Document ID: EPA-HQ-OPP-2004-0301-0008
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2004-09-10T04:00Z

Page
1
of
42
UNITED
STATES
ENVIRONMENTAL
PROTECTION
AGENCY
WASHINGTON,
D.
C.
20460
OFFICE
OF
PREVENTION,
PESTICIDES,
AND
TOXIC
SUBSTANCES
TXR
Number:

MEMORANDUM
DATE:
July
6,
2004
SUBJECT:
PHENOL/
SODIUM
PHENATE:
Toxicology
Chapter
for
the
AD
Preliminary
Risk
Assessment
Document.
PC
Code:
064001,
064002.
DP
Barcode:
.
Submission
Number:
.

FROM:
Michelle
M.
Centra,
Pharmacologist
Regulatory
Management
Branch
II
Antimicrobials
Division
(
7510C)

THROUGH:
Timothy
F.
McMahon,
Ph.
D.
Senior
Toxicologist
Antimicrobials
Division
(
7510C)

TO:
Najm
Shamim,
Ph.
D.
Science
Coordinator
Antimicrobials
Division
(
7510C)

and
Connie
Welch,
Branch
Chief
Ben
Chambliss,
Team
Leader
Antimicrobials
Division
(
7510C)

Attached
is
the
toxicology
chapter
for
Phenol
Reregistration
Eligibility
Decision
(
RED).

The
following
supporting
documents
were
used
to
generate
the
toxicology
chapter
of
the
Reregistration
Eligibility
Decision
(
RED)
for
phenol:

1.
Toxicity
Profile
of
Phenol/
Sodium
Phenate
2.
USEPA.
Toxicological
Review
of
Phenol.
Integrated
Risk
Information
System
(
IRIS).
September,
2002.
3.
Phenol­
Report
of
the
Antimicrobials
Division
Toxicology
End­
point
Selection
Committee
(
ADTC).
Page
2
of
42
PHENOL/
SODIUM
PHENATE
Reregistration
Case
Number:
4074
PC
Code:
064001,
064002
Toxicology
Disciplinary
Chapter
for
the
Reregistration
Eligibility
Decision
Document
Date
completed:
June
30,
2004
Contract
Number:
68­
W­
01­
036
Prepared
for
Antimicrobials
Division
Office
of
Pesticide
Programs
U.
S.
Environmental
Protection
Agency
Arlington,
VA
22202
Prepared
by
Samantha
J.
Jones,
Ph.
D.,
Toxicologist
Versar,
On­
Site
Contractor
for
Versar
6850
Versar
Center
P,
O.
Box
1549
Springfield,
VA
22151
Principal
Reviewer
_________________________________
Date
________________
Samantha
J.
Jones,
Ph.
D.

Disclaimer
This
data
Summary
may
have
been
altered
by
the
Antimicrobials
Division
subsequent
to
signing
by
Versar
personnel.

form:
FINAL
June
21,
2000
Page
3
of
42
EPA
Reviewer:
Michelle
M.
Centra,
Pharmacologist
Signature:
_______________________
Regulatory
Management
Branch
II
Date:
______________________
Antimicrobials
Division
1.0
HAZARD
CHARACTERIZATION
Phenol
(
hydroxybenzene,
carbolic
acid,
phenyl
hydroxide),
is
registered
with
the
Office
of
Pesticides
Programs
(
OPP)
as
an
active
ingredient
and
used
as
an
intermediate
in
the
production
of
epoxy
resins
and
various
other
products,
as
a
general
disinfectant,
and
in
medicinal
preparations.
It
is
used
to
control
Animal
Pathogenic
Bacteria
(
G­
and
G+
Vegetative),
Pseudomonas
SPP.,
Mycobacterium
SPP.
(
Tubercle
Bacilli),
Animal
Pathogenic
Fungi,
Hydrophilic
Viruses,
Poliovirus
Type
1,
Parvovirus,
Lipophilic
Viruses,
Vaccinia
Virus,
Influenza
A2
(
Hong
Kong,
Japan,
Japan
305/
57
Asian
Strain),
HIV­
I
(
Human
Immunodeficiency
Virus),
and
mold/
mildew.
Phenol
is
manufactered
by
Sporicidin
International
and
DR.
Novis
Smith
&
Company,
Incorporated.

Formulated
as
a
pressurized
and
ready­
to­
use
liquid,
phenol
is
registered
for
use
as
a
sanitizer,
bacteriostat,
fungicide/
fungistat,
tuberculocide,
disinfectant,
and
virucide
(
EPA
Reg.
No.
707­
159).
Phenol
has
a
number
of
use
sites
including
indoor
food
uses
in
eating
establishments
on
equipment
and
utensils,
non­
food
indoor
uses
in
commercial­
transportation
facilities,
institutional/
industrial
floors,
industrial
premises/
equipment,
laundry
equipment,
paints,
latex,
and
specialty
industrial
products.
Indoor
residential
uses
of
phenol
encompass
the
bathroom
premises,
hard
surfaces,
diaper
pails,
dogs/
canines,
household/
domestic
dwellings,
and
solid
waste
containers
(
garbage
cans).
Phenol
also
has
indoor,
medical
uses
on
surgical
instruments
and
pacemakers
(
critical
items),
catheters
and
inhalation
equipment
(
semi­
critical
items),
bedpans
and
furniture
(
noncritical
items),
non­
conductive
floors,
critical
premises
(
burn
wards),
noncritical
premises,
patient
premises,
and
institution
premises
(
human/
veterinary).
Additionally,
phenol
is
used
in
aquatic
non­
food
residential
areas
for
swimming
pool
water
systems.

Phenol
is
produced
through
both
natural
and
anthropogenic
processes.
It
is
naturally
occurring
in
some
foods,
in
human
and
animal
wastes,
and
in
decomposing
organic
material,
and
it
is
produced
endogenously
in
the
gut
from
the
metabolism
of
aromatic
amino
acids.
Phenol
has
been
isolated
from
coal
tar,
but
is
now
synthetically
manufactured.
Currently,
the
largest
use
of
phenol
is
as
an
intermediate
in
the
production
of
phenolic
resins,
which
are
used
in
the
plywood,
adhesive,
construction,
automotive,
and
appliance
industries.
Phenol
is
also
used
in
the
production
of
synthetic
fibers
such
as
nylon
and
for
epoxy
resin
precursors
such
as
bisphenol­
A.
Phenol
is
toxic
to
bacteria
and
fungi,
and
it
is
used
as
a
slimicide
and
disinfectant.
Because
of
its
anesthetic
effects,
phenol
is
used
in
medicines
such
as
ointments,
ear
and
nose
drops,
cold
sore
lotions,
throat
lozenges
and
sprays
(
such
as
those
sold
under
the
Cepastat
®
and
Chloraseptic
®
labels),
and
antiseptic
lotions.

The
acute
toxicity
database
for
phenol
technical
is
considered
complete.
No
additional
studies
are
required
at
this
time.
Phenol
has
a
moderate
order
of
acute
toxicity
via
the
oral
and
dermal
routes
of
exposure
(
Toxicity
Category
II
or
III)
and
produces
severe
and
marked
irritation
to
the
eyes
and
skin
(
Toxicity
Category
I
or
II).
Phenol
concentrations
used
in
acute
inhalation
studies
failed
to
induce
mortality
in
the
study
animals;
therefore,
toxicity
endpoints
and
a
toxicity
category
Page
4
of
42
could
not
be
established.
The
acute
toxicity
data
for
phenol
is
summarized
below
in
Table
2.

In
the
subchronic
database,
oral
range­
finding
studies
in
both
the
rat
and
the
mouse
were
completed.
Although
the
studies
were
non­
guideline
(
due
to
the
lack
of
subchronic
parameters),
systemic
toxicities
were
noted
at
10000
ppm
in
the
rat
and
mouse,
based
on
a
decrease
in
mean
body
weight
gain.
In
a
two­
week
inhalation
study,
rats
had
elevated
plasma
Mg2+
levels
(
Hypermagnesaemia)
and
exhibited
toxic
effects
in
the
central
nervous
system
(
CNS).

Phenol
was
administered
in
two
developmental
guideline
studies
in
the
rat
and
mouse
at
concentrations
of
30,
60,
or
120
mg/
kg/
day
and
70,
140,
or
280
mg/
kg/
day,
respectively.
There
was
no
evidence
of
toxicity
in
these
animals
at
concentrations
below
the
high­
dose.
Fetal
body
weight
was
significantly
reduced
at
120
and
280
mg/
kg/
day
in
both
rat
and
mouse
studies.
Additionally,
female
mice
experienced
increased
mortality
and
clinical
signs
of
CNS
toxicity
(
tremors,
ataxia,
lethargy)
at
the
high­
dose
(
280
mg/
kg/
day).
In
a
non­
guideline
developmental
study
(
Kavlock,
1990),
there
were
decreases
in
rat
maternal
body
weight
gain
in
maternal
and
offspring
In
a
two­
generational
reproductive
study
in
rats
exposed
to
200,
1000,
or
5000
ppm
phenol
in
drinking
water
for
10
weeks/
generation,
there
were
decreases
in
water
and
food
consumption,
body
weight
and
body
weight
gain
at
the
high­
dose
(
potential
reduced
palatability).
Offspring
toxic
effects
including
decreases
in
body
weight
and
litter
survival
were
observed
at
5000.
This
occurred
concurrently
with
maternal
toxicity
(
decreased
maternal
body
weight);
believed
to
be
secondary
to
the
animals'
aversion
to
the
flavor
of
the
phenol­
treated
water
and
resulted
in
decreased
maternal
as
well
as
offspring
body
weight.
In
a
non­
guideline
reproductive
study
(
Bishop,
et
al.
1997)
phenol
was
administered
to
mice
at
a
concentration
of
350
mg/
kg.
There
were
no
treatment­
related
clinical
signs
or
mortality
observed
in
maternal,
reproductive,
and
developmental
parameters
and
the
LOAEL
was
not
established
(
highest
dose
tested,
350
mg/
kg).

Two
carcinogenicity
studies
performed
by
the
National
Cancer
Institute
did
not
exhibit
an
incidence
of
neoplasms
in
male
and
female
mice
or
rats
following
administration
of
phenol,
with
the
exception
of
a
statistically
significant
increase
in
the
occurrence
of
leukemia,
lymphoma,
or
interstitial­
cell
tumors
in
low­
dose
male
rats.
Due
to
the
lack
of
significant
tumors
in
high­
dose
males
and
the
absence
of
significant
neoplasms
in
mice
and
female
rats,
phenol
was
found
to
be
non­
carcinogenic
in
the
2­
year
drinking
water
studies.
Although
phenol­
treated
rats
and
mice
experienced
a
decrease
in
mean
body
weight
and
body
weight
gain,
the
reduction
was
not
significantly
different
from
the
respective
controls
and
chronic
toxicity
was
not
observed
at
phenol
concentrations
up
to
5000
ppm.
A
20­
week
dermal
study
exhibited
effects
of
chronic
irritation
and
hair
growth
inhibition
with
administration
of
3
mg
phenol
(
in
200
uL
acetone).
A
single
papilloma
was
found
7
weeks
into
the
study,
but
there
was
no
evidence
that
it
was
significantly
increased
or
treatment­
related.
In
a
special,
mechanistic
study
there
was
no
evidence
of
tumor
initiation
or
hepatocyte
GSH
depletion
following
administration
of
100
mg/
kg/
day
phenol.

