ORYZALIN
PC
Code:
104201
Toxicology
Disciplinary
Chapter
for
the
Reregistration
Eligibility
Decision
(
or
Registration
Support)
Document
Date
completed:
16­
JUNE­
2003
Prepared
by:
William
Dykstra,
Ph.
D.
Health
Effects
Division
Office
of
Pesticide
Programs
U.
S.
Environmental
Protection
Agency
Arlington,
VA
22202
TXR#
0052045
form:
FINAL
June
21,
2000
EPA
Reviewer:
William
Dykstra,
Ph.
D.
,
Date
Reregistration
Branch
4
(
7509C)
EPA
Secondary
Reviewer:
Abdallah
Khasawinah,
Ph.
D.
,
Date
Reregistration
Branch
4
(
7509C)

TABLE
OF
CONTENTS
1.0
HAZARD
CHARACTERIZATION
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3
2.0
REQUIREMENTS
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4
3.0
DATA
GAP(
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5
4.0
HAZARD
ASSESSMENT
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5
4.1
Acute
Toxicity
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5
4.2
Subchronic
Toxicity
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6
4.3
Prenatal
Developmental
Toxicity
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11
4.4
Reproductive
Toxicity
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14
4.5
Chronic
Toxicity
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16
4.6
Carcinogenicity
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18
4.7
Mutagenicity
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20
4.8
Neurotoxicity
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21
4.9
Metabolism.
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22
4.10
Special/
Other
Studies
(
optional
section)
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23
5.0
TOXICITY
ENDPOINT
SELECTION
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24
5.1
See
Section
9.2
for
Endpoint
Selection
Table.
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24
5.2
Dermal
Absorption
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24
5.3
Classification
of
Carcinogenic
Potential
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25
6.0
FQPA
CONSIDERATIONS
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25
6.1
Special
Sensitivity
to
Infants
and
Children
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25
6.2
Recommendation
for
a
Developmental
Neurotoxicity
Study
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26
7.0
OTHER
ISSUES
(
optional
section)
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26
8.0
REFERENCES
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27
9.0
APPENDICES
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31
9.1
Toxicity
Profile
Summary
Tables
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31
9.1.1
Acute
Toxicity
Table
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31
9.1.2
Subchronic,
Chronic
and
Other
Toxicity
Tables
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31
9.2
Summary
of
Toxicological
Dose
and
Endpoints
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34
ORYZALIN/
JUNE/
2003
TRED
Toxicology
Chapter
3
1.0
HAZARD
CHARACTERIZATION
Oryzalin
is
of
low
acute
toxicity
by
oral,
dermal
and
inhalation
routes
of
exposure
(
Toxicity
Category
III
or
IV),
but
is
an
eye
and
skin
irritant
and
a
strong
dermal
sensitizer.
Developmental
studies
in
rats
and
rabbits
demonstrate
developmental
effects
in
the
presence
of
maternal
toxicity.
In
rabbits,
developmental
effects
include
decreased
live
fetuses,
increased
resorptions
and
increased
postimplantation
loss
in
the
presence
of
decreased
body
weight
gain
and
food
consumption
in
the
does.
In
rats,
decreased
fetal
weight
and
delayed
ossification
occurred
in
the
presence
of
decreased
body
weight
gain
and
food
consumption
in
the
dams.
Pup
toxicity
was
seen
as
decreased
day
21
body
weight
in
both
the
one­
generation
and
3­
generation
rat
reproduction
studies.

The
target
organs
of
toxicity
in
rats
and
dogs
are
the
thyroid,
kidney
and
liver.
There
is
no
evidence
of
neurotoxicity.
Parental
toxicity
consisted
of
increased
kidney
weight
and
kidney
histopathology
in
the
1­
generation
study
at
all
doses
tested
(
19.4/
22.3
­
178.8/
205.5
mg/
kg/
day)
and
decreased
body
weight
and
food
consumption
(
125/
149
mg/
kg/
day)
in
the
3­
generation
study.
In
the
90­
day
rat
feeding
study,
increased
kidney
weights
and
kidney
histopathology
(
50
­
300
mg/
kg/
day)
were
the
primary
findings.
The
thyroid
(
decreased
T4)
was
the
target
organ
in
the
1­
year
dog
gavage
study.
In
the
2­
year
rat
feeding
study
increased
thyroid
weights,
thyroid
histopathology
and
thyroid
tumors,
together
with
skin
tumors
and
mammary
gland
tumors
(
females),
were
identified.
Thyroid
tumors
are
common
to
the
dinitroaniline
class
of
herbicides,
of
which
oryzalin
is
a
member.
Oryzalin
was
classified
by
the
CARC
as
"
likely
to
be
a
human
carcinogen".
A
Q
1
*
of
0.00779
(
mg/
kg/
day)­
1
was
established
based
on
thyroid
tumors.
Only
decreased
weight
gain
was
consistently
seen
in
subchronic
and
chronic
mouse
studies.
There
was
no
tumorigenic
potential
in
mice
in
an
acceptable
cancer
study.
Oryzalin
is
mutagenic
in
the
sister
chromatid
exchange
by
intraperitoneally
injection,
but
not
oral
intubation,
and
is
also
positive
in
the
DNA
repair
test,
but
negative
in
the
Ames
assay,
and
UDS
assay.
The
CARC
required
a
mouse
micro
nucleus
assay
be
performed.

A
comparative
thyroid
assay
in
young
rats
and
adults
which
measures
hormone
levels,
organ
weights,
and
histopathology
is
a
critical
data
gap
and
is
required.
Additionally,
a
28
day
inhalation
study
and
a
mouse
micro
nucleus
assay
are
required.
ORYZALIN/
JUNE/
2003
TRED
Toxicology
Chapter
4
2.0
REQUIREMENTS
The
requirements
(
CFR
158.340)
for
food
use
for
oryzalin
are
listed
in
Table
1.
Use
of
the
new
guideline
numbers
does
not
imply
that
the
new
(
1998)
guideline
protocols
were
used.
Table
1.

Test
Technical
Required
Satisfied
870.1100
Acute
Oral
Toxicity
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870.1200
Acute
Dermal
Toxicity
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870.1300
Acute
Inhalation
Toxicity
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870.2400
Primary
Eye
Irritation
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870.2500
Primary
Dermal
Irritation
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870.2600
Dermal
Sensitization
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yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
870.3100
Oral
Subchronic
(
rodent)
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870.3150
Oral
Subchronic
(
nonrodent)
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870.3200
21­
Day
Dermal
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.
870.3250
90­
Day
Dermal
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870.3465
90­
Day
Inhalation
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.
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.
yes
yes
yes
no
no
yes
yes*
yes
­­

870.3700a
Developmental
Toxicity
(
rodent)
.
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870.3700b
Developmental
Toxicity
(
nonrodent)
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870.3800
Reproduction
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.
yes
yes
yes
yes
yes
yes
870.4100a
Chronic
Toxicity
(
rodent)
.
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.
870.4100b
Chronic
Toxicity
(
nonrodent)
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.
870.4200a
Oncogenicity
(
rat)
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.
870.4200b
Oncogenicity
(
mouse)
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.
870.4300
Chronic/
Oncogenicity
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.
yes
yes
yes
yes
yes
yes**
yes
yes**
yes
yes
870.5100
Mutagenicity
C
Gene
Mutation
­
bacterial
.
.
.
.
.
.
.
.
.
870.5300
Mutagenicity
C
Gene
Mutation
­
mammalian
.
.
.
.
.
.
870.5xxx
Mutagenicity
C
Structural
Chromosomal
Aberrations
870.5xxx
Mutagenicity
C
Other
Genotoxic
Effects
.
.
.
.
.
.
.
.
.
.
yes
yes
yes
yes
yes
yes
no
yes
870.6100a
Acute
Delayed
Neurotox.
(
hen)
.
.
.
.
.
.
.
.
.
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.
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.
.
870.6100b
90­
Day
Neurotoxicity
(
hen)
.
.
.
.
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.
.
870.6200a
Acute
Neurotox.
Screening
Battery
(
rat)
.
.
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.
.
.
.
.
870.6200b
90
Day
Neuro.
Screening
Battery
(
rat)
.
.
.
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.
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.
.
.
.
870.6300
Develop.
Neuro
.
.
.
.
.
.
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.
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.
.
.
no
no
­­

870.7485
General
Metabolism
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.7600
Dermal
Penetration
.
.
.
.
.
.
.
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.
.
yes
yes
yes
yes
Special
Studies
for
Ocular
Effects
Acute
Oral
(
rat)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
Subchronic
Oral
(
rat)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
Six­
month
Oral
(
dog)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.

*
The
one­
year
chronic
toxicity
dog
study
satisfies
the
Guideline
requirement
for
a
subchronic
dog
study.

**
The
2­
year
chronic
toxicity/
oncogenicity
rat
study
satisfies
the
Guideline
requirements
for
Chronic
Toxicity
(
rodent)
and
Oncogenicity
(
rat).
ORYZALIN/
JUNE/
2003
TRED
Toxicology
Chapter
5
3.0
DATA
GAP(
S)

­
a
28
day
inhalation
study
(
§
870.3465)
­
a
comparative
thyroid
assay
in
young
rats
and
adults
which
measures
hormone
levels,
organ
weights,
and
histopathology
(
no
guideline
reference)
­
a
mouse
micro
nucleus
assay
(
§
870.5395)

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

The
acute
oral,
dermal,
and
inhalation
toxicity
studies
are
of
low
acute
toxicity
with
all
studies
being
in
either
Toxicity
Category
III
or
IV
for
the
technical
and
85%
Surflan
®
Dry
Flowable.
With
the
technical,
the
acute
oral
LD
50
and
dermal
LD
50
were
greater
than
10,000
mg/
kg
and
2,000
mg/
kg
(
1
mortality/
20),
respectively.
The
clinical
signs
in
the
acute
oral
and
dermal
studies
were
ptosis,
urine
and
feces
colored
yellow,
and
leg
weakness,
respectively.
The
acute
oral
LD
50
is
greater
than
500
mg/
kg
for
the
formulation.
Additionally
with
the
formulation,
there
were
no
mortalities
and
toxic
signs
consisted
of
bright
yellow
urine,
poor
grooming
and
generalized
leg
weakness.
At
necropsy,
yellow
perineal
staining
was
reported
in
all
treated
females.
The
acute
dermal
LD
50
was
greater
than
5,000
mg/
kg.
There
were
no
mortalities,
toxic
signs,
or
necropsy
findings.
The
acute
inhalation
LC
50
for
the
technical
and
formulation
are
greater
than
3.17
mg/
L
and
3.48
mg/
L,
respectively,
with
no
mortalities,
slight
dyspnea
and
hypoactivity
immediately
postexposure
and
poor
grooming.
There
were
no
compound­
related
lesions
at
necropsy.

The
acute
toxicity
data
on
Oryzalin
technical
and
the
Oryzalin
85%
Surflan
®
Dry
Flowable
is
summarized
below
in
Table
2.

Table
2.
Acute
Toxicity
Data
on
ORYZALIN
Technical
Guideline
No./
Study
Type
MRID
No.
Results
Toxicity
Category
870.1100
Acute
oral
toxicity
00026592
LD
50
>
10
g/
kg
IV
870.1200
Acute
dermal
toxicity
00106681
LD
50
>
2,000
mg/
kg
III
ORYZALIN/
JUNE/
2003
TRED
Toxicology
Chapter
6
870.1300
Acute
inhalation
toxicity
41034201
LC
50
>
3.17
mg/
L
IV
870.2400
Acute
eye
irritation
00106681
corneal
opacity
clearing
within
7
days
III
870.2500
Acute
dermal
irritation
43910201
slight
erythema
IV
870.2600
Skin
sensitization
44574102
strong
sensitizer
Table
2.
Acute
Toxicity
Data
on
ORYZALIN
85%
Surflan
®
Dry
Flowable
Guideline
No./
Study
Type
MRID
No.
Results
Toxicity
Category
870.1100
Acute
oral
toxicity
00150104
LD
50
>
500
mg/
kg
III
870.1200
Acute
dermal
toxicity
00150104
LD
50
>
5,000
mg/
kg
IV
870.1300
Acute
inhalation
toxicity
00150104
LC
50
>
3.48
mg/
L
IV
870.2400
Acute
eye
irritation
00150104
slight
conjunctivitis,
iritis,
corneal
opacity
clearing
within
7
days
III
870.2500
Acute
dermal
irritation
00150104
slight
erythema
IV
870.2600
Skin
sensitization
00150104
not
a
sensitizer
4.2
Subchronic
Toxicity
Adequacy
of
data
base
for
subchronic
toxicity:
The
data
base
for
subchronic
toxicity
is
not
considered
complete.
A
28­
day
inhalation
study
and
a
comparative
thyroid
study
in
young
and
adult
rats
is
required.

Systemic
toxicity
in
rats
was
manifested
as
increased
kidney
weight
and
increased
incidence
of
hyaline
droplets.
In
subchronic
mouse
studies,
decreased
body
weight
gain
was
the
predominant
finding.

