Document ID: EPA-HQ-OPP-2002-0309-0007
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2002-12-03T05:00Z

OXADIAZON
109001
Toxicology
Disciplinary
Chapter
for
the
Reregistration
Eligibility
Decision
Document
Date
completed:
April
4,
2001
Health
Effects
Division
Office
of
Pesticide
Programs
U.
S.
Environmental
Protection
Agency
Arlington,
VA
22202
Prepared
by:

Linnea
J.
Hansen,
Ph.
D.

__________________________
Date
_________________

Nancy
McCarroll,
B.
S.

___________________________
Date
__________________

Reviewed
by:

Alberto
Protzel,
Ph.
D.,
Toxicology
Branch
Senior
Scientist
___________________________
Date
__________________

form:
FINAL
June
21,
2000
EPA
Reviewer:
Linnea
J.
Hansen,
Ph.
D.
,
Date
Toxicology
Branch
(
7509C)
Secondary
EPA
Reviewer:
Alberto
Protzel,
Ph.
D.,
Branch
Sr.
Scientist
,
Date
Toxicology
Branch
(
7509C)

TABLE
OF
CONTENTS
1.0
HAZARD
CHARACTERIZATION
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3
2.0
REQUIREMENTS
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5
3.0
DATA
GAP(
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7
4.0
HAZARD
ASSESSMENT
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4.1
Acute
Toxicity
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7
4.2
Subchronic
Toxicity
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8
4.3
Prenatal
Developmental
Toxicity
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11
4.4
Reproductive
Toxicity
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13
4.5
Chronic
Toxicity
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14
4.6
Carcinogenicity
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19
4.7
Mutagenicity
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23
4.8
Neurotoxicity
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26
4.9
Metabolism.
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26
4.10
Special/
Other
Studies
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28
5.0
TOXICITY
ENDPOINT
SELECTION
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29
5.1
See
Section
9.2
for
Endpoint
Selection
Table.
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29
5.2
Dermal
Absorption
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29
5.3
Classification
of
Carcinogenic
Potential
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29
6.0
FQPA
CONSIDERATIONS
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30
6.1
Special
Sensitivity
to
Infants
and
Children
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30
6.2
Recommendation
for
a
Developmental
Neurotoxicity
Study
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30
7.0
OTHER
ISSUES
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30
8.0
REFERENCES
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31
9.0
APPENDICES
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35
9.1
Toxicity
Profile
Summary
Tables
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36
9.1.1
Acute
Toxicity
Table
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36
9.1.2
Subchronic,
Chronic
and
Other
Toxicity
Tables
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36
9.2
Summary
of
Toxicological
Dose
and
Endpoints
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42
OXADIAZON
TECH.
Updated
April
4,
2001
RED
Toxicology
Chapter
3
1.0
HAZARD
CHARACTERIZATION
Oxadiazon
is
a
selective
pre­
emergent
herbicide
of
the
oxadiazole
class.
Like
other
oxadiazoles,
it
displays
light­
dependent
phytotoxicity
through
the
inhibition
of
protoporphyrinogen
oxidase.
Accumulation
of
protoporphyrin
IX
following
exposure
to
oxadiazon
has
been
demonstrated
in
plants,
yeast
and
mouse
liver
mitochondria.
At
present,
there
are
no
registered
food
or
feed
uses.
Aventis
CropScience
USA
is
supporting
use
of
oxadiazon
on
golf
courses,
ornamentals,
apartment/
condo
lawns,
athletic
fields,
parks,
playgrounds
and
cemeteries.
The
database
for
oxadiazon
is
largely
complete
and
provides
sufficient
information
to
characterize
toxicity.
The
only
data
gap
that
has
been
identified
at
this
time
is
the
submission
of
a
28­
day
inhalation
study
(
OPPTS
No.
870.3465).
This
study
was
not
a
guideline
requirement
for
oxadiazon,
but
has
been
requested
by
the
Agency
because
some
currently
registered
products
of
oxadiazon
are
spray
formulations.

In
acute
studies,
oxadiazon
is
only
slightly
toxic
(
Toxicity
Categories
III
or
IV)
with
an
oral
LD
50
>
5000
mg/
kg,
a
dermal
LD
50
>
2000
mg/
kg
and
an
inhalation
LC
50
>
1.94
mg/
L.
Oxadiazon
is
mildly
irritating
to
ocular
tissue
and
negligibly
irritating
to
the
skin
(
both
Toxicity
Category
III)
and
is
not
a
dermal
sensitizer.

The
major
target
organ
of
oxadiazon
is
the
liver.
Effects
were
consistent
among
the
species
tested
(
rat,
dog,
mouse)
in
both
subchronic
and
chronic
studies
and
typically
included
enlarged
livers
(
presumably
due
to
the
peroxisomal
proliferating
activity
of
oxadiazon),
along
with
increases
in
serum
clinical
chemistry
parameters
associated
with
hepatotoxicity
such
as
alkaline
phosphatase
and
serum
aspartate
or
alanine
aminotransferase.
Findings
in
rats
and
mice
included
fatty
changes,
pigmented
Kupffer
cells
and
bile
canaliculi
and
bile
duct
proliferation,
periacinar
swelling
and
pallor,
increased
acidophilic
cells,
hyperplasia
and
hepatocellular
necrosis.
No
treatment­
related
microscopic
lesions
were
observed
in
the
subchronic
dog
study
and
findings
in
the
chronic
study
were
only
observed
at
the
HDT
(
200
mg/
kg/
day),
where
only
2
animals/
sex
were
assigned
and
1
female
was
sacrificed
in
moribund
condition.
These
findings
included
increased
liver
weight
and
hepatocellular
histopathology
(
centriacinar
vacuolation,
periacinar
apoptosis
and
inflammation).
The
hematopoietic
system
also
appeared
to
be
a
target
of
oxadiazon
in
all
three
species,
based
on
mild
anemia
(
reductions
in
RBC,
hematocrit
and/
or
hemoglobin).
This
is
consistent
with
its
ability
to
inhibit
protoporphyrinogen
oxidase,
an
enzyme
involved
in
the
synthesis
of
both
heme
and
chlorophyll.
In
addition
to
effects
on
the
liver,
increased
pigmentation
in
the
kidney
was
observed
in
rats,
along
with
increased
BUN
and
kidney
weights.
Although
a
dose­
dependent
increase
in
thyroid
weight
was
observed
in
the
dog
subchronic
oral
toxicity
study
and
at
the
HDT
of
the
chronic
dog
studies,
treatment­
related
changes
in
thyroid
weights
or
gross/
microscopic
observations
were
not
observed
in
other
studies
(
thyroid
hormones
were
not
evaluated).
In
general,
males
appeared
to
be
slightly
more
sensitive
to
oxadiazon
than
females.

Oxadiazon
is
not
readily
absorbed
by
the
skin.
In
a
rat
dermal
absorption
study,
up
to

9%
of
the
applied
dose
was
absorbed
after
10
hours
of
exposure.
The
21­
day
rabbit
dermal
toxicity
study
supports
low
dermal
absorption:
no
toxicity
was
observed
at
the
limit
dose
of
1000
mg/
kg/
day.
OXADIAZON
TECH.
Updated
April
4,
2001
RED
Toxicology
Chapter
4
Following
long­
term
dietary
administration,
oxadiazon
caused
an
increased
incidence
of
hepatocellular
adenoma
and
carcinoma
in
rats
and
mice.
Consistent
findings
were
reported
in
a
total
of
4
acceptable
studies
in
2
species
(
2
mouse
and
2
rat
studies).
A
third
mouse
study
was
unacceptable,
although
increased
hepatocellular
tumors
were
also
observed
in
mice
of
both
sexes.
In
CD­
1
mice,
statistically
significant
increases
of
hepatocellular
adenoma
and
combined
adenoma/
adenocarcinoma
were
observed
at
all
dose
levels
tested
(

100
ppm)
in
both
males
and
females.
The
incidence
of
hepatocellular
carcinoma
was
increased
at
all
doses
in
males
but
only
at
the
two
highest
doses
in
females.
The
highest
dose
tested
exceeded
the
MTD
for
males,
based
on
excessive
mortality.
In
ICR­
JCL
mice,
adenomas,
carcinomas
and
combined
adenomas/
carcinomas
were
increased
in
males
at
the
highest
2
dose
levels
but
only
at
the
highest
dose
level
in
females.
In
SPF
Wistar
rats,
the
incidence
of
hepatocellular
adenomas
,
carcinomas
and
combined
adenomas/
carcinomas
was
increased
in
males
only.
A
second
study
in
F344
rats
showed
a
treatment­
related
increase
in
the
incidence
of
hepatocellular
carcinoma
and
combined
adenoma/
carcinoma
only
in
males.
A
classification
of
"
likely
to
be
carcinogenic
to
humans"
was
assigned
by
the
HED
Cancer
Assessment
Review
Committee
using
the
EPA
Draft
Guidelines
for
Carcinogen
Risk
Assessment
of
July,
1999.
A
quantitative
risk
(
Q
1*)
of
7.11
x
10­
2
(
mg/
kg/
day)­
1
was
calculated
as
the
most
potent
unit
risk,
based
on
the
incidence
of
male
mouse
liver
adenoma
and/
or
carcinoma
combined
tumor
rates
in
the
ICR­
JCL
mouse.

In
a
special
mechanistic
study
in
rats,
oxadiazon
induced
peroxisomal
proliferation
(
based
on
liver
enlargement,
peroxisomal
enzyme
induction
and
electron
microscopy)
after
a
14­
day
dietary
administration.
Some
peroxisomal
proliferator
compounds
are
known
to
be
liver
carcinogens,
but
the
HED
Mechanism
of
Toxicity
Assessment
Review
Committee
(
MTARC)
determined
that
there
are
insufficient
data
available
to
support
this
as
a
mechanism
of
carcinogenicity
for
oxadiazon
due
to
insufficient
data
showing
hepatocellular
proliferation,
lack
of
concordance
between
the
enzyme
induction
dose­
response
and
tumor
formation
and
an
unexplained
decrease
in
catalase,
which
is
normally
significantly
increased
by
peroxisomal
proliferator
compounds.

Oxadiazon
did
not
show
mutagenic
potential
in
any
in
vitro
assays
with
bacteria
(
S.
typhimurium
and
E.
coli)
or
mammalian
cells
(
TK
+/­
mouse
lymphoma
cells),
did
not
show
clastogenic
potential
in
the
in
vitro
Chinese
hamster
ovary
cell
chromosomal
aberration
assays
and
did
not
induce
unscheduled
DNA
synthesis
in
cultured
primary
rat
hepatocytes.
However,
a
dose­
related
increase
in
transformation
frequencies
was
observed
in
an
in
vitro
Syrian
hamster
kidney
BHK21
C13/
HRC1
cell
transformation
assay.

Significant
fetal
toxicity
(
fetal
loss
due
to
resorptions
and
post­
implantation
loss,
decreased
fetal
weight,
skeletal
variations)
was
observed
in
developmental
toxicity
studies
in
both
rats
and
rabbits.
These
fetal
effects
occurred
at
the
same
dose
levels
at
which
slight
maternal
toxicity
(
decreased
weight
gain/
weight
loss)
were
observed.
Offspring
survival
effects
were
also
observed
in
the
rat
two­
generation
reproduction
study.
No
toxicity
was
reported
at
the
lowest
dose
tested;
however,
in
the
range­
finding
study
at
higher
dose
levels,
fetal
and
neonatal
survival
were
also
sharply
reduced.
The
decreased
neonatal
survival
was
due
at
least
in
part
to
effects
on
lactation,
based
on
findings
of
inactive
mammary
glands
in
the
dams
at
necropsy.
It
is
likely
that
neonatal
OXADIAZON
TECH.
Updated
April
4,
2001
RED
Toxicology
Chapter
5
loss
may
have
resulted
from
starvation
and
would,
therefore,
be
an
effect
of
direct
maternal
toxicity.
Inactivity
of
the
mammary
tissue
as
a
possible
effect
of
endocrine
disruption
was
considered
but
was
not
found
to
be
likely
since
there
was
no
evidence
from
any
other
study
in
the
database
suggesting
endocrine
disruption.
No
fetal
malformations
were
observed
in
the
rat
or
rabbit
developmental
toxicity
studies;
however,
some
skeletal
variations
(
delayed
ossification,
asymmetric
pelvis)
were
reported.
The
above
findings
indicate
that
there
is
neither
qualitative
nor
quantitative
evidence
of
increased
susceptibility
of
rats
or
rabbits
following
in
utero
or
postnatal
exposure
to
oxadiazon.

Neurotoxicity
studies
are
not
required
for
oxadiazon
because
no
clinical
signs
of
toxicity
suggestive
of
neurobehavioral
alterations
nor
evidence
of
neuropathological
effects
were
observed
in
any
of
the
available
toxicity
studies.
There
was
no
evidence
for
neurodevelopmental
potential
of
oxadiazon
in
the
rat
and
rabbit
developmental
toxicity
studies,
nor
in
the
rat
two­
generation
reproductive
toxicity
study.

In
a
rat
metabolism/
pharmacokinetic
study,
oxadiazon
was
extensively
metabolized,
primarily
via
hydroxylation
and
glucuronide
conjugation.
However,
the
benzene
and
pyrozolidine
rings
were
not
modified.
Eighteen
(
18)
metabolites
were
identified
in
the
urine
and
feces,
of
which
4
urinary
and
5
fecal
metabolites
were
present
at
levels
greater
than
1%
of
the
dose.
After
7
days,


83%
of
the
administered
dose
was
excreted
in
the
urine
and
feces
(
total
recovery

94%)
for
all
dose
groups.
Females
excreted
more
radioactivity
in
the
urine
than
males.
The
excretion
of
radioactivity
into
the
urine
and
the
feces
was
sex
dependent
and
the
tissue
residues
were
very
low
in
all
tissues
except
liver
and
fat.
Low
doses
(
5
mg/
kg,
single
or
multiple)
of
oxadiazon
were
completely
absorbed,
metabolized
and
excreted
in
the
urine
and
feces
and
virtually
no
free
oxadiazon
was
found
in
the
urine.
At
this
dose,
the
rates
and
routes
of
excretion
of
radioactivity
were
similar.
At
high
dose
(
500
mg/
kg),
the
rate
of
excretion
was
affected
but
the
route
was
not.
Intact
oxadiazon
was
present
in
feces
only
and
was
dose­
related:
at
the
high
dose,
more
than
53%
of
the
administered
radioactivity
was
intact
oxadiazon
in
the
feces;
at
5
mg/
kg,
not
more
than
4.8%
of
the
dose
was
intact
oxadiazon
in
the
feces.

2.0
REQUIREMENTS
The
requirements
(
CFR
158.340)
for
non
food/
feed
(
turf)
uses
for
oxadiazon
are
shown
below
in
Table
1.
Use
of
the
new
guideline
numbers
does
not
imply
that
the
new
(
1998)
guideline
protocols
were
used.
OXADIAZON
TECH.
Updated
April
4,
2001
RED
Toxicology
Chapter
6
Table
1.
Data
requirements
for
Reregistration
of
Oxadiazon
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
yes1
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
C
Gene
Mutation
­
bacterial
.
.
.
.
.
.
.
.
.
870.5300
Mutagenicity
C
Gene
Mutation
­
mammalian
.
.
.
.
.
.
870.5375
Mutagenicity
C
Structural
Chromosomal
Aberrations
870.5550
Mutagenicity
C
Other
Genotoxic
Effects
.
.
.
.
.
.
.
.
.
.
yes
yes
yes
yes
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
no
no
no
no
­­
­­
­­
­­
­­

870.7485
General
Metabolism
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.7600
Dermal
Penetration
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
yes
no2
yes
yes
Special
Studies
for
Ocular
Effects
Acute
Oral
(
rat)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
Subchronic
Oral
(
rat)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
Six­
month
Oral
(
dog)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
no
no
no
­­
­­
­­

1
A
90­
day
inhalation
study
is
not
a
guideline
requirement
for
oxadiazon.
However,
a
28­
day
inhalation
study
has
been
requested
by
the
Agency
because
some
of
the
currently
registered
products
are
spray
formulations.
2
This
study
was
not
required
by
the
Agency,
but
was
submitted
as
additional
information
for
oxadiazon.
OXADIAZON
TECH.
Updated
April
4,
2001
RED
Toxicology
Chapter
7
3.0
DATA
GAPS
There
are
no
guideline
required
data
gaps.
However,
HIARC
has
recommended
the
submission
of
a
28­
day
inhalation
toxicity
study
in
the
rodent
because
some
of
the
currently
registered
products
are
spray
formulations.

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
of
oxadiazon
is
low
by
all
potential
routes
of
exposure
(
Toxicity
Category
IV,
oral
and
III,
dermal
and
inhalation).
Primary
eye
irritation
is
mild
and
skin
irritation
is
negligible
(
both
Category
III).
Oxadiazon
did
not
show
potential
for
dermal
sensitization
in
a
Buehler
test.

The
acute
toxicity
data
on
oxadiazon
technical
is
summarized
in
Table
2.