Phenol
is
characterized
as
Group
D;
the
not
classified
compounds
for
which
there
is
inadequate
or
no
human
or
animal
evidence
of
carcinogenicity.
The
updated
toxicological
review
in
the
EPA
IRIS
database
(
USEPA,
2002)
provides
a
summary
of
the
weight
of
the
evidence
with
respect
to
the
carcinogenic
potential
of
phenol.
Page
5
of
42
The
results
of
the
mutagenicity
studies
indicated
that
phenol
was
not
mutagenic
in
Salmonella
typhimurium
or
Drosophila
melanogaster
and
did
not
induce
micronuclei
or
bone
marrow
chromosomal
aberrations
in
mice.
However,
mutagenic
effects
were
observed
in
Chinese
Hamster
Ovary
cells
and
spermatocytes
in
mice
and
HL60
cells.
The
genotoxic
potential
of
phenol
appears
to
depend
on
the
competing
processes
of
activation
to
a
genotoxic
form
and
metabolic
inactivation
(
e.
g.,
via
conjugation).
Phenol
tended
to
be
negative
in
bacterial
gene
mutation
assays
but
was
positive
or
equivocal
in
mammalian
cell
gene
mutation
assays.
Phenol
tended
to
induce
micronuclei
in
mice
when
administered
intraperitoneally
but
was
negative
(
or
positive
only
at
very
high
doses)
when
administered
orally.
This
difference
is
likely
due
to
the
first­
pass
conjugation
and
inactivation
of
orally
administered
phenol.
Phenol
was
also
positive
in
in
vitro
micronucleus
tests
with
human
lymphocytes
and
Chinese
Hamster
Ovary
cells.
Results
from
DNA
damage
assays
are
inconsistent,
but
they
tend
to
show
that
phenol
can
cause
sister
chromatid
exchanges
or
cell
transformation
if
it
is
not
metabolically
inactivated.
Overall,
phenol
did
not
exhibit
strong
mutagenic
effects.

The
ADTC
committee
noted
neurotoxic
signs
from
acute
dermal
toxicity
studies
(
Brown,
et
al.
­
convulsions;
OTS
0515567­
tremors;
Conning,
et
al.­
stimulation
of
motor
nerve
endings
or
spinal
motor
centers)
and
a
15­
day
inhalation
study
(
tilting
plane
results
showed
an
effect
in
treated
rats).
There
were
no
neurotoxic
signs
of
phenol
noted
from
the
oral
studies
using
gavage
or
drinking
water
as
the
method
of
administration.
As
noted
in
the
IRIS
Toxicological
profile,
numerous
CNS
effects
have
been
observed
following
phenol
dosing.
Tremors
were
observed
in
one
animal
that
later
died
(
apparently
of
dehydration)
following
dosing
in
drinking
water
(
ClinTrials
BioResearch,
1998).
Tremors
have
also
been
observed
in
several
gavage
studies
in
rats
and
mice
(
43735402;
Dow
Chemical
Co.,
1994;
Moser
et
al.,
1995).
However,
in
a
specialized
13­
week
neurotoxicity
study
in
male
and
female
rats
that
included
an
FOB
and
a
detailed
neurohistopathology
evaluation
(
ClinTrials
BioResearch,
1998),
the
only
observed
nervous
system
effects
were
tremors
in
one
animal
and
decreased
motor
activity
in
females.
A
short­
term
gavage
screening
study
(
Moser,
et
al.
1995)
found
that
the
only
effect
in
an
FOB
was
a
marginal
decrease
in
motor
activity
and
increased
rearing
post­
exposure.
Part
of
this
could
be
attributed
to
the
dehydration
observed
in
the
study.

Phenol
is
essentially
completely
metabolized
in
24
hours.
Phenol
was
predominantly
conjugated
with
sulfate
and
lower
amounts
of
glucuronic
acid
and
the
metabolites
were
rapidly
excreted
in
the
urine.
The
major
metabolites
found
are
phenyl
sulfate,
quinol
sulfate,
phenyl
glucuronide,
and
quinol
glucuronide.

Phenol
is
readily
absorbed
by
the
inhalation,
oral,
and
dermal
routes.
The
portal­
of­
entry
metabolism
for
the
inhalation
and
oral
routes
appears
to
be
extensive
and
involves
sulfate
and
glucuronide
conjugation
and,
to
a
lesser
extent,
oxidation.
Once
absorbed,
phenol
is
widely
distributed
in
the
body,
although
the
levels
in
the
lung,
liver,
and
kidney
are
often
reported
as
being
higher
than
in
other
tissues
(
on
a
per­
gram­
tissue
basis).
Elimination
from
the
body
is
rapid,
primarily
as
sulfate
and
glucuronide
conjugates
in
the
urine,
regardless
of
the
route
of
administration.
Phenol
does
not
appear
to
accumulate
significantly
in
the
body.
Page
6
of
42
2.0
REQUIREMENTS
Table
1.
Requirements
(
CFR
158.340)
for
Food/
Feed
Use
for
Phenol/
Sodium
Phenate
Guideline
Number
and
Toxicity
Study
Required
Satisfied
870.1100
Acute
Oral
Toxicity
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.1200
Acute
Dermal
Toxicity
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.1300
Acute
Inhalation
Toxicity
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.2400
Primary
Eye
Irritation
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.2500
Primary
Dermal
Irritation
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.2600
Dermal
Sensitization
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
870.3100
Oral
Subchronic
(
Rodent)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.3150
Oral
Subchronic
(
Non­
Rodent)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.3200
21­
Day
Dermal
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.3250
90­
Day
Dermal
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
None
28­
Day
Inhalation
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
870.3700
Developmental
Toxicity
(
Rodent)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.3700
Developmental
Toxicity
(
Non­
rodent)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.3800
Reproduction
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
yes
yes
yes
yes
yes
yes
870.4100
Chronic
Toxicity
(
Rodent)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.4100
Chronic
Toxicity
(
Non­
rodent)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.4200
Oncogenicity
(
Rat)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.4200
Oncogenicity
(
Mouse)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.4300
Chronic/
Oncogenicity
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
870.5100
Mutagenicity
 
Gene
Mutation
­
bacterial
.
.
.
.
.
.
.
.
.
.
.
.
.
870.5300
Mutagenicity
 
Gene
Mutation
­
mammalian
.
.
.
.
.
.
.
.
.
.
870.5375
Mutagenicity
 
Structural
Chromosomal
Aberrations
.
.
.
.
870.5385
Mutagenicity
 
Structural
Chromosomal
Aberrations
.
.
.
.
870.5500
Mutagenicity
 
Other
Genotoxic
Effects
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.5550
Mutagenicity
 
Other
Genotoxic
Effects
.
.
.
.
.
.
.
.
.
.
.
.
.
.
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
870.6100
Acute
Delayed
Neurotox.
(
Hen)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.6100
90­
Day
Neurotoxicity
Hen)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.6200
Acute
Neurotox.
Screening
Battery
(
Rat)
.
.
.
.
.
.
.
.
.
.
.
.
.
870.6200
90
Day
Neuro.
Screening
Battery
(
Rat)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.6300
Develop.
Neuro
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
no
no
no
no
no
­­­
­­­
­­­
­­­
­­­

870.7485
General
Metabolism
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
870.7600
Dermal
Penetration
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
yes
yes
yes
yes
870.7200
Companion
Animal
Safety
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
no
no
3.0
DATA
GAPS
Based
on
the
availability
of
the
recent
EPA
IRIS
report,
in
addition
to
open
literature
data,
the
ADTC
considered
the
toxicity
database
for
phenol
adequate.
Therefore,
no
data
gaps
were
identified
for
the
hazard
characterization
of
phenol.

4.0
HAZARD
ASSESSMENT
4.1
Acute
Toxicity
Page
7
of
42
Adequacy
of
database
for
Acute
Toxicity:
The
acute
toxicity
database
for
phenol
is
considered
complete.
No
additional
studies
are
required
at
this
time.
Phenol
has
a
moderate
order
of
acute
toxicity
via
the
oral
and
dermal
routes
of
exposure
(
Toxicity
Category
II
or
III)
and
produces
severe
and
marked
irritation
to
the
eyes
and
skin
(
Toxicity
Category
I
or
II).
Phenol
concentrations
used
in
acute
inhalation
studies
failed
to
induce
mortality
in
the
study
animals;
therefore,
toxicity
endpoints
and
a
toxicity
category
could
not
be
established.
The
acute
toxicity
data
for
phenol
is
summarized
below
in
Table
2.