870.3100
90­
Day
Oral
Toxicity
­
Rat
ORYZALIN/
JUNE/
2003
TRED
Toxicology
Chapter
7
In
a
90­
day
oral
toxicity
study
(
MRID
44574103)
Oryzalin
(
97.3%
a.
i.,
lot
#
TSN100719)
was
administered
to
10
Fischer
344
rats/
sex/
dose
in
the
diet
at
targeted
dose
levels
of
0,
5,
50
or
300
mg/
kg/
day
(
actual
doses
were
0,
4.56,
45.88
or
276.34
mg/
kg
bw/
day
for
males
and
0,
4.65,
46.79
or
283.09
mg/
kg/
day
for
females).

All
animals
survived
to
study
termination.
The
only
treatment­
related
effect
was
discoloration
of
the
fur,
dark
urine
and
perineal
soiling
in
males
and
females
at
300
mg/
kg/
day
due
to
the
orangeyellowish
color
of
the
test
material.
Body
weight
was
significantly
decreased
(
3­
8%)
throughout
the
study
in
females
at
300
mg/
kg/
day;
overall
body
weight
gain
was
also
decreased
(
17%).
Food
consumption
in
females
at
300
mg/
kg/
day
was
decreased
(
7­
13%)
throughout
the
study.
Corneal
lesions
(
cloudiness
and
mineralization)
observed
in
both
treated
and
control
groups
were
not
considered
treatment­
related.
Hematology
parameters
(
RBC,
HGB
and
HCT)
were
decreased
in
males
and
females
at
300
mg/
kg/
day.
Males
at
300
mg/
kg/
day
had
increased
RBC
polychromasia.
Although
there
were
multiple
significant
clinical
chemistry
changes,
the
only
one
considered
treatment­
related
was
an
increased
total
bilirubin
in
males
at
300
mg/
kg/
day.
Higher
urine
pH
and
increased
number
of
triple
phosphate
crystals
were
observed
in
all
treated
animals.
These
findings
could
be
related
to
the
excretion
of
oryzalin
in
the
urine.
However,
both
sexes
at
300
mg/
kg/
day
also
had
lower
urine
specific
gravity
and
increased
numbers
of
animals
with
glucosuria
and
bilirubinuria;
males
at
300
mg/
kg/
day
had
a
greater
degree
of
proteinuria.
Some
of
these
effects
at
300
mg/
kg/
day
could
be
treatment­
related
as
there
were
kidney
alterations
on
necropsy.

At
necropsy,
absolute
and/
or
relative
kidney
and
liver
weights
were
significantly
increased
in
males
and
females
at
50
and
300
mg/
kg/
day.
Increased
absolute
and/
or
relative
spleen
weights
were
observed
in
males
and
females
at
300
mg/
kg/
day.
The
increases
in
relative
weight
of
the
heart
in
both
sexes
at
300
mg/
kg/
day
and
in
males
at
50
mg/
kg/
day
and
relative
weight
of
the
brain
in
females
at
300
mg/
kg/
day
were
attributable
to
lower
body
weights.
The
relative
weight
of
the
thyroid
was
significantly
increased
in
males
at
300
mg/
kg/
day;
the
absolute
and
relative
weights
were
increased
in
females
at
300
mg/
kg/
day.
These
thyroid
effects
were
not
considered
treatment­
related
as
there
were
no
histopathological
changes
in
the
organ.
Male
and
female
rats
at
50
or
300
mg/
kg/
day
had
an
increased
incidence
of
hyaline
droplet
formation
in
the
cytoplasm
of
the
proximal
tubular
epithelial
cells
in
the
outer
portion
of
the
cortex;
the
severity
was
increased
in
males
at
these
doses.
All
female
rats
at
300
mg/
kg/
day
had
very
slight
amount
of
brown
pigment
in
the
cytoplasm
of
the
proximal
tubules
of
the
outer
cortex.
Males
and
females
at
300
mg/
kg/
day
had
a
very
slight
degree
of
erythroid
hyperplasia
of
the
spleen.
One
female
at
50
mg/
kg/
day
also
had
this
change.
A
very
slight
increase
in
hematogenous
pigment
within
macrophages
of
the
spleen
was
present
in
3
of
10
females
at
50
mg/
kg/
day
and
10
of
10
females
at
300
mg/
kg/
day.
A
very
slight
increase
in
hematopoiesis
of
the
bone
marrow
was
present
in
5
of
10
males
and
9
of
10
females
at
300
mg/
kg/
day.
Hepatocellular
hypertrophy
was
observed
in
the
centrilobular
region
of
the
liver
in
3
of
10
males
at
300
mg/
kg/
day.

The
LOAEL
is
50
mg/
kg/
day,
based
on
increased
kidney
weights
and
increased
incidence
of
hyaline
droplet
formation
in
renal
tubular
epithelial
cells.
The
NOAEL
is
5
mg/
kg/
day.

This
90­
day
oral
toxicity
study
in
the
rat
is
acceptable
(
guideline)
and
satisfies
the
guideline
ORYZALIN/
JUNE/
2003
TRED
Toxicology
Chapter
8
requirement
for
a
90­
day
oral
toxicity
study
(
OPPTS
870.3100;
OECD
408)
in
the
rat.

870.3100
90­
Day
Oral
Toxicity
­
Mouse
In
a
90­
day
oral
toxicity
study
(
MRID
00026773)
Oryzalin
(
Compound
67019)
(
99.8%
a.
i.,
Lot#
9UA45)
was
administered
to15
B
6
C
3
F
1
mice/
sex/
dose
in
the
diet
at
dose
levels
of
0,
450,
900,
1800,
3650
or
8000
ppm
(
equivalent
to
approximately
0,
64,
129,
257,
521,
1143
mg/
kg
bw/
day
based
on
1
ppm
in
food
equals
0.15
mg/
kg/
day).
Assays
of
fresh
mash,
fresh
pellets
and
aged
(
3
½
months)
pellets
showed
that
the
concentrations
were
less
than
theoretical
values
(
77­
97%
for
fresh
mash,
71­
88%
for
fresh
pellets
and
78­
88%
for
aged
pellets).

There
were
no
treatment­
related
deaths
during
the
study.
Terminal
body
weight
was
comparable
to
controls
in
treated
males
but
was
significantly
decreased
(
12%)
in
females
at
8000
ppm.
There
were
no
treatment­
related
hematology
changes.
A
significant
decrease
in
BUN
and
slight
increase
in
alkaline
phosphatase
in
males
at
8000
ppm
was
not
considered
treatment­
related.
At
necropsy,
there
was
a
significant
increase
in
absolute
spleen
weights
in
females
at
8000
ppm.
Significant
increases
in
the
relative
weights
of
the
liver,
kidney
and
heart
of
male
mice
at
8000
ppm
and
increases
in
the
relative
weights
of
the
liver,
kidney
and
spleen
in
females
at
multiple
doses
were
not
considered
toxicologically
significant
as
they
were
slight.
On
histopathology,
there
was
an
increased
incidence
of
chronic
cystitis
in
females
at
900
ppm
and
above
and
of
pyelonephritis
in
females
at
1800
ppm
and
above;
however,
there
was
no
dose
response.
The
cystitis
was
characterized
by
the
accumulation
of
inflammatory
cells
within
all
layers
of
the
urinary
bladder.
The
pyelonephritis
was
characterized
by
the
accumulation
of
lymphoid
inflammatory
cells
within
the
interstitial
tissues
of
the
renal
pelvis
and
was
proposed
to
be
due
to
an
ascending
infection
secondary
to
the
chronic
cystitis.
The
pathogenesis
of
the
cystitis
is
unknown.
It
was
observed
in
1/
15
female
mice
treated
at
10000
ppm
for
three
months
(
MRID
00026774)
and
in
both
sexes
treated
for
one
year
at
3650
ppm
(
MRID
00038681)
but
was
not
observed
in
mice
treated
for
two
years
at
doses
up
to
8000
ppm
(
MRID
00244746).
All
studies
were
conducted
in
the
same
strain
and
at
the
same
laboratory.
If
the
cystitis
resulted
from
bladder
irritation
due
to
chemical
precipitation,
it
is
expected
that
both
sexes
would
be
affected
and
that
there
would
be
a
dose
response.
In
a
recent
study
(
MRID
44574104),
there
was
no
sex­
related
difference
in
the
metabolism
of
oryzalin
which
could
explain
finding
of
cystitis
in
only
one
species.
In
the
present
study,
since
there
was
no
dose
response
in
the
incidence
of
cystitis
and
it
occurred
in
only
one
sex,
it
is
not
considered
toxicologically
significant.
The
LOAEL
in
males
is
>
8000
ppm
[
1143
mg/
kg/
day
(
892
mg/
kg/
day
corrected
based
on
78%
of
theoretical
value)].
The
NOAEL
is

8000
ppm.
The
LOAEL
in
females
is
8000
ppm
[
approximately
1143
mg/
kg/
day
(
892
mg/
kg/
day
corrected
based
on
78%
of
theoretical
value)
based
on
decreased
terminal
body
weight.
The
NOAEL
is
3650
ppm
[
521
mg/
kg/
day
(
406
mg/
kg/
day
corrected
based
on
78%
of
theoretical
value)]
.

This
90­
day
oral
toxicity
study
in
the
mouse
is
acceptable
(
guideline)
and
satisfies
the
guideline
requirement
for
a
90­
day
oral
toxicity
study
(
OPPTS
870.3100;
OECD
408)
in
mice.
ORYZALIN/
JUNE/
2003
TRED
Toxicology
Chapter
9
870.3100
90­
Day
Oral
Toxicity
­
Mouse
In
a
90­
day
oral
toxicity
study
(
MRID
00026774)
Oryzalin
(
Compound
67019)
(
99.8%
a.
i.,
Lot#
X­
28607)
was
administered
to
20
B
6
C
3
F
1
mice/
sex
in
the
diet
at
a
dose
level
of10000
ppm
(
equivalent
to
approximately
1429
mg/
kg
bw/
day
based
on
1
ppm
in
food
equals
0.15
mg/
kg/
day).
Ten
B
6
C
3
F
1
mice/
sex
served
as
untreated
controls.
The
study
was
designed
to
evaluate
the
chronic
cystitis
observed
in
an
earlier
study
(
MRID
00026773)
at
doses

900
ppm.
Parameters
measured
included:
survival
and
clinical
observations,
weekly
body
weights,
clinical
chemistry,
urinalysis
(
50%
of
animals
at
2
days,
1,
2
and
3
weeks
and
3
months)
and
histopathology
on
urinary
bladder
and
kidneys.
The
concentration
of
oryzalin
in
fresh
mash
was
98%
of
theoretical
value
but
was
only
72%
in
pelleted
feed.
The
discrepancy
was
thought
to
be
due
to
difficulties
in
oryzalin
recovery
from
the
pellets
during
the
analysis,
which
was
noted
in
other
studies.

There
were
no
deaths
during
the
study.
During
the
first
week,
males
failed
to
gain
weight
and
females
lost
weight;
however,
both
sexes
gained
weight
thereafter
so
that
terminal
weights
in
treated
animals
were
only
slightly
decreased.
There
was
a
significant
increase
in
SGPT
and
glucose
in
treated
male
and
female
mice.
The
toxicological
significance
of
these
changes
is
unknown
since
only
limited
toxicology
parameters
were
evaluated.
A
decrease
in
creatinine
in
both
sexes
of
treated
mice
was
not
considered
toxicologically
significant.
There
were
no
treatment­
related
changes
on
urinalysis.
One
treated
female
had
an
elevation
in
BUN
and
chronic
cystitis,
which
was
characterized
by
accumulation
of
inflammatory
cells
within
all
layers
of
the
bladder.
This
lesion
is
similar
to
that
observed
in
multiple
females
at

900
ppm
in
another
90­
day
study
(
MRID
00026773).
However,
since
only
one
animal
was
affected
at
a
dose
10x
that
which
produced
cystitis
in
the
previous
study,
the
finding
is
not
considered
treatment­
related.
The
LOAEL
is
10000
ppm
(
approximately
1429
mg/
kg/
day)
based
on
failure
to
gain
weight
during
the
initial
weeks
of
dosing.
The
NOAEL
is
<
10000
ppm.

This
90­
day
oral
toxicity
study
in
the
mouse
is
acceptable
(
non­
guideline)
and
does
not
satisfy
the
guideline
requirement
for
a
90­
day
oral
toxicity
study
(
OPPTS
870.3100;
OECD
408)
in
mice.
It
was
intended
as
a
special
study
to
pursue
the
cause
of
chronic
cystitis
observed
in
oryzalintreated
mice
in
a
previous
study.

