TXR#
0051040
TXR#
0051040
August
12,
2002
August
12,
2002
OFFICE
OF
PREVENTION,
PESTICIDES
AND
MEMORANDUM:
TOXIC
SUBSTANCES
Subject:
107201:
The
Revised
Toxicology
Chapter
for
the
TRED
for
Hexazinone.

DP
Barcode:
D275620
Submission:
S598837
ReReg
Case#
0266
CAS#:
51235­
04­
02
From:
David
G
Anderson
RRB­
2
HED
(7509C)

To:
Carol
Christensen,
Risk
Assessor
RRB­
2
HED
(7509C)

Thru:
Alan
Nielsen,
BSS
RRB­
2,
HED
(7509C)

cc
Pauline
Wagner
The
Revised
Toxicology
Chapter
for
the
Tolerance
Reassessment
Evaluation
Decision
(TRED)
for
Hexazinone
is
attached.
The
old
developmental
toxicity
in
rabbits,
which
was
considered
a
data
gap
has
been
replaced
by
a
new
acceptable
developmental
toxicity
study
in
rabbits.
The
results
from
a
new
3
rd
HIARC
report
and
a
new
2
nd
FQPA
Safety
Committee
report
have
been
included.
­1­
Hexazinone
PC
Code:
107201
Toxicology
Disciplinary
Chapter
for
the
Tolerance
Reassessment
Evaluation
Decision
Document
Date
completed:
August
12,
2002
Prepared
for:
Health
Effects
Division
Office
of
Pesticide
Programs
U.
S.
Environmental
Protection
Agency
Arlington,
VA
22202
Prepared
by:

David
G
Anderson
form:
FINAL
June
21,
2000
­2­
TABLE
OF
CONTENTS
1.0
HAZARD
CHARACTERIZATION
........................................
­3­

2.0
REQUIREMENTS
.....................................................
­4­

3.0
DATA
GAP(
S)/
REQUIREMENT(
S)
.......................................
­5­

4.0
HAZARD
ASSESSMENT
...............................................
­5­
4.1
Acute
Toxicity
...................................................
­5­
4.2
Subchronic
Toxicity
...............................................
­5­
4.3
Prenatal
Developmental
Toxicity
......................................
­8­
4.4
Reproductive
Toxicity
............................................
­12­
4.5
Chronic
Toxicity
.................................................
­14­
4.6
Carcinogenicity
.................................................
­15­
4.7
Mutagenicity
...................................................
­18­
4.8
Neurotoxicity
...................................................
­22­
4.9
Metabolism
....................................................
­23­
4.10
Special/
Other
Studies
.............................................
­24­

5.0
TOXICITY
ENDPOINT
SELECTION
....................................
­24­
5.1
See
Section
9.2
for
Endpoint
Selection
Table.
...........................
­24­
5.2
Dermal
Absorption
...............................................
­24­
5.3
Classification
of
Carcinogenic
Potential
................................
­24­

6.0
FQPA
CONSIDERATIONS
............................................
­25­
6.1
Special
Sensitivity
to
Infants
and
Children
..............................
­25­
6.2
Recommendation
for
a
Developmental
Neurotoxicity
Study
.................
­25­

7.0
OTHER
ISSUES
......................................................
­25­

8.0
REFERENCES
.......................................................
­25­
Other
references
......................................................
­29­

9.0
APPENDICES
.....................................................
­30­
9.1
Toxicity
Profile
Summary
Tables
.....................................
­31­
9.1.1
Acute
Toxicity
Table
.......................................
­31­
9.1.2
Subchronic,
Chronic
and
Other
Toxicity
Tables
...................
­31­
9.2
Summary
of
Toxicological
Dose
and
Endpoints
..........................
­36­
HEXAZINONE/
107201/
August/
2002
TRED
Toxicology
Chapter
Page
3
of
38
1.0
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
blueberries.
Non­
crop
areas
include
ornamental
plants
and
forests.
Hexazinone
is
used
as
a
pre­
emergent,
post
emergence
herbicide.
It
is
applied
by
direct
spray
to
plants
and
to
soils.
There
are
no
non­
occupational
(residential)
uses.
Hexazinone
is
a
triazine
herbicide,
which
structurally
dissimilar
and
toxicology
different
from
other
triazines,
such
as
atrazine.
The
selectivity
of
triazine
herbicides
depends
on
the
plant's
ability
to
degrade
or
metabolize
the
parent
compound.
Sensitive
plants
have
limited
ability
to
metabolize
hexazinone.
Hexazinone
acts
through
inhibition
of
photosynthesis.
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
individually
small
amounts
of
conjugated
products
from
urine.
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.
The
21­
day
dermal
study
in
the
rabbit
showed
no
systemic
toxicity
and
mild
dermal
irritation
at
the
limit
dose.
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.
No
quantitative
or
qualitative
susceptibility
was
shown
in
the
prenatal
or
reproduction
studies.
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
maternal
and
fetal
weight
decrement
at
the
same
dose
levels.
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.
Hexazinone
is
clastogenic
in
one
in
vitro
test
for
chromosomal
aberrations,
but
negative
in
the
remaining
six
other
mutagenicity
studies
including
an
in
vivo
micronucleus
test
in
mouse
bone
marrow.
The
HIARC
requested
a
28­
day
inhalation
study
with
hexazinone
because
of
the
concern
for
potential
inhalation
exposure
based
on
the
use
pattern.

2.0
REQUIREMENTS
HEXAZINONE/
107201/
August/
2002
TRED
Toxicology
Chapter
Page
4
of
38
The
requirements
(40
CFR
158.340)
for
food
and
non
food
use
for
HEXAZINONE
are
in
Table
1.
Use
of
the
new
guideline
numbers
does
not
imply
that
the
new
(1998)
guideline
protocols
were
used.

Table
1.

Test
Technical
Required
Satisfied
870.1100
Acute
Oral
Toxicity
..............................
870.1200
Acute
Dermal
Toxicity
............................
870.1300
Acute
Inhalation
Toxicity
.........................
870.2400
Primary
Eye
Irritation
.............................
870.2500
Primary
Dermal
Irritation
..........................
870.2600
Dermal
Sensitization
..............................
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
870.3100
Oral
Subchronic
(rodent)
..........................
870.3150
Oral
Subchronic
(nonrodent)
......................
870.3200
21­
Day
Dermal
...................................
870.3250
90­
Day
Dermal
...................................
870.3465
90­
Day
Inhalation
................................
Yes
Yes
Yes
No
1
No
2
Yes
Yes
Yes
Yes
No
870.3700a
Developmental
Toxicity
(rodent)
...................
870.3700b
Developmental
Toxicity
(nonrodent)
...............
870.3800
Reproduction
...................................
Yes
Yes
Yes
Yes
Yes
Yes
870.4100a
Chronic
Toxicity
(rodent)
.........................
870.4100b
Chronic
Toxicity
(nonrodent)
......................
870.4200a
Oncogenicity
(rat)
...............................
870.4200b
Oncogenicity
(mouse)
............................
870.4300
Chronic/
Oncogenicity
...........................
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
870.5100
Mutagenicity—
Gene
Mutation
­
bacterial
...........
870.5300
Mutagenicity—
Gene
Mutation
­
mammalian
.........
870.5375
Mutagenicity—
Structural
Chromosomal
Aberrations
.
870.
5395
Mutagenicity—
Structural
Chromosomal
Aberrations.
870.5550
Mutagenicity—
Other
Genotoxic
Effects
............
Yes
Yes
Yes
Yes
Yes
No
3
Yes
Yes
Yes
Yes
870.6100a
Acute
Delayed
Neurotox.
(hen)
....................
870.6100b
90­
Day
Neurotoxicity
(hen)
........................
870.6200a
Acute
Neurotox.
Screening
Battery
(rat)
............
870.6200b
90
Day
Neuro.
Screening
Battery
(rat)
..............
870.6300
Develop.
Neuro
..................................
No
4
No
4
No
5
No
5
No
5




870.7485
General
Metabolism
..............................
870.7600
Dermal
Penetration
..............................
Yes
No
6
Yes
No
Special
Studies
for
Ocular
Effects
7
Acute
Oral
(rat)
..................................
Subchronic
Oral
(rat)
.............................
Six­
month
Oral
(dog)
.............................






1
Study
not
required
by
use
pattern.
2
A
28­
day
inhalation
study
was
recommended
by
the
HIARC
and
is
required.
3
Another
study
is
not
required.
4
Required
of
organophosphates
only.
5
Not
required
by
toxicity
pattern.
6
Study
is
optional.
7
Not
required
for
this
class
of
pesticides.

