Document ID: EPA-HQ-OPP-2002-0309-0010
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2002-12-03T05:00Z

UNITED
STATES
ENVIRONMENTAL
PROTECTION
AGENCY
WASHINGTON,
D.
C.
20460
OFFICE
OF
PREVENTION,
PESTICIDES
AND
TOXIC
SUBSTANCES
HED
DOC.
NO.
014469
DATE:
February
8,
2001
MEMORANDUM
SUBJECT:
Oxadiazon­
Report
of
the
Hazard
Identification
Assessment
Review
Committee.

FROM:
Nancy
E.
McCarroll,
Toxicologist
Toxicology
Branch
1
Health
Effects
Division
(
7509C)

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

TO:
Seyed
Tadayan,
Chemist
Chemistry
and
Exposure
Branch
I
Health
Effects
Division
(
7509C)

PC
Code:
109001
On
December
7,
2000,
the
Health
Effects
Division
(
HED)
Hazard
Identification
Assessment
Review
Committee
(
HIARC)
reviewed
the
recommendations
of
the
toxicology
reviewer
for
Oxadiazon
with
regard
to
the
acute
and
chronic
Reference
Doses
(
RfDs)
and
the
toxicological
endpoint
selection
for
use
as
appropriate
in
occupational/
residential
exposure
risk
assessments.
The
potential
for
increased
susceptibility
of
infants
and
children
from
exposure
to
Oxadiazon
was
also
evaluated
as
required
by
the
Food
Quality
Protection
Act
(
FQPA)
of
1996.
The
conclusions
drawn
at
this
meeting
are
presented
in
this
report.
Page
2
Committee
Members
in
Attendance
Members
present
were:
William
Burnam,
Pamela
Hurley,
David
Nixon,
Jess
Rowland,
Brenda
Tarplee,
and
Yung
Yang,

Member(
s)
in
absentia:
Elizabeth
Doyle
and
Elizabeth
Mendez
Data
evaluation
prepared
by:
Linnea
Hansen/
Nancy
E.
McCarroll,
Toxicologist
Branch
1
Also
in
attendance
were:
Ayaad
Assad,
Mike
Ioannou,
Alberto
Protzel,
Seyed
Tadayan
(
HED)
Jonathan
Chen
(
AD),
Veronique
La
Capra
(
SRRD)

Data
Evaluation
/
Report
Presentation:
December
7,
2000
Linnea
Hansen/
Nancy
E.
McCarroll
Toxicologists
Page
3
1.
INTRODUCTION
On
December
7,
2000,
the
Health
Effects
Division
(
HED)
Hazard
Identification
Assessment
Review
Committee
(
HIARC)
reviewed
the
recommendations
of
the
toxicology
reviewer
for
Oxadiazon
with
regard
to
the
acute
and
chronic
Reference
Doses
(
RfDs)
and
the
toxicological
endpoint
selection
for
use
as
appropriate
in
occupational/
residential
exposure
risk
assessments.
The
potential
for
increased
susceptibility
of
infants
and
children
from
exposure
to
Oxadiazon
was
also
evaluated
as
required
by
the
Food
Quality
Protection
Act
(
FQPA)
of
1996.

Oxadiazon,
5­
term­
butyl­
4­(
2,4­
dichloro­
5­
isopropoxyphenyl)­
1,3,4­
oxadiazol­
2­
one,
is
a
selective
pre­
emergent
and
early
post­
emergence
herbicide
that
is
effective
primarily
for
the
control
of
annual
grasses
and
broadleaf
weeds
in
turf.
Most
of
the
usage
is
allocated
to
golf
courses.
The
trade
name
for
Oxadiazon
in
the
U.
S.
is
Ronstar.
The
mechanism
of
action
is
contact
inhibition
by
affecting
young
shoots
as
they
grow
through
the
treated
zone
(
pre­
emergence)
and
complete
coverage
(
postemergence
Oxadiazon
destroys
cell
membranes
and
inhibits
photosynthesis,
probably
by
generating
oxidizing
radicals
in
light.
It
is
a
powerful
inhibitor
of
plant,
yeast
and
mouse
protoporphyrinogen
oxidase,
an
enzyme
critical
in
the
biosynthesis
of
chlorophyll
and
heme
(
Matringe
et
al.,
1989).
Oxadiazon
has
no
food
or
feed
uses.
There
are
currently
16
tolerances
in
CFR
180.346;
however,
the
registrant
will
delete
these
uses
so
that
the
tolerances
can
be
revoked.
The
Registrant
is
now
supporting
use
of
Oxadiazon
on
golf
courses,
apartment/
condo
lawns,
athletic
fields,
parks,
playgrounds
and
cemeteries.

Oxadiazon
has
the
following
structure:

Empirical
Formula:
C
15
H
18
Cl
2
N
2
O
3
Molecular
Weight:
345.22
Melting
Point:
88­
90

C
Boiling
Point:
Not
applicable
(
Oxadiazon
is
a
solid)
Density:
20

C
Vapor
Pressure
at
20

C:
<
1
x
10­
6
mm
Hg
Water
Solubility:
0.7
mg/
L
at
20

C
Log
Kow:
4.8
CAS
Number:
19666­
30­
9
Page
4
2.
HAZARD
IDENTIFICATION
2.1
Acute
Reference
Dose
(
RfD)

Not
required
since
there
are
no
food
or
feed
or
anticipated
food
or
feed
uses
for
this
pesticide.

2.2
Chronic
Reference
Dose
(
RfD)

Not
required
since
there
are
no
food
or
feed
or
anticipated
food
or
feed
uses
for
this
pesticide.

2.3
Occupational/
Residential
Exposure
2.3.1
Short­
Term
(
1­
7
days)
Incidental
Oral
Exposure
Study
Selected:
Developmental
Toxicity
in
Rats
Guideline
#:
870.3700;
83­
3a
MRID
No.:
40470202
Executive
Summary:
In
a
developmental
toxicity
study
(
MRID
40470202),
Oxadiazon
technical
(
96.3%)
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
slightly
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
post­
implantation
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
rangefinding
study.
In
the
range­
finding
study,
which
tested
at
10,
20,
40,
60
or
80
mg/
kg/
day
(
6
dams/
dose
group),
no
maternal
or
developmental
toxicity
was
observed
at
10
or
20
Page
5
mg/
kg/
day.
However,
at
40
mg/
kg/
day,
a
mean
fetal
resorption
rate
of
40%
(
53­
100%
in
3/
6
dams)
was
observed,
increasing
to
80­
90%
at
60
and
80
mg/
kg/
day.
Weights
of
surviving
fetuses
were
decreased.
Decreased
maternal
weights
were
also
observed
at

40
mg/
kg/
day
and
were
usually
correlated
with
the
increased
litter
resorption.
Therefore,
the
effects
seen
at
40
mg/
kg/
day
in
the
main
study
are
considered
a
threshold
response
for
Oxadiazon
under
the
conditions
of
the
main
study.
The
developmental
toxicity
LOAEL
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
is
12
mg/
kg/
day.