Table
2.
Acute
Toxicity
Profile
for
Phenol/
Sodium
Phenate
Guideline
Number
Study
Type/
Test
substance
(%
a.
i.)
MRID
Number/
Citation
Results
Toxicity
Category
870.1100
(
§
81­
1)
Acute
Oral­
Rat
Phenol
purity
>
99%
Berman,
et
al.
1994
LD50
=
400
(
297­
539)
mg/
kg/
day
II
870.110
(
§
81­
1)
Acute
Oral
­
Rat
Phenol
purity
100%
OTS
#
­
0515567
86­
870001405
LD50
=
1030
(
940­
1120)
mg/
kg/
day
III
870.1100
(
§
81­
1)
Acute
Oral­
Rat
Phenol
purity
not
reported
Flickinger.
1976
LD50
=
650
(
490­
860)
mg/
kg/
day
III
870.1200
(
§
81­
2)
Acute
Dermal­
Rat
Phenol
purity
not
reported
Brown,
et
al.
1975
LD50
(
Non­
occluded)
=
0.68
(
0.57­
0.78)
mL/
kg
LD50
(
Occluded)
=
0.50
mL/
kg
II
870.1200
(
§
81­
2)
Acute
Dermal­
Rabbit
Sodium
Phenate
purity
57%
OTS
#
­
0515564
86­
870001402
LD50
=
2350
(
1880­
2940)
mg/
kg/
day
III
870.1200
(
§
81­
2)
Acute
Dermal­
Rabbit
Phenol
purity
100%
OTS
#
­
0515567
86­
870001405
LD50
=
0.63
(
0.56­
0.70)
mL/
kg
II
870.1200
(
§
81­
2)
Acute
Dermal­
Rat
Phenol
purity
laboratory
reagent
grade
Conning,
et
al.
1970
LD50
=
669.4
mg/
kg/
day
II
870.1200
(
§
81­
2)
Acute
Dermal­
Rabbit
Phenol
purity
not
reported
Flickinger.
1976
LD50
=
850
(
600­
1200)
mg/
kg/
day
II
870.1300
(
§
81­
3)
Acute
Inhalation­
Rat
Phenol
purity
100%
OTS
#
­
0515567
86­
870001405
No
deaths
occurred
at
2.5
L/
min
for
8
hours
Not
established
870.1300
(
§
81­
3)
Acute
Inhalation­
Rat
Phenol
purity
not
reported
Flickinger.
1976
No
deaths
occurred
at
900
mg/
m3
for
8
hours
Irritation
and
timerelated
CNS
effects
Not
established
870.2400
(
§
81­
4)
Acute
Eye
Irritation­
Rabbit
Sodium
Phenate
purity
57%
OTS
#
­
0515564
86­
870001402
15%
solution
caused
corneal
necrosis
and
conjunctiva
lesions
II
870.2400
(
§
81­
4)
Acute
Eye
Irritation­
Rabbit
Phenol
purity
100%
OTS
#
­
0515567
86­
870001405
Severe
damage
to
the
cornea
at
15%
and
lesser
damage
in
5%
Not
established
Table
2.
Acute
Toxicity
Profile
for
Phenol/
Sodium
Phenate
Guideline
Number
Study
Type/
Test
substance
(%
a.
i.)
MRID
Number/
Citation
Results
Toxicity
Category
Page
8
of
42
870.2400
(
§
81­
4)
Acute
Eye
Irritation­
Rabbit
Phenol
purity
not
reported
Flickinger.
1976
Dose
not
provided.
Severe
conjunctiva,
iritis,
corneal
opacities
and
ulcerations
with
no
improvement
after
14
day
observation
period.
I
870.2500
(
§
81­
5)
Acute
Dermal
Irritation­
Rabbit
Sodium
Phenate
purity
57%
OTS
#
­
0515564
86­
870001402
Mild
to
marked
erythema
and
marked
capillary
injection
were
observed
in
50%
of
animals
tested
II
870.2500
(
§
81­
5)
Acute
Dermal
Irritation­
Rabbit
Phenol
purity
100%
OTS
#
­
0515567
86­
870001405
10%
solution
caused
moderate
to
marked
erythema
Not
established
870.2500
(
§
81­
5)
Acute
Dermal
Irritation­
Rabbit
Phenol
purity
not
reported
Flickinger.
1976
Corrosive
I
4.2
Subchronic
Toxicity
Adequacy
of
database
for
Subchronic
Toxicity:
The
database
for
subchronic
toxicity
is
considered
complete.
Oral
range­
finding
studies
in
both
the
rat
and
the
mouse
were
completed.
Although
the
studies
were
non­
guideline
(
due
to
the
lack
of
subchronic
parameters),
systemic
toxicities
were
noted
at
10000
ppm
in
the
rat
and
mouse,
based
on
a
decrease
in
mean
body
weight
gain.
In
a
two­
week
inhalation
study,
rats
had
elevated
plasma
Mg2+
levels
(
Hypermagnesaemia)
and
exhibited
toxic
effects
in
the
central
nervous
system
(
CNS).

Non­
Guideline
Subchronic
(
Oral)
Range­
Finding
Toxicity­
Rat
In
a
range­
finding
subchronic
90­
day
oral
toxicity
study
(
NIH
PB#
80­
1759),
groups
of
10
F344
rats/
sex/
dose
received
0,
100,
300,
1000,
3000,
or
10000
ppm
phenol
(
purity
not
reported)
in
drinking
water
for
13
weeks.
There
were
no
treatment­
related
clinical
signs
or
increases
in
mortality
(
100%
survival)
in
rats.
At
necropsy
no
tissue,
organ,
or
histomorphologic
alterations
were
associated
with
administration
of
phenol.
Rats
experienced
a
significant
depression
in
mean
body
weight
and
body
weight
gain
when
compared
to
control.
Animals
administered
phenol
at
concentrations
of
3000
ppm
or
less
exhibited
weight
gains
which
were
similar
to
control;
indicating
that
animals
were
unaffected
by
treatment.
However,
the
10000
ppm
dose
group
exhibited
decreases
in
mean
body
weight
that
were
16
and
26%
less
than
the
controls
in
male
and
female
treated
rats,
respectively
(
animals
weighed
in
week
12).
There
were
no
changes
observed
in
feed
consumption
following
phenol
administration.
Water
was
rejected
by
the
rats
at
the
highest
concentration
of
phenol
(
10000
ppm);
males
and
females
consumed
50
and
67%,
respectively,
of
control
water
levels.
Considering
the
test
article
was
administered
in
the
drinking
water,
palatability
at
the
high
dose
might
have
affected
the
water
consumption.
This
resulted
in
depressed
water
intake
in
the
subchronic
studies
for
both
male
and
female
rats.
The
low
and
high
doses
for
the
chronic
study
were
set
at
2500
and
5000
ppm,
respectively,
based
on
the
rejection
of
water
and
unacceptable
decreases
in
mean
weight
gain
at
the
10000
ppm
dose
level.
The
Subchronic
toxicity
NOAEL
is
3000
ppm.
The
Subchronic
toxicity
LOAEL
is
10000
ppm,
based
on
significant
decreases
in
mean
body
weight
gain.
Page
9
of
42
Non­
Guideline
Subchronic
(
Oral)
Range­
Finding
Toxicity­
Mouse
In
a
range­
finding
subchronic
90­
day
oral
toxicity
study
(
NIH
PB#
80­
1759),
groups
of
10
B6C3F
1
mice/
sex/
dose
received
0,
100,
300,
1000,
3000,
or
10000
ppm
phenol
(
purity
not
reported)
in
drinking
water
for
13
weeks.
There
were
no
treatment­
related
clinical
signs
or
increases
in
mortality
(
100%
survival)
in
mice.
Animal
mean
body
weight
and
body
weight
gain
were
unaffected
by
treatment
with
all
phenol
concentrations
except
at
10000
ppm.
The
high­
dose
treated
mice
exhibited
decreased
weight
gain
that
was
80%
less
than
control
for
males
and
33%
less
for
females.
The
weight
loss
that
resulted
in
depressed
mean
body
weights
for
both
male
and
female
mice
was
observed
during
the
first
7
weeks
of
treatment,
although
the
mice
exhibited
small
weight
gains
for
the
remainder
of
the
study.
Feed
consumption
for
treated
males
and
females
was
unaffected
by
phenol
but
water
consumption
at
10000
ppm
was
60
and
20%
of
controls
for
males
and
females,
respectively.
Considering
phenol
was
administered
in
the
drinking
water,
palatability
at
the
high
dose
might
have
affected
the
water
consumption;
resulting
in
the
depressed
water
intake
observed
in
the
subchronic
studies
for
both
male
and
female
mice.
The
range­
finding
study
results
indicated
the
dose
levels
for
the
carcinogenicity
study.
The
high
and
low
doses
were
set
at
2500
and
5000
ppm,
respectively,
based
on
animal
rejection
of
the
water
and
unacceptable
decreases
in
mean
weight
gain
at
the
10000
ppm
dose
level.
The
Subchronic
toxicity
NOAEL
is
3000
ppm.
The
Subchronic
toxicity
LOAEL
is
10000
ppm,
based
on
significant
decreases
in
mean
body
weight
gain.