Table
2.
Acute
Toxicity
Data
on
Oxadiazon
Guideline
No./
Study
Type
MRID
No.
Results
Toxicity
Category
870.1100
Acute
oral
toxicity
(
rat)
41866501
(
97.5%
a.
i.)
LD50
>
5000
mg/
kg

,

combined
IV
870.1200
Acute
dermal
toxicity
(
rabbit)
41866502
(
97.5%
a.
i.)
LD50
>
2000
mg/
kg,

,

combined
III
870.1300
Acute
inhalation
toxicity
(
rat)
41866503
(
93.7%
a.
i.)
LC50
>
1.94
mg/
L

,

combined
III
870.2400
Acute
eye
irritation
(
rabbit)
41866504
(
97.5%
a.
i.)
Mild
irritant
to
ocular
tissues
III
870.2500
Acute
dermal
irritation
(
rabbit)
41866505
(
97.5%
a.
i.)
Negligibly
irritating
to
skin
III
870.2600
Skin
sensitization
(
guinea
pig)
41230401
(
93.7%
a.
i.)
Not
a
dermal
sensitizer
(
Buehler
test)
­­

870.6200a
Acute
neurotoxicity
screening
battery
(
rat)
ND
­­
­­

ND
No
data
­
not
required
for
oxadiazon.
OXADIAZON
TECH.
Updated
April
4,
2001
RED
Toxicology
Chapter
8
4.2
Subchronic
Toxicity
Adequacy
of
data
base
for
subchronic
toxicity:
The
data
base
for
subchronic
toxicity
is
considered
complete
with
respect
to
the
guideline
requirements
for
a
non­
food/
feed
use.
However,
the
HIARC
has
recommended
the
submission
of
a
28­
day
inhalation
toxicity
study
because
some
of
the
currently
registered
products
are
spray
formulations.
In
the
rat,
liver
effects
from
subchronic
exposure
included
increased
weight,
increased
ALT,
AST,
alkaline
phosphatase
and
BUN,
and
microscopic
findings
such
as
increased
brown
pigmentation
of
Kupffer
cells
and
bile
canaliculi,
variable
hepatocyte
size
and
staining
and
necrosis.
In
addition,
decreased
red
blood
cell
parameters,
increased
splenic
hematopoietic
activity
and
vacuolization
of
cells
of
the
adrenal
gland
and
the
kidney
were
observed.
In
the
dog,
increased
liver
and
thyroid
weights
and
serum
levels
of
alkaline
phosphatase
and
ALT
were
reported,
but
no
liver
pathology
or
hematological
effects
were
observed
at
the
doses
tested.
No
toxicity
following
21
consecutive
daily
dermal
exposures
was
observed
in
rats
exposed
up
to
the
limit
dose
of
1000
mg/
kg/
day.

In
addition
to
the
Executive
Summaries
provided
below,
subchronic
toxicity
studies
are
summarized
in
capsule
form
in
Section
9.0
(
Appendix),
Table
9.1.2
(
toxicity
profile
table).

870.3100
90­
Day
Oral
Toxicity
­
Rat
In
a
90­
day
subchronic
oral
toxicity
study
(
MRID
00111804),
oxadiazon
as
RP
17623
(
tech.,
98.2%
a.
i.)
was
administered
to
CD
rats
(
10/
sex/
dose)
at
dietary
levels
of
0,
25,
100
or
1000
mg/
kg/
day)
for
13
weeks.
Clinical
signs,
body
weights
and
food
consumption
were
determined
weekly.
At
4
and
13
weeks,
hematology,
clinical
chemistry
and
urinalysis
determinations
were
performed.
Cholinesterase
activity
was
also
measured
in
erythrocytes
at
13
weeks.
Necropsy,
organ
weights
and
histology
examinations
were
performed
at
13
weeks.

Mortality
was
confined
to
one
high­
dose
male
at
week
10
and
one
high­
dose
female
at
week
12.
Other
clinical
signs
noted
at
1000
mg/
kg/
day
were:
hunched
appearance,
urine
stains,
rapid
respiration,
yellow
skin
pigmentation
and
loss
of
coordination
(
both
sexes).
Body
weight
(­
13
and
­
49%)
was
significantly
decreased
in
males
at
100
and
1000
mg/
kg/
day;
respectively,
and
in
females
(­
21%)
at
1000
mg/
kg/
day.
Food
consumption
was
significantly
reduced
for
both
sexes
at
the
high
dose.
Affected
hematological
parameters
included:
slight
decreases
in
hematocrit,
hemoglobin
and
erythrocyte
count
for
high­
dose
males
and
females
(
13
weeks).
ALP,
total
bilirubin,
SGPT
(
4
and
13
weeks)
BUN
and
SGOT
(
13
weeks)
were
increased
in
high­
dose
males
and
females.
Mid­
dose
males
also
had
increased
ALP,
SGOT
and
SGPT
values.
There
was
no
effect
on
cholinesterase
activity.
Significantly
increased
absolute
and
relative
liver
weights
were
seen
in
males
and
females
receiving
100
and
1000
mg/
kg/
day.
Microscopic
changes
were
also
apparent
for
intermediate
and
high­
dose
males
and
females.
At
1000
mg/
kg/
day
(
males
and
females)
and
100
mg/
kg/
day
(
males),
the
liver
contained
brown
pigment
in
the
Kupffer
OXADIAZON
TECH.
Updated
April
4,
2001
RED
Toxicology
Chapter
9
cells
and
bile
canaliculi,
marked
variability
in
cell
size
and
staining
properties
of
the
hepatocytes
and
necrotic
hepatocytes.
The
adrenals
contained
cytoplasmic
vacuolation
of
the
zona
fasciculata,
vacuolation
and
hypertrophy
of
cells
in
the
zona
reticularis
and
increased
vacuolation
of
the
zona
glomerulosa
(
males
and
females
at
1000
mg/
kg/
day).
Also
at
1000
mg/
kg/
day,
the
spleen
showed
increased
hematopoietic
activity
and
brown
pigmentation;
granular
pigmentation
and
vacuolation
were
reported
for
the
kidneys.
No
significant
effects
were
seen
at
25
mg/
kg/
day.
The
LOAEL
is
100
mg/
kg/
day,
based
on
decreased
body
weight,
increased
liver
weight,
hematological
changes
and
clinical
chemistry
and
pathological
changes
associated
with
damage
to
the
livers
of
males
and
females;
the
NOAEL
is
25
mg/
kg/
day.

This
90­
day
subchronic
oral
toxicity
study
in
the
rat
is
Acceptable/
guideline
and
satisfies
the
guideline
requirement
for
a
subchronic
toxicity
study
(
870.3100)
in
rodents.

870.3100
90­
Day
Oral
Toxicity
­
Mouse
A
90­
day
oral
toxicity
study
in
the
mouse
was
not
submitted.

870.3150
90­
Day
Oral
Toxicity
­
Dog
In
a
subchronic
oral
toxicity
study
(
MRID
00111805),
oxadiazon
(
tech.,
98.2%
a.
i.)
was
administered
to
4
Beagle
dogs/
sex/
dose
in
the
diet
for
the
initial
3
weeks
of
the
study
at
concentrations
of
0,
1000,
4000
or
10,000
ppm.
Due
to
unpalatability
of
the
diets,
the
test
material
was
administered
via
gelatin
capsule
from
weeks
4
to
13
at
0,
25,
100
or
1000
(
limit
dose)
mg/
kg/
day.
The
high­
dose
group
received
250
mg/
kg/
day
by
gelatin
capsule
during
week
4
instead
of
1000
mg/
kg/
day.
It
was
stated
that
a
single
high­
dose
male
died
during
week
4
due
to
incidental
causes
and
was
replaced
with
another
dog;
it
was
not
specified
if
the
replacement
animal
was
treated
or
untreated
prior
to
week
4.
No
statistical
analyses
were
provided.

At
25
mg/
kg/
day,
increased
abs/
rel
thyroid
weights
were
observed
in
males
(+
18/+
34%).
At
100
mg/
kg/
day,
increased
alkaline
phosphatase
during
weeks
4
and
13
(+
16
to
+
41%)
in
the
males
only;
increased
aspartate
aminotransferase
during
week
13
(+
14
to
+
26%)
in
males
and
females;
increased
abs/
rel
thyroid
weights
in
males
(+
26%/+
35%);
increased
relative
thyroid
weights
in
females
(+
34%);
increased
abs/
rel
liver
weights
(
males
+
15%/+
28%)
and
relative
liver
weights
in
females
(+
28%)
were
observed.
At
1000
mg/
kg/
day,
increased
alkaline
phosphatase
during
weeks
4
and
13
(+
23
to
+
181%)
in
the
males;
increased
aspartate
aminotransferase
during
weeks
4
and/
or
13
(+
10
to
+
80%)
in
males
and
females,
increased
abs/
rel
liver
weights
(+
24%/+
53%,
males
and
+
60%/+
34%,
females)
and
increased
abs/
rel
thyroid
weights
(+
30%/+
59%,
males
and
+
23%/+
39%,
females)
were
observed.
Large
reductions
in
food
consumption
were
noted
in
the
high
dose
males
during
the
first
3
weeks
of
treatment
(­
36
to
­
50%).
In
the
treated
females,
decreased
food
consumption
was
observed
during
the
first
3
weeks
of
treatment
at
the
low­
(­
4
to
­
20%),
mid­
(­
23
to
­
44%),
and
high­
dose
levels
(­
31
to
­
45%).
These
decreases
OXADIAZON
TECH.
Updated
April
4,
2001
RED
Toxicology
Chapter
10
were
attributed
to
unpalatability
of
the
test
substance
in
the
diet;
after
changing
to
capsule
administration,
food
consumption
did
not
show
a
clear
dose­
dependent
decrease.
No
treatment­
related
changes
in
body
weights,
clinical
signs
of
toxicity,
overall
body
weight
gains,
hematology,
urinalysis,
erythrocyte
cholinesterase
levels,
gross
or
microscopic
pathological
findings
were
observed.
The
systemic
toxicity
LOAEL
for
this
study
is

25
mg/
kg/
day,
based
on
increased
thyroid
weights
in
males.
The
systemic
toxicity
NOAEL
for
this
study
is
<
25
mg/
kg/
day.

This
study
is
classified
as
Acceptable/
guideline
(
870.3150)
and
satisfies
the
requirement
for
a
subchronic
oral
toxicity
study
in
dogs.
Although
a
NOAEL
was
not
identified
in
this
study,
a
NOAEL
of
5
mg/
kg/
day
was
identified
in
a
subsequently
conducted
chronic
oral
study
in
the
dog
(
MRID
41326401;
HED
Doc.
Nos.
008248
and
this
Doc.
No.).

870.3200
21­
Day
Dermal
Toxicity
B
Rat
In
a
21­
day
dermal
toxicity
study
(
MRID
41863602),
oxadiazon
technical
(
97.49%
a.
i.,
moistened
with
distilled
water)
was
applied
dermally
6
hrs/
day,
7
days/
week
for
3
weeks
to
8
male
and
8
female
New
Zealand
White
rabbits
per
dose
at
0,
100,
500
or
1000
mg/
kg/
day.

Treatment
with
oxadiazon
technical
had
no
effect
on
mortality,
body
weight,
body
weight
gain,
food
consumption,
hematology,
clinical
chemistry,
urinalysis,
organ
weights
or
gross
necropsy.
Dermal
irritation
(
erythema,
edema
and
eschar)
was
observed
in
treated
and
control
rabbits.
These
symptoms
first
appeared
during
the
second
week
and
persisted
throughout
the
study.
Histologically,
the
skin
lesions
include
acanthosis,
hyperkeratosis,
acute
and
chronic
dermatitis,
acute
folliculitis,
exudate
on
the
dermal
surface,
edema
and
hemorrhage,
which
are
characteristic
of
chronic
inflammation
and
occlusion.
Although
a
higher
incidence
of
erythema
and
edema
was
noticed
in
the
500
and
1000
mg/
kg
groups,
the
significance
of
these
findings
is
questionable.
The
investigator
overlooked
pharmacokinetic
principles
in
conducting
the
study.
The
approximate
area
of
the
test
article
treated
skin
was
25.9,
92.1
and
119.5
cm2
for
the
100,
500
and
1000
mg/
kg/
day
groups,
respectively,
which
indicates
that
the
administered
dose
(
mg/
cm2)
was
the
same
in
all
cases.
It
is
appropriate
to
apply
graded
concentrations
of
the
test
material
to
the
entire
test
area
(
i.
e.,
10
%
of
the
body
surface
area,
rather
than
a
fraction
of
the
test
area).
Even
though
appropriate
doses
were
not
tested,
the
highest
level
tested
reached
the
Limit
Dose.
The
results
suggest,
therefore,
that
at
the
Limit
Dose,
oxadiazon
Technical
is
not
an
irritant
to
rabbit
skin.
The
systemic
toxicity
and
local
(
dermal
irritation)
LOAELs
are
>
1000
mg/
kg/
day
and
the
NOAELs
are

1000
mg/
kg/
day.

This
study
is
classified
Acceptable/
guideline
and
satisfies
the
guideline
requirement
for
a
21­
day
dermal
study
(
870.3200)
in
the
rabbit.
OXADIAZON
TECH.
Updated
April
4,
2001
RED
Toxicology
Chapter
11
4.3
Prenatal
Developmental
Toxicity
Adequacy
of
data
base
for
Prenatal
Developmental
Toxicity:
The
data
base
for
prenatal
developmental
toxicity
of
oxadiazon
is
considered
complete.
No
additional
studies
are
required
at
this
time.
Similar
findings
were
reported
in
rats
and
rabbits,
although
the
sensitivity
of
fetuses
to
oxadiazon
was
greater
in
rats
than
in
rabbits.
In
rats,
fetal
toxicity
(
increased
resorptions/
postimplantation
loss,
decreased
fetal
weight
and
increased
incidence
of
incomplete
ossification
in
skull
and
vertebral
bones)
were
reported
at
40
mg/
kg/
day,
whereas
only
slightly
decreased
during
late
gestation,
due
at
least
in
part
to
the
fetal
loss
at
that
dose
level.
In
the
rabbit,
developmental
toxicity
(
increased
post­
implantation
loss
and
late
resorptions,
decreased
mean
fetal
weight
and
increased
incidence
of
bilateral
hind­
limb
flexure)
was
observed
at
the
highest
dose
tested
(
180
mg/
kg/
day),
whereas
maternal
toxicity
(
transient
weight
loss
and
decreased
food
consumption
during
and
after
treatment)
was
observed
at
mid
dose
(
60
mg/
kg/
day)
and
higher.

In
addition
to
the
Executive
Summaries
provided
below,
developmental
toxicity
studies
are
summarized
in
capsule
form
in
Section
9.0
(
Appendix),
Table
9.1.2
(
toxicity
profile
table).

870.3700a
Prenatal
Developmental
Toxicity
Study
­
Rat
In
a
developmental
toxicity
study
(
MRID
40470202),
oxadiazon
technical
(
96.3%
a.
i.)
was
administered
daily
by
gavage
in
10
ml
1%
aqueous
methylcellulose
vehicle/
kg
body
weight
from
Gestation
Days
6
through
15
to
groups
of
20
pregnant
Sprague­
Dawley
rats
per
dose
at
0,
3,
12
or
40
mg/
kg/
day.
Pregnant
females
were
examined
daily
for
signs
of
toxicity
and
body
weights
were
measured
on
Gestation
Days
0,
3,
6,
daily
through
Day
16
and
on
Days
18
and
20.
Dams
were
sacrificed
on
Day
20
and
uterine
contents
were
examined.

Very
little
maternal
toxicity
was
observed
at
any
dose.
Small
but
statistically
significant
decreases
in
body
weight
(­
2%
less
than
controls)
and
body
weight
gain
(­
10%)
in
the
highdose
females
at
Days
16­
20
were
possibly
due
to
resorptions
of
fetuses
(
decreased
maternal
body
weights
also
observed
at

40
mg/
kg/
day
in
the
range­
finding
study).
The
maternal
toxicity
LOAEL
is
40
mg/
kg/
day,
based
on
decreased
body
weight/
weight
gain.
The
maternal
toxicity
NOAEL
is
12
mg/
kg/
day.

Treatment­
related
fetal
toxicity
at
40
mg/
kg/
day
included:
slightly,
not
statistically
significantly
increased
fetal
resorptions
(
0.7/
dam
vs.
0.4/
dam,
controls)
and
postimplantation
loss
(
12.5%
vs.
8.2%,
controls)
and
significantly
decreased
body
weight
(­
4.5%
less
than
controls).
Developmental
effects
at
40
mg/
kg/
day
were
confined
to
increased
incidence
of
incomplete
ossification,
primarily
in
skull
and
vertebral
bones.
No
effects
were
seen
at
lower
doses.
No
treatment­
related
malformations
were
observed
at
the
doses
tested.
Fetal
effects
seen
in
this
study
are
considered
treatment­
related
based
on
the
steep
dose­
response
curve
(
for
fetal
loss
and
decreased
fetal
weight)
between
20­
60
mg/
kg/
day
in
the
preliminary
range­
finding
study.
Therefore,
the
effects
seen
at
40
mg/
kg/
day
are
considered
a
threshold
response
for
oxadiazon
under
the
conditions
of
the
OXADIAZON
TECH.
Updated
April
4,
2001
RED
Toxicology
Chapter
12
main
study.
The
developmental
toxicity
LOAEL
(
threshold)
is
40
mg/
kg/
day,
based
on
increased
fetal
resorptions/
postimplantation
loss,
decreased
fetal
weight
and
increased
incidence
of
incomplete
ossification.
The
developmental
toxicity
NOAEL
(
threshold)
is
12
mg/
kg/
day.

This
study
is
classified
Acceptable/
guideline
and
satisfies
the
guideline
requirement
for
a
developmental
toxicity
study
(
870.3700a)
in
the
rat.

870.3700b
Prenatal
Developmental
Toxicity
Study
­
Rabbit
In
a
developmental
toxicity
study
(
MRID
40470201),
oxadiazon
technical
(
95.6%
a.
i.)
was
administered
daily
by
gavage
in
5
ml
1%
aqueous
methylcellulose
vehicle/
kg
body
weight
from
gestation
days
6
through
19
to
groups
of
15
to
19
pregnant
New
Zealand
White
rabbits
per
dose
at
0,
20,
60
or
180
mg/
kg/
day.
Pregnant
females
were
examined
daily
for
signs
of
toxicity
and
body
weights
were
measured
on
Gestation
Days
0
and
6,
on
alternate
days
through
day
20
and
on
days
24
and
28.
Dams
were
sacrificed
on
Day
29
and
uterine
contents
were
examined.

Treatment­
related
maternal
toxicity
was
observed
at
60
mg/
kg/
day
as
transient
weight
loss
(­
0.01
kg
vs.
0.10
kg
gain,
controls;
p<
0.05)
and
slightly
decreased
food
consumption
during
the
first
half
of
treatment
(­
15%
less
than
controls,
treatment
days
6­
12;
not
statistically
significant).
These
effects
were
more
pronounced
at
180
mg/
kg/
day
and
showed
statistically
significant
reductions
in
weight
gain
and
marked
reductions
in
food
consumption
during
and
after
treatment.
The
maternal
toxicity
LOAEL
is
60
mg/
kg/
day,
based
on
transient
weight
loss
and
decreased
food
consumption
during
treatment.
The
maternal
toxicity
NOAEL
is
20
mg/
kg/
day.