3.0
DATA
GAP(
S)/
REQUIREMENT(
S)
HEXAZINONE/
107201/
August/
2002
TRED
Toxicology
Chapter
Page
5
of
38
1.
28­
Day
Inhalation
Study
(Confirmatory
study)
(Contact
Agency
before
conducting
test).

4.0
HAZARD
ASSESSMENT
4.1
Acute
Toxicity
Adequacy
of
data
base
for
acute
toxicity:
The
data
base
for
acute
toxicity
is
considered
complete.
No
additional
studies
are
required
at
this
time.

The
acute
toxicity
data
on
HEXAZINONE
technical
is
summarized
below.

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
41756701
(1991)
LC50
>
3.94
mg/
L(
4
hour)
III
81­
4
Primary
Eye
Irritation
00106003
(1982)
Irreversible
corneal
opacity,
Severe
I
81­
5
Primary
Skin
Irritation
00106004
(1982)
Mild
IV
81­
6
Dermal
Sensitization
41235005
(1989)
NA
Not
a
skin
sensitizer
4.2
Subchronic
Toxicity
Adequacy
of
data
base
for
subchronic
toxicity:
The
data
base
for
subchronic
toxicity
is
considered
adequate
for
reregistration.
Only
a
28­
day
inhalation
study
is
required
for
confirmation
at
this
time.
HEXAZINONE/
107201/
August/
2002
TRED
Toxicology
Chapter
Page
6
of
38
870.3100
90­
Day
Oral
Toxicity
­
Rat
EXECUTIVE
SUMMARY:
In
this
subchronic
oral
toxicity
study
(MRID
00104977),
hexazinone
(INA­
3674;
purity
not
provided;
Lot/
Batch
#
not
provided)
was
administered
in
the
diet
to
16
ChRCD
rats/
sex/
group
at
nominal
doses
of
0,
200,
1000,
or
5000
ppm
(equivalent
to
0/
0,
16.0/
16.4,
81.0/
87.3,
or
440.4/
450.7
mg/
kg
for
males/
females)
for
13
weeks.
After
4,
8,
and
13
weeks
on
the
test
diet,
10
of
the
16
rats/
sex/
dose
were
subjected
to
hematology,
clinical
chemistry,
and
urinalysis
tests.
After
13
weeks,
10
rats/
sex/
group
were
sacrificed
for
necropsy
and
histopathological
examination.
The
remaining
6
rats/
sex/
group
continued
on
the
test
diet
for
at
least
3
weeks
in
a
onegeneration
one­
litter
reproduction
study.
There
were
no
treatment­
related
effects
on
mortality,
clinical
signs,
food
consumption,
hematology,
urinalysis,
organ
weights,
or
histopathology.
No
data
were
provided
for
gross
pathology.
In
the
200
and
1000
ppm
animals,
all
parameters
examined
were
comparable
to
controls.
Body
weights
were
decreased
in
the
5000
ppm
animals
(94­
15%)
throughout
the
study.
Likewise,
overall
body
weight
gains
(calculated
by
the
reviewers)
were
decreased
in
this
group
(98­
20%).
Although
food
consumption
was
comparable
among
treated
animals
and
controls,
overall
(Days
0­
91)
mean
food
efficiency
was
decreased
(statistics
not
performed)
in
the
5000
ppm
males
(911%)
and
females
(915%)
compared
to
controls.
Food
efficiency
in
males
and
females
was
unchanged
for
the
first
28
days
of
the
study.
Males
showed
a
6%
and
9%
decrement
for
days
28­
56
and
days
56­
91,
respectively
at
5000
ppm.
Females
showed
a
25%
and
64%
decrement
in
food
efficiency
for
the
same
respective
days.
The
progressive
nature
of
the
reduced
food
efficiency,
especially
in
females,
supports
a
body
weight
decrement
at
5000
ppm
from
toxicity.
Alanine
aminotransferase
(ALT)
was
increased
(statistics
not
performed)
in
the
5000
ppm
females
at
1
(863%),
2
(863%),
and
3
(825%)
months.
However,
because
there
were
no
treatmentrelated
changes
in
liver
weights
or
histology,
increases
in
ALT
were
considered
of
equivocal
toxicological
significance.
For
all
other
clinical
chemistry
parameters
examined,
treatment
groups
were
either
comparable
to
controls,
sporadic,
or
differences
were
not
dose­
related.
Additionally,
in
the
one­
generation,
one­
litter
reproduction
study,
there
were
no
treatmentrelated
differences
in
pregnancy
rate
(fertility),
gestation,
number
of
pups
born,
pup
viability,
or
lactation.
However,
the
mean
pup
weight
was
lower
(924%;
statistics
not
performed)
in
the
5000
ppm
group
than
in
controls.
The
LOAEL
for
this
study
is
5000
ppm
(equivalent
to
440.4/
450.7
mg/
kg/
day
for
male/
females)
based
on
decreased
body
weights
and
food
efficiency.
The
NOAEL
is
1000
ppm
(equivalent
to
81.0/
87.3
mg/
kg/
day
for
males/
females).
The
submitted
study
is
classified
as
acceptable
does
satisfy
the
guideline
(§
82­
1a;
OPPTS
870.3100)
requirements
for
a
subchronic
oral
toxicity
study
in
the
rat.

870.3100
90­
Day
Oral
Toxicity
­
Mouse
HEXAZINONE/
107201/
August/
2002
TRED
Toxicology
Chapter
Page
7
of
38
No
study
is
required
or
available.

870.3150
90­
Day
Oral
Toxicity
­
Dog
EXECUTIVE
SUMMARY:
In
this
subchronic
oral
study
(MRID
00114484),
hexazinone
INA3674
97.5%
a.
i.;
Lot/
Batch#
not
provided)
was
administered
in
the
diet
to
4
beagle
dogs/
sex/
group
at
doses
of
0,
200,
1000,
or
5000
ppm
(equivalent
to
0/
0,
5.1/
7.0,
25.9/
31.6,
122.5/
137.3
mg/
kg/
day
for
males/
females)
for
13
weeks.
Homogeneity,
concentration,
and
stability
analyses
were
not
performed
on
the
test
diets.
No
mortalities
occurred
during
the
study.
Clinical
signs
and
hematology
were
unaffected
by
the
test
substance.
At
5000
ppm,
the
negative
overall
(Weeks
0­
13)
body
weight
gains
show
that
these
animals
were
unable
to
maintain
body
weight
(­
0.9
kg
in
males,
­0.3
kg
in
females).
Food
consumption
was
decreased
in
the
females
in
this
dose
group
at
Weeks
1
(941%)
and
2
(915%).
In
the
males,
food
consumption
was
comparable
among
treated
and
control
groups
throughout
the
study.
Findings
in
organ
weights
and
clinical
chemistry
at
5000
ppm
indicate
liver
toxicity
as
an
effect
of
treatment.
Absolute
liver
weights
were
increased
in
the
males
at
200
(810%),
1000
(821%),
and
5000
(826%)
ppm
and
in
the
females
at
5000
(833%)
ppm.
However,
relative
liver
weights
were
only
increased
at
5000
ppm
in
the
males
(827%)
and
females
(840%),
indicating
the
increases
in
absolute
liver
weights
at
200
and
1000
ppm
were
most
likely
due
to
increased
body
weights
in
these
animals
compared
to
controls.
Alkaline
phosphatase
levels
were
increased
in
the
males
and
females
in
this
dose
group
at
1
(846­
75%),
2
(886­
125%),
and
3
(8124­
214%)
months.
Serum
levels
of
this
enzyme
increased
as
the
study
progressed.
In
the
5000
ppm
males,
proteinuria
was
observed
at
Months
2
and
3
(1/
4
each
treated
vs
0/
4
in
any
other
dose
group).
Vacuolation
of
the
cytoplasm
of
the
cells
lining
the
Loop
of
Henle
was
observed
in
the
males
(1/
4
treated
vs
0/
4
controls)
and
females
(1/
4
treated
vs
0/
4
controls)
in
this
dose
group.
The
LOAEL
was
5000
ppm
(equivalent
to
122.5/
137.3
mg/
kg/
day
in
males/
females)
based
on
decreased
body
weight
gains,
increased
relative
liver
weights,
and
increased
alkaline
phosphatase
levels
in
both
sexes
and
transiently
decreased
food
consumption
in
the
females.
The
NOAEL
for
this
study
is
1000
ppm
(equivalent
to
25.9/
31.6
mg/
kg/
day
for
males/
females).
The
submitted
study
is
classified
as
acceptable
and
does
satisfy
the
guideline
(§
82­
1b;
OPPTS
870.3150)
requirement
for
a
subchronic
oral
toxicity
study
in
the
dog.
The
deficiencies
in
the
parameters
reported
did
not
appear
to
compromise
the
study
results.