Non­
Guideline
Two­
Week
Inhalation
Toxicity
(
Special
Study)­
Rat
In
an
inhalation
study
(
Dalin
and
Kristoffersson,
1984),
rats
were
exposed
to
phenol
(
purity
not
reported)
in
an
inhalation
chamber
(
air
flow,
600
±
10
L/
hr)
at
a
concentration
of
100
mg/
m3
for
15
days.
General
activity,
behavior,
and
locomotion
were
noted
frequently
throughout
the
exposure
period.
Immediately
prior
to
and
following
the
experiment
CNS
effects
were
studied
with
the
"
tilting­
plane"
method
(
based
on
the
ability
of
the
animal
to
cling
to
a
tilted
plane,
measured
in
degrees
of
an
angle).
There
were
treatment­
related
effects
observed
in
the
animal
activity
one
day
after
the
start
of
exposure.
On
days
3
and
4,
rats
exhibited
clear
motor
disorders,
such
as
impaired
balance
and
disordered
walking
rhythm.
Additionally,
sitting
positions
were
labile,
grooming
behavior
was
disturbed,
and
involuntary
neck
twitches
were
observed.
All
of
these
symptoms
were
relatively
mild
and
from
the
external
appearance
of
the
rats
the
animals
appeared
to
be
in
good
condition.
By
day
5
of
exposure
the
above
symptoms
faded
and
animals
appeared
sluggish
in
behavior
when
compared
to
controls.
There
were
no
treatment­
related
effects
in
food
and
water
consumption
or
body
weight
in
animals
exposed
to
phenol.
However,
the
CNS
effects
measured
by
the
"
tilting­
plane"
method
showed
significant
decreases
in
the
value
of
the
sliding
angle
after
exposure
to
phenol.
The
mean
sliding
angle
was
71.2
±
2.4
degrees
prior
to
phenol
administration
and
following
treatment
there
was
a
significant
decrease
(
6%)
to
66.8
±
1.7
degrees.
Hemoglobin,
hematocrit,
plasma
Na+,
Ca2+,
Cl­,
and
free
phenol
levels
were
not
affected
by
treatment
with
phenol.
However,
K+
and
Mg2+
levels
were
significantly
increased
with
1.3­
and
1.2­
fold
increases,
respectively,
after
phenol
exposure.
The
activities
of
plasma
enzymes
LDH,
GOT,
GPT,
and
GLDH
were
markedly
greater
in
the
phenol­
treated
animals
with
5.0­,
6.5­
,
2.8­,
and
2.2­
fold
increases,
respectively,
over
controls.
Rats
exposed
to
100
mg/
m3
phenol
showed
excitement
with
typical
muscular
twitching
and
later
depression.
Hypermagnesaemia
has
been
shown
to
block
neuromuscular
transmission
and
diminish
the
responsiveness
of
the
muscle
fibers
to
direct
stimulation.
Therefore,
the
elevated
plasma
Mg2+
levels
observed
in
phenol­
treated
animals
would
be
an
important
factor
in
the
depression
and
weakening
of
motor
functions
also
noted
in
rats.
Plasma
K+
levels
were
increased
significantly
and
this
elevation
may
be
a
sign
of
damage
to
liver
tissue.
In
this
study,
plasma
enzyme
values
(
LDH,
GOT,
GPT,
and
GLDH)
were
significantly
elevated
as
in
the
"
poisoning
pattern"
noted
for
organic
solvents
(
LDH>
GOT>
GPT>
GLDH).
This
pattern
indicates
that
the
phenol
concentration
used
in
this
study
(
100
mg/
m3)
is
sufficient
in
inducing
liver
damage
in
rats.
Page
10
of
42
4.3
Prenatal
Developmental
Toxicity
Adequacy
of
database
for
Prenatal
Developmental
Toxicity:
The
database
for
developmental
toxicity
is
considered
complete.
Phenol
was
administered
in
two
guideline
studies
in
the
rat
and
mouse
at
concentrations
of
30,
60,
or
120
mg/
kg/
day
and
70,
140,
or
280
mg/
kg/
day,
respectively.
There
was
no
evidence
of
toxicity
in
these
animals
at
concentrations
below
the
highdose
Fetal
body
weight
was
significantly
reduced
at
120
and
280
mg/
kg/
day
in
rat
and
mouse
studies,
respectively.
Additionally,
female
mice
experienced
increased
mortality,
and
clinical
signs
of
CNS
toxicity
(
tremors,
ataxia,
lethargy)
at
the
high­
dose
(
280
mg/
kg/
day).
In
a
non­
guideline
developmental
study
(
Kavlock,
1990),
there
were
decreases
in
maternal
body
weight
gain
in
maternal
and
offspring
870.3700
Prenatal
Developmental
Toxicity
Study
­
Rat
In
a
prenatal
developmental
toxicity
study
(
MRID
#
43735402)
92
prenatally­
exposed
mated
female
CD
rats,
23
rats/
dose
were
administered
phenol
(
99.9%
purity)
via
gavage
at
dose
levels
of
0,
30,
60,
or
120
mg/
kg/
day
from
gestation
days
(
GD)
6
to
15.
Females
were
weighed
daily
during
treatment
and
observed
for
clinical
signs
of
toxicity.
A
total
of
20­
23
females/
group
were
confirmed
to
be
pregnant
at
sacrifice
on
GD
20.
The
gravid
uterus
of
each
dam
was
weighed
and
the
urine
contents
examined
for
implantation
sites
and
fetus
vitality
(
live,
dead,
or
reabsorbed).
Each
live
fetus
was
weighed
and
examined
for
external,
visceral,
and
skeletal
malformations.
There
were
no
treatment­
related
clinical
signs,
increases
in
mortality
(
100%
survival),
or
decreases
in
body
weight
and
body
weight
gain
in
rats
dosed
with
phenol.
The
Maternal
toxicity
NOAEL
is
greater
than
or
equal
to
120
mg/
kg/
day
(
highest
dose
tested)
and
the
Maternal
toxicity
LOAEL
is
greater
than
120
mg/
kg/
day
(
not
established).
Treated
animals
exhibited
no
change
in
reproductive
parameters
when
compared
to
controls;
therefore,
the
Reproductive
toxicity
NOAEL
is
greater
than
or
equal
to
120
mg/
kg/
day
(
highest
dose
tested)
and
the
Reproductive
toxicity
LOAEL
is
greater
than
120
mg/
kg/
day
(
not
established).
There
were
no
treatmentrelated
effects
on
mean
live
fetal
body
weight/
litter
in
the
low­
and
mid­
dose
treated
groups.
However,
significant
reductions
from
the
control
in
mean
fetal
body
weight/
litter
was
observed
in
the
high­
dose
(
120
mg/
kg/
day)
group.
No
evidence
of
teratogenicity
was
observed
in
the
rats
following
administration
of
phenol
and
the
Developmental
toxicity
NOAEL
is
60
mg/
kg/
day.
The
Developmental
toxicity
LOAEL
is
120
mg/
kg/
day,
based
on
reduced
fetal
weight.
This
study
is
classified
as
Acceptable
and
satisfies
the
guideline
requirements.

In
an
unpublished
developmental
toxicity
study
conducted
according
to
GLP
guidelines
(
Argus
Research
Laboratories,
1997),
pregnant
Crl:
CDRBR
VAF/
Plus
Sprague­
Dawley
rats
(
25
per
group)
received
phenol
by
oral
gavage
on
GD
6
through
15.
Animals
were
dosed
3
times/
day
at
a
concentration
of
0,
20,
40,
or
120
mg
phenol/
kg
using
a
dosing
volume
of
10
mL/
kg.
The
corresponding
daily
doses
were
0,
60,
120,
and
360
mg/
kg/
day.
It
was
noted
that
the
test
material
was
90%
phenol
United
States
Pharmacopeia
(
USP);
the
dosage
calculations
were
adjusted
for
test
material
purity.
The
exposed
dams
were
observed
twice
a
day
for
viability
and
daily
for
clinical
signs,
abortions,
and
premature
deliveries.
In
addition,
the
maternal
body
weights
were
recorded
every
day,
and
food
consumption
was
also
recorded
periodically
(
every
1
B
2
days).
Rats
were
sacrificed
on
GD
20,
and
gross
necropsy
of
the
thoracic,
abdominal,
and
pelvic
viscera
was
performed.
The
number
of
corpora
lutea
in
each
ovary
was
recorded.
The
uterus
of
each
rat
was
excised
and
examined
for
number
and
distribution
of
implantations,
live
and
dead
fetuses,
and
early
and
late
resorption.
Each
fetus
was
weighed,
sexed,
and
examined
for
gross
external
alterations.
One­
half
of
the
fetuses
were
examined
for
soft
tissue
alterations,
and
the
rest
were
examined
for
skeletal
alterations.
Page
11
of
42
One
high­
dose
dam
died
on
GD
11.
This
death
was
attributed
to
phenol
treatment
because
it
occurred
only
at
the
high
dose,
although
there
were
no
adverse
clinical
observations
and
no
abnormal
necropsy
findings
in
this
animal.
Other
high­
dose
animals
exhibited
excess
salivation
and
tachypnea
(
rapid
breathing).
There
were
no
other
treatment­
related
clinical
observations
and
no
treatment­
related
necropsy
findings.
Dose­
dependent
decreases
in
body
weight
of
the
exposed
animals
were
observed.
Statistically
significant
decreases
from
control
in
both
maternal
body
weight
(
8%)
and
body
weight
gain
(
38%
for
GD
6
B
16)
were
observed
at
the
high
dose;
although
a
statistically
significant
decrease
in
body
weight
gain
(
11%)
was
observed
at
the
mid
dose,
the
decrease
at
the
mid
dose
(
relative
to
controls)
in
absolute
maternal
weight
at
the
end
of
dosing
(
3%)
was
not
statistically
significant.
Dose­
dependent
decreases
in
food
consumption
were
also
observed
during
the
dosing
period.
Fetal
body
weights
in
the
high­
dose
group
were
significantly
lower
than
those
of
the
controls,
by
5
B
7%.
The
high­
dose
group
had
a
statistically
significant
decrease
in
ossification
sites
on
the
hindlimb
metatarsals,
but
it
is
unlikely
that
this
small
change
is
biologically
significant.
The
incidence
of
litters
with
incompletely
ossified
or
unossified
sternal
centra
was
0/
23,
0/
25,
3/
23,
and
3/
24;
this
increase
was
not
statistically
significant.
There
were
small,
dose­
related
increases
in
the
number
of
litters
with
fetuses
with
"
any
alteration"
and
with
"
any
variation"
at
120
mg/
kg/
day
and
higher.
However,
neither
of
these
changes
was
statistically
significant,
and
the
response
was
not
clearly
dose­
related.
In
addition,
an
increase
in
total
variations
is
of
questionable
significance
in
the
absence
of
any
increase
in
individual
variations.
There
were
no
other
treatment­
related
effects
on
uterine
contents,
malformations,
or
variations.
The
maternal
NOAEL
was
60
mg/
kg­
day,
based
on
small
decreases
in
maternal
body
weight
gain
at
120
mg/
kg­
day,
and
the
developmental
NOAEL
was
120
mg/
kg­
day,
based
on
decreased
fetal
body
weight
and
delayed
ossification
at
360
mg/
kg­
day.

870.3700
Prenatal
Developmental
Toxicity
­
Mouse
In
a
prenatal
developmental
toxicity
study
(
MRID
#
43735401)
133
prenatally­
exposed
mated
female
CD­
1
mice,
31­
36
animals/
dose
were
administered
phenol
(
99.9%
purity)
by
gavage
at
dose
levels
of
0,
70,
140,
or
280
mg/
kg/
day
from
gestation
days
(
GD)
6
to
15.
Females
were
weighed
daily
during
treatment
and
observed
for
clinical
signs
of
toxicity.
Animals
were
sacrificed
on
GD
17.
The
gravid
uterus
of
each
dam
was
weighed
and
the
uterine
contents
examined
for
implantation
sites
and
fetus
vitality
(
live,
dead,
or
reabsorbed).
Each
live
fetus
was
weighed
and
examined
for
external,
visceral,
and
skeletal
malformations.
There
were
no
treatment­
related
clinical
signs
or
mortality
observed
in
the
maternal
low­
dose
group
(
70
mg/
kg/
day).
At
the
140
mg/
kg/
day
dose,
1/
31
animals
died
(
3.2%
mortality).
Mild
tremors
were
observed
in
mid­
dose
females
after
dosing
on
GD
6­
8;
however,
this
effect
was
not
observed
on
subsequent
treatment
days.
A
mortality
rate
of
14.3%
(
5/
35
animals)
was
noted
in
dams
of
the
280
mg/
kg/
day
dose
group.
Clinical
signs
of
toxicity
were
observed
in
these
mice
following
administration
of
phenol
and
included
tremors,
ataxia,
lethargy,
and
irritability.
The
mortality
in
mid­
and
high­
dose
treated
females
was
attributed
to
a
dosing
error.
There
was
a
significant
treatment­
related
decrease
(
10%
at
sacrifice,
GD
17)
in
mean
maternal
body
weight
of
the
280
mg/
kg/
day
treated
animals
when
compared
to
the
control
group.
Mean
maternal
body
weight
gain
was
statistically
reduced
from
the
control
in
the
280
mg/
kg/
day
dose
group
during
the
treatment
period
(
31%
decrease)
and
entire
gestation
period
(
28%
decrease).
Dams
administered
the
phenol
high­
dose
exhibited
a
66%
decrease
from
control
in
absolute
weight
gain.
The
Maternal
toxicity
NOAEL
is
140
mg/
kg/
day.
The
Maternal
toxicity
LOAEL
is
280
mg/
kg/
day,
based
on
increased
mortality
and
clinical
signs
of
CNS
toxicity
(
tremors,
ataxia,
and
lethargy).
There
were
no
changes
in
reproductive
parameters
in
treated
animals
when
compared
to
controls.
The
Reproductive
toxicity
NOAEL
is
greater
than
or
equal
to
280
mg/
kg/
day
(
highest
dose
tested).
The
Reproductive
toxicity
LOAEL
is
greater
than
280
mg/
kg/
day
(
not
established).
The
low
dose
and
mid
dose
groups
(
70
and
140
mg/
kg/
day)
did
not
exhibit
fetotoxicity
or
teratogenicity.
At
280
mg/
kg/
day,
an
increase
in
cleft
palate
was
observed
in
8
of
214
fetuses
(
3
litters),
although
this
increase
was
not
statistically
significant.
Phenol
was
fetotoxic
in
both
males
and
females
of
the
Page
12
of
42
high­
dose
(
280
mg/
kg/
day)
group
with
significant
reductions
(
18%)
from
control
in
the
mean
fetal
weight
of
treated
animals.
The
Developmental
toxicity
NOAEL
is
140
mg/
kg/
day.
The
Developmental
toxicity
LOAEL
is
280
mg/
kg/
day,
based
on
reduced
fetal
weight
and
an
increase
in
the
incidence
of
cleft
palate.
This
study
is
classified
as
Unacceptable,
although
upgradable
with
the
addition
of
on
food
consumption
data,
gross
necropsy
findings,
complete
developmental
endpoints,
and
individual
animal
data.

