TXR#

DATE:
4/
25/
02
MEMORANDUM
SUBJECT:
HEXAZINONE
­
2
nd
Report
of
the
Hazard
Identification
Assessment
Review
Committee.

FROM:
David
G.
Anderson
Toxicologist.
Reregistration
Branch­
2
Health
Effects
Division
(7509C)

THROUGH:
Jess
Rowland,
Co­
Chair
and
Elizabeth
Doyle,
Co­
Chair
Hazard
Identification
Assessment
Review
Committee
Health
Effects
Division
(7509C)

TO:
Carol
Christensen,
Risk
Assessor
Reregistration
Branch­
2
Health
Effects
Division
(7509C)

PC
Code:
107201
On
Dec
4,
2001,
the
Health
Effects
Division
(HED)
Hazard
Identification
Assessment
Review
Committee
(HIARC)
reviewed
the
recommendations
of
the
toxicology
reviewer
for
HEXAZINONE
with
regard
to
the
acute
and
chronic
Reference
Doses
(RfDs)
and
the
toxicological
endpoint
selection
for
use
as
appropriate
in
occupational/
residential
exposure
risk
assessments.
The
potential
for
increased
susceptibility
of
infants
and
children
from
exposure
to
HEXAZINONE
was
also
evaluated
as
required
by
the
Food
Quality
Protection
Act
(FQPA)
of
1996.
On
April
02,
2002,
HIARC
evaluated
the
need
for
an
additional
database
uncertainty
factor
for
the
lack
of
an
acceptable
prenatal
developmental
study
conducted
in
the
rabbit
under
the
new
OPP
10X
guidance
document.
The
conclusions
drawn
at
both
meetings
are
presented
in
this
report.
2
Committee
Members
in
Attendance
Members
present
were:
Ayaad
Assaad,
Bill
Burnam,
Jonathan
Chen,
Paula
Deschamp,
Pamela
Hurley,
John
Liccione,
Elizabeth
Mendez,
David
Nixon,
Jess
Rowland,
Virginia
Fornillo
Member(
s)
in
absentia:
Beth
Doyle
Data
evaluation
prepared
by:
David
G.
Anderson,
RRB2
Also
in
attendance
were:
Sherrie
Kinard,
Ken
Dockter,
Pauline
Wagner,
Diana
Locke
Data
Evaluation/
Report
presentation
David
G.
Anderson
Toxicologist
Report
Concurrence
Brenda
Tarplee,
Senior
Scientist
Science
Information
Management
Branch
3
1.
INTRODUCTION
On
December
4,
2001,
the
Health
Effects
Division
(HED)
Hazard
Identification
Assessment
Review
Committee
(HIARC)
reviewed
the
recommendations
of
the
toxicology
reviewer
for
HEXAZINONE
with
regard
to
the
acute
and
chronic
Reference
Doses
(RfDs)
and
the
toxicological
endpoint
selection
for
use
as
appropriate
in
occupational/
residential
exposure
risk
assessments.
The
potential
for
increased
susceptibility
of
infants
and
children
from
exposure
to
HEXAZINONE
was
also
evaluated
as
required
by
the
Food
Quality
Protection
Act
(FQPA)
of
1996.
On
April
02,
2002,
HIARC
evaluated
the
need
for
an
additional
database
uncertainty
factor
for
the
lack
of
an
acceptable
prenatal
developmental
study
conducted
in
the
rabbit
under
the
new
OPP
10X
guidance
document.
The
conclusions
drawn
at
both
meetings
are
presented
in
this
report.
The
last
review
of
the
hexazinone
toxicity
data
base
was
February
11,
1993,
by
the
RfD/
Peer
Review
Committee.
A
Reregistration
Eligibility
Document
was
issued
September,
1994
(EPA­
738­
F­
94­
019).

2.
HAZARD
IDENTIFICATION
2.1
Acute
Reference
Dose
(RfD)(
Population
Subgroup:
Females
13­
50)

Study
Selected:
Developmental
toxicity
Study
in
Rats
§
870.3700
MRID
No.:
40397501
Executive
Summary:
In
a
developmental
toxicity
study
(MRID
40397501),
hexazinone
(99.26%
a.
i.;
Lot#
S30306A,
Batch#
2/
36)
in
0.5%
methylcellulose
was
administered
orally
via
gavage
to
25
Crl:
CD
®
BR
female
rats/
group
at
dose
levels
of
0,
40,
100,
400,
or
900
mg/
kg
on
gestation
day
(GD)
7
through
16.
The
dosing
volume
was
10
mL/
kg
(calculated
by
reviewers).
All
dams
were
sacrificed
on
GD
22
and
their
fetuses
removed
by
cesarean
and
examined.

When
compared
to
concurrent
controls,
no
treatment­
related
changes
in
clinical
signs,
gross
pathology,
pregnancy
rate,
live
fetuses,
resorptions,
pre­
or
post­
implantation
loss,
corpora
lutea,
or
implantations
were
noted
at
any
dose
level
tested.
No
treatment­
related
findings
were
noted
in
the
100,
or
40
mg/
kg
groups.

In
the
900
mg/
kg
dams,
one
treatment­
related
death
occurred;
alopecia
and
an
enlarged
stomach
containing
fluid
and
food
were
noted
at
necropsy.
Decreased
(p<
0.05)
body
weight
gains
were
noted
during
GDs
15­
17
(937%)
and
17­
22
(917%).
In
addition,
body
weight
gains
were
decreased
(p<
0.05)
for
the
overall
(GDs
7­
17)
treatment
interval
(930%).
Gravid
uterine
weights
were
not
reported;
however,
adjusted
(for
gravid
uterine
weight)
terminal
body
weights
were
slightly
decreased
(96%;
p#0.05).
A
significant
(p#0.05)
trend
by
linear
combination
of
dose
ranks
from
ANOVA
was
noted
for
GDs
9­
11,
15­
17,
7­
17,
and
17­
22.
Decreased
(p#0.05)
food
consumption
was
observed
throughout
treatment
(GDs
7­
17;
916­
22%)
and
post­
treatment
(GDs
17­
22;
99%).
A
significant
(p#0.05)
trend
by
linear
combination
of
dose
ranks
from
ANOVA
was
noted
for
GDs
7­
9,
9­
11,
11­
13,
13­
15,
15­
17,
7­
17,
and
17­
22.
Also
a
significantly
decreased
food
consumption
was
seen
at
400
4
mg/
kg/
day
(GD9­
11;
91%)
and
(GD
7­
17;
98%).

In
addition,
relative
(to
body)
liver
weights
were
increased
(p#0.05)
in
the
400
(5.2%)
and
900
(5.6%)
mg/
kg
dams
compared
to
concurrent
controls
(4.9%).
Decreased
(p#0.05)
terminal
body
weights
were
noted
at
900
mg/
kg
(96%).
A
significant
(p#0.05)
trend
by
linear
combination
of
dose
ranks
from
ANOVA
was
noted
for
relative
liver
weights
and
adjusted
terminal
body
weights.
In
addition,
a
significant
(p#0.05)
trend
by
linear
combination
of
dose
ranks
from
ANOVA
was
noted
for
absolute
liver
weights.
Despite
this
trend,
the
observed
increases
in
absolute
liver
weights
at
100,
400,
and
900
mg/
kg
(81­
8%)
were
not
statistically
significant.
Liver
weight
findings
are
considered
equivocal.

The
maternal
LOAEL
is
400
mg/
kg/
day
based
on
decreased
food
consumption
during
dosing
and
nominal
decreases
in
body
weight
gain
from
day
7
to
day
17
and
at
all
measured
intervals
between
and
at
900
mg/
kg/
day
on
mortality
and
decreased
body
weight
gains
and
food
consumption.
The
maternal
NOAEL
is
100
mg/
kg/
day.

In
the
900
mg/
kg/
day
group,
male
and
female
fetal
weights
were
decreased
(921%;
p#0.05);
a
significant
(p#0.05)
trend
by
Jonckheere's
test
was
noted
for
this
parameter.
At
400
mg/
kg/
day,
only
female
fetal
weights
were
significantly
decreased
(2%)
but
were
not
considered
to
biologically
significantly
depressed.
At
900
mg/
kg/
day,
an
increased
(p#0.05)
incidence
of
misaligned
sternebra
(1),
a
variation,
was
observed
(fetal
incidence:
0.0217;
litter
incidence:
0.30)
relative
to
concurrent
controls
(fetal
incidence:
0.0066;
litter
incidence:
0.09).
In
addition,
an
increased
(p#0.05)
incidence
of
misaligned
sternebrae
(2+),
a
variation,
was
noted
(fetal
incidence:
0.0217;
litter
incidence:
0.30)
relative
to
concurrent
controls
(fetal
incidence:
0.0033;
litter
incidence:
0.04).
Furthermore,
an
increased
incidence
of
kidneys
with
no
papilla
was
observed
(fetal
incidence:
0.0347;
litter
incidence:
0.25)
relative
to
concurrent
controls
(fetal
incidence:
0.0062;
litter
incidence:
0.04).
Although
the
incidence
was
not
statistically
significant,
a
dose­
related
trend
(p#0.05)
was
observed.

The
developmental
toxicity
LOAEL
is
900
mg/
kg/
day,
based
on
decreased
male
and
female
fetal
weight
and
increased
incidence
of
kidneys
with
no
papilla
(malformation),
and
an
increased
incidence
of
misaligned
sternebrae
(variation).
The
developmental
toxicity
NOAEL
is
400
mg/
kg/
day.

The
developmental
toxicity
study
in
the
rat
is
classified
acceptable/
guideline
(OPPTS
870.3700;
§83­
3
a)
and
satisfies
the
guideline
requirement
for
a
developmental
toxicity
study
in
the
rat.

Dose
and
Endpoint
for
Establishing
RfD:
Developmental
NOAEL
is
400
mg/
kg/
day.
The
LOAEL
is
900
mg/
kg/
day
based
on
increased
kidneys
with
no
papillae
and
misaligned
sternebrae.

