inhalation
study
requirement
is
rejected.
The
new
developmental
toxicity
study
in
rabbits
is
acceptable
and
is
included
in
the
risk
assessment
and
the
database
uncertainty
factor
for
lack
of
a
developmental
toxicity
study
in
the
rabbit
is
removed.
Four
minor
comments
regarding
the
residue
chemistry
and
dietary
exposure
and
risk
assessment
are
also
reflected
in
the
documentation
for
the
hexazinone
TRED.
­2­
The
following
comments
were
received
from
DuPont
on
July
2
nd
,
2002.
The
comments
are
repeated
here
by
document
type
and
section
followed
by
the
Agency's
numbered
responses.

Toxicological
Chapter
for
the
TRED
for
Hexazinone
Section
2.0
REQUIREMENTS
C
Guideline
Numbers
need
to
be
filled
in
for
Structural
Chromosome
Aberrations
(870.
5375
and
870.5385)
and
Other
Genotoxic
Effects
(870.5550)

Agency
Response
1:
The
guideline
study
870.5385
is
unacceptable
and
will
not
be
listed
in
Table
1
(of
the
Toxicology
chapter).
The
guideline
study
870.5395
(an
acceptable
study)
will
listed
instead.

C
Although
not
listed
as
a
data
gap,
870.5100
"Gene
mutation
­
bacterial"
is
listed
as
a
requirement
that
is
not
satisfied.
DuPont
has
an
Ames
assay
for
the
75DF
formulation
that
was
conducted
for
another
country.
That
assay
was
conducted
in
both
Salmonella.
and
E.
Coli
at
up
to
5000
ug/
plate
(=
3750
ug/
plate
a.
i.)
and
was
negative
for
gene
mutations
in
both.
That
study
can
be
submitted,
if
needed,
to
satisfy
this
requirement.

Agency
Response
2:
The
new
study
in
Salmonella
and
E.
coli
(MRID#
457101001)
has
been
received
and
is
in
review,
however
no
data
gap
for
mutagenicity
was
determined
because
there
is
an
acceptable
in
vivo
mutation
study
and
there
is
insufficient
evidence
of
carcinogenicity
in
acceptable
studies.

Section
3.0
DATA
GAPS
C
It
is
unclear
as
to
why
a
28­
day
inhalation
study
is
being
requested.
For
which
risk
assessment
is
it
needed?
There
are
no
residential
uses
of
hexazinone.
Most
of
the
use
patterns
are
outside
the
scope
of
WPS.
The
Agency
comments
on
page
24
of
the
HIARC
document,
that
it
already
has
an
unreviewed
21­
day
inhalation
study
(MRID
#
00063972,
HLR
447­
76).
In
that
study,
groups
of
ten
male
rats
were
exposed
6
hours/
day,
5
day/
week
for
3
weeks
to
0
(control)
or
2.5
mg/
L
of
90%
wettable
powder
formulation
of
hexazinone
(~
600
mg
a.
i./
kg/
day).
Histopathology
examination
indicated
that
lung
changes
were
similar
between
control
and
hexazinone
exposed
rats.
Intermittent
weight
losses
were
noted
throughout
the
test
period
but
all
rats
showed
a
normal
rate
of
weight
gain
during
the
recovery
period.
The
Registrant
acknowledges
that
this
is
an
old
study
which
was
conducted
prior
to
issuance
of
current
guidelines.
However,
it
indicates
that
repeated
exposure
to
hexazinone
dust
poses
negligible
inhalation
risks
and
that
no
further
inhalation
testing
should
be
required.
­3­
Agency
Response
3:
The
21­
day
inhalation
study
(MRID#
00063972)
remains
an
unacceptable
study
(TXR
No.
0051033);
the
study
fails
to
meet
the
minimum
standard
for
review.
The
1976
study
is
unacceptable
because
it
is
a
two
page
summary
of
a
study,
with
no
meaningful
supporting
data.
In
addition,
there
is
considerable
doubt
about
the
particle
size
in
the
exposure
chamber.
A
particle
size
expressed
as
an
average
instead
of
a
mean
mass
areodynamic
diameter
is
not
meaningful.
Other
deficiencies
exist,
including:
(1)
failure
to
explain
dust
generator
type;
(2)
failure
to
note
the
sampling
area
with
respect
to
the
exposed
animal;
(3)
failure
to
supply
concentrations
of
various
mean
mass
areodynamic
diameters
of
various
particle
sizes;
(4)
inconsistency
in
expression
of
particle
sizes,
i.
e.,
average
of
7.8
µm(
2.3­
15
µm)
and
a
note
indicating
that
only
0.06%
of
the
hexazinone
was
less
than
10.9
µm;
(5)
no
individual
body
weight
data
or
individual
pathology
data
was
submitted;
(6)
only
5
of
the
10
animals
were
subjected
to
gross
and
histological
examination;
(7)
the
study
was
not
conducted
under
GLPs,
which
would
at
least
confirm
that
the
opinions
expressed
may
have
supporting
data;
and,
(8)
the
particle
size
of
7.8
µm
(even
if
incorrectly
expressed
as
an
average)
is
not
sufficiently
small
to
test
the
inhalation
toxicity
of
hexazinone.
The
paucity
of
lung
macrophages
containing
dust
particles
supports
low
exposure
to
the
lung.

If
the
registrant
can
show
that
there
is
no
inhalation
exposure
to
handlers,
a
data
waiver
will
be
considered.
If
the
registrant
wishes
to
resubmit
the
21­
day
inhalation
study
(MRID#
00063972)
with
the
missing
information
and
data,
OPP
will
review
it.
Until
this
information
is
reviewed
and
accepted,
the
21/
28­
day
inhalation
study
is
required
for
confirmation.

