Page
1
of
27
April
17,
2006
Memorandum
Subject:
Toxicology
Disciplinary
Chapter
for
the
Re­
Registration
Eligibility
Decision
(
RED)
Risk
Assessment
Active
Ingredient:
Ortho­
phenylphenol
and
salts
PC
Codes
064103,
064104,
064108
DP
Barcode:

From:
Timothy
F.
McMahon,
Ph.
D
Antimicrobials
Division
(
7510C)

To:
Rebecca
Miller,
Chemical
Review
Manager
Regulatory
Management
Branch
II
Antimicrobials
Division
(
7510C)
Page
2
of
27
1.0
HAZARD
CHARACTERIZATION
2­
phenylphenol
(
OPP)
is
a
white
flaky
crystal
soluble
only
in
alcohols
or
ethers.
The
potassium
and
sodium
salts
are
soluble
in
water.
Due
to
similarities
between
2­
phenylphenol
and
potassium
and
sodium
salts,
this
report
is
a
composite
of
toxicology
of
these
chemicals
is
composited
in
this
report.
Currently,
there
are
124
active
2­
phenylphenol
and
salts
registered.
Of
these
124,
seven
are
manufacturing
use/
technical
grade
active
ingredients
(
MUP/
TGAI)
products.

2­
phenylphenol
(
OPP)
is
a
bacteriostat,
microbiostat,
menaticide,
fumigant,
and
bacteriocide
chemical.
As
a
fungicide,
tolerances
have
been
established
(
40
CFR
180.129)
for
combined
residues
of
2­
phenylphenol
and
its
sodium
salt
from
postharvest
application
on
apples,
cantaloupes,
carrots,
cherries,
citrus,
cucumbers,
grapefruits,
kiwifruits,
kumquats,
lemons,
limes,
nectarines,
oranges,
bell
peppers,
peaches,
pears,
pineapples,
plums
and
prunes,
sweet
potatoes,
tangerines,
and
tomatoes.
In
addition,
OPP
is
used
in
applications
to
hard
surfaces
(
walls,
floors,
barns)
and
agricultural
premises
and
equipment,
wood
preservation
for
control
of
sapstain
and
mold,
food
handling
surfaces
and
equipment,
air
deodorization,
commercial
and
institutional
premises,
medical
premises,
residential
and
public
access
premises
(
carpet,
hard
surfaces,
crack
and
crevice
treatment),
material
preservatives
(
stains
and
paints,
metalworking
fluids,
textiles,
paper
slurries,
cement
mixtures,
glues
and
adhesives,
and
consumer,
household
and
institutional
cleaning
products).

The
acute
toxicity
database
for
OPP
and
salts
shows
that
by
the
oral
route,
a
Toxicity
Category
III
is
assigned
based
on
results
of
two
submitted
studies
(
MRIDs
43334201
and
43334204)
showing
oral
LD50
values
of
2733
mg/
kg
(
combined)
and
values
of
846
and
591
mg/
kg
(
males
and
females
respectively).
By
the
dermal
route,
an
LD50
value
of
>
5000
mg/
kg
was
obtained
in
a
submitted
study
(
MRID
00078779).
In
a
submitted
acute
inhalation
toxicity
study
(
MRID
42333101),
animals
exposed
nose­
only
to
an
aerosol
of
OPP
(
0.036
mg/
L)
showed
no
mortality;
however,
this
study
is
currently
not
acceptable
but
could
be
upgraded
if
information
is
provided
that
an
adequate
(
higher)
atmospheric
concentration
of
OPP
could
not
be
generated
and
that
smaller
particle
sizes
could
not
be
achieved.
A
primary
eye
irritation
study
was
conducted
(
MRID
00139884)
but
the
study
was
considered
unacceptable
because
the
observation
period
employed
in
the
study
(
7
days)
was
not
long
enough
to
assign
a
Toxicity
Category.
OPP
and
its
sodium
salt
are
severe
(
Toxicity
Category
I)
dermal
irritants.
OPP
and
its
sodium
salt
are
not
dermal
sensitizers.

For
subchronic
toxicity,
several
studies
from
the
open
literature
were
provided,
but
only
one
oral
(
MRID
40760206)
and
one
dermal
study
(
MRID
42881901)
are
considered
acceptable.

In
a
90­
day
oral
toxicity
test
(
MRID
40760206),
OPP
(>
98%
purity)
was
administered
in
feed
to
10
rats/
sex/
dose
at
concentrations
of
0,
0.156,
0.313,
0.625,
1.25,
or
2.5%
(
0,
182,
391,
761,
1669,
or
2798
mg/
kg/
day
and
0,
202,
411,
803,
1650,
or
3014
mg/
kg/
day
for
males
and
females,
Page
3
of
27
respectively)
for
13
weeks.
The
subchronic
toxicity
NOAEL
is
0.625
%
(
761
mg/
kg/
day,
males;
803
mg/
kg/
day,
females).
The
subchronic
toxicity
LOAEL
is
1.25%
(
1669
mg/
kg/
day,
males;
1650
mg/
kg/
day,
females),
based
on
significant
reductions
in
body
weight
gain
and
food
and
water
consumption.

In
a
21­
day
dermal
toxicity
study
(
MRID
42881901),
Fischer
344
rats
(
5/
sex)
were
administered
OPP
(
99.82%
a.
i.)
for
a
total
of
15
doses.
Rats
received
doses
of
0,
100,
500,
or
1000
mg/
kg/
day
for
6
hours
per
day.
The
highest
dose
tested,
1000
mg/
kg/
day,
a
limit
dose
for
repeated
dermal
dosing
regimens,
produced
no
significant
signs
of
systemic
toxicity.
Erythema
and
scaling
were
present
in
male
and
female
rats
at
the
500
and
1000
mg/
kg
dose
levels,
with
more
severe
irritation
in
the
females.
Microscopically,
an
increased
incidence
of
acanthosis
and
hyperkeratosis
was
observed
in
male
and
female
rats
at
the
500
and
1000
mg/
kg
dose
levels.
The
systemic
toxicity
NOAEL
is
greater
than
or
equal
to
1000
mg/
kg/
day
(
highest
dose
tested),
and
the
systemic
toxicity
LOAEL
is
greater
than
1000
mg/
kg/
day
(
not
established).
The
dermal
toxicity
NOAEL
is
100
mg/
kg/
day
based
on
an
increased
incidence
of
dermal
irritation
in
male
and
female
rats
at
the
LOAEL
of
500
mg/
kg/
day.

The
database
for
developmental
toxicity
is
considered
complete
with
two
studies.
In
one
study
(
MRID
92154037,
reformat
of
00067616
and
00164362),
OPP
(
99.69%
a.
i.)
in
cottonseed
oil
was
administered,
presumably
via
oral
gavage,
to
mated
female
Sprague­
Dawley
rats
(
37,
27,
27,
and
26/
group,
respectively)
at
dose
levels
of
0,
100,
300,
or
700
mg/
kg/
day
from
gestation
days
(
GD)
6
to
15,
inclusive.
Minimal
maternal
toxicity
was
noted
in
the
mid­
dose
group
(
91%
of
control)
and
greater
maternal
toxicity
was
noted
in
the
high­
dose
group
(
79%
of
control)
during
the
dosing
period
as
a
decrease
in
body
weight
gain.
No
developmental
toxicity
was
noted
in
the
dose
levels
tested.
In
a
second
prenatal
developmental
toxicity
study
(
MRID
41925001,
41925002,
and
41925003),
inseminated
New
Zealand
White
rabbits
(
7
females/
group)
were
administered
OPP
(
99.88%
a.
i.)
on
days
7­
19
of
presumed
gestation
by
oral
gavage
at
doses
of
0,
25,
100,
or
250
mg/
kg/
day.
There
were
no
statistically
or
biologically
significant
treatmentrelated
differences
in
the
incidence
of
fetal
malformations
or
variations
in
any
of
the
dose
groups
tested.
Findings
were
sporadic,
not
dose­
related
and/
or
within
the
range
of
historical
control
data.

In
a
2­
generation
reproductive
toxicity
study
(
MRID
43928801),
OPP
was
administered
to
Sprague­
Dawley
rats,
30/
sex/
dose,
in
the
diet
at
concentrations
of
0,
20,
100,
or
500
mg/
kg/
day.
No
treatment­
related
effects
were
observed
on
overall
mortality,
except
for
one
F0
male
rat
receiving
500
mg/
kg/
day
that
died
due
to
kidney
failure.
Urinary
bladder
calculi
observed
grossly
(
F0:
4/
30
vs.
0/
30
for
controls,
not
significant;
F1:
7/
30
vs.
0/
30
for
controls,
P<
0.05)
and
microscopically
(
F0
and
F1:
4/
30
vs.
0/
30,
not
significant)
at
500
mg/
kg/
day
in
adult
males
were
considered
treatment­
related.
Wet/
stained
ventrum
observed
in
the
F0
and
F1
adult
males
(
not
significant)
at
500
mg/
kg/
day
considered
treatment­
related.
Other
microscopic
lesions
attributed
to
treatment
of
male
rats
with
500
mg/
kg/
day
OPP
included
simple
transitional
cell
hyperplasia
(
F0
and
F1,
p<
0.05),
nodular/
papillary
transitional
cell
hyperplasia
of
the
urinary
bladder
(
F0
and
Page
4
of
27
F1,
p<
0.05)
and
chronic
inflammation
in
the
urinary
bladder
(
F0
and
F1,
p<
0.05).
The
average
severity
ratings
but
not
the
incidences
were
significantly
increased
(
p<
0.05)
for
chronic
inflammation
in
the
kidney
(
F0),
debris
in
the
renal
pelvis
(
F1),
and
dilation
of
the
ureter
(
F0).
No
treatment­
related
pathologic
lesions
were
observed
in
adult
females.
No
treatment­
related
effects
on
reproductive
function
or
performance
were
observed
in
male
or
female
rats
of
either
generation.
No
treatment­
related
effects
occurred
on
viability,
clinical
signs,
litter
size
at
birth,
or
at
the
end
of
lactation
or
sex
ratio
for
the
F1
or
F2
pups.
Body
weights
in
21­
day
old
pups
in
the
500
mg/
kg/
day
group
were
decreased
significantly
(
p<
0.01)
in
both
litters
of
each
generation.
F2b
pups
at
500
mg/
kg/
day
weighed
7%
less
(
p<
0.05)
than
controls
on
day
14
of
lactation;
no
other
statistically
significant
effects
on
pup
weights
were
observed.
Pup
weight
gain
at
500
mg/
kg/
day
was
reduced
by
12
to
14%
over
the
entire
lactation
period.
The
reduced
pup
weights
and
weight
gain
is
not
attributed
to
lactational
effects
in
the
dams,
but
is
considered
to
be
related
to
consumption
of
the
treated
food.
The
LOAEL
is
500
mg/
kg/
day
in
males
and
females,
based
on
reduced
body
weight
and
body
weight
gain
in
the
adults,
reduced
body
weight
in
21­
day
old
pups,
clinical
signs
in
adult
male
rats,
microscopic
lesions
in
the
kidneys,
and
gross
and
microscopic
lesions
in
the
urinary
bladder
of
adult
male
rats,
and
the
death
of
one
adult
male
rat
due
to
kidney
failure.
The
corresponding
NOAEL
is
100
mg/
kg/
day.
No
treatment­
related
reproductive
toxicity
occurred
in
male
or
female
rats;
therefore
the
reproductive
NOAEL
is
>
500
mg/
kg/
day.