Uncertainty
Factor
(UF):
1000
(10X
intraspecies
variation;
10X
interspecies
extrapolation;
and
10X
additional
database
uncertainty
factor)
5
Comments
about
Study/
Endpoint/
Uncertainty
Factor:
The
malformations
(kidneys
with
no
papillae)
are
presumed
to
occur
after
a
single
and
thus
appropriate
for
acute
risk
assessment.
An
additional
database
uncertainty
factor
of
10X
is
required
for
lack
of
an
acceptable
prenatal
developmental
study
conducted
in
the
rabbit.
The
rabbit
developmental
toxicity
study
submitted
to
the
Agency
is
classified
as
unacceptable
because
of
uncertainties
in
the
effects
at
the
LOAEL
(125
mg/
kg/
day
based
on
possible
skeletal
and
total
abnormalities).
Although
this
study
is
unacceptable,
there
is
some
confidence
in
the
NOAEL
of
50
mg/
kg/
day
which
is
almost
ten­
fold
lower
than
that
used
to
establish
the
acute
RfD.
A
factor
of
10X
is
necessary
(rather
than
3X)
because
when
an
additional
10X
factor
is
applied
to
the
NOAEL
of
400
mg/
kg
used
to
calculate
the
acute
RfD,
the
resulting
extrapolated
dose
is
40
mg/
kg
(400
÷
10
=
40)
which
is
comparable
to
the
rabbit
study
NOAEL
of
50
mg/
kg/
day.
Therefore,
an
additional
10X
database
uncertainty
factor
is
applied
to
the
acute
RfD
for
Females
13­
50
to
account
for
the
possibility
that
a
lower
NOAEL/
LOAEL
may
be
demonstrated
in
the
rabbit.

2.2
Acute
Reference
Dose
(RfD)(
General
Population)

An
appropriate
endpoint
attributable
to
a
single
dose
was
not
identified
in
the
oral
studies,
including
the
rat
and
rabbit
developmental
studies.

2.3
Chronic
Reference
Dose
(RfD)

Study
Selected:
One­
Year
Chronic
Dog
Study
Guideline
#:
870.4100
MRID
No.:
42162301
Executive
Summary:
In
a
one­
year
chronic
toxicity
study,
hexazinone
(98%
a.
i.,
Lot
No.
T02118994)
was
administered
to
groups
of
5
male
and
5
female
beagle
dogs
in
the
diet
at
concentrations
of
0,
200,
1500,
or
6000
ppm
(MRID
42162301).
Time­
weighted
average
doses
for
the
treated
groups
were
5.00,
41.24,
and
161.48
mg/
kg/
day,
respectively,
for
males
and
4.97,
37.57,
and
166.99
mg/
kg/
day,
respectively,
for
females.

All
animals
survived
to
scheduled
necropsy.
Treatment­
related
clinical
signs
of
toxicity
included
the
observation
of
thinness
in
1/
5
mid­
dose
males,
3/
5
high­
dose
males,
and
1/
5
high­
dose
females.
Body
weights
of
the
high­
dose
groups
were
significantly
(p
#
0.05)
less
than
those
of
the
control
throughout
most
of
the
study.
Final
body
weights
of
the
high­
dose
males
and
females
were
78%
and
67%,
respectively,
of
the
control
levels.
Food
consumption
by
the
high­
dose
groups
was
slightly
(n.
s.)
less
than
that
of
the
controls
throughout
the
study
with
statistical
significance
(p
#
0.05)
attained
for
females
at
week
52.
Overall
food
consumption
(weeks
1­
52)
for
high­
dose
males
and
females
was
85%
(n.
s.)
and
74%
(p
#
0.05),
respectively,
of
the
control
group
levels.
Body
weights
and
food
consumption
for
Acute
RfD
(Females
13­
50)
=
400
mg/
kg
=
0.40
mg/
kg
1000
(UF)
6
the
low­
and
mid­
dose
groups
were
not
affected
by
treatment.

No
treatment­
related
ophthalmological
lesions,
changes
in
urinalysis
parameters,
or
gross
necropsy
findings
were
noted.
A
moderate
macrocytic
anemia
was
observed
in
the
high­
dose
groups
as
evidenced
by
slight
or
significant
(p
#
0.05)
decreases
in
RBC
counts,
hemoglobin,
and
hematocrit
and
increases
in
MCV
and
MCH
in
one
or
both
sexes
throughout
the
study.
Cholesterol
levels
were
significantly
(p
#
0.05)
decreased
in
the
high­
dose
groups
beginning
at
week
13
for
males
(52­
64%
of
controls)
and
at
week
26
for
females
(45­
51%
of
controls).
Albumin
levels
were
significantly
(p
#
0.05)
decreased
in
the
mid­
dose
males
(93%
of
controls)
at
week
13
only,
and
in
the
high­
dose
males
(74­
78%
of
controls)
and
females
(75­
82%
of
controls)
throughout
the
study.
Beginning
on
week
13
or
26,
the
high­
dose
groups
had
aspartate
aminotransferase
levels
140­
203%
(p
#
0.05)
of
the
control
values
and
alanine
aminotransferase
levels
206­
276%
(p
#
0.05)
of
the
control
values.
Alkaline
phosphatase
levels
were
significantly
(p
#
0.05)
increased
in
the
mid­
dose
males
(259­
409%
of
controls)
and
females
(163­
194%
of
controls;
n.
s.)
beginning
at
week
26
and
in
the
high­
dose
males
(346­
1363%
of
controls)
and
females
(307­
559%
of
controls)
beginning
at
week
13.

For
the
high­
dose
animals,
decreases
in
absolute
testes
weights
in
males
and
kidney,
heart,
and
brain
weights
in
females
(­
12%)
and
increases
in
relative
liver
weights
in
males
and
females
were
considered
due
to
lower
final
body
weights
of
these
animals
as
compared
with
controls.

Microscopic
lesions
in
the
liver
of
high­
dose
animals
included
concentric
membranous
bodies
in
4
males
and
5
females,
centrilobular
single
cell
necrosis
in
3
males
and
3
females,
hepatocellular
pigment
in
3
males
and
3
females,
and
vacuolation
in
3
males
and
4
females.
In
addition
vacuolation
was
observed
in
one
mid­
dose
male
and
pigment
and
membranous
bodies
were
each
observed
in
one
mid­
dose
female.
These
lesions
were
not
seen
in
control
or
low­
dose
animals.

Therefore,
the
LOAEL
for
hexazinone
in
male
and
female
beagle
dogs
is
1500
ppm
(41.24
and
37.57
mg/
kg/
day,
respectively)
based
on
thinness
in
one
male
and
hepatotoxicity
as
evidenced
by
changes
in
clinical
chemistry
parameters
and
microscopic
lesions.
The
NOAEL
is
200
ppm
(5.00
and
4.97
mg/
kg/
day,
respectively).

This
study
is
classified
as
Acceptable/
Guideline
and
satisfies
the
guideline
requirements
for
a
chronic
toxicity
study
[OPPTS
870.4100
(§
83­
1b)]
in
dogs.

Dose
and
Endpoint
for
Establishing
RfD:
NOAEL
of
5.0
mg/
kg/
day.
The
LOAEL
is
38
mg/
kg/
day
based
on
elevated
clinical
chemistry
values
(serum
alkaline
phosphatase,
serum
aspartate
aminotransferase),
other
changes
in
clinical
chemistry
values,
liver
microscopic
findings
and
body
weight
decrement
and
clinical
observation
of
thinnest
in
one
male
(4
of
10
males
and
females
at
the
next
higher
dose).
7
Uncertainty
Factor(
s):
100
Comments
about
Study/
Endpoint/
Uncertainty
Factor(
s):
The
study
is
of
the
appropriate
duration.
The
RfD/
peer
Review
Committee
chose
the
same
value
in
1994,
which
formed
the
basis
of
the
Chronic
RfD
for
the
1994
RED.
An
additional
database
uncertainty
factor
to
account
for
the
lack
of
an
acceptable
rabbit
developmental
study
is
not
necessary
when
assessing
chronic
dietary
exposure
since
the
NOAEL
of
5.0
mg/
kg/
day
in
the
dog
used
to
establish
the
chronic
RfD
is
ten­
fold
below
that
seen
in
the
rabbit
study
and
is
considered
to
be
adequately
protective.

2.4
Occupational/
Residential
Exposure
2.4.1
Short­
Term
(1
Day
­
1
Month)
and
Intermediate­
Term
(1
Month
­6
Months)
Incidental
Oral
Exposure
Toxicity
endpoints
for
incidental
oral
exposure
were
not
selected
since
there
are
no
residential
exposure
based
on
the
current
use
pattern
and
none
is
anticipated
in
the
future.

2.4.2
Dermal
Absorption
No
dermal
absorption
study
is
available.
For
dermal
absorption,
the
NOAEL
from
the
21­
day
dermal
toxicity
study
at
the
limit
dose
of
1000
mg/
kg/
day
was
considered
a
lower
bound
for
the
LOAEL,
which
was
compared
with
LOAEL
of
250
mg/
kg/
day
from
the
range­
finding
rabbit
study
(MRID#
00028863).
The
ratio
of
these
two
numbers
was
used
to
estimate
a
dermal
absorption
factor
of
25%.
The
range­
finding
study
was
chosen
instead
of
the
main
rabbit
developmental
toxicity
study
(MRID#
00028863)
for
comparison
because
the
main
study
was
considered
to
be
unacceptable
for
regulatory
purposes.

Dermal
Absorption
Factor:
25%

Comments
about
Study/
Endpoint:
The
use
of
a
25%
dermal
absorption
factor
for
route
to
route
extrapolation
of
oral
studies
to
occupational
dermal
exposure
would
be
protective
of
the
developmental
effects
seen
in
the
rat
study.

2.4.3
Short­
Term
Dermal
(1
Day
­
1
Month)
Exposure
Chronic
RfD
=
5.0
mg/
kg/
day
(NOAEL)
=
0.05
mg/
kg/
day
100
(UF)
8
Study
Selected:
None
MRID
No.:
None
Executive
Summary:
None
Dose
and
Endpoint
for
Risk
Assessment:
Not
applicable
Comments
about
Study/
Endpoint:
No
hazard
and
no
quantification
required.
There
were
no
systemic
effects
at
1000
mg/
kg/
day,
limit
dose,
in
the
21­
day
dermal
study
in
rabbits
(MRID#
41309005).
The
oral
developmental
NOAEL
(400
mg/
kg/
day)
in
conjunction
with
the
use
of
25%
dermal
absorption
factor
yields
a
dermal
equivalent
dose
of
1600
mg/
kg/
day
[(
400/
0.25)=
1600
mg/
kg/
day],
which
is
higher
than
the
limit
dose
in
the
rabbit
21­
day
dermal
study
and
thus
would
address
the
concerns
for
developmental
toxicity
seen
at
900
mg/
kg/
day.

2.4.4
Intermediate­
Term
Dermal
(1­
6
Months)
and
Long­
Term
Dermal
(longer
than
6
Months)
Exposure
Study
Selected:
Chronic
Feeding
Study
in
Dogs
§
870.4100
MRID
No.:
42162301
Executive
Summary:
[See
Section
2.3
on
the
Chronic
Reference
Dose
(RfD).]

Dose/
Endpoint
for
Risk
Assessment:
NOAEL
is
based
on
elevated
clinical
chemistry
values
(serum
alkaline
phosphatase,
serum
aspartate
aminotransferase),
other
changes
in
clinical
chemistry
values,
liver
microscopic
findings
and
body
weight
decrement
and
the
clinical
observation
of
thinnest
in
one
males
at
38
mg/
kg/
day.