Treatment­
related
fetal
toxicity
at
180
mg/
kg/
day
included:
increased
postimplantation
loss
and
late
resorptions
(
18.85%
vs.
8.6%,
controls;
p<
0.05),
decreased
mean
fetal
weight
(­
10%)
and
increased
incidence
of
bilateral
hind­
limb
flexure
(
4.2%
of
fetuses,
3
litters
affected
vs.
0%,
controls).
Marginal
developmental
effects
at
180
mg/
kg/
day
were:
increased
incidence
of
rib
abnormalities,
delayed/
incomplete
ossification
in
several
bones
and
asymmetrical
pelvis.
No
effects
were
seen
at
lower
doses
and
there
were
no
treatmentrelated
malformations
observed
at
any
dose
tested.
The
developmental
toxicity
LOAEL
is
180
mg/
kg/
day,
based
on
increased
postimplantation
loss,
decreased
mean
fetal
weight,
increased
bilateral
hind­
limb
flexure
and
possibly
delayed/
incomplete
ossification
of
several
bones.
The
developmental
toxicity
NOAEL
is
60
mg/
kg/
day.

This
study
is
classified
Acceptable/
guideline;
it
satisfies
the
guideline
requirement
for
a
non­
rodent
developmental
toxicity
study
(
870.3700b)
in
the
rabbit.

4.4
Reproductive
Toxicity
OXADIAZON
TECH.
Updated
April
4,
2001
RED
Toxicology
Chapter
13
Adequacy
of
data
base
for
Reproductive
Toxicity:
The
data
base
for
reproductive
toxicity
is
considered
complete.
No
additional
studies
are
required
at
this
time.
In
the
rat
two­
generation
reproductive
toxicity
study,
no
maternal,
offspring
or
reproductive
effects
were
reported
at
any
dose
tested
up
to
200
ppm
(
15.5
mg/
kg/
day).
However,
in
the
range­
finding
study
at

400
ppm
(
38
mg/
kg/
day),
significant
toxicity
to
the
offspring
(
fetal/
neonatal
mortality)
and
the
dams
(
inactive
mammary
tissue,
decreased
gestational
weight,
due
at
least
in
part
to
fetal
mortality)
was
observed.
The
neonatal
mortality
was
probably
related
to
the
mammary
tissue
effects
in
the
dams.

In
addition
to
the
Executive
Summaries
provided
below,
the
reproductive
toxicity
study
is
summarized
in
capsule
form
in
Section
9.0
(
Appendix),
Table
9.1.2
(
toxicity
profile
table).

870.3800
Reproduction
and
Fertility
Effects
­
Rat
In
a
2­
generation
reproduction
study
(
MRID
41239801;
range­
finding
study
MRID
41240301)
oxadiazon
(
96.6%
a.
i.)
was
administered
in
the
diet
continuously
to
CD
rats
(
30
rats/
sex/
dose)
at
0,
20,
60
or
200
ppm
(
equivalent
to
an
average
daily
intake
[
M/
F]
of
0,
1.50/
1.84,
4.65/
5.63
or
15.50/
18.20
mg/
kg/
day,
average
of
P
and
F
1
generation
premating
food
consumption).
Dose
levels
were
selected
based
on
the
results
of
the
1­
generation
range­
finding
study,
which
tested
at
0,
50,
100,
200,
400
or
800
ppm
(
6
animals/
sex/
dose,
4
weeks
premating
exposure).
The
P
animals
were
exposed
to
the
test
substance
beginning
at
approximately
6
weeks
of
age
for
14
weeks
prior
to
mating
and
continuing
until
sacrifice
after
weaning
(
post­
partum
day
25).
F
1
pups
selected
(
30/
sex/
dose)
to
produce
the
F
2
generation
were
exposed
to
the
same
dosage
as
their
parents
beginning
at
postnatal
day
(
PND)
25
for
14
weeks
premating
and
continuously
throughout
the
rest
of
the
study
until
weaning
of
the
F
2
offspring
(
postpartum
day
25).
Liver,
kidneys,
ovaries,
uterus,
prostate,
epididymis,
testes
and
seminal
vesicles
were
weighed
and
examined
for
gross/
microscopic
pathology.
Mammary
gland,
pituitary
and
vagina
were
examined
for
pathological
changes.
The
1­
generation
range­
finding
study
tested
in
6
dams/
dose
group
at
dietary
concentrations
of
0,
50,
100,
200,
400
or
800
ppm
(
0,
5/
5,
9/
9,
19/
19,
36/
38
or
67/
75
mg/
kg/
day,
respectively),
administered
beginning15
days
prior
to
initiation
of
mating
until
lactation
day
4.
No
treatment­
related
findings
were
reported
at

200
ppm;
effects
at
400
and
800
ppm
are
discussed
below.

There
was
no
evidence
of
treatment­
related
changes
in
clinical
signs,
mortality,
body
weights
or
weight
gains,
food
consumption,
food
efficiency,
organ
weights
or
microscopic
or
macroscopic
pathology
observed
in
P
or
F
1
adults
in
the
main
study.
Slight
liver
alterations
in
F
1
adults
at
200
ppm
(+
6%
relative
liver
weight,
females,
periacinar
hepatocellular
hypertrophy,
males)
were
considered
an
adaptive
response.
However,
at
400
ppm
in
the
range­
finding
study,
markedly
decreased
gestational
weight
gain
(­
34%
below
controls,
primarily
after
GD
13)
was
observed
(
due
largely
to
increased
fetal
loss).
At
800
ppm,
decreased
maternal
weight
gain
of
­
38%
below
controls,
also
primarily
after
GD
13,
blood
in
the
urine
in
the
cage
paper
of
males
and
blood
in
the
nares/
face/
urogenital
region
of
1
dam
were
observed.
The
LOAEL
(
main
study)
for
parental
toxicity
is
>
200
ppm
(
15.5
mg/
kg/
day;
HDT
in
main
study);
however,
a
LOAEL
of
400
ppm
(
38
OXADIAZON
TECH.
Updated
April
4,
2001
RED
Toxicology
Chapter
14
mg/
kg/
day),
based
on
decreased
gestational
weight
gain,
was
observed
in
the
rangefinding
study.
The
parental
toxicity
NOAEL
(
main
study)
is

200
ppm.

No
differences
in
reproductive
parameters
in
P
or
F
1
parental
animals,
nor
in
F
1
or
F
2
offspring
viability,
clinical
signs,
body
weight
or
body
weight
gain,
developmental
landmarks,
auditory
or
ophthalmological
function
or
macroscopic
pathology
were
observed
in
the
main
study.
However,
in
the
range­
finding
study,
pronounced
reproductive/
offspring
toxicity
at
400
ppm
in
the
4
dams
that
littered
(
5
pregnant)
included
inactive/
pale
mammary
tissue,
reduced
litter
size
and
increased
gestation
length
(+
1
day).
Pre­/
perinatal
mortality
resulted
in
total
litter
losses
for
all
dams
by
day
1
postpartum
(
17
offspring
were
examined:
20%
late
resorptions,
7.7%
dead
fetus,
73%
without
milk
in
stomach).
At
800
ppm,
2
dams
littered
but
all
were
late
resorptions;
4
dams
that
failed
to
litter
had
blood
in
their
cage
on
GD
23
(
implantation
sites/
dam
were
comparable
to
controls).
The
reproductive/
offspring
toxicity
LOAEL
(
main
study)
is
>
200
ppm
(
15.5
mg/
kg/
day;
HDT
in
main
study);
however,
a
LOAEL
of
400
ppm
(
38
mg/
kg/
day),
based
on
inactive
mammary
tissue
and
fetal/
pup
death,
was
observed
in
the
range­
finding
study.
The
reproductive/
offspring
toxicity
NOAEL
(
main
study)
is

200
ppm.

This
reproductive
toxicity
study
in
the
rat
is
classified
Acceptable/
guideline
(
870.3800)
and
satisfies
the
guideline
requirement
for
a
multigenerational
reproductive
toxicity
study
in
rats.
Although
no
significant
effects
were
observed
at

200
ppm
in
the
main
or
rangefinding
studies,
pronounced
reproductive/
offspring
toxicity,
including
complete
litter
loss,
was
observed
at

400
ppm.
At
the
Hazard
Identification
Assessment
Review
Committee
(
HIARC)
meeting,
held
December
7,
2000
(
see
HED
Document
No.
014469),
it
was
concluded
that
the
neonatal
loss
seen
at
400
ppm
was
attributable
to
maternal
effects
(
i.
e.,
inactive
mammary
tissue
resulting
in
possible
starvation
of
the
pups
which
was
manifested
as
73%
of
the
examined
offspring
without
milk
in
their
stomachs).
The
HIARC
further
concluded
that
the
inactivity
of
mammary
tissue
may
have
been
related
to
endocrine
disruption.
However,
this
finding
was
not
considered
to
be
likely
because
there
was
no
supporting
evidence
of
possible
endocrine
disruption
observed
in
any
other
study
in
the
Oxadiazon
database.

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.
In
the
Wistar
rat,
males
were
more
sensitive
to
oxadiazon
than
females
and
the
NOAEL
of
10
ppm
(
0.36
mg/
kg/
day)
was
based
on
centrilobular
swelling
in
male
rat
liver
at
100
ppm
(
3.5
mg/
kg/
day).
Oxadiazon
caused
hepatic
toxicity,
demonstrated
by
alterations
in
liver­
related
blood
enzymes
(
males),
liver
enlargement
and
microscopic
pathology
(
hepatocellular
swelling
and
increased
acidophilic
foci
of
cellular
alteration,
brown
pigmentation
and
bile
duct
proliferation).
Liver
tumors
were
also
increased
by
treatment
(
see
Section
for
details).
Mild
anemia
was
observed
in
males.
In
addition,
oxadiazon
caused
renal
OXADIAZON
TECH.
Updated
April
4,
2001
RED
Toxicology
Chapter
15
toxicity
(
increased
BUN,
brown
pigmentation
in
the
proximal
tubular
cells
and
cortical
interstitial
tissues
in
both
sexes
and
incidence
of
chronic
nephropathy
in
males).
F344
rats
had
similar
treatment­
related
effects,
including
anemia
in
males,
increased
liver­
related
blood
enzymes
primarily
in
males,
increased
urine
color
and
bilirubin/
urobilinogen,
increased
liver
and
kidney
weights,
microscopic
liver
effects
such
as
hypertrophy,
fatty
change
and
necrosis
and
pigmented
nephrosis.
In
the
dog,
the
liver
was
also
the
primary
target
organ,
as
demonstrated
by
liver
enlargement.
Evidence
of
liver
pathology
and
serum
enzyme
alterations,
increased
blood/
bilirubin
in
the
urine,
increased
kidney
and
thyroid
weights
(
and
possibly
anemia
in
1
female)
were
observed
only
at
a
relatively
high
dose
(
200
mg/
kg/
day)
in
which
only
2/
sex
dogs
were
evaluated
and
1
female
was
sacrificed
in
moribund
condition.

In
addition
to
the
Executive
Summaries
provided
below,
chronic
toxicity
studies
are
summarized
in
capsule
form
in
Section
9.0
(
Appendix),
Table
9.1.2
(
toxicity
profile
table).

870.4300
Chronic
Toxicity/
Carcinogenicity
B
Rat
(
1)
In
a
chronic/
carcinogenicity
toxicity
study
(
MRID
Nos.
00149003
[
main
study]/
MRID
00157780
[
additional
data]),
oxadiazon
(
tech.,
99.9%
a.
i.)
was
administered
to
Fischer
344
rats
(
76/
sex/
dose)
in
the
diet
at
dose
levels
of
0,
10,
100,
1000
or
3000
ppm
(
mean
consumption
per
group:
equivalent
to
0,
0.5,
4.8,
50.9
or
163.1
mg/
kg/
day
for
males
or
0,
0.6,
5.9,
60.9
or
192.7
mg/
kg/
day
for
females)
for
24
months.
Parameters
examined
included:
(
1)
twice
daily
observations,
(
2)
weekly
body
weights
and
food
consumption,
(
3)
ophthalmic
examinations
(
all
animals
at
pretest
and
10
rats/
group
at
6,
12
and
24
months),
(
4)
standard
hematology,
clinical
chemistry
and
urinalysis
(
10
rats/
group
at
6,
12
and
24
months),
and
(
5)
gross
necropsy,
organ
weights
and
histology
(
10
rats/
group
at
6
and
12
months
and
all
survivors
at
24
months).

There
were
no
effects
on
mortality.
At
1000
and
3000
ppm,
clinical
signs
included
emaciation,
anemia
and
brown
colored
urine;
ophthalmic
examinations
revealed
narrowing
of
the
fundus
vasculature
(
males
at
1000
ppm
and
both
sexes
at
3000
ppm).
Significant
decreases
(
p<
0.05­
0.001)
in
body
weight
gain
were
apparent
in
rats
of
both
sexes
receiving
1000
or
3000
ppm
and
significant
decreases
in
food
consumption
were
recorded
for
both
sexes
starting
at
week
3
(
males)
and
week
6
(
females).
Consistent
hematological
findings
indicative
of
anemia
at
3000
ppm
(
both
sexes)
were:
significantly
decreases
erythrocyte
counts,
hematocrit,
hemoglobin,
mean
corpuscular
volume,
mean
corpuscular
hemoglobin
and
mean
corpuscular
hemoglobin
concentration.
Anemia
was
also
present
in
males
at
1000
ppm
and
appeared
to
be
less
severe
in
females.
Adverse
effects
on
urinalysis
parameters
were
confined
to
the
two
highest
dose
groups
(
both
sexes)
and
included:
urine
color,
strongly
positive
bilirubin
and
urobilinogen.
Significantly
affected
clinical
chemistry
parameters
included:
reduced
glucose
levels
(
males

1000
ppm
at
6
and
12
months;
females
3000
ppm
at
6
months);
increased
total
protein
(
consistent
effect
only
in
the
females
at

100
ppm
and
generally
at
all
sampling
intervals);
increased
total
cholesterol
(
males
at
1000
ppm
and
both
sexes
at
3000
ppm)
and
increased
bilirubin
(
males

1000
ppm
at
6
and
12
months;
females
3000
ppm
at
6
months).
In
addition,
significant
increases
OXADIAZON
TECH.
Updated
April
4,
2001
RED
Toxicology
Chapter
16
in
GOT,
GPT,
AP
and
BUN
generally
correlated
well
with
liver
morphological
changes
at

1000
ppm
(
males).
Similarly,
increased
absolute
and
relative
liver
and
kidney
weights
at

1000
ppm
(
both
sexes)
correlated
well
with
liver
and
kidney
histopathology
effects.
At
termination,
oxadiazion
also
induced
increased
absolute
and
relative
liver
weights
at
100
ppm
(
females).
Non­
neoplastic
pathology
included:
hepatocyte
changes
consisting
of
progressive
alterations
from
hypertrophy
through
fatty
changes
to
necrosis
were
noted
in
males
receiving
1000
and
3000
ppm
and
females
receiving
3000
ppm.
Other
non­
neoplastic
changes
noted
in
both
sexes
were:
pigmented
nephrosis
and
fat
replacement
in
the
pancreas
at
1000
ppm
and
basophilic
changes
in
the
adrenal
glands
at
3000
ppm.
The
LOAEL
is
100
ppm
(
4.8
mg/
kg/
day)
based
on
increased
absolute
liver
weights
in
males
and
females
and
increased
total
serum
protein
in
females.
The
NOAEL
is
10
ppm
(
0.5
mg/
kg/
day).

Neoplastic
findings
were:
increased
incidences
of
benign
and
malignant
liver
tumors
in
males
at
1000
and
3000
ppm
after
prolonged
exposure
to
hepatotoxic
doses.
In
addition,
there
was
no
decrease
in
latency
for
liver
neoplasia.
Dosing
was
considered
adequate
in
males
and
the
data
support
a
presumption
that
the
maximum
tolerated
dose
(
MTD)
lies
between
100
and
1000
ppm.

This
chronic/
carcinogenicity
study
in
the
rat
is
Acceptable/
Guideline
and
satisfies
the
guideline
requirement
for
a
combined
chronic/
carcinogenicity
study
(
870.4300)
in
the
rat.

(
2)
In
a
chronic/
oncogenicity
toxicity
study
(
MRID
40993401),
oxadiazon
(
tech.,
95.9%
a.
i.)
was
administered
to
SPF
Wistar
rats
(
80/
sex/
dose)
in
the
diet
at
dose
levels
of
0,
3,
10,
100
or
1000
ppm
(
equivalent
to
0,
0.106,
0.36,
3.5
or
39
mg/
kg/
day
for
males
or
0,
0.131,
0.44,
4.2
or
44
mg/
kg/
day
for
females)
for
104
weeks.
Clinical
signs
were
monitored
daily.
Body
weights
were
determined
weekly
for
the
first
26
weeks
and
biweekly,
thereafter;
food
consumption
was
determined
weekly
for
20
rats/
group.
Groups
of
8
rats/
sex/
group
were
sacrificed
at
weeks
26,
52
and
78
and
10
animals/
sex/
group
at
104
weeks
were
subjected
to
hematology,
biochemistry
and
urinalysis
examinations.
All
80
rats/
sex/
dose
were
reportedly
examined
for
histopathology.
Dose
selection
was
based
on
a
preliminary
4­
week
range
finding
study
with
10,
100,
1000
or
3000
ppm.
At
1000
and
3000
ppm,
signs
of
toxicity
included:
anemia
(
males­­
both
groups;
females­­
3000
ppm,
only),
effects
on
biochemical
parameters
associated
with
hepato­
renal
disorders
(
increased
GOT,
GPT,
ALP,
BUN,
total
cholesterol
and/
or
urobilinogen),
and
liver
and
kidney
weight
changes
accompanied
by
a
dark
color.