This
study
is
classified
Acceptable/
guideline;
it
satisfies
the
guideline
requirement
for
a
developmental
toxicity
study
(
83­
3a)
in
the
rat.

Dose
and
Endpoint
for
Risk
Assessment:
NOAEL
for
maternal
effects
=
12
mg/
kg/
day.
LOAEL
=
40
mg/
kg/
day
based
on
slight
decrease
in
body
weight/
body
weight
gain
at
Days
16­
20.

Comments
about
Study/
Endpoint/
Uncertainty
Factor(
s):
This
dose
and
endpoint
were
considered
appropriate
because
the
critical
effect
(
body
weight
decrements)
occurred
during
the
treatment
period
(
Gestation
Days
16­
20)
which
encompasses
the
exposure
period
of
concern
(
1­
7
days)
and
is
appropriate
for
the
population
of
concern
(
infants
and
children).

2.3.2
Intermediate­
Term
(
7
Days
to
Several
Months)
Incidental
Oral
Exposure
Study
Selected:
Developmental
Toxicity
in
Rats
Guideline
#:
870.3700;
83­
3a
MRID
No.:
40470202
Executive
Summary:
See
Short­
term
(
1­
7
Days)
Incidental
Oral
Exposure
Dose
and
Endpoint
for
Risk
Assessment:
NOAEL
for
maternal
effects
=
12
mg/
kg/
day.
LOAEL
=
40
mg/
kg/
day
based
on
slight
decrease
in
body
weight/
body
weight
gain
at
Days
16­
20.

Comments
about
Study/
Endpoint:
The
dose
and
endpoint
were
considered
appropriate
because
the
NOAEL
in
the
90­
day
studies
were
higher
than
the
NOAEL
of
this
study.
The
NOAEL
from
the
developmental
study
was
selected
because
the
lower
maternal
NOAEL
may
reflect
greater
sensitivity
of
the
pregnant
rat.

2.3.3
Dermal
Absorption
Dermal
Absorption
Factor:
9%
from
the
dermal
penetration
study
(
10­
hour
reading)

MRID
No.:
44588101
Page
6
Executive
Summary:
In
a
dermal
penetration
study
(
MRID
44588101),
14C­
Oxadiazon
(
Lot
No.
GXR
396A­­
99.6%
radiochemical
purity,
mixed
with
unlabeled
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/
or
bound
to
the
skin
and
the
percent
absorbed
at
10
hours
was
6.05%
and
2.65%
(
5.45

g/
cm2),
4.71%
and
0.63%
(
39.2

g/
cm2),
and
1.03%
and
0.05%
(
523

g/
cm2),
respectively.
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.
Consequently,
the
percent
bound
to
the
skin
and
the
percent
absorbed
in
a
10­
hour
period
is
6.05
and
2.65
%,
respectively.
For
the
purposes
of
risk
assessment,
the
sum
of
both
is
8.70%.

This
study
is
classified
Acceptable/
guideline;
it
satisfies
the
guideline
requirement
for
a
dermal
penetration
study
(
85­
3)
in
the
rat.

Comments
about
Dermal
Absorption:
None
2.3.4
Short­
Term
Dermal
(
1­
7
days)
Exposure
Study
Selected:
Developmental
Toxicity
in
Rats
Guideline
#:
870.3700;
83­
3a
MRID
No.:
40470202
Executive
Summary:
See
Short­
term
(
1­
7
Days)
Incidental
Oral
Exposure
Dose
and
Endpoint
for
Risk
Assessment:
NOAEL
for
developmental
effects
=
12
mg/
kg/
day.
LOAEL
=
40
mg/
kg/
day
based
on
increased
fetal
resorptions/
postimplantation
loss,
decreased
fetal
weight
and
increased
incidence
of
incomplete
ossification.

Comments
about
Study/
Endpoint:
A
dermal
study
was
submitted
in
which
no
systemic
effects
were
seen
up
to
the
limit
dose.
However,
since
dermal
studies
do
not
evaluate
developmental
effects
and
there
is
a
concern
for
increased
susceptibility
of
the
fetus
to
the
test
compound,
Page
7
the
Committee
decided
that
the
rat
developmental
study
was
more
appropriate
to
set
the
dermal
endpoint
in
conjunction
with
a
dermal
absorption
factor.

2.3.5
Intermediate­
Term
Dermal
(
7
Days
to
Several
Months)
Exposure
Study
Selected:
Developmental
Toxicity
in
Rats
Guideline
#:
870.3700;
83­
3a
MRID
No.:
40470202
Executive
Summary:
See
Short­
term
Incidental
Oral
Exposure
Dose
and
Endpoint
for
Risk
Assessment:
See
Short­
term
Incidental
Dermal
Exposure
Comments
about
Study/
Endpoint:
See
Comments
for
Short­
Term
Dermal
Study/
Endpoint.

2.3.6
Long­
Term
Dermal
(
Several
Months
to
Life­
Time)
Exposure
Studies
Selected:
Combined
Chronic
Feeding/
Oncogenicity­
Rat
Guideline
870.4300/
[
83­
5]

MRID
Nos:
(
1)
40993401
(
2)
00149003/
00157780
Executive
Summary:
In
a
chronic/
oncogenicity
toxicity
study
(
MRID
No.
40993401),
Oxadiazon
(
95.9%)
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,
Page
8
78
and
104).
There
were
no
consistent
hematological
effects
in
the
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,
ALP,
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.
Nonneoplastic
pathology
in
the
liver
at
1000
ppm
included:

centrilobular
hepatocellular
swelling
(

and

)
;

acidophilic
foci
of
cellular
alteration
(

)
;
brown
pigmentation
in
the
liver
(

and

)
;
and
bile
duct
proliferation
(

)
.
At
100
ppm,

centrilobular
hepatocellular
swelling
was
also
seen
in
the
males.
Brown
pigmentation
in
the
proximal
tubular
cells
and
in
cortical
interstitial
tissue
(

and

)
;
and
chronic
nephropathy
(

)
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.