Comments
about
Study/
Endpoint:
The
elevation
in
clinical
chemistry
parameters
were
seen
at
3
and
6
months
and
thus
appropriate
for
the
exposure
period.
Since
an
oral
NOAEL
was
selected,
a
25%
dermal
absorption
factor
should
be
used
for
route
to
route
extrapolation.

2.4.5
Short­
Term
Inhalation
Exposure
(1
day
to
1
Month)

Study
Selected:
Developmental
Toxicity
in
the
Rat
§
870.3700
MRID
No.:
40397501
Executive
Summary:
[See
Section
2.1
Acute
Reference
Dose
(RfD).]

Dose/
Endpoint
for
Risk
Assessment:
The
maternal
NOAEL
of
100
mg/
kg/
day
based
on
based
on
maternal
body
weight
and
food
consumption
decrement
at
400
mg/
kg/
day.
9
Comments
about
Study/
Endpoint:
In
the
absence
of
a
inhalation
study
an
oral
NOAEL
was
selected.
Absorption
via
the
inhalation
route
is
assumed
to
be
equivalent
to
oral
absorption.

2.4.6
Intermediate­
Term
inhalation
(1
Month
to
6
Months)
and
Long­
Term
Inhalation
(longer
than
6
Months)
Exposure.

Study
Selected:
Chronic
Feeding
Study
in
Dogs
§
870.4100
MRID
No.:
42162301
Executive
Summary:
[See
Section
2.3
on
the
Chronic
Reference
Dose
(RfD).]

Dose/
Endpoint
for
Risk
Assessment:
NOAEL
of
5.0
mg/
kg/
day
based
on
elevated
clinical
chemistry
values
(serum
alkaline
phosphatase,
serum
aspartate
aminotransferase),
other
changes
in
clinical
chemistry
values,
liver
microscopic
findings
and
body
weight
decrement
and
clinical
observation
of
thinnest
in
one
males
at
38
mg/
kg/
day.

Comments
about
Study/
Endpoint:
The
affects
seen
in
clinical
chemistry
values
at
3,
6
and
12
months
are
appropriate
for
these
exposure
periods.
Absorption
via
the
inhalation
route
is
presumed
to
be
equivalent
to
oral
absorption.

2.5
Margins
of
Exposure
for
Occupational/
Residential
Risk
Assessment
A
margin
of
exposure
of
100
is
adequate
for
occupational
dermal
and
inhalation
exposure.
There
is
no
non­
occupational
(residential)
exposures
identified
at
this
time.

2.6
Recommendation
for
Aggregate
Exposure
Risk
Assessments
Aggregate
exposure
risk
assessment
is
not
required
since
there
are
no
non­
occupational
(residential)
uses
at
the
present
time.

3.
CLASSIFICATION
OF
CARCINOGENIC
POTENTIAL
3.1
Combined
Chronic
Toxicity/
Carcinogenicity
Study
in
Rats
MRID
No.:
00108638
Executive
Summary:
In
this
combined
chronic/
oncogenicity
study
(MRID
00108638),
hexazinone
(94­
96%
a.
i.;
Lot/
Batch
#:
6897­
40
and
74.25)
was
administered
in
the
diet
to
ChR­
CD
rats
(36/
sex/
group)
for
up
to
25
months
at
nominal
doses
of
0,
0,
200,
1000,
or
2500
ppm
(equivalent
to
0,
0,
10.2,
53.4,
and
138.3
mg/
kg/
day
in
males
and
0,
0,
12.5,
67.5,
and
178.6
mg/
kg/
day
in
females).
10
No
treatment­
related
differences
were
observed
in
mortality,
clinical
signs,
food
consumption,
hematology,
clinical
chemistry,
organ
weights,
and
gross
or
microscopic
pathology.
No
adverse
effects
were
observed
in
the
200
ppm
animals.
There
were
several
signs
of
general
toxicity,
but
a
target
organ
could
not
be
clearly
identified
at
any
dose.

Terminal
body
weights
were
decreased
8%
in1000
ppm
and
20%,
p#0.05,
in
the
2500
ppm
females.
A
decrease
in
overall
body
weight
gain
(Days
0­
728;
calculated
by
the
reviewers)
was
also
observed
in
the
1000
(­
10%)
and
2500
ppm
(­
25%)
females.
Nominal
decreases
in
body
weight
and
body
weight
gain
(­
3
to
­5%)
occurred
in
males
at
1000
ppm
during
the
study,
which
may
have
been
biologically
significant
at
the
end
of
the
study
(­
12%
body
weight
and
­14%
for
body
weight
gain).

Decreases
(p­
values
not
calculated)
in
total
food
efficiency
were
observed
in
females
at
1000
(­
10%)
and
2500
ppm
(­
25%)
and
in
males
at
1000
ppm
during
the
study
with
overall
decrement
in
food
efficiency
in
1000
ppm
males
(­
10%).
In
males
at
2500
ppm,
food
efficiency
was
depressed
for
the
first
6
months
of
the
study
(­
25%),
but
from
6
months
to
the
end
of
the
study,
it
was
increased
139%.

The
reviewer
noted
problems
interpreting
the
body
weights
and
food
efficiency
in
males
at
the
top
dose
level,
which
were
not
consistent
with
the
mid­
dose
level.
For
the
first
6
months
of
the
study
in
males,
a
body
weight
decrement
due
to
probable
toxicity
was
seen
at
1000
and
2500
ppm.
After
6
months
food
efficiency
in
males
at
the
1000
ppm
remained
less
than
controls
(­
56%)
while
food
efficiency
at
2500
ppm
in
males
was
higher
than
controls
(+
139%)(
Table
4).
By
the
end
of
the
study,
male
body
weight
at
1000
ppm
was
­12%
and
body
weight
gain
­14%,
where
as
body
weight
and
body
weight
gain
in
males
at
2500
ppm
was
+3%
for
both
weight
and
gain.
The
reason
for
this
recovery
in
male
body
weight
decrement
at
2500
ppm
is
unknown,
but
it
appears
to
be
real.
[Since
absolute
and
relative
liver
weights
were
decreased
in
males
at
2500
ppm,
liver
enzyme
induction
allowing
the
recovery
seems
unproven.]
The
body
weight
decrement
at
1000
and
2500
ppm
with
recovery
in
body
weight
at
2500
ppm
indicates
the
an
adequate
dose
level
to
test
for
carcinogenicity
in
males
was
approached,
but
probably
not
attained.
Other
treatment
groups
were
similar
to
the
average
of
concurrent
controls.

Dosing
was
considered
adequate
based
on
decreased
body
weights,
body
weight
gains,
and
food
efficiency
in
the
2500
and
1000
ppm
females
and
food
efficiency
and
body
weights
in
the
2500
ppm
males
for
the
first
6
months.
Body
weight
(­
12%)
and
body
weight
gain
(­
14%)
in
males
at
1000
ppm
were
decreased
at
the
end
of
the
study,
in
addition
overall
food
efficiency
(­
14%)
was
decreased
by
the
end
of
the
study.

Thus
female
body
weight
and
body
weight
gain
was
decreased
sufficiently
to
adequately
test
for
carcinogenicity.
Male
body
weight
and
body
weight
gain
at1000
ppm
appeared
to
be
adequate
to
test
for
carcinogenicity
by
the
end
of
the
study,
but
the
lack
of
dose
response
in
male
body
weight
and
body
11
weight
gain
at
2500
ppm
(showing
recovery
after
6
months
such
that
body
weight
and
body
weight
gain
were
higher
than
control
values)
may
indicate
problems
with
the
interpretation
of
the
body
weights
and
body
weight
gains
at
1000
ppm.

In
the
2500
ppm
males,
creatinine
was
increased
(NS)
in
the
urine
at
months
18
and
24
and
bilirubin
was
detected
at
month
18
and
24.
The
Sponsor
reported
that
the
urine
was
more
alkaline
in
the
2500
ppm
treatment
groups
(data
not
reported).
Also
at
2500
ppm,
decreased
(p#0.05)
absolute
and
relative
liver
and
kidney
organ
weights
were
observed
in
the
males
and
increased
(p#0.05)
relative
(to
body)
stomach
and
kidney
organ
weights
were
observed
in
the
females.
However,
histopathological
data
did
not
corroborate
these
findings.

The
LOAEL
is
1000
ppm
for
males
and
females
(equivalent
to
53.3
for
males
and
67.5
mg/
kg/
day
for
females)
based
on
decreased
body
weight
and
food
efficiency
in
males
and
females.
In
males
at
2500
ppm
the
body
weight
decrement
and
food
efficiency
decrement
occurred
only
for
the
first
6
months
of
the
study.
The
NOAEL
is
200
ppm
for
males
and
females
(10.2
for
males
and
12.5
mg/
kg/
day
for
females).

Neoplasm
data
were
evaluated
by
two
pathologists.
An
increase
incidence
of
thyroid
C­
cell
adenomas
was
observed
in
the
2500
ppm
males,
but
when
analyzed
by
the
Fisher's
exact
test
(p>
0.10)
or
life­
table
methods
(p>
0.20)
no
significant
differences
were
observed
between
controls
and
treated
groups.
Using
life­
table
analyses
a
significant
(p<
0.05)
dose­
response
trend
was
observed
in
thyroid
C­
cell
tumors
in
only
one
of
the
two
pathology
reports.
Female
rats
did
not
show
any
potential
for
C­
cell
thyroid
adenomas.
The
incidence,
malignancy
and
latency
of
tumors
were
comparable
among
control
and
treated
rats
of
both
sexes.

Under
the
conditions
of
this
study,
carcinogenic
potential
of
hexazinone
is
considered
negative.

The
submitted
study
is
classified
as
acceptable
for
guideline
870.4300
combined
chronic/
carcinogenicity
study
in
rats.

Discussion
of
Tumor
Data:
Neoplasm
data
were
evaluated
by
two
pathologists.
An
increase
incidence
of
thyroid
C­
cell
adenomas
was
observed
in
the
2500
ppm
males,
but
when
analyzed
by
the
Fisher's
exact
test
(p>
0.10)
or
life­
table
methods
(p>
0.20)
no
significant
differences
were
observed
between
controls
and
treated
groups.
Using
life­
table
analyses
a
significant
(p<
0.05)
dose­
response
trend
was
observed
in
thyroid
C­
cell
tumors
in
only
one
of
the
two
pathology
reports.
Female
rats
did
not
show
any
potential
for
C­
cell
thyroid
adenomas.
The
incidence,
malignancy
and
latency
of
tumors
were
comparable
among
control
and
treated
rats
of
both
sexes.
The
study
in
rats
does
not
support
a
carcinogenic
potential
for
hexazinone.