There
were
no
adverse
effects
on
mortality,
clinical
signs
or
food
consumption.
Treatment
related
effects
included:
decreased
body
weight
gain
for
high­
dose
males
generally
throughout
the
study;
statistically
significant
body
weight
losses
(­
8.9%)
were
reported
for
the
10­
and
1000
ppm
females
only
at
study
termination.
Hematological
parameters
significantly
affected
were:
decreased
hematocrit
and
hemoglobin
(
high­
dose
males
at
week
26)
and
decreased
mean
corpuscular
volume
and
mean
corpuscular
hemoglobin
(
high­
dose
males
at
weeks
26,
78
and
104).
There
were
no
consistent
hematological
effects
in
the
OXADIAZON
TECH.
Updated
April
4,
2001
RED
Toxicology
Chapter
17
females.
The
generalized
changes
in
the
blood
elements
of
male
rats
are
indicative
of
anemia
which
was
most
evident
at
week
26.
Significantly
affected
clinical
chemistry
parameters
included:
increased
LDH,
ALT,
GOT,
GPT,
total
and
direct
bilirubin
and
total
cholesterol
for
high­
dose
males
at
week
26;
no
toxicologically
significant
effects
were
seen
in
the
females
of
any
dose
group.
At
1000
ppm,
males
also
showed
increased
urobilinogen
at
week
26.
Increased
liver
weights
were
seen
in
high­
dose
males
and
females
throughout
the
study
and
statistically
significant
increases
in
kidneys
(
both
sexes)
and
testis
(
males)
were
also
consistently
seen
at
1000
ppm.
Non­
neoplastic
pathology
in
the
liver
at
1000
ppm
included:
increased
centrilobular
hepatocellular
swelling
(
males
and
females);
increased
acidophilic
foci
of
cellular
alteration
(
males);
brown
pigmentation
in
the
liver
(
males
and
females);
and
bile
duct
proliferation
(
males)
At
100
ppm,
increased
centrilobular
hepatocellular
swelling
was
also
seen
in
the
males.
Brown
pigmentation
in
the
proximal
tubular
cells
and
in
cortical
interstitial
tissue
(
males
and
females);
and
chronic
nephropathy
(
females)
were
also
recorded
for
the
kidneys
of
high­
dose
rats.
The
LOAEL
is
100
ppm
(
3.5
mg/
kg/
day)
based
on
centrilobular
swelling
in
the
male
rat
livers;
the
NOAEL
is
10
ppm
(
0.36
mg/
kg/
day).

Neoplastic
findings
were:
increased
incidence
of
liver
adenomas
in
males
at
100
(
p<
0.05)
and
1000
ppm
(
p<
0.010);
liver
carcinomas
were
also
increased
at
1000
ppm
in
both
sexes
but
not
significantly.
Dosing
was
considered
adequate
in
males
based
on
signs
of
transient
anemia,
increased
serum
enzyme
activity,
bilirubin
and
liver
weight,
decreased
body
weight
gain,
and
pathological
changes
in
the
liver
(
centrilobular
hepatocellular
swelling
and
foci
of
cellular
alteration).
Females
were
considered
to
be
tested
at
a
dose
below
the
maximum
tolerated
dose
(
MTD).
However,
since
the
NOAEL
and
LOAEL
were
defined
for
males
(
0.36/
3.5
mg/
kg/
day),
the
hypothetical
values
for
females
are
expected
to
be
higher.
Hence,
the
NOAEL
and
LOAEL
for
males
are
considered
to
be
protective
for
females.

The
pathology
report
for
this
chronic/
carcinogenicity
study
in
the
rat
was
considered
incomplete;
thus,
the
overall
study
was
listed
as
Supplementary.
At
this
time,
no
additional
information
is
being
requested
because
the
results
are
consistent
with
an
acceptable
rat
chronic/
carcinogenicity
study
(
MRID
No.
0014003/
00157780)
that
satisfies
the
guideline
requirement.
Similarly,
the
presence
of
liver
neoplasms
confirms
the
evidence
of
a
carcinogenic
effect
seen
in
MRID
No.
0014003/
00157780.
After
review
of
the
data
from
this
study
by
the
Cancer
Assessment
Review
Committee
(
CARC),
however,
it
was
concluded
that
this
deficiency
did
not
compromise
the
integrity
of
the
study
or
the
interpretation
of
the
results
[
see
Cancer
Assessment
Document­­
Evaluation
of
the
Carcinogenic
Potential
of
Oxadiazon
(
Third
Review),
dated
April
2001].
Using
this
rationale,
the
study
is
now
upgraded
and
listed
as
Acceptable/
guideline
and
satisfies
the
guideline
requirement
for
a
combined
chronic
toxicity/
carcinogenicity
study
in
the
rat
(
870.4300).

870.4100b
Chronic
Toxicity
­
Dog
In
a
one­
year
chronic
oral
toxicity
study
(
MRID
No.
41326401),
oxadiazon
(
tech.,
94.9%
OXADIAZON
TECH.
Updated
April
4,
2001
RED
Toxicology
Chapter
18
a.
i.)
was
administered
orally
via
capsules
once
a
day
to
five
groups
of
Beagle
dogs
(
4
males
and
4females/
group
dosed
with
0,
5,
20
or
60
mg/
kg/
day;
2
males
and
2
females
dosed
with
200
mg/
kg/
day).
Dose
selection
was
based
on
the
findings
of
a
preliminary
study
showing
that
dogs
could
not
tolerate
360
mg/
kg/
day
and
that
minimal
changes
were
seen
at
60
mg/
kg/
day.
Parameters
examined
in
all
animals
included:
(
1)
daily
observations;
(
2)
weekly
body
weights
and
food
consumption;
(
3)
ophthalmic
examinations
at
pretest
and
week
51;
(
4)
standard
hematology
(
pretest
and
at
weeks
12,
24
and
50),
clinical
chemistry
(
pretest
and
at
weeks
24
and
50)
and
urinalysis;
(
5)
bone
marrow
analysis
at
week
52;
and
(
6)
gross
necropsy,
organ
weights
and
histology.
Due
to
the
small
number
of
animals
tested
(
2/
sex,
1
female
sacrificed
at
week
11)
and
that
they
were
rejected
due
to
lower
body
weight
from
inclusion
in
the
range­
finding
study,
the
findings
in
the
200
mg/
kg/
day
dogs
were
considered
to
be
supplementary
information.

There
were
no
effects
on
mortality,
clinical
signs,
food
consumption,
hematology,
urinalysis
or
ophthalmic
examinations.
At
60
mg/
kg/
day,
clinical
biochemical
changes
in
the
males
(
3
of
4)
included
significant
(
p<
0.05)
elevations
(

+
35%)
in
aspartate
aminotransferase
(
AST)
at
all
intervals.
For
females,
ALT
and
AST
values
were
significantly
decreased
at
week
24
(­
32%
to
­
40%),
an
effect
not
considered
of
toxicological
significance.
No
other
alterations
in
biochemical
parameters
were
considered
to
be
an
effect
of
oxadiazon.
In
males,
significant
increases
in
relative
liver
weights
were
seen
at
60
(+
39%)
and
200
(+
61%)
mg/
kg/
day;
absolute
liver
weights
were
also
increased
at
60
(+
28%)
and
200
(+
41%)
mg/
kg/
day
but
statistical
significance
was
not
attained.
The
response
was
doserelated
with
weight
increases
of
+
7,
+
23
or
+
28%
(
absolute)
and
+
7,
+
21
and
+
28%
(
relative)
at
5,
20
or
60
mg/
kg/
day,
respectively.
In
females,
significant
increases
in
absolute
liver
weight
were
noted
at
levels

20
mg/
kg/
day
(+
35%
and
+
44%
at
20
and
60
mg/
kg/
day,
respectively);
a
nonsignificant
+
21%
increase
was
seen
at
5
mg/
kg/
day.
Relative
female
liver
weights
also
showed
a
dose­
related
response
with
a
+
7,
+
10
or
+
38%
increases
at
5,
20
or
60
mg/
kg/
day,
respectively.
However,
organ
weight
changes
and
increased
blood
levels
of
AST
were
not
definitively
associated
with
a
pathological
condition
in
the
liver.
At
200
mg/
kg/
day,
one
female
was
sacrificed
in
moribund
condition.
Observed
effects
included
pallor,
thinness,
decreased
weight
gain,
possible
anemia
(
based
on
hematological
changes,
brown
urine
in
the
sacrificed
female
and
blood/
bilirubin
in
the
urine
of
the
surviving
female),
clinical
chemistry
alterations
(
increased
ALT,
phosphorous;
decreased
glucose,
total
cholesterol,
protein
and
potassium),
increased
liver,
spleen,
kidney
and
thyroid
weights
(
also
lower
testes
weights)
and
hepatocellular
histopathology
(
centriacinar
hepatocytic
vacuolation,
periacinar
apoptosis
and
periacinar
inflammation
in
females).
The
systemic
toxicity
LOAEL
is
20
mg/
kg/
day,
based
on
hepatic
toxicity
(
increased
absolute
and
relative
female
liver
weight
accompanied
by
similar
changes
in
the
absolute
and
relative
liver
weights
for
both
sexes
at
60
mg/
kg/
day).
The
systemic
toxicity
NOAEL
is
5
mg/
kg/
day.

This
study
is
classified
Acceptable/
Guideline
and
satisfies
the
guideline
requirement
for
a
non­
rodent
chronic
oral
toxicity
study
(
870.4100b)
in
the
dog.
OXADIAZON
TECH.
Updated
April
4,
2001
RED
Toxicology
Chapter
19
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.
An
increased
incidence
of
hepatocellular
neoplasms
were
observed
in
both
rats
(
F344
and
Wistar)
and
mice
(
CD­
1
and
ICR­
JCL).
In
mice,
liver
tumor
incidence
was
increased
in
both
sexes,
whereas
in
rats
the
males
were
affected.

In
addition
to
the
Executive
Summaries
provided
below,
carcinogenicity
studies
are
summarized
in
capsule
form
in
Section
9.0
(
Appendix),
Table
9.1.2
(
toxicity
profile
table).

870.4300a
Chronic
Toxicity/
Carcinogenicity
Study
­
rat
See
Section
4.5
(
Chronic
Toxicity),
above
for
the
executive
summaries.

870.4200b
Carcinogenicity
(
feeding)
­
Mouse
(
1)
In
a
mouse
oncogenicity
study
(
MRID
No.
00115733),
oxadiazon
(
tech.,
99.3%
a.
i.)
was
administered
in
the
diet
to
CD­
1
mice
(
70/
sex/
group)
for
up
to
105
weeks
at
0,
100,
300,
1000,
or
2000
ppm
(
equivalent
to
0/
0,
12/
14,
37/
44,
122/
143,
or
254/
296
mg/
kg/
day
[
M/
F],
respectively).

At
2000
ppm,
significantly
decreased
survival
(
and
a
dose­
related
positive
trend
for
decreased
survival)
were
observed
in
males
(
at
termination,
43%,
24%,
36%,
27%
and
4%,
control
to
high
dose)
and
in
females
(
at
termination,
56%,
41%,
53%,
43%
and
29%).
During
the
first
26
weeks
of
treatment,
29/
70
high­
dose
males
died
or
were
sacrificed
in
extremis.
It
was
stated
that
these
animals
were
generally
pale,
inactive,
weak,
hypothermic
and
exhibited
tremor
and
piloerection.
Thoracic
serosanguineous
fluid
was
observed
in
these
males
at
gross
necropsy
(
15/
29
treated
vs
6/
70
total
controls
affected
and
1
of
2
controls
that
died
by
week
26).
At
histological
examination,
the
following
were
also
observed
(#
of
animals):
hypercellular
spleens
(
18);
diffuse,
necrotic
myocarditis
(
20);
periacinar
hepatocytic
pallor
(
12);
hepatic
single
cell
necrosis
(
16);
and
pigmented
Kupffer
cells
(
8).
An
increase
(
p<
0.05
or
0.01)
in
the
total
incidence
of
distended
abdomen
was
observed
at
various
intervals
in
all
treated
males
(
80­
90%
treated
vs
60­
61%
controls).
Pale
eyes
were
observed
in
females
(
50­
60%
treated
vs
31%
controls).
At
1000
and
2000
ppm,
increased
(
p<
0.05
or
0.01)
incidence
of
pallor
was
observed
(
40­
46%
treated
vs
21%
controls)
during
the
study.
At
2000
ppm,
body
weights
were
reduced
in
males
at
week
104
(

12%,
not
analyzed
statistically).
Reductions
(
p<
0.05
or
0.01)
in
mean
body
weight
gain
were
observed
in
the
males
during
weeks
1­
13
(

13%)
and
for
weeks
0­
104
(

26%);
during
weeks
66­
92,
weight
loss
was
greater
at
high
dose
than
controls
(­
7
g
vs.
­
2
g,
respectively).
Slight
anemia,
as
indicated
by
decreased
(
p<
0.05,
0.01,
or
0.001)
hematocrit
(­
5
to
­
30%),
hemoglobin
(­
6
to
­
28%),
and
erythrocyte
count
(­
12
to
­
32%),
was
observed
in
the
1000
ppm
males
and
2000
ppm
males
and
females.
Neutrophil
count
was
slightly
increased
at
2000
ppm
in
males
(­
83%)
and
females
(­
117%)
at
termination,
OXADIAZON
TECH.
Updated
April
4,
2001
RED
Toxicology
Chapter
20
possibly
reflecting
a
mild
inflammatory
response.

Increases
(
p<
0.05,
0.01,
or
0.001)
with
respect
to
concurrent
controls
were
observed
in
absolute
and
relative
(
to
body
weight)
liver
weights
in
all
male
treatment
groups
(+
45%/+
52%,
+
46%/+
57%,
+
107%/+
120%
and
+
86%/+
120%)
and
in
the
1000
and
2000
ppm
female
groups
(+
48/+
53%
and
+
103%/+
102%).
At
gross
necropsy,
increased
incidence
of
hepatic
pale
areas/
foci
and
masses
were
observed
in
all
male
groups
when
excluding
animals
that
died
before
week
27
(
pale
areas/
foci
36%­
59%
treated
vs
4%
controls;
masses
41%­
47%
treated
vs
27%
controls)
and
all
female
groups
(
pale
areas/
foci
11%­
19%
treated
vs
7%
controls;
masses
10%­
26%
treated
vs
3%
controls).
In
addition,
raised
areas
in
the
liver
were
observed
in
the
300,
1000,
and
2000
ppm
females
(
10­
11%
vs
1%
control).
Increases
in
large,
eosinophilic
hepatocytes
were
observed
in
all
male
and
female
groups
without
a
clear
dose­
response
(
7­
23
treated
affected
vs
0­
3
controls,
N
=
70,
all
groups).
Slight
to
moderate
hepatic
amyloidosis
was
increased
in
all
male
treatment
groups
(
9­
22
treated
affected
vs.
0
controls)
and
in
high­
dose
females
(
12/
70
treated
vs
3/
70
controls).
Increased
incidence
of
pigmented
Kupffer
cells
(
7/
41
treated
vs
0/
70
controls)
were
observed
in
males
that
did
not
die
by
week
26.
Food
consumption,
food
efficiency,
and
water
consumption
(
visually
inspected,
only)
for
both
sexes
at
all
doses
were
unaffected
by
treatment
with
oxadiazon
at
any
tested
dose.
The
systemic
toxicity
LOAEL
is

100
ppm
for
males
and
females
(
equivalent
to
12/
14
mg/
kg/
day
[
M/
F])
based
on
clinical
signs,
gross
and
microscopic
liver
lesions
in
both
sexes,
and
increased
liver
weights
in
males.
The
systemic
toxicity
NOAEL
is
<
100
ppm.

Under
the
conditions
of
this
study,
there
was
an
increased
incidence
of
hepatocellular
neoplasms
in
males
and
females.
Incidences
of
hepatocellular
adenomas
were
increased
(
p<
0.05,
0.01,
or
0.001)
in
all
groups
of
treated
males
(
27.9%,
51.4%,
68.6%,
56.5%
and
53.7%­
68.6%,
control
to
high
dose)
and
females
(
4.4%,
18.8%,
25.7%,
32.9%
and
41.2%)
treatment
groups.
These
were
outside
of
historical
control
ranges
of
males
(
0­
12%)
in
all
groups,
including
controls,
and
of
females
(
0­
14%)
for
all
treated
groups.
The
incidences
of
adenocarcinomas
were
increased
(
p<
0.05
or
not
significant)
in
all
male
treatment
groups
(
7.4%,
20.0%,
24.3%,
24.6%
and
24.4%,
control
to
high
dose)
and
in
the
1000
and
2000
ppm
female
groups
(
12.9%
and
10.3%
vs
1.5%,
controls).
The
incidences
were
outside
of
historical
control
ranges
for
males
(
0­
8%)
in
all
treatment
groups
and
females
(
0­
6%)
at

1000
ppm.
The
incidences
of
combined
adenomas
and
adenocarcinomas
were
increased
(
p<
0.05,
0.01,
or
0.001)
in
all
male
(
29,4%,
57.1%,
74.3%,
63.8%
and
68.3%)
and
female
(
5.9%,
18.8%,
27.1%,
38.6%
and
47.1%)
treatment
groups
(
no
historical
controls
provided
for
combined
neoplasms).
Dosing
was
considered
adequate
based
on
the
finding
of
liver
toxicity
at
all
doses.

The
submitted
study
is
classified
as
Acceptable/
guideline
(
870.4200b)
and
satisfies
the
guideline
requirements
for
a
carcinogenicity
study
in
mice.

(
2)
In
a
chronic/
oncogenicity
toxicity
study
(
MRID
40993301),
oxadiazon
(
tech.,
95.9%
a.
i.)
was
administered
to
80
ICR­
JCL
mice
(
80/
sex/
dose)
in
the
diet
at
0,
3,
10,
100
or
1000
OXADIAZON
TECH.
Updated
April
4,
2001
RED
Toxicology
Chapter
21
ppm
(
equivalent
to
0,
0.315,
1.09,
10.6
or
113
mg/
kg/
day
for
males
or
0,
0.278,
0.92,
9.3
or
99
mg/
kg/
day
for
females)
for
98­
99
weeks
(
the
study
was
scheduled
to
run
for
104
weeks
but
due
to
deaths,
it
was
terminated
at
98­
99
weeks).
Clinical
signs
were
monitored
daily.
Body
weights
were
determined
weekly
for
the
first
26
weeks
and
biweekly,
thereafter;
food
consumption
was
determined
twice
weekly
for
8
cages
(
4
mice/
cage).
Groups
of
9­
10
mice/
sex/
group
were
sacrificed
at
weeks
52
and
98/
99
were
subjected
to
hematology,
biochemistry,
urinalysis
and
pathology
analysis.