870.3200
21/
28­
Day
Dermal
Toxicity
–
Rabbit
EXECUTIVE
SUMMARY:
In
a
repeated
dose
dermal
toxicity
study
(MRID
41309005),
groups
of
five
male
and
five
female
New
Zealand
White
rabbits
received
applications
of
0,
50,
400,
or
1000
mg/
kg/
day
Hexazinone
technical
(>
98%,
Lot
No.
T02118994)
in
distilled
water,
6
hours/
day
for
21
HEXAZINONE/
107201/
August/
2002
TRED
Toxicology
Chapter
Page
8
of
38
consecutive
days.
There
were
no
treatment­
related
deaths,
clinical
signs,
hematological
or
clinical
chemistry
effects,
organ
weight
effects
or
gross
or
histopathological
effects
attributable
to
treatment.
No
treatment­
related
body
weight,
food
consumption,
or
food
efficiency
effects
were
observed.
Treatment­
related
dermal
irritation
was
observed
on
rabbits
in
all
treatment
groups,
including
controls.
Slight
erythema
was
noted
on
3/
5
control
females,
4/
5
low­
dose
males,
4/
5
low­
dose
females,
and
all
mid­
and
high­
dose
males
and
females.
Slight
edema
was
noted
on
1/
5
control
female,
1/
5
high­
dose
male,
and
1/
5
high­
dose
female.
These
dermal
effects
were
not
considered
toxicologically
significant.
The
systemic
and
dermal
NOAEL
for
Hexazinone
technical
in
male
and
female
rabbits
is
the
limit
dose
of
1000
mg/
kg/
day.
The
systemic
and
dermal
LOAEL
were
not
identified.
This
study
is
classified
as
Acceptable/
Guideline
and
does
satisfy
the
guideline
requirements
for
a
repeated­
dose
dermal
study
[OPPTS
870.3200
(§
82­
2)]
in
rabbits.

870.3465
90­
Day
Inhalation
–
Rat
No
study
is
available.
The
HIARC
determined
that
a
28­
day
inhalation
study
is
required
to
address
the
concern
for
inhalation
exposure
due
in
part
to
the
irritating
properties
of
hexazinone.
The
Agency
should
be
contacted
prior
to
conducting
this
study.
A
two
page
summary
of
a
21­
day
inhalation
study
has
been
submitted
(MRID#
00063972),
which
is
unacceptable
due
to
failure
to
submitted
a
complete
report
of
the
study
and
probable
unacceptable
particle
sizes.

4.3
Prenatal
Developmental
Toxicity
Adequacy
of
data
base
for
Prenatal
Developmental
Toxicity:
The
data
base
for
prenatal
developmental
toxicity
is
complete.
There
was
no
quantitative
or
qualitative
evidence
of
increased
susceptibility
following
in
utero
exposure
to
the
acceptable
rat
study
or
the
unacceptable
rabbit
study.
In
rats,
maternal
toxicity
was
seen
at
a
lower
dose
than
developmental
toxicity,
and
in
rabbits,
developmental
effects
occurred
at
the
same
dose
level
as
maternal
toxicity.

870.3700a
Prenatal
Developmental
Toxicity
Study
­
Rat
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
HEXAZINONE/
107201/
August/
2002
TRED
Toxicology
Chapter
Page
9
of
38
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
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
by
2%
(insufficient
to
be
considered
an
effect).
At
necropsy,
an
increased
(p#0.05)
incidence
of
misaligned
sternebrae
(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,
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.
HEXAZINONE/
107201/
August/
2002
TRED
Toxicology
Chapter
Page
10
of
38
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.

870.3700a
Prenatal
Developmental
Toxicity
Study
­
Rat
EXECUTIVE
SUMMARY:
In
a
developmental
toxicity
study
(MRID
00114486),
hexazinone
(97.5%
a.
i.;
Code#
INA­
3674­
19,
Lot/
Batch#
N.
B.
6849­
30
[6842­
29];
no
further
information
provided)
was
administered
orally
in
the
diet
to
25­
27
ChR­
CD
female
rats/
group
at
dose
levels
of
0,
200,
1000,
or
5000
ppm
(equivalent
to
0,
18.9,
94.5,
and
482.0
mg/
kg)
on
GD
6
through
15.
All
dams
were
sacrificed
on
GD
21
and
their
fetuses
removed
by
cesarean
and
examined.
When
compared
to
concurrent
controls,
no
treatment­
related
changes
in
food
consumption,
or
number
of
implantations,
live
fetuses,
dead
fetuses,
or
premature
deliveries
were
noted.
It
was
stated
that
no
treatment­
related
changes
in
mortality,
clinical
signs,
or
gross
pathology
were
observed;
however
no
data
were
provided.
Gravid
uterine
weights
were
not
reported.
Sex
ratios,
the
number
of
corpora
lutea,
pre­
implantation
loss,
and
post­
implantation
loss
were
not
reported
and
could
not
be
calculated
without
individual
data
(not
provided).
Throughout
the
study,
standard
deviations
were
not
calculated,
individual
data
were
not
provided,
and
statistical
analyses
were
not
performed.
Mean
body
weight
gains
and
food
efficiency
were
decreased
during
treatment
(GDs
6­
16).
At
5000
ppm,
mean
body
weight
gains
were
decreased
by
74%
compared
to
concurrent
controls.
In
addition,
food
efficiency
during
the
treatment
interval
was
0.84
(vs.
3.0
in
controls).
At
5000
ppm,
markedly
decreased
body
weights
were
observed
at
GDs
16
(919%)
and
21
(912%).
Additionally
at
5000
ppm,
the
number
of
females
showing
partial
resorption
(excluding
complete
resorptions)
was
56.5%.
This
incidence
exceeded
the
concurrent
control
incidence
(39.1%);
however,
it
was
within
the
range
of
historical
controls
(mean
was
40.6%,
range
was10.5­
77.8%).
The
maternal
LOAEL
is
5000
ppm
(equivalent
to
482
mg/
kg/
day)
based
on
decreased
body
weights,
body
weight
gains,
and
food
efficiency.
The
maternal
NOAEL
is
1000
ppm
(equivalent
to
94.5
mg/
kg/
day).
No
treatment­
related
findings
were
noted
in
the
fetuses
at
200,
1000,
or
5000
ppm.
The
developmental
toxicity
LOAEL
was
not
observed.
The
developmental
toxicity
NOAEL
is
5000
ppm
(equivalent
to
482.0
mg/
kg/
day).
This
developmental
toxicity
study
in
the
rat
is
classified
unacceptable/
upgradable
pending
submission
of
the
following
information:

­
Individual
maternal
and
fetal
data
­
Statistical
analyses
of
the
data
­
Environmental
conditions
of
the
testing
laboratory
­
Gross
pathology
data.
­
Sex
ratios,
the
number
of
corpora
lutea,
pre­
implantation
loss,
and
post­
implantation
loss
­
Litter
incidence
for
fetal
necropsy
findings
­
Clinical
signs
and
mortality
data
HEXAZINONE/
107201/
August/
2002
TRED
Toxicology
Chapter
Page
11
of
38
870.3700b
Prenatal
Developmental
Toxicity
Study
­
Rabbit
EXECUTIVE
SUMMARY:
In
a
developmental
toxicity
study
(MRID
45677801)
[DXP­
A3674]
hexazinone
(98.78
%
a.
i.,
batch/
lot#
DXP­
A3694­
329)
was
administered
to
22
female
[Hra:(
NZW)
SPF
strain]
rabbits/
group
by
gavage]
at
dose
levels
of
0,
20,
50,
125
or
175
mg/
kg
bw/
day
from
days
7
through
28
of
gestation.
Maternal
toxicity
was
demonstrated
by
statistically
significant
findings
at
125
mg/
kg/
day
of
a
body
weight
gain
decrement
of
­102
g
between
gd
7­
9
and
­57
g
between
gd
9­
11,
food
consumption
decrement
of
18%,
abortions,
death
and
clinical
signs
such
as
diarrhea,
stained
cageboard
and
tail.
Only
1
dam
and
1
litter
survived
to
termination
at
175
mg/
kg/
day.
The
maternal
LOAEL
is
125
mg/
kg
bw/
day,
based
on
body
weight
gain
decrement,
decreased
food
consumption,
abortions,
death
and
clinical
signs
including
abnormal
gait
at
175
mg/
kg/
day.
The
maternal
NOAEL
is
50
mg/
kg
bw/
day.
No
dose
related
external,
visceral
or
skeletal
findings
were
noted.
Since
only
1
dam
with
1
litter
survived
to
termination
at
the
175
mg/
kg/
day
dose,
evaluation
of
embryo/
fetal
effects
at
this
dose
are
meaningless.
Random
malformations
were
seen
in
control
and
the
highest
dose
group
with
no
dose
relationship.
Mean
male
and
female
fetal
weight
was
reduced
by
5%
and
female
fetal
weight
was
reduced
by
10%
at
125
mg/
kg/
day.
Although
this
weight
reduction
was
not
list
as
being
statistically
significant,
the
author
stated
that
this
slight
weight
reduction
at
125
mg/
kg/
day
was
a
developmental
effect
level
and
this
reviewer
agrees.
The
developmental
LOAEL
is
125
mg/
kg
bw/
day,
based
on
mean
male
and
female
fetal
weight
decrement
and
female
fetal
weight
decrement.
The
developmental
NOAEL
is
50
mg/
kg
bw/
day.

