HED
DOC.
NO.
014555
CANCER
ASSESSMENT
DOCUMENT
EVALUATION
OF
THE
CARCINOGENIC
POTENTIAL
OF
OXADIAZON
(
THIRD
REVIEW)

FINAL
REPORT
1­
MAY­
2001
CANCER
ASSESSMENT
REVIEW
COMMITTEE
HEALTH
EFFECTS
DIVISION
OFFICE
OF
PESTICIDE
PROGRAMS
Oxadiazon
(
3
rd
Review)
Cancer
Assessment
Document
Final
Report
ii
DATA
PRESENTATION:
Nancy
McCarroll,
Toxicologist
DOCUMENT
PREPARATION:
Sanjivani
Diwan,
Executive
Secretary
COMMITTEE
MEMBERS
IN
ATTENDANCE:
(
Signature
indicates
concurrence
with
the
assessment
unless
otherwise
stated).

Karl
Baetcke
William
Burnam
Kerry
Dearfield
Vicki
Dellarco
Yiannakis
Ioannou
Nancy
McCarroll
Esther
Rinde
Joycelyn
Stewart
Clark
Swentzel
Linda
Taylor
NON­
COMMITTEE
MEMBERS
IN
ATTENDANCE
(
Signature
indicates
concurrence
with
the
pathology
report
and
statistical
analysis
of
data,
respectively)

John
M.
Pletcher
Pathology
Consultant
Lori
Brunsman,
Statistical
Analysis
Veronique
LaCapra
CRM
(
SRRD)
Seyed
Tadayon
Chemist
(
Chem
and
Exposure)

_______________________________________________________________________________
Oxadiazon
(
3
rd
Review)
Cancer
Assessment
Document
Final
Report
iii
CONTENTS
Executive
Summary
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iv
I.
Introduction
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1
II.
Background
Information
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1
III.
Evaluation
of
Carcinogenicity
Evidence
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2
1.
Combined
Chronic
Toxicity/
Carcinogenicity
Study
in
Wistar
Rats
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2
2.
Combined
Chronic
Toxicity/
Carcinogenicity
Studies
in
ICR­
JCL
mice
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8
IV.
Other
Toxicology
Data
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13
1.
Mutagenicity
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13
2.
Structure
Activity
Relationships
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15
3.
Mode
of
Action
Studies.
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.17
V.
Committee's
Assessment
of
the
Weight­
of­
the
Evidence
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18
VI.
Classification
of
Carcinogenic
Potential
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19
VII.
Quantification
of
Carcinogenic
Potential.
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20
VIII.
Bibliography
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21
Oxadiazon
(
3
rd
Review)
Cancer
Assessment
Document
Final
Report
iv
EXECUTIVE
SUMMARY
On
March
7,
2001,
the
Cancer
Assessment
Review
Committee
(
CARC)
of
the
Health
Effects
Division
(
HED)
of
the
Office
of
Pesticide
Programs
met
to
reevaluate
the
carcinogenic
potential
of
oxadiazon.

In
the
original
carcinogenicity
assessment,
oxadiazon
was
classified
as
a
Group
B2,
probable
human
carcinogen,
based
on
the
increased
incidence
of
malignant
or
combined
benign
and
malignant
liver
tumors
in
multiple
species
(
CD
­
1
mice
and
F344
rats
of
one
or
both
sexes)
and
in
multiple
experiments
(
two
mouse
studies
and
one
rat
study
(
1984;
HED
Document
No.
004097).
On
September
3,
1986
during
the
2nd
meeting,
the
Toxicology
Branch
Peer
Review
Committee
reaffirmed
the
earlier
classification
of
oxadiazon
as
a
Group
B2
carcinogen
but
there
was
a
minority
opinion
that
the
agent
should
be
placed
in
Group
C,
possible
human
carcinogen
(
1987;
HED
Document
No.
007798).
Based
on
weight­
of­
the­
evidence
for
oxadiazon,
the
Scientific
Advisory
Panel
reiterated
the
minority
view
(
1987;
HED
Document
No.
007798).
Subsequently,
the
cancer
classification
for
oxadiazon
was
revised
to
a
Group
C
carcinogen
and
for
the
quantification
of
human
cancer
risk,
a
linear
low
dose
extrapolation
approach
was
recommended
(
1987;
HED
Document
No.
007798).
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).

At
the
March
7,
2001
CARC
meeting,
information/
data
previously
not
available
to
the
Peer
Review
Committee
were
considered
which
included
chronic
toxicity/
carcinogenicity
studies
in
Wistar
rats
and
ICR­
JCL
mice.
In
the
rat
study,
oxadiazon
was
administered
in
the
diet
to
groups
of
80
male
and
80
female
Wistar
rats
at
concentrations
of
0,
3,
10,
100
or
1000
ppm
(
0,
0.106,
0.36,
3.5
or
39
mg/
kg/
day
for
males
and
0,
0.131,
0.44,
4.2
or
44
mg/
kg/
day
for
females,
respectively)
for
up
to
104
weeks.
In
the
mouse
study,
oxadiazon
was
administered
to
groups
of
80
male
and
80
female
ICR­
JCL
mice
at
dietary
concentrations
of
0,
3,
10,
100
or
1000
ppm
(
0,
0.315,
1.09,
10.6
or
113
mg/
kg/
day
for
males
and
0,
0.278,
0.92,
9.3
or
99
mg/
kg/
day
for
females,
respectively)
for
98/
99
weeks.
The
Registrant
also
submitted
mechanistic
studies
to
support
the
proposed
mode
of
action
for
liver
tumor
induction
observed
in
these
studies.

The
CARC
concluded
that:

!
There
was
clear
evidence
that
oxadiazon
was
carcinogenic
to
male
Wistar
rats
because:
1)
There
were
statistically
significant
positive
trends
for
liver
adenomas,
carcinomas
and
combined
adenomas/
carcinomas.
There
was
a
statistically
significant
increase
by
pair­
wise
comparison
with
the
controls
for
liver
adenomas
and
combined
liver
adenomas/
carcinomas
at
100
and
1000
ppm
and
for
liver
carcinomas
at
1000
ppm
indicating
a
malignant
component
to
the
liver
tumors;
and
2)
The
incidences
of
liver
adenomas
at
100
ppm
and
1000
ppm
and
carcinomas
at
1000
ppm
were
outside
the
published
range
of
spontaneous
incidences
in
Wistar
rats
(
range:
adenomas,
0%­
2.5%;
carcinomas,
0%­
2.5%).
The
highest
dose
level
tested
in
this
study
was
considered
to
be
Oxadiazon
(
3
rd
Review)
Cancer
Assessment
Document
Final
Report
v
adequate
and
not
excessive
in
male
rats
because
there
were
decreases
in
body
weight
gains
and
the
clinical
and
histopathological
liver
changes
observed
were
not
severely
adverse.
The
survival
of
the
animals
was
not
affected
by
the
treatment.
There
was
a
statistically
significant
increasing
trend
for
liver
carcinomas
in
females
but
there
was
no
significant
increase
in
liver
tumors
in
treated
females
by
pair­
wise
comparisons
with
controls.
The
Committee
determined
that,
for
female
rats,
the
highest
dose
was
adequate
based
on
an
increased
incidence
of
chronic
nephropathy.
The
CARC
concluded
that
the
increased
incidence
of
liver
tumors
observed
in
the
male
rats
was
treatment­
related.