In
a
one
year
chronic
toxicity
study
in
dogs
(
MRID
41656401),
OPP
was
administered
by
gavage
to
groups
of
male
and
female
beagle
dogs
at
doses
of
0,
30,
100,
or
300
mg/
kg/
day
five
days
a
week
for
52
weeks.
Systemic
toxicity
was
observed
at
300
mg/
kg/
day
in
the
form
of
increased
incidence
of
emesis
and
volume
of
emesis
(
supported
by
the
results
of
a
range­
finding
study
where
200
and
400
mg/
kg/
day
produced
increased
emesis).
Weight
gain
was
decreased
in
female
dogs
at
the
high
dose
(
84%
of
control
at
study
end).
Food
efficiency
was
also
slightly
decreased
in
high
dose
female
dogs
compared
to
control
at
90
and
365
days.
The
systemic
NOAEL
was
determined
to
be
100
mg/
kg/
day,
based
on
clinical
signs
of
toxicity,
reduced
body
weight
gain,
and
reduced
food
efficiency
at
300
mg/
kg/
day.

In
mutagenicity
studies
submitted
to
the
Agency,
OPP
showed
generally
negative
responses.
Most
of
the
submitted
bacterial
reverse
mutation
tests
were
negative,
but
one
test
(
MRID#
470233020)
showed
a
weakly
positive
response
in
one
bacterial
strain
(
TA1535)
in
the
absence
of
metabolic
activation,
with
2.05
to
2.9
fold
increases
at
OPP
concentrations
of
60­
200
µ
g/
plate.
In
an
in
vitro
mammalian
cell
gene
mutation
test
(
MRID470233020)
with
99%
OPP,
results
were
negative
except
for
a
dose­
related
general
toxicity.
An
In
vitro
mammalian
chromosome
aberration
test
(
470233020)
was
negative
using
99%
pure
OPP.
The
study
was
conducted
on
Chinese
hamster
fibroblast
cell
line
and
Chinese
hamster
ovary
cells.
A
study
on
Unscheduled
DNA
synthesis
in
rat
hepatocyte
cultures
was
negative
for
all
doses.
Toxic
effects
were
observed
at
the
1
x10­
3
and
1
x10­
2
M
dose
levels.
However,
the
non­
linearity
of
the
responses
observed
suggests
that
the
tumor
response
observed
in
this
rat
study
with
OPP
is
consistent
with
a
threshold
effects
involving
oxidative
damage
and
direct
DNA
damaging
effect.
Page
5
of
27
An
in
vitro
sister
chromatid
exchange
assay
(
MRID
470233020)
using
99%
a.
i.
OPP
showed
a
slight
increase
in
sister
chromatid
exchanges
without
metabolic
activation.
At
dose
levels
of
14.9,
20.0,
and
29.9
µ
g/
ml,
OPP
showed
only
a
weak
response
in
CHO
cells
in
the
absence
of
metabolic
activation.

The
available
data
show
no
significant
neurotoxic
effects
from
administration
of
the
chemical
in
experimental
animal
studies.

The
metabolism
and
pharmacokinetics
of
ortho­
phenylphenol
have
been
examined
in
studies
from
the
peer
reviewed
scientific
literature
(
Reitz
et
al.,
1983;
Bartels
et
al.,
1998).
An
oral
dose
of
ortho­
phenylphenol
can
be
directly
conjugated
with
glucuronic
acid
or
sulfate
to
form
the
glucuronide
and
sulfate
conjugate
or
can
be
metabolized
by
cytochrome
P­
450
isozymes
to
form
hydroxylated
metabolites
(
phenylhydroquinone
and
2,4
dihydroxybiphenyl)
which
are
then
in
turn
conjugated
with
glucuronic
acid
or
sulfate.
At
doses
below
approximately
200
mg/
kg,
ortho­
phenylphenol
is
found
primarily
in
urine
as
the
glucuronide
and
sulfate
conjugates
in
both
rats
and
mice.
With
increasing
dose,
however,
the
metabolic
profile
changes
and
this
has
been
postulated
to
be
related
to
the
carcinogenic
mode
of
action
for
ortho­
phenylphenol.
Briefly,
biotransformation
of
OPP
initially
involves
formation
of
phenolic
metabolites
(
such
as
2,4'­
dihydroxyphenyl
and
phenylhydroquinone)
in
the
liver
through
the
action
of
cytochrome
P­
450
(
demonstrated
by
Ozawa
et
al.
[
Xenobiotica
30(
10),
1005­
1017,
2000],
by
rat
CYP2C11
and
possibly
CYP2E1,
and
human
CYP1A2.
OPP,
phenylhydroquinone,
and
2,4'­
dihydroxybiphenyl
can
themselves
undergo
conjugation
reactions
through
the
action
of
either
sulfotransferase
or
glucuronidation
phase
II
reactions.
Phenylhydroquinone
can
also
be
converted
to
phenyl­
1,4­
benzoquinone
by
a
secondary
peroxidase­
mediated
activation
in
the
kidney
and/
or
bladder
involving
the
prostaglandin
endoperoxide
synthase
(
PHS)
complex.
The
involvement
of
PHS
has
been
suggested
on
the
basis
of
data
submitted
to
the
Office
of
Pesticide
Programs
(
D203250),
where
in
vitro
incubations
were
conducted
with
microsomal
PHS
from
ram
seminal
vesicles
using
ortho­
phenylphenol
(
OPP)
or
the
metabolites
phenylhydroquinone
(
PHQ)
and
2­
phenyl­
1,4­
benzoquinone
(
PBQ).
This
study
demonstrated
a
role
for
PHS
in
conversion
of
PHQ
to
PBQ.

2.0
Toxicology
Data
Requirements
Technical
Test
Required
Satisfied
870.1100
Acute
Oral
Toxicity
.....................................
870.1200
Acute
Dermal
Toxicity
................................
870.1300
Acute
Inhalation
Toxicity
............................
870.2400
Primary
Eye
Irritation
..................................
Y
Y
Y
Y
Y
Y
N
N
Page
6
of
27
Technical
Test
Required
Satisfied
870.2500
Primary
Dermal
Irritation.............................
870.2600
Dermal
Sensitization....................................
870.6100
Acute
Delayed
Neurotox.
(
Hen)...................
870.6200a
....
Acute
Neurotox.
Screening
Battery
(
Rat)
Y
Y
N
N
Y
Y
870.3100
Oral
Subchronic
(
Rodent)
............................
870.3150
Oral
Subchronic
(
Non­
Rodent)
....................
870.3200
21­
Day
Dermal
............................................
870.3250
90­
Day
Dermal
............................................
870.3465
90­
Day
Inhalation........................................
Y
Y
Y
N
Held
in
reserve
Y
Y
Y
870.3700aDevelopmental
Toxicity
(
rodent)
................
870.3700bDevelopmental
Toxicity(
non­
rodent).........
870.3800
Reproduction
...............................................
Y
Y
Y
Y
Y
Y
870.4100aChronic
Toxicity
(
Rodent)
..........................
870.4100bChronic
Toxicity
(
Non­
rodent)
...................
870.4200aOncogenicity
(
Rat)
.....................................
870.4200bOncogenicity
(
Mouse)
................................
870.4300
Chronic/
Oncogenicity..................................
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
870.5100
MutagenicityGene
Mutation
­
bacterial
........
870.5300
MutagenicityGene
Mutation
­
mammalian
...
870.5395
MutagenicityMammalian
erythrocyte
micronucleus
Y
Y
Y
N
Y
Y
N
870.6100
90­
Day
Neurotoxicity
(
hen)
.........................
870.6200b90
Day
Neuro.
Screening
Battery
(
Rat).......
870.6300
Develop.
Neuro............................................
N
N
N
­­
­­
­­

870.7485
General
Metabolism.....................................
870.7600
Dermal
Penetration
......................................
Y
Y
Y
Y
3.0
DATA
GAPS
The
acute
inhalation
toxicity
study
might
be
upgraded
if
additional
information
is
provided
on
generation
of
the
test
atmosphere
as
indicated
in
the
review.
The
primary
eye
irritation
study
should
be
repeated
as
the
observation
period
post­
dosing
(
7
days)
was
not
long
enough
to
establish
a
Toxicity
Category.
A
repeat
dose
inhalation
toxicity
study
is
held
in
reserve
pending
the
outcome
of
the
preliminary
risk
assessment.
Page
7
of
27
4.0
HAZARD
ASSESSMENT
4.1
Acute
Toxicity
The
acute
toxicity
database
for
OPP
and
salts
shows
that
by
the
oral
route,
a
Toxicity
Category
III
is
assigned
based
on
results
of
two
submitted
studies
(
MRIDs
43334201
and
43334204)
showing
oral
LD50
values
of
2733
mg/
kg
(
combined)
and
values
of
846
and
591
mg/
kg
(
males
and
females
respectively).
By
the
dermal
route,
an
LD50
value
of
>
5000
mg/
kg
was
obtained
in
a
submitted
study
(
MRID
00078779).
In
a
submitted
acute
inhalation
toxicity
study
(
MRID
42333101),
animals
exposed
nose­
only
to
an
aerosol
of
OPP
(
0.036
mg/
L)
showed
no
mortality;
however,
this
study
is
currently
not
acceptable
but
could
be
upgraded
if
information
is
provided
that
an
adequate
(
higher)
atmospheric
concentration
of
OPP
could
not
be
generated
and
that
smaller
particle
sizes
could
not
be
achieved.
A
primary
eye
irritation
study
was
conducted
(
MRID
00139884)
but
the
study
was
considered
unacceptable
because
the
observation
period
employed
in
the
study
(
7
days)
was
not
long
enough
to
assign
a
Toxicity
Category.
OPP
and
its
sodium
salt
are
severe
(
Toxicity
Category
I)
dermal
irritants.
OPP
and
its
sodium
salt
are
not
dermal
sensitizers.