Dose
selection
was
based
on
a
preliminary
4­
week
range
finding
study
with
0,
10,
100,
1000
or
3000
ppm.
Liver
weights
were
increased
in
males
at
100,
1000
and
3000
ppm
and
in
females
at
1000
and
3000
ppm.
Signs
of
anemia
were
reported
for
both
sexes
at

1000
ppm.
Elevated
GOT
and
GPT
(
indicative
of
hepatic
toxicity)
was
also
evident
at
1000
and
3000
ppm
(
males)
and
3000
ppm
(
females).

There
were
no
consistent
adverse
effects
on
mortality,
clinical
signs,
body
weight
or
food
consumption.
Hematological
parameters
significantly
affected
in
male
mice
were:
decreased
hematocrit,
hemoglobin
and
erythrocyte
counts
(
all
exposure
groups
at
week
52
but
not
at
week
98);
and
decreased
mean
corpuscular
volume
and
mean
corpuscular
hemoglobin
(
high­
dose
males
at
weeks
52
and
98).
In
females,
significantly
decreased
hemoglobin,
mean
corpuscular
volume
and
decreased
mean
corpuscular
hemoglobin
were
observed
at
1000
ppm
after
52
weeks
of
treatment.
The
generalized
changes
in
these
blood
elements
are
indicative
of
anemia
which
was
most
evident
in
the
males
at
week
52.
Significantly
affected
clinical
chemistry
parameters
at
1000
ppm
included:
increased
GLP,
GOT,
ALP
and
BUN
(
males
and
females)
and
at
100
ppm
were:
increased
GLP
and
GOT
(
males).
High­
dose
males
also
had
brownish
colored
urine
at
week
52.
Significantly
increased
liver
weights
(
absolute/
relative)
were
seen
in
high­
dose
males
at
weeks
52
and
98
and
in
high­
dose
females
at
week
98.
Significant
increases
in
absolute
and
relative
adrenal
(
males,
week
98)
and
kidney
(
females,
week
98)
weights
were
also
seen
at
1000
ppm.
Non­
neoplastic
pathology
at
1000
ppm
included:
increased
centrilobular
hepatocellular
swelling
(
females);
increased
diffuse
hepatocellular
swelling
(
males);
brown
pigmentation
in
the
liver
and
proximal
tubules
of
the
kidney
(
males
and
females);
extramedullary
hematopoiesis
(
females)
diffuse
hepatocellular
necrosis
(
males)
and
increased
auricular
thrombus
(
males).
At
100
ppm,
increased
diffuse
hepatocellular
swelling
and
brown
pigmentation
in
the
liver
were
also
seen
in
the
males.
The
LOAEL
is
100
ppm
(
10.6
mg/
kg/
day)
based
on
anemia,
hepatocellular
swelling,
necrosis
and
the
formation
of
brown
pigment
in
the
liver
and
kidneys
of
male
mice.
This
latter
finding
is
consistent
with
the
established
mechanism
of
action
of
oxadiazon
in
plants,
(
i.
e.,
inhibition
of
porphyrin
biosynthesis).
The
NOAEL
is
10
ppm
(
1.09/
0.92
mg/
kg/
day
for
males/
females).

Neoplastic
findings
were:
significant
increases
(
p<
0.05­<
0.001)
in
liver
adenomas
and
carcinomas
in
males
and
females
at
1000
ppm;
liver
adenomas
and
carcinomas
were
also
significantly
increased
at
100
ppm
in
males.
OXADIAZON
TECH.
Updated
April
4,
2001
RED
Toxicology
Chapter
22
The
pathology
report
for
this
chronic/
carcinogenicity
study
in
the
mouse
was
considered
incomplete;
thus,
the
overall
study
was
listed
as
Supplementary.
At
this
time,
additional
information
is
not
being
requested
because
the
results
are
consistent
with
an
acceptable
mouse
carcinogenicity
study
(
MRID
No.
00115733)
that
satisfies
the
guideline
requirement.
Similarly,
the
presence
of
liver
neoplasms
confirms
the
evidence
of
a
carcinogenic
effect
seen
in
other
mouse
long­
term
studies
(
MRID
No.
00044322
and
00115733).
After
review
of
the
data
from
this
study
by
the
Cancer
Assessment
Review
Committee
(
CARC),
however,
it
was
concluded
that
this
deficiency
did
not
compromise
the
integrity
of
the
study
or
the
interpretation
of
the
results
[
see
Cancer
Assessment
Document­­
Evaluation
of
the
Carcinogenic
Potential
of
Oxadiazon
(
Third
Review),
dated
April
2001].
Using
this
rationale,
the
study
is
now
upgraded
and
listed
as
Acceptable/
guideline
(
870.4200b).

(
3)
In
an
oral
mouse
oncogenicity
study
(
MRID
00044322),
oxadiazon
(
tech.
95.5%
a.
i.)
was
administered
in
the
diet
to
CD­
1
mice
(
60/
sex/
group)
for
up
to
104
weeks
at
0,
300,
1000
or
2000
ppm
(
equivalent
to
0/
0,
48/
62,
153/
201,
and
319/
417
mg/
kg/
day
[
M/
F],
respectively.
Actual
daily
dosage
may
have
been
slightly
lower,
based
on
the
analytical
diet
concentrations).
At
study
initiation,
high­
dose
animals
received
3000
ppm
diets.
Due
to
high
mortality,
the
compound
was
removed
from
the
high­
dose
diet
for
weeks
2
and
3,
then
dosing
was
re­
initiated
at
2000
ppm.
Animals
that
died
during
weeks
1­
5
(
10
males,
3
females)
were
replaced
with
parallel
treated
animals
or
control
replacement
animals
that
had
not
previously
received
the
test
article.
No
interim
sacrifice
was
performed.

Toxicity
to
the
liver
was
observed
at
all
doses.
At
300
ppm,
statistically
significantly
increased
serum
alkaline
phosphatase
(+
60%
above
controls)
and
ALT
or
SGPT
(+
270%)
in
females,
along
with
a
non­
significant
increase
in
AST
or
SGOT
(+
76%,
females)
and
ALT
(+
75%,
males),
and
statistically
significant
increases
in
abs/
rel
liver
weights
in
both
males
(+
26%/+
34%)
and
females
(+
50%/+
60%)
were
observed.
These
parameters
usually
showed
dose­
dependent
increases
at

1000
ppm.
Grossly
visible
liver
masses
(
combined
males/
females
38%
vs.
9%,
controls)
and
liver
microscopic
lesions
(
bile
duct
proliferation,
pigmented
macrophages,
diffuse
hepatocellular
hyperplasia,
nodular
hyperplasia,
nodular
hypertrophy
and
centrilobular
hypertrophy)
were
increased
at

300
ppm
in
both
sexes.
Some
of
these
lesions
did
not
show
a
dose­
response,
but
were
still
considered
treatmentrelated
At
1000
ppm,
significantly
increased
serum
alkaline
phosphatase
(+
620%),
AST
(+
104%),
ALT
(+
218%)
and
cholesterol
(+
82%)
were
observed
in
males,
and
possibly
lenticular
degeneration
in
the
eyes
of
males
(
10%
vs.
0,
controls).
At
2000
ppm,
most
of
these
parameters
showed
additional
increases
and
significantly
increased
cholesterol
in
females
(+
81%),
increased
lenticular
degeneration
in
the
eyes
of
males
(
25%
vs.
0%,
controls)
and
liver
focal
necrosis
in
males
(
54%
vs.
35%,
controls)
and
females
(
41%
vs.
25%,
controls)
were
also
observed.
A
16%
decrease
in
hematocrit
in
males
was
considered
of
equivocal
biological
significance.
Survival
(
after
lowering
of
high
dose
to
2000
ppm),
clinical
signs,
body
weights,
food
consumption/
efficiency
and
urine
occult
blood
in
both
sexes
were
unaffected
at
all
dose
levels.
The
systemic
toxicity
LOAEL
is

300
ppm
(
approximately
48/
62
[
M/
F]
mg/
kg/
day)
based
on
increased
liver
effects
in
both
sexes.
OXADIAZON
TECH.
Updated
April
4,
2001
RED
Toxicology
Chapter
23
The
systemic
toxicity
NOAEL
is
<
300
ppm.

Under
the
conditions
of
this
study,
there
was
evidence
of
an
increased
incidence
of
hepatocellular
carcinoma
in
both
sexes.
The
increase
was
significant
(
p<
0.01)
in
both
sexes
at
1000
(
males
­
24/
60
or
40%
vs
5/
60
or
8.3%,
controls;
females
­
12/
61
or
19.7%
vs
1/
60
or
1.7%,
controls)
and
2000
ppm
(
27/
69
or
39.1%,
males
and
13/
63
or
20.6%,
females).
The
incidence
at
300
ppm
in
both
males
(
7/
60
or
11.7%)
and
females
(
4/
60
or
6.7%)
was
not
significant.
Dosing
was
considered
adequate
based
on
the
finding
of
liver
toxicity
at
all
doses.

The
submitted
study
is
classified
as
Unacceptable/
guideline
(
870.4200b).
Although
several
study
deficiencies
were
identified,
the
additional
information
is
not
being
requested
at
this
time
because
the
results
are
consistent
with
an
acceptable
mouse
carcinogenicity
study
(
MRID
00157780;
also
under
MRID
00149003)
that
satisfies
the
guideline
requirement.
In
the
current
study,
the
following
were
noted:
(
1)
the
summary
tables
of
the
gross
pathology
findings
(
Tables
9
and
10)
were
illegible
in
the
only
study
copy
available
for
review
and
(
2)
it
was
unclear
from
the
study
report
what
system
of
classification
of
liver
proliferative
and
neoplastic
microscopic
lesions
were
used
in
this
study
compared
to
current
conventions
of
classification.
Although
hepatocellular
carcinomas
were
increased
in
treated
animals,
no
adenomas
were
reported,
which
are
generally
observed
as
part
of
the
tumor
progression.

4.7
Mutagenicity
Adequacy
of
data
base
for
Mutagenicity:
The
data
base
for
mutagenicity
is
considered
adequate
based
on
pre­
1991
mutagenicity
guidelines.
Overall,
the
available
data
indicate
that
oxadiazon
is
not
mutagenic,
but
does
cause
neoplastic
cell
transformation
in
vitro.
The
acceptable
bacterial
assays
conducted
with
97.49%
technical
oxadiazon
were
negative.
Similarly,
neither
95.5%
nor
recrystallized
oxadiazon
(
100%)
were
mutagenic
or
clastogenic
in
cultured
mammalian
cells
and
did
not
cause
UDS
in
primary
rat
hepatocytes.
There
is,
however,
evidence
that
oxadiazon
induced
neoplastic
transformation
in
Syrian
hamster
kidney
cells
both
in
the
presence
and
the
absence
of
S9
activation.
This
positive
finding
is
consistent
with
the
evidence
from
the
mouse
and
rat
long­
term
bioassays
in
which
the
incidence
of
liver
tumors
was
increased.

Gene
Mutation
870.5100
­
Bacterial
Reverse
Gene
Mutation
Assay
and
870.5500
­
Bacterial
DNA
Repair
Assay
MRID
00069893
Acceptable/
guideline
Doses
tested:
In
Salmonella
typhimurium
strains
TA1535,
TA1537,
TA98
and
TA100
and
Escherichia
coli
strain
WP2
hcr­,
100­
2500

g/
plate
and
10­
1000

g/
plate
w/
o
S9
activation
and
10­
1000

g/
plate
w/
S9.
Bacillis
subtilis
strains
H17
and
M45,
20­
2000

g/
plate
w/
o
activation.

Negative.
Cytotoxicity
not
observed.
OXADIAZON
TECH.
Updated
April
4,
2001
RED
Toxicology
Chapter
24
870.5100
­
Bacterial
Reverse
Gene
Mutation
MRID
41871701
Acceptable/
guideline
Doses
tested:
In
Salmonella
typhimurium
strains
TA1535,
TA1537,
TA1538,
TA98
and
TA100,
50­
5000

g/
plate
w/
and
w/
o
S9
activation.

Negative
up
to
cytotoxic
doses
(
3330

g/
plate)
in
absence
of
S9
and
up
to
5000

g/
plate
in
presence
of
S9
(
not
cytotoxic
at
any
dose
tested
+
S9).
Insoluble
at

500

g/
plate.

870.5300
­
In
Vitro
Mammalian
Gene
Mutation
Assay
MRID
00115726
Acceptable/
guideline
Doses
tested:
In
L5178Y
TK+/­
mouse
lymphoma
cells,
15.6,
31.3,
250,
500
or
1000

g/
mL
(
trial
1)
and
50,
300,
600,
800
or
1000

g/
mL
(
trial
2)
w/
o
S9;
3.91,
7.81,
15.6,
31.3
or
62.5

g/
mL
(
trial
1),
20,
30,
40,
60,
80
or
100

g/
mL
(
trial
2)
and
100,
120,
140,
160,
180
or
200

g//
L
(
trial
3)
w/
S9.

Negative
up
to
cytotoxic
levels
(
1000

g/
mL
w/
S9
and
200

g/
mL
w/
o
S9).
Insoluble
at

62.5

g/
mL.

870.5300
­
In
Vitro
Mammalian
Gene
Mutation
Assay
MRID
00115729
Acceptable/
guideline
Doses
tested:
In
L5178Y
TK+/­
mouse
lymphoma
cells,
oxadiazon
recrystallise
(
100%
a.
i.)
31.3,
62.5,
125,
250,
500
or
1000

g/
mL
w/
o
S9
and
15.6,
31.3,
62.5,
125
or
250

g/
mL
w/
S9.

Negative
up
to
cytotoxic
doses
(
1000

g/
mL
w/
o
S9
and
250

g/
mL
w/
S9).
Insoluble
at
250

g/
mL.
OXADIAZON
TECH.
Updated
April
4,
2001
RED
Toxicology
Chapter
25
Cytogenetics
870.5375
­
In
Vitro
Mammalian
Cell
Chromosomal
Aberration
Assay
MRID
00115728
Acceptable/
guideline
Doses
tested:
In
Chinese
hamster
ovary
cells,
oxadiazon
recrystallise
(
100%
a.
i.)
at
2.0,
6.7,
20,
66.7,
200,
667
or
2000

g/
mL
w/
o
S9
and
0.667,
2.0,
6.7,
20.0,
66.7,
200,
667
or
1000

g/
mL
w/
S9
(
trial
1);
and
at
200,
300,
400,
500
or
600

g/
mL
w/
S9
(
trial
2).

Negative
up
to
cytotoxic
concentrations
(
200

g/
mL
w/
o
S9
and

500

g/
mL
w/
S9).
Insoluble
at
667

g/
mL
w/
o
S9
and
200

g/
mL
w/
S9.

870.5375
­
In
Vitro
Mammalian
Cell
Chromosomal
Aberration
Assay
MRID
00115730
Acceptable/
guideline
Doses
tested:
oxadiazon
tech.
(
95.5%
a.
i.)
in
Chinese
Hamster
ovary
cells
at
0.416,
1.25,
4.16,
12.5,
41.6
or
125

g/
mL
(
trial
1)
and
12.5,
25,
50
or
75

g/
ml
w/
o
S9
(
trial
2)
and
1.25,
4.16,
41.6
or
125

g/
mL
w/
S9
(
trial
2).

Negative
up
to
cytotoxic
concentrations
(

75

g/
mL
w/
o
S9
and

41.6

g/
mL
w/
S9).
Insoluble
at
416

g/
mL.

870.5395
­
Mammalian
Erythrocyte
Micronucleus
Test
MRID
00073288
Unacceptable/
guideline
(
not
upgradable)
Doses
tested:
In
CD­
1
mice,
0,
500,
100
or
200
mg/
kg
(
2
gavage
doses
24
hr
apart).
Harvested
6
hr
after
second
dose.

Negative;
however
was
unacceptable
because
the
6
hr
sampling
time
could
have
missed
an
effect
and
no
evidence
that
target
tissue
was
reached.

870.5395
­
Mammalian
Erythrocyte
Micronucleus
Test
MRID
00073289
Unacceptable/
guideline
(
not
upgradable)
Doses
tested:
In
CD­
1
mice,
0,
500,
1000
or
2000
mg/
kg,
2
gavage
doses
24
hrs
apart.
Harvest
6
hrs
post­
treatment.

Negative;
however
was
unacceptable
because
the
6
hr
sampling
time
could
have
missed
an
effect
and
no
evidence
that
target
tissue
was
reached.

870.5395
­
Mammalian
Erythrocyte
Micronucleus
Test
MRID
00073290
Unacceptable/
guideline
(
not
upgradable)
Doses
tested:
In
CD­
1
mice,
0,
500,
1000
or
2000
mg/
kg,
2
gavage
doses
24
hrs
apart.
Harvest
6
hrs
post­
treatment.

Negative;
however
was
unacceptable
because
the
6
hr
sampling
time
could
have
missed
an
effect.
Clinical
signs
of
toxicity
observed
at
2000
mg/
kg.

Other
Genotoxicity
870.5550
­
Unscheduled
DNA
Synthesis
MRID
00115723
Acceptable/
guideline
Doses
tested:
In
primary
rat
hepatocytes,
1.0,
2.5,
5.0,
10,
25,
50
250
or
1000

g/
mL,
18
hr
exposure.

Negative
up
to
cytotoxic
concentrations
(
100­
500

g/
ml).

870.5550
­
Unscheduled
DNA
Synthesis
MRID
00115727
Acceptable/
guideline
Doses
tested:
In
primary
rat
hepatocytes,
0.5,
1.0,
2.0,
5.0,
10,
25
or
50

g/
mL.