!
There
was
clear
evidence
that
oxadiazon
was
carcinogenic
to
male
and
female
ICRJCL
mice
because:
There
were
statistically
significant
positive
trends
for
liver
adenomas,
carcinomas
and
combined
adenomas/
carcinomas
in
both
sexes.
There
were
also
statistically
significant
increases
by
pair­
wise
comparison
of
the
dosed
groups
with
the
controls
for
liver
adenomas
and
carcinomas
as
well
as
for
combined
liver
adenomas/
carcinomas
at
100
and
1000
ppm
for
males
and
at
1000
ppm
for
females.
There
was
a
malignant
component
to
the
liver
tumors
in
both
sexes.
The
highest
dose
level
tested
was
considered
to
be
adequate
and
not
excessive
in
both
sexes
based
on
increased
liver
weights
and
histopathological
changes
in
the
liver
at
1000
ppm
which
were
not
severely
adverse.
The
Committee
concluded
that
there
were
treatment­
related
increases
in
both
benign
and
malignant
liver
tumors
in
male
and
female
mice.

The
positive
results
of
an
in
vitro
cell
transformation
assay
are
in
concordance
with
the
findings
of
in
vivo
rodent
bioassays.

!
A
battery
of
acceptable
mutagenicity
assays
indicated
that
oxadiazon
was
not
mutagenic.

!
The
mechanistic
studies
provide
insufficient
data
to
determine
whether
a
threshold
mechanism
exists
for
the
induction
of
liver
tumors
observed
in
rats
and
mice.
Nevertheless,
the
formation
of
brown
pigment
in
the
liver
and
kidneys
of
rats
and
mice
is
consistent
with
the
known
inhibitory
action
of
oxadiazon
toward
protoporphyrinogen
oxidase,
a
critical
enzyme
in
chlorophyll
and
heme
biosynthesis.

In
accordance
with
the
EPA
Draft
Guidelines
for
Carcinogen
Risk
Assessment
(
July,
1999),
the
CARC
classified
oxadiazon
into
the
category
"
Likely
to
be
carcinogenic
to
humans"
based
on
the
following
weight­
of­
the­
evidence
considerations:

1.
Treatment­
related
benign
and
malignant
liver
tumors
were
observed
in
two
species.
There
was
clear
evidence
that
oxadiazon
induced
a
statistically
significant
increase
in
liver
tumors
in
male
Wistar
rats
and
male
and
female
ICR­
JCL
mice.
The
findings
of
liver
tumors
are
consistent
with
the
results
of
earlier
studies
in
male
F­
344
rats
and
male
and
female
CD
mice.
The
positive
results
from
an
in
vitro
cell
transformation
assay
are
in
concordance
with
the
results
of
in
vivo
rodent
bioassays.

2.
Oxadiazon
was
not
mutagenic.
However,
it
causes
cell
transformation
in
vitro;
these
results
are
in
concordance
with
the
carcinogenicity
seen
in
in
vivo
rodent
studies.
Oxadiazon
(
3
rd
Review)
Cancer
Assessment
Document
Final
Report
vi
The
Committee
recommended
a
low
dose
linear
extrapolation
approach
for
the
quantification
of
human
cancer
risk
based
on
the
most
potent
liver
tumors
in
rats
and
mice.
This
approach
is
supported
by
the
inadequacy
of
data
on
the
mode
of
action
for
oxadiazon­
induced
liver
tumors
in
rodents.
Oxadiazon
(
3
rd
Review)
Cancer
Assessment
Document
Final
Report
1
I.
INTRODUCTION
According
to
the
original
carcinogenicity
assessment
for
oxadiazon,
the
pesticide
was
ranked
as
a
Group
B2,
probable
human
carcinogen
(
1984;
HED
Document
No.
004097).
The
rationale
for
the
classification,
Group
B2,
was
based
on
the
increased
incidence
of
malignant
or
combined
malignant
and
benign
liver
tumors
in
multiple
species
(
CD
­
1
mice
and
F344
rats
of
one
or
both
sexes)
and
in
multiple
experiments
(
two
mouse
studies
and
one
rat
study).
The
Toxicology
Branch
Peer
Review
of
this
agent
was
later
held
on
September
3,
1986
and
the
Committee
affirmed
the
earlier
classification
of
oxadiazon
as
a
Group
B2
carcinogen
but
there
was
a
minority
opinion
that
the
agent
should
be
placed
in
Group
C,
possible
human
carcinogen
(
1987;
HED
Document
No.
007798).
Review
of
the
weight­
of­
the­
evidence
on
oxadiazon
by
the
Scientific
Advisory
Panel
reiterated
this
minority
view
(
1987;
HED
Document
No.
007798).
At
that
time,
the
Agency's
decision
on
the
carcinogenic
potential
of
oxadiazon
concurred
with
the
Scientific
Advisory
Panel's
(
SAP)
classification
of
oxadiazon
as
a
Group
C
carcinogen
(
1987;
HED
Document
No.
007798).
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).
For
the
quantification
of
human
cancer
risk
a
linear
low
dose
extrapolation
approach
was
recommended
(
Q1*=
1.4
x
10­
1(
mg/
kg/
day)­
1
).

On
March
7,
2001,
the
Cancer
Assessment
Review
Committee
(
CARC)
met
to
reconsider
the
carcinogenicity
classification
of
oxadiazon
under
the
draft
Agency
Cancer
Risk
Assessment
Guidelines
(
1999)
for
the
human
cancer
risk
assessment.
At
this
meeting,
information/
data
previously
not
available
or
relevant
to
this
review
were
presented
by
Nancy
McCarroll
of
the
Toxicology
Branch.
These
include
a
chronic/
carcinogenicity
toxicity
study
in
Wistar
rats
(
MRID
No.
40993401),
a
carcinogenicity
study
in
ICR­
JCL
mice
(
MRID
No.
40993301),
genetic
toxicology
as
well
as
mechanistic
studies
and
data
on
structurally­
related
compounds.
Based
on
the
available
studies,
the
quantitative
risk
to
humans
was
also
evaluated.

II.
BACKGROUND
INFORMATION
Oxadiazon
(
P.
C.
Code:
109001,
CAS
Number:
19666­
30­
9,
5­
tert­
butyl­
4­(
2,4­
dichloro­
5­
isopropoxyphenyl)­
1,3,4­
oxadiazol­
2­
one),
also
known
as
Ronstar,
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.
It
has
no
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.
Oxadiazon
destroys
cell
membranes
and
inhibits
photosynthesis,
probably
by
generating
oxidizing
radicals
in
the
presence
of
light
and
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
(
3
rd
Review)
Cancer
Assessment
Document
Final
Report
2
.
Figure
1.
Chemical
Structure
of
Oxadiazon
III.
EVALUATION
OF
CARCINOGENICITY
AND
OTHER
EVIDENCE
4.
Previous
Chronic
Toxicity/
Carcinogenicity
Studies
Earlier
tumor
data
for
Oxadiazon
in
F­
344
rats
and
CD­
1
mice
were
discussed
previously
(
HED
Document
NO.
007798,
dated
August
27,
1987)
and
are
not
reiterated
here.