The
developmental
toxicity
study
in
the
rabbit
is
classified
acceptable
(guideline)
and
satisfies
the
guideline
requirement
for
a
developmental
toxicity
study
(OPPTS
870.3700;
OECD
414)
in
the
rabbit.

870.3700b
Prenatal
Developmental
Toxicity
Study
­
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.
When
compared
to
concurrent
controls,
no
treatment­
related
changes
in
mortality,
clinical
signs,
body
weights,
gross
pathology,
fetal
weights,
sex
ratios,
pre­
implantation
or
post­
implantation
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
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38
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
rabbits
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
the
doses
were
not
analyzed
and
that
a
repeat
rabbit
developmental
toxicity
was
currently
being
conducted.

4.4
Reproductive
Toxicity
Adequacy
of
data
base
for
Reproductive
Toxicity:
The
data
base
for
reproductive
toxicity
is
considered
complete.
No
additional
studies
are
required
at
this
time.
There
was
no
evidence
of
qualitative
or
quantitative
susceptibility
in
a
two­
generation
study
of
reproduction.

870.3800
Reproduction
and
Fertility
Effects
­
Rat
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
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
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38
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
middose
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.
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.
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TRED
Toxicology
Chapter
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14
of
38
4.5
Chronic
Toxicity
Adequacy
of
data
base
for
chronic
toxicity:
The
data
base
for
chronic
toxicity
is
considered
complete.
No
additional
studies
are
required
at
this
time.
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.

870.4100a
Chronic/
Carcinogenic
Toxicity
­
Rat
See
Section
below
on
Carcinogenicity
study
in
rats
(870.4300
Chronic/
Carcinogenicity
in
rats).

870.4100b
Chronic
Toxicity
­
Dog
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
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)
HEXAZINONE/
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TRED
Toxicology
Chapter
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15
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38
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.

4.6
Carcinogenicity
Adequacy
of
data
base
for
Carcinogenicity:
The
data
base
for
carcinogenicity
is
considered
complete.
No
additional
studies
are
required
at
this
time.
HED's
Carcinogenicity
Peer
Review
Committee
classified
hexazinone
as
a
Group
D
chemical
(not
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
only
in
female
mice,
but
no
significant
difference
was
seen
by
pair­
wise
comparison
(CPRC
Report
dated
July
27,
1994).

870.4200b
Carcinogenicity
(feeding)
­
Mouse
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.
HEXAZINONE/
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2002
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Toxicology
Chapter
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38
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
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.
Re­
evaluation
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
dose­
dependent
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:
HEXAZINONE/
107201/
August/
2002
TRED
Toxicology
Chapter
Page
17
of
38
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.

870.4300
Chronic/
Carcinogenicity
Study
­
rat
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).
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
HEXAZINONE/
107201/
August/
2002
TRED
Toxicology
Chapter
Page
18
of
38
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
at
1000
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
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
Ccell
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.

4.7
Mutagenicity
Adequacy
of
data
base
for
Mutagenicity:
The
data
base
for
Mutagenicity
is
considered
adequate
based
on
pre­
1991
mutagenicity
guidelines.
The
lack
of
an
acceptable
in
vitro
reverse
mutation
study
is
mitigated
by
an
acceptable
in
vivo
mutation
study,
and
adequate
carcinogenicity
studies.
Hexazinone
was
found
to
be
positive
for
mutagenicity
in
one
chromosomal
aberration
assay
HEXAZINONE/
107201/
August/
2002
TRED
Toxicology
Chapter
Page
19
of
38
(in
vitro
cytogenics)
(MRID#
00130709),
but
negative
in
the
remaining
studies.
It
is
concluded
that
the
test
material
was
clastogenic
in
both
of
the
non­
activated
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
INA3674
112
(hexazinone,
technical)
is
clastogenic
in
an
acceptable
study.

Gene
Mutation
4.7.1
Guideline
870.5100,
Reverse
mutation
in
Salmonella
EXECUTIVE
SUMMARY:
In
a
reverse
gene
mutation
assay
in
bacteria
(MRID
40826201),
strains
TA98,
TA100,
TA1535,
TA1537
and
TA1538
of
S.
typhimurium
were
exposed
to
S­
triazine2,4
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.
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
have
used
higher
doses.

4.7.2
Guideline
870.5300,
Gene
mutation
at
HGPRT
locus
EXECUTIVE
SUMMARY:
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.
HEXAZINONE/
107201/
August/
2002
TRED
Toxicology
Chapter
Page
20
of
38
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
were
not
plated
for
mutation
determination
due
to
cytotoxicity
and
in
both
Trials
1
and
2,
those
cultures
treated
at
13.9
mM
were
excluded
from
analysis
because
no
mutants
were
seen.
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.

4.7.3
Guideline:
870.5375:
In
vitro
mammalian
cytogenics
(chromosomal
aberrations)
in
Chinese
hamster
CHO
cells.

EXECUTIVE
SUMMARY:
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
HEXAZINONE/
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August/
2002
TRED
Toxicology
Chapter
Page
21
of
38
presence
and
absence
of
S9­
mix.

This
study
is
classified
as
Acceptable/
guideline
and
satisfies
the
requirement
for
FIFRA
Test
4.7.4
Guideline
870.5385:
In
vivo
cytogenics
assay
in
rat
bone
marrow
cells
EXECUTIVE
SUMMARY:
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
post­
treatment.
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.
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.

4.7.5
Guideline
870.5395:
Micronucleus
assay
in
mouse
bone
marrow
EXECUTIVE
SUMMARY:
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
satisfies
the
requirement
for
FIFRA
Test
Guideline
[OPPTS
870.5395
(§
84­
2)]
for
in
vivo
cytogenetic
mutagenicity
data.
HEXAZINONE/
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2002
TRED
Toxicology
Chapter
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22
of
38
4.7.6
Guideline
8760.5550:
Unscheduled
DNA
synthesis
assay
in
rat
hepatocytes
EXECUTIVE
SUMMARY:
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.
Compliance
statements
were
not
provided.

4.8
Neurotoxicity
Adequacy
of
data
base
for
Neurotoxicity:
No
neurotoxicity
data
are
required.

870.6100
Delayed
Neurotoxicity
Study
­
Hen
Study
is
not
required
of
hexazinone,
which
is
not
an
organophosphate.

870.6200
Acute
Neurotoxicity
Screening
Battery
Study
not
required
870.6200
Subchronic
Neurotoxicity
Screening
Battery
Study
not
required.
HEXAZINONE/
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August/
2002
TRED
Toxicology
Chapter
Page
23
of
38
870.6300
Developmental
Neurotoxicity
Study
Study
not
required.

4.9
Metabolism
Adequacy
of
data
base
for
metabolism:
The
data
base
for
metabolism
is
considered
to
be
complete.
No
additional
studies
are
required
at
this
time.