Adequacy
of
database
for
Acute
Toxicity:

Table
1.
Acute
Toxicity
Profile
for
OPP
and
Salts
Guideline
Number
Study
Type/
Test
substance
(%
a.
i.)
MRID
Number/
Citation
Results
Toxicity
Category
870.1100
(
§
81­
1)
Acute
Oral­
Rat
OPP
purity
99.9%
43334201
LD50
=
2733
mg/
kg
III
870.1100
(
§
81­
1)
Acute
Oral­
Rat
OPP,
sodium
salt
purity
99.1%
43334204
LD50
=
846
mg/
kg
(
male)
LD50
=
591
mg/
kg
(
female)
III
870.1200
(
§
81­
2)
Acute
Dermal­
Rat
OPP
99.73%
a.
i.
00078779
LD50
>
5000
mg/
kg
IV
870.1300
(
§
81­
3)
Acute
Inhalation
 
Rat
OPP
99.9%
a.
i.
42333101
Unacceptable
study
NA
870.2400
(
§
81­
4)
Primary
Eye
Irritation
 
Rabbit
Dowicide
®
1
00139884
Unacceptable
study
NA
870.2500
(
§
81­
5)
Primary
Dermal
Irritation­
Rabbit
OPP
purity
99.9%
43334202
Primary
Irritant
I
Page
8
of
27
Table
1.
Acute
Toxicity
Profile
for
OPP
and
Salts
Guideline
Number
Study
Type/
Test
substance
(%
a.
i.)
MRID
Number/
Citation
Results
Toxicity
Category
870.2600
(
§
81­
6)
Dermal
Sensitization
­
Guinea
pig
OPP
purity
99.9%
43334203
Not
a
sensitizer.
No
870.2600
(
§
81­
6)
Dermal
Sensitization
­
Guinea
pig
OPP,
sodium
salt
purity
99.1%
43334205
Not
a
sensitizer.
No
4.2
Subchronic
Toxicity
Adequacy
of
database
for
Subchronic
Toxicity:
For
subchronic
toxicity,
several
studies
from
the
open
literature
were
provided,
but
only
one
oral
and
one
dermal
study
are
considered
acceptable
(
MRID
40760206
and
42881901,
respectively).

870.3100
90­
day
Oral
Toxicity
 
Rats
In
a
90­
day
oral
toxicity
test
(
MRID
40760206)
designed
to
determine
the
subchronic
toxicity
effects
of
repeated
dietary
exposure
to
OPP
(>
98%
purity)
in
F344/
DuCrj
rats.
OPP
was
administered
in
feed
to
10
rats/
sex/
dose
at
concentrations
of
0,
0.156,
0.313,
0.625,
1.25,
or
2.5%
(
0,
182,
391,
761,
1669,
or
2798
mg/
kg/
day
and
0,
202,
411,
803,
1650,
or
3014
mg/
kg/
day
for
males
and
females,
respectively)
for
13
weeks.
Animals
were
observed
twice
daily
for
changes
in
body
weight
and
food
and
water
consumption.

Mortality
occurred
in
treated
animals
within
2
weeks
of
initiating
the
study,
with
death
in
20%
of
males
(
4
days
into
study)
and
10%
of
females
(
8
days
into
study)
in
the
2.5%
dose
group.
Food
consumption
was
slightly
decreased
in
males
and
females
of
the
1.25%
dose
group.
Males
administered
2.5%
OPP
exhibited
significant
decreases
from
control
in
food
intake.
The
discrepancy
in
food
intake
was
greatest
in
the
first
week
but
decreased
as
the
study
progressed.
Females
of
this
group
also
exhibited
a
reduction
in
food
consumption
that
was
significantly
less
than
the
control
until
week
8;
however,
the
decreased
food
intake
trend
continued
throughout
the
remainder
of
the
study.
Additionally,
the
2.5%
rats
spilled
an
excessive
amount
of
feed
at
the
initial
stage
of
the
study
and
they
tended
to
be
thin
throughout
the
study
period.

There
were
no
other
effects
on
food
consumption
in
animals
of
the
other
dose
levels
except
for
males
treated
with
0.313%
OPP.
These
rats
showed
significant
increases
in
food
consumption
and
food
intake/
body
weight
that
appeared
to
be
reflected
in
the
body
weight
changes.
Overall
the
feeding
efficiency
(
increase
in
body
weight
over
unit
time
in
grams/
feed
intake
in
grams)
was
slightly
lower
in
groups
fed
on
feed
containing
high
OPP
concentrations.
Page
9
of
27
Water
consumption
was
significantly
decreased
from
controls
in
the
first
week
of
the
study
in
the
1.25
and
2.5%
dose
groups.
There
were
no
significant
changes
from
controls
in
body
weight
gain
in
animals
treated
with
OPP
concentrations
equal
to
or
less
than
0.625%.
Weight
gain
was
inhibited
in
males
and
females
of
the
1.25%
dose
group,
with
maximum
inhibition
ratios
of
14
and
7%,
respectively.
The
significant
weight
loss
of
1.25%
females
occurred
in
the
first
8
weeks
of
the
study.
Body
weight
gain
was
significantly
reduced
from
controls
in
both
male
and
female
rats
in
the
2.5%
OPP
dose
group.

The
hemoglobin
(
Hgb)
and
mean
red
blood
corpuscle
hemoglobin
concentration
(
MCHC)
were
significantly
lower
than
controls
in
1.25
and
2.5%
females,
while
hematological
analyses
in
the
2.5%
males
showed
significant
decreases
from
controls
in
red
blood
corpuscles
(
RBC),
Hgb,
and
MCHC.
There
was
a
slight
tendency
for
animals
to
be
anemic
in
groups
fed
higher
dosages
of
OPP.
No
treatment­
related
effects
were
observed
in
the
serum
analyses.
Pathological
and
histological
observations
indicated
treatment­
related
inflammation
of
the
kidneys
in
both
male
and
female
rats
(
most
pronounced
in
the
2.5%
group)
and
abnormal
growth
in
the
mucous
membrane
of
the
male
bladder
(
most
pronounced
in
the
1.25%
group).

The
subchronic
toxicity
NOAEL
is
0.625%
(
761
mg/
kg/
day,
males;
803
mg/
kg/
day,
females).
The
subchronic
toxicity
LOAEL
is
1.25%
(
1669
mg/
kg/
day,
males;
1650
mg/
kg/
day,
females),
based
on
significant
reductions
in
body
weight
gain
and
food
and
water
consumption.

This
study
is
classified
as
Acceptable
­
Guideline.

870.3200
21­
Day
Dermal
Toxicity
Study
 
Rat
In
a
21­
day
dermal
toxicity
study
(
MRID
42881901)
of
systemic
toxicity
in
Fischer
344
rats,
male
and
female
(
5/
sex/
dose)
were
administered
OPP
(
99.82%
a.
i.)
over
a
21
day
study
period
for
a
total
of
15
doses
of
0,
100,
500,
or
1000
mg/
kg/
day
for
6
hours
per
day.

The
highest
dose
tested,
1000
mg/
kg/
day,
a
limit
dose
for
repeated
dermal
dosing
regimens,
produced
no
significant
signs
of
systemic
toxicity.
Erythema
and
scaling
was
present
in
male
and
female
rats
at
the
500
and
1000
mg/
kg
dose
levels,
with
more
severe
irritation
effects
observed
in
the
females.
Microscopically,
an
increased
incidence
of
acanthosis
and
hyperkeratosis
was
observed
in
male
and
female
rats
at
the
500
and
1000
mg/
kg
dose
levels.

The
systemic
toxicity
NOAEL
is
greater
than
or
equal
to
1000
mg/
kg/
day
(
highest
dose
tested),
and
the
systemic
toxicity
LOAEL
is
greater
than
1000
mg/
kg/
day
(
not
established).
The
dermal
toxicity
NOAEL
is
100
mg/
kg/
day
based
on
an
increased
incidence
of
dermal
irritation
reactions
in
male
and
female
rats
observed
at
the
LOAEL
of
500
mg/
kg/
day.
Page
10
of
27
This
study
is
classified
as
Acceptable­
Guideline.

4.3
Prenatal
Developmental
Toxicity
Adequacy
of
database
for
Prenatal
Developmental
Toxicity:
The
database
for
developmental
toxicity
is
considered
complete
with
two
acceptable
guideline
studies,
one
in
the
rat
(
MRID
92154037,
reformat
of
00067616
and
00164362)
and
another
in
the
rabbit
(
MRID
41925001,
41925002,
and
41925003).

870.3700
Prenatal
Developmental
Toxicity 
Rat
In
a
prenatal
developmental
toxicity
study
(
MRID
92154037,
reformat
of
00067616
and
00164362),
OPP
(
purity
99.69%)
in
cottonseed
oil,
was
administered
presumably
by
oral
gavage
(
not
specified)
to
groups
of
37,
27,
27,
and
26
rats/
dose
by
gavage
at
dose
levels
of
0,
100,
300,
or
700
mg/
kg/
day,
respectively,
from
gestation
days
(
GD)
6
to
15,
inclusive.
The
animals
were
checked
daily
from
gestation
day
6
for
indications
of
toxicity.
Body
weights
were
recorded
daily
from
gestation
days
6
through
15
and
on
gestation
days
16
and
21.
Food
and
water
consumption
were
measured
at
3
day
intervals
beginning
on
gestation
day
6.
Examinations
at
sacrifice
consisted
of
a
determination
of
the
number
and
position
of
live,
dead,
and
resorbed
fetuses
and
staining
of
apparent
nonpregnant
uteri
along
with
liver
weights.