Negative
up
to
cytotoxic
concentrations
(

100

g/
ml).
OXADIAZON
TECH.
Updated
April
4,
2001
RED
Toxicology
Chapter
26
Nonguideline
­
In
vitro
cell
transformation
MRID
00115703
Acceptable/
non­
guideline
Doses
tested:
In
Syrian
hamster
BHK21
C13/
HRC1
cells,
12.5,
25,
50,
100
or
200

g
technical
oxadiazon/
mL
and
25,
50,
100,
200
or
400

g
recrystallized
oxadiazon;
both
tested
w/
and
w/
o
S9
activation.

Positive
in
the
presence
and
absence
of
S9
metabolic
activation.
At
the
LD
50
or
HDT,
transformation
frequencies
exceeded
5X
solvent
control
w/
and
w/
o
S9
for
both
oxadiazon
and
recrystallized
oxadiazon.

4.8
Neurotoxicity
Adequacy
of
data
base
for
neurotoxicity:
These
studies
are
not
required
at
this
time
because
there
was
no
evidence
of
potential
neurotoxicity
in
the
database.

4.9
Metabolism
and
Dermal
Penetration
Adequacy
of
data
base
for
metabolism
and
dermal
penetration:
The
data
base
for
metabolism
is
considered
to
be
complete.
No
additional
studies
are
required
at
this
time.
In
rats,
oxadiazon
was
extensively
metabolized
and
most
was
excreted
in
both
urine
and
feces
during
the
7
days
following
dosing.
Although
at
the
low
dose
(
5
mg/
kg),
only
a
small
amount
of
parent
compound
was
excreted,
at
high
dose
(
500
mg/
kg),
as
much
as
53%
of
unchanged
oxadiazon
was
excreted
in
the
feces.
Females
tended
to
excrete
more
of
the
administered
dose
in
the
urine
than
males.
A
total
of
18
metabolites
were
identified
in
the
urine
and
feces.

Two
studies
not
required
by
the
guidelines
were
also
submitted.
In
a
dermal
absorption
study
in
the
rat,
penetration
was
shown
to
be
less
than
10%
in
rats
exposed
for
up
to
10
hrs.
A
14­
day
dietary
study
in
the
rat
was
also
submitted
in
which
peroxisomal
proliferative
effects
were
examined.
In
this
study,
liver
enlargement,
proliferation
of
hepatocyte
peroxisomes
and
induction
of
several
peroxisomal
enzymes
were
observed.
However,
activity
of
catalase,
usually
induced
by
such
compounds,
was
decreased
by
oxadiazon
treatment.
Hepatocellular
proliferation
was
not
evaluated.

In
addition
to
the
Executive
Summaries
provided
below,
the
metabolism
and
dermal
penetration
studies
are
summarized
in
capsule
form
in
Section
9.0
(
Appendix),
Table
9.1.2
(
toxicity
profile
table).

870.7485
Metabolism
­
Rat
In
a
metabolism/
pharmacokinetic
study
(
MRIDs
42324701,
42663601),
five
Crl:
CD(
SD)
BR
rats
of
each
sex
were
dosed
with
14C­
labeled
oxadiazon
at
a
single
oral
dose
of
5
mg/
kg
or
500
mg/
kg,
and
multiple
doses
of
5
mg/
kg
unlabeled
oxadiazon
for
14
days
followed
by
a
single
oral
dose
of
labeled
oxadiazon
at
5
mg/
kg
on
day
15.
At
low
doses
(
5
mg/
kg,
single
or
multiple),
oxadiazon
was
completely
absorbed,
metabolized
and
excreted
in
the
urine
and
feces;
virtually
no
free
oxadiazon
was
found
in
the
urine.
At
this
OXADIAZON
TECH.
Updated
April
4,
2001
RED
Toxicology
Chapter
27
dose,
the
rates
and
routes
of
excretion
of
radioactivity
were
similar.
At
500
mg/
kg,
the
rate
of
excretion
was
affected
but
the
route
was
not.
The
excretion
of
radioactivity
into
the
urine
and
the
feces
was
sex
dependent
and
the
tissue
residues
were
very
low
in
all
tissues
except
liver
and
fat.
Over
a
7­
day
period,
85
to
93%
of
the
test
compound
administered
was
excreted
in
the
urine
and
feces.
The
radioactivity
recovered
in
the
urine,
feces
and
tissues
exceeded
94%
of
the
dose
and
was
sex­
related.
Females
excreted
more
radioactivity
in
the
urine
than
males.
The
metabolism
of
oxadiazon
in
rats
was
extensive,
but
the
benzene
and
pyrozolidine
rings
were
not
modified.
Eighteen
(
18)
metabolites
were
identified
in
the
urine
and
feces.
Four
urinary
and
5
fecal
metabolites
were
present
at
levels
greater
than
1%
of
the
dose.
Among
the
9
metabolites,
U2,
U7
and
U10
from
the
urine
correspond
to
F2,
F7
and
F9
of
the
feces.
Female
rats
were
efficient
metabolizers
and
the
urine
was
unique
in
that
metabolites
U4
and
U5
were
excreted
in
the
urine
only.
In
addition
to
5
fecal
metabolites,
intact
oxadiazon
was
present
in
feces
only
and
was
dose­
related.
At
the
high
dose
more
than
53%
of
the
administered
radioactivity
was
intact
oxadiazon
in
the
feces;
at
5
mg/
kg,
not
more
than
4.8%
of
the
dose
was
intact
oxadiazon
in
the
feces.
This
observation
is
consistent
with
extensive
absorption
followed
by
excretion
in
the
feces
by
way
of
the
bile.

This
study
is
classified
Acceptable/
guideline
and
satisfies
the
Guideline
requirements
(
870.7385)
for
a
metabolism
study
for
oxadiazon
in
the
rat.

870.7600
Dermal
Absorption
­
Rat
In
a
dermal
penetration
study
(
MRID
44588101),
14C­
oxadiazon
(
99.6%
a.
i.,
radiochemical
purity,
mixed
with
unlabelled
oxadiazon
technical,
96%
a.
i.)
in
1%
aqueous
carboxymethyl
cellulose
was
administered
dermally
to
groups
of
24
male
Sprague
Dawley
rats/
dose
at
5.45,
39.2
or
523

g/
cm2
for
exposure
durations
of
0.5,
1,
2,
4,
10
or
24
hours
per
dose
(
4
rats/
exposure
time).
Urine
and
feces
were
collected;
skin
was
excised
and
blood,
residual
urine
and
carcasses
were
collected
and
analyzed.
Recovery
of
radioactivity
ranged
from
83.2%
to
106%
of
administered
dose.

The
quantity
of
oxadiazon
in
washed
skin
during
the
exposure
phase
ranged
from
0.06­
0.38,
0.59­
3.31
or
2.88­
15.32

g/
cm2
at
the
low,
mid
or
high
dose,
respectively.
As
a
percentage
of
the
administered
dose,
these
were
equivalent
to
1.09%­
6.89%,
1.50%­
8.45%
or
0.55%­
2.93%
(
low
to
high
dose,
respectively).
In
general,
the
amount
of
absorbed
test
material
was
not
detectable
during
the
first
2
hours
of
exposure.
Absorption
(

g/
cm2)
was
low
throughout
exposure
and
ranged
from
0.06­
0.6,
0.05­
2.00
or
0.05­
2.62

g/
cm2
(
low
to
high
dose,
respectively)
at
4
to
24
hours;
as
a
percent
of
the
administered
dose,
these
were
equivalent
to
1.11%­
11.0%,
0.39%­
5.11%
or
0.01%­
0.50%,
respectively.
The
percent
of
test
material
on
the
skin
versus
the
percent
absorbed
at
10
hours
was
6.05%
vs.
2.65%
(
5.45

g/
cm2),
4.71%
vs.
0.63%
(
39.2

g/
cm2)
and
1.03%
vs.
0.05%
(
523

g/
cm2).
Since
the
percent
of
dose
absorbed
decreased
with
increasing
dose
and
the
quantity
absorbed
was
essentially
the
same,
the
results
indicate
that
absorption
but
not
dermal
uptake
was
saturated
at
39.2
and
523

g/
cm2.
OXADIAZON
TECH.
Updated
April
4,
2001
RED
Toxicology
Chapter
28
This
study
is
classified
Acceptable/
guideline;
it
satisfies
the
guideline
requirement
for
a
dermal
penetration
study
(
870.7600)
in
the
rat.

4.10
Special/
Other
Studies
A
14­
day
dietary
study
evaluating
peroxisomal
proliferation
by
oxadiazon
in
the
rat
was
submitted.
In
addition
to
the
Executive
Summary
provided
below,
this
study
is
summarized
in
capsule
form
in
Section
9.0
(
Appendix),
Table
9.1.2
(
toxicity
profile
table).

In
a
special
mechanistic
study
(
MRID
No.
42310001),
oxadiazon
(
tech.,
95.6%
a.
i.)
was
orally
administered
to
groups
of
male
Sprague­
Dawley
rats
(
10
rats/
dose)
at
0,
20,
200
or
500
mg/
kg/
day
for
14
days.
Clinical
signs
were
monitored
daily.
Body
weights,
food
consumption
and
water
consumption
were
determined
daily.
After
14
days
of
treatment,
animals
were
sacrificed
and
organ
weights
were
determined.
Livers
were
prepared
for
microscopic
examination
(
high­
dose
only)
and
liver
homogenates
from
all
dose
levels
were
assessed
for
protein,
glucose
6­
phosphatase,
catalase,
palmitoyl
CoA
oxidation,
palmitoyl
carnitine
transferase
and
acetyl
carnitine
transferase.

There
were
no
adverse
effects
on
mortality,
clinical
signs,
body
weight
or
food
and
water
consumption.
Absolute
and
relative
liver
weights
were
significantly
(
p<
0.05)
increased
at
200
and
500
mg/
kg/
day.
Thyroid
and
kidney
weights
were
unaffected
by
treatment.
Significant
(
p<
0.05)
effects
on
liver
biochemistry
at
200
and
500
mg/
kg/
day
were:
decreased
catalase
(­
62
and
­
72%,
respectively);
increased
palmitoyl
CoA
oxidation
(+
43
and
+
98%,
respectively);
increased
palmitoyl
carnitine
transferase
(+
92
and
113%,
respectively);
and
increased
acetyl
carnitine
transferase
(+
296
and
569%,
respectively).
Nonsignificant
changes
noted
for
these
parameters
in
the
20­
mg/
kg/
day
group
were:
increased
palmitoyl
CoA
oxidation
(+
13%);
increased
palmitoyl
carnitine
transferase
(+
6%);
and
increased
acetyl
carnitine
transferase
(+
57%).
In
addition,
glucose
6­
phosphatase
was
significantly
inhibited
at
500
mg/
kg/
day.
Data
for
these
enzyme
levels
indicate
dose­
dependent
increases
in
peroxisomal
enzyme
activity
(
in
particular
palmitoyl
Co
A
and
acetyl
carnitine
transferase
as
well
as
the
mitochondrial
associated
palmitoyl
carnitine
transferase).
Ultrastructural
changes
seen
after
treatment
with
500
mg/
kg/
day
included:
peroxisome
proliferation,
increased
lipids,
sinusoidal
dilation,
and
rough
endoplasmic
reticulum
damage.
The
generalized
changes
in
the
enzyme
levels
indicate
dose­
dependent
increases
in
peroxisomal
enzyme
activity
(
in
particular
palmitoyl
Co
A
and
acetyl
carnitine
transferase
as
well
as
the
mitochondrial
associated
palmitoyl
carnitine
transferase).
The
LOAEL
is
20
mg/
kg/
day
(
lowest
treatment
level)
based
on
increased
peroxisomal
enzyme
activity
(
in
particular
palmitoyl
Co
A
and
acetyl
carnitine
transferase)
at
all
dose
levels.
This
study
does
not
define
a
NOAEL
(<
20
mg/
kg/
day).

This
special
peroxisome
proliferation
study
in
the
rat
is
Acceptable/
non­
guideline
for
the
purpose
for
which
it
was
intended.
OXADIAZON
TECH.
Updated
April
4,
2001
RED
Toxicology
Chapter
29
5.0
TOXICITY
ENDPOINT
SELECTION
5.1
See
Section
9.2
for
Endpoint
Selection
Table.

5.2
Dermal
Absorption
Dermal
Absorption
Factor:
9
%

The
HIARC
(
December
7,
2000)
determined
that
a
dermal
absorption
factor
of
9%
should
be
used
for
risk
assessment.
The
dermal
absorption
factor
is
based
on
the
dermal
absorption
observed
(
6.05%
absorbed
+
2.65%
bound
=
8.7%)
after
a
10
hr
exposure
in
a
rat
dermal
absorption
study
(
MRID
44588101).

The
dermal
absorption
factor
is
required
for
the
short­
term,
intermediate­
term
and
long­
term
dermal
risk
assessments
since
oral
doses
were
administered
in
the
study
selected
for
these
exposure
periods
(
rat
developmental
toxicity
study).

5.3
Classification
of
Carcinogenic
Potential
5.3.1
Discussion
of
Findings
Oxadiazon
was
evaluated
for
carcinogenicity
for
the
third
time
by
the
HED
Cancer
Assessment
Review
Committee
on
March
7,
2001
(
HED
Document
No.
014555).
This
reevaluation
was
prompted
by
the
submission
of
a
mouse
and
a
rat
carcinogenicity
study
that
were
not
previously
available
to
the
Agency
for
review.
A
treatment­
related
increase
in
the
incidence
of
hepatocellular
benign
and
malignant
tumors
was
identified
in
these
new
studies
in
male
Wistar
rats
(
MRID
40993401)
and
in
male
and
female
ICR­
JCL
mice
(
MRID
40993301).
The
results
of
the
new
studies
are
consistent
with
those
of
the
previously
reviewed
studies
on
F344
rats
(
MRIDs
00149003,
00157780)
and
CD­
1
mice
(
MRIDs
00044322,
00115733).
The
findings
of
these
studies
are
summarized
above
in
the
Hazard
Assessment
(
see
Section
4.6).
The
quantitative
risk
[
Q
1
*
(
mg/
kg/
day)­
1
]
was
also
recalculated
as
shown
below,
based
on
evaluation
of
the
new
data
(
Memorandum
from
L.
Brunsman
to
N.
McCarroll
dated
February
1,
2001).
The
available
mechanistic
data
on
the
peroxisomal
proliferative
properties
of
oxadiazon
were
considered
insufficient
to
support
a
threshold
mechanism
for
hepatocellular
carcinogenesis
(
see
Section
7.0,
below).

5.3.2
Classification
of
Carcinogenic
Potential
Oxadiazon
is
classified
as
"
likely
to
be
a
human
carcinogen",
using
the
classification
system
of
the
EPA
Draft
Guidelines
for
Carcinogen
Risk
Assessment
(
July,
1999).
Hepatocellular
tumors
were
identified
in
two
species
and
2
sexes
(
in
mice;
only
males
showed
significant
increases
in
rats).

5.3.3
Quantification
of
Carcinogenic
Potential
OXADIAZON
TECH.
Updated
April
4,
2001
RED
Toxicology
Chapter
30
The
Q
1
*
(
mg/
kg/
day)­
1
calculated
for
oxadiazon
is
7.11
x
10­
2
mg/
kg/
day,
based
on
male
mouse
liver
adenoma
and/
or
carcinoma
combined
tumor
rates
from
the
98­
week
dietary
study
(
MRID
40993301).

6.0
FQPA
CONSIDERATIONS
6.1
Special
Sensitivity
to
Infants
and
Children
In
the
rabbit
developmental
study,
there
was
no
evidence
of
either
a
quantitative
or
qualitative
increase
in
the
sensitivity
of
fetuses.
However,
in
the
rat
developmental
study,
very
little
maternal
toxicity
(
small
but
significant
decrease
in
body
weight,
­
2%
and
decrease
in
body
weight
gain,
­
10%)
was
seen
at
the
maternal
and
developmental
LOAEL
(
40
mg/
kg/
day).
By
contrast,
effects
on
offspring
at
this
LOAEL
were
severe
(
increased
post­
implantation
loss
and
late
resorptions
and
decreased
fetal
weight).
Neonatal
effects
(
LOAEL
of
38
mg/
kg/
day,
based
on
neonatal
losses)
in
the
dose
rangefinding
phase
of
the
two
generation
reproduction
study
in
rats
were
attributable
to
maternal
effects
(
i.
e.,
inactive
mammary
tissue)
at
that
dose.
Based
on
weight­
of­
the­
evidence
considerations,
the
Committee
concluded
that
the
overall
data
provide
no
clear
evidence
of
either
a
qualitative
or
quantitative
increase
in
susceptibility
of
rats
or
rabbits
to
in
utero
and/
or
postnatal
oxadiazon
exposure.

6.2
Recommendation
for
a
Developmental
Neurotoxicity
Study
The
HIARC
recommended
against
requiring
a
developmental
neurotoxicity
study.
This
decision
was
based
on
results
showing
no
evidence
of
neurotoxicity
in
any
study
in
the
database
which
included:
chronic
(
rats,
mice,
dogs),
subchronic
(
rat
or
rabbit),
reproduction
(
rat)
or
developmental
(
rat
or
rabbit)
studies.

7.0
OTHER
ISSUES
Many
compounds
that
induce
hepatic
peroxisomal
proliferation
also
are
hepatic
carcinogens.
Because
the
special
mechanistic
study
demonstrated
that
oxadiazon
caused
hepatocellular
peroxisomal
proliferation,
the
MTARC
evaluated
the
complete
database
to
determine
whether
it
supported
peroxisomal
proliferation
as
a
mechanism
of
action
for
hepatocellular
carcinogenesis
in
rats
and
mice
(
meeting
of
February
8,
2001).
Based
on
weight­
of­
the­
evidence
considerations,
the
MTARC
determined
that
although
oxadiazon
did
not
show
mutagenic
potential
and
peroxisomal
proliferation
may
be
a
possible
mode
of
action
for
hepatocellular
carcinogenesis
by
oxadiazon,
the
data
were
insufficient
to
support
this
mechanism.
The
weaknesses
in
the
database
included:
(
1)
no
cell
proliferation
data
were
provided
for
rats
or
mice;
(
2)
a
good
concordance
between
the
dose­
response
for
peroxisomal
enzymatic
activity
and
tumor
formation
was
not
observed
and
(
3)
the
role
of
decreased
catalase
activity,
which
is
generally
increased
by
peroxisomal
proliferator
compounds,
was
not
explained
by
the
authors
of
the
submitted
mechanistic
study.
OXADIAZON
TECH.
Updated
April
4,
2001
RED
Toxicology
Chapter
31
8.0
REFERENCES
00044322
Gunderson,
G.,
Jefferson,
N.
D.,
Blair,
M.,
Spicer,
E.
J.
F.
and
Nelson,
L.
W.
(
1980)
Life­
time
Oncogenicity
Study
in
Mice.
International
Research
and
Development
Corp.
IRDC
No.
347­
008,
June
5,
1980.
Unpublished
study.