2.
Combined
Chronic
Toxicity/
Carcinogenicity
Study
in
Wistar
Rats
Reference
Y.
Shirasu
(
1987).
Oxadiazon
­
24
Month
Chronic
Toxicity
and
Carcinogenicity
Study
in
Rats.
Institute
of
Environmental
Toxicology,
Tokyo,
Japan;
Study
No.
Not
listed;
Report
dated
February
1987.
(
Unpublished)
MRID:
40993401
A.
Experimental
Design
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.
All
80
rats/
sex/
dose
were
reportedly
examined
for
histopathology.

B.
Discussion
of
Tumor
Data
Oxadiazon
(
3
rd
Review)
Cancer
Assessment
Document
Final
Report
3
The
incidences
of
liver
tumors
in
male
and
female
rats
are
presented
in
Tables
1
and
2,
respectively.
For
males,
there
were
statistically
significant
(
p<
0.01)
increasing
trends
for
liver
adenomas,
carcinomas
and
combined
adenomas/
carcinomas
(
Table
1).
There
were
also
significant
increases
in
the
pair­
wise
comparisons
with
the
controls
for
liver
adenomas
at
100
ppm
(
p<
0.05)
and
1000
ppm
(
p<
0.01),
carcinomas
at
1000
ppm
(
p<
0.05)
and
combined
adenomas/
carcinomas
at
100
ppm
(
p<
0.05)
and
1000
ppm
(
p<
0.01).
For
female
rats,
there
was
a
statistically
significant
increasing
trend
(
p<
0.05)
for
liver
carcinomas
only
and
no
significant
increases
in
pair­
wise
comparisons
of
the
treated
groups
with
the
controls
were
noted
for
liver
adenomas,
carcinomas
and
combined
adenomas/
carcinomas
(
Table
2).

Historical
control
data
were
not
provided
by
the
performing
laboratory;
however,
the
spontaneous
incidences
of
liver
tumors
in
Wistar
rats
reported
by
Welsh
and
Poteracki
(
1994)
are
as
follows:
males­­
adenomas:
1.02%,
range
0­
2.5%;
carcinomas:
0.88%,
range
0­
2.5%;
females­
adenomas:
2.34%,
range
0­
12%;
carcinomas:
0.88%,
range
0­
10%.
The
incidences
of
adenomas
at
100
and
1000
ppm
(
9%
and
13%
,
respectively)
and
carcinomas
(
10%)
at
1000
ppm
in
males
exceeded
the
range
of
available
spontaneous
incidences.
The
incidences
of
liver
carcinomas
(
4%)
in
females
did
not
exceed
the
range
of
available
spontaneous
incidences.
The
Committee
concluded
that
the
increase
in
liver
tumors
in
male
rats
was
treatment
related.

C.
Non­
neoplastic
Lesions
In
1991,
the
Agency
requested
the
Registrant
to
provide
new
pathology
summary
tables
and
indicate
the
exact
number
of
each
tissue
that
was
examined
(
HED
Document
No.
008949)
because
the
exact
number
of
tissues/
organs
examined
could
not
be
verified
by
the
Reviewers.
No
correspondence
regarding
this
request
has
been
presented
to
HED.
However,
the
recent
review
of
data
by
the
HED
statistician
indicated
that
none
of
the
animals
were
excluded
from
the
analyses.
Therefore,
the
Committee
concluded
that
the
integrity
of
the
study
or
the
interpretation
of
the
results
is
not
compromised
by
this
data
deficiency.

The
histopatholgical
examination
revealed
increases
in
non­
neoplastic
changes
in
the
liver
at
1000
ppm.
These
included:
centrilobular
liver
swelling
(

and

)
;
acidophilic
foci
of
cellular
alteration
(

)
;
and
brown
pigmentation
in
the
Stellate
cells
(

and

)
(
Table
3).
At
100
ppm,
a
significant
(
p<
0.05)
increase
in
the
number
of
males
with
centrilobular
liver
swelling
was
seen.
Brown
pigmentation
in
the
proximal
tubular
cells
(

and

)
and
in
cortical
interstitial
tissue
(

)
as
well
as
chronic
nephropathy
(

)
were
also
noted
in
the
kidneys
of
high­
dose
rats.
Oxadiazon
(
3
rd
Review)
Cancer
Assessment
Document
Final
Report
4
Table
1.
Oxadiazon
­
SPF
Wistar
Rat
Study
Male
Liver
Tumor
Rates+
and
Exact
Trend
Test
and
Fisher's
Exact
Test
Results
(
p
values)­
(
Brunsman,
2001)

Dose
(
ppm)

0
3
10
100
1000
Adenomas
(%)

p
=
0/
53
(
0)

0.001**
1/
55
(
2)

0.509
1/
54
(
2)

0.505
5a/
54
(
9)

0.030*
7a
/
52
(
13)

0.006**

Carcinomas
(%)

p=
0/
53
(
0)

0.000**
0/
55
(
0)

1.000
0/
54
(
0)

1.000
0/
54
(
0)

1.000
5b/
52
(
10)

0.027*

Combined
(%)

p
=
0/
53
(
0)

0.000**
1/
55
(
2)

0.509
1/
54
(
2)

0.505
5/
54
(
9)

0.030*
12/
52
(
23)

0.000**
+
Number
of
tumor
bearing
animals/
Number
of
animals
examined,
excluding
those
that
died
or
were
sacrificed
before
week
53.
a
First
adenoma
observed
simultaneously
at
week
78
in
interim
sacrifice
animals,
doses
100
and
1000
ppm.
b
First
carcinoma
observed
at
week
78
in
an
interim
sacrifice
animal,
dose
1000
ppm.

Note:
26­
and
56­
week
interim
sacrifice
animals
are
not
included
in
this
analysis.
There
were
no
liver
tumors
in
any
interim
sacrifice
animals
at
26
or
52
weeks.

Significance
of
trend
denoted
at
control.

Significance
of
pair­
wise
comparison
with
control
denoted
at
dose
level.

If
*,
then
p
<
0.05.

If
**,
then
p
<
0.01.
Oxadiazon
(
3
rd
Review)
Cancer
Assessment
Document
Final
Report
5
Table
2.
Oxadiazon
­
SPF
Wistar
Rat
Study:

Female
Liver
Tumor
Rates+
and
Exact
Trend
Test
and
Fisher's
Exact
Test
Results
(
p
values)­
(
Brunsman,
2001)

Dose
(
ppm)

0
3
10
100
1000
Adenomas
(%)

p
=
1a/
52
(
2)

0.550
1/
52
(
2)

0.752
1/
55
(
2)

0.738
1/
53
(
2)

0.748
1/
55
(
2)

0.738
Carcinomas
(%)

p=
0/
52
(
0)

0.042*
0/
52
(
0)

1.000
0/
55
(
0)

1.000
0/
53
(
0)

1.000
2b/
55
(
4)

0.262
Combined
(%)

p
=
1/
52
(
2)

0.098
1/
52
(
2)

0.752
1/
55
(
2)

0.738
1/
53
(
2)

0.748
3/
55
(
5)

0.330
+
Number
of
tumor
bearing
animals/
Number
of
animals
examined,
excluding
those
that
died
or
were
sacrificed
before
week
53.
a
First
adenoma
observed
at
week
103,
dose
0
ppm.
b
First
carcinoma
observed
at
week
104,
dose
1000
ppm
Note:
26
­
and
52­
week
interim
sacrifice
animals
are
not
included
in
this
analysis.
There
were
no
liver
tumors
in
any
in
terim
sacrifice
animals
at
26
and
56
weeks.
Significance
of
trend
denoted
at
control.