Minimal
maternal
toxicity
was
noted
in
the
mid­
dose
group
(
91%
of
control)
and
greater
maternal
toxicity
was
noted
in
the
high
dose
group
(
79%
of
control)
during
the
dosing
period
as
a
decrease
in
body
weight
gain.
Food
consumption
and
food
efficiency
were
slightly
reduced
in
the
mid
and
high
dose
groups
during
the
dosing
period.
Also,
the
high
dose
group
had
reduced
liver
weights.
The
maternal
toxicity
NOAEL
is
100
mg/
kg/
day
based
on
decreased
body
weight
gains,
food
consumption
and
food
efficiency.
The
maternal
toxicity
LOAEL
is
300
mg/
kg/
day.

No
developmental
toxicity
was
noted
at
the
dose
levels
tested.
The
developmental
toxicity
NOAEL
is
greater
than
or
equal
to
700
mg/
kg/
day
(
highest
dose
tested).
The
developmental
toxicity
LOAEL
is
greater
than
700
mg/
kg/
day
(
not
established).

This
study
is
classified
as
Acceptable
­
Guideline.

870.3700
Prenatal
Developmental
Toxicity
 
Rabbit
In
a
prenatal
developmental
toxicity
study
in
rabbits
(
MRID
41925001,
41925002,
and
41925003),
inseminated
New
Zealand
White
rabbits
(
7
females/
group)
were
administered
OPP
(
99.88%
a.
i.)
on
days
7­
19
of
presumed
gestation
by
oral
gavage
at
doses
of
0,
25,
100,
or
250
mg/
kg/
day.
All
animals
were
observed
daily
for
signs
of
toxicity
during
the
course
of
the
study
with
body
weights
recorded
on
gestation
days
0,
20,
and
28
and
then
daily
during
the
dosing
Page
11
of
27
period.
Any
animal
that
died
or
was
sacrificed
on
study
and
all
surviving
animals
at
study
termination
were
subjected
to
complete
necropsy.
Fetuses
were
examined
for
external,
visceral,
and
skeletal
alterations.

Administration
of
ortho­
phenylphenol
produced
evidence
of
systemic
toxicity
at
the
100
mg/
kg/
day
(
mid­
dose)
and
250
mg/
kg/
day
(
high­
dose)
levels.
An
increase
in
mortality
occurred
at
the
highest
dose
tested
(
three
dams
compared
to
one
dam
in
the
control
group).
Treatmentrelated
alterations
in
microscopic
kidney
structure,
primarily
consisting
of
inflammation
and
tubular
degeneration,
were
noted
only
in
the
high­
dose
animals.
Although
observations
of
blood
in
the
feces,
urine,
or
cage
pan
was
noted
in
the
mid­
dose
(
three
dams
compared
to
one
control
dam)
and
high­
dose
(
6
dams
compared
to
one
control
dam)
groups,
these
effects
were
determined
to
be
of
no
toxicological
significance
because
there
was
no
correlation
of
these
effects
with
signs
of
abortion
and/
or
gross/
microscopic
pathologies.
The
maternal
toxicity
NOAEL
is
100
mg/
kg/
day
and
the
maternal
toxicity
LOAEL
is
250
mg/
kg/
day
based
upon
increased
incidence
of
mortality
and
renal
inflammation/
tubular
degeneration.

There
were
no
statistically
or
biologically
significant
treatment­
related
differences
in
the
incidence
of
fetal
malformations
or
variations
in
any
of
the
dose
groups
tested.
Findings
were
sporadic,
not
dose­
related
and/
or
within
the
range
of
historical
control
data.
Therefore,
the
developmental
toxicity
NOAEL
is
greater
than
or
equal
to
250
mg/
kg/
day
(
highest
dose
tested)
and
the
developmental
LOAEL
is
greater
than
250
mg/
kg/
day
(
not
established).

This
study
is
classified
as
Acceptable
­
Guideline.

4.4
Reproductive
Toxicity
Adequacy
of
database
for
Reproductive
Toxicity:
There
was
one
acceptable/
guideline
2­
generation
reproductive
toxicity
study
(
MRID
43928801).
OPP
was
administered
to
groups
of
30
male
and
30
female
Sprague­
Dawley
rats
in
the
diet
at
concentrations
delivering
doses
of
0,
20,
100,
or
500
mg/
kg/
day.

870.3800
Reproduction
and
Fertility
Effects
 
Rat
In
a
two­
generation
reproduction
study
(
MRID
43928801)
OPP
(
99+%
a.
i.,
Lot
#
PW08118LW)
was
administered
to
groups
of
30
male
and
30
female
Sprague­
Dawley
rats
in
the
diet
at
concentrations
delivering
doses
of
0,
20,
100,
or
500
mg/
kg/
day.
Each
group
was
administered
the
control
or
test
diets
continuously
for
10
weeks
prior
to
mating,
during
mating,
gestation,
and
lactation
through
the
production
of
two
litters
(
F1a,
F1b,
F2a,
and
F2b)
including
a
14­
or
20­
day
rest
period
after
the
first
litters
were
weaned.
The
F1
parents
were
selected
when
the
pups
were
21
days
of
age;
the
pups
were
weaned
onto
the
same
diets
as
received
by
their
parents.
The
dietary
concentrations
were
adjusted
weekly
based
on
the
food
consumption
and
body
weight
of
the
previous
week
to
maintain
a
constant
dose
(
mg/
kg/
day)
except
during
gestation,
lactation,
Page
12
of
27
and
from
weaning
through
week
3
of
the
premating
period
for
F1
pups.
During
these
times,
the
animals
received
the
same
dietary
concentrations
of
test
material
as
the
respective
groups
during
the
last
week
of
the
F0
premating
period.

No
treatment­
related
effects
were
observed
in
male
or
female
adult
rats
administered
OPP
at
concentrations
of
20
or
100
mg/
kg/
day.
No
treatment­
related
effects
were
observed
on
overall
mortality,
except
for
one
F0
male
rat
receiving
500
mg/
kg/
day
that
died
due
to
kidney
failure.
The
only
treatment­
related
clinical
sign
of
toxicity
was
urine
staining
in
5/
30
(
p<
0.05)
F0
and
8/
30
(
p=
0.01)
F1
males
given
500
mg/
kg/
day
compared
with
0/
30
for
each
control
group.
A
500
mg/
kg/
day,
body
weights
at
the
end
of
the
70­
day
premating
period
were
decreased
by
2%
(
not
significant)
in
F0
males,
7%
(
p<
0.01)
in
F0
females,
11%
(
p<
0.01)
in
F1
males,
and
9%
(
p<
0.01)
in
F1
females.
At
the
end
of
the
study
(
day
175),
body
weights
were
decreased
by
5%
(
not
significant)
in
the
F0
males
and
by
11%
(
p<
0.01)
in
F1
males
administered
500
mg/
kg/
day.
Corresponding
reductions
in
weight
gain
during
the
70­
day
premating
period
were
­
9
and
­
10%
for
F0
and
F1
males
and
­
19
and
­
8%
for
F0
and
F1
females
at
500
mg/
kg/
day
compared
with
weight
gain
in
the
controls.
Reductions
in
weight
gain
after
175
days
of
treatment
were
­
19
and
­
10%
in
the
F0
and
F1
males.
In
contrast
to
weight
gain,
food
consumption
by
males
and
females
of
both
parental
generations
administered
500
mg/
kg/
day
generally
exceeded
that
of
controls,
and
the
F1
dams
weighed
6
to
8%
less
(
P<
0.05
or
<
0.01)
than
controls
and
the
F1
dams
weighed
5%
to
8%
less
(
not
significant,
p<
0.05
or
p<
0.01)
than
controls.
Weight
gain
in
500
mg/
kg/
day
group
dams
during
gestation
was
similar
to
that
of
controls
ranging
from
+
1
to
­
7%
of
the
control
value
for
both
parental
generations;
during
lactation,
weight
gain
for
all
treated
groups
in
both
generation
ranged
from
­
57
to
+
288%
and
showed
no
clear
dose­
related
trends.
For
the
first
124
days
of
lactation,
food
consumption
in
dams
receiving
500
mg/
kg/
day
ranged
from
103
to
112%
of
the
control
values.

Urinary
bladder
calculi
observed
grossly
(
F0:
4/
30
vs.
0/
30
for
controls,
not
significant;
F1:
7/
30
vs.
0/
30
for
controls,
P<
0.05)
and
microscopically
(
F0
and
F1:
4/
30
vs.
0/
30,
not
significant)
at
500
mg/
kg/
day
in
adult
males
were
considered
to
be
related
to
treatment
with
the
test
material.
Wet/
stained
ventrum
observed
(
F0:
2/
30
vs.
0/
30
for
control,
not
significant;
F1:
5/
30
vs.
0/
30
for
controls,
not
significant)
at
500
mg/
kg/
day
in
adult
males
was
considered
to
be
treatment­
related.
Other
microscopic
lesions
attributed
to
treatment
of
male
rats
with
500
mg/
kg/
day
of
the
test
material
included
simple
transitional
cell
hyperplasia
(
F0:
22/
30
vs.
1/
30;
F1:
27/
30
vs.
0/
30;
p<
0.05),
nodular/
papillary
transitional
cell
hyperplasia
of
the
urinary
bladder
(
F0:
16/
30
vs.
1/
30;
F1:
19/
30
vs.
0/
30;
p<
0.05)
and
chronic
inflammation
in
the
urinary
bladder
(
F0:
13/
30
vs.
0/
30;
F1:
12/
30
vs.
0/
30;
p<
0.05).
The
average
severity
ratings
but
not
the
incidences
were
significantly
increased
(
p<
0.05)
for
chronic
inflammation
in
the
kidney
[
F0:
4/
30
(
2.8)
vs.
0/
30]
debris
in
the
renal
pelvis
[
F1:
4/
30
(
2.5)
vs.
0/
30],
and
dilation
of
the
ureter
[
F0:
4/
30
(
1.8)
vs.
0/
30].
No
treatment­
related
pathologic
lesions
were
observed
in
adult
females.