870.3100
One­
Year
Oral
Toxicity
­
Mouse
In
a
one­
year
oral
toxicity
study
(
MRID
00038681)
Oryzalin
(
Compound
67019)
(
99.8%
a.
i.,
Lot#
X­
28607)
was
administered
to15
B
6
C
3
F
1
mice/
sex/
dose
in
the
diet
at
dose
levels
of
0,
500,
1350
or
3650
ppm
(
equivalent
to
approximately
0,
71,
193
or
521
mg/
kg
bw/
day
based
on
1
ppm
in
food
equals
0.15
mg/
kg/
day).
The
concentration
of
oryzalin
in
fresh
mash
was
fresh
approached
the
theoretical
value;
however,
the
concentrations
in
the
fresh
and
aged
pellets
was
much
lower.
The
discrepancy
was
thought
to
be
due
to
difficulties
in
oryzalin
recovery
from
the
pellets
during
the
analysis,
which
was
noted
in
other
studies.
The
mean
content
of
N­
nitrosodipropylamine,
a
B
2
ORYZALIN/
JUNE/
2003
TRED
Toxicology
Chapter
1
According
to
IRIS,
male
rats
administered
N­
nitrosodi­
N­
propylamine
in
the
drinking
water
at
doses
of
1.8
mg/
kg/
day,
5
days/
week
for
30
weeks
developed
liver
carcinomas,
esophageal
papillomas
and
carcinomas
and
nasal
adenocarcinomas.
Rats
of
both
sexes
treated
in
a
similar
manner
with
0.9
mg/
kg/
day
developed
esophageal
carcinomas
and
forestomach
tumors.
No
studies
in
mice
are
included
in
the
IRIS
report.

10
probable
human
carcinogen,
in
the
diet
was
0.24
±
0.011
ppm.
1
There
were
no
treatment­
related
effects
on
survival,
clinical
signs
of
toxicity
or
body
weights.
There
was
a
significant
decrease
in
hemoglobin
and
RBC
values
in
males
and
females,
respectively,
at
3650
ppm.
The
decreases
were
slight
and
within
the
normal
range
for
this
laboratory;
therefore,
the
effects
are
not
considered
toxicologically
significant.
A
number
of
significant
differences
in
clinical
chemistry,
including
decrease
in
BUN
in
males
at
1350
ppm,
decrease
in
creatinine
in
males
at
1350
and
3650
ppm,
increase
in
bilirubin
in
males
at
3650
ppm
and
increase
in
alkaline
phosphatase
in
all
treated
females,
were
not
considered
toxicologically
significant
because
they
were
within
normal
limits.
In
male
mice,
significant
increases
in
relative
kidney
(
1350
and
3650
ppm),
heart
(
3650
ppm)
and
testes
(
1350
and
3650
ppm)
weights
were
not
considered
toxicologically
significant
because
they
were
slight.
On
histopathology,
chronic
cystitis
was
observed
in
1/
15
males
and
3/
15
females
at
3650
ppm
vs
0/
15
in
controls.
Pyelonephritis
was
observed
in
2/
15
males
and
2/
15
females
at
3650
ppm
and
1/
15
males
at
1350
ppm
vs
1/
15
male
and
0/
15
female
controls.
The
cystitis
was
characterized
by
the
accumulation
of
inflammatory
cells
within
all
layers
of
the
urinary
bladder.
The
pyelonephritis
was
characterized
by
the
accumulation
of
lymphoid
inflammatory
cells
within
the
interstitial
tissues
of
the
renal
pelvis.
A
second
urinary
tract
lesion
observed
in
males
was
obstruction
and
extreme
urinary
bladder
distension.
It
occurred
in
both
treated
and
control
animals
and
was
associated
with
injury
to
the
penis
during
fighting.
The
pathogenesis
of
the
cystitis
is
unknown.
It
was
observed
in
1/
15
female
mice
treated
at
10000
ppm
for
three
months
(
MRID
00026774)
and
in
females
at
900
ppm
and
above,
with
no
dose
response,
in
another
subchronic
study
(
MRID
00026773.
It
was
not
observed
in
mice
treated
for
two
years
at
doses
up
to
8000
ppm
(
MRID
00244746).
All
studies
were
conducted
in
the
same
strain
and
at
the
same
laboratory.
If
the
cystitis
resulted
from
bladder
irritation
due
to
chemical
precipitation,
it
is
expected
that
both
sexes
would
be
affected
and
that
there
would
be
a
dose
response.
In
a
recent
study
(
MRID
44574104),
there
was
no
sex­
related
difference
in
the
metabolism
of
oryzalin
which
could
explain
finding
of
cystitis
in
only
one
species.
Based
on
the
inconsistent
findings
in
other
studies,
the
chronic
cystitis
is
not
considered
toxicologically
significant.
The
LOAEL
is
>
3650
ppm
(
approximately
521
mg/
kg/
day).
The
NOAEL
is

3650
ppm
(
approximately
193
mg/
kg/
day).

This
chronic
study
in
the
mouse
is
acceptable
(
guideline)
and
satisfies
the
guideline
requirement
for
a
chronic
oral
study
[
OPPTS
870.4100,
OECD
452]
in
mice.

870.3200
21/
28­
Day
Dermal
Toxicity
B
Rat
ORYZALIN/
JUNE/
2003
TRED
Toxicology
Chapter
11
In
a
21­
day
dermal
toxicity
study
(
MRID
No.
00150106
),
oryzalin
(
98.4
%
a.
i.,
L­
1385A)
was
applied
to
the
shaved
skin
of
5
New
Zealand
White
rabbits/
sex/
dose
at
dose
levels
of
0
or
1,000
mg/
kg
bw/
day,
6
hours/
day
for
7
days/
week
during
a
21­
day
period.

No
changes
in
mortality,
mean
body
weight
or
mean
body
weight
gains,
and
food
consumption
were
observed
in
the
test
group
as
compared
to
controls.
Total
bilirubin
levels
were
decreased
by
29%
in
males
and
31%
in
females
due
to
oryzalin
treatment.
Thyroid
and
parathyroid
weights
were
increased
by
27%
(
absolute
weight)
and
26%
(
relative
weight)
in
oryzalin­
treated
male
rabbits.
Increase
in
thyroid
and
parathyroid
weights
in
oryzalin­
treated
females
was
not
significant.
Gross
pathological
and
histopathological
parameters
remain
unchanged
due
to
oryzalin
treatment.
The
LOAEL
is
1000
mg/
kg
bw/
day,
based
on
bilirubin
changes
in
males
and
females
and
weight
of
thyroid
and
parathyroids
in
males.
A
NOAEL
is
not
established.

This
21­
day
dermal
toxicity
study
in
the
rabbits
is
acceptable
(
non­
guideline)
and
does
satisfy
the
guideline
requirement
for
a
21­
day
dermal
toxicity
study
(
OPPTS
870.3200
;
OECD
410).

4.3
Prenatal
Developmental
Toxicity
Adequacy
of
data
base
for
Prenatal
Developmental
Toxicity:
The
data
base
for
prenatal
developmental
toxicity
is
considered
complete.
No
additional
studies
are
required
at
this
time.

Developmental
studies
in
rats
and
rabbits
demonstrate
developmental
effects
in
the
presence
of
maternal
toxicity.
In
rabbits,
developmental
effects
include
decreased
live
fetuses,
increased
resorptions
and
increased
postimplantation
loss
in
the
presence
of
decreased
body
weight
gain
and
food
consumption
in
the
does.
In
rats,
decreased
fetal
weight
and
delayed
ossification
occurred
in
the
presence
of
decreased
body
weight
gain
and
food
consumption
in
the
dams.

870.3700a
Prenatal
Developmental
Toxicity
Study
­
Rat
In
a
developmental
toxicity
study
(
MRID
41163801)
Oryzalin
(
96.2%
a.
i.,
lot
#
L1385A)
was
administered
to
25
female
Crl:
CD(
SD)
rats/
dose
by
gavage
at
dose
levels
of
0,
50,
225
or
1000
mg/
kg
bw/
day
from
days
6
through
15
of
gestation.

There
were
no
deaths
during
the
study.
The
only
clinical
sign
of
toxicity
was
increased
alopecia
at1000
mg/
kg/
day.
Yellow­
orange
urine
observed
in
all
treated
animals
was
due
to
urinary
elimination
of
the
test
material.
Mean
body
weight
gain
was
significantly
decreased
by
11%
and
22%
in
the
225
and
1000
groups,
respectively,
over
the
course
of
the
study.
The
overall
effect
was
mostly
due
to
the
decreases
during
the
initial
days
of
treatment
(
days
6­
9)
when
the
225
ORYZALIN/
JUNE/
2003
TRED
Toxicology
Chapter
12
mg/
kg/
day
group
had
a
36%
decrease
and
the
1000
mg/
kg/
day
group
had
a
negative
weight
gain.
Corrected
body
weight
gain
was
non­
significantly
decreased
(
7%)
at
225
mg/
kg/
day
and
significantly
(
26%)
at1000
mg/
kg/
day.
Mean
food
consumption
was
significantly
decreased
in
the
225
(
6­
11%)
and
1000
mg/
kg/
day
(
5­
49%)
groups
during
days
6­
9
and
10­
13.
The
maternal
LOAEL
is
225
mg/
kg
bw/
day,
based
on
decreased
body
weight
gain
and
food
consumption.
The
maternal
NOAEL
is
50
mg/
kg
bw/
day.

Pre­
implantation
loss
was
non­
significantly
increased
in
the
225
and
1000
mg/
kg/
day
groups.
Mean
fetal
body
weights
were
significantly
decreased
in
the
225
mg/
kg/
day
males
(
8%)
and
females
(
11%)
and
1000
mg/
kg/
day
males
(
19%)
and
females
(
23%)
groups.
There
was
incomplete
ossification
of
multiple
bones,
including
the
forepaw
metacarpals,
vertebral
column,
pelvic
girdle
and
skull
in
the
225
and
1000
mg/
kg/
day
groups.
The
developmental
LOAEL
is
225
mg/
kg
bw/
day,
based
on
decreased
fetal
body
weights
and
increased
incidence
of
incomplete
ossification
of
multiple
bones.
The
developmental
NOAEL
is
50
mg/
kg
bw/
day.

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

870.3700b
Prenatal
Developmental
Toxicity
Study
­
Rabbit
In
a
developmental
toxicity
study
(
MRIDs
00026785,
00052557
and
00073552)
Compound
67019
(
oryzalin;
97.4%
a.
i.,
lot
#
X28491)
was
administered
to
15
Dutch
Belted
rabbits/
dose
by
gavage
(
5
ml/
kg
body
weight)
at
dose
levels
of
0,
25,
55
or
125
mg/
kg
bw/
day
from
days
6
through
18
inclusively
of
gestation.

One
animal
at
125
mg/
kg/
day
dose
died
on
gestation
day
(
GD)
26;
necropsy
showed
that
the
cause
of
death
was
an
acute
upper
respiratory
infection.
One
animal
at
55
mg/
kg/
day
was
sacrificed
due
to
a
gavage
error
on
GD
10;
another
animal
in
this
group
aborted
on
GD
28.
There
was
a
non­
significant
decreased
body
weight
gain
during
the
treatment
period
for
the
55
and
125
mg/
kg/
day
groups
(
loss
of
0.1
and
0.18
kg,
respectively,
vs
gain
of
0.02
kg
in
the
control).
Overall
body
weight
gain
was
decreased
in
the
55
and
125
mg/
kg/
day
groups
which
was
statistically
significant
only
in
the
125
mg/
kg/
day
group.
Food
consumption
was
decreased
in
the
55
and
125
mg/
kg/
day
groups
throughout
the
study
but
more
adversely
during
the
treatment
period.
There
was
a
decrease
in
the
number
of
corpora
lutea
(
not
considered
due
to
dosing),
and
live
fetuses,
and
an
increase
in
resorptions
and
postimplantation
loss
in
the
55
and
125
mg/
kg/
day
groups,
although
none
of
the
changes
were
statistically
significant
and
some
were
not
doseresponsive
Therefore,
the
toxicological
significance
of
these
findings
is
questionable.

The
maternal
LOAEL
is
55
mg/
kg
bw/
day,
based
on
decreased
body
weight
gain
and
food
consumption.
The
maternal
NOAEL
is
25
mg/
kg
bw/
day.

The
developmental
LOAEL
is
55
mg/
kg
bw/
day,
based
on
decrease
in
the
number
of
live
ORYZALIN/
JUNE/
2003
TRED
Toxicology
Chapter
13
fetuses,
and
an
increase
in
resorptions
and
postimplantation
loss.
The
developmental
NOAEL
is
25
mg/
kg
bw/
day.

Although
the
number
of
animals
in
the
study
(
15)
was
less
than
the
current
requirement
of
20
rabbits,
the
study
does
meet
the
guideline
requirement
of
12
pregnant
rabbits.
This
developmental
toxicity
study
in
the
rabbit
is
classified
acceptable
(
guideline)
and
satisfies
the
guideline
requirement
for
a
developmental
toxicity
study
(
OPPTS
870.3700;
OECD
414)
in
rabbits.

870.3700b
Prenatal
Developmental
Toxicity
Study
­
Rabbit
In
a
developmental
toxicity
study
(
MRID
00098461)
Compound
67019
(
oryzalin;
97.0%
a.
i.,
lot
number
9SY47)
was
administered
to
two
replicates
of
15
Dutch
Belted
rabbits/
dose
by
gavage
(
5
ml/
kg
body
weight)
at
dose
levels
of
0,
10,
25,
55
or
125
mg/
kg
bw/
day
from
days
6
through
18
inclusively
of
gestation.

The
pregnancy
rates
of
both
replicate
studies
were
very
low,
and
the
HIARC
concluded
that
when
the
replicate
studies
are
combined,
the
combined
data
are
less
than
marginally
acceptable.