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.
Using
the
more
recent
terminology,
the
study
is
now
listed
as
Unacceptable/
guideline
(
MRID
No.
40993401).

Executive
Summary:
In
a
chronic/
carcinogenicity
toxicity
study
(
00149003/
00157780),
Oxadiazon
(
99.9%)
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
(

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
Page
9
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
(


1000
ppm
at
6
and
12
months;

3000
ppm
at
6
months);
increased
total
protein
(
consistent
effect
only
in
the

at

100
ppm
and
generally
at
all
sampling
intervals);
increased
total
cholesterol
(

at
1000
ppm
and
both
sexes
at
3000
ppm)
and
increased
bilirubin
(


1000
ppm
at
6
and
12
months;

3000
ppm
at
6
months).
In
addition,
significant
increases
in
GOT,
GPT,
AP
and
BUN
generally
correlated
well
with
liver
morphological
changes
at

1000
ppm
(

)
.
Similarly,
increased
absolute
and
relative
liver
and
kidney
weights
at

1000
ppm
(
both
sexes)
correlated
well
with
liver
and
kidney
histopathology
effects.
At
termination,
Oxadiazon
also
induced
increased
absolute
and
relative
liver
weights
at
100
ppm
(

)
.
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
nonneoplastic
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
(
5
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.

This
chronic/
carcinogenicity
study
in
the
rat
is
Acceptable
(
Guideline)
and
satisfies
the
guideline
requirement
for
a
combined
chronic/
carcinogenicity
study
(
83­
5)
in
the
rat
(
MRID
Nos.
00149003
[
main
study]/
MRID
00157780
[
additional
data]).

Dose
and
Endpoint
for
Risk
Assessment:
NOAEL
=
0.36
mg/
kg/
day.
LOAEL
=
3.5
mg/
kg/
day
based
on
centrilobular
swelling
in
the
male
rat
livers.

Comments
about
Study/
Endpoint:
The
pathology
report
for
the
selected
chronic/
carcinogenicity
study
in
the
rat
was
considered
incomplete
and
the
overall
study
was
listed
as
Supplementary
(
Unacceptable).
However,
no
additional
information
is
being
requested
because
the
results
are
consistent
with
an
acceptable
rat
chronic/
carcinogenicity
study
(
MRID
No.
0014003/
00157780).
This
study
was
chosen
by
IRIS
in
1986
to
set
the
chronic
RfD
for
Oxadiazon.
The
NOAEL
and
LOAEL
for
this
study
was
0.5
and
5
mg/
kg/
day,
respectively,
based
on
increased
liver
weights
in
both
sexes
and
increased
serum
protein
in
females.
Thus,
the
findings
from
MRID
No.
0014003/
00157780
support
the
selected
NOAEL
and
LOAEL.
In
addition,
liver
neoplasms
in
males
were
present
in
both
Page
10
studies
and
confirms
the
evidence
of
a
carcinogenic
effect.
While
both
studies
were
in
good
agreement,
the
study
selected
for
this
endpoint
(
MRID
No.
40993401)
is
considered
Unacceptable.
The
HIARC
concluded,
however,
that
in
combination
with
the
Acceptable
study
used
by
IRIS
and
within
the
context
of
the
entire
database,
MRID
No.
40993401
was
Acceptable
for
endpoint
selection.
Additionally,
since
an
oral
NOAEL
was
selected
for
this
risk
assessment,
the
dermal
absorption
factor
should
be
used
for
route­
to­
route
extrapolation.

2.3.7
Inhalation
Exposure
(
All
Durations)

Studies
Selected:

Short­
and
Intermediate­
Term:
Developmental
Oral
Study
in
Rats
(
MRID
No.
40470202)
NOAEL
=
12
mg/
kg/
day
Executive
Summary:
See
Short­
term
Incidental
Oral
Exposure
Long­
Term:
Combined
Chronic
Feeding
/
Oncogenicity
in
Rats
(
MRID
Nos.
40993401
and
0014003/
00157780)
NOAEL
=
0.36
mg/
kg/
day
Executive
Summaries:
See
Long­
Term
Dermal
(
Several
Months
to
Life­
Time)
Exposure
Comments
about
Study/
Endpoint:
With
the
exception
of
an
acute
inhalation
study
(
MRID
No.
41866503)
in
which
Oxadiazon
was
placed
in
Category
III
(
LC
50
>
1.94
mg/
L),
no
other
inhalation
studies
are
available
for
this
risk
assessment.
Consequently,
the
HIARC
recommended
the
submission
of
a
28­
day
inhalation
toxicity
study.
Until
that
time,
the
HIARC
recommended
using
route­
to­
route
extrapolation
since
the
doses
identified
for
the
short
and
intermediate
term
and
for
the
long
term
inhalation
exposures
are
from
oral
studies.
The
following
route­
to­
route
extrapolation
steps
should
be
followed:

Step
1:
Convert
the
inhalation
exposure
(

g/
lb
a.
i.)
using
a
100%
inhalation
absorption
rate
(
default
value),
application
rate
and
acres
treated
to
an
oral
equivalent
dose
(
mg/
kg/
day).

Step
2:
Convert
the
dermal
exposure
(
mg/
kg/
day)
using
9%
as
the
dermal
absorption
rate,
application
rate
and
acres
treated
to
an
oral
equivalent
dose
(
mg/
kg/
day).
This
dose
should
be
combined
with
the
converted
oral
dose
in
Step
1.

Step
3:
To
calculate
the
MOE's,
the
combined
dose
from
Step
II
should
be
compared
to
the
oral
NOAEL
of
12
mg/
kg/
day
for
the
Short­
and
Intermediate­
term
exposure
scenarios
and
to
the
oral
NOAEL
of
0.36
mg/
kg/
day
for
the
Long­
term
exposure
scenarios.
Page
11
2.3.8
Margins
of
Exposure
for
Occupational/
Residential
Risk
Assessments
There
are
no
food
or
feed
uses
of
Oxadiazon.
For
nonoccupational
and
occupational
exposure
risk
assessments,
a
MOE
of
100
is
required
for
dermal
and
inhalation
exposures.
The
Registrant
is
now
supporting
use
of
Oxadiazon
on
golf
courses,
apartment/
condo
lawns,
athletic
fields,
parks,
playgrounds
and
cemeteries.
Many
of
these
sites,
including
golf
courses
are
considered
a
residential
use
with
respect
to
the
post­
application
risk
assessment.