Non­
Guideline
Developmental
Toxicity
­
Rat
In
a
prenatal
developmental
(
gavage)
toxicity
study
(
Narotsky
and
Kavlock
1995)
phenol
(
99+%
purity)
was
administered
once
daily
from
gestation
days
(
GD)
6­
19
for
a
total
exposure
period
of
14
days
to
groups
of
17
prenatally­
exposed
Fischer
344
rats/
dose
at
concentrations
of
40
or
53.3
mg/
kg/
day.
Dams
were
observed
throughout
pregnancy.
Litters
were
examined
postnatally
and
after
final
examination
dams
were
sacrificed
and
uterine
implantation
sites
were
counted.
Pups,
14
live
litters/
dose,
were
maintained
for
21
days.
There
were
no
treatment­
related
effects
in
mortality
(
100
survival)
of
rats
receiving
phenol
for
14
days.
Clinical
signs
of
toxicity
following
administration
of
both
dose
levels
of
phenol
were
observed
and
included
altered
respiration
(
e.
g.,
rales
and
dyspnea).
Maternal
weight
loss
was
similar
to
control
levels
after
two
treatments
but
significantly
reduced
weight
gains
were
observed
after
4
and
10
treatments
between
GD
6­
20.
Maternal
body
weight
gain
was
reduced
21
and
24%
from
controls
in
animals
treated
with
40.0
and
53.3
mg/
kg/
day
phenol,
respectively.
The
Maternal
toxicity
NOAEL
is
less
than
40
mg/
kg/
day
(
lowest
dose
tested).
The
Maternal
toxicity
LOAEL
is
40
mg/
kg/
day,
based
on
reduced
body
weight,
body
weight
gain,
and
respiratory
distress
(
rales
and
dyspnea).
One
lowand
two
high­
dose
animals
experienced
full
resorption
resulting
in
significantly
reduced
litter
sizes
and
a
marginally
significant
increase
in
prenatal
loss
in
the
high
dose
group.
The
three
dams
with
resorbed
litters
had
severe
respiratory
signs
and
an
additional
high­
dose
female
also
had
severe
respiratory
signs
with
excessive
perinatal
mortality
in
its
litter.
The
high­
dose
dam
had
markedly
reduced
pup
weights
on
postnatal
day
(
PND)
1
resulting
in
a
marginally
significant
reduction
for
the
group.
Kinked
tails
were
observed
in
2
of
the
4
survivors
in
this
litter.
The
Reproductive
toxicity
NOAEL
is
less
than
40
mg/
kgday
(
lowest
dose
tested).
The
Reproductive
toxicity
LOAEL
is
40
mg/
kg/
day,
based
on
increased
incidence
of
resorption
and
significantly
reduced
litter
size.
The
percentage
loss
of
prenatal
litters
was
4,
13,
and
22%
for
0,
40,
and
53.3
mg/
kg/
day,
respectively.
Developmental
effects
were
evident
only
in
litters
with
dams
exhibiting
severe
respiratory
signs,
other
females
with
similar
respiratory
effects
successfully
maintained
apparently
normal
litters.
The
developmental
effects
of
phenol
were
isolated
to
four
litters:
Three
(
one
from
low­
dose
group)
were
fully
resorbed
and
the
fourth
exhibited
high
perinatal
mortality.
Postnatal
loss
was
minimal
with
a
small
increase,
less
than
5%,
at
the
high
dose.
Changes
in
pup
weights
were
minimal
and
did
not
vary
significantly
from
control
levels.
Kinked
tails
were
also
noted
in
one
litter
at
53.3
mg/
kg/
day.
The
Developmental
toxicity
NOAEL
is
less
than
40
mg/
kg/
day
(
lowest
dose
tested).
The
Developmental
toxicity
LOAEL
is
40
mg/
kg/
day,
based
on
increased
incidence
of
perinatal
loss.

4.4
Reproductive
Toxicity
Adequacy
of
database
for
Reproductive
Toxicity:
The
database
for
reproductive
toxicity
is
considered
complete.
No
additional
studies
are
required
at
this
time.
In
a
two­
generational
reproductive
study
in
rats
exposed
to
200,
1000,
or
5000
ppm
phenol
for
10
weeks/
generation,
there
were
decreases
in
water
and
food
consumption,
body
weight
and
body
weight
gain
at
the
high­
dose
(
potential
reduced
palatibility).
Offspring
toxic
effects
including
decreases
in
body
weight
and
litter
survival
were
observed
at
5000.
This
occurred
concurrently
with
maternal
toxicity
(
decreased
maternal
body
weight);
believed
to
be
secondary
to
the
animals'
aversion
to
the
flavor
of
the
phenol­
treated
water
and
resulted
in
decreased
maternal
as
well
as
offspring
body
Page
13
of
42
weight.
In
a
non­
guideline
reproductive
study
(
Bishop,
et
al.
1997)
phenol
was
administered
to
mice
at
a
concentration
of
350
mg/
kg.
There
were
no
treatment­
related
clinical
signs
or
mortality
observed
in
maternal,
reproductive,
and
developmental
parameters
and
the
LOAEL
was
not
established
(
highest
dose
tested,
350
mg/
kg).

870.3800
Reproduction
and
Fertility
Effects
­
Rat
In
a
reproductive
and
fertility
effects
toxicity
study
(
Ryan,
et
al.
2001)
phenol
(
100%
purity)
was
administered
to
groups
of
30
Sprague­
Dawley
rats/
sex/
dose
in
drinking
water
at
concentrations
of
200,
1000,
or
5000
ppm
(
14,
70,
and
310
mg/
kg/
day
for
males
and
20,
93,
and
350
mg/
kg/
day
for
females,
respectively,
for
both
generations).
The
parental
(
P1)
generation
was
treated
10
weeks
prior
to
mating,
during
mating
(
2
weeks),
gestation,
lactation,
and
until
sacrifice.
Females
were
allowed
to
go
through
natural
parturition.
The
offspring
of
P1
was
weaned
on
PND
22
and
at
least
1
rat/
sex/
litter
was
selected
to
receive
phenol
for
11
weeks
prior
to
mating.
These
F1
pairs
were
treated
in
a
similar
regimen
as
the
P1.
The
F2
generation
was
culled
to
4
pups/
sex/
litter
on
PND
4,
although
phenol
was
not
administered.
After
weaning,
all
of
the
F2
pups
and
F1
sires
and
dams
were
sacrificed.
All
animals
were
examined
daily
during
gestation
and
weekly
thereafter.
At
least
20
rats/
sex/
group
in
the
P1
and
F1
generations
were
subjected
to
a
gross
necropsy
and
tissue
examination,
while
the
F2
animals
were
euthanized
and
discarded
without
necropsy.
There
were
3
mortalities
in
the
P1
generation
male
rats
(
1
control
died
spontaneously
prior
to
cohabitation
and
2
high­
dose
died
accidentally
during
bleeding
and
from
a
bladder
infection
during
cohabitation),
although
these
were
not
considered
to
be
treatment­
related.
Reduced
palatability
of
the
phenol­
treated
drinking
water
was
likely
the
cause
of
death
in
three
high­
dose
pups
of
the
F1
generation.
Three
F1
dams,
1
each
from
the
control,
low­
dose,
and
high­
dose
groups
died
spontaneously,
but
not
considered
treatment­
related.
Minimal
signs
of
clinical
toxicity
(
discolored
or
wet
inguinal
fur
and
redness
around
the
nose
or
eyes)
were
observed
in
cases
of
mortality.
These
signs
were
observed
in
all
groups;
however,
the
incidence
was
higher
in
the
phenol­
treated
rats.

There
were
no
treatment­
related
effects
observed
for
food
and
water
consumption,
body
weight,
and
organ
weight
in
the
200
and
1000
ppm
dose
groups.
However,
high­
dose
animals
treated
with
5000
ppm
phenol
exhibited
significant
changes
from
control.
Males
exhibited
a
23%
decrease
in
water
consumption
in
weeks
1
and
10,
while
females
exhibited
reductions
of
32
and
37%
in
weeks
1
and
10,
respectively.
The
decrease
in
water
consumption
at
the
high­
dose
may
have
been
a
result
of
reduced
palatability
of
the
treated
drinking
water.
Parental
food
consumption
was
significantly
reduced
10
and
12%
from
control
in
males
(
at
week
1)
and
females
(
at
weeks
1
and
2),
respectively.
There
were
treatment­
related
decreases
from
control
in
body
weight
and
body
weight
gain
in
P1
generation
rats
treated
with
phenol.
These
reductions
were
concomitant
with
decreases
in
food
and
water
consumption
and
observed
in
the
high­
dose
rats.
Male
body
weights
were
8%
less
than
controls
in
week
10
while
the
female
body
weights
were
7
and
10%
less
than
controls
at
weeks
1
and
10,
respectively.
Body
weight
gain
reductions
were
also
significant
decreased
with
reductions
of
12
and
29%
for
male
and
female
rats,
respectively.
Following
treatment
with
5000
ppm
phenol,
the
absolute
organ
weight
of
male
seminal
vesicles
was
12%
less
than
control.
Similarly,
the
absolute
organ
weights
of
adrenals,
brain,
ovaries,
and
spleen
in
the
females
were
reduced
16,
5,
18,
and
13
%,
respectively.
Animal
final
body
weights
were
significantly
reduced
from
controls
in
the
high­
dose
group
with
decreases
of
9
and
12%
for
male
and
female
rats,
respectively.