No
animals
died
during
the
study.
In
the
first
replicate,
one
animal
each
in
the
25
mg/
kg/
day
group
and
125
mg/
kg/
day
groups
aborted
on
gestation
day
(
GD)
26
and
15,
respectively.
There
was
no
treatment­
related
effect
on
body
weight
gain.
There
was
a
slight
decrease
in
food
consumption
in
the
55
mg/
kg/
day
(
85%
of
control)
and
125
mg/
kg/
day
(
84%)
groups
during
the
treatment
period
of
the
second
replicate.
There
was
no
evidence
of
a
treatment­
related
effect
on
the
combined
Cesarean
section
parameters
for
both
replicates;
however,
the
fertility
rates
were
low
in
all
groups.
The
maternal
LOAEL
is
55
mg/
kg
bw/
day,
based
on
decreased
food
consumption.
The
maternal
NOAEL
is
25
mg/
kg
bw/
day.

There
was
no
evidence
of
developmental
toxicity.
The
developmental
LOAEL
was
not
established.
The
developmental
NOAEL
is
125
mg/
kg
bw/
day.

The
pregnancy
rates
of
both
replicate
studies
were
very
low,
and
the
HIARC
concluded
that
when
the
replicate
studies
are
combined,
the
combined
data
are
less
than
marginally
acceptable
and,
therefore,
the
developmental
toxicity
study
in
the
rabbit
is
classified
unacceptable/
not
upgradable
and
does
not
satisfy
the
guideline
requirement
for
a
developmental
toxicity
study
(
OPPTS
870.3700;
OECD
414)
in
rabbits.

4.4
Reproductive
Toxicity
Adequacy
of
data
base
for
Reproductive
Toxicity:
The
data
base
for
reproductive
toxicity
is
considered
complete.
No
additional
studies
are
required
at
this
time.
ORYZALIN/
JUNE/
2003
TRED
Toxicology
Chapter
14
Pup
toxicity
was
seen
as
decreased
day
21
body
weight
in
both
the
one­
generation
and
3­
generation
rat
reproduction
studies.

870.3800
Reproduction
and
Fertility
Effects
­
Rat
In
a
three­
generation
reproduction
study
(
MRIDs
00038564
and
00042908)
Compound
67019
[
Oryzalin
(
99%
a.
i.,
lot
#
X­
28607)]
was
administered
to
25
Fischer
344
rats/
sex/
dose
in
the
diet
at
concentrations
of
0,
0.025,
0.075
and
0.225%
or
0,
250,
750
and
2250
ppm
(
equivalent
to
approximately
0,
13,
40
and
125
mg/
kg/
day
for
males;
0,
16,
48
and
149
mg/
kg/
day
for
females).
Four
adults
died
during
the
study
but
none
of
the
deaths
was
considered
treatment­
related.
The
only
clinical
signs
were
dry,
yellow
urogenital
staining
and
yellow
discoloration
of
fur
in
treated
animals.
There
was
no
treatment­
related
effect
on
body
weight,
body
weight
gain
or
food
consumption
in
the
F
0
generation.
Body
weight
was
non­
significantly
decreased
in
the
F
1
and
F
2
males
(
8­
10%)
and
females
(
8­
15%)
in
the
0.225%
group
at
the
end
of
the
treatment
period.
This
effect
was
due
in
part
to
decreased
weanling
weights
of
offspring.
Body
weight
gain
was
decreased
slightly
but
significantly
in
the
F
1
generation
males
(
5%)
and
females
(
12%)
at
0.225%.
Food
consumption
was
decreased
slightly
and
non­
significantly
in
the
F
1
and
F
2
males
(
6­
13%)
and
females
(
8­
18%)
in
the
0.225%
group.

There
was
no
treatment­
related
effect
on
reproduction
parameters.

The
parental
systemic
LOAEL
was
0.225%
(
approximately
125
mg/
kg/
day
in
males
and
149
mg/
kg/
day
in
females)
based
on
decreased
body
weight,
body
weight
gain
and
food
consumption.
The
parental
systemic
NOAEL
0.075%
(
approximately
40
mg/
kg/
day
in
males
and
48
mg/
kg/
day
in
females).

The
reproductive
LOAEL
was
not
established.
The
reproductive
NOAEL
was
0.225%
concentration
(
approximately
125
mg/
kg/
day
in
males
and
149
mg/
kg/
day
in
females).

Mean
weight
in
the
F
1
and
F
2
pups
was
comparable
to
controls
on
Day
1
but
was
decreased
in
the
high
dose
on
Day
21
(
4­
12%,
p

0.05
in
F
2
generation).
The
offspring
LOAEL
was
0.225%
(
approximately
125
mg/
kg/
day
in
males
and
149
mg/
kg/
day
in
females)
based
on
decreased
body
weight
on
Day
21.
The
offspring
NOAEL
was
0.075%
(
approximately
40
mg/
kg/
day
in
males
and
48
mg/
kg/
day
in
females).

This
study
is
acceptable
(
guideline)
and
satisfies
the
guideline
requirement
for
a
multigeneration
reproductive
study
(
OPPTS
870.3800);
OECD
416
in
the
rat.

870.3800
Reproduction
and
Fertility
Effects
­
Rat
In
a
one­
generation
reproduction
study
(
MRID
42401501)
EL­
119
[
Oryzalin
(
97.6%
a.
i.
for
Study
R21990;
96.5%
a.
i.
for
Study
R10991,
lot
#
88­
1282)]
was
administered
to
40
Fischer
344
rats/
sex/
dose
in
the
diet
at
concentrations
of
0,
0.025,
0.075
and
0.225%
(
equivalent
to
0,
0,
19.4,
58.7
and
178.8
mg/
kg/
day
for
males;
0,
22.3,
68.2
and
205.5
mg/
kg/
day
for
females).
This
study
ORYZALIN/
JUNE/
2003
TRED
Toxicology
Chapter
15
was
conducted
to
supplement
a
three­
generation
reproduction
study
(
MRIDs
00038564
and
00042908)
and
provide
histopathology
on
the
reproductive
organs
of
parental
animals.
Histopathology
was
also
conducted
on
the
kidney
and
liver
which
are
considered
the
target
organs
for
oryzalin.

There
were
no
deaths
during
the
study.
The
only
clinical
signs
were
dry,
yellow
urogenital
staining
and
yellow
discoloration
of
fur
in
animals
in
the
0.075%
and
0.225%
groups.
Body
weight
was
slightly
but
significantly
decreased
during
the
premating
period
in
the
high­
dose
F
0
males
(
4%)
and
females
(
6­
8%)
and
during
the
growth
period
in
the
high­
dose
F
1
males
(
6­
7%)
and
females
(
10­
12%).
Body
weight
in
F
1
mid­
dose
females
was
slightly
but
significantly
decreased
(
3­
4%)
during
the
growth
period.
Body
weight
gain
was
also
slightly
but
significantly
decreased
during
the
premating
period
in
the
high­
dose
F
0
males
(
4%)
and
females
(
9­
11%)
and
during
the
growth
period
in
the
high­
dose
F
1
females
(
16%).
Mean
food
consumption
during
premating
was
significantly
decreased
in
the
high­
dose
F
0
males
(
2­
14%)
and
females
(
4­
14%)
and
during
the
growth
period
in
the
high­
dose
F
1
females
(
5­
8%).
Mean
body
weight
was
slightly
but
significantly
decreased
in
the
high­
dose
females
during
gestation
(
5­
7%)
and
lactation
(
6­
10%).
Mean
body
weight
gain
was
decreased
(
12%
of
control)
in
the
high­
dose
females
during
gestation
and
significantly
decreased
in
the
latter
part
of
gestation
in
the
mid­
(
13­
56%)
and
high­
dose
(
38­
76%)
groups.

There
was
no
evidence
of
a
treatment­
related
effect
on
reproduction
parameters.
On
necropsy
of
the
F
0
generation,
there
was
a
dose­
related
significant
increase
in
the
absolute
and
relative
weights
of
the
kidneys
in
all
treated
males.
There
was
a
significant
increase
in
absolute
kidney
weight
in
the
mid­
dose
females
and
a
significant
increase
in
the
relative
kidney
weights
in
the
mid­
and
high­
dose
females.
There
was
a
dose­
related
increase
in
the
absolute
and
relative
liver
weights
in
all
treated
males
and
in
the
mid
and
high
dose
females.
In
the
F
1
generation,
absolute
and
relative
kidney
and
liver
weights
were
significantly
increased
in
males
of
all
treatment
groups.
Relative
kidney
weights
were
significantly
increased
in
all
treated
females.
Absolute
and
relative
liver
weights
were
significantly
increased
in
the
mid
and
high
dose
females.
On
microscopic
examination,
there
was
a
dose­
related
increase
in
incidence
and
severity
of
bilateral
cortical
tubular
hyaline
droplets
in
the
kidneys
of
all
treated
males
and
females
in
both
generations.
Females
in
the
mid­
and
high­
dose
groups
of
both
generations
also
had
an
increased
incidence
of
cortical
tubular
necrosis.
There
was
no
evidence
of
treatment­
related
microscopic
hepatic
changes
in
the
treated
animals.
The
parental
systemic
LOAEL
was
<
0.025%
(
19.4
mg/
kg
bw/
day
in
males
and
22.3
mg/
kg
bw/
day
in
females),
based
on
increased
kidney
weights
(
males)
and
increased
incidence
of
bilateral
cortical
tubular
hyaline
droplets
in
the
kidneys.
The
parental
systemic
NOAEL
was
not
established.

The
reproductive
LOAEL
was
not
established.
The
reproductive
NOAEL
was
0.225%
concentration
(
178.8
mg/
kg/
day
in
males
and
205.5
mg/
kg/
day
in
females).

Mean
weight
in
the
F
1
pups
was
comparable
to
controls
on
Day
1
but
was
decreased
in
the
high
dose
males
(
13%)
and
females
(
13%)
on
Day
21.
The
offspring
LOAEL
was
0.225%
(
178.8
mg/
kg/
day
in
males
and
205.5
mg/
kg/
day
in
females)
based
on
decreased
body
weight
on
ORYZALIN/
JUNE/
2003
TRED
Toxicology
Chapter
16
Day
21.
The
offspring
NOAEL
was
0.075%
concentration
(
58.7
mg/
kg/
day
for
males
and
68.2
mg/
kg/
day
for
females).

This
study
is
acceptable
(
non­
guideline)
and
does
not
satisfy
the
guideline
requirement
for
a
multi­
generation
reproductive
study
(
OPPTS
870.3800);
OECD
416
in
the
rat.
The
study
was
conducted
to
supplement
a
three­
generation
reproduction
study
(
MRIDs
00038564,
00042908)
and
provide
more
histopathological
data
on
reproductive
and
target
organs.

4.5
Chronic
Toxicity
Adequacy
of
data
base
for
chronic
toxicity:
The
data
base
for
chronic
toxicity
is
considered
complete.
No
additional
studies
are
required
at
this
time.

870.4100a
(
870.4300)
Chronic
Toxicity
B
Rat
In
a
combined
chronic
/
carcinogenicity
study
(
MRIDs
00026779,
00044332
and
00070569),
Oryzalin
[
96.5%
(
Lot
X23607)
or
96%
(
Lot
9SY47)]
was
administered
to
a
total
of
120
Fischer
rats/
sex/
dose
in
the
diet
at
dose
levels
of
0,
300,
900
or
2700
ppm
(
equivalent
to
0,
12.16,
36.86
and
112.46
mg/
kg
bw/
day
in
males;
0,
13.82,
42.89
and
135.86
mg/
kg
bw/
day
in
females)
for
two
years.
Two
replicate
studies
were
conducted;
the
results
are
combined
as
the
studies
were
conducted
at
the
same
time
using
the
same
protocol.
The
study
report
states
that
an
assay
for
nitroso­
di­
n­
propylamine
content
in
the
diet
indicated
very
low
levels
were
present;
however,
the
Appendix
referred
to
for
the
analysis
is
not
included.

Survival
was
significantly
decreased
in
the
2700
ppm
males
and
females
at
Month
24
of
the
study.
Mean
body
weight
gain
was
statistically
significantly
decreased
in
the
2700
ppm
males
(
8­
17%)
during
the
last
year
of
the
study,
throughout
the
study
in
the
2700
ppm
females
(
14­
37%)
and
occasionally
in
the
900
ppm
females
(
4­
13%).
Food
consumption
was
comparable
between
treated
and
control
groups.
Feed
efficiency
was
decreased
in
the
2700
ppm
females.
RBC
parameters
(
Hgb,
Hct
and
RBC)
were
significantly
decreased
in
the
2700
ppm
males
and
females
and
in
the
900
ppm
females.