2.4
Recommendation
for
Aggregate
Exposure
Risk
Assessments
Since
there
are
no
food
uses,
aggregate
exposure
will
be
limited
to
combining
the
dermal
and
inhalation
exposure
components
since
oral
equivalents
were
selected.

3
CLASSIFICATION
OF
CARCINOGENIC
POTENTIAL
3.1
Combined
Chronic
Toxicity/
Carcinogenicity
Study
in
Rats
Guideline
#:
870.4300/
[
83­
5]

MRID
No.:
00149003/
00157780
Executive
Summary:
In
a
chronic/
carcinogenicity
toxicity
study
(
00149003/
00157780),
Oxadiazon
(
99.9%)
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
(

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
(


1000
ppm
at
6
and
12
months;

3000
ppm
at
6
months);
increased
total
protein
(
consistent
effect
only
in
the

at

100
ppm
and
generally
at
all
Page
12
sampling
intervals);
increased
total
cholesterol
(

at
1000
ppm
and
both
sexes
at
3000
ppm)
and
increased
bilirubin
(


1000
ppm
at
6
and
12
months;

3000
ppm
at
6
months).
In
addition,
significant
increases
in
GOT,
GPT,
AP
and
BUN
generally
correlated
well
with
liver
morphological
changes
at

1000
ppm
(

)
.
Similarly,
increased
absolute
and
relative
liver
and
kidney
weights
at

1000
ppm
(
both
sexes)
correlated
well
with
liver
and
kidney
histopathology
effects.
At
termination,
Oxadiazon
also
induced
increased
absolute
and
relative
liver
weights
at
100
ppm
(

)
.
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
nonneoplastic
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
(
5
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).

Discussion
of
Tumor
Data:
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.

Adequacy
of
the
Dose
Levels
Tested:
Dosing
was
considered
adequate
in
males
and
in
females
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
(
83­
5)
in
the
rat
(
MRID
Nos.
00149003
[
main
study]/
MRID
00157780
[
additional
data]).

MRID
No.:
40993401
Executive
Summary:
In
a
chronic/
oncogenicity
toxicity
study
(
MRID
No.
40993401),
Oxadiazon
(
95.9%)
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.
Page
13
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
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,
ALP,
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.
Nonneoplastic
pathology
in
the
liver
at
1000
ppm
included:

centrilobular
hepatocellular
swelling
(

and

)
;

acidophilic
foci
of
cellular
alteration
(

)
;
brown
pigmentation
in
the
liver
(

and

)
;
and
bile
duct
proliferation
(

)
At
100
ppm,

centrilobular
hepatocellular
swelling
was
also
seen
in
the
males.
Brown
pigmentation
in
the
proximal
tubular
cells
and
in
cortical
interstitial
tissue
(

and

)
;
and
chronic
nephropathy
(

)
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).

Discussion
of
Tumor
Data:
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.

Adequacy
of
the
Dose
Levels
Tested:
Dosing
was
considered
adequate
in
males
based
on
signs
of
transient
anemia,

serum
enzyme
activity,

bilirubin
and
liver
weight,

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.
Using
the
more
recent
terminology,
the
study
is
now
listed
as
Unacceptable/
guideline
(
MRID
No.
40993401).
Page
14
3.2
Carcinogenicity
Study
in
Mice
Guideline
#:
870.4200/
[
83­
2]

MRID
No.:
00115733
Executive
Summary:
In
a
mouse
oncogenicity
study
(
MRID
No.
00115733),
Oxadiazon
(
tech.,
99.3%
a.
i.,
Lot/
Batch
#
BES
2253)
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
30%),
hemoglobin
(

6­
28%),
and
erythrocyte
count
(

12­
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,
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
doseresponse
(
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
Page
15
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.

Discussion
of
Tumor
Data:
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).

Adequacy
of
the
Dose
Levels
Tested:
Dosing
was
considered
adequate
based
on
the
finding
of
liver
toxicity
at
all
doses.

The
submitted
study
is
classified
as
Acceptable/
guideline
(
§
83­
2b)
and
satisfies
the
guideline
requirements
for
a
carcinogenicity
study
in
mice
(
MRID
No.
00115733).

MRID
No.:
00044322
Executive
Summary:
In
an
oral
mouse
oncogenicity
study
(
MRID
00044322),
Oxadiazon
(
95.5%
a.
i.,
Lot/
Batch
#
MAG
405)
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
Page
16
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
treatment­
related.
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.
The
systemic
toxicity
NOAEL
is
<
300
ppm.

Discussion
of
Tumor
Data:
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.

Adequacy
of
the
Dose
Levels
Tested:
Dosing
was
considered
adequate
based
on
the
finding
of
liver
toxicity
at
all
doses.

The
submitted
study
is
classified
as
Unacceptable/
guideline
(
§
83­
2b).
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
No.
00149003/
00157780)
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
(
MRID
No.
00044322).

MRID
No.:
40993301
Page
17
Executive
Summary:
In
a
chronic/
oncogenicity
toxicity
study
(
MRID
No.
40993301),
Oxadiazon
(
95.9%)
was
administered
to
80
ICR­
JCL
mice
(
80/
sex/
dose)
in
the
diet
at
0,
3,
10,
100
or
1000
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
(

)
and
3000
ppm
(

)
.

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
(
highdose
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
(

and

)
and
at
100
ppm
were:
increased
GLP
and
GOT(

)
.
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
(

week
98)
and
kidney
(

week
98)
weights
were
also
seen
at
1000
ppm.
Non­
neoplastic
pathology
at
1000
ppm
included:

centrilobular
hepatocellular
swelling
(

)
;

diffuse
hepatocellular
swelling
(

)
;
brown
pigmentation
in
the
liver
and
proximal
tubules
of
the
kidney
(

and

)
;
extramedullary
hematopoiesis
(

)
diffuse
hepatocellular
necrosis
(

)
and

auricular
thrombus
(

)
.
At
100
ppm,

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

/

)
.

Discussion
of
Tumor
Data:
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.
Page
18
Adequacy
of
the
Dose
Levels
Tested:
Dosing
was
considered
adequate
in
males
and
females
based
on
anemia
and
pathological
changes
in
the
liver
at
the
highest
dose
tested.

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).
Using
the
more
recent
terminology,
the
study
is
now
listed
as
Unacceptable/
guideline
(
MRID
No.
40993301).