In
the
dams
there
were
no
treatment­
related
effects
on
body
weight
gain
during
the
lactation
phase
of
the
study.
However,
throughout
gestation
and
lactation
the
mean
maternal
body
weight
was
significantly
lower
in
the
high­
dose
animals
compared
to
controls.
Mean
body
weight
gains
were
approximately
10,
12,
and
11%
less
than
controls
for
the
pre­
mating,
gestation,
and
lactation
Page
14
of
42
periods,
respectively.
There
were
treatment­
related
decreases
from
controls
in
F1
body
weight
in
the
5000
ppm
phenol­
treated
rats.
The
statistically
significant
dose­
dependent
decreases
from
controls
were
5,
15,
18,
20,
and
29%
on
PND
0,
4,
7,
14,
and
21,
respectively.
These
decreases
occurred
concomitantly
with
the
maternal
toxicity
(
decrease
in
maternal
body
weight).
The
lower
maternal
body
weight
may
have
contributed
to
the
lower
birth
weight
of
F1
generation
as
a
result
of
the
decreased
food
and
water
consumption
during
lactation
and
decreased
palatability.
The
Maternal
Toxicity
NOAEL
is
1000
ppm
in
the
P1
generation.
The
Maternal
Toxicity
LOAEL
is
5000
ppm,
based
on
decreases
in
water
and
food
consumption,
body
weight
and
body
weight
gain
in
the
P1
generations.
These
effects
are
associated
with
flavor
aversion
to
phenol
in
the
drinking
water.

There
were
no
treatment­
related
effects
on
reproductive
performance
in
either
generation
(
P1
and
F1).
The
estrus
cycle,
epididymal
sperm
count,
motility,
sperm
morphology,
testicular
sperm
count,
and
production
rate
were
unaffected
by
phenol
treatment
in
the
P1
and
F1
generations.
However,
testicular
sperm
count
and
production
rate
were
significantly
increased
from
control
in
the
high­
dose
group
of
the
F1
generation.
This
was
ascribed
to
lower
testis
weight
rather
than
to
a
true
alteration
in
sperm
count
or
production,
based
on
the
lack
of
effects
at
the
mid­
dose
level.
The
Reproductive
Toxicity
NOAEL
is
greater
than
or
equal
to
5000
ppm
in
the
P1
and
F1
generations
(
highest
dose
tested).
The
Reproductive
Toxicity
LOAEL
is
greater
than
5000
ppm
in
the
P1
and
F1
generations
(
not
established).

The
daily
consumption
of
food
and
water
was
decreased
from
controls
for
the
F1
generation
highdose
group.
Food
and
water
consumption
declines
were
concomitant
with
reductions
in
body
weight.
Body
weight
gain
was
significantly
decreased
in
the
5000
ppm
phenol
treated
group
at
the
end
of
the
pre­
mating
phase
for
males,
whereas
in
females
it
was
only
reduced
during
gestation
(
data
not
included).
However,
the
percent
of
offspring
alive
after
PND
0
were
significantly
decreased
in
the
5000
ppm
treated
groups
with
a
10%
decrease
on
PND
4
for
the
P1
generation
and
decreases
of
28
and
24%
on
PND
4
and
7­
21,
respectively,
for
the
F1
generation.
After
culling,
the
percent
survival
was
similar
across
all
groups.
The
percent
survival
was
similarly
affected
in
the
F2
generation;
however,
survival
in
the
high­
dose
group
remained
affected
after
culling
and
was
reduced
on
PND
7­
21.
The
decreased
survival
of
the
high­
dose
treated
group
was
likely
a
result
of
the
maternal
toxicity
(
decreased
body
weight
and
water
consumption)
that
occurred
at
this
dose.

The
F1
generation
experienced
significant
decreases
in
absolute
organ
weights
at
all
three
dose
levels.
The
absolute
weight
of
the
prostate
in
males
was
significantly
less
than
the
control
in
the
low­,
mid­,
and
high­
dose
groups
with
decreases
of
15,
17,
and
16%,
respectively.
There
were
significant
reductions
at
the
mid­
and
high­
dose
treated
males
with
absolute
organ
weight
decreases
of
10
and
16%
for
adrenals
and
13
and
20%
for
spleen,
respectively.
The
remaining
organs
experienced
absolute
organ
weights
significantly
decreased
from
controls
in
the
high­
dose
group
only.
Final
body
weights
of
the
F1
generation
were
significantly
reduced
from
controls
in
the
high­
dose
group
with
decreases
of
18
and
11%
for
male
and
female
rats,
respectively.
The
F2
generation
pre­
weaning
growth
pattern
was
similar
to
the
F1
generation
with
significant
decreases
of
7,
20,
20,
21,
and
28%
in
litter
body
weight
from
control
on
PND
),
4,
7,
14,
and
21,
respectively.
Similarly
to
F1
generation,
the
decreased
maternal
body
weight
(
F1
dams)
and
reduced
palatability
were
likely
significant
factors
that
contributed
to
the
decreased
body
weights
in
the
high­
dose
F2
generation.
There
were
treatment­
related
effects
for
both
F1
and
F2
generations
with
increases
in
litter
mortality
(
more
so
in
the
F2
generation)
and
reduced
offspring
body
weights
in
the
high­
dose
group.
This
occurred
concurrently
with
maternal
toxicity
(
decreased
maternal
body
weight);
believed
to
be
secondary
to
the
animals'
aversion
to
the
flavor
of
the
phenol­
treated
water
and
resulted
in
decreased
maternal
as
well
as
offspring
body
weight.
There
were
delays
in
vaginal
patency
of
F1
females
(
38.3
days
for
treated
females
vs.
34.6
days
for
control
females)
and
preputial
separation
of
F1
males
(
47.8
days
for
treated
males
vs.
44
days
for
Page
15
of
42
control
males)
observed
with
decreases
in
pre­
and
post­
weaning
body
weights
in
the
high­
dose
group.
Therefore,
the
onset
of
puberty
was
delayed
and
attributed
to
decreased
food
and
water
consumption
and
reduced
body
weight.
The
Offspring
Toxicity
NOAEL
is
1000
ppm.
The
Offspring
Toxicity
LOAEL
is
5000
ppm
based
on
decreases
in
body
weight
of
F1
and
F2
offspring,
decreases
in
litter
survival
of
P1
and
F1
offspring,
and
delays
in
preputial
separation
in
F1
males
and
vaginal
patency
in
F1
females.

4.5
Chronic
Toxicity
Adequacy
of
database
for
Chronic
Toxicity:
The
database
for
chronic
phenol
toxicity
in
rats
and
mice
is
presented
in
the
NIH
PB#
80­
1759
study
of
the
carcinogenicity
database.

4.6
Carcinogenicity
Adequacy
of
database
for
Carcinogenicity:
The
database
for
carcinogenicity
is
considered
complete.
No
additional
studies
are
required
at
this
time.
The
two
carcinogenicity
studies
performed
by
the
National
Cancer
Institute
produced
no
incidences
of
neoplasms
in
male
and
female
mice
or
rats
following
administration
of
phenol,
with
the
exception
of
a
statistically
significant
increase
in
the
occurrence
of
leukemia,
lymphoma,
or
interstitial­
cell
tumors
in
lowdose
male
rats.
Due
to
the
lack
of
significant
tumors
in
high­
dose
males,
females,
and
mice,
phenol
was
found
to
be
non­
carcinogenic
in
the
2­
year
drinking
water
studies.
Although
phenoltreated
rats
and
mice
experienced
a
decrease
in
mean
body
weight
and
body
weight
gain,
the
reduction
was
not
significantly
different
from
the
respective
controls
and
there
was
no
chronic
toxicity
at
concentrations
up
to
5000
ppm.
A
20­
week
dermal
study
exhibited
effects
of
chronic
irritation
and
hair
growth
inhibition
with
administration
of
3
mg
phenol
(
in
200
uL
acetone).
A
single
papilloma
was
found
7
weeks
into
the
study,
but
there
was
no
evidence
that
it
was
significantly
increased
or
treatment­
related.
In
a
special,
mechanistic
study
there
was
no
evidence
of
tumor
initiation
or
hepatocyte
GSH
depletion
following
administration
of
100
mg/
kg/
day
phenol.

870.4200
Carcinogenicity
­
Rat
In
a
24­
month
carcinogenicity
study
(
NIH
PB#
80­
1759),
groups
of
50
F344
rats/
sex/
dose
were
administered
0,
2500,
or
5000
ppm
phenol
(
98.47%
purity,
lot
#
79380)
in
the
drinking
water
for
103
weeks.
There
were
treatment­
related
increases
in
mortality
in
rats
and
survival
rates,
calculated
over
105
weeks
(
103
weeks
of
study
plus
2
week
acclimation
period),
were
52,
44,
and
60%
(
males)
and
76,
78,
and
74%
(
females)
for
controls,
low­
dose,
and
high­
dose
animals,
respectively.
A
positive
dose­
related
trend
in
mortality
in
either
sex
was
not
significant
according
to
the
Tarone
test.
Food
consumption
was
unaffected
by
treatment,
but
dose­
related
decreases
in
water
consumption
were
80
(
2500
ppm)
and
90%
(
5000
ppm)
of
controls.
Considering
the
test
article
was
administered
in
the
drinking
water,
reduced
palatability
may
account
for
decreased
consumption
of
water.
There
were
no
other
treatment­
related
clinical
signs
related
to
the
consumption
of
phenol
in
drinking
water.
Male
and
female
treated
rats
exhibited
decreased
mean
body
weight
and
body
weight
gain
when
compared
to
controls
in
both
high­
and
low­
dose
groups.
This
deviation
from
the
controls
was
observed
for
most
of
the
study
and
tended
to
increase
with
time.
Maximum
differences
in
mean
body
weight
between
treated
and
control
animals
occurred
at
week
96
for
male
rats
with
decreases
of
9
and
15%
for
low­
and
high­
dose
groups,
respectively.
Treated
females
exhibited
a
maximum
weight
difference
at
week
96;
low­
and
high­
dose
animal
weights
were
7
and
9%
lower
than
controls,
respectively.
The
mean
body
weight
changes
observed
in
treated
rats
increased
over
time
with
greater
deviations
from
the
controls
following
administration
of
5000
ppm
(
high
dose)
of
phenol.
At
study
termination,
body
weight
gains
were
Page
16
of
42
7
and
13%
lower
than
control
for
treated
males
and
3
and
11%
lower
than
control
for
treated
females
for
low­
and
high­
doses,
respectively.
The
toxicity
NOAEL
is
greater
than
or
equal
to
5000
ppm
(
highest
dose
tested)
for
both
male
and
female
rats.
The
toxicity
LOAEL
is
greater
than
5000
ppm
(
not
established).