No
treatment­
related
effects
on
reproductive
function
or
performance
were
observed
in
male
or
female
rats
of
either
generation.
No
treatment­
related
effects
occurred
on
viability,
clinical
Page
13
of
27
signs,
litter
size
at
birth,
or
at
the
end
of
lactation
or
sex
ratio
for
the
F1
or
F2
pups.
Body
weights
in
21­
day
old
pups
in
the
500
mg/
kg/
day
group
were
decreased
significantly
(
p<
0.01)
in
both
litters
of
each
generation
(­
10
to
­
12%).
F2b
pups
at
500
mg/
kg/
day
weighed
7%
less
(
p<
0.05)
than
controls
on
day
14
of
lactation;
no
other
statistically
significant
effects
on
pup
weights
were
observed.
Pup
weight
gain
at
500
mg/
kg/
day
was
reduced
by
12
to
14%
over
the
entire
lactation
period.
The
reduced
pup
weights
and
weight
gain
is
not
attributed
to
lactational
effects
in
the
dams,
but
is
considered
to
be
related
to
consumption
of
the
treated
food.

The
parental
toxicity
LOAEL
is
500
mg/
kg/
day
in
males
and
females,
based
on
reduced
body
weight
and
body
weight
gain
in
the
adults,
reduced
body
weight
in
21­
day
old
pups,
clinical
signs
in
adult
male
rats,
microscopic
lesions
in
the
kidneys,
and
gross
and
microscopic
lesions
in
the
urinary
bladder
of
adult
male
rats,
and
the
death
of
one
adult
male
rat
due
to
kidney
failure.
The
parental
toxicity
NOAEL
is
100
mg/
kg/
day.
No
treatment­
related
reproductive
toxicity
occurred
in
male
or
female
rats;
therefore
the
reproductive
NOAEL
is
>
500
mg/
kg/
day.

This
study
is
classified
as
Acceptable
­
Guideline.

4.5
Chronic
Toxicity
Adequacy
of
database
for
Chronic
Toxicity:
The
database
is
considered
adequate
for
chronic
toxicity
of
OPP.

870.4300
Combined
chronic
toxicity
/
Carcinogenicity
 
Rat
In
a
combined
chronic
toxicity
/
carcinogenicity
study
(
MRID
43954301)
CDF
rats
from
SASCO,
Inc.,
Madison
WI
received
OPP
(
99.5 
100%
a.
i.;
Batch
#
S­
01­
93,
Mixture
of
Bayer
AG,
Leverkusen,
Germany
and
Dow,
Midland,
Michigan)
in
the
diet
for
24
months
at
dose
levels
of
0,
800,
4000
and
8000
ppm
in
males,
and
0,
800,
4000,
and
10000
ppm
in
females
(
39,
200,
and
402
mg/
kg/
day
for
males
for
the
800,
4000,
and
8000
ppm
dose
groups
and
49,
248,
and
647
mg/
kg/
day
for
females
fat:
the
800,
4000,
and
10000
ppm
dose
groups).
Interim
sacrifice
groups
of
twenty
animals/
sex
for
control
and
high
dose
groups
and
ten
animals/
sex
for
low
and
mid
dose
groups
were
sacrificed
at
12
months.
Systemic
toxicity
was
noted
as
decreased
body
weights
(
p
<
0.05)
and
body
weight
gains
in
both
males
and
females
of
the
mid
and
high
dose
groups
during
the
first
13
weeks
of­
the
study
(
for
the
2­
year
carcinogenicity
group).
At
study
termination,
only
the
high
dose
groups
had
reduced
body
weights
(
p
<
0.05)
and
body
weight
gains.
Food
consumption
was
slightly
decreased
in
the
2­
year
carcinogenicity
group
in
the
high
dose
group
at
all
time
points
measured
and
was
decreased
in
the
mid
dose
females
at
13
weeks.
Food
efficiency
determined
for
the
first
13
weeks
was
slightly
decreased
in
the
mid
dose
group
and
greatly
decreased
in
the
high
dose,
group.
There
was
an
increase
in
observed
masses
in
the
Page
14
of
27
urinary
bladder
of
high
dose
males
at
24
months.
High
dose
females
had
an
increased
incidence
of
kidneys
with
pitted
zones
at
24
months.
Mid
and
high
dose
females
had
an
increase
in
wet/
stained
ventrum
at
12
months
and
both
high
dose
males
and
females
had
a
similar
observation
at
24
months,
this
was
attributed
to
the
urine
and
red
staining
in
the
perigenital
area
noted
in
the
clinical
observation
data.
Non­
neoplastic
observations
noted
an
increase
in
incidence
of
calculus
in
the
kidneys
in
high
dose
males
at
the
12
month
sacrifice
and
the
24
month
study
termination.
There
was
also
increased
hyperplasia
of
the
urinary
bladder
at
12
and
24
months
in
high
dose
males
(
and
high
dose
females
at
24
months)
along
with
an
increase
in
congestion,
hemorrhage,
mineralization
and
necrosis
of
the
urinary
bladder
at
24
months
in
high
dose
males.
High
dose
males
and
females
also
had
an
increase
in
cysts
of
the
kidney
at
24
months.
High
dose
females
had
an
increase
in
hyperplasia
of
the
kidney
along
with
increased
infarct,
acute
inflammation
and
mineralization
of
the
kidney.
Based
on
the
results
of
this
study,
the
Systemic
Toxicity
NOEL
is
equal
to
800
ppm
(
39
mg/
kg/
day
for
males
and
49
mg/
kg/
day
for
females
and
the
Systemic
Toxicity
LOEL
is
equal
to
4000
ppm
(
200
mg/
kg/
day
for
males
and
248
mg/
kg/
day
for
females)
based
on
decreased
body
weight
gains,
decreased
food
consumption
and
reduced
food
efficiency,
and
increased
clinical
and
gross
pathological
signs
of
toxicity.

This
study
is
classified
as
Acceptable
 
Guideline.

In
a
carcinogenicity
study
(
MRID#
43545501)
B6C3F1
albino
mice
(
50/
sex/
dose
group)
from
Charles
River
Laboratory,
Portage,
MI
received
ortho­
phenylphenol
(
99.88%
a.
i.;
Lot#
8800005­
24,
mixture
of
Dow
Chemical
Company
and
Miles,
Inc.
products)
in
the
diet
for
24
months
at
dose
levels
of
0
250,
500
and
1000
Mg/
kg/
day.
A
satellite
group
of
ten
animals/
sex/
dose
group
were
sacrificed
at
12
months.

Systemic
toxicity
was
noted
in
treated
females
at
3
months
as
decreased
body
weight
gain
(
10­
12%),
statistically
significant
but
not
dose
related.
At
12
and
24
months
there
was
a
14­
25%
decrease
in
body
weight
gain
in
males
and
females
of
the
mid
dose
and
a
27­
38%
decrease
in
the
high
dose
groups.
Treated
females
had
a
slightly
reduced
food
consumption
during
the
first
90
days.
Food
efficiency
for
this
period
was
slightly
reduced
for
the
male
dose
groups
and
variable
for
the
female
dosed
groups
(
no
dose
response
effect).
At
1
year
there
was
no
treatment
related
effects
on
food
consumption
and
at
2
years
there
was
a
slight
increase
in
food
consumption
in
all
treated
groups.
There
was
an
increase
in
absolute
and
relative
liver
weights
at
12
and
24
months
in
all
treated
males
and
females;
also,
treated
males
had
increased
adrenal
absolute
and
relative
weights
at
24
months.
Spleen
weights
(
absolute
and
relative)
in
the
males
and
females
were
reduced
in
all
treated
groups.
The
Systemic
Toxicity
LOEL
is
less
than
or
equal
to
250
mg/
kg/
day
and
the
Systemic
Toxicity
NOEL
lees
than
250
mg/
kg/
day
based
on
increased
liver
and
reduced
spleen
weights
and
gross
observations
in
the
liver
of
all
treated
animals
This
study
is
classified
as
Core­
Minimum
data
and
satisfies
the
guideline
requirement
(
83­
2b)
for
a
carcinogenicity
study
in
the
mouse.
Page
15
of
27
4.6
Carcinogenicity
Adequacy
of
database
for
Carcinogenicity:
The
database
for
carcinogenicity
of
OPP
is
considered
adequate.

870.4300
Chronic
Toxicity/
Carcinogenicity
Study
 
Rat
In
a
combined
chronic
toxicity/
carcinogenicity
study
(
MRID
43954301)
CDF
rats
from
SASCO,
Inc.,
Madison,
WI
received
ortho­
phenylphenol,
Technical
Grade
(
99.5­
100%
a.
i.;
Batch
#
S­
01­
93,
Mixture
of
Bayer
AG,
Leverkusen,
Germany
and
Dow,
Midland,
Michigan)
in
the
diet
for
24
months
at
dose
levels
of
0,
800,
4000
and
8000
ppm
in
males
(
39,
200,
and
402
mg/
kg/
day,
respectively)
and
0,
800,
4000,
and
10000
ppm
in
females
(
49,
248,
and
647
mg/
kg/
day,
respectively).
An
interim
sacrifice
group
of
twenty
animals/
sex
for
control
and
high
dose
groups
and
ten
animals/
sex
for
the
low
and
mid
dose
groups
were
sacrificed
at
12
months.

Male
rats
had
significant
increasing
trends,
and
significant
differences
in
the
pair­
wise
comparisons
of
the
8000
ppm
dose
group
with
the
controls,
for
urinary
bladder
papillomas,
transitional
cell
carcinomas,
and
papillomas
and/
or
transitional
cell
carcinomas
combined,
all
at
p
<
0.01
(
Table
2).
The
statistical
analyses
of
the
male
rats
were
based
upon
Peto's
Prevalence
Test
(
L.
Brunsman,
5/
19/
05,
TXR
No.
0053394).
There
were
no
compound­
related
increases
in
tumors
in
female
rats
870.4200
Carcinogenicity
 
Mouse
In
a
carcinogenicity
study
(
MRID#
43545501)
B6C3F1
albino
mice
(
50/
sex/
dose
group)
from
Charles
River
Laboratory,
Portage,
MI
received
ortho­
phenylphenol
(
99.88%
a.
i.;
Lot#
8800005­
24,
mixture
of
Dow
Chemical
Company
and
Miles,
Inc.
products)
in
the
diet
for
24
months
at
dose
levels
of
0
250,
500
and
1000
Mg/
kg/
day.
A
satellite
group
of
ten
animals/
sex/
dose
group
were
sacrificed
at
12
months.