3.3
Classification
of
Carcinogenic
Potential
According
to
the
Cancer
Assessment
Review
Committee
report,
dated
August
27,
1987
(
HED
Document
No.
007798),
the
original
peer
review
(
September
9,
1986)
placed
Oxadiazon
into
Group
B2
(
probable
human
carcinogen)
but
there
was
a
minority
opinion
that
the
agent
should
be
placed
in
Group
C
(
possible
human
carcinogen).
Review
of
the
weightof
the­
evidence
on
Oxadiazon
by
the
Scientific
Advisory
Panel
(
dated
November
20,
1987)
reiterated
this
minority
view.
Consequently,
the
current
Agency
decision
on
the
carcinogenic
potential
of
Oxadiazon
concurs
with
the
Scientific
Advisory
Panel's
(
SAP)
classification
of
Oxadiazon
as
a
group
C
carcinogen.
The
updated
Q
1*
has
been
set
at
1.4
x
10­
1(
mg/
kg/
day)­
1
in
human
equivalents.
The
rationale
for
the
original
classification
as
group
B2
was
based
on
the
increased
incidence
of
malignant
or
combined
malignant
and
benign
liver
tumors:
a)
in
multiple
species
(
CD
­
1
mice
and
F344
rats
of
one
or
both
sexes)
and
in
multiple
experiments
(
liver
tumors
in
two
mouse
studies
and
in
one
rat
study).
The
decision
to
reclassify
Oxadiazon
as
a
Group
C
carcinogen
was
based
on
the
rationale
that
liver
tumors
were
produced
in
two
of
the
three
positive
studies
(
one
mouse
study
and
one
rat
study)
at
doses
that
exceeded
the
maximum
tolerated
dose
(
MTD).
Since
that
time,
a
new
chronic/
oncogenicity
toxicity
study
in
rats
(
MRID
No.
40993401)
and
a
new
carcinogenicity
study
in
mice
(
MRID
No.
40993301)
have
been
submitted
to
the
Agency.
The
HIARC
recommended
that
the
Q1*
be
revisited
and
that
the
CARC
reconvene
to
evaluate
these
more
recent
studies.

4
MUTAGENICITY
4.1
Summaries
Nine
acceptable
mutagenicity
studies
were
available
for
review;
summaries
of
these
studies
with
MRID
numbers
are
presented
below:

GENE
MUTATION
Page
19
a)
Salmonella
typhimurium/
Escherichia
coli
reverse
gene
mutation
assay.
The
assay
was
negative
in
S.
typhimurium
strains
TA1535,
TA1537,
TA1538,
TA98
and
TA100
and
E.
coli
WP2
hcr­
up
to
the
highest
dose
tested
(
2500

g/
plate
­
S9;
1000

g/
plate
+
S9)
of
99.18%
Oxadiazon.
The
study
is
acceptable
and
satisfies
the
guideline
requirements
(
870.5100/
84­
2)
for
a
bacterial
gene
mutation
assay
(
MRID
No.
00069893).

b)
S.
typhimurium
reverse
gene
mutation
assay:
The
assay
was
negative
in
S.
typhimurium
strains
TA1535,
TA1537,
TA1538,
TA98
and
TA100
exposed
to
97.49%
Oxadiazon
up
to
5000

g/
plate+/­
S9;
cytotoxicity
was
seen
at

3330

g/
plate
­
S9.
The
study
is
acceptable
and
satisfies
the
guideline
requirements
(
870.5100/
84­
2)
for
a
bacterial
reverse
mutation
assay
(
MRID
No.
41871701).

c)
L5178Y
TK
+/­
mouse
lymphoma
cell/
mammalian
activation
forward
mutation
assay:
The
assay
was
negative
in
cells
treated
with
Oxadiazon
(
95.5%
a.
i.)
up
to
reproducibly
cytotoxic
levels
in
the
absence
of
S9
activation
(
1000

g/
mL)
and
severely
cytotoxic
doses
(

200

g/
mL)
with
S9
activation.
Oxadiazon
was
insoluble
at

62.5

g/
mL.
The
study
is
acceptable
and
satisfies
the
guideline
requirements
(
870.5300/
84­
2)
for
a
mammalian
cell
gene
mutation
assay
(
MRID
No.
00115726).

d)
L5178Y
TK
+/­
mouse
lymphoma
cell/
mammalian
activation
forward
mutation
assay:
The
assay
was
negative
in
cells
treated
with
recrystallized
Oxadiazon
(
100%
a.
i.)
up
to
cytotoxic
levels
(
1000

g/
mL
­
S9;
250

g/
mL
+
S9).
Oxadiazon
was
insoluble
at
concentrations

250

g/
mL.
The
study
is
acceptable
and
satisfies
the
guideline
requirements
(
870.5300/
84­
2)
for
a
mammalian
cell
gene
mutation
assay
(
MRID
00115729).

CHROMOSOME
ABERRATIONS
e)
In
vitro
chromosome
aberration
assay
in
Chinese
hamster
ovary
(
CHO)
cells:
The
assay
was
negative
in
cells
treated
with
Oxadiazon
(
95.5%
a.
i.)
up
to
cytotoxic
concentrations
(
75

g/
mL
­
S9;
41.6

g/
mL
+
S9)
and
the
limit
of
solubility
(

416

g/
mL).
The
study
is
acceptable
and
satisfies
the
guideline
requirements
(
870.5373/
84­
2)
for
a
mammalian
cell
chromosome
aberration
assay
(
MRID
00115730).

f)
In
vitro
chromosome
aberration
assay
in
Chinese
hamster
ovary
(
CHO)
cells:
The
assay
was
negative
in
cells
treated
with
recrystallized
Oxadiazon
(
100%
a.
i.)
up
to
cytotoxic
concentrations
(
200

g/
mL
­
S9;
500

g/
mL
+
S9)
and
the
limit
of
solubility
(
667

g/
mL
­
S9;
200

g/
mL
+
S9).
The
study
is
acceptable
and
satisfies
the
guideline
requirements
(
870.5373/
84­
2)
for
a
mammalian
cell
chromosome
aberration
assay
(
MRID
00115728).

OTHER
MUTAGENIC
MECHANISMS
Unscheduled
DNA
synthesis(
UDS)

g)
UDS
in
primary
rat
hepatocytes
assay:
The
test
was
negative
in
hepatocytes
exposed
to
Oxadiazon
(
95.5%
a.
i.)
up
to
cytotoxic
concentrations
(

100
µ
g/
mL)
and
the
limit
of
Page
20
solubility
(

50
µ
g/
mL).
The
study
is
acceptable
and
satisfies
the
guideline
requirements
(
870.5550/
84­
2)
for
a
UDS
assay
(
MRID
No.
00115727).

h)
UDS
in
primary
rat
hepatocytes
assay:
The
test
was
negative
in
hepatocytes
exposed
to
recrystallized
Oxadiazon
(
100%
a.
i.)
up
to
cytotoxic
concentrations
(
100­
500
µ
g/
mL)
and
the
limit
of
solubility
(

25
µ
g/
mL).
The
study
is
acceptable
and
satisfies
the
guideline
requirements
(
870.5550/
84­
2)
for
a
UDS
assay
(
MRID
No.
00115723).