Significance
of
pair­
wise
comparison
with
control
denoted
at
dose
level.

If
*,
then
p
<
0.05.

If
**,
then
p
<
0.01.

Table
3.
Non­
neoplastic
Lesions
in
the
Liver
of
Wistar
Rats
Fed
Dietary
Administrations
of
Oxadiazon
for
104
Weeks
Oxadiazon
(
3
rd
Review)
Cancer
Assessment
Document
Final
Report
6
Lesions
of
the
Liver
Malesa
Group
(
ppm)
Femalesa
Group
(
ppm)

0
3
10
100
1000
0
3
10
100
1000
Centrilobular
hepatocellular
Swelling
1
2
1
8*
52*
3
2
1
9
33**

Foci
of
Cellular
Alteration
(
acidophilic)
9
14
14
9
18*
12
10
8
14
9
Brown
Pigmentation
of
Stellate
Cells
0
0
0
1
35***
4
1
4
1
12**

Focal
Hepatocellular
Fatty
Change
3
7
7
10*
8
9
10
3
8
5
a
80
animals/
sex
were
reportedly
examined
at
each
dose
level.
*
Significantly
different
(
p<
0.05)
than
the
vehicle
control
by
Fisher's
Exact
Test.
**
Significantly
different
(
p<
0.01)
than
the
vehicle
control
by
Fisher's
Exact
Test.
***
Significantly
different
(
p<
0.001)
than
the
vehicle
control
by
Fisher's
Exact
Test.

Selected
non­
neoplastic
changes
in
the
kidney,
which
were
considered
to
be
treatment­
related,
are
shown
in
Table
4.
At
1000
ppm,
these
included:
brown
pigmentation
in
the
proximal
tubular
cells
(
p<
0.001,


)
,
brown
pigmentation
in
the
cortical
interstitial
tissue
(
p<
0.001,

)
,
and
chronic
nephropathy
(
p<
0.01,

)
.
At
lower
doses,
non­
neoplastic
lesions
were
comparable
to
the
vehicle
control
values.

Table
4.
Non­
neoplastic
Lesions
in
the
Kidneys
of
Wistar
Rats
Fed
Dietary
Administrations
of
Oxadiazon
for
104
Weeks
Oxadiazon
(
3
rd
Review)
Cancer
Assessment
Document
Final
Report
7
Lesions
of
the
Kidneys
Malesa
Group
(
ppm)
Femalesa
Group
(
ppm)

0
3
10
100
1000
0
3
10
100
1000
Brown
Pigmentation
in
Proximal
Tubular
Cells
3
4
1
2
50***
6
5
8
13
20***

Brown
Pigmentation
in
Cortical
Interstitial
Tissue
2
0
0
1
49***
0
0
1
1
2
Chronic
Nephropathy
28
28
33
36
37
11
16
15
14
26**

a
80
animals/
sex
were
reportedly
examined
at
each
dose
level.
*
Significantly
different
(
p<
0.05)
than
the
vehicle
control
by
Fisher's
Exact
Test.
**
Significantly
different
(
p<
0.01)
than
the
vehicle
control
by
Fisher's
Exact
Test.
***
Significantly
different
(
p<
0.001)
than
the
vehicle
control
by
Fisher's
Exact
Test
C.
Adequacy
of
Dosing
for
Assessment
of
Carcinogenic
Potential
Statistical
evaluation
of
mortality
indicated
no
significant
incremental
changes
with
increasing
doses
of
oxadiazon
in
the
male
and
female
rats
(
Brunsman,
2001).
The
dosing
at
the
highest
dose
(
1000
ppm)
was
considered
to
be
adequate
and
not
excessive
in
male
rats
based
on
decreased
body
weight
gain
(
generally
throughout
the
study),
signs
of
transient
anemia
(
evident
at
week
26),
increased
serum
enzyme
activity
(
LDH


63%;
ALP

245%;
SGOT

151%;
SGPT

646%),
increased
bilirubin
and
increased
liver
and
kidney
weights
with
associated
pathological
changes
at
1000
ppm
which
were
not
severely
adverse
(
Refer
to
Table
3
for
details).

For
females
at
1000
ppm,
there
was
a
decrease
in
the
terminal
body
weight
(­
8.9%).
However,
the
findings
were
confounded
by
apparently
fairly
large
standard
deviations.
With
the
exception
of
decreased
terminal
body
weight,
there
were
no
significant
differences
from
controls
in
body
weight
measurements.
Significant
increases
in
liver
and
kidney
weights
were
seen
only
at
week
26
and
78
(
kidney
only).
While
increases
in
liver
weight
and
findings
of
liver
pathology
were
reported
for
females
at
1000
ppm,
these
effects
were
either
less
consistent
or
occurred
less
frequently
than
those
observed
in
males
at
this
level.
Other
findings
(
anemia,
increased
serum
enzymes
and
pathological
change
such
as
foci
of
cellular
alteration)
showing
evidence
of
toxicity,
which
were
generally
confined
to
the
high
dose
were
not
noted
in
females.
However,
there
was
a
significant
increase
in
the
incidence
of
chronic
nephropathy
among
high
dose
females.
The
Committee,
therefore,
concluded
that
the
highest
dose
tested
in
female
rats
was
adequate
to
assess
the
carcinogenic
potential
of
oxadiazon.
Oxadiazon
(
3
rd
Review)
Cancer
Assessment
Document
Final
Report
8
2.
Combined
Chronic
Toxicity/
Carcinogenicity
Study
in
ICR­
JCL
Mice
Reference
Y.
Shirasu
(
1987).
Oxadiazon­
23
Month
Chronic
Toxicity
and
Oncogenicity
Study
in
Mice.
Institute
of
Environmental
Toxicology,
Tokyo,
Japan;
Study
No.
Not
listed;
Report
dated
February
1987.
(
Unpublished)
MRID:
40993301
A.
Experimental
Design
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).
Groups
of
9­
10
mice/
sex/
group
were
sacrificed
at
weeks
52
were
subjected
to
pathology
analysis.