Adequacy
of
the
Dose
Levels
Tested:
The
dose
levels
in
female
rats
was
adequate
to
test
for
the
carcinogenic
potential
hexazinone.
There
was
an
adequate
body
weight
decrement
and
body
weight
12
gain
decrement
at
the
two
top
dose
levels.
The
dose
levels
in
male
rats
approached
an
adequate
dose
level
to
test
for
carcinogenic
potential
of
hexazinone.
There
may
have
been
an
adequate
body
weight
and
body
weight
gain
at
the
mid­
dose
level
at
the
end
of
the
study
to
test
for
carcinogenic
potential
of
hexazinone,
however
body
weights
of
males
at
the
top
dose
level
behaved
atypically.
At
the
top
dose
level,
males
showed
a
adequate
body
weight
decrement
only
for
the
first
6
months
of
the
study
and
by
the
end
of
the
study,
body
weights
were
higher
than
the
average
of
the
two
controls.
The
reason
for
this
reversible
body
weight
decrement
is
unknown,
but
the
top
dose
level
in
males
was
one­
half
the
top
dose
level
of
5000
ppm
in
the
90­
day
subchronic
study
in
males
where
liver
toxicity
was
seen.
These
body
weight
decrements
in
males
and
females
are
supported
by
a
corresponding
decrements
in
food
efficiency.

3.2
Carcinogenicity
Study
in
Mice
MRID
No.
41359301,42509301
and
4320290
§
870.4200
Executive
Summary:
In
this
mouse
oncogenicity
study
(MRIDs
00079203,
41359301,
42509301
and
43202901),
hexazinone
($95%
a.
i.;
Lot/
Batch
#:
H­
11,
265
and
265­
2)
was
administered
in
the
diet
to
CD­
1
mice
(80/
sex/
group)
for
up
to
104
weeks
at
nominal
doses
of
0,
200,
2500
or
10,000
ppm
(equivalent
to
28,
366
and
1635
mg/
kg/
day
in
males
and
0,
34,
450
and
1915
mg/
kg/
day
in
females).

No
treatment­
related
differences
were
observed
in
mortality,
food
consumption,
food
efficiency
or
hematology.

Hepatotoxicity
was
evident
at
the
terminal
sacrifice.
Macroscopic
liver
nodule/
mass
(%
treated
vs
%
controls;
n
=
28­
55)
was
observed
in
males
at
2500
(39%
vs
7%)
and
10,000
ppm
(33%).
Increased
incidences
(%
treated
vs
0%
controls;
n
=
38­
55)
in
the
following
microscopic
liver
lesions
were
observed:
hyperplastic
nodule(
s)
(includes
both
foci
of
cellular
alteration
and
adenoma)
in
males
at
2500
(39%
vs
20%)
and
10,000
ppm
(36%)
and
in
females
at
10,000
ppm
(15%
vs
3%);
and
necrosis
(severity
and
type
unspecified)
in
the
10,000
ppm
males
(36%
vs
7%).
Centrilobular
hepatocyte
hypertrophy
was
observed
(%
treated
vs
%
controls)
at
the
terminal
sacrifice
(n
=
38­
55)
in
males
at
2500
(18%
vs
0%)
and
10,000
ppm
(98%)
and
in
females
at
10,000
ppm
(46%
vs
0%)
and
in
the
dead
and
moribund
males
(n
=
25­
40)
at
2500
(44%
vs
0%)
and
10,000
ppm
(60%).
Increased
(p#0.05
or
0.01)
liver/
gall
bladder
weights
were
observed
at
10,000
ppm
in
males
in
both
absolute
and
relative
to
body
weights
and
in
females
in
relative
to
body
weight.

Other
signs
of
toxicity
were
evident.
Distal
tail
tip
sloughing
and/
or
discoloration
was
observed
at
10,000
ppm
in
males
at
Weeks
13­
104
and
in
females
at
Weeks
5
and
13­
104.
Macroscopically,
tip
of
tail
missing/
sloughed
was
observed
at
the
terminal
sacrifice
in
the
10,000
ppm
males
(31%
vs
5%)
and
females
(61%
vs
11%)
and
in
the
dead
and
moribund
10,000
ppm
females
(46%
vs
2%).
The
toxicological
significance
of
these
findings
was
unclear.
Minor
decreases
(p#0.05
or
0.01)
in
body
13
weights
were
observed
in
the
10,000
ppm
treatment
groups
at
Weeks
13­
104
in
both
sexes.
Overall
body
weight
gains
(calculated
by
the
reviewers)
were
decreased
in
the
10,000
ppm
males
(925%)
and
females
(931%).
The
LOAEL
is
2500
ppm
for
males
(equivalent
to
366
mg/
kg/
day)
based
on
gross
liver
nodules/
masses,
hyperplastic
nodules
in
the
liver
and
centrilobular
hepatocyte
hypertrophy
and
10,000
ppm
for
females
(equivalent
to
1915
mg/
kg/
day
[limit
dose])
based
on
decreased
body
weights,
increased
relative
liver/
gall
bladder
weights,
hyperplastic
nodules
and
centrilobular
hepatocyte
hypertrophy.
The
NOAEL
is
200
ppm
(equivalent
to
28
mg/
kg/
day)
for
males
and
2500
ppm
(equivalent
to
450
mg/
kg/
day)
for
females.

Liver
samples
were
first
evaluated
using
the
term
hyperplastic
nodule
which
did
not
clearly
distinguish
neoplasia
from
non­
neoplasia.
Reevaluation
was
conducted
to
make
this
distinction,
and
no
significant
differences
were
observed
between
the
treatment
groups
and
the
concurrent
controls.
However
positive
trends
(p<
0.05)
were
observed
(%
treated
vs
%
controls)
in
focus/
foci
of
cellular
alteration
in
males,
hepatocellular
neoplasm(
s)
(including
adenoma,
sarcoma,
carcinoma,
leukemia,
and
lymphoma)
in
females,
and
singular
hepatocellular
adenoma
in
females.
Focus/
foci
of
cellular
alteration
were
observed
in
males
at
2500
(11.3%
vs
5.0%)
and
10,000
ppm
(24.1%)
and
females
at
10,000
ppm
(12.5%
vs
3.8%)
beginning
at
Week
57.
Singular
hepatocellular
adenoma
was
observed
in
the
10,000
ppm
females
(7.5%
vs
2.5%)
beginning
at
Week
77.
Hepatocellular
neoplasm(
s)
were
observed
in
the
10,000
ppm
females
(8.8%
vs
2.5%).
A
carcinoma
in
the
10,000
ppm
treatment
groups
was
first
observed
at
Week
65.
The
incidence
of
carcinomas
were
within
historical
control
ranges
for
each
sex,
while
the
incidence
of
adenomas
were
increased
by
3.21%
in
the
10,000
ppm
females.
A
dosedependent
increase
in
adenomas
was
not
observed
in
males.
The
Health
Effects
Division
Carcinogenicity
Peer
Review
Committee
(CPRC)
concluded
that
hexazinone
should
be
classified
as
a
Group
D
(not
classifiable
as
to
human
carcinogenicity)(
7/
27/
94).

Under
the
conditions
of
this
study,
evidence
of
carcinogenic
potential
was
equivocal:
a
positive
trend
test
for
neoplasia
was
observed
in
female
mice,
but
no
significant
difference
was
determined
by
pair­
wise
comparison.

The
submitted
study
is
classified
as
acceptable
for
guideline
870­
4200
carcinogenicity
study
in
mice.

Discussion
of
Tumor
Data:
A
dose­
dependent
increase
in
adenomas
was
not
observed
in
males.
Under
the
conditions
of
this
study,
evidence
of
carcinogenic
potential
was
equivocal:
a
positive
trend
test
for
neoplasia
was
observed
in
female
mice,
but
no
significant
difference
was
determined
by
pairwise
comparison.

Adequacy
of
the
Dose
Levels
Tested:
Adequate
dose
levels
were
used
in
male
and
female
mice
to
test
for
the
carcinogenic
potential
of
hexazinone.
Liver
toxicity
was
seen
at
the
top
dose
level
in
males
and
females.

3.3
Classification
of
Carcinogenic
Potential
HED's
Carcinogenicity
Peer
Review
Committee
classified
hexazinone
as
a
Group
D
Chemical
(not
14
classifiable
as
to
human
carcinogenicity)
(7/
27/
94).
This
classification
was
based
on
the
following
weight
of
evidence
considerations.
In
rats,
females
showed
no
evidence
for
carcinogenicity;
males
showed
a
significant
trend
only
for
thyroid
adenomas.
In
mice,
the
evidence
of
carcinogenicity
was
equivocal:
a
positive
trend
test
for
liver
tumors
was
observed
in
female
mice,
but
no
significant
difference
was
seen
by
pair­
wise
comparison
(CPRC
Report
dated
July
27,
1994).

4.
MUTAGENICITY
The
required
mutagenicity
testing
is
complete.
This
section
was
copied
from
the
1994
RED
for
Hexazinone
and
the
updated
DERs.
One
mutagenicity
study
was
submitted
since
the
1994
RED
was
written;
a
negative
in
vivo
mammalian
micronucleus
test
in
mouse
bone
marrow
cells
(MRID#
45124401).

Hexazinone
was
found
to
be
positive
for
mutagenicity
in
one
chromosomal
aberration
assay
(in
vitro
cytogenics)
(MRID#
00130709),
but
negative
in
the
remaining
studies.
It
is
concluded
that
the
test
material
was
clastogenic
in
both
of
the
nonactivated
trials
and
was
also
clastogenic
in
the
one
adequate
S9­
activated
trials.
Under
both
test
conditions,
concentrations
providing
evidence
of
clastogenicity
induced
an
acceptable
level
of
cytotoxicity
(>
50%
relative
cell
survival).
Thus,
the
findings
can
not
be
considered
to
be
a
secondary
effect
of
cytotoxicity.
Nevertheless,
the
outcome
of
the
induced
structural
damage
(i.
e.,
primarily
chromatid
and
chromosome
breaks)
is
unclear
since
these
types
of
structural
aberrations
would
not
likely
be
passed
on
to
daughter
cells.
Because
unambiguous
positive
results
were
achieved,
it
was
concluded
that
the
study
provided
adequate
evidence
that
INA­
3674­
112
(hexazinone,
technical)
is
clastogenic
in
an
acceptable
study.

Guideline
870.5100
Gene
Mutation
Assay
in
Ames
Test:
Hexazinone
was
tested
with
metabolic
activation
(rat
liver
microsomal
fraction
commonly
known
as
S­
9
fraction,
plus
cofactors)
at
concentrations
ranging
from
400
to
2000
ug/
plate
and
without
metabolic
activation
at
concentrations
ranging
from
200
to
1000
ug/
plate.
The
strains
of
Salmonella
typhimurium
used
were
TA1535,
TA1537,
TA1538,
TA98
and
TA100.
No
increases
in
reverse
mutations
were
observed
at
any
concentration.
Positive
results
were
obtained
with
standard
reference
mutagens
(positive
controls)(
MRID
00098982).