870.7485
Metabolism
­
Rat
EXECUTIVE
SUMMARY:
A
metabolism
study
(MRID
00109237
&
00140162)
was
conducted
to
evaluate
the
absorption,
distribution,
metabolism,
and
excretion
of
hexazinone
in
male
and
female
CD
rats.
Radiolabeled
(
14
C
at
position
2
or
4
on
the
cyclohexyl
ring)
hexazinone,
(Lot
#
not
reported,
purity
>95%,
radiochemical
purity
>99%)
was
administered
by
gavage
to
groups
of
one
male
and
one
female
rat
at
concentrations
of
14
mg/
kg
or
1000
mg/
kg.
A
third
group
of
two
male
and
two
female
rats
received
unlabeled
hexazinone
(~
5
mg/
kg/
day)
in
the
diet
for
three
weeks
before
being
given
a
single
14
mg/
kg
radiolabeled
gavage
dose.
Mass
balance
was
excellent
and
ranged
from
95­
102%
recovery
for
all
treatment
groups.
Based
on
the
amount
of
radiolabel
recovered
in
the
urine
and
cage
wash,
absorption
of
the
test
material
was
at
least
83%
with
no
dose­
or
sex­
dependent
differences
noted.
By
72
hours
after
treatment,
essentially
none
of
the
radiolabeled
test
material
was
present
in
the
tissues.
Urine
was
the
primary
route
of
elimination
accounting
for
~83%
of
the
administered
dose.
Urinary
elimination
was
rapid
and
~96%
complete
within
48
hours
of
treatment.
No
apparent
sex
or
dose­
related
differences
were
found.
Fecal
excretion
was
a
minor
route
of
elimination,
accounting
for
~16%
of
the
dose
and
was
rapid
with
~95%
occurring
within
72
hours
of
treatment.
Once
again,
no
apparent
sex
or
dose­
related
differences
were
found.
Essentially
none
of
the
parent
compound
was
found
in
the
urine
(-83%
of
dose)
or
feces
(-16%
of
dose)
of
male
and
female
rats
following
multiple
low­
dose
or
a
single
high­
dose
treatment
with
hexazinone.
(Molecular
structures
of
the
parent
and
metabolites
can
be
found
in
Section
IV,
Appendix.)
3­(
4­
hydroxycyclohexyl)­
6­(
dimethylamino)­
1­
methyl­
1,3,5­
triazine­
2,4(
1H,
3H)­
dione
(metabolite
A)
and
3­(
4­
hydroxycyclohexyl)­
6­(
methylamino)­
1­
methyl­
1,3,5­
triazine­
2,4(
1H,
3H)
dione
(metabolite
C)
comprised
~66
and
28%,
respectively,
of
the
identified
fecal
metabolites
in
males
and
females.
These
two
metabolites
resulted
from
hydroxylation
of
the
cyclohexyl
ring
and
differed
only
by
the
metabolic
conversion
of
the
6­
dimethyl
amine
to
a
secondary
methyl
amine.
No
sex­,
or
dose­
related
differences
in
the
formation
and
excretion
of
these
metabolites
were
found.
Three
metabolites
were
identified
in
the
urine
of
males
and
females
(metabolite
A
and
C,
-57%
and
-28%
of
identified
metabolites,
respectively)
.
Two
of
the
metabolites
were
identical
to
those
found
in
the
feces
.
The
third
metabolite
(3­(
cyclohexyl)­
6­(
methylamino)­
1­
methyl­
1,3,5­
triazine­
2,4(
1H,
3H)­
dione)
(metabolite
B,
-9%
of
urinary
metabolites)
resulted
from
demethylation
of
HEXAZINONE/
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August/
2002
TRED
Toxicology
Chapter
Page
24
of
38
the
6­
dimethyl
amine
group
to
form
a
secondary
amine
without
hydroxylation
of
the
4­
position
on
the
cyclohexyl
ring.
Approximately
3%
of
the
urine
metabolites
were
unidentified
polar
compounds
and
5%
were
isolated
from
the
hydrolyzed
urine,
suggesting
they
had
undergone
glucuronide
or
sulfate
conjugation.
No
differences
between
the
sexes
or
dose
groups
in
the
metabolic
conversion
of
hexazinone
were
found.
This
metabolism
and
disposition
study
with
rats
is
considered
Acceptable/
Nonguideline
and
does
satisfy
the
requirements
for
a
Metabolism
and
Pharmacokinetics
Study
[OPPTS
870.7485
(§
85­
1)].
Major
deficiencies
include
the
use
of
1­
2
male
and
female
rats/
group;
no
submission
of
test
material
lot
numbers,
stability,
or
dose
confirmation
data;
and
study
dates.

4.10
Special/
Other
Studies
None
available.

5.0
TOXICITY
ENDPOINT
SELECTION
5.1
See
Section
9.2
for
Endpoint
Selection
Table.

5.2
Dermal
Absorption
No
dermal
absorption
study
is
available.
For
dermal
absorption,
the
NOAEL
from
the
21­
day
dermal
toxicity
study
(MRID
41309005)
at
the
limit
dose
of
1000
mg/
kg/
day
was
considered
a
lower
bound
for
the
LOAEL,
which
was
compared
with
the
LOAEL
of
125
mg/
kg/
day
from
the
rabbit
developmental
toxicity
study
(MRID
45677801).
The
ratio
of
these
two
numbers
was
used
to
estimate
a
dermal
absorption
factor
of
12.5%.

Dermal
Absorption
Factor:
12.5
%

5.3
Classification
of
Carcinogenic
Potential
5.3.1
Conclusions
There
was
no
evidence
of
treatment
related
tumors
in
chronic
rat
studies
and
insufficient
evidence
in
mouse
studies.

5.3.2
Classification
of
Carcinogenic
Potential
The
RfD/
Peer
Review
Committee
has
classified
hexazinone
as
a
group
D
chemical;
no
evidence
of
carcinogenicity
in
rats
and
in
mice
insufficient
evidence
of
human
carcinogenic
potential.

5.3.3
Quantification
of
Carcinogenic
Potential
HEXAZINONE/
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August/
2002
TRED
Toxicology
Chapter
Page
25
of
38
Not
required.

6.0
FQPA
CONSIDERATIONS
6.1
Special
Sensitivity
to
Infants
and
Children
There
was
no
evidence
of
quantitative
or
qualitative
postnatal
susceptibility
in
a
twogeneration
study
of
reproduction.
There
was
no
quantitative
or
qualitative
evidence
of
increased
susceptibility
following
in
utero
exposure
to
rats
or
rabbits
in
developmental
toxicity
studies.
In
rats,
developmental
toxicity
was
seen
at
the
highest
dose
level
tested,
and
in
rabbits,
developmental
effects
were
seen
at
the
same
dose
showing
maternal
toxicity.

6.2
Recommendation
for
a
Developmental
Neurotoxicity
Study
No
neurotoxic
potential
was
seen
in
any
of
the
studies.
A
developmental
neurotoxicity
study
is
not
required.

7.0
OTHER
ISSUES
None
8.0
REFERENCES:

MRID
00028863.
Unknown
(1980)
Teratology
Study
in
Rabbits.
E.
I.
du
Pont
de
Nemours
and
Company,
Inc.,
Haskell
Laboratory
for
Toxicology
and
Industrial
Medicine,
Newark,
DE.
Laboratory
Project
Id.:
Haskell
Laboratory
Report
No.
201­
522,
February
14,
1980.
Unpublished.

MRID
00063972.
Sarver,
J.
W.
(1976)
Three­
Week
Inhalation
Hazard
Study
on
Vel­
par(
R)
Dust:
Haskell
Laboratory
Report
No.
477­
76.
Rev.
(Un­
published
study
received
Jun
9,
1978
under
352­
388;
submitted
by
E.
I.
du
Pont
de
Nemours
&
Co.,
Wilmington,
Del.

MRID
00076956.
McCooey,
K.
T.,
and
Krahn,
D.
F.
(1980).
Chinese
Hamster
Ovary
Cell
Assay
for
Mutagenicity.
E.
I.
du
Pont
de
Nemours
and
Company,
Haskell
Laboratory
for
Toxicology
and
Industrial
Medicine,
Elkton
Road,
Newark,
DE
19711.
Haskell
Laboratory
Report
No.:
56­
81,
MR
No.:
0581­
865,
HEXAZINONE/
107201/
August/
2002
TRED
Toxicology
Chapter
Page
26
of
38
December
1,
1980.
Unpublished.

MRID
00079203.
Unknown
(1981)
Two­
Year
Feeding
Study
in
Mice.
International
Research
and
Development
Corporation,
Mattawan,
MI.
Laboratory
Project
Id.:
HLO414
81,
June
23,
1981.
Unpublished.

MRID
00104974
Morrow,
R.
(1973)
Skin
Absorption
Toxicity
ALD
and
Skin
Irritancy
Test:
Haskell
Laboratory
Report
No.
503­
73.
(Unpublished
study
received
Dec
5,
1973
under
352­
EX­
85;
submitted
by
E.
I.
du
Pont
de
Nemours
&
Co.,
Inc.,
Wilmington,
DE
MRID
00104977.
Sherman,
H.
et.
al.
(1973)
Ninety­
Day
feeding
Study
in
Rats
with
INA­
3674.
Haskell
Laboratory.
Laboratory
Study
Id.:
235­
73,
May
21,
1973.
Unpublished.

MRID
00106003
Dashiell,
O.;
Henry,
J.
(1982)
Eye
Irritation
Test
in
Rabbits­­
EPA
Pesticide
Registration
[INA­
3674­
122]:
Haskell
Laboratory
Report
No.
251­
82.
(Unpublished
study
received
Jul
7,
1982
under
352­
399;
submitted
by
E.
I.
du
Pont
de
Nemours
&
Co.,
Inc.,
Wilmington,
DE.