In
vitro
cell
transformation
I)
In
vitro
cell
transformation
assay
in
Syrian
hamster
kidney
BHK21
C13/
HRC1
cells:
The
test
was
positive
both
with
and
without
S9
activation,
based
on
the
induction
of
transformation
frequencies
(
TFs)

5
times
the
solvent
control
value
at
the
LD
50
.
Oxadiazon
(
90%
a.
i.)
and
recrystallized
Oxadiazon
(
100
%
a.
i.)
were
tested
up
to
cytotoxic
concentrations
with
LD
50
values
in
the
absence
of
S9­
mix
of
118
µ
g/
mL
and
200
µ
g/
mL,
respectively.
In
the
presence
of
S9­
mix,
the
LD
50
of
Oxadiazon
was
69
µ
g/
mL;
however,
the
LD
50
for
recrystallized
Oxadiazon
was
not
determined
as
cell
viability
was
78%
of
the
solvent
control
at
the
highest
dose
tested
(
400
µ
g/
mL).
The
transformation
frequencies
(
the
number
of
transformed
colonies/
106
surviving
cells)
at
the
LD
50
concentrations
were
128
and
79
for
cells
treated
with
Oxadiazon
in
the
absence
and
presence
of
S9­
mix,
respectively,
compared
to
the
solvent
control
values
of
4
and
5,
respectively.
Recrystallized
Oxadiazon
induced
transformation
frequencies
of
55
at
the
LD
50
in
the
absence
of
S9­
mix
and
60
at
the
highest
dose
tested
in
the
presence
of
S9­
mix.
A
positive
dose­
response
trend
was
generally
apparent
for
both
concentrations.
This
study
is
classified
as
acceptable
(
nonguideline)
(
MRID
No.
00115703).
Page
21
4.2
Conclusions
In
addition
to
the
above
two
S.
typhimurium
reverse
gene
mutation
assays
(
Ames
test),
seven
Ames
tests
submitted
by
the
sponsor
were
considered
inadequate
(
see
HED
Document
No.
002168).
Nevertheless,
results
from
these
assays
indicated
that
an
impurity
(
identified
as
24,865
RP)
in
Oxadiazon
formulations
was
mutagenic
in
S.
typhimurium
strains
TA98
and/
or
TA100
in
the
presence
of
S9
activation.
Lots/
batches
of
Oxadiazon
with
purity
levels

90%
that
contained
this
impurity
were
also
positive.
As
summarized
above,
the
acceptable
bacterial
assays
with

97.49%
Oxadiazon
were
negative
(
MRID
Nos.
00069893
and
41871701).
Similarly,
neither
95.5%
Oxadiazon
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
both
formulations
induced
neoplastic
transformation
in
Syrian
hamster
kidney
cells
both
in
the
presence
and
in
the
absence
of
S9
activation.
The
finding
of
positive
cell
transformation
supports
the
evidence
from
mouse
bioassays
(
MRID
Nos.
00444322,
00115733
and
40993301)
and
the
rat
long­
term
studies
(
MRID
Nos.
00149003/
00157780
and
40993401)
of
liver
tumor
induction.
Overall,
the
data
indicate
that
Oxadiazon
is
not
mutagenic
but
does
cause
neoplastic
cell
transformation
in
vitro.

5
FQPA
CONSIDERATIONS
5.1
Adequacy
of
the
Data
Base:

Acceptable
prenatal
toxicity
studies
in
rats
and
rabbits
with
Oxadiazon
have
been
submitted
to
the
Agency.
An
acceptable
reproductive
toxicity
study
in
rats
with
Oxadiazon
was
also
submitted.
Hence,
there
are
no
data
gaps
for
the
assessment
of
the
effects
of
Oxadiazon
following
in
utero
exposure
or
the
effects
on
young
animals
following
early
exposure.

Neither
acute
nor
subchronic
neurotoxicity
studies
were
submitted
to
the
Agency.
It
is
not,
however,
expected
that
Oxadiazon
is
a
neurotoxicant
since
none
of
the
acute,
subchronic,
chronic,
developmental
or
reproductive
toxicity
studies
showed
evidence
of
an
effect
on
the
nervous
system.

5.2
Neurotoxicity:

No
neurotoxicity
studies
were
submitted
to
the
Agency.

5.3
Developmental
Toxicity
a.
Developmental
Toxicity
Study
in
the
Rat
(
ORAL)
Guideline
#:
870.3700;
83­
3
MRID
No.:
40470202
Page
22
Executive
Summary:
In
a
developmental
toxicity
study
(
MRID
40470202),
Oxadiazon
technical
(
96.3%)
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
slightly
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
post­
implantation
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
rangefinding
study.
In
the
range­
finding
study,
which
tested
at
10,
20,
40,
60
or
80
mg/
kg/
day
(
6
dams/
dose
group),
no
maternal
or
developmental
toxicity
was
observed
at
10
or
20
mg/
kg/
day.
However,
at
40
mg/
kg/
day,
a
mean
fetal
resorption
rate
of
40%
(
53­
100%
in
3/
6
dams)
was
observed,
increasing
to
80­
90%
at
60
and
80
mg/
kg/
day.
Weights
of
surviving
fetuses
were
decreased.
Decreased
maternal
weights
were
also
observed
at

40
mg/
kg/
day
and
were
usually
correlated
with
the
increased
litter
resorption.
Therefore,
the
effects
seen
at
40
mg/
kg/
day
in
the
main
study
are
considered
a
threshold
response
for
Oxadiazon
under
the
conditions
of
the
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;
it
satisfies
the
guideline
requirement
for
a
developmental
toxicity
study
(
83­
3a)
in
the
rat.

b.
Developmental
Toxicity
Study
in
the
Rabbit
(
ORAL)
Guideline
#:
870.3700;
83­
3
MRID
No.:
40470201
Executive
Summary:
In
a
developmental
toxicity
study
(
MRID
40470201),
Oxadiazon
technical
(
95.6%
)
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
Page
23
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
treatment­
related
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
nonrodent
developmental
toxicity
study
(
83­
3b)
in
the
rabbit.