Male
mice
had
significant
increasing
trends,
and
significant
differences
in
the
pair­
wise
comparisons
of
the
1000
mg/
kg/
day
dose
group
with
the
controls,
for
liver
adenomas
and
adenomas
and/
or
carcinomas
combined,
all
at
p<
0.01
(
L.
Brunsman,
5/
19/
05,
TXR
No.
0053394).
There
was
also
a
significant
difference
in
the
pair­
wise
comparison
of
the
500
mg/
kg/
day
dose
group
with
the
controls
for
liver
adenomas
and/
or
carcinomas
combined,
at
p
<
0.05.
Female
mice
had
a
significant
difference
in
the
pair­
wise
comparison
of
the
250
ppm
dose
group
with
the
controls
for
liver
carcinomas
at
p<
0.05.
There
were
no
other
statistically
significant
findings
for
female
mice
(
L.
Brunsman,
5/
19/
05,
TXR
No.
0053394).

This
study
is
classified
as
Core­
Minimum.
Page
16
of
27
4.7
Mutagenicity
An
analysis
of
the
genetic
toxicology
data
from
over
130
studies
with
OPP
was
undertaken
by
Brusick
(
2005)
who
found
that
there
was
no
indication
of
gene
mutations
in
bacteria
or
in
mammalian
cells
such
as
Chinese
hamster
ovary
(
CHO)
cells
and
that
positive
results
with
mouse
lymphoma
(
Tk+/­)
were
generally
associated
with
cytotoxicity.
Similarly,
clastogenicity,
which
was
the
most
frequently
observed
type
of
genotoxicity,
was
consistently
linked
with
cytotoxicity.
For
OPP,
the
most
common
type
of
structural
chromosome
damage
was
chromosome
breaks,
an
event
that
Brusick
describes
as
typically
resulting
in
cell
death.
Mixed
results
were
found
in
studies
assessing
direct
interaction
with
DNA
damage.
Based
on
the
weight­
of
­
the­
evidence
analysis,
it
was
concluded
that
positive
findings
in
genetic
toxicology
tests
were
related
to
`
excessive
cytotoxicity,
not
direct
DNA
damage".
Furthermore,
Brusick
(
2005)
states
that
agents
that
shift
the
normal
cellular
antioxidative
balance
and
induce
cytotoxicity
are
considered
threshold­
dependent
because
exposure
levels
that
do
not
produce
alterations
in
homeostais
do
not
produce
DNA
damage
(
i.
e.,
genotoxicity).
In
other
words,
oxidative
damage,
eventually
leading
to
cell
lethality,
only
occurs
at
concentrations
that
have
exceeded
the
levels
that
can
be
handled
by
normal
homeostasis.
This
observation
is
supported
by
the
analysis
of
the
carcinogenic
mechanism
of
2­
phenylphenate
by
Niho
et
al.
(
2002).
From
the
dose­
and
time­
response
studies
with
OPP
and
urinary
bladder
carcinogenicity
in
rats,
investigators
found
that
the
tumor
induction
was
a
high­
dose
phenomenon,
producing
a
steep
dose
response
at
15,000
and
20,000
ppm
but
negative
at
10,000
ppm.
Similarly,
a
steep
time
response
curve
was
plotted
with
transitional
cell
carcinoma
development
only
seen
in
4%
of
the
animals
after
24
weeks
of
continuous
oral
exposure
but
increasing
dramatically
after
24
(
53%)
and
52
(
71%)
weeks.
The
non­
linearity
of
this
response
suggested
to
the
authors
that
the
tumor
response
observed
in
these
studies
with
OPP
is
consistent
with
a
threshold
effect.

4.8
Neurotoxicity
Adequacy
of
database
for
Neurotoxicity:
Although
there
are
no
studies
conducted
specifically
addressing
neurotoxicity
of
OPP,
the
available
data
suggest
no
significant
neurotoxic
effects
of
OPP
in
experimental
animals.

4.9
Metabolism
and
Pharmacokinetics
Adequacy
of
database
for
Metabolism
and
Pharmacokinetics:

The
metabolism
and
pharmacokinetics
of
ortho­
phenylphenol
have
been
examined
in
studies
from
the
peer
reviewed
scientific
literature
(
Reitz
et
al.,
1983;
Bartels
et
al.,
1998).
An
oral
dose
of
ortho­
phenylphenol
can
be
directly
conjugated
with
glucuronic
acid
or
sulfate
to
form
the
glucuronide
and
sulfate
conjugate
or
can
be
metabolized
by
cytochrome
P­
450
isozymes
to
form
hydroxylated
metabolites
(
phenylhydroquinone
and
2,4
dihydroxybiphenyl)
which
are
then
in
Page
17
of
27
turn
conjugated
with
glucuronic
acid
or
sulfate.
At
doses
below
approximately
200
mg/
kg,
ortho­
phenylphenol
is
found
primarily
in
urine
as
the
glucuronide
and
sulfate
conjugates
in
both
rats
and
mice.
With
increasing
dose,
however,
the
metabolic
profile
changes
and
this
has
been
postulated
to
be
related
to
the
carcinogenic
mode
of
action
for
ortho­
phenylphenol.
Briefly,
Biotransformation
of
OPP
initially
involves
formation
of
phenolic
metabolites
(
such
as
2,4'­
dihydroxyphenyl
and
phenylhydroquinone)
in
the
liver
through
the
action
of
cytochrome
P­
450
(
demonstrated
by
Ozawa
et
al.
[
Xenobiotica
30(
10),
1005­
1017,
2000],
by
rat
CYP2C11
and
possibly
CYP2E1,
and
human
CYP1A2.
OPP,
phenylhydroquinone,
and
2,4'­
dihydroxybiphenyl
can
themselves
undergo
conjugation
reactions
through
the
action
of
either
sulfotransferase
or
glucuronidation
phase
II
reactions.
Phenylhydroquinone
can
also
be
converted
to
phenyl­
1,4­
benzoquinone
by
a
secondary
peroxidase­
mediated
activation
in
the
kidney
and/
or
bladder
involving
the
prostaglandin
endoperoxide
synthase
(
PHS)
complex.
The
involvement
of
PHS
has
been
suggested
on
the
basis
of
data
submitted
to
the
Office
of
Pesticide
Programs
(
D203250),
where
in
vitro
incubations
were
conducted
with
microsomal
PHS
from
ram
seminal
vesicles
using
ortho­
phenylphenol
(
OPP)
or
the
metabolites
phenylhydroquinone
(
PHQ)
and
2­
phenyl­
1,4­
benzoquinone
(
PBQ).
This
study
demonstrated
a
role
for
PHS
in
conversion
of
PHQ
to
PBQ.

The
presence
of
PHS
in
the
bladder
epithelium
has
been
proposed
by
Kolachana
et
al.
(
Carcinogenesis
12(
1):
145­
149,
1991)
as
possibly
responsible
for
the
activation
of
phenylhydroquinone
to
reactive
intermediates
in
the
bladder
and
kidney.
The
generation
of
PBQ
is
considered
dose­
dependent,
appearing
in
increased
quantity
only
at
higher
(>
200
mg/
kg/
day)
doses
of
OPP.
The
shift
in
biotransformation
products
with
increased
dose
of
OPP
has
been
postulated
to
be
associated
with
the
non­
linear
response
observed
in
tumorigenicity
of
the
urinary
bladder
and
liver,
involving
oxidative
damage
to
cells
and
subsequent
regenerative
hyperplasia.
With
continued
exposure,
this
process
leads
to
development
of
tumors.

5.0
TOXICITY
ENDPOINT
SELECTION
5.1
See
Section
7.1,
Summary
of
Toxicological
Doses
and
Endpoint
Selection,
Table
2.

5.2
Dermal
Absorption
Dermal
Absorption
Factor:
There
are
no
available
animal
studies
on
the
magnitude
of
dermal
absorption
of
ortho­
phenylphenol.
One
study
(
Timchalk
et
al.,
1996)
reported
a
dermal
absorption
value
of
43%
after
application
to
the
forearm
of
six
human
volunteers.
However,
there
are
currently
significant
scientific
and
political
issues
with
respect
to
the
Agency
utilizing
results
from
human
studies
for
conduct
of
risk
assessments.
Therefore,
the
default
value
of
100%
must
be
used
for
dermal
absorption
until
such
time
that
an
acceptable
dermal
absorption
study
in
animals
is
available
or
issues
with
respect
to
use
of
results
from
human
studies
are
resolved.
Page
18
of
27
5.3
Classification
of
Carcinogenic
Potential
In
accordance
with
the
EPA
Final
Guidelines
for
Carcinogen
Risk
Assessment
(
March
29,
2005),
the
CARC
classified
OPP
as
"
Not
Likely
to
be
Carcinogenic
to
Humans"
based
on
convincing
evidence
that
a
non­
linear
mode
of
action
for
bladder
tumors
was
established
in
rats.
High
doses
of
OPP
lead
to
saturation
of
phase
II
detoxification
enzyme
pathways,
resulting
in
increased
amounts
of
the
oxidative
metabolites
PHQ
and/
or
PBQ.
The
generation
of
PBQ
is
considered
dose­
dependent,
appearing
in
increased
quantity
only
at
higher
doses
of
OPP
(>
200
mg/
kg/
day).
The
shift
in
biotransformation
products
with
increased
dose
of
OPP
has
been
postulated
to
be
associated
with
the
non­
linear
response
observed
in
tumorigenicity
of
the
urinary
bladder,
involving
oxidative
damage
to
cells
and
subsequent
regenerative
hyperplasia.
With
continued
exposure,
this
process
leads
to
development
of
tumors.
Evidence
suggests
that
there
are
not
sufficient
oxidative
metabolites
generated
in
vivo
to
result
in
a
genotoxic
mode
of
action,
but
that
a
non­
genotoxic
mode
of
action
is
operative.

Although
there
is
some
mode
of
action
data
for
the
mouse
liver
tumors,
the
nature
of
these
tumors
and
their
response
(
benign
tumors
in
one
sex
at
the
limit
dose
and
one­
half
the
limit
dose
in
a
susceptible
strain)
would
not
be
the
basis
for
quantification
of
human
risk.
However,
data
do
suggest
that
this
tumor
type
may
also
arise
from
a
non­
linear
mode
of
action.