MRID
00106004
Dashiell,
O.;
Hinckle,
L.
(1982)
Skin
Irritation
Test
on
Rabbits
for
EPA
Pesticide
Registration:
Haskell
Laboratory
Report
No.
203­
82.
(Unpublished
study
received
Jul
7,
1982
under
352­
399;
submitted
by
E.
I.
du
Pont
de
Nemours
&
Co.,
Inc.,
Wilmington,
DE
MRID
00108638.
Kaplan,
A.
M.,
Frazier,
C.
V.,
et
al.
(1977)
Long­
Term
Feeding
Study
in
Rats
with
INA­
3674.
E.
I.
du
Pont
de
Nemours
and
Company,
Inc.,
Haskell
Laboratory
for
Toxicology
and
Industrial
Medicine,
Newark,
DE.
Laboratory
Project
Id.:
Haskell
Laboratory
Report
No.
353­
77,
May
13,
1977.
Unpublished
MRID
00109237.
Repisarda,
C.
(1982).
Metabolism
of
14
C­
labeled
hexazinone
in
the
rat.
E.
I.
duPont
de
Nemours
and
Co.,
Biochemicals
Dept.,
Research
Div.,
Experimental
Station,
Wilmington,
DE
19898.
Document
No.
AMR­
79­
82.
Unpublished.

MRID
00114484.
Sherman,
H.
et
al.
(1973)
Three­
Month
Feeding
Study
in
Dogs
with
INA3674
E.
I.
du
Pont
de
Nemours
and
Company,
Inc.,
Haskell
Laboratory
for
Toxicology
and
Industrial
Medicine,
Newark,
DE.
Laboratory
Project
Id.:
Haskell
Laboratory
Report
No.
408­
73,
September
12,
1973.
Unpublished.
HEXAZINONE/
107201/
August/
2002
TRED
Toxicology
Chapter
Page
27
of
38
MRID
00114486.
Culik,
R.,
et
al.
(1974)
Teratogenic
Study
in
Rats
with
INA­
3674.
E.
I.
du
Pont
de
Nemours
and
Company,
Inc.,
Haskell
Laboratory
for
Toxicology
and
Industrial
Medicine,
Newark,
DE.
Laboratory
Project
Id.:
Haskell
Laboratory
Report
No.
265­
74,
April
9,
1974.
Unpublished.

MRID
00130708.
Summers,
J.
C.
(1983)
Unscheduled
DNA
Synthesis/
Rat
Hepatocytes
In
Vitro.
E.
I.
du
Pont
de
Nemours
and
Co.,
Inc.,
Haskell
Laboratory
for
Toxicology
and
Industrial
Medicine,
Elkton
Road,
P.
O.
Box
50,
Newark,
Delaware
19711.
Laboratory
Report
No.:
766­
82,
MR
No.:
4508­
001,
Date
Issued:
January
4,
1983.
Unpublished.

MRID
00130709.
Valachos,
D.,
Irr,
J.
and
Krahn,
D.
F.(
1982)
In
Vitro
Assay
for
Chromosome
Aberrations
in
Chinese
Hamster
Ovary
(CHO)
Cells.
E.
I.
du
Pont
Nemours
and
Co.,
Inc.,
Haskell
Laboratory
for
Toxicology
and
Industrial
Medicine,
Elkton
Road,
P.
O.
Box
50,
Newark,
Delaware
19711.
Laboratory
Report
No.
768­
82,
MR
No.
4508­
001,
December
3,
1982.
Unpublished.

MRID
00131355.
Farrow,
M.
G.,
Cortina,
T.
and
Zito,
M.
(1982).
In
Vivo
Bone
Marrow
Cytogenetic
Assay
in
Rats
with
H#
14,555:
Final
Report.
Hazleton
Laboratories
America,
Inc.,
9200
Leesburg
Turnpike,
Vienna,
Virginia
22180.
HLA
Project
number:
201­
573,
December
9,
1982.
Unpublished.

MRID
00140162.
Rhodes,
R.
C.,
Jewell,
R.
A.,
Sherman,
H.
(No
date).
Metabolism
of
"Velpar"
weed
killer
in
the
rat.
E.
I.
duPont
de
Nemours
and
Co.,
Biochemicals
Dept.,
Experimental
Station
and
Haskell
Laboratory
for
Toxicology
and
Industrial
Medicine,
Wilmington,
DE
19898.
No
document
or
report
number.
Results
published
in
J.
Agric.
and
Food
Chem.,
28,
303
(1980)

MRID
40397501.
Mullin,
L.
S.
(1987)
Teratogenicity
Study
of
INA­
3674
in
Rats.
E.
I.
du
Pont
de
Nemours
and
Company,
Inc.,
Haskell
Laboratory
for
Toxicology
and
Industrial
Medicine,
Newark,
DE.
Laboratory
Project
Id.:
Haskell
Laboratory
Report
No.
748­
86,
January
30,
1987.
Unpublished.

MRID
40826201.
J.
F.
Russell
Jr.
and
D.
F.
Krahn
(1977).
Mutagenicity
Evaluation
of
Striazine
2,4(
1H,
3H)­
dione,
3­
cyclohexyl­
6­
dimethylamino­
1­
methyl­
in
Salmonella
typhimurium.
E.
I.
du
Pont
de
Nemours
and
Company,
Inc.,
Haskell
Laboratory
for
Toxicology
and
Industrial
Medicine,
Elkton
Road,
P.
O.
Box
50,
Newark,
Delaware
19714.
Haskell
Laboratory
Report
No.
588­
77,
MR
No.
0581­
693;
Date
Issued:
July
29,
1977.
Unpublished.

MRID
41235004
Hutton,
J.
(1989)
Acute
Oral
Toxicity
Study
with
IN
A3674­
207
in
HEXAZINONE/
107201/
August/
2002
TRED
Toxicology
Chapter
Page
28
of
38
Male
and
Female
Rats:
Project
ID
347­
89.
Unpublished
study
prepared
by
E.
I.
du
Pont
de
Nemours
and
Co.
34
p.

MRID
41235005
Pharmakon
Research
International,
Inc.
(1989)
Closed
Patch
Repeated
Insult
Dermal
Sensitization
Study
(Buehler
Method)
with
IN
A3674
­207
in
Guinea
Pigs:
Project
ID
446­
89.
Unpublished
study
pre­
pared
by
E.
I.
du
Pont
de
Nemours
and
Co.,
Inc.
35
p.

MRID
41309005.
Malek,
D.
(1989).
Repeated
Dose
Dermal
Toxicity:
21­
Day
Study
with
DPXA3674
207
(Hexazinone)
in
Rabbits.
E.
I.
du
Pont
de
Nemours
and
Company,
Inc.,
Haskell
Laboratory
for
Toxicology
and
Industrial
Medicine,
P.
O.
Box
50,
Elkton
Road,
Newark,
DE
19714.
Study
No.
HLA
673­
89.
November
22,
1989.
Unpublished.

MRID
41359301.
Goldenthal,
E.
I.
(1989)
Supplement
1
to:
Two­
Year
Feeding
Study
in
Mice
with
Hexazinone.
International
Research
and
Development
Corporation,
Mattawan,
MI.
Laboratory
Project
Id.:
HLO­
414­
81,
November
22,
1989.
Unpublished.

MRID
41756701
Shapiro,
R.
(1990)
Acute
Inhalation­
Limit
Test:
Hexazinone,
Batch
#
GG1­
15:
Lab
Project
Number:
T­
452.
Unpublished
study
prepared
by
Product
Safety
Labs.
24
p.

MRID
42066501.
Mebus,
C.
A.
(1991).
Reproductive
and
fertility
effects
with
IN­
A3674­
207;
multigeneration
reproduction
study
in
rats.
Haskell
Laboratory,
Newark,
Delaware.
Study
No.
HLA­
404­
91.
September
11,
1991.
Unpublished.

MRID
42162301.
Dalgard,
D.
W.
(1991)
Chronic
toxicology
study
in
dogs
with
DPX­
A3674­
207
(Hexazinone).
Hazleton
Washington,
Inc.,
9200
Leesburg
Turnpike,
Vienna,
VA
22182.
Laboratory
Study
No.
201­
905.
November
5,
1991.
Unpublished.

MRID
42509301.
Slone,
Jr.,
T.
W.
(1992)
Supplement
1
to:
Two­
Year
Feeding
Study
in
Mice
with
Hexazinone.
E.
I.
du
Pont
de
Nemours
and
Company,
Newark,
DE.
Laboratory
Project
Id.:
HLO­
414­
81,
October
2,
1992.
Unpublished.