A
new
Rabbit
Developmental
Toxicity
Study
has
recently
been
submitted.
(DuPONT­
7405,
MRID
45677801).

Agency
Response
4:
The
recently
submitted
developmental
toxicity
study
in
rabbits
(MRID
42677801)
is
acceptable
and
will
be
included
in
the
risk
assessment
of
hexazinone
(TXR#
0050786).
The
acceptability
of
the
study
and
its
use
in
risk
assessment
are
reflected
throughout
the
HED
chapters
of
the
Hexazinone
TRED.
The
database
uncertainty
factor
(10x)
is
removed
from
the
assessment
of
risk
as
a
result
of
hexazinone
exposure.

Section
4.0
HAZARD
ASSESSMENT
Acute
Toxicity,
Page
5.
References:
The
references
for
all
the
acute
tox
citations
have
been
omitted
from
the
reference
list.
Should
they
be
included?
­4­
Agency
Response
5:
The
references
are
included.

Acute
Dermal
Rabbit,
add
date
(1973).

Agency
Response
6:
The
date
is
added.

Acute
Inhalation:
Is
not
correct
as
written
since
an
LC50>
3.94
mg/
L
(4
hour)
would
be
a
toxicity
category
IV.
Either
add
a
note
similar
to
that
used
in
the
HIARC
document
(Section
8)
that
this
was
on
a
25%
formulation
AND/
OR
cite
the
1973
study
on
the
technical
material
00104975
LC50>
7.5
mg/
L
(1
hour)
~
LC50
1.9
mg/
L
(4
hours)
that
was
mentioned
in
the
HIARC
report
Section
8.0.
Either
study
(3.94
x
0.25
or
7.5/
4)
would
result
in
a
toxicity
category
III.

Agency
Response
7:
Acute
inhalation
is
correct
as
written
and
will
not
be
changed.
The
acute
inhalation
study
used
to
support
the
data
requirements
was
changed
from
a
study
performed
in
1973
to
a
study
performed
in
1990.
The
acute
inhalation
study
performed
in
1990
(MRID#
41756701)
is
a
study
of
the
technical
grade
of
hexazinone
and
results
in
classification
as
an
acute
toxicity
category
III.
This
result
is
reflected
in
the
HED
Chapter
of
the
risk
assessment,
the
toxicology
chapter
and
all
HIARC
documents
(1/
16/
02,
4/
29/
02
and
8/
12/
02).

Subchronic
Toxicity,
870.3200,
Subchronic
Dermal,
Page
7.
Should
read
"
870.3200
21/
28
Day
Dermal
Toxicity
­
Rabbit"
since
the
guideline
is
for
either
rats
or
rabbits
and
the
study
was
conducted
in
rabbits.

Agency
Response
8:
The
guideline
toxicity
study
870.3200
listed
as
a
21/
28
day
dermal
toxicity
study
in
the
rat
will
be
changed
to
21/
28
day
dermal
toxicity
study
in
the
rabbit
since
the
study
was
conducted
in
this
species.

90­
Day
Inhalation,
870.3465,
Page
8.
As
described
above,
the
registrant
does
not
agree
that
this
is
a
data
gap
because
the
Agency
has
an
unreviewed
21­
day
repeated
dose
inhalation
study.

Agency
Response
9:
See
Agency
Response
3
(above).

Prenatal
Developmental,
870.3700b,
Toxicity
Study
­
Rabbit,
Page
10.
This
should
be
updated
to
reflect
that
a
new
rabbit
developmental
study
was
submitted
(5/
19/
02
MRID
45677801).

Agency
Response
10:
See
Agency
Response
4
(above).

4.7
Mutagenicity:
Overview.
For
clarification,
we
recommend
inserting
the
following
wording
into
the
last
sentence
of
the
mutagenicity
overview.
"Because
unambiguous
positive
results
were
achieved,
it
was
concluded
that
the
study
­5­
provided
adequate
evidence
that
INA­
3674­
112
(hexazinone
technical)
is
clastogenic
in
vitro
in
an
acceptable
study.
[However,
negative
results
were
obtained
in
two
studies
which
assessed
chromosome
damage
in
vivo."]

Agency
Response
11:
The
in
vivo
studies
for
chromosomal
damage
are
listed
as
negative.
There
is
no
reason
to
repeat
the
results
in
the
last
sentence
of
the
4.7
Mutagenicity
Overview
section
of
the
Toxicology
Chapter.

Page
20,
870.5375
Mid
paragraph
"In
the
presence
of
S­
9
mix,
no
statistically
significant
increases
in
chromosome
aberrations
were
seen
in
Trial
1;
however,
very
low
positive
control
values
indicated
a
problem
with
the
S9­
mix."
Delete
the
latter
part
of
the
sentence;
it
is
incorrect.
Positive
control
values
in
both
trials
produced
strong
positive
results
(Trial
1
28­
32%
abnormal
cells,
Trial
2
36­
40%
abnormal
cells).

Agency
Response
12:
The
statement
will
be
deleted
from
the
Toxicology
chapter.

Page
21,
870.5385
After,
"Unacceptable….
The
study
does
not
satisfy
the
requirement
for
FIFRA
Test
Guidelines."
Add,
"However
this
Guideline
is
fulfilled
by
an
acceptable
mouse
micronucleus
study."