Guideline
870.5100
Reverse
mutation
assay:
In
a
reverse
gene
mutation
assay
in
bacteria
(MRID
40826201),
strains
TA98,
TA100,
TA1535,
TA1537
and
TA1538
of
S.
typhimurium
were
exposed
to
Striazine
2,4(
1H,
3H)­
dione,
3­
cyclohexyl­
6­
dimethylamino­
1­
methyl­
(95%
a.
i.)
in
ethanol
at
concentrations
of
200,
400,
600,
800
and
1000
:g/
plate
without
mammalian
metabolic
activation
(S9­
mix)
and
at
concentrations
of
400,
800,
1200,
1600
and
2000
:g/
mL
with
S9­
mix.
The
S9­
fraction
was
obtained
from
Aroclor
1254
induced
male
Crl:
CD(
SD)
BR
rat
liver.

The
maximum
concentrations
of
S­
triazine­
2,4(
1H,
3H)­
dione,
3­
cyclohexyl­
6­
dimethylamino­
1­
methyl­
tested
produced
little
or
no
cytotoxicity,
were
not
limited
by
solubility
and
were
not
a
limit
dose
for
the
assay.
No
statistically
significant
increases
in
the
number
of
revertants
per
plate
or
positive
linear
dose­
response
were
seen.
The
solvent
and
positive
controls
induced
acceptable
responses
in
the
corresponding
strains.
There
was
no
evidence
of
induced
mutant
colonies
over
background.
15
This
study
is
classified
as
Unacceptable.
It
does
not
satisfy
the
requirement
for
FIFRA
Test
Guideline
[OPPTS
870.5100
(§
84­
2)]
for
in
vitro
mutagenicity
[bacterial
reverse
gene
mutation]
data
and
should
be
repeated
using
higher
doses.

Guideline
870.5300:
Gene
Mutation
Assay
in
Mammalian
Cells:
In
a
mammalian
cell
gene
mutation
assay
at
the
HGPRT
locus
(MRID
No.
00076956),
Chinese
hamster
CHO­
K1­
BH4
cells
cultured
in
vitro
were
exposed
to
INA­
3674­
112,
(Lot
No.
7612­
5E6E,
95%
a.
i.)
in
ethanol
in
two
trials.
Concentrations
used
in
Trial
1
were
2.0,
11.1,
13.1,
13.9
and
14.3
mM
under
nonactivated
conditions
and
concentrations
of
2.0,
7.9,
8.9,
9.3
and
9.9
mM
under
activated
conditions
(S9­
mix).
Concentrations
used
in
Trial
2
were
2.0,
5.9,
11.1,
13.1
and
13.9
mM
without
S9­
mix
and
concentrations
of
2.0,
7.9,
8.9,
9.3
and
9.9
mM
with
S9­
mix.
The
S9­
fraction
was
obtained
from
Aroclor
1254
induced
male
Charles
River
CD®
rat
livers.

INA­
3674­
112
was
tested
up
to
cytotoxic
concentrations.
In
Trial
1,
the
cultures
treated
at
14.3
mM
­S9
were
not
plated
for
mutation
determination
due
to
cytotoxicity
in
both
Trials
1
and
2.
Cytotoxicity
was
also
noted
at
9.9
mM
+S9.
No
statistically
significant
increases
in
mutant
frequency
over
solvent
control
values
were
seen
with
or
without
S9­
mix
in
either
Trial
1
or
2.
The
expected
marked
increase
in
the
mutation
were
seen
with
the
positive
controls.
There
was,
however,
no
indication
that
INA­
3674­
112
induced
a
mutagenic
effect
either
in
the
presence
or
the
absence
of
S9
activation.

This
study
is
classified
as
acceptable.
It
satisfies
the
requirement
for
FIFRA
Test
Guideline
OPPTS
[870.5300
(§
84­
2)]
for
in
vitro
mutagenicity
(mammalian
forward
gene
mutation)
data.

Guideline:
870.5395
Mouse
bone
marrow
micronucleus
assay:
In
a
Crl:
CD­
1
(ICR)
BR
mouse
bone
marrow
micronucleus
assay
(MRID
45124401),
5
mice/
sex/
dose/
harvest
time
were
treated
orally
with
Hexazinone
25L
(Lot
No.
9912033,
25%
Hexazinone
a.
i.
(24.5%
by
analysis)
and
75%
inert
ingredients)
at
doses
of
1000,
2000
and
3000
mg/
kg.
Bone
marrow
cells
were
harvested
at
24
and
48
hours
post­
treatment
and
examined
for
micronucleated
polychromatic
erythrocytes
(MPCEs).
The
vehicle
was
Milli­
Q
®
water.

Signs
of
toxicity
noted
at
3000
mg/
kg
included:
death,
convulsions,
half­
shut
eyes,
head­
tilt,
irregular
respiration,
lethargy,
low
carriage,
pallor,
prostration,
uncontrollable
spinning,
shovel­
nosing,
straining
up
on
toes
and
tremors.
Micronuclei
were
scored
in
bone
marrow
from
mice
treated
at
3000
mg/
kg
and
from
the
solvent
and
positive
controls.
Mice
from
the
two
lower
dose
groups
were
not
evaluated
for
micronuclei
induction.
No
statistically
significant
increases
in
the
frequency
of
MPCEs
or
in
the
PCE/
NCE
ratio
over
the
solvent
control
values
were
seen
in
either
sex
at
either
the
24
or
48
hour
harvest
time.
The
solvent
and
positive
control
values
were
appropriate
and
within
the
testing
laboratory's
historical
control
ranges.
There
was
no
evidence
that
Hexazinone
25L
induced
a
clastogenic
or
aneugenic
effect
in
bone
marrow
at
any
harvest
time.

This
study
is
classified
as
Acceptable/
Guideline.
It
satisfy
the
requirement
for
FIFRA
Test
Guideline
[OPPTS
870.5395
(§
84­
2)]
for
in
vivo
cytogenetic
mutagenicity
data.
16
Guideline
870.5375
Structural
Chromosome
Aberration
Assay;
In
vitro
Cytogenetic
Assay:
In
a
mammalian
cell
cytogenetics
assay
(MRID
No.
00130709),
Chinese
hamster
ovary
CHO­
K1
­BH4
cell
cultures
were
exposed
to
INA­
3674­
112
(Hexazinone,
95%
a.
i.)
in
ethanol
in
two
separate
trials.
Exposure
was
for
two
hours
with
activation
and
for
10
hours
without
activation.
Cells
were
harvested
10
hours
after
the
start
of
treatment.
In
Trial
1,
cells
were
treated
at
concentrations
of
1.58,
3.94,
15.85
and
19.82
mM
without
metabolic
activation
(S9­
mix)
and
at
concentrations
of
0.32,
3.17,
7.93
and
15.85
mM
with
S9­
mix.
In
Trial
2,
cells
were
treated
at
concentrations
of
1.58,
3.94,
7.93
and
15.85
without
S9­
mix
and
at
concentrations
of
0.32,
3.17,
7.93
and
15.85
mM
with
S9­
mix.
The
S9­
fraction
was
obtained
from
Aroclor
1254
induced
CD
rat
livers.

INA­
3674­
112
was
tested
up
to
cytotoxic
concentrations.
Based
on
the
results
of
a
preliminary
cytotoxicity
test,
upper
concentrations
of
23.78
mM
without
S9­
mix
and
47.56
mM
with
S9­
mix
were
selected
for
the
first
cytogenetic
assay
but
these
concentrations
proved
excessively
cytotoxic
and
were
not
scored
for
chromosomal
aberrations.
Without
S9
activation,
statistically
significant
increases
(p<
0.01)
in
structural
aberrations
per
cell
(excluding
gaps),
lesions
per
cell
and
percent
abnormal
cells
were
seen
at
15.85
mM
(Trials
1
and
2)
and
19.82
mM
(tested
in
Trial
1
only).
Relative
percent
survival
(RPS)
at
this
level
was
.50%.
The
percent
abnormal
cells
averaged
over
all
cultures
from
both
trials
was
28.0%
and
21.5%
at
19.82
and
15.85
mM,
respectively,
compared
to
the
solvent
control
values
of
2.0%
(0.5%
ethanol
in
Trial
2)
and
7.0%
(0.75%
ethanol
in
Trial
1).
The
percent
abnormal
cells
in
positive
control
cultures
was
18%
in
both
Trial
1
(4.83
mM
EMS)
and
Trial
2
(6.44
mM
EMS).
In
the
presence
of
S9­
mix,
no
statistically
significant
increases
in
chromosomal
aberration
induction
were
seen
in
Trial
1;
however,
very
low
positive
control
values
indicated
a
problem
with
the
S9­
mix.
Statistically
significant
increases
were
seen
at
15.85
mM
in
Trial
2;
RPS
at
15.85
mM
was
75%.
There
was
a
statistically
significant
dose­
related
trend
for
all
three
parameters.
The
statistically
significant
(p
<0.01)
increases
at
15.85
mM
remained
when
the
data
from
Trial
1
and
2
were
combined
(average
of
20%
abnormal
cells
compared
to
10%
for
the
solvent
control).
The
predominant
aberrations
with
or
without
S9­
mix
were
chromatid
and
isochromatid
breaks.
Solvent
and
positive
controls
(except
the
positive
control
in
Trial
1
with
S9­
mix)
induced
the
appropriate
responses.
INA­
3674­
112
was
positive
for
the
induction
of
structural
chromosomal
aberrations
in
both
the
presence
and
absence
of
S9­
mix.

This
study
is
classified
as
Acceptable/
guideline
and
satisfies
the
requirement
for
FIFRA
Test
Guideline
[OPPTS
870.5375
(§
84­
2)]
for
in
vitro
cytogenetic
mutagenicity
data.

Guideline
870.5385
Structural
Chromosome
Aberration
Assay;
In
vivo
Cytogenetic
Assay:
In
a
mammalian
cell
cytogenetics
assay
(MRID
00131355),
in
bone
marrow
cells
of
Sprague­
Dawley
CD
rats,
three
rats/
dose/
sex/
harvest
time
were
exposed
to
H#
14,555
in
corn
oil
(
assumed
100%
a.
i.)
at
doses
of
100,
300
and
1000
mg/
kg
by
oral
gavage.
Bone
marrow
cells
were
harvested
at
6,
12,
24
and
48
hours
posttreatment

The
highest
dose
tested
(1000
mg/
kg)
was
lethal.
A
major
limitation
of
this
study
was
the
number
of
animals
treated
and
the
number
of
cells
analyzed
per
animal.
At
most,
three
rats/
sex/
dose/
harvest
time
were
treated
with,
at
most,
50
cells
per
rat
analyzed.
Few
or
no
analyzable
cell
were
available
from
many
rats.
Positive
control
values
were
significantly
(p=
0.03)
increased.
There
was
no
evidence
that
H#
14,
14,555
induced
an
increase
in
the
incidence
of
chromosomal
aberrations
in
the
bone
marrow
cells
of
treated
animals.
17
This
study
is
classified
as
Unacceptable.
The
number
of
cells
analyzed
and
the
number
of
rats
treated
was
insufficient.
The
study
does
not
satisfy
the
requirement
for
FIFRA
Test
Guideline
[OPPTS
870.5385
(§
84­
2)]
for
in
vivo
cytogenetic
mutagenicity
data.