5.4
Reproductive
Toxicity
Two
Generation
Reproduction
Study
in
Rats
(
dietary)
Guideline
#:
870.3800;
83­
4a
MRID
Nos.
41230301(
Dose­
range
finding
study)/
41239801
(
Main
study)

Executive
Summary:
In
a
2­
generation
reproduction
study
(
MRID
41239801;
range­
finding
study
MRID
41240301)
Oxadiazon
(
96.6%
a.
i.,
batch
#
DA459)
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
Page
24
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
beginning
15
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
mg/
kg/
day),
based
on
decreased
gestational
weight
gain,
was
observed
in
the
range­
finding
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/
neonatal
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
[
§
83­
4(
a)]
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
range­
finding
studies,
pronounced
reproductive/
offspring
toxicity,
including
complete
litter
loss,
was
observed
at

400
ppm.
The
HIARC
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
Page
25
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.

5.5
Additional
Information
from
Literature
Sources
(
if
available)

No
additional
information
was
obtained
from
the
open
literature
for
developmental,
reproductive
or
neurotoxic
effects
of
Oxadiazon.

5.2
Determination
of
Susceptibility
There
was
qualitative
evidence
of
increase
susceptibility
of
fetuses
in
the
rat
developmental
study.
In
this
study,
very
little
maternal
toxicity
(
a
small
but
significant
decrease
in
body
weight,
­
2%
and
a
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).
In
the
two
generation
study
in
rats,
neonatal
effects
(
LOAEL
of
38
mg/
kg/
day,
based
on
neonatal
losses)
in
the
dose
range­
finding
phase
of
testing
and
the
lack
of
milk
in
the
pup
stomach
were
considered
to
be
attributable
to
maternal
effects
(
i.
e.,
inactive
mammary
tissue)
at
38
mg/
kg/
day.
The
findings
of
post­
implantation
loss
associated
with
the
lack
of
milk
could
be
due
to
endocrine
disruption.
There
was,
however,
no
evidence
(
qualitative
or
quantitative)
of
increased
susceptibility
in
the
developmental
rabbit
study
following
in
utero
exposure
or
in
the
two­
generation
reproduction
study
following
pre­
or
post­
natal
exposure.

5.3
Recommendation
for
a
Developmental
Neurotoxicity
Study
The
Committee
concluded
that
a
developmental
neurotoxicity
study
was
not
recommended.
This
decision
was
based
on
results
showing
no
evidence
of
neurotoxicity
in
any
study
in
the
database
which
included:
chronic
(
rats,
mice
and
dogs),
subchronic
(
rat
or
rabbit),
reproduction
(
rat)
or
developmental
(
rat
or
rabbit)
toxicity
studies.

6
HAZARD
CHARACTERIZATION
Oxadiazon
is
a
selective
pre­
emergent
herbicide
of
the
oxadiazole
class
which
displays
light­
dependent
phytotoxicity
through
the
accumulation
of
protoporphyrin
IX
in
plants,
yeast
and
mouse
liver
mitochondria.
At
present,
there
are
no
registered
food
or
residential
uses.
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
and/
or
90­
day
inhalation
study.

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.
Page
26
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.
Although
treatmentrelated
microscopic
lesions
of
the
liver
were
not
observed
in
dog
subchronic
or
chronic
oral
studies,
findings
in
rats
and
mice
included
pigmented
Kupffer
cells
and
bile
canaliculi,
periacinar
pallor,
increased
acidophilic
cells
and
hepatocellular
necrosis.
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).
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,
treatment­
related
changes
in
thyroid
weights
or
gross/
microscopic
observations
were
not
observed
in
other
studies
(
thyroid
hormones
were
not
evaluated).

In
a
rat
dermal
absorption
study,
up
to

9%
of
the
applied
dose
was
absorbed
after
10
hours
of
exposure.
Dermal
toxicity
studies
(
21­
day
rabbit)
support
low
dermal
absorption:
no
toxicity
was
observed
at
the
limit
dose
of
1000
mg/
kg/
day.

Following
long­
term
dietary
administration,
Oxadiazon
caused
an
increased
incidence
of
hepatocellular
adenoma
and
carcinoma
in
rats
and
mice.
In
mice,
statistically
significant
increases
of
hepatocellular
adenoma
and
combined
adenoma/
adenocarcinoma
were
observed
at
all
four
dose
levels
tested
(

100
ppm)
in
males
and
females.
The
incidence
of
hepatocellular
adenocarcinoma
was
increased
at
all
doses
in
males
but
only
at
the
two
highest
doses
(
1000
and
2000
ppm;
significant
at
1000
ppm)
in
females.
The
highest
dose
tested
in
males
(
2000
ppm)
exceeded
the
MTD
based
on
excessive
mortality.
In
SPF
Wistar
rats,
the
incidence
of
hepatocellular
adenomas
was
increased
in
males;
adenocarcinomas
were
increased
but
not
significantly
in
both
sexes
at
the
highest
dose
tested
(
1000
ppm).
A
second
study
in
F344
rats
showed
an
increased
incidence
of
hepatocellular
adenoma
and
adenocarcinoma
only
in
males
at
1000
and
3000
ppm.
A
classification
of
Group
C
(
possible
human
carcinogen)
and
a
Q
1*
of
1.4
x
10­
1
(
mg/
kg/
day)­
1
were
assigned
by
the
HED
Cancer
Peer
Review
Committee
in
conjunction
with
the
recommendations
of
the
Scientific
Advisory
Panel.
Since
that
time,
a
new
chronic/
oncogenicity
toxicity
study
in
rats
and
a
new
carcinogenicity
study
in
mice
have
been
submitted
to
the
Agency
and
are
being
evaluated
for
their
impact
on
the
cancer
classification
and
the
Q
1*.