Agency
Response
13:
Section
4.7.4
Guideline
870.5385:
In
vivo
cytogenics
assay
in
rat
bone
marrow
cells
will
not
be
changed.
The
mouse
micronucleus
test
is
listed
as
acceptable
in
Section
4.7.5
and
there
is
no
reason
to
repeat
the
results
in
Section
4.7.4.

Page
22,
870.5395
Change
the
last
sentence
from
"It
satisfy
the
requirements…."
to
"It
satisfies
the
requirements…."

Agency
Response
14:
The
correction
is
accepted.

Section
6.0
FQPA
CONSIDERATIONS
Page
25.
The
Agency
assigned
an
additional
10x
database
uncertainty
factor
(UFdb)
because
a
rabbit
developmental
study
was
unacceptable
due
to
uncertainties
in
the
LOEL.
Immediately
after
the
HIARC
report
issued,
the
Registrant
submitted
a
new
rabbit
developmental
study
(DuPont­
7405,
MRID
45677801)
to
the
Agency.
The
new
rabbit
developmental
study
was
conducted
using
current
guidelines
and
confirmed
the
results
of
the
previous
rabbit
developmental
study.
The
maternal
and
fetal
rabbit
NOAEL
was
50
mg/
kg/
day.
The
maternal
and
fetal
LOAEL
was
125
mg/
kg/
day.
Once
the
new
rabbit
study
is
reviewed,
if
it
is
selected
as
the
basis
of
the
ARfD,
the
registrant
believes
the
extra
10x
UFdb
should
be
removed.
­6­
Agency
Response
15:
See
Agency
Response
4.

Acute
Toxicity
Table.
Header
should
read:
"Acute
Toxicity
Data
on
HEXAZINONE"
NOT
"Acute
Toxicity
Data
on
FENBUTATIN­
OXIDE."

Agency
Response
16:
The
heading
for
the
table
"Acute
Toxicity
Data
on
FENBUTATIN­
OXIDE"
will
be
changed
to
"Acute
Toxicity
Data
on
HEXAZINONE."

Subchronic,
Chronic,
and
Other
Toxicity
Tables.
Registrant
comments
have
been
made
above
regarding
removal
of
the
28­
day
inhalation
study
requirement,
the
submission/
MRID
of
a
new
prenatal
developmental
study,
and
the
availability
of
an
unsubmitted
gene
mutation
assay
(with
a
75DF
formulation)
in
Salmonella
and
E.
Coli.

Agency
Response
17:
See
Agency
Responses
3,
4,
and
2,
respectively.

Summary
of
Toxicological
Endpoints.
Registrant
restates
that
additional
10x
UFdb
should
be
removed
after
new
rabbit
developmental
toxicity
study
is
reviewed
and
questions
the
need
for
establishment
of
long­
term
occupational
endpoints.

Agency
Response
18:
See
Agency
Response
4.
The
Long­
Term
endpoints
were
selected
for
completeness
and
for
potential
future
need.
­7­
Hazard
Identification
and
Review
Committee
(HIARC)
Report
Acute
Dietary
Reference
Dose
Females
13­
50
pp.
3­
5.
For
setting
the
acute
reference
dose
(ARfD)
for
females
of
childbearing
age,
the
Agency
has
selected
a
rat
developmental
study
with
NOAELs
of
100
and
400
mg/
kg
for
maternal
and
fetal
effects,
respectively.
The
Agency
assigned
an
additional
10x
database
uncertainty
factor
(UFdb
)
because
a
rabbit
developmental
study
was
unacceptable
due
to
uncertainties
in
the
LOEL.
A
UFdb
factor
of
10x
rather
than
3x
was
used
because,
based
on
extrapolation
to
the
rabbit
pilot
NOEL
of
50
mg/
kg
in
the
previous
study,
it
was
concluded
the
difference
between
rabbits
and
rats
may
be
greater
than
3x.
The
resulting
ARfD
was
0.4
mg/
kg
(400
mg/
kg
/
1000).

Immediately
after
the
HIARC
report
issued,
the
Registrant
submitted
a
new
rabbit
developmental
study
(DuPont­
7405,
MRID
45677801)
to
the
Agency.
The
new
rabbit
developmental
study
was
conducted
using
current
guidelines
and
confirmed
the
results
of
the
previous
rabbit
developmental
study.
The
maternal
and
fetal
rabbit
NOEL
was
50
mg/
kg/
day.
The
maternal
and
fetal
LOEL
was
125
mg/
kg/
day
based
on
weight
effects,
which
were
only
slight
in
the
fetus.
A
higher
dose,
175
mg/
kg/
day
produced
severe
maternal
toxicity.

Once
the
new
rabbit
study
is
reviewed,
if
it
is
selected
as
the
basis
of
the
ARfD,
the
registrant
believes
the
extra
10x
UFdb
should
be
removed.
If
selected,
this
would
result
in
an
ARfD
of
0.5
mg/
kg
(50
mg/
kg
/
100).
This
is
essential
the
same
(slight
improvement)
as
the
current
ARfD,
and
thus
there
will
be
essentially
no
change
in
the
acute
dietary
risk
assessment.

Agency
Response
19:
The
rabbit
developmental
toxicity
study
has
been
reviewed
and
accepted
by
the
Agency.
The
database
uncertainty
factor
of
10X
is
removed
from
the
acute
dietary
risk
assessment.
However,
the
Agency
retains
the
use
of
the
developmental
toxicity
study
in
the
rat
as
the
basis
for
the
acute
reference
dose
for
females
13­
50
years
of
age
(acute
reference
dose
is
4.0
mg/
kg/
day).

Chronic
Reference
Dose,
Last
line
page
6
–
typographical
error.
"The
LOAEL
is…
based
on…[
findings
listed]
and
clinical
observations
of
thinnest
in
one
male."
Should
read
"thin
appearance
in
one
male."