Guideline
870.5550
Other
Genotoxic
Effects
Assay;
In
an
unscheduled
DNA
synthesis
assay
(MRID
00130708),
primary
rat
hepatocyte
cultures
were
exposed
to
INA­
3674­
112
(Lot
No.
7612­
5E6E,
95%
a.
i.)
in
ethanol
for
18
hours
at
concentrations
of
1
x
10
­5
,
1
x
10
­4
,
1
x
10
­3
,
1
x
10
­2
,
0.1,
1.0,
10.0
and
30.0
mM
in
Trial
1
and
at
concentrations
of
1
x
10
­5
,
1
x
10
­4
,
1
x
10
­3
,
1
x
10
­2
,
0.1,
1.0,
5.0,
10.0
and
30.0
mM
in
Trial
2.

INA­
3674­
112
was
tested
up
to
the
highest
achievable
concentration
in
the
solvent.
Two
slides
per
dose,
25
cells
per
slide
were
evaluated
for
UDS
induction
in
Trial
1.
One
slide
per
dose,
25
cells
per
slide
were
evaluated
in
Trial
2.
The
author
did
not
report
that
the
slides
were
coded
prior
to
analysis.
The
average
net
nuclear
grain
counts
of
test
material
treated
cells
in
Trial
1
were
all
less
than
zero
with
the
exception
of
one
slide
at
1
x
10
­5
mM
(0.1
±
9.6)
and
one
slide
at
1.0
mM
(1.6
±
5.2).
The
average
net
nuclear
grain
count
was
below
zero
for
all
test
material
concentrations
in
Trial
2
with
the
exception
of
0.1
mM
where
the
average
net
nuclear
grain
count
was
0.0
±
2.9.
The
criterion
for
a
positive
response
was
an
average
net
nuclear
grain
count
of
at
least
five
in
two
experiments
at
any
tested
concentration.
The
results
were
thus
negative.
The
number
of
cells
in
repair
was
not
reported.
The
solvent
and
positive
(DMBA)
controls
induced
the
appropriate
responses.

There
was
no
evidence
that
unscheduled
DNA
synthesis,
as
determined
by
radioactive
tracer
procedures
[nuclear
silver
grain
counts]
was
induced.

This
study
is
classified
as
Acceptable/
Guideline.
It
satisfies
the
requirement
for
FIFRA
Test
Guideline;
OPPTS
870.5550
[§
84­
2]
for
other
genotoxic
mutagenicity
data.

5.
FQPA
CONSIDERATIONS
5.1
Adequacy
of
the
Data
Base
The
toxicity
data
base
for
FQPA
considerations
is
incomplete.
The
rabbit
developmental
toxicity
study
is
unacceptable/
upgradable
because
doses
were
not
analyzed
and
some
required
maternal
and
fetal
data
were
missing,
such
that
developmental
effects
seen
in
the
study
could
not
be
discounted
or
confirmed.
The
study
was
otherwise
acceptably
conducted.
Another
rabbit
developmental
toxicity
study
is
currently
in
progress.
A
rat
developmental
toxicity
study
is
acceptable
and
the
2­
generation
reproduction
study
is
acceptable.
The
remaining
toxicity
data
base
is
adequate.

5.2
Neurotoxicity
Data:

No
neurotoxicity
studies
have
been
conducted.
The
chronic
dog
study
showed
a
statistically
18
significant
absolute
brain
weight
decrement
of
12­
13%
in
the
female
dogs,
however,
these
dogs
showed
severe
malnutrition.
The
individual
animal
dog
data
showed
that
the
two
dogs
showing
the
largest
decreased
body
weight
from
the
initial
body
weight
also
showed
the
lowest
brain
weight.
This
severe
body
weight
decrement
in
females
may
have
resulted
in
nutritional
deficiencies
indirectly
affecting
the
brain
weight.
The
brain
weight
decrement
was
not
considered
to
be
a
direct
effect
of
hexazinone.
No
significant
changes
in
brain
weight
were
seen
in
the
rat
studies.

5.3
Developmental
Toxicity
5.3.1
Developmental
toxicity
in
rats
Executive
Summary:
In
a
developmental
toxicity
study
(MRID
40397501),
hexazinone
(99.26%
a.
i.;
Lot#
S30306A,
Batch#
2/
36)
in
0.5%
methylcellulose
was
administered
orally
via
gavage
to
25
Crl:
CD
®
BR
female
rats/
group
at
dose
levels
of
0,
40,
100,
400,
or
900
mg/
kg
on
gestation
day
(GD)
7
through
16.
The
dosing
volume
was
10
mL/
kg
(calculated
by
reviewers).
All
dams
were
sacrificed
on
GD
22
and
their
fetuses
removed
by
cesarean
and
examined.

When
compared
to
concurrent
controls,
no
treatment­
related
changes
in
clinical
signs,
gross
pathology,
pregnancy
rate,
live
fetuses,
resorptions,
pre­
or
post­
implantation
loss,
corpora
lutea,
or
implantations
were
noted
at
any
dose
level
tested.
No
treatment­
related
findings
were
noted
in
the
100,
or
40
mg/
kg
groups.

In
the
900
mg/
kg
dams,
one
treatment­
related
death
occurred;
alopecia
and
an
enlarged
stomach
containing
fluid
and
food
were
noted
at
necropsy.
Decreased
(p<
0.05)
body
weight
gains
were
noted
during
GDs
15­
17
(937%)
and
17­
22
(917%).
In
addition,
body
weight
gains
were
decreased
(p<
0.05)
for
the
overall
(GDs
7­
17)
treatment
interval
(930%).
Gravid
uterine
weights
were
not
reported;
however,
adjusted
(for
gravid
uterine
weight)
terminal
body
weights
were
slightly
decreased
(96%;
p#0.05).
A
significant
(p#0.05)
trend
by
linear
combination
of
dose
ranks
from
ANOVA
was
noted
for
GDs
9­
11,
15­
17,
7­
17,
and
17­
22.
Decreased
(p#0.05)
food
consumption
was
observed
throughout
treatment
(GDs
7­
17;
916­
22%)
and
post­
treatment
(GDs
17­
22;
99%).
A
significant
(p#0.05)
trend
by
linear
combination
of
dose
ranks
from
analysis
of
variance
(ANOVA)
was
noted
for
GDs
7­
9,
9­
11,
11­
13,
13­
15,
15­
17,
7­
17,
and
17­
22.
Also
a
significantly
decreased
food
consumption
was
seen
at
400
mg/
kg/
day
(GD9­
11;
91%)
and
(GD
7­
17;
98%).

In
addition,
relative
(to
body)
liver
weights
were
increased
(p#0.05)
in
the
400
(5.2%)
and
900
(5.6%)
mg/
kg
dams
compared
to
concurrent
controls
(4.9%).
Decreased
(p#0.05)
terminal
body
weights
were
noted
at
900
mg/
kg
(96%).
A
significant
(p#0.05)
trend
by
linear
combination
of
dose
ranks
from
ANOVA
was
noted
for
relative
liver
weights
and
adjusted
terminal
body
weights.
In
addition,
a
significant
(p#0.05)
trend
by
linear
combination
of
dose
ranks
from
ANOVA
was
noted
for
absolute
liver
weights.
Despite
this
trend,
the
observed
19
increases
in
absolute
liver
weights
at
100,
400,
and
900
mg/
kg
(81­
8%)
were
not
statistically
significant.
Liver
weight
findings
are
considered
equivocal.

The
maternal
LOAEL
is
400
mg/
kg/
day
based
on
decreased
food
consumption
during
dosing
and
nominal
decreases
in
body
weight
gain
from
day
7
to
day
17
and
at
all
measured
intervals
between
and
at
900
mg/
kg/
day
on
mortality
and
decreased
body
weight
gains
and
food
consumption.
The
maternal
NOAEL
is
100
mg/
kg/
day.

In
the
900
mg/
kg/
day
group,
male
and
female
fetal
weights
were
decreased
(921%;
p#0.05);
a
significant
(p#0.05)
trend
by
Jonckheere's
test
was
noted
for
this
parameter.
At
400
mg/
kg/
day,
the
female
fetal
weights
that
were
significantly
decreased
were
not
considered
to
be
biologically
significant.
At
necropsy,
an
increased
(p#0.05)
incidence
of
misaligned
sternebra
(1),
a
variation,
was
observed
(fetal
incidence:
0.0217;
litter
incidence:
0.30)
relative
to
concurrent
controls
(fetal
incidence:
0.0066;
litter
incidence:
0.09).
In
addition,
an
increased
(p#0.05)
incidence
of
misaligned
sternebrae
(2+),
a
variation,
was
noted
(fetal
incidence:
0.0217;
litter
incidence:
0.30)
relative
to
concurrent
controls
(fetal
incidence:
0.0033;
litter
incidence:
0.04).
Furthermore,
an
increased
incidence
of
kidneys
with
no
papilla
was
observed
(fetal
incidence:
0.0347;
litter
incidence:
0.25)
relative
to
concurrent
controls
(fetal
incidence:
0.0062;
litter
incidence:
0.04).
Although
the
incidence
was
not
statistically
significant,
a
doserelated
trend
(p#0.05)
was
observed.

The
developmental
toxicity
LOAEL
is
900
mg/
kg/
day,
based
on
decreased
male
and
female
fetal
weight,
increased
incidence
of
kidneys
with
no
papilla
(malformation),
and
an
increased
incidence
of
misaligned
sternebrae
(variation).
The
developmental
toxicity
NOAEL
is
400
mg/
kg/
day.

The
developmental
toxicity
study
in
the
rat
is
classified
acceptable/
guideline
(OPPTS
870.3700;
§83­
3
a)
and
satisfies
the
guideline
requirement
for
a
developmental
toxicity
study
in
the
rat.

An
unacceptable
developmental
feeding
study
in
the
rat
shows
(MRID#
00114486)
a
maternal
body
weight
decrement
at
482
mg/
kg/
day
with
a
NOAEL
of
94.5
mg/
kg/
day
with
a
developmental
NOAEL
of
482mg/
kg/
day.
This
study
tends
to
add
support
the
acceptable
rat
developmental
(by
gavage)
toxicity
study.