The
absolute
weight
of
the
following
organs
was
increased
in
one
or
both
replicates
in
the
2700
ppm
animals:
liver
(
males),
thyroid
(
males),
heart
(
males)
and
adrenal
(
females).
The
absolute
weight
of
the
liver
was
also
increased
in
the
900
ppm
males.
The
relative
(
to
body
weight)
weight
of
the
following
organs
was
increased
in
one
or
both
replicates
in
the
following
organs:
liver
(
both
sexes),
thyroid
(
males),
kidneys
(
both
sexes),
spleen
(
females),
adrenal
(
females)
and
testes
(
males).
The
absolute
weights
of
the
liver
and
kidneys
were
also
increased
in
the
900
ppm
males
and
females.
Only
microscopic
alterations
were
observed
in
the
thyroid
and
spleen;
therefore,
the
toxicological
significance
of
the
increases
in
the
other
organs
is
questionable.
ORYZALIN/
JUNE/
2003
TRED
Toxicology
Chapter
17
In
one
replicate,
there
was
a
non­
significant
increase
in
the
incidence
of
extramedullary
hematopoiesis
of
the
spleen
in
the
2700
ppm
females.
In
the
other
replicate,
there
was
an
nonsignificant
increase
in
the
incidence
of
skin
lesions
(
abscess,
edema,
keratin
cyst
and
suppurative
dermatitis)
in
the
2700
ppm
males
and
females
and
an
increase
in
the
incidence
of
purulent
endometritis
in
the
2700
ppm
females.
In
both
replicates,
there
was
a
dose­
related
increase
in
cystic
follicles
and
focal
follicular
hyperplasia
of
the
thyroid
which
was
most
pronounced
in
the
900
and
2700
ppm
group
males
and
females.

The
LOAEL
in
males
is
2700
ppm
(
112.46
mg/
kg/
day),
based
on
decreased
survival,
decreased
body
weight
gain,
decreased
hematology
parameters,
increased
thyroid
weight,
increased
incidence
of
skin
lesions
and
microscopic
findings
in
the
thyroid.
The
NOAEL
is
900
ppm
(
36.86
mg/
kg/
day).

The
LOAEL
in
females
is
900
ppm
(
42.89
mg/
kg/
day),
based
on
decreased
body
weight
gain,
decreased
hematology
parameters
and
increased
microscopic
findings
in
the
thyroid.
The
NOAEL
is
300
ppm
(
13.82
mg/
kg/
day).

This
chronic/
carcinogenicity
study
in
the
rat
is
acceptable(
guideline)
and
satisfies
the
guideline
requirement
for
a
chronic/
carcinogenicity
study
OPPTS
870.4300);
OECD
453]
in
rats.
Although
some
clinical
pathology
parameters
were
not
measured,
ophthalmology
examinations
were
not
conducted
and
clinical
observations
were
not
reported,
these
deficiencies
did
not
affect
the
study
results.

870.4100b
Chronic
Toxicity
­
Dog
In
a
chronic
toxicity
study
(
MRID
40024801),
compound
67019
[
Oryzalin
(
98.9%
a.
i.,
Lot
#
L­
1385A)]
was
administered
to
four
young
adult
beagle
dogs/
sex/
dose
in
capsules
at
dose
levels
of
0,
1.5,
5,
15,
or
50
mg/
kg
bw/
day
for
one
year.
The
15
mg/
kg/
day
dose
was
changed
twice
during
the
study
due
to
the
lack
of
overt
toxicity.
The
dogs
in
this
group
received
daily
doses
of
15,
250
or
500
mg/
kg/
day
for
weeks
0­
14,
15­
32
and
33
to
termination,
respectively.

All
animals
survived
the
study,
except
for
one
male
treated
at
50
mg/
kg/
day
that
was
sacrificed
moribund
in
week
52
due
to
severe
chronic
dermatitis.
There
were
no
clinical
signs
of
toxicity
and
no
treatment­
related
effects
on
body
weight,
body
weight
gain,
food
consumption,
ophthalmic
examinations,
electrocardiograms
and
urinalysis.
There
were
some
statistically
significant
changes
in
hematology
parameters
(
decreases
in
RBC,
HCT,
HGB;
increases
in
platelets
and
MCHC);
however,
there
was
no
dose­
response
and
the
effects
were
transient.
Therefore,
the
changes
were
not
considered
toxicologically
significant.
There
were
statistically
significant
increases
in
cholesterol,
alkaline
phosphatase,
and
total
bilirubin,
and
decreases
in
ALT,
AST
and
phosphorus
in
males
and
females
at
15/
250/
500
mg/
kg/
day
at
some
of
the
testing
intervals;
however,
there
was
no
evidence
that
the
magnitude
of
the
effects
responded
to
increasing
doses.
T
4
concentrations
were
measured
on
weeks
47,
50
and
51.
The
values
were
significantly
decreased
at
ORYZALIN/
JUNE/
2003
TRED
Toxicology
Chapter
18
week
47
in
the
500
mg/
kg/
day
males
and
at
weeks
47,
50
and
51
in
the
500
mg/
kg/
day
females.
There
were
also
significant
decreases
in
the
1.5
mg/
kg/
day
females
at
weeks
50
and
51.
A
TSH
stimulation
test
was
conducted
on
week
51.
The
T
4
values
were
significantly
decreased
in
the
1.5
and
500
mg/
kg/
day
females;
however,
the
animals
in
these
groups
responded
in
a
normal
manner
to
the
stimulation
(
two­
to
four­
fold
increase
in
T
4).
At
necropsy,
there
was
a
statistically
significant
increase
in
the
absolute
weight
of
the
liver
in
females
at
500
mg/
kg/
day
and
a
decrease
in
the
absolute
weight
of
the
adrenals
in
the
50
and
500
mg/
kg/
day
males.
The
relative
(
to
body
weight)
weights
of
the
liver,
brain
and
kidney
were
increased
in
the
500
mg/
kg/
day
males;
the
absolute
weight
of
the
liver
was
increased
in
the
500
mg/
kg/
day
females.
The
toxicological
significance
of
the
organ
weight
effects
is
questionable
as
there
were
no
accompanying
microscopic
changes.
One
male
and
female
each
in
the
500
mg/
kg/
day
group
were
observed
to
have
enlarge
thyroids
on
gross
examination;
however,
the
organs
were
normal
on
microscopic
examination.
Two
males
in
this
group
had
"
follicular
prominence";
the
toxicological
significance
of
these
findings
is
questionable
since
the
thyroid
weights
were
not
increased.
The
LOAEL
is
15/
250/
500
mg/
kg/
day
based
on
a
slight
decrease
in
thyroid
function
(
decreased
T4
concentrations,
primarily)
in
both
sexes.
The
NOAEL
is
50
mg/
kg/
day.

This
chronic
study
in
the
dog
is
acceptable
(
guideline)
and
satisfies
the
guideline
requirement
for
a
chronic
oral
study
[
OPPTS
870.4100,
OECD
452]
in
the
dog.

4.6
Carcinogenicity
Adequacy
of
data
base
for
Carcinogenicity:
The
data
base
for
carcinogenicity
is
considered
complete.
No
additional
studies
are
required
at
this
time.

Thyroid,
skin
and
mammary
gland
(
females)
tumors
were
produced
in
Fischer
344
rats,
whereas
B6C3F1
mice
were
negative
for
carcinogenicity.

870.4200a
Carcinogenicity
Study
­
rat
In
a
combined
chronic/
carcinogenicity
study
(
MRIDs
00026779,
00044332
and
00070569),
Oryzalin
[
96.5%
(
Lot
X23607)
or
96%
(
Lot
9SY47)]
was
administered
to
a
total
of
120
Fischer
rats/
sex/
dose
in
the
diet
at
dose
levels
of
0,
300,
900
or
2700
ppm
(
equivalent
to
0,
12.16,
36.86
and
112.46
mg/
kg
bw/
day
in
males;
0,
13.82,
42.89
and
135.86
mg/
kg
bw/
day
in
females)
for
two
years.
Two
replicate
studies
were
conducted;
the
results
are
combined
as
the
studies
were
conducted
at
the
same
time
using
the
same
protocol.
The
study
report
states
that
an
assay
for
nitroso­
di­
n­
propylamine
content
in
the
diet
indicated
very
low
levels
were
present;
however,
the
Appendix
referred
to
for
the
analysis
is
not
included.

Survival
was
significantly
decreased
in
the
2700
ppm
males
and
females
at
Month
24
of
the
study.
Mean
body
weight
gain
was
statistically
significantly
decreased
in
the
2700
ppm
males
(
8­
17%)
during
the
last
year
of
the
study,
throughout
the
study
in
the
2700
ppm
females
(
14­
37%)
and
occasionally
in
the
900
ppm
females
(
4­
13%).
Food
consumption
was
comparable
between
ORYZALIN/
JUNE/
2003
TRED
Toxicology
Chapter
19
treated
and
control
groups.
Feed
efficiency
was
decreased
in
the
2700
ppm
females.
RBC
parameters
(
Hgb,
Hct
and
RBC)
were
significantly
decreased
in
the
2700
ppm
males
and
females
and
in
the
900
ppm
females.

The
absolute
weight
of
the
following
organs
was
increased
in
one
or
both
replicates
in
the
2700
ppm
animals:
liver
(
males),
thyroid
(
males),
heart
(
males)
and
adrenal
(
females).
The
absolute
weight
of
the
liver
was
also
increased
in
the
900
ppm
males.
The
relative
(
to
body
weight)
weight
of
the
following
organs
was
increased
in
one
or
both
replicates
in
the
following
organs:
liver
(
both
sexes),
thyroid
(
males),
kidneys
(
both
sexes),
spleen
(
females),
adrenal
(
females)
and
testes
(
males).
The
absolute
weights
of
the
liver
and
kidneys
were
also
increased
in
the
900
ppm
males
and
females.
Only
microscopic
alterations
were
observed
in
the
thyroid
and
spleen;
therefore,
the
toxicological
significance
of
the
increases
in
the
other
organs
is
questionable.

In
one
replicate,
there
was
a
non­
significant
increase
in
the
incidence
of
extramedullary
hematopoiesis
of
the
spleen
in
the
2700
ppm
females.
In
the
other
replicate,
there
was
an
nonsignificant
increase
in
the
incidence
of
skin
lesions
(
abscess,
edema,
keratin
cyst
and
suppurative
dermatitis)
in
the
2700
ppm
males
and
females
and
an
increase
in
the
incidence
of
purulent
endometritis
in
the
2700
ppm
females.
In
both
replicates,
there
was
a
dose­
related
increase
in
cystic
follicles
and
focal
follicular
hyperplasia
of
the
thyroid
which
was
most
pronounced
in
the
900
and
2700
ppm
group
males
and
females.

The
LOAEL
in
males
is
2700
ppm
(
112.46
mg/
kg/
day),
based
on
decreased
survival,
decreased
body
weight
gain,
decreased
hematology
parameters,
increased
thyroid
weight,
increased
incidence
of
skin
lesions
and
microscopic
findings
in
the
thyroid.
The
NOAEL
is
900
ppm
(
36.86
mg/
kg/
day).

The
LOAEL
in
females
is
900
ppm
(
42.89
mg/
kg/
day),
based
on
decreased
body
weight
gain,
decreased
hematology
parameters
and
increased
microscopic
findings
in
the
thyroid.
The
NOAEL
is
300
ppm
(
13.82
mg/
kg/
day).

Carcinogenic
findings
occurred
in
both
sexes.
Follicular
cell
thyroid
tumors
and
skin
tumors
occurred
in
both
sexes,
whereas
fibroadenomas
of
the
mammary
gland
occurred
in
females.

This
chronic/
carcinogenicity
study
in
the
rat
is
acceptable(
guideline)
and
satisfies
the
guideline
requirement
for
a
chronic/
carcinogenicity
study
OPPTS
870.4300);
OECD
453]
in
rats.
Although
some
clinical
pathology
parameters
were
not
measured,
ophthalmology
examinations
were
not
conducted
and
clinical
observations
were
not
reported,
these
deficiencies
did
not
affect
the
study
results.

870.4200b
Carcinogenicity
(
feeding)
­
Mouse
ORYZALIN/
JUNE/
2003
TRED
Toxicology
Chapter
20
In
two
separate
replicates
(
MRIDs
00244746,
00244747
and
00244748),
Oryzalin
(
96.5%
a.
i.;
Lot
X­
28607)
was
administered
to
40
B6C3F
1
mice/
sex/
dose/
replicate
in
the
diet
at
dose
levels
of
500,
1350
or
3650
ppm
(
equivalent
to
approximately
71,
193
or
521
mg/
kg
bw/
day
based
on
1
ppm
equals
0.150
mg/
kg/
day)
for
two
years.
Sixty
(
60)
B6C3F
1
mice/
sex/
replicate
served
as
untreated
controls.
Since
the
studies
were
conducted
using
the
same
protocol,
results
were
combined.

The
12­
month
mortality
was
decreased
in
treated
males
and
increased
in
treated
females
but
survival
was
comparable
at
the
end
of
the
study.
There
was
no
evidence
of
a
treatment­
related
increase
in
clinical
observations.
Minor
decreases
in
body
weight
gain
were
observed
in
treated
males
during
the
study.
At
three
months,
weight
gain
was
non­
significantly
decreased
13%
in
one
replicate
and
at
24
months
was
significantly
decreased
18%
in
the
other
replicate.
Body
weight
gain
was
significantly
decreased
17­
35%
in
females
at
3650
ppm
from
12
months
until
termination.
Food
consumption
was
not
measured
due
to
spillage;
therefore,
the
actual
mg/
kg/
day
doses
of
oryzalin
intake
could
not
be
calculated.