Agency
Response
20:
The
statement
is
changed
to
read
"thinness
in
one
male"
(p.
12
of
HIARC
report
TXR
No.
0051033
dated
August
12,
2002).

Occupational/
Residential
Exposure.
It
is
not
clear
to
the
Registrant
why
the
occupational
and
residential
exposure
Sections
2.4.1
through
2.6
were
included
in
a
food
Tolerance
Reassessment.
There
are
no
residential
uses
of
hexazinone,
that
could
contribute
to
the
aggregate
exposure.
It
is
the
Registrant's
understanding
that
occupational
exposure
assessment
is
beyond
the
scope
of
Tolerance
Reassessment.
­8­
Occupational
exposure
was
addressed
under
the
1994
Reregistration
Eligibility
Document.
It
was
noted
that
a
number
of
the
major
uses
of
hexazinone
were
outside
the
scope
of
the
Worker
Protection
Standard
(WPS).
While
agricultural
uses
and
use
on
sod
farms
was
within
WPS;
use
on
pastures,
rangeland,
plants
grown
for
other
than
commercial
purposes,
ornamental
plants
in
parks
and
golf
course,
and
no­
agricultural
uses
such
as
vegetation
along
rights­
of­
way
were
outside
of
the
scope
of
WPS.
No
worker
exposure
assessment
was
conducted.

Therefore
the
Registrant
considers
the
selection
of
Occupational/
Residential
endpoints
(e.
g.,
dermal
and
inhalation
exposure
scenarios)
to
not
be
relevant
to
Tolerance
Reassessment.
Nonetheless,
we
offer
the
following
comments
to
the
endpoint
selection,
should
these
endpoints
be
considered
relevant
in
the
future.

Agency
Response
21:
These
comments
will
not
be
addressed
as
occupational
and
residential
exposure
as
risk
assessment
was
not
performed
for
the
HED
Chapter
of
the
Hexazinone
TRED.
These
endpoints
were
selected
for
completeness
of
the
toxicological
database
and
for
potential
future
need.

Dermal
Absorption.
The
review
states
that
"No
dermal
absorption
study
is
available."
It
would
be
clearer
to
say
that
"No
dermal
penetration
study
is
available.
For
an
estimate
of
dermal
penetration,
the
NOAEL
from
the
21­
day
rabbit
dermal
toxicity
study…."
Also,
for
clarification,
add
the
MRID
of
the
rabbit
21­
day
study
(MRID
41309005).

The
Agency
extrapolated
a
dermal
absorption
factor
by
comparing
the
NOAEL
in
a
21­
day
dermal
study
in
rabbits
to
the
LOAEL
from
a
rabbit
developmental
rangefinding
study.
A
25%
dermal
absorption
factor
was
derived.

Rabbit
Pilot
Developmental
LOAEL
(oral)
=
250
mg/
kg
=
25%
Rabbit
21­
Day
Dermal
NOAEL
1000
mg/
kg
However,
the
new
rabbit
developmental
study
(DuPont­
7405,
MRID
45677801)
indicates
there
is
a
greater
difference
between
oral
and
dermal
toxicity
than
indicated
by
the
above
calculation.
Further,
since
no
LOAEL
was
actually
established
on
the
Rabbit
21­
Day
Dermal
study,
use
of
a
dermal
NOAEL
in
comparison
to
an
oral
LOAEL,
overestimates
the
potential
dermal
penetration.
Based
on
the
new
rabbit
developmental
study,
dermal
absorption
is
no
greater
than
12.5%

Rabbit
Developmental
LOAEL
(oral)
=
125
mg/
kg
=<
12.5%
Rabbit
21­
Day
Dermal
NOAEL
>
1000
mg/
kg
­9­
Agency
Response
22:
A
dermal
absorption
factor
of
12.5%
is
defined
in
the
recent
HIARC
report.
(TXR
No.
0051033
dated
August
12,
2002)

Short­
Term
(1
Day
–
1
Month)
Dermal
Exposure
and
Intermediate
Term
(1­
6
Months)
and
Long­
Term
(>
6
Months)
Dermal
Exposures.

Under
2.4.3,
the
Agency
states
the
Dose
and
Endpoint
for
Risk
Assessment
for
short­
term
dermal
Exposure
is
Not
Applicable
and
that
No
Hazard
and
No
Quantification
are
required
(based
on
no
effects
in
the
21­
day
dermal
study
in
rabbits).
However,
in
the
next
section
(2.4.4)
the
Agency
proceeds
to
select
longer­
term
dermal
endpoints
based
on
the
chronic
dog
study
NOEL
(5
mg/
kg/
day)
and
a
25%
dermal
absorption
factor
(i.
e.
equivalent
to
20
mg/
kg/
day).
For
intermediate­
term
scenarios,
we
believe
selection
of
a
subchronic
endpoint
would
be
more
appropriate
than
selection
of
the
chronic
dog
study
with
a
25%
absorption
factor.
It
is
also
consistent
wit
the
Agency
guidance
document,
Toxicology
Endpoint
Selection
Process
(February,
1997).
Based
on
the
labeled
uses
for
hexazinone,
we
do
not
believe
a
long­
term
dermal
exposure
scenario
is
relevant.
It
is
difficult
to
identify
a
scenario
where
there
would
be
daily,
lifetime
uninterupted
dermal
exposure
to
hexazinone.