00069893
Shirasu,
Y.,
Moriya,
M.
and
Kato,
K.
(
1976)
Microbial
Mutagenic
Study
on
Oxadiazon.
Institute
of
Environmental
Toxicology,
Nissan
Chemical
Industries,
Ltd.,
Japan.
No
study/
report
no.
provided.
Report
dated
June
4,
1976.
Unpublished
study.

00073288
Pasquet,
J.
and
Fournier,
E.
(
1980)
Oxadiazon
(
17
623
R.
P.),
Batch
BES
2253:
Micronucleus
Test
in
the
Mouse.
Rhone­
Poulenc,
Centre
Nicolas
Grillet,
France.
Laboratory
Report
No.
20
512/
E.
February
22,
1980.
Unpublished
study.

00073289
Pasquet,
J.
and
Fournier,
E.
(
1980)
Oxadiazon
(
17
623
R.
P.),
Batch
CA
76
204:
Micronucleus
Test
in
the
Mouse.
Rhone­
Poulenc,
Centre
Nicolas
Grillet,
France.
Laboratory
Report
No.
20
513E.
February
22,
1980.
Unpublished
study.

00073290
Pasquet,
J.
and
Fournier,
E.
(
1980)
Compound
24
865
R.
P.:
Micronucleus
Test
in
the
Mouse.
Rhone­
Poulenc,
Centre
Nicolas
Grillet,
France.
Laboratory
Report
No.
20
533E.
March
13,
1980.
Unpublished
study.

00111801
McGee,
G.;
Freeman,
L.;
Jolly,
E.
(
1972)
Subacute
Dermal
Toxicity
Study
in
Rabbits.
K
G
Laboratories
Division,
Parsippany,
NJ.
Laboratory
Reference
No:
A­
404.
March
22,
1972.
Unpublished
study.

00111804
Weatherholtz,
W.
and
Voelker,
R.
(
1970)
13­
week
Dietary
Administration­­
Rats:
RP
17623.
TRW,
Inc.,
Vienna,
VA.
Study
No.
656­
114.
May
28,
1970.
Unpublished
study.

00111805
Weatherholtz,
W.
and
Voelker,
R.
(
1970)
13­
week
Oral
Administration­­
Dogs:
RP
17623.
TRW,
Inc.,
Vienna,
VA.
Project
No.
656­
115.
May
22,
1970.
Unpublished
study.

00115703
Hossack,
D.
J.
N.
and
Daniel,
M.
R.
(
1982)
Oxadiazon
Lot
CA
76
204
and
Recrystallized
Oxadiazon
17
623
RP
Cell
Transformation
Test
for
Carcinogenicity.
Huntingdon
Research
Centre,
England.
Laboratory
report
number
RNP
152A/
79368,
July
29,
1982.
Unpublished
study.

00115723
Myhr,
B.
C.
and
McKeon,
M.
(
1982)
Evaluation
of
Oxadiazon
Recristallise
in
the
Primary
Rat
Hepatocyte
Unscheduled
DNA
Synthesis
Assay.
Litton
Bionetics,
Inc.,
Kensington,
MD.
LBI
Project
No.
20991.
June,
1982.
Unpublished
study.

00115726
Cifone,
M.
A
and
Balinas,
V.
(
1982)
Mutagenicity
Evaluation
of
Oxadiazon
in
the
Mouse
Lymphoma
Forward
Mutation
Assay.
Litton
Bionetics,
Inc.,
Kensington,
MD.
LBI
Project
OXADIAZON
TECH.
Updated
April
4,
2001
RED
Toxicology
Chapter
32
No.
20999.
Unpublished
study.

00115727
Myhr,
B.;
McKeon,
M.
(
1982)
Evaluation
of
Oxadiazon
(
Lot
MAG
405)
in
the
Primary
Rat
Hepatocyte
Unscheduled
DNA
Synthesis
Assay.
Litton
Bionetics,
Inc.,
Kensington,
MD.
LBI
Project
No.
21001.
June,
1980.
Unpublished
study.

00115728
Galloway,
S.
and
Lebowitz,
H.
(
1982)
Mutagenicity
Evaluation
of
Oxadiazon
Recristallise,
Lot
BOS
2
385
in
an
in
vitro
Cytogenetic
Assay
Measuring
Chromosome
Aberration
Frequencies
in
Chinese
Hamster
Ovary
(
CHO)
Cells.
Litton
Bionetics,
Inc.,
Kensington,
MD.
LBI
Project
No.
21000.
July,
1982.
Unpublished
study.

00115729
Cifone,
M.
and
Balinas,
V.
(
1982)
Mutagenicity
Evaluation
of
Oxadiazon
Recristallise
in
the
Mouse
Lymphoma
Forward
Mutation
Assay.
Litton
Bionetics,
Inc.,
Kensington,
MD.
LBI
Project
No.
20999.
April,
1982.
Unpublished
study.

00115730
Galloway,
S.
and
Lebowitz,
H.
(
1982)
Mutagenicity
Evaluation
of
Oxadiazon,
Lot
MAG
405
in
an
in
vitro
Cytogenetic
Assay
Measuring
Chromosome
Aberration
Frequencies
in
Chinese
Hamster
Ovary
(
CHO)
Cells.
Litton
Bionetics,
Inc.,
Kensington,
MD.
LBI
Project
No.
21000.
July,
1982.
Unpublished
study.

00115733
Amyes,
S.
J.,
Macrae,
S.
M.,
King,
D.
J.
and
Whitney,
J.
C
(
1982)
Oxadiazon:
Oncogenicity
in
Dietary
Administration
to
Mice
for
Period
of
105
Weeks.
Life
Science
Research,
England.
Laboratory
Report
No.
82/
RH0004/
245.
September
17,
1982.
Unpublished
study.

00149003
Kudo,
S.,
Takeuchi,
T.,
Hayashi,
K.
et
al.
(
1981)
Twenty­
four
Month
Chronic
Toxicity
Study
of
Oxiadiazon
in
Rats.
Nippon
Institute
for
Biological
Science
and
Institute
of
Environmental
Toxicology.
No
study/
report
no.
July,
1981.
Unpublished
study.

00157780
Nippon
Institute
for
Biological
Science
(
1986)
Twenty­
four
Month
Chronic
Toxicity
Study
of
Oxadiazon
in
Rats:
Revised
Data
Tables
per
EPA
Request.
Unpublished
data.

40470201
Tesh,
J.
M.,
Ross,
F.
W.,
Bailey,
G..
P.,
Wilby,
O.
K.
and
Tesh.,
S.
A.
(
1987)
Oxadiazon:
Teratology
Study
in
the
Rabbit.
Life
Sciences
Research,
England.
Laboratory
Project
ID
87/
RHA095/
534.
September
14,
1987.
Unpublished
study.

40470202
Tesh,
J.
M.,
McAnulty,
P.
A.,
Wightman,
T.
J.,
McCloskey,
B.
A.,
Wilby,
O.
K.
and
Tesh,
S.
A.
(
1987)
Oxadiazon:
Teratology
Study
in
the
Rat:
Laboratory.
Life
Science
Research,
England.
Project
ID
87/
RHA093/
356
(
Preliminary
Study
87/
RHA092/
040).
August
3,
1987.
Unpublished
study.

40993301
Shirasu,
Y.
(
1987)
Oxadiazon­­
23
Month
Oral
Chronic
Toxicity
and
Oncogenicity
Study
in
Mice.
Institute
of
Environmental
Toxicology,
Tokyo,
Japan.
Study
No.
not
listed.
February,
1987.
Unpublished
study.
OXADIAZON
TECH.
Updated
April
4,
2001
RED
Toxicology
Chapter
33
40993401
Y.
Shirasu
(
1987).
Oxadiazon
­
24
Month
Chronic
Toxicity
and
Oncogenicity
Study
in
Rats.
Institute
of
Environmental
Toxicology,
Tokyo,
Japan;
Study
No.
not
listed.
February
1987.
Unpublished
study.

41230401
Siglin,
J.
(
1988)
Delayed
contact
hypersensitivity
study
in
guinea
pigs
with
oxadiazon
(
EPA).
Springborn
Life
Sciences,
Inc.,
Spencerville,
OH.
Laboratory
Study
No.
3147.26.
December
20,
1988.
Unpublished
study.

41239801
Tesh,
J.
M.,
McAnulty,
P.
A.
and
Higgins,
C.
(
1988)
Oxadiazon:
Effects
of
Dietary
Administration
Upon
Reproductive
Performance
of
Rats
Treated
Continuously
Throughout
Two
Successive
Generations.
Life
Sciences
Research,
England.
Project
ID
88/
RHA097/
366.
October
7,
1988.
Unpublished
study.

41240301
Tesh,
J.;
McAnulty,
P.;
Wightman,
T.;
et
al.
(
1987)
Oxadiazon:
Effects
of
Dietary
Administration
Upon
Reproductive
Performance
in
the
Rat:
Dosage
Range
Finding
Study.
Life
Sciences
Research,
England.
Project
ID
87/
RHA096/
434.
August
3,
1987.
Unpublished
study.

41326401
Chapman,
E.
A.
(
1989)
Oxadiazon:
Toxicity
Study
by
Oral
(
Capsule)
Administration
to
Beagle
Dogs
for
52
Weeks.
Life
Sciences
Research
Ltd.,
England.
Lab
Project
Number
88/
0763.
November
29,
1989.
Unpublished
study.

41863602
Siglin,
J.
C.
(
1991)
21­
Day
Dermal
Toxicity
Study
in
Rabbits
with
Oxadiazon
Technical.
Springborn
Labs,
Inc.,
Spencerville,
OH.
Lab
Project
Number:
3147.86.
March
20,
1991.
Unpublished
study.

41866501
Rush,
R.
E.
(
1990)
Acute
Oral
Toxicity
Study
in
Rats
with
Oxadiazon.
Springborn
Laboratories,
Inc.,
Spencerville,
OH.
Lab
Project
Number
3147.84.
August
14,
1990.
Unpublished
study
041866502
Rush,
R.
E.
(
1990)
Acute
Dermal
Toxicity
Study
in
Rabbits
with
Oxadiazon.
Springborn
Laboratories,
Inc.,
Spencerville,
OH.
Lab
Project
Number
3147.85.
August
14,
1990.
Unpublished
study.

41866503
Michlewicz,
K.
G.
(
1988)
Acute
Inhalation
Toxicity
Study
of
Oxadiazon
in
Rats­
Limit
Test.
Springborn
Laboratories,
Inc.,
Spencerville,
OH.
Lab
Project
Number
3147.24.
December
20,
1988.
Unpublished
study.

41866504
Rush,
R.
E.
(
1991)
Primary
Eye
Irritation
Study
in
Rabbits
with
Oxadiazon.
Springborn
Laboratories,
Inc.,
Spencerville,
OH.
Lab
Project
Number
3147.110.
April
19,
1991.
Unpublished
study.

41866505
Rush,
R.
E.
(
1991)
Primary
Skin
Irritation
Study
in
Rabbits
with
Oxadiazon.
Springborn
Laboratories,
Inc.,
Spencerville,
OH.
Lab
Project
Number
3147.111.
April
11,
1991.
OXADIAZON
TECH.
Updated
April
4,
2001
RED
Toxicology
Chapter
34
Unpublished
study.

41871701
L.
F.
Stankowski,
Jr,
(
1991).
Ames
Salmonella
Plate
Incorporation
Assay
on
Oxadiazon.
Pharmalon
Research
International
Inc.,
Waverly,
PA.
Study
No.
PH
301­
RP­
001­
91.
April
30,
1991.
Unpublished
study.

42310001
Price,
S.
C.
(
1991)
Studies
on
Morphological
and
Biochemical
Changes
in
the
Livers
of
Rats
Treated
for
14
Days
with
Oxadiazon.
Robens
Institute
of
Health
and
Safety,
Surrey,
England.
Study
Number
R190/
0312.
January
9,
1991.
Unpublished
study.

42324701
Powles,
P.
(
1992)
(
14C)­
Oxadiazon:
Absorption,
Distribution,
Metabolism,
and
Excretion
in
the
Rat:
[
Final
Report].
Hazleton
UK,
England.
Study
No.
7120­
68/
118.
May
11,
1992.
Unpublished
study.

42663601
Powles,
P.
(
1993):
(
14C)­
Oxadiazon:
Absorption,
Distribution
Metabolism
and
Excretion
in
the
Rat.
[
Amendment
to
Final
Report
MRID
No.
42324701]
Hazleton
UK,
England.
Study
No.
7120­
68/
118.
February
9,
1993.
Unpublished
study.

44588101
Cheng,
T.
(
1996)
Dermal
Absorption
of
14C­
Oxadiazon
in
Male
Rats
(
Preliminary
and
Definitive
Phases)
Corning
Hazleton,
Vienna,
VA.
Lab
Project
Number:
CHW
6224­
224.
September
27,
1996.
Unpublished
study.
OXADIAZON
TECH.
Updated
April
4,
2001
RED
Toxicology
Chapter
35
9.0
APPENDICES
Tables
for
Use
in
Risk
Assessment
OXADIAZON
TECH.
Updated
April
4,
2001
RED
Toxicology
Chapter
36
9.1
Toxicity
Profile
Summary
Tables
9.1.1
Acute
Toxicity
Table
­
See
Section
4.1
9.1.2
Subchronic,
Chronic
and
Other
Toxicity
Tables
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Results
SUBCHRONIC
TOXICITY
STUDIES
870.3100
90­
Day
oral
toxicity
(
CD
rat)
00111804
(
1970)
Acceptable/
guideline
0,
25,
100
or
1000
mg/
kg/
d
(
diet)
NOAEL
=
25
mg/
kg/
day
LOAEL
=
100
mg/
kg/
day
based
on
decreased
body
weight,
increased
liver
weight,
hematological
changes
and
clinical
chemistry
and
pathological
changes
associated
with
liver
damage.

870.3150
90­
Day
oral
toxicity
in
(
Beagle
dog)
00111805
(
1970)
Acceptable/
guideline
0,
25,
100
or
1000
mg/
kg/
d
(
capsule)
NOAEL
<
25
mg/
kg/
day
LOAEL

25
mg/
kg/
day
based
on
increased
thyroid
weights
in
males.

870.3200
21­
Day
dermal
toxicity
(
NZW
rabbit)
41863602
(
1991
)
Acceptable/
guideline
0,
100,
500
or
1000
mg/
kg/
day
NOAEL

1000
mg/
kg/
day.
LOAEL
>
1000
mg/
kg/
day.

DEVELOPMENTAL
AND
REPRODUCTIVE
TOXICITY
STUDIES
870.3700a
Prenatal
developmental
(
SD
rat)
40470202
(
1987)
Acceptable/
guideline
0,
3,
12
or
40
mg/
kg/
day
(
gavage)
Maternal
NOAEL
=
12
mg/
kg/
day.
LOAEL
=
40
mg/
kg/
day
based
on
decreased
body
weight/
weight
gain.
Developmental
NOAEL
=
12
mg/
kg/
day
LOAEL
=
40
mg/
kg/
day
based
on
increased
fetal
resorptions/
implantation
loss,
decreased
pup
weight
and
increased
incidence
of
incomplete
ossification.

870.3700b
Prenatal
developmental
(
NZW
rabbit)
40470201
(
1987)
Acceptable/
guideline
0,
20,
60
or
180
mg/
kg/
day
(
gavage)
Maternal
NOAEL
=
20
mg/
kg/
day
LOAEL
=
60
mg/
kg/
day
based
on
transient
weight
loss
during
the
first
week
of
treatment.
Developmental
NOAEL
=
60
mg/
kg/
day
LOAEL
=
180
mg/
kg/
day
based
on
increased
postimplantation
loss
and
late
resorptions,
decreased
fetal
weight
and
increased
bilateral
hind­
limb
flexure.
OXADIAZON
TECH.
Updated
April
4,
2001
RED
Toxicology
Chapter
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Results
37
870.3800
Reproduction
and
fertility
effects
(
CD
rat)
41239801
(
1988)
Acceptable/
guideline
0,
20,
60
or
200
ppm
(
M/
F
0,
1.5/
1.84,
4.65/
5.63
or
15.50/
18.20
mg/
kg/
day,
premating)
Parental/
Systemic
NOAEL

15.5
mg/
kg/
day
LOAEL
>
15.5
mg/
kg/
day
(
decreased
gestational
weight
gain
in
RF
study
at
38
mg/
kg/
day).
Reproductive
NOAEL

15.5
mg/
kg/
day
LOAEL
>
15.5
mg/
kg/
day
(
inactive
mammary
tissue,
fetal/
neonatal
mortality
in
the
RF
study
at
38
mg/
kg/
day).
Offspring
NOAEL

15.5
mg/
kg/
day
LOAEL
>
15.5
mg/
kg/
day
(
fetal/
neonatal
mortality
in
the
RF
study
at
38
mg/
kg/
day).

CHRONIC
TOXICITY
AND
CARCINOGENICITY
STUDIES
870.4100a
Chronic
toxicity
(
rat)
See
870.4300,
Combined
chronic
toxicity/
carcinogenicity
870.4100b
Chronic
toxicity
(
Beagle
dog)
41326401(
1989)
Acceptable/
guideline
0,
5,
20
or
60
mg/
kg/
day
(
capsule)
NOAEL
=
5
mg/
kg/
day
LOAEL
=
20
mg/
kg/
day
based
on
increased
liver
weight.