B.
Discussion
of
Tumor
Data
The
incidences
of
liver
tumors
in
male
and
female
mice
are
presented
in
Table
5
and
6,
respectively.
For
male
mice,
statistically
significant
increasing
trends
(
p<
0.01)
were
observed
for
liver
adenomas,
carcinomas
and
combined
adenomas/
carcinomas
(
Table
5).
There
were
also
significant
increases
by
pair­
wise
comparisons
of
the
100
and
1000
ppm
dose
groups
with
the
controls
for
liver
adenomas,
combined
adenomas/
carcinomas
(
both
at
p
<
0.01)
and
carcinomas
(
p
<
0.05
and
p<
0.01,
respectively).
No
significant
increases
were
noted
at
lower
doses
(
3
or
10
ppm).
For
female
mice,
statistically
significant
increasing
trends
(
p<
0.01)
were
noted
for
liver
adenomas,
carcinomas
and
combined
adenomas/
carcinomas
(
Table
6).
There
were
statistically
significant
increases
by
pair­
wise
comparison
of
the
1000
ppm
dose
group
with
the
controls
for
adenomas
(
p<
0.01),
carcinomas
(
p
<
0.05)
and
combined
adenomas/
carcinomas
(
p
<
0.01).
Historical
control
data
were
not
provided
by
the
performing
laboratory.

Table
5.
Oxadiazon
­
ICR­
JCL
Mouse
Study:

Male
Liver
Tumor
Rates+
and
Exact
Trend
Test
and
Fisher's
Exact
Test
Results
(
p
values)­
(
Brunsman,
2001)
Oxadiazon
(
3
rd
Review)
Cancer
Assessment
Document
Final
Report
9
Dose
(
ppm)

0
3
10
100
1000
Adenomas
(%)

p
=
2/
69
(
3)

0.000**
7/
71
(
10)

0.090
2/
71
(
3)

0.676
12/
69
(
17)

0.005**
16a/
71
(
23)

0.000**

Carcinomas
(%)

p=
3/
69
(
4)

0.000**
1/
71
(
1)

0.299
4/
71
(
6)

0.516
11/
69
(
16)

0.023*
29b/
71
(
41)

0.000**

Combined
(%)

p
=
5/
69
(
7)

0.000**
8/
71
(
11)

0.300
6/
71
(
8)

0.520
23/
69
(
33)

0.000**
45/
71
(
63)

0.000**
+
Number
of
tumor
bearing
animals/
Number
of
animals
examined,
excluding
those
that
died
before
week
46.
a
First
adenoma
observed
at
week
52
in
an
interim
sacrifice
animal,
dose
1000
ppm.
b
First
carcinoma
observed
at
week
46,
dose
1000
ppm.

Note:
Significance
of
trend
denoted
at
control.

Significance
of
pair­
wise
comparison
with
control
denoted
at
dose
level.

If
*,
then
p
<
0.05.
If
**,
then
p
<
0.01.
Oxadiazon
(
3
rd
Review)
Cancer
Assessment
Document
Final
Report
10
Table
6.
Oxadiazon
­
ICR­
JCL
Mouse
Study:
Female
Liver
Tumor
Rates+
and
Exact
Trend
Test
and
Fisher's
Exact
Test
Results
(
p
values)­
(
Brunsman,
2001)

Dose
(
ppm)

0
3
10
100
1000
Adenomas
(%)

p
=
0/
52
(
0)

0.000**
0/
53
(
0)

1.000
1a/
46
(
2)

0.469
1a/
48
(
2)

0.480
8a/
51
(
16)

0.003**

Carcinomas
(%)

p=
1/
52
(
2)

0.000**
0/
53
(
0)

0.495
0/
46
(
0)

0.531
1/
48
(
2)

0.732
7b/
51
(
14)

0.028*

Combined
(%)

p
=
1/
53
(
2)

0.000**
0/
53
(
0)

0.495
1/
46
(
2)

0.721
2/
48
(
4)

0.470
15/
51
(
29)

0.000**
+
Number
of
tumor
bearing
animals/
Number
of
animals
examined,
excluding
those
that
died
or
were
sacrificed
before
week
53.
a
First
adenoma
observed
at
week
99
in
final
sacrifice
animal
simultaneously
in
doses
of
10,
100
and
1000
ppm.
b
First
carcinoma
observed
at
week
83,
dose
1000
ppm.

Note:
Interim
sacrifice
animals
are
not
included
in
this
analysis.
There
were
no
liver
tumors
in
any
interim
sacrifice
animals.

Significance
of
trend
denoted
at
control.

Significance
of
pair­
wise
comparison
with
control
denoted
at
dose
level.

If
*,
then
p
<
0.05.
If
**,
then
p
<
0.01.
Oxadiazon
(
3
rd
Review)
Cancer
Assessment
Document
Final
Report
11
In
addition
to
liver
tumors
in
females,
a
significant
(
p<
0.05)
increase
by
pair­
wise
comparison
of
the
1000
ppm
dose
group
with
the
controls
was
noted
for
malignant
lymphoma
(
Table
7);
however,
no
dose­
response
was
evident.
The
Committee
concluded
that
these
tumors
were
not
treatment­
related
because
there
was
no
dose­
response,
the
tumor
response
was
variable
and
these
tumors
were
not
seen
in
the
male
mice.
In
addition,
these
tumors
were
also
not
reported
in
the
previously
performed
mouse
carcinogenicity
and
rat
chronic/
carcinogenicity
studies
with
oxadiazon.
The
historical
control
data
were
not
available
for
comparison.

Table
7.
Oxadiazon
­
ICR­
JCL
Mouse
Study:
Female
Lymphoma
Tumor
Rates+
and
Exact
Trend
Test
and
Fisher's
Exact
Test
Results
(
p
values)­
(
Brunsman,
2001)

Dose
(
ppm)

0
3
10
100
1000
Malignant
Lymphoma
(%)

p
=
16/
80
(
20)

0.067
25/
79
(
32)

0.067
19/
80
(
24)

0.351
21a/
80
(
26)

0.227
27/
80
(
34)

0.037*

+
Number
of
tumor
bearing
animals/
Number
of
animals
examined,
excluding
those
that
died
before
week
19.
a
First
malignant
lymphoma
observed
at
week
19,
dose
100
ppm.
Significance
of
trend
denoted
at
control.
Significance
of
pair­
wise
comparison
with
control
denoted
at
dose
level.
If
*,
then
p
<
0.05.
If
**,
then
p
<
0.01.

C.
Non­
neoplastic
Lesions:

In
1991,
the
Agency
requested
the
Registrant
to
provide
new
pathology
summary
tables
and
indicate
the
exact
number
of
each
tissue
that
was
examined
(
HED
Document
No.
008949)
because
the
exact
number
of
tissues/
organs
examined
could
not
be
verified
by
the
Reviewers.
No
correspondence
regarding
this
request
has
been
presented
to
HED.
However,
the
recent
review
of
data
by
the
HED
statistician
indicated
that
none
of
the
animals
were
excluded
from
the
analyses.
Therefore,
the
Committee
concluded
that
the
integrity
of
the
study
or
the
interpretation
of
the
results
is
not
compromised
by
this
data
deficiency.
Oxadiazon
(
3
rd
Review)
Cancer
Assessment
Document
Final
Report
12
The
non­
neoplastic
changes
in
the
liver
observed
in
male
and
female
mice
are
listed
in
Table
8.
At
1000
ppm,
there
was
a
significant
increase
in
the
incidence
of
centrilobular
liver
swelling
(
p<
0.001

)
,
diffuse
liver
swelling
(
p<
0.001

and

)
,
brown
pigment
disposition
(
p<
0.001

and

)
,
and
bile
duct
proliferation
(
p<
0.001

)
.
The
incidence
of
diffuse
liver
swelling
and
brown
pigment
disposition
was
also
significantly
increased
at
100
ppm
(
p<
0.001)
but
only
in
the
males.
The
formation
of
brown
pigment
in
the
liver
and
kidneys
of
male
mice
is
consistent
with
the
inhibition
of
porphyrin
biosynthesis
by
oxadiazon.