 
The
registrant
believes
that
the
route
specific
rabbit
dermal
study
is
the
most
appropriate
study
to
estimate
subchronic
human
dermal
exposure.
The
Agency
has
concluded
that
the
repeated
dose
rabbit
study
(MRID
41309005)
meets
guidelines
and
is
acceptable.
It
measured
the
proper
endpoints
to
identify
hexazinone
toxicity
(including
body
weights,
clinical
chemistry,
liver
histology).
Considering
lifespan
differences,
it
is
of
appropriate
duration
for
short
term
and
intermediate
endpoint
selection.

 
However,
if
the
Agency
deems
that
the
duration
of
the
subchronic
rabbit
dermal
study
is
insufficient,
acceptable
subchronic
oral
studies
of
longer
duration
(90
days)
are
available.
The
NOAELs
from
the
rat
and
dog
90­
day
studies
were
84
and
29
mg/
kg,
respectively.
Again
the
dog
is
the
most
sensitive
species,
but
the
subchronic
NOAEL
is
more
appropriate.

 
As
noted
in
the
discussion
above,
the
25%
absorption
factor
derived
by
comparing
a
LOAEL
on
a
rabbit
pilot
developmental
study
to
the
NOAEL
on
the
rabbit
subchronic
dermal
study
overestimated
the
Dermal
Absorption
Factor
which,
in
reality,
is
likely
to
be
less
than
12.5%.
Using
the
dog
subchronic
NOAEL
(29
mg/
kg/
day)
and
applying
a
more
appropriate
dermal
absorption
factor
<12.5%
would
result
in
an
estimated
dermal
endpoint
of
>
232
mg/
kg/
day.
This
is
much
more
comparable
to
the
actual
dermal
NOAEL
determined
from
the
21­
day
rabbit
study.
­10­
Also
typographical
error
in
2.4.4
"thinnest
in
one
males"
should
read
"thin
appearance
in
one
male"

Agency
Response
23:
The
Agency's
rationale
for
endpoint
selection
are
included
in
the
updated
HIARC
document
(TXR
No.
0051033
dated
August
12,
2002)
and
the
Agency
will
not
comment
further
at
this
time.
See
Agency
Response
22
concerning
the
dermal
absorption
factor.

Intermediate
(1­
6
Months)
and
Long­
Term
(>
6
Months)
Inhalation
Exposure
Typographical
error
"thinnest
in
one
males"
should
read
"thin
appearance
in
one
male."

Agency
Response
24:
This
error
is
noted
and
will
be
changed
in
the
Toxicology
chapter.

Section
4.0
Mutagenicity
For
clarification,
we
recommend
inserting
the
following
wording
into
the
last
sentence
of
the
mutagenicity
overview
(additions
are
in
bold).
"Because
unambiguous
positive
results
were
achieved,
it
was
concluded
that
the
study
provided
adequate
evidence
that
INA­
3674­
112
(hexazinone
technical)
is
clastogenic
in
vitro
in
an
acceptable
study.
However,
negative
results
were
obtained
in
two
studies
which
assessed
chromosome
damage
in
vivo."

General
Comment:
for
consistency
with
the
rest
of
the
document,
INA­
3674­
112
should
be
changed
to
hexazinone
or
hexazinone
technical.

Agency
Response
25:
See
Agency
Response
11.

Guideline
870.5300:
Gene
Mutation
Assay
in
Mammalian
Cells.
Conclusion
should
be
bolded
as
with
others
studies.
"There
was,
however,
no
indication
that
INA­
3674­
112
induced
mutagenic
effect
in
either
the
presence
or
the
absence
of
S9
activation."

Agency
Response
26:
The
comment
is
accepted
as
suggested
by
the
registrant.
(Section
4.2,
p.
21
of
the
3
rd
Report
of
the
HIARC,
TXR
No.
0051033
dated
August
12,
2002.)

Guideline
870.5395:
Mouse
Bone
Marrow
Micronucleus
Assay.
Change
the
last
sentence
from
"It
satisfy
the
requirements…."
to
"It
satisfies
the
requirements…."

Agency
Response
27:
See
Agency
Response
14.

Guideline
870.5375:
Structural
Chromosome
Aberration
Assay;
In
vitro
Cytogenetic
Assay.
Mid
paragraph
"In
the
presence
of
S­
9
mix,
no
statistically
­11­
significant
increases
in
chromosome
aberrations
were
seen
in
Trial
1;
however,
very
low
positive
control
values
indicated
a
problem
with
the
S9­
mix."
Delete
the
latter
part
of
the
sentence;
it
is
incorrect.
Positive
control
values
in
both
trials
produced
strong
positive
results
(Trial
1
28­
32%
abnormal
cells,
Trial
2
36­
40%
abnormal
cells).

Agency
Response
28:
See
Agency
Response
12.

Guideline
870.5385:
Structural
Chromosome
Aberration
Assay;
In
vivo
Cytogenetic
Assay.
Fourth
sentence
of
second
paragraph,
"Few
or
no
analyzable
cell
were
available…"
should
be
"Few
or
no
analyzable
cells
were
available…"

Agency
Response
29:
Editorial
comment
will
be
made.

Section
4.5,
Guideline
870.5395:
After,
"Unacceptable….
The
study
does
not
satisfy
the
requirement
for
FIFRA
Test
Guidelines."
add,
"However,
this
Guideline
is
fulfilled
by
an
acceptable
mouse
micronucleus
study."

Agency
Response
30:
See
Agency
Response
13.

Section
5
FQPA
Considerations
Developmental
Toxicity,
Developmental
Toxicity
in
the
Rabbit.
Last
paragraph
should
be
upgraded
to
indicate
a
Rabbit
Developmental
Toxicity
(45677801)
has
just
been
submitted
but
not
yet
been
reviewed.