Minor
alterations
in
clinical
pathology
parameters
were
not
consistent
between
replicates
and
were
judged
not
to
be
biologically
significant.
On
necropsy,
the
absolute
weight
of
the
uterus
was
decreased
in
the
1350
and
3650
ppm
groups;
the
relative
weight
of
the
uterus
was
decreased
in
this
group
in
one
replicate
only.
On
histopathology,
there
was
a
decreased
incidence
of
cystic
endometrial
hyperplasia
in
females
at
3650
ppm.
The
toxicological
significance
of
these
uterine
findings
is
questionable.
No
other
non­
neoplastic
findings
were
considered
treatment­
related.

The
LOAEL
is
conservatively
established
at
3650
ppm
(
521
mg/
kg/
day),
based
on
decreased
body
weight
gain.
The
NOAEL
is
1350
ppm
(
193
mg/
kg/
day).

The
carcinogenic
potential
was
negative.

This
carcinogenicity
study
in
the
mice
is
acceptable
(
guideline)
and
satisfies
guideline
requirement
for
a
carcinogenicity
study
[
OPPTS
870.4200;
OECD
451]
in
mice.

4.7
Mutagenicity
Adequacy
of
data
base
for
Mutagenicity:
The
data
base
for
Mutagenicity
is
considered
incomplete
based
on
1991
mutagenicity
guidelines.
A
mouse
micro
nucleus
study
is
required.

Oryzalin
was
not
mutagenic
in
bacteria.
However,
there
is
evidence
of
damage
to
DNA
as
indicated
by
the
evidence
in
bacteria
and
weak
SCE
induction
in
the
bone
marrow
of
Chinese
hamsters
via
intraperitoneal
but
not
oral
routes
of
exposure.
In
contrast,
UDS
was
not
seen
in
treated
primary
rat
hepatocytes.
Although
the
data
suggest
DNA
damage,
it
appears
that
this
effect
on
DNA
is
not
manifested
as
gene
mutations.
No
conclusion
can
be
reached
regarding
ORYZALIN/
JUNE/
2003
TRED
Toxicology
Chapter
21
chromosme
aberrations,
since
no
acceptable
study
is
available.
To
resolve
this
issue,
a
mouse
micronucleus
assay
is
required.

Gene
Mutation
Guideline
#
870.5100,
Ames
Assay
MRID
00130427
Acceptable
Oryzalin
was
negative
for
mutagenic
activity
against
several
strains
of
histidine
auxotrophs
of
Salmonella
typhimurium
and
tryptophan
auxotrophs
of
Escherichia
coli
(
WP2uvrA­)
both
in
the
presence
and
absence
of
S­
9
over
the
concentrations
tested
(
25­
300
ug/
plate)

Cytogenetics
Guideline
#
870.5915,
Sister
Chromatid
Exchange
MRID
00087801
Acceptable
Oryzalin
was
tested
in
Chinese
hamster
bone
marrow
cells
to
evaluate
sister
chromatid
exchange
with
intraperitoneal
or
oral
doses
of
200,
300,
400,
or
500
mg/
kg
of
oryzalin.
Cytotoxicity
was
produced
at
400
and
500
mg/
kg
oryzalin.
Oryzalin
produced
SCE
in
the
bone
marrow
when
administered
intraperitoneally,
but
not
orally.

Other
Genotoxicity
Guideline
#
870.5550,
Unscheduled
DNA
Synthesis
MRID
00086801
Acceptable
Oryzalin
was
negative
in
an
unscheduled
DNA
synthesis
test
in
rat
hepatocytes
up
to
cytotoxic
levels
(>
500
nmoles/
mL)

Guideline
#
870.5500,
DNA
Repair
Test
MRID
44574101
Acceptable
Oryzalin
was
positive
in
a
DNA
repair
test
at
125
and
250
ug/
disc
without
S­
9
and
42.5
and
85
ug/
disc
with
S­
9
in
the
recombination­
proficient
H17
(
rec+)
and
recombination­
deficient
M45
(
rec­)
strains
of
Bacillus
subtilis.

4.8
Neurotoxicity
Adequacy
of
data
base
for
Neurotoxicity:
Since
there
was
no
evidence
of
neurotoxicity
in
any
study,
these
studies
are
not
required
at
this
time.

4.9
Metabolism
Adequacy
of
data
base
for
metabolism:
The
data
base
for
metabolism
is
considered
to
be
complete.
No
additional
studies
are
required
at
this
time.
ORYZALIN/
JUNE/
2003
TRED
Toxicology
Chapter
22
870.7485
Metabolism
­
Rat
In
a
metabolism
study
(
MRID
44574104),
C14­
Oryzalin
(
98.4%
a.
i.,
lot
#
B930­
94,
ring­
labeled),
was
administered
to
eight
groups
of
3
Fischer
344
rats/
sex/
dose
by
gavage
at
dose
levels
of
5
or
50
mg/
kg.
Two
groups
at
each
dose
level
were
sacrificed
at
1
hr,
24
hr
or
7
days
post­
dosing.
An
additional
two
groups
in
which
the
animals
had
bile
duct
cannulations
were
sacrificed
at
24
hr
post­
dosing.

Oryzalin
absorption
was
rapid
with
peak
blood
radioactivity
levels
reached
by
0.5­
1
and
2­
3
hr
post­
dosing
with
the
5
mg/
kg
and
50
mg/
kg
doses,
respectively.
Overall
absorption
was
greater
than
71%
for
both
dose
levels.

Blood
radioactivity
decreased
post­
dosing
in
a
bi­
exponential
fashion
for
both
dose
levels.
At
5
mg/
kg,
there
was
a
rapid
 ­
elimination
phase
(
t
½
=
4­
5
hr
and

8
hr
for
5
mg/
kg
and
50
mg/
kg,
respectively)
and
a
slower
 ­
elimination
phase
(
t
½
=
51­
63
hr
and
61­
66
hr
for
5
mg/
kg
and
50
mg/
kg,
respectively).
The
blood
concentration­
time
course
curve
(
AUC)
across
dose
levels
demonstrated
an
increase
in
AUC
that
was
not
proportional
to
the
increase
in
administered
dose.
The
10­
fold
increase
in
dose
was
followed
by
a
3­
fold
increase
in
AUC,
suggesting
that
the
blood
clearance
of
14C­
oryzalin
may
be
a
saturable
process.

In
total,
<
9%
of
the
5
mg/
kg
dose
was
recovered
in
tissues
24
hr
post­
dosing.
At
7
days
postdosing
the
only
tissues
with
>
0.1%
of
dose
were
the
carcass
(
0.5­
0.6%),
blood
(
0.17­
0.3%),
skin
(
0.17­
0.29%)
and
liver
(
0.11­
0.13%).
At
50
mg/
kg,
by
24
hr
post­
dosing,
no
tissue
contained
more
than
3%
of
the
dose.
The
GI/
ingesta
contained

2­
3%,
while
the
blood,
carcass,
skin
and
liver
contained

0.4­
1.7%.
By
7
days
post­
dosing,
only
the
carcass
and
skin
had
>
0.5%
of
the
dose.
A
limited
number
of
tissues
were
examined
from
the
bile
duct
cannulated
animals
at
24
hr
post­
dosing.
At
5
mg/
kg,
the
GI/
ingesta
contained
4%
of
the
dose,
followed
by
carcass,
skin
and
blood
with
2­
5%
of
the
dose.
At
50
mg/
kg,
the
GI/
ingesta
contained
about
10%
of
the
dose,
followed
by
carcass
and
skin
with
approximately
3%
of
the
dose.

Neither
volatile
organics
nor
14CO
2
in
expired
air
contained
sufficient
radioactivity
to
quantify.
Urine
was
the
primary
route
of
elimination.
At
5
mg/
kg,
urine
comprised
approximately
42%
of
the
dose
at
24
hr
post­
dosing
and
48­
52%
at
7
days
post­
dosing.
Approximately
30%
of
the
5
mg/
kg
dose
was
recovered
in
the
feces
at
24
hr
and
approximately
35­
39%
at
7
days
post­
dosing.
Males
and
females
at
5
mg/
kg
eliminated
greater
than
80%
of
the
dose
by
24
hr
and
greater
than
88%
by
7
days
post­
dosing.
At
50
mg/
kg,
radioactivity
recovered
in
the
urine
was
49­
53%
by
24
hr
and
42­
51%
by
7
days
post­
dosing.
At
this
dose,
feces
accounted
for
approximately
35%
of
the
dose
at
24
hr
and
40­
43%
by
7
days.
Males
and
females
eliminated
greater
than
85%
of
the
50
mg/
kg
by
24
hr.
There
were
no
sex
differences
at
either
dose.

The
HPLC
analysis
of
urine,
bile,
feces,
and
selected
tissues
demonstrated
extensive
overall
metabolism
of
oryzalin.
The
metabolic
profiles
were
comparable
between
the
sexes
and
between
ORYZALIN/
JUNE/
2003
TRED
Toxicology
Chapter
23
the
low
and
high
dose
groups.
No
parent
was
detected
in
the
urine
or
feces
at
either
dose;
however,
small
amounts
were
detected
in
some
of
the
tissues
(
liver,
kidney
and
spleen).
Twentyseven
metabolites
were
detected
by
HPLC
in
male
and
female
pooled
urine.
Three
of
the
metabolites
in
male
urine
each
accounted
for
>
5%
of
the
dose
(
U­
4,
U­
10
and
U­
19)
and
one
additional
metabolite
accounted
for
>
5%
of
the
dose
(
U­
23)
in
females.
Other
peaks
accounted
for
<
5%
of
the
dose.
A
chemical
structure
was
proposed
for
these
four
metabolites.
Twenty
metabolites
were
detected
in
the
feces
of
males
and
females.
A
single
metabolite
which
accounted
for
greater
than
5%
of
the
50
mg/
kg
dose
in
males
and
females
co­
eluted
with
metabolite
U­
10
in
the
urine.
In
male
excreta,
two
additional
peaks
(
U­
8
and
U­
12)
accounted
for
greater
than
5%
of
the
dose
when
fecal
data
(
F­
13
and
F­
16)
were
combined
with
urine
data
at
5
mg/
kg.
A
structure
was
proposed
for
U­
8
but
the
data
for
U­
12
were
inconclusive.
Based
on
these
results,
a
scheme
for
the
metabolism
of
oryzalin
was
proposed.

4.10
Special/
Other
Studies
None
5.0
TOXICITY
ENDPOINT
SELECTION
5.1
See
Section
9.2
for
Endpoint
Selection
Table.

5.2
Dermal
Absorption
­
Monkey
In
a
dermal
absorption
study
(
MRID
No.
43207001),
two
Rhesus
monkeys/
sex
were
administered
14C­
labeled
oryzalin
(
2

Ci/
kg
BW,
97.8­
98.5%
a.
i.,
Lot
#
553­
T84­
067)
equivalent
approximately
to
2.0
mg/
kg
bw,
intravenously
as
well
as
dermally
to
approximately
6
cm2
of
body
surface
area
and
monitored
up
to
168
hrs.
Absolute
alcohol
was
used
as
a
vehicle
with
0.2
ml
for
intravenous
dosing
and
0.05
ml
for
topical
application.
For
intravenous
administration,
mean
radioactivity
of
43%
was
collected
in
the
urine
at
7
days
post­
dose,
with
26%
present
in
first
24
hrs.
In
the
feces,
mean
radioactivity
of
41%
was
measured
at
7
days
post­
dose
with
30%
occurring
within
the
first
24
hours.
For
topical
application,
the
mean
radioactivities
determined
at
168
hours
post­
dose
were
1%
for
urine
and
0.6%
for
feces.
Approximately,
73%
of
the
topically
applied
dose
was
recovered
in
the
dressing
and
washes
24
hrs
after
application.
Comparison
of
the
dermal
and
intravenous
results
indicate
the
percent
absorbed
dermal
dose
as
1.6%,
1.9%
and
2.3%
based
on
the
blood
concentration
(
AUC)
or
total
(
urine
and
feces)
excretion
or
urinary
excretion,
respectively.
For
human
risk
assessment,
2.3%
may
be
used
as
the
dermal
absorption
value.

Although
rats
are
recommended
species
for
the
dermal
penetration
study,
the
study
using
monkeys
is
acceptable
and
satisfies
the
guideline
requirement
(
guideline
§
85­
3,
OPPTS
Number
870.7600)
since
the
test
species
are
close
to
humans.
ORYZALIN/
JUNE/
2003
TRED
Toxicology
Chapter
1
See
memo
­
Deriving
Q
1
*
s
Using
the
Unified
Interspecies
Scaling
Factor,
P.
A.
Fenner­
Crisp,
Director,
HED,
7/
1/
94.

24
Dermal
Absorption
Factor:
2.3%

5.3
Classification
of
Carcinogenic
Potential
In
accordance
with
the
EPA
Draft
Guidelines
for
Carcinogen
Risk
Assessment
(
July
1999),
the
CARC
classified
oryzalin
into
the
category
"
Likely
to
be
Carcinogenic
to
Humans".
The
Committee
further
recommended
using
a
linear
low­
dose
extrapolation
approach
for
the
quantification
of
human
cancer
risk
based
on
female
rat
combined
follicular
cell
thyroid
tumors.