5.3.2
Developmental
Toxicity
in
the
rabbit
Executive
Summary:
In
a
developmental
toxicity
study
(MRID
00028863),
hexazinone
(100%
a.
i.;
Lot/
batch
#
E21216A)
was
administered
orally
via
gavage
in
a
dosing
volume
of
1
mL/
kg)
to
17
female
New
Zealand
White
rabbits/
group
at
dose
levels
of
0,
20,
50,
or
125
mg/
kg
on
GD
6
through
19.
All
does
(except
those
that
died
or
delivered
prematurely)
were
sacrificed
on
GD
29,
and
their
fetuses
removed
by
cesarean
and
examined.
20
When
compared
to
concurrent
controls,
no
treatment­
related
changes
in
mortality,
clinical
signs,
body
weights,
gross
pathology,
fetal
weights,
sex
ratios,
pre­
implantation
or
postimplantation
losses,
or
the
number
of
corpora
lutea,
implantations,
resorptions,
live
fetuses,
or
dead
fetuses
were
observed.

At
125
mg/
kg,
food
consumption
was
decreased
(p#0.05),
relative
to
concurrent
controls,
at
the
beginning
of
treatment
from
GD
7
through
11
(961­
89%).
Decreases
in
food
consumption,
that
were
not
statistically
significant,
continued
throughout
treatment
(GDs
12­
19;
92­
37%).
Diminished
food
consumption
resulted
in
decreased
(not
statistically
significant)
body
weight
gains
in
the
does
(­
241.5
g)
relative
to
concurrent
controls
(­
7.2
g)
during
GDs
6­
11.
However,
weight
gain
in
these
animals
recovered
quickly
and
was
higher
than
control
animals
during
subsequent
treatment
intervals
(GDs
11­
15
and
15­
19).

The
maternal
LOAEL
is
125
mg/
kg/
day
based
on
transient
decreases
in
food
consumption
and
body
weight
gains.
The
maternal
NOAEL
is
50
mg/
kg/
day.

At
125
mg/
kg/
day,
the
following
skeletal
variations
were
noted
(data
presented
as
fetal
incidence
vs.
0
controls):
(i)
lagging
ossification
in
extremities
(0.0882);
(ii)
malaligned
thoracic
vertebrae
(0.0294);
and
(iii)
flexed
wrist(
s)
(0.0294).
In
addition,
non­
ossified
thumb,
an
anomaly,
was
noted
at
an
increased
incidence
(0.0294)
relative
to
concurrent
controls
(0).
In
the
absence
of
historical
control
data,
these
findings
are
considered
treatment­
related.
In
addition,
it
could
not
be
determined
how
many
of
these
nominally
increased
incidences
were
from
different
litters,
which
would
have
increased
concern
for
developmental
toxicity.

The
developmental
toxicity
LOAEL
is
125
mg/
kg/
day,
based
on
possible
skeletal
abnormalities
and
total
abnormalies.
The
developmental
toxicity
NOAEL
is
50
mg/
kg/
day.

The
developmental
toxicity
study
in
the
rabbit
is
classified
unacceptable/
upgradable,
pending
submission
of
acceptable
purity,
concentration,
stability
and
litter
data
and
historical
control
data.
A
letter
dated
9/
26/
01
from
the
registrant
provided
no
additional
information
about
this
rabbit
developmental
toxicity
study
other
than
that
the
doses
were
not
analyzed
and
that
a
repeat
rabbit
developmental
toxicity
was
currently
being
conducted.

5.4
Reproductive
Toxicity
5.4.1
Executive
Summary:
In
a
two­
generation
reproduction
study,
hexazinone
(98%
a.
i.,
Lot
No.
T02118994)
was
administered
to
groups
of
30
male
and
30
female
Sprague­
Dawley
rats
in
the
diet
at
concentrations
of
0,
200,
2000,
or
5000
ppm
(MRID
42066501).
One
litter
was
produced
in
the
first
generation
and
two
litters
were
produced
in
the
second
generation.
Test
substance
intake
for
the
treated
F0
groups
was
11.8,
117,
and
294
mg/
kg/
day,
respectively,
for
21
males
and
14.3,
143,
and
383
mg/
kg/
day,
respectively,
for
females.
Test
substance
intake
for
the
treated
F1
groups
was
15.3,
154,
and
399
mg/
kg/
day,
respectively,
for
males
and
17.7,
180,
and
484
mg/
kg/
day,
respectively,
for
females.
F0
and
F1
parental
animals
were
administered
test
or
control
diet
for
73
or
105
days,
respectively,
prior
to
mating,
throughout
mating,
gestation,
and
lactation,
and
until
necropsy.

Deaths
of
several
F0
and
F1
parental
animals
were
considered
incidental
to
treatment.
No
treatment­
related
clinical
signs
of
toxicity
were
observed
in
the
adult
animals
of
either
generation.
Gross
necropsy
was
unremarkable
and
no
microscopic
lesions
were
observed
in
selected
tissues
from
the
reproductive
tracts
of
male
and
female
parental
animals.

Body
weights
and
body
weight
gains
of
the
F0
males
were
not
affected
by
treatment.
Premating
body
weight
gains
by
the
mid­
and
high­
dose
F0
females
were
76%
and
62%
(p
#
0.05
for
both),
respectively,
of
the
control
level
resulting
in
final
premating
body
weights
93%
and
87%
(p
#
0.05),
respectively,
of
the
controls.
Body
weights
of
the
high­
dose
F1
males
and
females
were
significantly
reduced
(p
#
0.05)
during
the
premating
interval
with
overall
weight
gains
87%
and
82%,
respectively,
of
the
control
group
amounts.
Reductions
in
body
weights
and
body
weight
gains
during
premating
for
the
mid­
and
high­
dose
F0
and
high­
dose
F1
dams
continued
during
gestation
and
lactation.
Food
consumption
during
premating
was
similar
between
the
treated
and
control
groups
for
males
and
females
of
both
generations.
However,
during
gestation
significantly
(p
#
0.05)
lower
food
consumption
was
noted
for
the
high­
dose
F1
dams
during
production
of
both
litters
and
for
the
mid­
dose
F1
dams
during
production
of
the
second
litter.

There
was
a
statistically
significant
increase
in
absolute
P0
testes
weight
that
appeared
to
be
dose
related,
but
a
nominally
decrease
absolute
F1
adult
testes
weight
in
the
5000
ppm
dose
groups.
The
F1
testes
weight
change
did
not
appear
to
dose
related.
The
testes
weight
changes
in
males
would
appear
to
be
incidental.

Therefore,
the
systemic
toxicity
LOAEL
is
2000
ppm
(117­
154
mg/
kg/
day
for
males
and
143­
180
mg/
kg/
day
for
females)
based
on
reduced
body
weight
and
body
weight
gains
by
F1
males
and
F0
and
F1
females.
The
systemic
toxicity
NOAEL
is
200
ppm
(11.8­
15.3
mg/
kg/
day
for
males
and
14.3­
17.7
mg/
kg/
day
for
females).
No
reproductive
effects
were
seen
in
the
study
except
for
the
weight
effects
on
offspring.
Live
birth
and
viability
indices
and
litter
survival
were
similar
between
the
treated
and
control
groups.
The
lactation
index
for
the
F2b
high­
dose
litters
was
85.8%
(p
#
0.05)
compared
to
97.5%
for
the
control
group.
Pup
body
weights
were
decreased
throughout
lactation
in
the
mid­
and
high­
dose
groups
of
all
litters
as
compared
with
the
control
groups
with
statistical
significance
(p
#
0.05)
attained
at
most
time
points.
The
lower
pup
body
weights
were
more
pronounced
in
females
than
in
males.
F1
and
F2a
female
pup
weights
were
statistically
significantly
decreased
at
birth,
day
7
and
14
of
lactation
at
$2000
ppm.
There
were
no
obvious
reproductive
effects
other
than
the
pup
weight
decrement.
22
Therefore,
the
offspring
LOAEL
is
2000
ppm
(117­
154
mg/
kg/
day
for
males
and
143­
180
mg/
kg/
day
for
females)
based
on
reduced
female
pup
body
weights
at
birth
and
during
lactation.
The
reproductive
toxicity
NOAEL
was
200
ppm
(11.8­
15.3
mg/
kg/
day
for
males
and
14.3­
17.7
mg/
kg/
day
for
females).

This
study
is
classified
as
Acceptable/
Guideline
and
satisfies
the
guideline
requirements
for
a
reproductive
toxicity
study
[OPPTS
870.3800
(§
83­
4)]
in
rats.

5.5
Additional
Information
from
Literature
Sources
(if
available)

The
published
literature
found
on
hexazinone
were
the
papers
on
the
same
studies
submitted
to
the
Agency
[
Kennedy,
GL
and
Kaplan,
AM
(1984)
Chronic
Toxicity,
Reproductive,
and
Teratogenic
Studies
of
Hexazinone.
Fundemental
and
applied
Toxicology
4,
960­
971.].
No
other
relevant
literature
on
the
toxicity
was
found.

5.6
Determination
of
Susceptibility
No
quantitative
or
qualitative
evidence
of
increased
susceptibility
was
seen
following
in
utero
or
pre/
post
natal
exposure
to
rats.
The
rabbit
developmental
study
is
classified
as
unacceptable
because
of
technical
deficiencies.
On
April
2,
2002,
the
HIARC
concluded
that
susceptibility
in
this
species
could
not
be
assessed.
Since
the
unacceptable
study
indicates
that
a
lower
NOAEL/
LOAEL
may
be
demonstrated
in
the
rabbit,
the
committee
concluded
that
an
additional
database
uncertainty
factor
is
warranted
in
the
absence
of
this
study.
Additionally,
the
Committee
concluded
that
the
hazard­
based
special
FQPA
safety
factor
is
1x
is
adequate
because
there
is
not
evidence
of
susceptibility
in
rats
and
a
database
uncertainty
factor
is
applied
to
the
acute
RfD
for
the
lack
of
a
rabbit
developmental
toxicity
study.

5.7
Determination
of
the
Need
for
Developmental
Neurotoxicity
Study
The
weight
of
evidence
does
not
suggest
the
need
for
a
Developmental
Neurotoxicity
study.

5.7.1
Evidence
that
suggest
requiring
a
Developmental
Neurotoxicity
study:

1.
The
structurally
related
pesticide,
Atrazine,
causes
CNS
related
changes
in
prolactin
secretion,
which
is
related
to
reproductive
senescence
in
Sprague
Dawley
rats
through
continuous
estrus
from
decreasing
LH
release,
but
this
effect
would
require
a
special
study
and
would
not
be
detected
by
a
neurotoxicity
study.