Other
treatment­
related
findings
included
a
significant
increase
in
the
incidence
of
auricular
hardening
or
thrombus
in
the
heart
of
high­
dose
males
(
p<
0.05)
and
a
significant
(
p<
0.001)
increase
in
brown
pigment
disposition
in
the
proximal
tubules
of
high­
dose
male
kidneys.

Table
8.
Non­
neoplastic
Lesions
in
the
Liver
of
ICR­
JCL
Mice
Fed
Dietary
Administrations
of
Oxadiazon
for
98­
98
Weeks
Lesions
of
the
Liver
Malesa
Group
(
ppm)
Femalesa
Group
(
ppm)

0
3
10
100
1000
0
3
10
100
1000
Centrilobular
Hepatocellular
Swelling
1
1
0
3
2
1
0
1
1
14***

Diffuse
Hepatocellular
Swelling
1
2
5
45***
67***
3
5
1
2
24***

Brown
Pigmentation
Disposition
4
3
5
47***
59***
0
1
0
3
35***

Extra
medullary
Hematopoiesis
1
2
6
1
0
13
10
7
6
4*

Diffuse
Hepatocellular
Necrosis
1
2
4
16***
7*
0
0
0
0
0
Bile
Duct
Proliferation
0
0
0
1
15***
0
0
0
0
0
a
80
animals/
sex
were
reportedly
examined
at
each
dose
level.
*
Significantly
different
(
p<
0.05)
than
the
vehicle
control
by
Fisher's
Exact
Test.
**
Significantly
different
(
p<
0.01)
than
the
vehicle
control
by
Fisher's
Exact
Test.
***
Significantly
different
(
p<
0.001)
than
the
vehicle
control
by
Fisher's
Exact
Test.
Oxadiazon
(
3
rd
Review)
Cancer
Assessment
Document
Final
Report
13
D.
Adequacy
of
Dosing
for
Assessment
of
Carcinogenic
Potential
Statistical
evaluation
of
mortality
indicated
no
significant
incremental
changes
with
increasing
doses
of
oxadiazon
in
the
male
and
female
rats
(
Brunsman,
2001).
The
CARC
considered
the
dosing
to
be
adequate
and
not
excessive
in
males
and
females
based
on
anemia
and
pathological
changes
in
the
liver
at
the
highest
dose
tested
(
HDT)
which
were
not
severely
adverse
(
Refer
to
Table
8
for
details).
The
treatment
related
effects
observed
at
1000
ppm
(
HDT)
included
transient
anemia
(
evident
at
week
52)
in
males
and
females,
increased
serum
enzymes
(
SGPT
(

275­
300%)
,
SGOT
(

117%),
ALP
(

325%)
and
BUN
(

44%)
(

and

)
and
at
100
ppm:
increased
SGPT
(

147%)
(

)
),
increased
liver
weights
(
absolute
and
relative)
in
males
at
week
52
and
98
and
in
females
at
week
98
and
increased
absolute
and
relative
adrenal
(

­­
week
98)
and
kidney
(

­­
week
98)
weights.

IV.
OTHER
TOXICOLOGY
DATA
A.
Mutagenicity
and
Cell
Transformation
Overall,
the
data
indicate
that
oxadiazon
is
not
mutagenic
but
does
cause
neoplastic
cell
transformation
in
vitro
in
Syrian
hamster
kidney
BHK21
C13/
HRC1
cells.
Nine
acceptable
mutagenicity
studies
were
available
for
review.
These
studies
satisfy
the
pre­
1991
FIFRA
guideline
requirements
.
The
summaries
of
these
studies
are
presented
below:

GENE
MUTATION
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
(
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
(
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
(
MRID
No.
00115726).
Oxadiazon
(
3
rd
Review)
Cancer
Assessment
Document
Final
Report
14
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;
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)
(
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;
MRID
00115728).

OTHER
MUTAGENIC
MECHANISMS
g)
Unscheduled
DNA
Synthesis(
UDS)
in
primary
rat
hepatocytes
assay:
The
test
was
negative
in
hepatocytes
exposed
to
oxadiazon
(
95.5%
a.
i.)
to
cytotoxic
concentrations
(

100
µ
g/
mL)
and
the
limit
of
solubility
(

50
µ
g/
mL)
(
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)
(
MRID
No.
00115723).

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,
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).
Oxadiazon
(
3
rd
Review)
Cancer
Assessment
Document
Final
Report
15
2.
Conclusions
Acceptable
bacterial
assays
with

97.49%
oxadiazon
were
negative
for
gene
mutations
in
Salmonella
typhimurium
and
Escherichia
coli
(
MRID
Nos.
00069893
and
41871701).
Similarly,
neither
95.5%
oxadiazon
nor
recrystallized
Oxadiazon
(
100%)
were
mutagenic
or
clastogenic
in
cultured
mammalian
cells
(
MRID
Nos.
00115726,
00115729,
00115728
and
00115730)
and
did
not
cause
UDS
in
primary
rat
hepatocytes
(
MRID
Nos.
00115727
and
00115723).
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
(
MRID
No.
00115703).
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.

B.
Structural
Activity
Relationships
The
two
structurally
related
compounds,
azafenidin
and
sulfentrazone,
are
nonmutagenic
and
are
not
hepatocarcinogens
in
rats
or
mice.

Oxadiazon
belongs
to
the
class
of
oxadiazoles.
While
oxadiazon
is
only
somewhat
similar
in
structure
to
other
pesticides
that
have
a
chlorinated
phenol
ring
and
a
heterocyclic
ring
(
Figure
2),
it
shares
some
biological
properties
with
azafenidin
and
sulfentrazone
(
i.
e.,
inhibition
of
protoporphyrinogen
oxidase
and/
or
adverse
effects
on
the
hematopoietic
system
and
the
liver
of
rodents).
Sulfentrazone
produced
equivocal
results
in
the
mouse
lymphoma
forward
mutation
assay,
was
not
mutagenic
in
Salmonella
and
was
neither
clastogenic
nor
aneugenic
in
vivo.
There
was
also
no
evidence
of
a
carcinogenic
effect
in
2­
year
bioassays
in
rats
and
mice
(
EPA,
1999).
Azafenidin
was
not
mutagenic
in
the
available
studies.
The
CARC
agreed
that
the
consensus
classification
for
male
rat
thyroid
tumors
seen
following
administration
of
azafenidin
should
be
in
"
Data
are
inadequate"
category
but
no
additional
cancer
studies
were
considered
necessary
nor
would
there
be
any
quantification
of
human
cancer
risk.(
CARC,
1999;
HED
Doc
#
013794).