In
addition,
the
non­
cancer
assessment
for
OPP
established
a
chronic
Reference
Dose
value
of
39
mg/
kg/
day
from
the
combined
chronic
toxicity/
carcinogenicity
study
in
rats
(
MRIDs
43954301,
44852701,
44832201)
based
on
decreased
body
weight
gains,
decreased
food
consumption
and
reduced
food
efficiency,
and
increased
clinical
and
gross
pathological
signs
of
toxicity
at
the
LOAEL
of
200
mg/
kg/
day.
The
selection
of
39
mg/
kg/
day
as
the
chronic
RfD
value
is
sufficiently
protective
of
the
key
events
involved
in
the
carcinogenic
mode
of
action,
which
are
not
present
at
doses
below
200
mg/
kg/
day.
Thus,
the
precursor
events
leading
to
development
of
bladder
and
liver
tumors
are
not
likely
to
occur
using
the
selected
chronic
RfD
value
and
this
value
is
thus
protective
against
development
of
tumors
and,
therefore,
cancer
is
not
an
issue.

6.0
FQPA
CONSIDERATIONS
6.1
Developmental
Toxicity
Study
Conclusions
Developmental
toxicity
studies
for
OPP
are
available
in
both
the
rat
and
rabbit,
as
summarized
in
this
toxicology
chapter.
Both
studies
were
well
conducted
and
considered
acceptable
by
the
Agency.
The
examination
of
these
studies
shows
that
adverse
effects
in
offspring
occurred
at
doses
higher
than
those
producing
maternal
toxicity.
In
addition,
the
effects
on
offspring
were
not
considered
more
severe
than
those
occurring
in
maternal
animals.
Therefore,
there
is
no
Page
19
of
27
increased
concern
for
developmental
toxicity
of
OPP
when
comparing
effects
in
adult
animals
with
those
in
offspring.
This
conclusion
is
similar
to
that
reached
by
the
Department
for
Environment,
Food
and
Rural
Affairs
of
the
Pesticides
Safety
Directorate
in
their
1993
publication
on
the
Evaluation
of
2­
phenyl
phenol.

6.2
Reproductive
Toxicity
Study
Conclusions
An
acceptable
two­
generation
reproduction
toxicity
study
conducted
according
to
Agency
guidelines
is
available
for
OPP.
There
were
no
toxicologically
significant
effects
on
reproductive
parameters
in
this
study.
Therefore,
there
is
no
increased
concern
for
potential
reproductive
toxicity
of
OPP.

6.3
Information
from
Literature
Sources
Peer
reviewed
scientific
literature
is
available
on
both
the
reproductive
and
developmental
toxicity
of
OPP
(
IPCS,
1999).
None
of
these
studies
indicates
increased
concern
for
developmental
or
reproductive
toxicity
of
OPP.

6.4
Pre­
and/
or
Postnatal
Toxicity
A.
Determination
of
Susceptibility
From
the
available
data
submitted
to
the
Agency
and
the
available
peer
reviewed
scientific
literature
on
developmental
and
reproductive
toxicity,
there
was
no
increased
concern
for
susceptibility
from
exposure
to
OPP.

B.
Degree
of
Concern
Analysis
and
Residual
Uncertainties
There
are
no
residual
uncertainties
identified
from
examination
of
the
available
data
on
developmental
and
reproductive
toxicity
of
OPP.
Available
submitted
studies
are
well­
conducted
and
identify
clear
dose­
response
relationships
for
parental
and
offspring
toxicity.
Peer
reviewed
literature
supports
the
findings
of
the
submitted
studies.

C.
Proposed
Hazard­
based
Special
FQPA
Safety
Factor(
s):

The
special
hazard­
based
FQPA
safety
factor
can
be
reduced
to
1x
for
OPP.

6.5
Recommendation
for
a
Developmental
Neurotoxicity
Study
There
is
no
need
for
a
developmental
neurotoxicity
study
with
OPP
at
this
time.
The
available
data
show
no
significant
neurotoxic
effects
from
administration
of
the
chemical
in
experimental
animal
studies.
Page
20
of
27
7.0
SUMMARY
OF
TOXICOLOGICAL
DOSES
AND
ENDPOINTS
FOR
OPHENYLPHENOL
FOR
USE
IN
HUMAN
RISK
ASSESSMENT
7.1
Summary
Table
of
Toxicological
Dose
and
Endpoint
Selection
(
Table
2)

Table
2
Summary
of
Toxicological
Doses
and
Endpoints
for
OPP
for
Use
in
Human
Risk
Assessments
Exposure
Scenario
Dose
Used
in
Risk
Assessment
(
mg/
kg/
day)
Target
MOE,
UF,
Special
FQPA
SF,
for
Risk
Assessment
Study
and
Toxicological
Effects
Dietary
Risk
Assessments
Acute
Dietary
(
general
population
and
females
13­
49)
No
appropriate
endpoints
were
identified
that
represent
a
single
dose
effect.
Therefore,
this
risk
assessment
is
not
required.

Chronic
Dietary
(
all
populations)
NOAEL
=
39
mg/
kg/
day
FQPA
SF
=
1
UF
=
100
(
10x
inter­
species
extrapolation,
10x
intra­
species
variation)

Chronic
RfD
(
cPAD)
=
0.39
mg/
kg/
day
Combined
oral
toxicity/
carcinogenicity
study
in
rats
(
MRID
43954301,
44852701,
44832201)

LOAEL
of
200
mg/
kg/
day
based
upon
decreased
body
weight,
body
weight
gain,
food
consumption
and
food
efficiency,
increased
clinical
and
gross
pathological
signs
of
toxicity.

Non­
Dietary
Risk
Assessments
Incidental
Oral
Short­
Term
(
1
­
30
days)
NOAEL
(
maternal)
=
100
mg/
kg/
day
Target
MOE
=
100
(
10x
inter­
species
extrapolation,
10x
intra­
species
variation)
FQPA
SF
=
1
Developmental
(
gavage)
toxicity
studies
in
rats
(
MRID
00067616,
92154037)
and
rabbits
(
MRID
41925003;
co­
critical
developmental
toxicity
study)

Maternal
LOAEL
of
300
mg/
kg/
day
based
upon
clinical
observations
of
toxicity,
decreased
weight
gain,
food
consumption
and
food
efficiency
observed
in
the
rat
developmental
toxicity
study.
Page
21
of
27
Table
2
Summary
of
Toxicological
Doses
and
Endpoints
for
OPP
for
Use
in
Human
Risk
Assessments
Exposure
Scenario
Dose
Used
in
Risk
Assessment
(
mg/
kg/
day)
Target
MOE,
UF,
Special
FQPA
SF,
for
Risk
Assessment
Study
and
Toxicological
Effects
Incidental
Oral
Intermediate­
Term
(
1
­
6
months)
NOAEL
=
39
mg/
kg/
day
Target
MOE
=
100
(
10x
inter­
species
extrapolation,
10x
intra­
species
variation)

FQPA
SF
=
1
Combined
oral
toxicity/
carcinogenicity
study
in
rats
(
MRID
43954301,
44852701,
44832201)

LOAEL
of
200
mg/
kg/
day
based
upon
decreased
body
weight,
body
weight
gain,
food
consumption
and
food
efficiency,
increased
clinical
and
gross
pathological
signs
of
toxicity.

Dermal
Short­
Term
(
1
­
30
days)

(
residential
and
occupational)
NOAEL
(
dermal)
=
100
mg/
kg/
day
Target
MOE
=
100
(
10x
inter­
species
extrapolation,
10x
intra­
species
variation)
21­
Day
Dermal
toxicity
study
in
rats
(
MRID
42881901)

LOAEL
(
dermal)
of
500
mg/
kg/
day
based
upon
dermal
irritation
(
erythema,
scaling)
at
the
site
of
test
substance
application.

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

(
residential
and
occupational)
NOAEL
=
39
mg/
kg/
daya
Target
MOE
=
100
(
10x
inter­
species
extrapolation,
10x
intra­
species
variation)
Combined
oral
toxicity/
carcinogenicity
study
in
rats
(
MRID
43954301,
44852701,
44832201)

LOAEL
of
200
mg/
kg/
day
based
upon
decreased
body
weight,
body
weight
gain,
food
consumption
and
food
efficiency
(
effects
observed
as
early
as
13
weeks
in
this
study),
increased
clinical
and
gross
pathological
signs
of
toxicity.

Inhalation
Short­
Term
(
1
­
30
days)

(
residential
and
occupational)
NOAEL
(
maternal)
=
100
mg/
kg/
dayb
Target
MOE
=
100
(
10x
inter­
species
extrapolation,
10x
intra­
species
variation)
.

An
additional
10x
factor
for
route­
toroute
extrapolation
is
used
to
determine
the
need
for
an
inhalation
toxicity
study
Developmental
(
gavage)
toxicity
studies
in
rats
(
MRID
00067616,
92154037)
and
rabbits
(
MRID
41925003;
co­
critical
developmental
toxicity
study)

Maternal
LOAEL
of
300
mg/
kg/
day
based
upon
clinical
observations
of
toxicity,
decreased
weight
gain,
food
consumption
and
food
efficiency
observed
in
the
rat
developmental
toxicity
study.
Page
22
of
27
Table
2
Summary
of
Toxicological
Doses
and
Endpoints
for
OPP
for
Use
in
Human
Risk
Assessments
Exposure
Scenario
Dose
Used
in
Risk
Assessment
(
mg/
kg/
day)
Target
MOE,
UF,
Special
FQPA
SF,
for
Risk
Assessment
Study
and
Toxicological
Effects
Inhalation
Intermediate­
and
Long­
Term
(
1
­
6
months
and
>
6
months)

(
residential
and
occupational)
NOAEL
=
39
mg/
kg/
dayb
Target
MOE
=
100
(
10x
interspecies
extrapolation,
10x
intra­
species
variation)

An
additional
10x
factor
for
route­
toroute
extrapolation
is
used
to
determine
the
need
for
an
inhalation
toxicity
study.
Combined
oral
toxicity/
carcinogenicity
study
in
rats
(
MRID
43954301,
44852701,
44832201)

LOAEL
of
200
mg/
kg/
day
based
upon
decreased
body
weight,
body
weight
gain,
food
consumption
and
food
efficiency
(
effects
observed
as
early
as
13
weeks
in
this
study),
increased
clinical
and
gross
pathological
signs
of
toxicity.