5.3.1
Quantification
of
Carcinogenic
Potential
The
unit
risk,
Q
1
*
(
mg/
kg/
day)­
1,
of
Oryzalin
based
upon
female
rat
thyroid
follicular
cell
combined
adenoma
and
carcinoma
tumor
rates
is
7.79
x
10­
3
in
human
equivalents
(
converted
from
animals
to
humans
by
use
of
the
3/
4'
s
scaling
factor
­
Tox_
Risk
program,
Version
3.5,
K.
Crump,
1994)
1.
The
dose
levels
used
from
the
105­
week
dietary
study
were
0,
300,
900,
and
2700
ppm
of
Oryzalin.
The
corresponding
tumor
rates
for
the
female
rat
combined
thyroid
follicular
cell
tumors
were
1/
55,
1/
58,
3/
54,
and
9/
50,
respectively.

6.0
FQPA
CONSIDERATIONS
6.1
Special
Sensitivity
to
Infants
and
Children
The
HIARC
concluded
that
there
is
not
a
concern
for
pre­
and/
or
postnatal
toxicity
resulting
from
exposure
to
oryzalin.

There
was
no
indication
of
pre­/
or
postnatal
quantitative
increased
susceptibility
in
the
developmental
studies
in
rats
and
rabbits
or
the
one­
generation
and
three­
generation
reproduction
studies
in
rats.
However,
there
was
an
indication
of
qualitative
prenatal
increased
susceptibility
in
the
rabbit
developmental
study.
At
the
LOAEL
of
55
mg/
kg/
day,
does
had
decreased
body
weight
and
food
consumption,
while
there
were
decreased
live
fetuses,
increased
resorptions
and
increased
post
implantation
loss
in
the
offspring.

Since
there
is
qualitative
evidence
of
increased
susceptibility
of
the
young
following
exposure
to
oryzalin
in
the
rabbit
developmental
study,
HIARC
performed
a
Degree
of
Concern
Analysis
to:
(
1)
to
determine
the
level
of
concern
for
the
effects
observed
when
considered
in
the
context
of
all
available
toxicity
data;
and
(
2)
identify
any
residual
uncertainties
after
establishing
toxicity
endpoints
and
traditional
uncertainty
factors
to
be
used
in
the
risk
assessment
of
this
chemical.
If
ORYZALIN/
JUNE/
2003
TRED
Toxicology
Chapter
25
residual
uncertainties
are
identified,
HIARC
examines
whether
these
residual
uncertainties
can
be
addressed
by
a
special
FQPA
safety
factor
and,
if
so,
the
size
of
the
factor
needed.
The
results
of
the
HIARC
Degree
of
Concern
analysis
for
oryzalin
follow.
There
was
low
concern
for
the
qualitative
susceptibility
seen
in
the
developmental
rabbit
study,
since
the
dose­
response
was
well
characterized;
there
was
a
clear
NOAEL/
LOAEL
for
maternal
and
developmental
toxicities:
There
are
no
residual
uncertainties
for
pre
and/
or
post
natal
toxicities
since
the
doses
selected
for
overall
risk
assessments
will
address
the
concerns
seen
in
the
prenatal
developmental
toxicity
study.

The
special
FQPA
safety
factor
was
reduced
to
1x
because,
there
are
low
concerns
and
no
residual
uncertainties
for
pre
and/
or
post
natal
toxicity.

Note:
This
FQPA
assessment
assumes
that
the
exposure
databases
(
dietary
food,
drinking
water,
and
residential)
are
complete
and
that
the
risk
assessment
for
each
potential
exposure
scenario
includes
all
metabolites
and/
or
degradates
of
concern
and
does
not
underestimate
the
potential
risk
for
infants
and
children.

6.2
Recommendation
for
a
Developmental
Neurotoxicity
Study
Based
on
the
weight
of
evidence
presented,
the
HIARC
concluded
that
a
developmental
neurotoxicity
study
is
not
required
for
oryzalin.

A.
Evidence
that
suggest
requiring
a
Developmental
Neurotoxicity
study:
There
is
no
evidence
for
requiring
a
DNT
B.
Evidence
that
do
not
support
a
need
for
a
Developmental
Neurotoxicity
study:
There
is
no
evidence
of
neurotoxicity
in
any
study.

There
is
no
evidence
of
neuropathology
in
any
study.

7.0
OTHER
ISSUES
The
HIARC
did
require
a
comparative
thyroid
assay
in
young
and
adult
rats
which
included
hormonal
measurements
for
thyroid
function,
since
T4
levels
were
affected
in
the
one­
year
dog
study
and
thyroid
weight
and
histopathology,
as
well
as
thyroid
tumors
were
produced
in
the
2­
year
rat
feeding
study.
The
absence
of
the
comparative
thyroid
study,
however,
did
not
result
in
a
database
uncertainty
factor
of
10x
(
UFDB
of
10x)
being
applied
to
the
acute
(
females
13­
50)
and
chronic
RfD
and
all
residential
scenarios
due
to
new
HIARC
guidance
provided
by
OPP
management.
ORYZALIN/
JUNE/
2003
TRED
Toxicology
Chapter
26
8.0
REFERENCES
in
MRID
order
MRID
No.

00026773
Kitchen,
D.
N.
(
1979).
The
Toxicological
Evaluation
of
Oryzalin
(
Compound
67019)
Given
to
Mice
in
the
Diet
for
Three
Months.
Toxicology
Division,
Lilly
Research
Laboratories,
Greenfield,
IN.
Study
M­
9276,
June
1979.
Unpublished.

00026774
Kitchen,
D.
N.
(
1979).
The
Toxicological
Evaluation
of
Oryzalin
(
Compound
67019)
Given
to
Mice
in
the
Diet
for
Three
Months.
Toxicology
Division,
Lilly
Research
Laboratories,
Greenfield,
IN.
Study
M­
9058,
June
1979.
Unpublished.

00026779,
00044332,
00070569
Carter,
J.
L.
(
1980).
Combined
Chronic/
Oncogenicity
Study
of
Oryzalin
Administered
in
Feed
to
F­
344
Rats
for
24
Months.
Replicate
Studies
No.
R­
167
and
R­
177
Performed
by
Eli
Lilly
and
Company
Research
Laboratories,
Greenfield,
IN;
Sponsor:
Elanco
Products
Co.,
Indianapolis,
IN.
dated
March,
1980.
Unpublished.

00038681
Kitchen,
D.
N.
(
1979).
The
Toxicological
Evaluation
of
Oryzalin
(
Compound
67019)
Given
to
Mice
in
the
Diet
for
One
Year.
Toxicology
Division,
Lilly
Research
Laboratories,
Greenfield,
IN.
Study
M­
9137,
June
1979.
Unpublished.

00086801
Jordan,
W.
H.
(
1981).
The
Effect
of
Oryzalin
(
Compound
67019)
on
the
Induction
of
DNA
Repair
Synthesis
in
Primary
Cultures
of
Adult
Rat
Hepatocytes,
Toxicology
Division,
Lilly
Research
Laboratories,
Greenfield,
IN.
Study
810217­
337­
UDS,
June
1981.
Unpublished.

00087801
Jordan,
W.
H.
(
1981).
The
Effect
of
Oryzalin
(
Compound
67019)
on
the
in
vivo
Induction
of
Sister
Chromatid
Exchange
in
Bone
Marrow
of
Chinese
Hamsters,
Toxicology
Division,
Lilly
Research
Laboratories,
Greenfield,
IN.
Studies
810601SCE,
810707SCE,
810720SCE,
December,
1981.
Unpublished.
ORYZALIN/
JUNE/
2003
TRED
Toxicology
Chapter
27
00106681
Dermal
Toxicity
and
Eye
Irritation
Studies;
Study
B­
D­
6­
68
and
Study
B­
E­
5­
68;
Lilly
Research
Laboratories;
December
29,
1972
00130427
Jordan,
W.
H.
(
1983).
The
Effect
of
Oryzalin
(
Compound
67019)
on
the
Induction
of
Reverse
Mutations
in
Salmonella
typhimurium
Using
the
Ames
Test,
Toxicology
Division,
Lilly
Research
Laboratories,
Greenfield,
IN.
Study
830214AMS1188,
June
1983.
Unpublished.

00150104
Acute
Oral
Toxicity
Study;
Lilly
Research
Laboratories;
Study
No.
R­
O­
215­
84;
November
13,
1984;
Acute
Dermal
Toxicity
and
Irritation
Study;
Lilly
Research
Laboratories;
Study
No.
B­
D­
173­
84;
Primary
Eye
Irritation
Study;
Lilly
Research
Laboratories;
Study
No.
B­
E­
187­
84;
November
5,
1984.;
Acute
Inhalation
Toxicity
Study;
Lilly
Research
Laboratories;
Study
No.
R­
H­
71­
84;
November
6,
1984.;
Dermal
Sensitization
Study;
Lilly
Research
Laboratories;
Study
No.
G­
01584;
January,
1985.

00244746,
00244747,
00244748
Carter,
J.
L.
(
1981).
Oncogenicity
Study
of
Oryzalin
Administered
in
Feed
to
B6C3F1
Mice
for
24
Months.
Eli
Lilly
Studies
No.
ML­
9087
and
M­
9097;
Performed
by
Eli
Lilly
and
Company
Research
Laboratories,
Greenfield,
IN.
Sponsor:
Elanco
Products
Co.,
Indianapolis,
IN.
dated
March,
1981;
Unpublished
40024801
Jordan,
W.
H.
(
1986).
A
One
Year
Chronic
Oral
Toxicity
Study
of
Oryzalin
in
Beagle
Dogs.
Hazleton
Laboratories
America,
Inc.
Study
Number
6180­
102.
dated
November
12,
1986.
Sponsor:
Elanco
Products
Co.,
Indianapolis,
IN.
Unpublished.

41034201
Acute
Inhalation
Toxicity
Study;
Report
R­
H­
001­
88;
Toxicology
Division,
Lilly
Research
Laboratories;
June
15,
1989.

43910201
Gilbert,
K.
S.
(
1996).
Oryzalin.
Primary
Dermal
Irritation
Study
in
New
Zealand
White
Rabbits;
DowElanco
Laboratory;
Lab
Project
Study
ID:
DR­
0320­
8068­
001B;
January
25,
1996.
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JUNE/
2003
TRED
Toxicology
Chapter
28
44574101
Aiuchi,
M.
(
1996).
DNA
Repair
Test
(
Rec­
assay)
with
Oryzalin
in
Bacterial
System,
Nippon
Experimental
Medical
Research
Institute
Co.,
Ltd.,
(
JAPAN),
Laboratory
Project
No.
H­
96014,
November
18,
1996.
Unpublished.

44574102
Glaza,
S.
M.
(
1996).
Dermal
Sensitization
Study
of
Oryzalin
in
Guinea
Pigs­
Maximization
Test.
Corning
Hazleton,
Inc.,
Madison,
WI.
Laboratory
ID
No.
CAW
6736­
100.
September
13,
1996.

44574103
Stabbing,
K.
E.,
Copse,
PF.,
Yan,
B.
L.
(
1996).
Oryzalin:
13­
Week
Dietary
Toxicity
Study
in
F344
Rats.
Dow
Laboratory
Study
ID
DR­
0320­
8068­
004.
Dow
Chemical
Company,
Midland,
MI.
dated
June
20,
1996.
Unpublished.

44574104
Mendrala,
A.
L.,
Markham,
D.
A.,
Hansen,
S.
C.
(
1997).
Oryzalin:
Metabolism
of
C14­
Oryzalin
in
Fischer
344
Rats.
Dow
Laboratory
Project
Study
ID
DR­
0320­
8068­
005.
Dow
Chemical
Company,
Midland,
MI.
dated
January
17,
1997.
Unpublished.
ORYZALIN/
JUNE/
2003
TRED
Toxicology
Chapter
29
9.0APPENDICES
Tables
for
Use
in
Risk
Assessment
ORYZALIN/
JUNE/
2003
TRED
Toxicology
Chapter
30
9.1
Toxicity
Profile
Summary
Tables
9.1.1
Acute
Toxicity
Table
­
See
Section
4.1
9.1.2
Subchronic,
Chronic
and
Other
Toxicity
Tables
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Results
870.3100
90­
Day
oral
toxicity
rodents
44574103
(
1996)
Acceptable/
guideline
0,
5,
50,
300
mg/
kg/
d
M:
0,
4.56,
45.88,
276.34
mg/
kg/
d
F:
0,
4.65,
46.79,
283.09
mg/
kg/
d
NOAEL
=
5
mg/
kg/
day
[
M/
F]
LOAEL
=
50
mg/
kg/
day
based
on
increased
kidney
weights
and
increased
incidence
of
hyaline
droplet
formation
in
renal
tubular
epithelial
cells.

870.3200
21/
28­
Day
dermal
toxicity
00150106
(
1985)
Acceptable/
Nonguideline
0,
1000
mg/
kg/
d
NOAEL
<
1,000
mg/
kg/
day
LOAEL
=
1,000
mg/
kg/
day
based
on
decreased
bilirubin
levels
in
both
sexes
and
increased
thyroid
weight
in
males.