Agency
Response
31:
See
Agency
Response
4.
The
receipt
and
acceptance
of
the
developmental
toxicity
study
in
the
rabbit
is
reflected
throughout
the
HED
risk
assessment
documents,
including
the
revised
HIARC
report
(TXR
No.
0051033
dated
August
12,
2002.)

Determination
of
the
Need
for
Developmental
Neurotoxicity
Study,
Evidence
that
suggest
requiring
a
Developmental
Neurotoxicity
Study.
Atrazine
should
not
be
considered
as
evidence
suggesting
requirement
of
a
developmental
neurotoxicity.
Although
atrazine
and
hexazinone
contain
a
triazine
ring,
there
are
significant
structural
differences
that
contribute
substantial
differences
in
the
biological
response
to
these
molecules
by
laboratory
animals.
EPA
reached
a
similar
conclusion
in
the
Toxicology
Disciplinary
Chapter
for
the
Tolerance
Reassessment
and
Evaluation
Decision
Document,
Section
1.0
–
Hazard
Characterization
(May
16,
2002).
The
critical
structural
differences
include
substitutions
of
a
cyclohexyl
and
a
methyl
group
on
the
ring
nitrogens
and
the
presence
of
two
ring
oxo
groups
in
hexazinone.
As
a
result,
hexazinone
is
less
aromatic
in
character
than
the
chloro­
s­
triazines.
Collectively,
these
structural
differences
are
considered
to
contribute
differences
in
toxicological
properties.
Hexazinone
has
been
classified
­12­
as
a
triazine­
dione
by
EPA,
which
further
indicates
this
Agency
acknowledges
its
differences
from
the
chloro­
s­
triazine
herbicide
class.

Hexazinone
has
been
extensively
tested
for
safety
to
mammals.
A
key
difference
between
hexazinone
and
atrazine
and
other
members
of
the
chloro­
s­
triazine
class
is
that
chronic
exposures
to
the
latter
produce
a
characteristic
mammary
tumor
response
in
Sprague­
Dawley
rats.
The
mode
of
action
for
this
chloro­
s­
triazine
induced
tumor
response
has
been
associated
with
altered
endocrine
activity
unique
to
this
rat
strain.
In
contrast
hexazinone
does
not
induce
rat
mammary
tumors,
which
indicates
the
absence
of
the
endocrine
modulation
responsible
for
this
effect.
Additional
evidence
supporting
the
absence
of
endocrine
effects
with
hexazinone
includes
the
absence
of
endocrine
organ
effects
and
effects
on
reproduction
and
development.
The
differences
in
chemical
structures
are
considered
to
be
critical
to
the
observed
differences
in
toxicological
response
between
hexazinone
and
the
chloro­
s­
triazines.

Agency
Response
32:
As
stated
in
the
HED
Chapter
of
the
hexazinone
risk
assessment,
there
was
no
evidence
of
endocrine
disruption
in
the
hexazinone
toxicological
database.
However,
when
appropriate
screening
and/
or
testing
protocols
have
been
developed
through
the
Endocrine
Disruptor
Screening
Program
(EDSP)
hexazinone
may
be
subject
to
additional
screening
and/
or
testing
to
further
characterize
effects
related
to
endocrine
disruption.

Section
7.0
Data
Gaps
"HIARC
has
requested
a
28­
day
inhalation
study
because
of
the
concern
for
inhalation
exposure
based
on
the
use
pattern"

 
It
is
unclear
as
to
which
use
pattern
is
being
considered.
There
are
no
residential
uses
of
hexazinone.
Most
of
the
use
patterns
are
outside
the
scope
of
WPS.
Since
no
use
patterns
of
concern
are
identified,
it
is
impossible
to
determine
duration
of
exposure.

 
On
the
same
page
that
it
requests
a
28­
day
inhalation
study,
the
Agency
notes
that
it
already
has
an
unreviewed
21­
day
inhalation
study
(MRID
#
00063972,
HLR
447­
76).
In
that
study,
groups
of
ten
male
rats
were
exposed
6
hours/
day,
5
day/
week
for
3
weeks
to
0
(control)
or
2.5
mg/
L
of
90%
wettable
powder
formulation
of
hexazinone.
Using
the
guidance
in
(Whalan
EPA,
1997)
this
represents
an
exposure
of
greater
than
600
mg/
kg/
day
(2.25
mg
hexazinone
a.
i./
L
x
11.38
L/
hr
respiration
x
6
hr/
day
exposure/
0.25
kg
body
weight
).
Histopathology
examination
indicated
that
lung
changes
were
similar
between
control
and
hexazinone
exposed
rats.
Intermittent
weight
losses
were
noted
throughout
the
test
period
but
all
rats
showed
a
normal
rate
of
weight
gain
during
the
recovery
period
.
­13­
The
Registrant
acknowledges
that
this
is
an
old
study
which
was
conducted
prior
to
issuance
of
current
guidelines.
However,
it
clearly
indicates
that
repeated
exposure
to
hexazinone
dust
poses
negligible
inhalation
risk.
It
also
suggests
that
no
further
inhalation
testing
is
required
since
no
lung
toxicity
was
identified
and
since
the
exposure
producing
minimal
to
moderate
toxicity
was
two
orders
of
magnitude
higher
than
the
chronic
NOAEL
that
has
just
been
selected
by
the
Agency
to
set
an
inhalation
endpoint.
Therefore
the
oral
endpoint
selected
is
overly
protective.
In
the
interest
of
conservation
of
animals
we
strongly
urge
that
available
information
be
considered
before
the
Agency
request
another
study
and
the
repeated
dose
inhalation
be
removed
as
a
data
gap.