Cancer
Classification:
OPP
is
classified
as
A
Not
likely
to
be
carcinogenic
below
a
specific
dose
range."
Quantitation
of
cancer
risk
is
not
required.

UF
=
uncertainty
factor,
DB
UF
=
data
base
uncertainty
factor,
FQPA
SF
=
special
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,
MOE
=
margin
of
exposure
a
A
default
dermal
absorption
factor
of
100%
is
used
because
an
oral
endpoint
was
selected
for
the
intermediate­
and
long­
term
dermal
exposure
scenarios
and
there
are
no
acceptable
dermal
absorption
studies
in
animals
available.
b
The
inhalation
absorption
factor
of
100%
(
default
value,
assuming
oral
and
inhalation
absorption
are
equivalent)
should
be
used
since
an
oral
endpoint
was
selected
for
the
inhalation
exposure
scenarios.

8.0
TOXICITY
PROFILE
TABLES
8.1
Acute
Toxicity
Profile
Table
­
(
See
Section
4.1,
Acute
Toxicity,
Table
1).

8.2
Subchronic,
Chronic
and
Other
Toxicity
Profiles
Table
(
Table
3)
Page
23
of
27
Table
3:
Subchroninc,
Chronic,
and
other
Toxicity
Profiles
for
OPP
and
its
Sodium
salt.
Guideline
Number/
Study
Type/
Test
Substance
(%
a.
i.)
MRID
Number
(
Year)/
Citation/
Classification/
Doses
Results
870.3100
Subchronic
oral
­
Rats
OPP
purity
>
98%
MRID
40760206
Iguchi,
et
al.
(
1984)
Acceptable
­
Guideline
0,
0.156,
0.313,
0.625,
1.25,
or
2.5%
(
0,
182,
391,
761,
1669,
or
2798
mg/
kg/
day
(
males)
0,
202,
411,
803,
1650,
or
3014
mg/
kg/
day
(
females))
Subchronic
Toxicity:
NOAEL
=
761
mg/
kg/
day
(
males)
=
803
mg/
kg/
day
(
females)
LOAEL
=
1669
mg/
kg/
day
(
males)
=
1650
mg/
kg/
day
(
females)
Based
on
significant
reductions
in
body
weight
gain
and
food
and
water
consumption.

Mortality
occurred
at
the
high
dose
groups
within
2
weeks
of
study
initiation
in
20%
of
the
males
and
10%
of
females.
Food
consumption
was
slightly
decreased
in
males
and
females
of
the
two
high
doses.
Water
consumption
was
significantly
decreased
from
controls
in
the
first
week
of
the
study
in
the
two
high
dose
groups.
The
hemoglobin
(
Hgb)
and
mean
red
blood
corpuscle
hemoglobin
concentration
(
MCHC)
were
significantly
lower
at
the
two
high
doses
in
females
and
in
males
at
the
high
dose.
No
treatment­
related
effects
were
observed
in
the
serum
analyses.
Pathological
and
histological
observations
indicated
treatment­
related
inflammation
of
the
kidneys
in
both
males
and
females
and
abnormal
growth
in
the
mucous
membrane
of
the
male
bladder
(
most
pronounced
in
the
1.25%,
1669
and
1650
mg/
kg/
day,
dose
groups).

870.3200
21­
day
dermal
­
Rat
OPP
purity
99.82%
MRID
42881901
Zempel
and
Szabo
(
1993)
Acceptable
­
Guideline
0,
100,
500,
or
1000
mg/
kg/
day,
6
hours
per
day,
15
doses
Dermal
Toxicity:
NOAEL
=
100
mg
/
kg/
day
LOAEL
=
500
mg
/
kg/
day,
based
on
increased
incidence
of
dermal
irritation
Systemic
Toxicity:
NOAEL
 
1000
mg/
kg/
day
(
highest
dose
tested)
LOAEL
>
1000
mg/
kg/
day
(
not
established)

Erythema,
scaling,
and
an
increased
incidence
of
acanthosis
and
hyperkeratosis
was
observed
in
male
and
female
rats
at
the
500
and
1000
mg/
kg
dose
levels.
From
the
data
in
this
study,
female
rats
appeared
to
be
more
sensitive.
Page
24
of
27
Table
3:
Subchroninc,
Chronic,
and
other
Toxicity
Profiles
for
OPP
and
its
Sodium
salt.
Guideline
Number/
Study
Type/
Test
Substance
(%
a.
i.)
MRID
Number
(
Year)/
Citation/
Classification/
Doses
Results
870.3700
Developmental
 
Rat
OPP
purity
99.69%
MRID
92154037
Reformat
of
67616
and
164362
John,
et
al.
(
1978)
Acceptable
­
Guideline
0,
100,
300,
or
700
mg/
kg/
day,
GD
6
to
15
Maternal
Toxicity:
NOAEL
=
100
mg/
kg/
day
LOAEL
=
300
mg/
kg/
day,
based
on
decreased
body
weight
gains,
food
consumption,
and
food
efficiency.

Developmental
Toxicity:
NOAEL
 
700
mg/
kg/
day
(
highest
dose
tested)
LOAEL
>
700
mg/
kg/
day
(
not
established)

Decreased
body
weight
gain
was
observed
at
the
mid
(
91%
of
control)
and
high­
dose
(
79%
of
control)
groups.
Food
consumption
and
food
efficiency
were
slightly
reduced
in
the
mid
and
high­
dose
groups.
Also,
the
high­
dose
group
had
reduced
liver
weights.

870.3700
Developmental
 
Rabbit
OPP
purity
99.88%
MRIDs
41925001
(
rangefinding
41925002
(
pilot),
and
41925003
(
developmental)
Zablotney,
et
al.
(
1991)
Acceptable
­
Guideline
0,
25,
100,
or
250
mg/
kg/
day,
GD
7
to
19
Maternal
toxicity
NOAEL
=
100
mg/
kg/
day
LOAEL
=
250
mg/
kg/
day,
based
on
increased
incidence
of
mortality
and
renal
inflammation/
tubular
degeneration.

Developmental
toxicity
NOAEL
 
250
mg/
kg/
day
(
highest
dose
tested)
LOAEL
>
250
mg/
kg/
day
(
not
established)

At
the
highest
dose
tested,
an
increase
in
mortality
(
three
dams
compared
to
one
dam
in
the
control
group)
and
treatment­
related
alterations
in
microscopic
kidney
structure,
primarily
consisting
of
inflammation
and
tubular
degeneration,
were
noted.
Although
observations
of
blood
in
the
feces,
urine,
or
cage
pan
was
noted
in
the
mid­
dose
(
three
dams
compared
to
one
control
dam)
and
high­
dose
(
6
dams
compared
to
one
control
dam)
groups,
these
effects
were
determined
to
be
of
no
toxicological
significance
because
there
was
no
correlation
of
these
effects
with
signs
of
abortion
and/
or
gross/
microscopic
pathologies.
Page
25
of
27
Table
3:
Subchroninc,
Chronic,
and
other
Toxicity
Profiles
for
OPP
and
its
Sodium
salt.
Guideline
Number/
Study
Type/
Test
Substance
(%
a.
i.)
MRID
Number
(
Year)/
Citation/
Classification/
Doses
Results
870.3800
Reproduction
 
Rat
OPP
purity
>
99%
MRIDs
43928801
Acceptable
­
Guideline
0,
20,
100,
or
500
mg/
kg/
day
Maternal
toxicity
NOAEL
=
100
mg/
kg/
day
LOAEL
=
500
mg/
kg/
day,
based
on
increased
reduced
body
weight
and
body
weight
gain
in
adults,
reduced
body
weight
in
21­
day
old
pups,
clinical
signs
in
adult
male
rats,
microscopic
lesions
in
the
kidneys,
and
gross
microscopic
lesions
in
the
urinary
bladder
of
adult
male
rats,
and
the
death
of
one
adult
male
rat
due
to
kidney
failure.

Reproductive
Toxicity:
NOAEL
 
500
mg/
kg/
day
(
highest
dose
tested)
LOAEL
>
500
mg/
kg/
day
(
not
established)

870.4300
Combined
chronic
toxicity/
Carcinogenicity
 
Rat
OPP
purity
99.5
­
100%
MRID
43954301,
supplemental
submissions
MRID
448322701
and
44852701
Wahle
and
Christenson
(
1996)
Acceptable
­
Guideline
0,
800,
4000,
or
8000
ppm
(
males)
(
0,
39,
200,
or
402
mg/
kg/
day)
0,
800,
4000,
or
10,000
ppm
(
females)
(
0,
49,
248,
or
647
mg/
kg/
day)
Systemic
Toxicity:
NOAEL
=
800
ppm
=
39
mg/
kg/
day
(
males)
=
49
mg/
kg/
day
(
females)
LOAEL
=
4000
ppm
=
200
mg/
kg/
day
(
males)
=
248
mg/
kg/
day
(
females)
Based
on
decreased
body
weight
gains,
food
consumption
and
food
efficiency,
and
increased
clinical
and
gross
pathological
signs
of
toxicity.

870.4200
Carcinogenicity
 
Mouse
OPP
purity
99.88%
MRID
43545501
Quast
and
McGuirk
(
1995)
Acceptable
­
Guideline
0,
250,
500,
or
1000
mg/
kg/
day)
Systemic
Toxicity:
NOAEL
<
250
mg/
kg/
day
LOAEL
=
250
mg/
kg/
day
Based
on
increased
liver
and
reduced
spleen
weights
and
gross
observations
in
the
liver
of
all
treated
animals.
Page
26
of
27
9.0
REFERENCES
41925001
(
MRID):
Zablotny,
C.
L.,
et
al.
(
1991):
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phenylphenol
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13­
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24­
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41925002
(
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Zablotny,
C.
L.,
et
al.
(
1991):
Ortho­
phenylphenol
(
OPP):
Gavage
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in
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(
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C.
L.,
et
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(
1991):
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(
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Gavage
Teratology
Study
in
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Zealand
White
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MI.
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42881901
(
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J.
A.
and
J.
R.
Szabo
(
1993):
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1996):
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PHENYLPHENOL:
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92­
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44832201
(
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MRID
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KS.
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92­
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44852701
(
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S.
and
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1996):
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(
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Brunsman,
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