870.3700a
Prenatal
developmental
in
rodents
41163801,
41640201
(
1989)
Acceptable/
Guideline
0,
50,
225,
1,000
mg/
kg/
d
Maternal
NOAEL
=
50
mg/
kg/
day
LOAEL
=
225
mg/
kg/
day
based
on
decreased
body
weight
gain
and
food
consumption.
Developmental
NOAEL
=
50
mg/
kg/
day
LOAEL
=
225
mg/
kg/
day
based
on
increase
in
preimplantation
loss,
decreased
fetal
weight,
and
incomplete
ossification.

870.3700b
Prenatal
developmental
in
nonrodents
00026785,
00052557,
00073552
(
1979)
Acceptable/
Guideline
0,
25,
55,
125
mg/
kg/
d
Maternal
NOAEL
=
25
mg/
kg/
day
LOAEL
=
55
mg/
kg/
day
based
on
decreased
body
weight
gain
and
food
consumption.
Developmental
NOAEL
=
25
mg/
kg/
day
LOAEL
=
55
mg/
kg/
day
based
on
decrease
in
live
fetuses,
increase
in
resorptions,
and
increase
in
postimplantation
loss.

870.3700b
Prenatal
developmental
in
nonrodents
00098461
(
1982)
Unacceptable/
Not
upgradable
0,
10,
25,
55
125
mg/
kg/
d
Pregnancy
rates
were
less
than
marginally
acceptable
Maternal
NOAEL
=
25
mg/
kg/
day
LOAEL
=
55
mg/
kg/
day
based
on
decreased
food
consumption.
Developmental
NOAEL
=
125
mg/
kg/
day
LOAEL
>
125
mg/
kg/
day
[
HDT].
ORYZALIN/
JUNE/
2003
TRED
Toxicology
Chapter
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Results
31
870.3800
Reproduction
and
fertility
effects
­
one
generation
42401501
(
1992)
Acceptable/
Nonguideline
0,
250,
750,
2,250
ppm
M:
0,
19.4,
58.7,
178.8
mg/
kg/
d
F:
0,
22.3,
68.2,
205.5
mg/
kg/
d
Parental/
Systemic
NOAEL
<
19.4/
22.3
mg/
kg/
day
LOAEL
>
19.4/
22.3
mg/
kg/
day
based
on
increased
kidney
weight
in
males
and
increased
incidence
of
bilateral
cortical
tubular
hyaline
droplets
in
the
kidney
in
both
sexes.
Reproductive
NOAEL
=
178.8/
205.5
mg/
kg/
day
LOAEL
>
178.8/
205.5
mg/
kg/
day
[
HDT].
Offspring
NOAEL
=
58.7/
68.2
mg/
kg/
day
LOAEL
=
178.8/
205.5
mg/
kg/
day
based
on
decreased
pup
body
weight
on
Day
21.

870.3800
Reproduction
and
fertility
effects
­
three
generation
00038564,
00042908
(
1980)
Acceptable/
Guideline
0,
250,
750,
2,250
ppm
M:
0,
13,
40,
125
mg/
kg/
d
F:
0,
16,
48,
149
mg/
kg/
d
Parental/
Systemic
NOAEL
=
40/
48
mg/
kg/
day
LOAEL
=
125/
149
mg/
kg/
day
based
on
decreased
body
weight,
body
weight
gain,
food
consumption.
Reproductive
NOAEL
=
125/
149
mg/
kg/
day
LOAEL
>
125/
149
mg/
kg/
day
[
HDT]
.
Offspring
NOAEL
=
40/
48
mg/
kg/
day
LOAEL
=
125/
149
mg/
kg/
day
based
on
decreassed
pup
body
weight
on
Day
21.

870.4100b
Chronic
toxicity
dogs
40024801
(
1986)
Acceptable/
Guideline
0,
1.5,
5,
15/
250/
500,
50
mg/
kg/
d
NOAEL
=
50
mg/
kg/
day
LOAEL
=
15/
250/
500
mg/
kg/
day
based
on
slight
decrease
in
thyroid
function
in
both
sexes
(
decreased
T
4
levels).

870.4200
Chronic
Toxicity/
Carcino
genicity
rats
00026779,
00044332,
00070569
(
1980)
Acceptable/
Guideline
0,
300,
900,
2700
ppm
M:
0,
12.16,
36.86,
112.46
mg/
kg/
d
F:
0,
13.82,
42.89,
135.86
mg/
kg/
d
NOAEL
=
13.82
mg/
kg/
day
(
F)
and
36.86
mg/
kg/
day
(
M)
LOAEL
=
42.89
mg/
kg/
day
(
F)
and
112.46
mg/
kg/
day
(
M)
mg/
kg/
day
based
on
decreased
body
weight
gain,
decreased
hematology
parameters,
and
increased
microscopic
findings
in
the
thyroid
in
females
and
decreased
survival,
decreased
weight
gain,
decreased
hematology
parameters,
increased
thyroid
weight,
increased
incidence
of
skin
lesions,
and
microscopic
findings
in
the
thyroid
in
males.
Follicular
cell
thyroid
tumors
in
both
sexes,
skin
tumors
in
both
sexes,
and
mammary
gland
tumors
in
females
ORYZALIN/
JUNE/
2003
TRED
Toxicology
Chapter
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Results
32
870.4300
Carcinogenicity
mice
00244746,
00244747,
00244748
(
1981)
Acceptable/
Guideline
0,
500,
1350,
3650
ppm
0,
71,
193,
521
mg/
kg/
d
NOAEL
=
193
mg/
kg/
day
LOAEL
=
521
mg/
kg/
day
based
on
decreased
body
weight
gain.
(
no)
evidence
of
carcinogenicity
Gene
Mutation
870.5100,
Ames
Assay
00130427
(
1983)
Acceptable/
Guideline
25­
300
ug/
plate
Oryzalin
was
negative
against
several
strains
of
Salmonella
typhimurium
and
Escherichia
coli
(
WP2uvrA­)
both
in
the
presence
and
absence
of
metabolic
activation.

Cytogenetics
870.5915,
Sister
Chromatid
Exchange
00087801
(
1981)
Acceptable/
Guideline
200,
300,
400,
or
500
mg/
kg
Oryzalin
was
tested
in
Chinese
hamster
bone
marrow
cells
to
evaluate
sister
chromatid
exchange
intraperitoneal
or
oral
doses.
Cytotoxicity
was
produced
at
400
and
500
mg/
kg
oryzalin.
Oryzalin
produced
SCE
in
the
bone
marrow
when
administered
intraperitoneally,
but
not
orally.

Other
Effects
870.5550,
Unscheduled
DNA
Synthesis
00086801
(
1981)
Acceptable/
Guideline
>
500
nmoles/
mL
Oryzalin
was
negative
in
an
unscheduled
DNA
synthesis
in
rat
hepatocytes
up
to
cytotoxic
levels
(>
500
nmoles/
mL).

Other
Effects
870.5500,
DNA
Repair
Test
44574101
Acceptable/
Guideline
42.5,
85,
125,
or
250
ug/
disc
Oryzalin
was
positive
in
a
DNA
repair
test
at
125
and
250
ug/
disc
without
S­
9
and
42.5
and
85
ug/
disc
with
S­
9
in
the
recombinant­
proficient
H17
(
rec+)
and
recombination­
deficient
M45
(
rec­)
strains
of
Bacillus
subtilis.

870.7485
Metabolism
and
pharmacokinetic
s
44574104
(
1997)
Acceptable/
Guideline
5,
50
mg/
kg
C14­
Oryzalin
Rapid
absorption,
comparable
metabolism
between
sexes,
small
amounts
in
liver,
kidney,
spleen
870.7600
Dermal
penetration
in
Monkey
43207001
(
1986)
Acceptable/
Nonguideline
0,
2.0
mg/
kg
C14­
Oryzalin
2.3%
dermal
penetration
Special
studies
none
none
ORYZALIN/
JUNE/
2003
TRED
Toxicology
Chapter
33
9.2
Summary
of
Toxicological
Dose
and
Endpoints
for
Oryzalin
for
Use
in
Human
Risk
Assessment1
Exposure
Scenario
Dose
Used
in
Risk
Assessment,
UF
FQPA
SF
and
Endpoint
for
Risk
Assessment
to
be
completed
later
for
risk
assessment
Study
and
Toxicological
Effects
Acute
Dietary
females
13­
50
years
of
age
NOAEL
=
25
mg/
kg/
day
UF
=
100
Acute
RfD
=
0.25
mg/
kg/
day
FQPA
SF
=
1x
aPAD
=
acute
RfD
FQPA
SF
=
0.25
mg/
kg/
day
Rabbit
Developmental
Study
LOAEL
=
55
mg/
kg/
day
based
on
decreased
live
fetuses,
increased
resorptions,
and
increased
postimplantation
loss.

Chronic
Dietary
all
populations
NOAEL=
13.82
mg/
kg/
day
UF
=
100
Chronic
RfD
=
0.14
mg/
kg/
day
FQPA
SF
=
1x
cPAD
=
chr
RfD
FQPA
SF
=
0.14
mg/
kg/
day
2­
Year
Rat
Feeding
Study
LOAEL
=
42.89
mg/
kg/
day
based
on
decreased
body
weight
gain,
decreased
hematology
parameters,
and
increased
microscopic
findings
in
the
thyroid.

Short­
Term
Incidental
Oral
(
1­
30
days)

(
Residential)
oral
study
NOAEL=
25
mg/
kg/
day
LOC
for
MOE
=
100
(
Residential,
includes
the
FQPA
SF)
Rabbit
Developmental
Study
LOAEL
=
55
mg/
kg/
day
based
on
based
on
decreased
body
weight
gain
and
food
consumption
in
does.

Intermediate­
Term
Oral
(
30
days
­
6
months)

(
Residential)
oral
study
NOAEL=
13.82
mg/
kg/
day
LOC
for
MOE
=
100
(
Residential,
includes
the
FQPA
SF)
2­
Year
Rat
Feeding
Study
LOAEL
=
42.89
mg/
kg/
day
based
on
decreased
body
weight
gain,
decreased
hematology
parameters,
and
increased
microscopic
findings
in
the
thyroid..
ORYZALIN/
JUNE/
2003
TRED
Toxicology
Chapter
Exposure
Scenario
Dose
Used
in
Risk
Assessment,
UF
FQPA
SF
and
Endpoint
for
Risk
Assessment
to
be
completed
later
for
risk
assessment
Study
and
Toxicological
Effects
34
Short­
Term
Dermal
(
1­
30
days),
Intermediate­
Term
Dermal
(
1­
6
months)
and
Long­
Term
Dermal
(>
6
months)

(
Occupational/
Residential)
dermal
study
LOAEL=
1000
mg/
kg/
day
LOC
for
MOE
=
300
(
Occupational)

LOC
for
MOE
=
300
(
Residential,
includes
the
FQPA
SF)
21­
Day
Dermal
Toxicity
Study
LOAEL
=
1000
mg/
kg/
day
based
on
increased
thyroid
weights
in
males,
and
increased
bilirubin
in
both
sexes.

Short­
Term
Inhalation
(
1­
30
days)

(
Occupational/
Residential)
inhalation
(
or
oral)
study
NOAEL=
25
mg/
kg/
day
(
inhalation
absorption
rate
=
100%)
LOC
for
MOE
=
100
(
Occupational)

LOC
for
MOE
=
100
(
Residential,
includes
the
FQPA
SF)
Rabbit
Developmental
Study
LOAEL
=
55
mg/
kg/
day
based
on
decreased
body
weight
gain
and
food
consumption
in
does.

Intermediate­
Term
Inhalation
(
1
­
6
months)
and
Long­
Term
Inhalation
(>
6
months)

(
Occupational/
Residential)
inhalation
(
or
oral)
study
NOAEL=
13.82
mg/
kg/
day
(
inhalation
absorption
rate
=
100%)
LOC
for
MOE
=
100
(
Occupational)

LOC
for
MOE
=
100
(
Residential,
includes
the
FQPA
SF)
2­
Year
Rat
Feeding
Study
LOAEL
=
42.89
mg/
kg/
day
based
on
decreased
body
weight
gain,
decreased
hematology
parameters,
and
increased
microscopic
findings
in
the
thyroid..

Cancer
(
oral,
dermal,
inhalation)
"
Likely"
to
be
carcinogenic
to
humans
low­
dose
extrapolation
based
on
thyroid
follicular
cell
tumors;
Q1*
=
0.00779
(
mg/
kg/
day)­
1
increases
in
thyroid
follicular
cell
tumors
in
both
sexes,
skin
tumors
in
both
sexes
and
fibroadenomas
in
females
ORYZALIN/
JUNE/
2003
TRED
Toxicology
Chapter
35
1
UF
=
uncertainty
factor,
FQPA
SF
=
FQPA
safety
factor,
NOAEL
=
no
observed
adverse
effect
level,
LOAEL
=
lowest
observed
adverse
effect
level,
PAD
=
population
adjusted
dose
(
a
=
acute,
c
=
chronic)
RfD
=
reference
dose,
LOC
=
level
of
concern,
MOE
=
margin
of
exposure