Agency
Response
33:
See
Agency
Response
3
(above).

For
the
rabbit
developmental
toxicity
data
gap
we
recommend
changing
the
statement
"is
expected
to
be
submitted"
to
"was
not
submitted
in
enough
time
for
review
prior
to
issuance
of
this
document"

Agency
Response
34:
This
statement
has
been
removed
from
the
most
recent
HIARC
report
(August
12,
2002,
TXR
0051033)
and
the
receipt
and
acceptance
of
the
developmental
toxicity
study
in
the
rabbit
is
reflected
appropriately
in
all
supporting
documentation
to
the
HED
risk
assessment.
­14­
HED
Chapter
of
the
Hexazinone
TRED
Section
1.0
Executive
Summary
The
most
significant
recommendation,
in
our
view,
contained
in
the
draft
documents
pertains
to
the
revocation
of
tolerances
and
associated
use
of
hexazinone
on
grass.
We
acknowledge
that
guidelines
and
interpretations
regarding
the
practicality
of
grower
control
over
cattle
grazing
intervals
have
changed
since
data
supporting
this
use
pattern
were
last
submitted.
However,
as
indicated
in
your
review,
this
is
a
rather
minor
use
and
our
information
indicates
that
the
current
label
restrictions
regarding
cutting
and
grazing
are
being
complied
with.
Therefore,
the
tolerances
supporting
the
use
are
sufficient.
Given
the
above,
we
request
that
the
existing
tolerances
and
use
pattern
be
maintained
while
we
conduct
new
residue
work
to
support
EPA's
interpretation
regarding
a
zero
day
grazing
interval.

Agency
Response
35:
The
Agency
cannot
reassess
the
tolerances
for
pasture
and
rangeland
grasses
without
these
data.
These
data
remain
outstanding
for
hexazinone
and
must
be
fulfilled
before
tolerance
reassessment
can
be
completed.
Therefore,
no
changes
are
made
to
the
Executive
Summary
concerning
this
issue.

We
understand
that
our
recently
submitted
Rabbit
Developmental
Toxicity
Study
(DuPont­
7405,
MRID
45677801)
was
not
reviewed
in
time
to
be
included
in
the
Draft
TRED.
In
view
of
the
pivotal
importance
of
this
study
to
the
overall
conclusions
of
the
final
TRED
(specifically,
the
current
proposal
to
declare
a
significant
gap
in
the
toxicology
data
base,
the
selection
of
appropriate
end
points
for
regulatory
purposes
and
the
imposition
of
an
additional
10X
safety
factor
due
to
an
incomplete
data
base),
we
respectfully
request
that
this
study
be
reviewed
as
quickly
as
possible
to
be
included
in
the
final
TRED.

Agency
Response
36:
See
Agency
Response
4
(above).

We
also
note
in
the
toxicology
review
that
"Gene
mutation
–
bacterial"
is
listed
as
an
unsatisfied
requirement.
We
have
recently
submitted
(June
28,
2002,
no
MRID
yet
assigned)
a
new
Ames
assay
with
the
75
DF
formulation
which
we
believe
will
satisfy
this
requirement.

Agency
Response
37:
See
Agency
Response
2
(above).

Finally,
we
do
not
believe
a
28­
day
inhalation
study
should
be
required
until
the
existing
and
submitted
21­
day
inhalation
study
(MRID
00063972)
has
been
reviewed.
­15­
Agency
Response
38:
See
Agency
Response
3
(above).

Section
3.0
Hazard
Characterization
Hazard
Profile.
Table
1:
Acute
Toxicity:
For
Inhalation
LC50>
3.94
mg/
L
(4
hour),
add
(25%
formulation).

Agency
Response
39:
See
Agency
Response
7
(above).

Table
2:
Toxicity
Profile.
870.3465,
"A
28­
day
inhalation
study
is
required."
As
noted
in
the
HIARC
document,
an
unreviewed
21­
day
inhalation
study
is
available
(MRID
00063972)
which
indicates
that
repeated
exposure
to
hexazinone
dust
poses
negligible
inhalation
risks
and
that
no
further
inhalation
testing
should
be
required.
The
Registrant
requests
that
existing
data
be
reviewed
before
additional
testing
is
required.

Agency
Response
40:
See
Agency
Response
3
(above).
No
change
is
made
in
response
to
this
comment.

870.3700b
Prenatal
Developmental
Toxicity.
Unacceptable/
Upgradeable.
The
registrant
has
submitted
a
new
rabbit
developmental
study
(DuPONT­
7405,
MRID
45677801)
which
addressed
the
deficiencies
and
supports
the
conclusions
of
the
original
study
Agency
Response
41:
See
Agency
Response
4
(above).
This
study
is
acceptable
and
appropriately
listed
in
the
Toxicological
Profile
Table
2
in
the
HED
Chapter
of
the
Hexazinone
Risk
Assessment.

870.5100
Reverse
mutation
in
Samonella
Strains.
Unacceptable:
DuPont
has
conduct
a
Ames
assay
for
the
75DF
formulation
in
both
Salmonella
and
E.
Coli
at
up
to
5000
ug/
plate
(=
3750
ug/
plate
a.
i.)
that
can
be
submitted,
if
needed,
to
satisfy
this
requirement.
The
results
were
negative
for
gene
mutations
in
both
species.

Agency
Response
42:
See
Agency
Response
2
(above).

870.5385
In
vivo
Rat
Bone
Marrow
Cytogenetics
Assay.
Unacceptable.
Add,
"However
this
Guideline
is
fulfilled
by
an
acceptable
mouse
micronucleus
study."