5.7.2
Evidence
that
do
not
support
the
need
for
a
Developmental
Neurotoxicity
study
1.
No
evidence
of
neurotoxicity
or
neuropathology
was
seen
in
the
database.
23
2.
A
12­
13%
absolute
female
brain
decrement
was
seen
in
the
chronic
dog
study,
but
the
brain
weight
decrement
was
associated
with
severe
body
weight
decrement.
The
brain
weight
decrement
may
have
been
secondary
to
the
malnutrition
in
these
animals
and
not
directly
due
to
neurotoxic
effects
of
hexazinone
6.
HAZARD
CHARACTERIZATION
Hexazinone
is
a
herbicide
used
to
control
a
broad
spectrum
of
weeds
including
woody
plants
in
alfalfa,
rangeland,
pastures,
woodlands,
pineapple,
sugarcane
and
blue
berries.
Non­
crop
areas
include
ornamental
plants
and
forests.
Hexazinone
is
used
as
a
pre­
emergent,
post
emergence
herbicide
as
well
as
by
direct
spray
and
soil
applications.
There
are
no
non­
occupational
(residential)
uses.

Hexazinone
has
low
acute
toxicity
by
the
oral
(Category
III),
dermal
(Category
IV
)
and
inhalation
routes
(Category
III).
Primary
eye
irritation
is
severe,
causing
corneal
opacity
and
moderate
irritation
in
unwashed
eyes
(Category
I).
It
causes
mild
skin
irritation
and
is
classified
Category
IV
for
skin
irritation.
It
is
not
a
skin
sensitizer
in
the
Guinea
pig.

Body
weight
decrement
and
liver
toxicity
were
the
most
frequent
effects
shown
in
studies
with
hexazinone.
Liver
toxicity
was
seen
in
the
chronic
dog
and
mouse
studies.
Body
weight
decrement
was
seen
in
the
chronic
rat
studies
and
the
studies
on
reproduction.

In
a
reproduction
study,
pup
weight
decrement
occurred
at
the
same
dose
as
parental
body
weight
decrement.
No
reproductive
effects
were
seen
in
the
study
other
than
pup
weight
decrement.
The
rat
prenatal
study
showed
fetal
weight
decrement
and
possibly
renal
malformations
but
no
increased
susceptibility.
The
rabbit
study
possibly
showed
skeletal
anomalies
and
delayed
ossifications
at
the
highest
dose
tested,
however
it
is
classified
as
unacceptable
and
susceptibility
in
this
species
could
not
be
assessed.

The
21­
day
dermal
study
in
the
rabbit
showed
no
systemic
toxicity
and
mild
dermal
irritation
at
the
limit
dose.

The
chronic
study
in
dogs
showed
severe
body
weight
decrement,
changes
in
liver
related
clinical
chemistry
values,
and
microscopic
lesions.

Body
weight
decrement
was
seen
in
a
chronic
carcinogenicity
studies
in
rats
and
mice.
Liver
toxicity
was
seen
in
mice.
The
mouse
carcinogenicity
study
showed
an
increased
trend
for
liver
carcinomas,
but
no
pair
wise
significant
increases.
The
rat
study
showed
no
carcinogenic
potential.
Based
on
these
studies
in
rats
and
mice,
hexazinone
was
classified
in
a
group
D,
not
classifiable
as
a
carcinogen.

Rat
metabolism
studies
showed
that
hexazinone
was
rapidly
absorbed
and
excreted
and
essentially
no
difference
in
the
metabolism
of
males
and
females
at
high
or
low
dose
levels.
Almost
no
parent
hexazinone
was
recovered
in
urine
or
feces.
Two
major
metabolites
were
recovered
from
feces
and
urine,
in
addition
to
lesser
amounts
of
a
third
metabolite
and
small
amounts
conjugated
products
from
urine.
24
7.
Data
Gaps
The
HIARC
requested
a
28­
day
inhalation
study
with
hexazinone
because
of
the
concern
for
potential
inhalation
exposure
based
on
the
use
pattern..
The
rabbit
developmental
toxicity
study
is
classified
as
unacceptable.
Another
study
in
the
rabbit,
requested
by
Cal
EPA,
is
expected
to
be
submitted
to
OPP
as
well.

8.
ACUTE
TOXICITY
Acute
Toxicity
of
Hexazinone
Guideline
No.
Study
Type
MRIDs
#
Results
Toxicity
Category
81­
1
Acute
Oral/
Rat
41235004
(1989)
LD50
=
1200
mg/
kg
III
81­
2
Acute
Dermal/
Rabbit
00104974
LD50
>5278
mg/
kg
IV
81­
3
Acute
Inhalation
00104975
(1973)
LC50
>
7.50
mg/
L(
1
hour)
LC50
>1.9
mg/
L
1
Equivalent
to
340
mg/
kg
2
III
81­
4
Primary
Eye
Irritation
00106003
(1982)
Irreversible
corneal
opacity,
Severe
3
I
81­
5
Primary
Skin
Irritation
00106004
(1982)
Mild
IV
81­
6
Dermal
Sensitization
41235005
(1989)
NA
Not
a
skin
sensitizer
81­
8
Acute
Neurotoxicity
Not
conducted
1
One
hour
inhalation
study
on
technical
converted
to
probable
no
effects
at
4
hours.
Consistent
with
an
unreviewed
three
week
inhalation
study
(MRID#
00063972)
showing
no
significant
toxic
effects.
The
effects
seen
were
consistent
with
dust
inhalation
at
2.5
mg/
mL,
the
only
dose
tested.
Another
acute
4
hour
inhalation
study
in
rats
showed
no
effects
at
3.9
mg/
L
using
a
25%
a.
i.
granular
product
(MRID#
41756701).
2
Calculated
by
the
reviewer
from
the
following
information
from
Whalan
(1998).
This
conversion
generally
is
not
considered
valid,
especially
for
irritating
substances.
{[(
1.9
mg/
L
x
1
x
9.13
x
4
x
1)/(
0.204
kg)]
=
340
mg/
kg}
3
The
toxicity
category
was
based
on
the
corneal
opacity.
Irritation
not
counting
opacity
was
tox
category
III.
25
9.
SUMMARY
OF
TOXICOLOGY
ENDPOINT
SELECTION
Summary
of
Toxicology
Endpoint
Selection
for
Hexazinone
Exposure
Scenario
Dose
(mg/
kg/
day)
UF
/MOE
Hazard
Based
Special
FQPA
Safety
Factor
Endpoint
for
Risk
Assessment
Dietary
Risk
Assessments
Acute
Dietary
females
13­
50
years
of
age
NOAEL
=
400
UF
=
100
Acute
RfD
=
0.40
mg/
kg/
day
UFdb
=
10
Developmental
Toxicity
­
Rat
Decreased
male
and
female
fetal
weight,
kidneys
with
no
papilla
(malformation)
and
misaligned
sternebrae
(variation)

Acute
Dietary
general
population
including
infants
and
children
An
appropriate
endpoint
attributable
to
a
single
dose
was
not
identified
in
the
oral
studies,
including
the
rat
and
rabbit
developmental
studies.

Chronic
Dietary
all
populations
NOAEL=
5.0
UF
=
100
Chronic
RfD
=
0.05
mg/
kg/
day
N/
A
Chronic
one­
year
feeding
­
Dog
LOAEL
=
41.24
male;
37.57
female
mg/
kg/
day
based
on
severe
body
weight
decrement
and
clinical
chemistry
changes
including
elevated
aspartate
aminotransferase
and
alkaline
phosphatase.

Incidental
Oral
Short­
Term
(1
­
30
Days)
Residential
Only
There
are
no
residential
uses
at
the
present
time
and
therefore,
endpoints
were
not
selected.

Incidental
Oral
Intermediate­
Term
(1
­
6
Months)
Residential
Only
There
are
no
residential
uses
at
the
present
time
and
therefore,
endpoints
were
not
selected.

Non­
Dietary
Risk
Assessments
Dermal
Short­
Term
(1
­
30
days)
No
hazard
was
identified,
therefore
quantification
of
risk
is
not
required.
No
systemic
toxicity
was
seen
at
the
limit
dose
following
repeat
dermal
application,
and
there
were
no
concerns
for
developmental
or
reproductive
toxicity.

Residential
Occupational
Exposure
Scenario
Dose
(mg/
kg/
day)
UF
/MOE
Hazard
Based
Special
FQPA
Safety
Factor
Endpoint
for
Risk
Assessment
26
Dermal
Intermediate­
Term
1
(1
­
6
Months)
Oral
NOAEL=
5.0
mg/
kg/
day
N/
A
Chronic
one­
year
feeding
­
Dog
LOAEL
=
41.24
male;
37.57
female
mg/
kg/
day
based
on
severe
body
weight
decrement
and
clinical
chemistry
changes
including
elevated
aspartate
aminotransferase
and
alkaline
phosphatase.
Residential
N/
A
Occupational
MOE=
100
Dermal
Long­
Term
1
(1
­
6
Months)
Oral
NOAEL=
5.0
mg/
kg/
day
N/
A
Chronic
one­
year
feeding
­
Dog
LOAEL
=
41.24
male;
37.57
female
mg/
kg/
day
based
on
severe
body
weight
decrement
and
clinical
chemistry
changes
including
elevated
aspartate
aminotransferase
and
alkaline
phosphatase.
Residential
N/
A
Occupational
MOE=
100
Inhalation
Short­
Term
2
(1
­
30
days)
Oral
NOAEL=
100
mg/
kg/
day
Developmental
Toxicity
­
Rat
LOAEL=
400
mg/
kg/
day
based
on
decreases
in
maternal
food
consumption
and
dose
related
body
weight
decrement.
Residential
N/
A
Occupational
MOE=
100
Inhalation
Intermediate­
Term
(1
­
6
Months)
Oral
NOAEL=
5.0
mg/
kg/
day
N/
A
Chronic
one­
year
feeding
­
Dog
LOAEL
=
41.24
male;
37.57
female
mg/
kg/
day
based
on
severe
body
weight
decrement
and
clinical
chemistry
changes
including
elevated
aspartate
aminotransferase
and
alkaline
phosphatase.
Residential
N/
A
Occupational
MOE=
100
Inhalation
Long­
Term
(>
6
Months)
Oral
NOAEL=
5.0
mg/
kg/
day
N/
A
Chronic
one­
year
feeding
­
Dog
LOAEL
=
41.24
male;
37.57
female
mg/
kg/
day
based
on
severe
body
weight
decrement
and
clinical
chemistry
changes
including
elevated
aspartate
aminotransferase
and
alkaline
phosphatase.
Residential
N/
A
Occupational
MOE=
100
Cancer
Classification:
D
­
Not
Classifiable
as
to
human
carcinogenicity
1
Since
an
oral
NOAEL
was
selected
25%
dermal
absorption
factor
should
be
used
for
route
to
route
exposures.
27
2
Since
an
oral
NOAEL
was
selected
100%
inhalation
absorption
factor
should
be
used
for
route
to
route
exposures.