MRID
43202901.
Slone,
Jr.,
T.
W.,
(1994)
Supplement
No.
3:
Two­
Year
Feeding
Study
in
Mice
with
Hexazinone.
E.
I.
du
Pont
de
Nemours
and
Company,
Newark,
DE.
Laboratory
Project
Id.:
HLO­
414­
81,
April
11,
1994.
Unpublished.

MRID
45124401.
Ford,
L.
S.
(2000)
Hexazinone
25L:
Mouse
Bone
Marrow
Micronucleus
HEXAZINONE/
107201/
August/
2002
TRED
Toxicology
Chapter
Page
29
of
38
Assay.
DuPont
Pharmaceuticals
Company,
Safety
Assessment
Section,
Stine
Haskell
Research
Center,
P.
O.
Box
30,
Elkton
Road,
Newark,
Delaware
19714­
3507.
Laboratory
Project
ID:
DuPont
3852;
Company
Study
Number:
THA­
00­
02­
47,
April
12,
2000.
Unpublished.

MRID
45677801.
Munley,
SM
(2002)
Hexazinone
(DPX­
A3674)
Technical:
Developmental
Toxicity
Study
in
Rabbits.
EI
du
Pont
de
Nemours
and
Co.
Laboratory
report
number
DuPont­
7405,
May
3,
2002.
Unpublished
Other
references:

U.
S.
EPA
Report:
Peer
Review
of
Hexazinone
(August
12,
1992).

U.
S.
EPA
Report:
RfD/
Peer
Review
Report
of
Hexazinone
(March
24,
1993).

U.
S.
EPA
Report:
Carcinogenicity
Peer
Review
of
Hexazinone.
(July
27,
1994).

U.
S.
EPA
Report:
Hexazinone­
3
rd
Report
of
the
Hazard
Identification
Assessment
Review
Committee
(TXR#
0051033).

U.
S.
EPA
Report:
Hexazinone
­
2
nd
Report
of
the
FQPA
Safety
Factor
Committee
(TXR#
0051049).
HEXAZINONE/
107201/
August/
2002
TRED
Toxicology
Chapter
Page
30
of
38
9.0
APPENDICES
Tables
for
Use
in
Risk
Assessment
HEXAZINONE/
107201/
August/
2002
TRED
Toxicology
Chapter
Page
31
of
38
9.1
Toxicity
Profile
Summary
Tables
9.1.1
Acute
Toxicity
Table
Acute
Toxicity
Data
on
HEXAZINONE
Guideline
No./
Study
Type
MRID
No.
Results
Toxicity
Category
870.1100
Acute
oral
toxicity
41235004
LD50
=
1200
mg/
kg
III
870.1200
Acute
dermal
toxicity
00104974
LD50
>
5278
mg/
kg
IV
870.1300
Acute
inhalation
toxicity
41756701
(1990)
LC50
>
3.94
mg/
L(
4
hour)
III
870.2400
Acute
eye
irritation
00106003
Irreversible
corneal
opacity
I
870.2500
Acute
dermal
irritation
00106004
Mild
IV
870.2600
Skin
sensitization
41235005
Not
a
dermal
sensitizer
in
the
Buehler
test
in
Guinea
pigs
NA
9.1.2
Subchronic,
Chronic
and
Other
Toxicity
Tables
Guideline
No./
Study
Type
MRID
No.
(year)/
Classification
/Doses
Results
870.3100
90­
Day
oral
toxicity
rats
0010977
(1973)
Dose:
0,
200,
1000,
5000
ppm
(equivalent
to
0,
16.0/
16.4,
81.0/
87.3,
440/
451
mg/
kg/
day,
male/
female)
Acceptable
NOAEL
=
1000
ppm
(81.0/
87.3
mg/
kg/
day
male/
female)
LOAEL
=
5000
ppm
(440/
451
mg/
kg/
day
male/
female)
based
decreased
body
weight
and
food
efficiency.

870.3150
90­
Day
oral
toxicity
in
dogs
00114484
(1973)
Doses
of
0,
200,
1000,
or
5000
ppm
(equivalent
to
0/
0,
5.1/
7.0,
25.9/
31.6,
122.5/
137.3
mg/
kg/
day,
males/
females)

Acceptable
NOAEL
=
1000
ppm
(equivalent
to
25.9/
31.6
mg/
kg/
day
for
males/
females).
LOAEL
=
5000
ppm
(equivalent
to
122.5/
137.3
mg/
kg/
day
in
males/
females)
based
on
decreased
body
weight
gains,
increased
relative
liver
weights,
and
increased
alkaline
phosphatase
levels
in
both
sexes
and
transiently
decreased
food
consumption
in
the
females.
HEXAZINONE/
107201/
August/
2002
TRED
Toxicology
Chapter
Guideline
No./
Study
Type
MRID
No.
(year)/
Classification
/Doses
Results
Page
32
of
38
870.3200
21/
28­
Day
dermal
toxicity
in
rabbits
41309005
(1989)
Doses:
0,
50,
400,
or
1000
mg/
kg/
day
Acceptable
NOAEL
=
1000
mg/
kg/
day.
LOAEL
=
was
not
identified
for
systemic
and
dermal
toxicity.

870.3250
90­
Day
dermal
toxicity
Not
required
870.3465
21­
Day
inhalation
toxicity
in
the
rat
00063972
(1976)
Dose:
0,
2.5
mg/
L
Unacceptable/
upgradable
No
documentation
was
submitted
with
a
summary
of
an
inhalation
study.

870.3465
90­
Day
inhalation
toxicity
The
90­
day
inhalation
study
is
not
required,
however
a
28­
Day
inhalation
study
is
required
(contact
Agency
prior
to
conducting
study)

870.3700a
Prenatal
developmental
in
rats
40397501
(1980)
Doses:
0,
40,
100,
400,
or
900
mg/
kg
Acceptable
Maternal
NOAEL
=
100
mg/
kg/
day
LOAEL
=
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.
Developmental
NOAEL
=
400
mg/
kg/
day
LOAEL
=
900
mg/
kg/
day
based
on
decreased
female
fetal
weight,
and
increased
incidence
of
kidneys
with
no
papilla
(malformation),
and
an
increased
incidence
of
misaligned
sternebrae
(variation).

870.3700a
Prenatal
developmental
in
rats
00114486
(1974)
Doses:
0,
200,
1000,
or
5000
ppm
(equivalent
to
0,
18.9,
94.5,
and
482.0
mg/
kg)
Unacceptable/
Upgradable
Maternal:
NOAEL
is
1000
ppm
(equivalent
to
94.5
mg/
kg/
day).
LOAEL
=
5000
ppm
(equivalent
to
482
mg/
kg/
day)
based
on
decreased
body
weights,
body
weight
gains,
and
food
efficiency.
Developmental:
NOAEL
=
5000
ppm
(equivalent
to
482.0
mg/
kg/
day).
LOAEL
was
not
observed.
HEXAZINONE/
107201/
August/
2002
TRED
Toxicology
Chapter
Guideline
No./
Study
Type
MRID
No.
(year)/
Classification
/Doses
Results
Page
33
of
38
870.3700b
Prenatal
developmental
in
rabbits
45677801
(2002)
Doses:
0,
50,
125,
175
mg/
kg/
day
Acceptable
Maternal:
NOAEL
=
50
mg/
kg/
day.
LOAEL
=
125
mg/
kg/
day
based
body
weight
and
food
consumption
decrement.
Developmental:
NOAEL
=
50
mg/
kg/
day.
LOAEL
=
125
mg/
kg/
day
based
on
5%
decrement
in
male
and
female
fetal
weight
and
a
10%
decrement
in
female
fetal
weight.

870.3700b
Prenatal
developmental
in
rabbits
00028863
(1980)
Doses:
0,
20,
50,
or
125
mg/
kg
Unacceptable/
Upgradable
Maternal
NOAEL
=
50
mg/
kg/
day
LOAEL
=
125
mg/
kg/
day
based
on
transient
decreases
in
food
consumption
and
body
weight
gains.
Developmental
NOAEL
=
50
mg/
kg/
day
LOAEL
=
125
mg/
kg/
day
based
on
possible
skeletal
abnormalities
and
total
abnormalies.