870.4200
Carcinogenicity
(
CD­
1
mouse)
00044322
(
1980)
Unacceptable/
guideline
0,
300,
1000
or
2000
ppm
(
M/
F
0,
48/
62,
153/
201
or
319/
417
mg/
kg/
day),
in
diet
NOAEL
<
48
mg/
kg/
day
LOAEL

48
mg/
kg/
day
based
on
increased
liver
weight,
serum
enzymes
related
to
liver
damage
and
microscopic
pathology
in
the
liver
of
both
sexes.
Evidence
of
carcinogenicity­
increased
incidence
of
hepatocellular
carcinoma,
both
sexes
at

48/
62
mg/
kg/
day.

870.4200
Carcinogenicity
(
CD­
1
mouse)
00115733
(
1982)
Acceptable/
guideline
0,
100,
300,
1000
or
2000
ppm
(
M/
F
0,
12/
14,
37/
44,
122/
143
or
254/
296
mg/
kg/
day),
in
diet
NOAEL

12
mg/
kg/
day
LOAEL
<
12
mg/
kg/
day
based
on
clinical
signs,
increased
liver
weights
in
males
and
increased
microscopic
pathology
in
the
liver
of
both
sexes.
Evidence
of
carcinogenicity
­
increased
incidence
of
hepatocellular
neoplasms
(
adenoma,
combined
adenoma/
carcinoma)
in
both
sexes
at
all
doses
tested
(
carcinoma
alone
increased
in
all
male
groups
and
at

143
mg/
kg/
day
in
females).

870.4200
Carcinogenicity
(
ICR­
JCL
mouse)
40993301
(
1987)
Acceptable/
guideline
0,
3,
10,
100
or
1000
ppm
(
M/
F
0,
0.315/
0.278,
1.09/
0.92,
10.6/
9.3
or
113/
99
mg/
kg/
day),
in
diet
NOAEL
=
1.09
mg/
kg/
day
LOAEL
=
10.6
mg/
kg/
day
based
on
anemia
and
microscopic
lesions
in
the
liver
and
kidneys
(
all
in
males).
Evidence
of
carcinogenicity
­
increased
incidence
of
hepatocellular
neoplasms
(
adenomas,
carcinomas
and
combined
adenomas/
carcinomas
in
males
at

10.6
mg/
kg/
day
and
in
females
at
99
mg/
kg/
day).
OXADIAZON
TECH.
Updated
April
4,
2001
RED
Toxicology
Chapter
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Results
38
870.4300
Combined
chronic
toxicity/
carcinogenicity
(
F344
rat)
00149003,
00157780
(
1982,
1986)
Acceptable/
guideline
0,
10,
100,
1000
or
3000
ppm
(
M/
F
0,
0.5/
0.6,
5.9/
4.8,
50.9/
60.9
or
163.1/
192.7
mg/
kg/
day,
in
diet
NOAEL
=
0.5
mg/
kg/
day
LOAEL
=
4.8
mg/
kg/
day
based
on
increased
liver
weights
in
both
sexes
and
increased
total
serum
protein
in
females.
Evidence
of
carcinogenicity
­
increased
incidence
of
hepatocellular
neoplasms
in
males
(
adenomas
and
combined
adenomas/
carcinomas
in
males
at

50.9
mg/
kg/
day).

870.4300
Combined
chronic
toxicity/
carcinogenicity
(
Wistar
rat)
40993401
(
1987)
Acceptable/
guideline
0,
3,
10,
100
or
1000
ppm
(
M/
F
0,
0.106/
0.131,
0.36/
0.44,
3.5/
4.2
or
39/
44
mg/
kg/
day)
NOAEL
=
0.36
mg/
kg/
day
LOAEL
=
3.5
mg/
kg/
day
based
on
increased
incidence
of
hepatocellular
centrilobular
swelling
in
males.
Evidence
of
carcinogenicity­
increased
incidence
of
hepatocellular
neoplasms
in
males
(
adenomas
and
combined
adenomas/
carcinomas
at

4.2
mg/
kg/
day
and
carcinomas
at
39
mg/
kg/
day).

MUTAGENICITY
AND
CELL
TRANSFORMATION
STUDIES
870.5100
Gene
Mutation
Bacterial
reverse
gene
mutation
assay
and
870.5500
Bacterial
DNA
Repair
Assay
00069893
(
1976)
Acceptable/
guideline
S.
typhimurium
and
E.
coli
100­
2500
and
10­
1000

g/
plate
w/
o
S9
and
10­
1000

g/
plate
w/
S9.
B.
subtilis
20­
2000

g/
plate
w/
o
S9.
Negative
in
S.
typhimurium
strains
TA1535,
TA1437,
TA1538,
TA98
and
TA100;
E.
coli
strain
WP2
hcr­
and
B.
subtilis
strains
H17
and
M45
(
cytotoxicity
not
observed
).

870.5100
Gene
Mutation
Bacterial
reverse
gene
mutation
assay
41871701
(
1991)
Acceptable/
guideline
50­
5000

g/
plate
w/
o
or
w/
S9.
Negative
in
S.
typhimurium
strains
TA1535,
TA1537,
TA1538,
TA98
and
TA100
(
cytotoxicity
observed
at

3330

g/
plate
w/
o
S9
but
not
w/
S9).
Insoluble
at

500

g/
plate.

870.5300
Gene
Mutation
In
vitro
mammalian
cell
forward
gene
mutation
assay
00115726
(
1982)
Acceptable/
guideline
15.6­
1000

g/
mL
(
Trial
1),
50­
1000

g/
mL
(
Trial
2),
both
w/
o
S9;
3.91­
62.5
(
Trial
1),
20­
100
(
Trial
2)
and
100­
200

g/
mL
(
Trial
3),
all
w/
S9.
Negative
in
L5178Y
TK+
mouse
lymphoma
cells
(
cytotoxicity
observed
at
1000

g/
mL
w/
o
S9
and

200

g/
mL
w/
S9).
Insoluble
at

62.5

g/
mL.

870.5300
Gene
Mutation
In
vitro
mammalian
cell
forward
gene
mutation
assay
00115729
(
1982)
Acceptable/
guideline
31.3­
1000

g/
mL
w/
o
S9
and
15.6­
250

g/
mL
w/
S9
Negative
in
L5178Y
TK+
mouse
lymphoma
cells
(
cytotoxicity
observed
at
1000

g/
mL
w/
o
S9
and
250

g/
mL
w/
S9).
Insoluble
at
250

g/
mL.
OXADIAZON
TECH.
Updated
April
4,
2001
RED
Toxicology
Chapter
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Results
39
870.5375
Cytogenetics
In
vitro
mammalian
cell
chromosomal
aberration
assay
00115728
(
1982)
Acceptable/
guideline
2­
2000

g/
mL
w/
o
S9;
0.667­
2000

g/
mL
(
Trial
1)
and
200­
600

g/
mL
(
Trial
2),
both
w/
S9.
Negative
in
Chinese
hamster
ovary
(
CHO)
cells
(
cytotoxicity
observed
at
200

g/
mL
w/
o
S9
and
500

g/
mL
w/
S9).
Insoluble
at
667

g/
mL
w/
o
S9
and
200

g/
mL
w/
S9.

870.5375
Cytogenetics
In
vitro
mammalian
cell
chromosomal
aberration
assay
00115730
(
1982)
Acceptable/
guideline
0.416­
125

g/
mL
(
Trial
1)
and
12.5­
75

g/
mL
(
Trial
2),
both
w/
o
S9;
1.25­
125

g/
mL
w/
S9
(
trial
2).
Negative
in
Chinese
hamster
ovary
(
CHO)
cells
(
cytotoxicity
at
75

g/
mL
w/
o
S9
and
41.6

g/
mL
w/
S9).
Insoluble
at
416

g/
mL.

870.5395
Cytogenetics
Mammalian
erythrocyte
micronucleus
test
0073288
(
1980)
Unacceptable/
guideline
(
not
upgradable)
0,
500,
1000
or
2000
mg/
kg
100%
oxadiazon
Negative
up
to
limit
dose
of
2000
mg/
kg,
but
early
sampling
time
(
6
hr
post­
dosing)
may
have
missed
peak
time
of
mutagenic
effect.
No
signs
of
toxicity
were
observed.

870.5395
Cytogenetics
Mammalian
erythrocyte
micronucleus
test
0073289
(
1980)
Unacceptable/
guideline
(
not
upgradable)
0,
500,
1000
or
2000
mg/
kg
Negative
up
to
limit
dose
of
2000
mg/
kg
,
but
early
sampling
time
(
6
hr
post­
dosing)
may
have
missed
peak
time
of
mutagenic
effect.
No
signs
of
toxicity
were
observed.

870.5395
Cytogenetics
Mammalian
erythrocyte
micronucleus
test
00732890
(
1980)
Unacceptable/
guideline
(
not
upgradable)
0,
500,
1000
or
2000
mg/
kg
24865
RP
(
99%),
an
oxadiazon
impurity
Negative
up
to
limit
dose
of
2000
mg/
kg,
but
early
sampling
time
(
6
hr
post­
dosing)
may
have
missed
peak
time
of
mutagenic
effect.
Clinical
signs
of
toxicity
observed
at

1000
mg/
kg
including
2
deaths
at
2000
mg/
kg.

870.5550
Other
Effects
Unscheduled
DNA
synthesis
assay
00115723
(
1982)
Acceptable/
guideline
1.0
to
1000

g/
mL
Negative
in
primary
rat
hepatocytes
after
18
hrs
(
cytotoxicity
observed
at
100­
500

g/
mL).

870.5550
Other
Effects
Unscheduled
DNA
synthesis
assay
00115727
(
1982)
Acceptable/
guideline
0.5
to
50

g/
mL
Negative
in
primary
rat
hepatocytes
after
18
hrs
(
cytotoxicity
observed
at
50

g/
mL).
OXADIAZON
TECH.
Updated
April
4,
2001
RED
Toxicology
Chapter
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Results
40
Nonguideline
Other
Effects
In
vitro
cell
transformation
00115703
(
1982)
Acceptable/
nonguideline
12.5­
200

g/
mL
w/
and
w/
o
S9
for
technical
oxadiazon;
25­
400

g/
mL
for
recrystallized
oxadiazon
(
100%)
w/
S9
or
w/
o
S9.
Dose­
related
induction
of
cell
transformation
above
background
levels
observed
w/
S9
and
w/
o
S9
activation
in
Syrian
hamster
kidney
cells
(
BHK21
C13/
HRC1
cells)
for
both
technical
and
recrystallized
oxadiazon.

METABOLISM,
DERMAL
PENETRATION
AND
SPECIAL
MECHANISTIC
STUDIES
870.7485
Metabolism
and
pharmacokinetics
(
Crl:
CD(
SD)
BR
rat)
42324701,
42663601
(
1992,
1993)
Acceptable/
guideline
5
mg/
kg
14C­
oxadiazon
(
single
dose),
5
mg/
kg
(
14­
day
dose
of
oxadiazon
+
1
dose
of
14C­
oxadiazon,
day
15)
or
500
mg/
kg
14Coxadiazon
(
gavage)
At
5
mg/
kg,
oxadiazon
is
completely
absorbed,
metabolized
and
excreted
in
urine
and
feces
(
no
parent
compound
in
urine;
<
5%
in
feces.
At
500
mg/
kg,
53%
of
administered
dose
was
excreted
in
feces
as
parent
compound.
For
both
groups,

83%
of
administered
dose
was
excreted
in
urine
and
feces
(
total
recovery

94%)
by
7
days'
post­
dosing.
Females
tended
to
excrete
more
radioactivity
in
urine
than
males.
Oxadiazon
was
metabolized
primarily
by
hydroxylation
and
glucuronide
conjugation,
but
benzene
and
pyrozolidine
rings
were
not
metabolized.
A
total
of
18
metabolites
were
identified
in
urine
and
feces
(
4
urinary,
5
fecal
metabolites
present
at
>
1%
of
administered
dose).

870.7600
Dermal
penetration
(
SD
rat)
44588101(
1996)
Acceptable/
guideline
5.45,
39.2
or
523

g/
cm2
(
exposure
times
of
0.5,
1,
2,
4,
10
or
24
hrs)
Total
absorption
9%
of
administered
dose
following
10
hr
exposure
(
6.05%
in
skin
and
2.65%
absorbed).
Absorption
but
not
dermal
uptake
saturated
at
39.2
and
523

g/
cm2.

Special
studies
(
nonguideline)
­
Peroxisomal
proliferation
(
SD
rat)
42310001
(
1991)
Acceptable/
nonguideline
0,
20,
200
or
500
mg/
kg/
day
in
diet
for
14
days
NOAEL
<
20
mg/
kg/
day.

LOAEL
=
20
mg/
kg/
day,
based
on
increased
peroxisomal
enzyme
(
palmitoyl
CoA
and
acetylcarnitine
transferase)
activities.
At
200
mg/
kg/
day,
liver
enlargement
and
at
500
mg/
kg/
day,
ultrastructural
changes
(
peroxisomal
proliferation
and
microsomal
alterations)
were
also
observed.
However,
catalase
was
decreased
by
treatment.
OXADIAZON
TECH.
Updated
April
4,
2001
RED
Toxicology
Chapter
41
9.2
Summary
of
Toxicological
Dose
and
Endpoints
for
Oxadiazon
for
Use
in
Human
Risk
Assessment1
EXPOSURE
SCENARIO
DOSE
(
mg/
kg/
day)
ENDPOINT
STUDY
Acute
Dietary
NOAEL=
N/
A
UF
=
N/
A
This
risk
assessment
is
not
required
at
this
time
because
there
are
no
food
or
feed
uses
for
Oxadiazon
Chronic
Dietary
NOAEL
=
N/
A
UF
=
N/
A
This
risk
assessment
is
not
required
at
this
time
because
there
are
no
food
or
feed
uses
for
Oxadiazon
Cancer
Q1*
of
7.11
x
10­
2
(
mg/
kg/
day)­
1in
human
equivalentsa,
based
on
increased
incidence
of
combined
hepatocellular
adenomas/
carcinomas
in
male
ICR­
JCL
mice.
"
Possibly
a
human
carcinogen",
based
on
increased
incidence
of
hepatocellular
tumors
in
four
of
the
five
positive
studies
(
two
mouse
studies
and
two
rat
studies)
at
doses
that
exceeded
the
maximum
tolerated
dose.
Combined
Chronic
Toxicity/
Carcinogenicity
Studies
in
Rats
MRID
Nos.
00149003/
00157780
and
40993401
Carcinogenicity
Studies
in
Mice
MRID
Nos.
00115733
and
40993301
(
increased
liver
tumors
also
observed
in
both
sexes
in
an
unacceptable
mouse
oncogenicity
study,
MRID
00044322).

Incidental
Oral,
Short­
Term
NOAEL=
12
Maternal
effects
Reduced
body
weight/
body
weight
gain
at
40
mg/
kg/
day
(
LOAEL).
Developmental
Toxicity
­
Rat
MRID
No.
40470202
Incidental
Oral,
Intermediate­
Term
NOAEL=
12
Maternal
effects
Reduced
body
weight/
body
weight
gain
at
40
mg/
kg/
day
(
LOAEL).
Developmental
Toxicity
­
Rat
MRID
No.
40470202
Dermal,
Short­
Term
NOAEL=
12
Developmental
effects
Increased
fetal
resorptions/
postimplantation
loss,
increased
incidence
of
incomplete
ossification
at
40
mg/
kg/
day
(
LOAEL).
For
this
risk
assessment,
the
dermal
absorption
factor
of
9%
is
applied.
Developmental
Toxicity
­
Rat
MRID
No.
40470202
OXADIAZON
TECH.
Updated
April
4,
2001
RED
Toxicology
Chapter
42
EXPOSURE
DOSE
(
mg/
kg/
day)
ENDPOINT
STUDY
Dermal,
Intermediate­
Term
NOAEL=
12
Developmental
effect
Increased
fetal
resorptions/
postimplantation
loss,
increased
incidence
of
incomplete
ossification
at
40
mg/
kg/
day
(
LOAEL).
For
this
risk
assessment,
the
dermal
absorption
factor
of
9%
is
applied.
Developmental
Toxicity
­
Rat
MRID
No.
40470202
Dermal,
Long­
Term
NOAEL=
0.36
Increased
centrilobular
swelling
in
male
livers
at
3.5
mg/
kg/
day
(
LOAEL).
For
this
risk
assessment,
the
dermal
absorption
factor
of
9%
is
applied.
Combined
Chronic
Feeding/
Oncogenicity
­
Rat
MRID
Nos.
40993401,
00149003/
00157780
Inhalation,
Short­
Term
NOAEL=
12
Developmental
effect
Increased
fetal
resorptions/
postimplantation
loss,
increased
incidence
of
incomplete
ossification
at
40
mg/
kg/
day
(
LOAEL).
For
this
risk
assessment,
use
a
route­
to­
route
extrapolation
and
a
100%
absorption
rate
(
default
value).
Developmental
Toxicity
­
Rat
MRID
No.
40470202
Inhalation,
Intermediate­
Term
NOAEL=
12
Developmental
effect
Increased
fetal
resorptions/
postimplantation
loss,
increased
incidence
of
incomplete
ossification
at
40
mg/
kg/
day
(
LOAEL).
For
this
risk
assessment,
use
a
route­
to­
route
extrapolation
and
a
100%
absorption
rate
(
default
value).
Developmental
Toxicity
­
Rat
MRID
No.
40470202
Inhalation,
Long­
Term
NOAEL=
0.36
Increased
centrilobular
swelling
in
male
livers
at
3.5
mg/
kg/
day
(
LOAEL).
Use
a
route­
toroute
extrapolation
and
a
100%
absorption
rate
(
default
value)
Combined
Chronic
Feeding/
Oncogenicity
­
Rat
MRID
Nos.
40993401,
00149003/
00157780
OXADIAZON
TECH.
Updated
April
4,
2001
RED
Toxicology
Chapter
43
SignOff
Date:
7/
10/
01
DP
Barcode:
D266361
HED
DOC
Number:
014614
Toxicology
Branch:
TOX1