Various
neoplasms
were
observed
in
both
control
and
treated
rats.
The
low­
dose
male
rats
exhibited
increased
tumor
occurrence
over
controls.
Pheochromocytomas
of
the
adrenal
medulla
were
found
in
44%
of
low­
dose
males;
significantly
higher
(
p=
0.046)
than
the
26%
in
controls
and
18%
in
high­
dose
males.
The
incidence
of
either
leukemia
or
lymphomas
in
high­
and
lowdose
males
were
higher
than
controls,
but
were
only
significantly
higher
(
p=
0.008)
in
low­
dose
treated.
The
incidence
of
interstitial­
cell
tumors
in
the
testis
of
males
is
also
significantly
higher
(
p=
0.05)
in
low­
dose
males
than
control;
found
in
49
of
the
50
animals.
Results
of
histopathologic
examinations
suggest
phenol
may
have
increased
the
incidence
of
pheochromocytoma,
leukemia
or
lymphoma
in
low­
dose
male
rats.
Females
did
not
exhibit
increased
incidences
of
tumors
at
any
time
in
this
study.
No
significant
tumors
could
be
clearly
associated
with
the
administration
of
phenol
due
to
the
lack
of
significant
tumors
in
high­
dose
males
and
absence
of
any
significant
neoplasms
in
females
as
well
as
the
high
spontaneous
tumor
rate
observed
in
matched
controls.
Phenol
was
not
carcinogenic
for
either
male
or
female
F344
rats
in
this
2
year
carcinogenicity
drinking
water
study.

870.4200
Carcinogenicity
­
Mouse
In
a
24­
month
carcinogenicity
study
(
NIH
PB#
80­
1759),
groups
of
50
B6C3F1
mice/
sex/
dose
received
0,
2500,
or
5000
ppm
phenol
(
98.47%
purity,
lot
#
79380;
purity
not
reported,
lots
#
A4X
and
B4A)
in
drinking
water
for
103
weeks.
There
was
a
treatment­
related
increase
in
mortality
in
mice
and
the
rate
of
survival
was
calculated
for
the
entire
study
of
103
weeks
and
included
a
2
week
acclimation
period
at
the
beginning
of
study
for
a
total
of
105
weeks.
Survival
rates
were
84,
90,
and
96%
(
males)
and
82,
80,
and
84%
(
females)
for
controls,
low­
dose,
and
high­
dose,
respectively.
Other
than
a
reduced
tendency
to
fight
observed
among
treated
male
mice
at
the
beginning
of
week
80
there
were
no
treatment­
related
clinical
signs
from
the
consumption
of
phenol
in
drinking
water.
Food
consumption
was
unaffected
by
treatment
while
water
consumption
of
treated
animals
was
75%
(
2500
ppm)
and
50­
60%
(
5000
ppm)
of
controls.
Considering
phenol
was
administered
in
the
drinking
water,
reduced
palatability
may
account
for
decreased
consumption
of
water.
Male
and
female
treated
mice
exhibited
decreased
mean
body
weights
when
compared
to
controls
in
both
high­
and
low­
dose
groups.
This
deviation
from
the
controls
was
observed
for
most
of
the
study
and
tended
to
increase
with
time.
Body
weights
varied
between
treated
and
control
animals
as
early
as
2
weeks
(
approximately
1
g
variation)
into
the
study
although
maximum
differences
were
not
observed
until
week
100
for
males,
with
decreases
from
control
of
13
and
18%
for
low­
and
high­
dose
treated
mice,
respectively.
The
maximum
variation
for
females
between
treated
and
control
animals
occurred
at
week
85
in
which
decreases
of
8
and
12%
from
control
were
observed
in
low­
and
high­
dose
groups,
respectively.
At
the
conclusion
of
the
study,
body
weights
for
treated
males
were
3
(
low­
dose)
and
9%
(
highdose
less
than
control
while
treated
females
were
6
and
10%
less
than
control
at
the
low­
and
high­
doses,
respectively.
The
toxicity
NOAEL
is
greater
than
or
equal
to
5000
ppm
(
highest
dose
tested)
for
male
and
female
mice.
The
toxicity
LOAEL
is
greater
than
5000
ppm
(
not
established).

Neoplasms
observed
in
treated
animals
were
of
the
usual
number
and
type
found
in
mice.
Uterine
endometrial
stromal
polyps
were
increased
in
5
of
48
high­
dose
female
mice,
although
this
was
not
significantly
different
from
similar
historical
control
mice.
Any
other
neoplasms
noted
were
occurrences
normally
associated
with
aged
B6C3F
1
mice
and
were
not
treatment
related.
Results
of
the
histopathologic
examinations
suggest
phenol
was
not
toxic
or
carcinogenic
to
B6C3F
1
mice
under
the
conditions
of
this
2
year
drinking
water
carcinogenic
bioassay.
No
tumor
at
any
site
in
Page
17
of
42
the
mice
could
be
clearly
associated
with
the
administration
of
phenol
in
this
study.
Non­
Guideline
­
Mechanistic
Study
­
Mouse
In
a
mechanistic
study
(
Stenius,
et
al.
1989)
phenol
(>
99.57%
purity)
was
administered
to
10
partially
(
70%)
hepatectomized
male
Sprague­
Dawley
rats
by
gavage
5
days/
week
for
7
weeks
at
a
concentration
of
100
mg/
kg/
day.
Animals
were
sacrificed,
by
decapitation,
1
week
after
last
treatment.
Sections
of
the
rat
liver
were
prepared
and
stained
to
measure
for
induction
of
 ­
glutamyltranspeptidase
(
GGT)
positive
enzyme­
altered
foci
as
an
indicator
of
tumor
initiation.
Additional
studies
involved
single
oral
administrations
of
phenol
to
measure
inductions
of
hepatic
ornithine
decarboxylase
(
ODC),
glutathione
(
GSH)
depletion,
and
in
vivo
lipid
peroxidation.
Phenol
did
not
increase
the
number
or
volume
of
foci
and
was
found
to
have
no
tumor­
initiating
properties
within
the
confines
of
this
study.
Lipid
peroxidation
was
not
induced
following
administration
of
phenol
as
measured
by
malondialdehyde
(
MDA)
in
the
urine.
There
were
small
and
inconsistent
effects
observed
in
hepatic
ODC
in
which
there
was
an
increase
at
the
mid­
dose,
but
a
decrease
at
the
high­
dose.
Observed
measurements
of
hepatic
ODC
were
18.8,
32.3,
and
11.4
pmol/
mg/
h
for
the
phenol
doses
of
0,
50,
and
100
mg/
kg/
day,
respectively.
Phenol
did
not
induce
GSH
depletion
in
hepatocytes.
Phenol
is
not
a
potent
stimulator
of
foci
development
and
can
be
regarded
as
a
negative
control
in
this
study
because
it
is
not
susceptible
to
oxidationreduction
reactions.
The
Subchronic
toxicity
NOAEL
is
greater
than
or
equal
to
100
mg/
kg/
day
(
highest
dose
tested).
The
Subchronic
toxicity
LOAEL
is
greater
than
100
mg/
kg/
day
(
not
established).

4.7
Mutagenicity
Mutagenicity
studies
were
from
open
literature
studies,
with
the
exception
of
one
gene
mutation
toxicology
study
(
Malcolm,
et
al.
1985;
Acceptable­
Guideline).
The
results
of
these
studies
indicate
that
phenol
was
not
mutagenic
in
Salmonella
typhimurium
or
Drosophila
melanogaster
and
did
not
induce
micronuclei
or
bone
marrow
chromosomal
aberrations
in
mice.
However,
mutagenic
effects
were
observed
in
Chinese
Hamster
Ovary
cells
and
spermatocytes
in
mice
and
HL60
cells.
The
genotoxic
potential
of
phenol
appears
to
depend
on
the
competing
processes
of
activation
to
a
genotoxic
form
and
metabolic
inactivation
(
e.
g.,
via
conjugation).
Phenol
tended
to
be
negative
in
bacterial
gene
mutation
assays
but
was
positive
or
equivocal
in
mammalian
cell
gene
mutation
assays.
Phenol
tended
to
induce
micronuclei
in
mice
when
administered
intraperitoneally
but
was
negative
(
or
positive
only
at
very
high
doses)
when
administered
orally.
This
difference
is
likely
due
to
the
first­
pass
conjugation
and
inactivation
of
orally
administered
phenol.
Phenol
was
also
positive
in
in
vitro
micronucleus
tests
with
human
lymphocytes
and
CHO
cells.
Results
from
DNA
damage
assays
are
inconsistent,
but
they
tend
to
show
that
phenol
can
cause
sister
chromatid
exchanges
or
cell
transformation
if
it
is
not
metabolically
inactivated.
Overall,
phenol
did
not
exhibit
strong
mutagenic
effects.

Bacterial
Reverse
Mutation
Test
in
Salmonella
typhimurium
Mutagenicity
Assay;
OPPTS
870.5100
[
§
84­
2].
In
a
microbial
reverse
gene
mutation
assay
(
Florin,
et
al.
1980)
Salmonella
typimurium
strains
TA
98,
TA
100,
TA
1535,
and
TA
1537
were
exposed
to
one
dose
of
phenol
(
purity
not
reported)
at
a
concentration
of
3
umol/
plate
in
the
presence
and
absence
of
metabolic
activation
(
derived
from
aroclor­
or
methylcholanthrene­
induced
rats).
The
mutagenic
response
was
verified
with
positive
controls,
N­
methyl­
N'­
nitro­
N­
nitrosoguanisine
for
S9­
and
2­
aminoanthracene
for
S9+
experiments.
Positive
controls
elicited
the
appropriate
responses
in
the
corresponding
assays;
however,
there
was
no
evidence
that
phenol
induced
a
mutagenic
effect
in
any
strain
with
or
without
metabolic.

Bacterial
Reverse
Mutation
Test
in
Salmonella
typhimurium
Mutagenicity
Assay;
OPPTS
870.5100
[
§
84­
2].
In
a
bacterial
reverse
mutation
assay
(
Haworth,
et
al.
1983)
Salmonella
Page
18
of
42
typhimurium
strains
TA
98,
TA
100,
TA
1535,
and
TA
1537
were
exposed
to
phenol
(
99.5%
purity)
at
concentrations
of
0,
33,
100,
333,
1000,
2500,
or
3333

g/
plate
in
the
presence
and
absence
of
metabolic
activation
from
aroclor­
induced
rats
and
hamsters.
Concurrent
positive
controls
included
2­
aminoanthracene
(
2­
AA)
for
S9+
and
for
S9­
4­
nitro­
o­
phenylenediamine
(
NOPD),
sodium
azide
(
SA),
and
9­
aminoacridine
(
9­
AAD).
There
was
no
evidence
of
induced
mutant
colonies
over
background.
Positive
controls
produced
appropriate
responses
in
corresponding
strains
of
the
bacterial
reverse
mutagenesis
test.
S.
typhimurium
did
not
show
mutagenic
activity
in
the
presence
or
absence
of
metabolic
activation
following
administration
of
phenol.