870.3800
Reproduction
and
fertility
effects
in
rats
42066501
(1991)
Doses:
0,
200,
2000
or
5000
ppm
M:
0,
11.8,
117
or
294
mg/
kg/
day
F:
0,
14.3,
143
or
383
mg/
kg/
day
Acceptable
Parental/
Systemic
NOAEL
=
14.3
mg/
kg/
day
LOAEL
=
143
mg/
kg/
day
based
on
male
body
weight
decrement.
Reproductive
NOAEL
=
383
mg/
kg/
day
LOAEL
=
None
based
on
no
effects
on
or
organs
of
reproduction.
Offspring
NOAEL
=
14.3
mg/
kg/
day
LOAEL
=
143
mg/
kg/
day
based
on
reduced
female
pup
weight
at
birth
and
during
lactation.

870.4100a
Chronic
toxicity
in
rats
See
870.4300
NOAEL
=
LOAEL
=

870.4100b
Chronic
toxicity
dogs
42162301
(1991)
Doses:
0,
200,
1500,
or
6000
ppm
(equivalent
to
5.00/
4.97,
41.24/
37.6
and
161/
167
mg/
kg/
day,
male/
female.

Acceptable
NOAEL
=
200
ppm
(5.0/
5.0
mg/
kg/
day,
male/
female)
LOAEL
=
1500
ppm
(41.2
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.

870.4200
Carcinogenicity
rats
See
below
870.4300
No
evidence
of
carcinogenicity
HEXAZINONE/
107201/
August/
2002
TRED
Toxicology
Chapter
Guideline
No./
Study
Type
MRID
No.
(year)/
Classification
/Doses
Results
Page
34
of
38
870.4200
Carcinogenicity
mice
00079203
(1981),
41359301
(1989),
42509301
(1992)
and
43202901
(1994)
Doses:
0,
0,
200,
2500
or
10,000
ppm
(equivalent
to
28/
34,
366/
450
and
1635/
1915
mg/
kg/
day,
male/
female)

Acceptable
NOAEL
=
200/
2500
ppm
(28/
450
mg/
kg/
day,
male/
female,
respectively)
LOAEL
=
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.
Insufficient
evidence
for
carcinogenicity.

870.4300
Combined
chronic/
carcinogenicity/
rats
00108638
(1977)
Doses:
0,
200,
1000,
or
2500
ppm
(equivalent
to
0,
10.2/
12.5,
53.4/
67.5,
or
138/
179
mg/
kg/
day,
male/
female)

Acceptable
NOAEL
=
200
ppm
for
males
and
females
(10.2/
12.5
mg/
kg/
day,
male/
female).
LOAEL
=
1000
ppm
for
males
and
females
(equivalent
to
53.3/
67.5
mg/
kg/
day,
male/
female)
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
carcinogenic
potential
of
hexazinone
is
considered
negative.

Gene
mutation
870.5100;
Reverse
mutation
in
Salmonella
strains
40826201
(1977)
200,
400,
600,
800
and
1000
:g/
plate
­S9
and
400,
800,
1200,
1600
and
2000
:g/
mL
+
S9­
mix.

Unacceptable
No
mutagenic
potential
was
seen,
but
doses
insufficent
to
cause
cell
toxicity.

Gene
mutation
870.5300;
hamster
CHO
cells/
HPRT
assay
00076956
(1980)
Trial
1
were
2.0,
11.1,
13.1,
13.9
and
14.3
mM
­S9
and
2.0,
7.9,
8.9,
9.3
and
9.9
mM
+S9.
Trial
2
were
2.0,
5.9,
11.1,
13.1
and
13.9
mM
­S9
and
2.0,
7.9,
8.9,
9.3
and
9.9
mM
+
S9.
Acceptable
No
evidence
of
mutagenic
potential
at
cytotoxic
doses.
HEXAZINONE/
107201/
August/
2002
TRED
Toxicology
Chapter
Guideline
No./
Study
Type
MRID
No.
(year)/
Classification
/Doses
Results
Page
35
of
38
Cytogenics
870.5375;
Chromosomal
aberrations
in
hamster
CHO
cells
00130709
(1982)
In
Trial
1,
1.58,
3.94,
15.85
and
19.82
mM
­S9
and
0.32,
3.17,
7.93
and
15.85
mM
+
S9.
In
Trial
2,
1.58,
3.94,
7.93
and
15.85
­S9
0.32,
3.17,
7.93
and
15.85
mM
+
S9
Acceptable
Positive
for
structural
chromosomal
aberrations
with
and
without
S9.

Other
Effects
870.5385,
In
vivo
Rat
bone
marrow
cytogenics
assay
00131355
(1982)
Rat
doses:
100,
300
or
1000
mg/
kg
Unacceptable
No
evidence
of
mutagenic
potential,
but
insufficient
animals
and
cells
were
tested.

Other
Effects
870.5395
Mouse
bone
marrow
micronucleus
test
45124401
(2000)
Mouse
doses:
1000,
2000
and
3000
mg/
kg
Acceptable
No
evidence
of
clastogenic
or
aneugenic
effect
in
bone
marrow
at
toxic
doses..

Other
Effects
870.5550,
UDS
in
rat
hepatocytes
00130708
(1983)
Trial
1:
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
and
Trial
2:
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.
Acceptable
No
evidence
of
mutagenic
potential
at
precipitating
dose
levels.

870.6200a
Acute
neurotoxicity
screening
battery
Not
required
870.6200b
Subchronic
neurotoxicity
screening
battery
Not
required
870.6300
Developmental
neurotoxicity
Not
required
­
HEXAZINONE/
107201/
August/
2002
TRED
Toxicology
Chapter
Guideline
No./
Study
Type
MRID
No.
(year)/
Classification
/Doses
Results
Page
36
of
38
870.7485
Metabolism
and
pharmacokinetics
in
the
rat
00140162
&
00109237
(1980
&1982)
Acceptable
No
parent
was
seen
in
urine
or
feces,
which
was
rapidly
absorbed
and
excreted.
Two
identified
metabolites
resulted
from
hydroxylation
of
the
cyclohexyl
ring
and
differed
only
by
the
metabolic
conversion
of
the
6­
dimethyl
amine
to
a
secondary
methyl
amine.
No
sex­,
or
doserelated
differences
in
the
formation
and
excretion
of
these
metabolites
were
found.

870.7600
Dermal
penetration
Not
required
Special
studies
None
submitted
9.2
Summary
of
Toxicological
Dose
and
Endpoints
for
HEXAZINONE
for
Use
in
Human
Risk
Assessment
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
=
4.0
mg/
kg/
day
1x
Developmental
Toxicity
­
Rat
LOAEL
is
900
mg/
kg/
day
based
on
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
1x
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.
HEXAZINONE/
107201/
August/
2002
TRED
Toxicology
Chapter
Exposure
Scenario
Dose
(mg/
kg/
day)
UF
/MOE
Hazard
Based
Special
FQPA
Safety
Factor
Endpoint
for
Risk
Assessment
Page
37
of
38
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
Dermal
Intermediate­
Term
1
(1
­
6
Months)
Oral
NOAEL=
5.0
mg/
kg/
day
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
MOE=
N/
A
N/
A
Occupational
MOE=
100
N/
A
Dermal
Long­
Term
1
(1
­
6
Months)
Oral
NOAEL=
5.0
mg/
kg/
day
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
MOE=
N/
A
N/
A
Occupational
MOE=
100
N/
A
Inhalation
Short­
Term
2
(1
­
30
days)
Oral
NOAEL=
50
mg/
kg/
day
Developmental
Toxicity
­
Rabbit
LOAEL
=
125
mg/
kg/
day
based
on
decreases
in
maternal
food
consumption
and
dose
related
body
weight
decrement
and
fetal
weight
decrement.
Residential
MOE=
N/
A
N/
A
Occupational
MOE=
100
N/
A
HEXAZINONE/
107201/
August/
2002
TRED
Toxicology
Chapter
Exposure
Scenario
Dose
(mg/
kg/
day)
UF
/MOE
Hazard
Based
Special
FQPA
Safety
Factor
Endpoint
for
Risk
Assessment
Page
38
of
38
Inhalation
Intermediate­
Term
(1
­
6
Months)
Oral
NOAEL=
5.0
mg/
kg/
day
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
MOE
=
N/
A
N/
A
Occupational
MOE=
100
N/
A
Inhalation
Long­
Term
(>
6
Months)
Oral
NOAEL=
5.0
mg/
kg/
day
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
MOE=
N/
A
N/
A
Occupational
MOE=
100
N/
A
Cancer
Classification:
D
­
Not
Classifiable
as
to
human
carcinogenicity
1
Since
an
oral
NOAEL
was
selected
12.5%
dermal
absorption
factor
should
be
used
for
route
to
route
exposures.
2
Absorption
via
the
inhalation
route
is
assumed
to
be
equivalent
to
oral
absorption.
N/
A
=
Not
Applicable;
there
are
no
residential
uses.