In
a
special
mechanistic
study
in
rats,
Oxadiazon
induced
peroxisomal
proliferation
(
based
on
peroxisomal
enzyme
induction
and
electron
microscopy)
after
a
14­
day
dietary
administration.
Although
some
peroxisomal
proliferator
compounds
are
known
to
be
liver
carcinogens,
there
are
insufficient
data
available
to
support
this
as
a
mechanism
of
carcinogenicity
for
Oxadiazon.
Similarly,
Oxadiazon
did
not
show
mutagenic
potential
in
any
in
vitro
assays
with
bacteria
(
S.
typhimurium
and
E.
coli)
or
mammalian
cells
(
TK
+/­
mouse
lymphoma
Page
27
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
and
in
a
rat
two­
generation
reproduction
study.
Neonatal
survival
was
also
sharply
reduced
in
the
reproduction
study.
The
latter
finding
was
due
at
least
in
part
to
effects
on
lactation,
based
on
findings
of
inactive
mammary
glands
in
the
dams
at
necropsy.
These
fetal/
neonatal
effects
occurred
at
the
same
dose
levels
at
which
maternal
toxicity
(
decreased
weight
gain/
weight
loss)
were
observed.
It
is
likely
that
neonatal
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
although,
some
skeletal
variations
(
delayed
ossification,
asymmetric
pelvis)
were
reported.
There
was,
however,
no
evidence
(
qualitative
or
quantitative)
of
increased
susceptibility
in
the
developmental
rabbit
study
following
in
utero
exposure
or
in
the
two­
generation
reproduction
study
following
pre­
or
post­
natal
exposure.

No
neurotoxicity
studies
have
been
submitted
for
Oxadiazon.
However,
the
available
data
do
not
indicate
a
need
for
neurotoxicological
testing.
No
clinical
signs
of
toxicity
suggestive
of
neurobehavioral
alterations
nor
evidence
of
neuropathological
effects
were
observed
in
the
available
oral
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.

Based
on
pharmacokinetics/
metabolism
studies
in
the
rat,
low
doses
(
5
mg/
kg,
single
or
multiple)
of
Oxadiazon
were
completely
absorbed,
metabolized
and
excreted
in
the
urine
and
feces;
virtually
no
free
Oxadiazon
was
found
in
the
urine.
At
this
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
(
4)
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.
Only
conjugates
of
glucuronic
acid
were
present
in
urine;
there
was
no
evidence
of
sulphate
conjugates.
The
identified
glucuronides
were
those
of
metabolites
RP
29585
and
RP25496.
In
addition
to
5
fecal
metabolites,
intact
Oxadiazon
was
present
in
feces
Page
28
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.

7
DATA
GAPS
HIARC
has
requested
the
submission
of
a
28­
day
inhalation
study.

8
ACUTE
TOXICITY
Acute
Toxicity
of
Oxadiazon
Guideline
No.
Study
Type
MRIDs
#
Results
Toxicity
Category
870.1100/
[
81­
1]
Acute
Oral;
Rat
97.5
%
a.
i.
41866501
LD
50
=
>
5000
mg/
kg
(


,
combined)
IV
870.1200/
81­
2
Acute
Dermal;
Rabbit
97.5
%
a.
i.
41866502
LD
50
=
>
2000
mg/
kg
(


,
combined)
III
870.1300/
81­
3
Acute
Inhalation;
Rat
93.7
%
a.
i.
41866503
LC
50
=
>
1.94
mg/
L
(


,
combined)
III
870.2400/
81­
4
Primary
Eye
Irritation;
Rabbit
97.5
%
a.
i.
41866504
Mild
irritant
to
ocular
tissue
III
870.2500/
81­
5
Primary
Skin
Irritation;
Rabbit
97.5
%
a.
i.
41866505
Negligibly
irritating
to
skin
III
870.2600/
81­
6
Dermal
Sensitization;
Guinea
pig
93.7%
a.
i.
41230401
Not
a
dermal
sensitizer
(
Buehler
test)
­­

81­
8
Acute
Neurotoxicity
ND
9
SUMMARY
OF
TOXICOLOGY
ENDPOINT
SELECTION
The
doses
and
toxicological
endpoints
selected
for
various
exposure
scenarios
are
summarized
below.
Page
29
EXPOSURE
SCENARIO
DOSE
(
mg/
kg/
day)
ENDPOINT
STUDY
Acute
Dietary
NOAEL=
N/
A
UF
=
N/
A
This
risk
assessment
is
not
required
because
there
are
no
food
or
feed
uses
for
Oxadiazon
Chronic
Dietary
NOAEL
=
N/
A
UF
=
N/
A
This
risk
assessment
is
not
required
because
there
are
no
food
or
feed
uses
for
Oxadiazon
Cancer
Q
1*
of
1.4
x
10­
1
(
mg/
kg/
day)­
1in
human
equivalentsa
Group
C
"
possible
human
carcinogen",
based
on
liver
tumors
produced
in
two
of
the
three
positive
studies
(
one
mouse
study
and
one
rat
study)
at
doses
that
exceeded
the
maximum
tolerated
dose.
Combined
Chronic
Toxicity/
Carcinogenicity
Study
in
Rats
MRID
Nos.
00149003/
00157780;
Carcinogenicity
Study
in
Mice
MRID
Nos.
00115733
Incidental
Oral,
Short­
and
Intermediate­
Term
NOAEL=
12
Reduced
body
weight/
body
weight
gain
at
40
mg/
kg/
day
(
LOAEL).
Developmental
Toxicity
­
Rat
MRID
No.
40470202
Dermal,
Shortand
Intermediate­
Term
NOAEL=
12
Increased
fetal
resorptions/
postimplantation
loss,
decreased
fetal
weight
and
increased
incidence
of
incomplete
ossification
at
40
mg/
kg/
day
(
LOAEL)
b.
Developmental
Toxicity
­
Rat
MRID
No.
40470202
Page
30
EXPOSURE
DOSE
(
mg/
kg/
day)
ENDPOINT
STUDY
Dermal,
Long­
Term
NOAEL=
0.36
Increased
centrilobular
swelling
in
male
livers
at
3.5
mg/
kg/
day
(
LOAEL)
b.
Combined
Chronic
Feeding/
Oncogenicity
­
Rat
MRID
Nos.
40993401,
00149003/
00157780
Inhalation,
Short­
Term
NOAEL=
12
Reduced
body
weight/
body
weight
gain
at
40
mg/
kg/
day
(
LOAEL)
c
.
Developmental
Toxicity
­
Rat
MRID
No.
40470202
Inhalation,
Intermediate­
Term
NOAEL=
12
Reduced
body
weight/
body
weight
gain
at
40
mg/
kg/
day
(
LOAEL)
c
.
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)
c.
Combined
Chronic
Feeding/
Oncogenicity
­
Rat
MRID
Nos.
40993401,
00149003/
00157780
a
Q
1*
may
change
awaiting
the
outcome
of
the
CARC
revisit.
b
For
this
risk
assessment,
the
dermal
absorption
factor
of
9%
should
be
applied.
c
For
this
risk
assessment,
use
a
route­
to­
route
extrapolation
and
a
100%
absorption
rate
(
default
value).