HEXAZINONE
TOLERANCE
REASSESSMENT
ELIGIBILITY
DECISION
TOXICOLOGY
CHAPTER
FOR
THE
TRED
5/
30/
02
DuPONT
COMMENTS
2.0
REQUIREMENTS
·
Guideline
Numbers
need
to
be
filled
in
for
Structural
Chromosome
Aberrations
(870.
5375
and
870.5385)
and
Other
Genotoxic
Effects
(870.5550)

·
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.

1.03
DATA
GAPS
1.
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.

2.
A
new
Rabbit
Developmental
Toxicity
Study
has
recently
been
submitted.
(DuPONT­
7405,
MRID
45677801)

1.03
HAZARD
ASSESSMENT
4.1
Acute
Toxicity
Page
5
References:
The
references
for
all
the
acute
tox
citations
have
been
omitted
from
the
reference
list.
Should
they
be
included?

Acute
Dermal
Rabbit
Add
date
(1973)
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.

4.2
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.

870.3465
Page
8
90­
Day
Inhalation
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
870.3700b
Prenatal
Developmental
Toxicity
Study
–
Rabbit
Page
10
This
should
be
updated
to
reflect
that
a
new
rabbit
developmental
study
was
submitted
(5/
19/
02
MRID
45677801)

4.7
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."

4.7.3
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).
4.7.4
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."

4.7.5
Page
22
870.5395
Change
the
last
sentence
from
"It
satisfy
the
requirements…."
to
"It
satisfies
the
requirements…."

6.0
FQPA
CONSDERATIONS
6.1
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.

8.0
REFERENCES
Acute
Toxicity
references
have
been
omitted.

9.0
APPENDICES
Insert
page
break
before
appendices
9.1.1
Acute
Toxicity
Table
Header
should
read:
"Acute
Toxicity
Data
on
HEXAZINONE"
NOT
"Acute
Toxicity
Data
on
FENBUTATIN­
OXIDE"

9.1.2
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.

9.2
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.