Agency
Response
43:
See
Agency
Response
13
(above).

FQPA
Considerations
and
Dose
Response
Assessment:
Acute
Reference
Dose
Females
13­
50.
The
Agency
assigned
an
additional
10x
database
uncertainty
factor
because
a
rabbit
developmental
study
was
unacceptable
due
to
uncertainties
in
the
LOEL.
A
new
rabbit
developmental
study
(DuPont­
7405,
MRID
­16­
45677801)
to
the
Agency
which
addresses
the
deficiencies
and
supports
the
previous
study.
Once
the
new
rabbit
study
is
reviewed,
the
registrant
believes
the
extra
10x
uncertainty
factor
should
be
removed.

Agency
Response
44:
See
Agency
Response
4
(above).

Acute
Aggregate
Risk
Assessment.
The
headings
for
the
last
three
columns
for
Table
11
(page
42)
should
specify
µg/
l
rather
than
g/
l.

Agency
Response
45:
The
headings
are
written
as
µg/
l
in
Table
11.
­17­
Report
of
the
FQPA
Safety
Factor
Committee
3.
Degree
of
Concern
and
Residual
Uncertainties.
For
setting
the
acute
reference
dose
(ARfD)
for
females
of
childbearing
age,
the
Agency
assigned
an
additional
10x
database
uncertainty
factor
(UFdb
)
because
a
rabbit
developmental
study
was
unacceptable
due
to
uncertainties
in
the
LOEL.
A
UFdb
factor
of
10x
rather
than
3x
was
used
because,
based
on
extrapolation
to
the
rabbit
pilot
NOEL
of
50
mg/
kg
in
the
previous
study,
it
was
concluded
the
difference
between
rabbits
and
rats
may
be
greater
than
3x.

Immediately
after
the
HIARC
report
issued,
the
Registrant
submitted
a
new
rabbit
developmental
study
(DuPont­
7405,
MRID
45677801)
to
the
Agency.
The
new
rabbit
developmental
study
was
conducted
using
current
guidelines
and
confirmed
the
results
of
the
previous
rabbit
developmental
study.
The
maternal
and
fetal
rabbit
NOAEL
was
50
mg/
kg/
day.
The
maternal
and
fetal
LOAEL
was
125
mg/
kg/
day
based
on
weight
effects,
which
were
only
slight
in
the
fetus.
A
higher
dose,
175
mg/
kg/
day
produced
severe
maternal
toxicity.

Once
the
new
rabbit
study
is
reviewed,
if
it
is
selected
as
the
basis
of
the
ARfD,
the
registrant
believes
the
extra
10x
UFdb
should
be
removed.

Agency
Response
46:
See
Agency
Response
4
(above).
The
receipt
and
acceptance
of
the
developmental
toxicity
study
in
the
rabbit
is
also
reflected
in
report
Hexazinone
2
nd
Report
of
the
FQPA
Safety
Factor
Committee
(TXR
No.
0051049
dated
August
8,
2002.)
­18­
Dietary
Risk
Assessment
An
acute
endpoint
is
only
given
for
females
13­
50.
We
assume
this
group
is
considered
by
EPA
to
be
the
most
sensitive
sub­
population.

Agency
Response
47:
The
toxic
endpoint
with
which
acute
dietary
exposure
is
assessed
is
a
decrease
in
male
and
female
fetal
body
weight
and
increased
incidence
of
malformations
and
variations
of
the
fetus.
Because
the
toxic
endpoint
for
acute
dietary
exposure
concerns
in
utero
exposure,
the
risk
assessment
is
performed
for
females
of
childbearing
age
(females
13­
50)
since
only
members
of
this
group
are
at
risk
of
being
pregnant
at
the
time
of
exposure.

In
several
places
we
note
the
risk
assessment
is
based
on
the
reassessed
tolerances
for
blueberry,
pineapple,
and
sugarcane.
For
blueberries
and
pineapple
0.3
ppm
is
utilized,
presumably
one­
half
of
the
new
proposed
tolerance
of
0.6
ppm.
However,
for
sugarcane
0.6
ppm
(tolerance)
is
utilized.
This
appears
to
be
an
inconsistency.
Stated
differently,
it
is
not
clear
to
us
why
0.3
ppm
was
selected
for
blueberry
and
pineapple
while
0.6
ppm
was
selected
for
sugarcane.

Agency
Response
48:
This
was
an
error
and
has
been
corrected
in
the
documents
prepared
for
Phase
III
of
the
public
participation
process.
Residue
estimates
for
blueberry
and
pineapple
are
0.6
ppm.
(See
Revised
Acute
and
Chronic
Dietary
Exposure
Assessment
for
the
Hexazinone
TRED,
July
30,
2002.)

Clarity
is
needed
around
the
definition
of
LOQ.
There
are
both
enforcement
methods
(sum
of
LOQs
is
0.55
ppm)
and
data
collection
methods
(sum
of
LOQs
is
0.3
ppm).
We
recommend
that
the
enforcement
LOQs
be
used
consistently
throughout
the
document.

Agency
Response
49:
The
LOQ's
for
the
enforcement
method
is
used
for
dietary
exposure
estimates.

We
note
that
a
more
up
to
date
consumption
database
exists,
CSFII
94­
96/
98.
Why
was
the
older
database,
CSFII
89­
92,
used?

Agency
Response
50:
At
this
time,
it
is
Agency
policy
to
use
the
CSFII
1988­
1992
food
consumption
database
to
perform
dietary
exposure
and
risk
assessment.