Figure
2.
Structural
Activity
Relationships:
Oxadiazon
and
Related
Structures
Oxadiazon
(
3
rd
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Assessment
Document
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16
N
N
O
O
Cl
Cl
O
CH
3
CH
3
CH
3
C
H
3
CH
3
N
N
O
Cl
Cl
O
N
CH
N
N
O
Cl
Cl
O
N
CH
Oxadiazon
Azafenidin
Sulfentrazone
Oxadiazon
(
3
rd
Review)
Cancer
Assessment
Document
Final
Report
17
N
N
O
Cl
Cl
NH
N
CH
3
S
O
O
CH
3
F
F
C.
Mode
of
Action
Studies
The
Mechanism
of
Toxicity
Assessment
Review
Committee
(
MTARC)
determined
that
the
available
information
does
not
support
the
proposed
non­
genotoxic
mode
of
action
for
oxadiazon­
induced
liver
tumors
in
rodents
(
McCarroll,
2001).

The
mechanistic
studies
including
an
unpublished
study
in
Sprague
Dawley
rats
(
MRID
No.
42310001)
and
a
published
study
by
Richert
et
al.,
1996
in
Sprague
Dawley
rats,
CD­
1
mice
and
Beagle
dogs
were
presented
to
the
MTARC
on
February
8,
2001.
The
committee
concluded
that
peroxisome
proliferation
may
be
a
possible
mode
of
action
for
oxadiazon­
induced
liver
tumors
in
rats
and
mice.
However,
there
are
deficiencies
in
the
database
which
include
lack
of
cell
proliferation
data
in
rat
and
mouse
studies,
lack
of
concordance
between
the
dose
response
for
peroxisomal
enzymatic
activity
and
liver
tumor
induction,
and
decrease
rather
than
increase
in
catalase
activity.
Therefore,
the
available
information
is
inadequate
to
determine
the
mode
of
action
for
oxadiazon­
induced
liver
tumors
in
rodents.

V.
COMMITTEE'S
ASSESSMENT
OF
THE
WEIGHT­
OF­
THE­
EVIDENCE
1.
Carcinogenicity
The
CARC
concluded
that:
Oxadiazon
(
3
rd
Review)
Cancer
Assessment
Document
Final
Report
18
!
In
the
combined
chronic
toxicity/
carcinogenicity
study
in
Wistar
rats,
there
was
clear
evidence
that
oxadiazon
was
carcinogenic
to
male
rats
because:
1)
There
were
statistically
significant
(
p<
0.01)
positive
trends
for
liver
adenomas,
carcinomas
and
combined
adenomas/
adenocarcinomas.
There
was
also
a
statistically
significant
(
p<
0.05
or
p<
0.01)
increase
by
pair­
wise
comparisons
of
the
100
and
1000
ppm
(
3.5
and
39
mg/
kg/
day,
respectively)
dose
groups
with
the
controls
for
liver
adenomas
(
9%
and
13%
,
respectively,
vs
0%
in
controls)
and
combined
adenomas/
carcinomas
(
9%
and
23%
vs
0%
in
controls)
as
well
as
liver
carcinomas
(
10%
vs
0%
in
controls)
at
1000
ppm;
and
2)
The
incidences
of
liver
adenomas
and
carcinomas
were
outside
the
range
for
the
published
spontaneous
rates
(
range
both
for
liver
adenomas
and
carcinomas
:
0%­
2.5%).
For
females,
there
was
a
statistically
significant
increasing
trend
for
liver
carcinomas
but
there
were
no
significant
pair­
wise
comparisons
of
liver
tumors
in
treated
females.

The
highest
dose
level
tested
was
considered
to
be
adequate
and
not
excessive
for
males
based
on
decreased
body
weight
gains
as
well
as
clinical
and
the
clinical
and
histopatholgical
liver
changes
observed
which
were
not
severely
adverse.
For
female
rats,
the
highest
dose
was
considered
to
be
adequate
and
not
excessive
based
on
an
increased
incidence
of
chronic
nephropathy
and
liver
changes.
The
survival
of
the
animals
was
not
affected
by
the
treatment.
The
CARC
concluded
that
the
increases
in
both
the
benign
and
malignant
liver
tumors
in
the
male
rats
were
treatment­
related.

!
In
the
combined
chronic
toxicity/
carcinogenicity
study
in
ICR­
JCL
mice,
there
was
clear
evidence
that
oxadiazon
was
carcinogenic
to
male
and
female
mice
because:
1)
There
were
statistically
significant
(
p<
0.01)
positive
trends
for
liver
adenomas,
carcinomas
and
combined
adenomas/
carcinomas
in
males
and
females.
For
males,
there
were
also
statistically
significant
(
p<
0.05
or
p<
0.01)
increases
by
pair­
wise
comparisons
of
the
100
and
1000
ppm
(
10.6
and
113
mg/
kg/
day,
respectively)
dose
groups
with
the
controls
for
liver
adenomas
(
17%
and
23%,
respectively,
vs
3%
in
controls),
carcinomas
(
33%
and
63%,
respectively,
vs
4%
in
controls)
and
combined
adenomas/
carcinomas
(
16%
and
41%
,
respectively,
vs
7%
in
controls).
For
females,
there
were
also
statistically
significant
(
p<
0.05
or
<
0.01)
increases
by
pair­
wise
comparisons
of
the
1000
ppm
dose
group
(
99
mg/
kg/
day)
with
the
controls
for
liver
adenomas
(
16%
vs
0%
in
controls),
carcinomas
(
14%
vs
2%
in
controls)
and
combined
adenomas/
carcinomas
(
29%
vs
2%
in
controls).
The
increase
in
the
incidence
of
lymphomas
in
females
was
not
considered
to
be
treatment­
related
because
there
was
no
doseresponse
the
tumor
response
was
variable
and
this
type
of
tumor
was
not
seen
in
male
mice
or
in
earlier
studies.

The
highest
dose
level
tested
for
the
male
and
female
mice
was
considered
to
be
adequate
and
not
excessive
based
on
the
findings
of
anemia
and
histopatholgical
Oxadiazon
(
3
rd
Review)
Cancer
Assessment
Document
Final
Report
19
changes
in
the
liver
which
were
not
severely
adverse.
There
were
no
adverse
effects
on
the
body
weight
gain
and
survival
of
the
animals.
The
Committee
concluded
that
the
increases
in
both
benign
and
malignant
liver
tumors
in
male
and
female
mice
were
treatment­
related.

The
positive
results
in
an
in
vitro
cell
transformation
assay
are
in
concordance
with
the
findings
of
liver
tumor
induction
in
the
in
vivo
rodent
studies.

2.
Mutagenicity
The
CARC
concluded
that
oxadiazon
was
negative
for
mutagenic
potential
in
a
battery
of
acceptable
mutagenicity
studies
which
satisfy
the
pre­
1991
FIFRA
guideline
requirements.
These
studies
included
reverse
gene
mutation
assays
in
bacteria,
a
mouse
lymphoma
forward
gene
mutation
assay,
chromosome
aberration
assays,
and
UDS
assays.
No
new
studies
were
requested
by
the
CARC.

3.
Structure­
Activity
Relationships
The
structurally­
related
compounds,
azafenidin
and
sulfentrazone,
are
neither
mutagenic
nor
liver
carcinogens
in
rats
or
mice.

4.
Mode
of
Action
Studies
The
MTARC
concluded
that
the
available
mechanistic
data
are
insufficient
to
determine
whether
oxadiazon­
induced
liver
tumors
in
the
rats
and
mice
were
associated
with
peroxisome
proliferation.
Nevertheless,
the
formation
of
brown
pigment
in
the
liver
and
kidneys
of
rats
and
mice
is
consistent
with
the
inhibition
of
porphyrin
biosynthesis
by
oxadiazon.
It
is
caused
by
the
disruption
of
the
biosynthetic
pathways
producing
heme
that
leads
to
accumulation
of
precursors
throughout
the
body.

VI.
CLASSIFICATION
OF
CARCINOGENIC
POTENTIAL
In
accordance
with
the
EPA
Draft
Guidelines
for
Carcinogen
Risk
Assessment
(
July,
1999),
the
CARC
classified
oxadiazon
into
the
category
"
Likely
to
be
carcinogenic
to
humans"
based
on
the
following
weight­
of­
the­
evidence
considerations:
Oxadiazon
(
3
rd
Review)
Cancer
Assessment
Document
Final
Report
20
1.
Treatment­
related
benign
and
malignant
liver
tumors
were
observed
in
two
species.
There
was
clear
evidence
that
oxadiazon
induced
both
benign
and
malignant
liver
tumors
in
male
Wistar
rats
and
male
and
female
ICR­
JCL
mice.
Liver
tumors
were
also
noted
in
earlier
studies
with
F­
344
rats
and
CD­
1
mice
using
higher
doses
of
oxadiazon
that
exceeded
the
MTD.

2.
Oxadiazon
was
not
mutagenic.
However,
it
causes
cell
transformation
in
vitro;
these
results
are
in
concordance
with
the
carcinogenicity
seen
in
in
vivo
rodent
studies.

3.
The
available
mechanistic
studies
do
not
support
a
non­
genotoxic
mode
of
action
for
oxadiazon
­
induced
liver
tumors
in
rodents.

VII.
QUANTIFICATION
OF
CARCINOGENIC
POTENTIAL
.
For
human
cancer
risk
assessment,
the
CARC
recommended
using
a
linear
low
dose
extrapolation
approach
based
on
the
most
potent
liver
tumors
in
the
rats
and
mice.
This
approach
is
supported
by
the
inadequacy
of
data
on
the
mode
of
action
for
oxadiazon­
induced
liver
tumors
in
rodents.
Oxadiazon
(
3
rd
Review)
Cancer
Assessment
Document
Final
Report
21
VII.
BIBLIOGRAPHY
MRID
No.
CITATION
40993401
Shirasu,
Y.
(
1987).
Oxadiazon
­
24
Month
Chronic
Toxicity
and
Carcinogenicity
Study
in
Rats.
Institute
of
Environmental
Toxicology,
Tokyo,
Japan;
Study
No.
Not
listed;
Report
dated
February
1987.
(
Unpublished).
HED
Doc.#
08949.

40993301
Shirasu,
Y.
(
1987).
Oxadiazon­
23
Month
Chronic
Toxicity
and
Carcinogenicity
Study
in
Mice.
Institute
of
Environmental
Toxicology,
Tokyo,
Japan;
Study
No.
Not
listed;
Report
dated
February
1987.
(
Unpublished).
HED
Doc.#
08949.

­­­­­­­­­
Brunsman,
L.
L.
(
2001).
Oxadiazon
Qualitative
Risk
Assessment
(
Q
1
*)
Based
on
SPF
Wistar
Rat
and
ICR_
JCL
Mouse
Dietary
Studies.
A
memorandum
from
Lori
L.
Brunsman,
Science
Analyses
Branch,
Health
Effects
Division
to
Nancy
McCarroll,
Toxicology
Branch,
Health
Effects
Division,
dated
February
14,
2001.
HED
Doc
#
014470.

­­­­­­­­­
CARC.
(
1999).
Evaluation
of
the
carcinogenic
potential
of
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Assessment
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Cancer
Assessment
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Health
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Office
of
Pesticide
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Final
Report
dated
October
18,
1999.
HED
Doc
#
013794.

­­­­­­­­­
EPA
(
1999).
Office
of
Pesticide
Programs
List
of
Chemicals
Evaluated
for
Carcinogenic
Potential.
Memorandum
from
William
Burnam
to
Division
Directors,
Office
of
Pesticide
Programs,
Environmental
Protection
Agency.
August
25,
1999.

­­­­­­­­­
Farber,
T.
M..
(
1987).
Classification
of
Oncogenic
Potential
of
Oxadiazon.
Memorandum
from
Theodore
M.
Farber,
Health
Evaluation
Division
to
Edwin
F.
Tinsworth,
Registration
Division,
Office
of
Pesticide
Programs,
U.
S.
EPA.,
dated
August
27,
1987.
HED
Doc
#
007798.

­­­­­­­­­
Litt,
B.
D.
(
1984).
Carcinogenicity
Risk
Assessment
for
Oxadiazon.
Memorandum
from
Bertram
D.
Litt,
Toxicology
Branch
to
Richard
Mountfort
Registration
Division,
Office
of
Pesticide
Programs,
U.
S.
EPA.,
dated
November
21,
1984.
HED
Doc#
004097.

­­­­­­­­
Matringe,
M.,
Camadro,
J.
M.,
Labbe,
P.,
Scalla,
R.
(
1989).
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oxidase
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LS
82­
556
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M&
B
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FEBS
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35­
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Oxadiazon
(
3
rd
Review)
Cancer
Assessment
Document
Final
Report
22
­­­­­­­­­
McCarroll,
N.
(
2001).
Oxadiazon:
Assessment
of
Mode
of
Action
on
Liver
Carcinogenicity.
A
memorandum
from
Nancy
McCarroll,
Toxicology
Branch
to
William
Burnham,
Immediate
Office,
Office
of
Pesticide
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U.
S.
EPA.,
dated
February
28,
2001.

­­­­­­­­­
Quest,
J.
A.
(
1987).
2nd
Peer
Review
of
Oxadiazon.
A
memorandum
from
John
A.
Quest,
Toxicology
Branch
to
Richard
Mountfort
Registration
Division,
Office
of
Pesticide
Programs,
U.
S.
EPA.,
dated
April
14,
1987.
HED
Doc
#
07798
­­­­­­­­
Richert,
L.,
Price,
S.,
Chesne,
C.,
Maita,
K.
Carmichael,
N.
(
1996).
Comparison
of
the
induction
of
hepatic
peroxisome
proliferation
by
the
herbicide
Oxadiazon
in
vivo
in
rats,
mice,
and
dogs
and
in
vitro
in
rat
and
human
hepatocytes.
Toxicol.
Appl.
Pharmacol
141:
35­
43.

­­­­­­­­
Welsh,
K.
M.
And
Poteracki,
J.
(
1994).
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