Bacterial
Reverse
Mutation
Test
in
Salmonella
typhimurium
Mutagenicity
Assay;
OPPTS
870.5100
[
§
84­
2].
In
a
bacterial
reverse
mutation
assay
(
Pool
and
Lin,
1982)
histidine­
requiring
mutants
of
Salmonella
typhimurium
bacterial
strains,
TA
98,
TA
100,
TA
1535,
TA
1537,
and
TA
1538,
were
exposed
to
phenol
(
98%
or
analytical
grade
purity)
at
concentrations
of
0.5,
5,
50,
500,
or
5000
µ
g/
plate.
Phenol
was
administered
to
4
plates/
dose
in
the
presence
and
absence
of
metabolic
activation
derived
from
aroclor­
induced
Sprague­
Dawley
rats.
Positive
controls,
2
µ
g/
plate
sodium
azide
(
TA
100,
TA
1535),
3
µ
g/
plate
2­
Nitrofluorene
(
TA
98,
TA
1538),
and
60
µ
g/
plate
9­
aminoacridine
(
TA
1537)
were
used
in
the
absence
of
metabolic
activation
while
5
µ
g/
plate
2­
aminoanthracene
served
for
all
experiments
performed
in
the
presence
of
metabolic
activation.
A
treatment­
related
toxicity
effect
was
observed
at
the
highest
dose,
5000
µ
g/
plate,
as
was
indicated
by
the
thinning
of
the
bacterial
background
lawn
and
a
reduced
number
of
spontaneous
revertants
(
11­
100%
decreases
in
mutant
colonies
in
presence
and
absence
of
S9).
For
the
remaining
test
doses,
phenol
did
not
significantly
induce
mutant
colonies
over
background.
The
number
of
histidine
revertants
scored
in
the
presence
of
phenol
never
more
than
slightly
exceeded
the
number
of
spontaneously
arising
revertants.
A
small,
dose­
related
increase
in
mutant
colonies
was
observed
in
the
TA
100
­
S9
experiment
with
the
non­
cytotoxic
doses
of
phenol
(
11­
14%
increase
for
phenol
concentrations
ranging
from
0.5
to
500
µ
g/
plate);
however,
this
increase
never
reached
a
doubling
of
the
number
of
spontaneous
revertants
and
was
not
significant.
There
was
no
evidence
of
mutagenic
activity
following
administration
of
phenol
to
5
bacterial
strains
of
S.
typhimurium
in
the
presence
or
absence
of
metabolic
activation.

Bacterial
Reverse
Mutation
Test
in
Salmonella
typhimurium
Mutagenicity
Assay;
OPPTS
870.5100
[
§
84­
2].
In
a
bacterial
reverse
mutation
assay
(
Gocke,
et
al.
1981)
histidine­
requiring
mutants
of
S.
typhimurium
bacterial
strains,
TA
98,
TA
100,
TA
1535,
TA
1537,
and
TA
1538,
were
exposed
to
phenol
(
purity
not
reported)
at
concentrations
of
approximately
9,
12,
54,
78,
or
90
µ
moles/
plate
in
the
presence
and
absence
of
metabolic
activation
from
aroclor­
induced
rats
or
hamsters.
The
numbers
of
his+
revertants
observed
with
phenol
treatment
indicated
no
evidence
of
induced
mutant
colonies
over
background
following
administration
of
phenol
in
the
absence
of
metabolic
activation.
However,
in
the
presence
of
metabolic
activation,
mutant
colonies
were
increased
with
His+
revertants/
plate
observed
at
the
maximum
level
at
the
mid­
dose
(
54
µ
mole/
plate)
and
individual
increases
of
14,
21,
143,
121,
and
57%
over
control
were
measured
at
the
concentrations
of
9,
12,
54,
78,
and
90
µ
mole/
plate,
respectively.
The
higher
concentrations,
78
and
90
µ
mole/
plate,
exhibited
lower
amounts
of
his+
revertants
than
54
µ
mole/
plate,
but
were
still
well
above
control
levels.
Phenol
was
not
mutagenic
in
the
bacterial
strains
in
the
absence
of
metabolic
activation,
but
mutagenic
effects
were
measured
by
a
significant
increase
over
control
in
histidine
revertants
in
the
presence
of
metabolic
activation;
predominantly
in
the
Ames
tester
strains
of
S.
typhimurium
that
are
sensitive
for
frameshift
mutatgens
(
ie.,
TA
98).

Sex­
Linked
Recessive
Lethal
Test
in
Drosophila
melanogaster
Mutagenicity
Assay;
OPPTS
870.5275
[
§
84­
2].
In
an
in
vivo
microbial
gene
mutation
assay
(
Gocke,
et
al.
1981)
Berlin
K
(
wild­
type)
and
Basc
strains
of
Drosophila
melanogaster
were
exposed
to
phenol
(
purity
not
reported)
via
an
adult
feeding
method
at
a
concentration
of
50
mM
(
one
dose
close
to
the
LD
50).
Approximately
1200
X­
chromosomes
were
tested
per
experiment
in
each
of
3
successive
broods
Page
19
of
42
(
3,
3,
and
4
days,
respectively)
with
3543,
3458,
and
2139
chromosomes
tested
for
sex­
linked
recessive
lethals
in
Broods
1,
2,
and
3,
respectively.
There
were
no
significant
increases
in
recessive
lethals
observed
following
administration
of
phenol
to
Broods
1,
2,
and
3
with
only
17
(
0.48%),
6
(
0.17%),
and
7
(
0.33%)
sex­
linked
recessive
lethals,
respectively,
measured
in
the
chromosomes
tested.
After
feeding
phenol
to
adult
flies,
the
frequency
of
recessive
lethals
was
increased,
but
not
to
significant
levels.
Phenol
was
not
mutagenic
within
the
confines
of
this
study.

Sex­
Linked
Recessive
Lethal
Test
in
Drosophila
melanogaster
Mutagenicity
Assay;
OPPTS
870.5275
[
§
84­
2].
In
an
in
vivo
microbial
gene
mutation
assay
(
Woodruff,
1985)
the
Basc
strain
of
male
Drosophila
melanogaster
was
exposed
to
phenol
(
99.9%
purity)
in
an
adult
feeding
study
at
concentrations
of
0
or
2000
ppm
and
in
an
adult
injection
study
at
concentrations
of
0
or
5250
ppm.
In
the
feeding
assay,
males
were
treated
with
phenol
at
0
and
200
ppm
in
5761
and
6641
tests,
respectively,
for
3
days
in
glass
shell
vials
containing
a
glass
fiber
disc
soaked
with
0.2
to
0.5
mL
of
solution.
The
test
solution,
0.2
to
0.3

L,
was
injected
in
6357
and
5887
tests
at
the
0
and
5250
ppm
doses
of
phenol,
respectively,
in
the
injection
assay.
Cytotoxic
effects
were
observed
in
the
high­
dose
groups
with
a
30%
mortality
at
2000
ppm
in
the
feeding
study
and
6%
at
5250
ppm
in
the
injection
study.
Sterility
was
also
observed
in
8%
of
the
tests
at
5250
ppm
phenol
(
injection
assay).
Sex­
linked
recessive
lethal
mutations
in
the
feeding
study
were
7
(
0.12%)
and
11
(
0.17%)
at
the
0
and
2000
ppm
doses,
respectively.
In
the
injection
study,
5
(
0.08%)
and
6
(
0.10%)
recessive
lethal
mutations
were
observed
at
0
and
5250
ppm,
respectively.
One
cluster
of
32
lethals
and
one
cluster
of
86
lethals
were
observed
in
the
treated
feeding
experiment.
The
sex­
linked
recessive
lethal
mutations
in
treated
flies
were
not
significantly
different
from
those
found
in
controls.
Phenol
was
not
mutagenic
in
the
Basc
strain
of
male
D.
melanogaster
at
the
concentrations
used
in
this
study.

In
Vitro
Mammalian
Cell
Gene
Mutation
Test
in
Chinese
Hamster
Ovary
(
CHO)
Cells;
OPPTS
870.5300
[
§
84­
2].
In
an
in
vitro
mammalian
gene
mutation
assay
(
Paschin
and
Bahitova,
1982)
the
induction
of
point
mutations
in
mammalian
somatic
cells
at
the
hypoxanthine­
guanine
phosphoriboxyl
transferase
(
HGPRT)
locus
of
V79
was
measured
in
CHO
cells
exposed
to
individual
phenol
("
pure"
grade)
at
concentrations
of
0,
25,
50,
100,
250,
or
500
µ
g/
mL
or
a
mixture
of
12
µ
g/
mL
benzo[
a]
pyrene
and
phenol
at
concentrations
of
0,
100,
250,
or
500
µ
g/
mL.
The
selective
agent,
8­
azaguanine
(
AG),
was
added
to
determine
resistant
(
AGr)
mutants.
For
each
dose
10­
12
petri
dishes
were
used
and
experiments
were
performed
in
triplicate.
There
were
no
treatment­
related
effects
on
cell
survival
at
individual
phenol
concentrations
up
to
and
including
250
µ
g/
mL.
At
the
500
µ
g/
mL
dose,
cell
survival
was
approximately
55%
of
control.
The
combination
of
various
doses
of
phenol
with
a
constant
concentration
of
benzo[
a]
pyrene
(
12
µ
g/
mL)
resulted
in
decreased
cell
survival
at
all
three
doses
of
phenol;
100
(
45%

)
,
250
(
83%

)
,
and
500
µ
g/
mL
(
99%

)
.
At
phenol
concentrations
of
25,
50,
100,
250,
and
500
µ
g/
mL,
there
were
dose­
dependent
increases
of
1.2­,
1.2­,
1.7­,
2.5­,
and
4.3­
fold,
respectively,
in
the
number
of
revertant
colonies.
Statistically
significant
increases
of
52
and
72%
were
observed
in
the
frequency
of
AGr
(
selective
agent,
8­
azaguanine
added
to
determine
resistant
mutants)
mutants
over
spontaneous
levels
at
250
and
500
µ
g/
mL,
respectively.
The
combination
of
phenol
with
benzo[
a]
pyrene
at
a
concentration
of
12
µ
g/
mL,
exhibited
an
increase
in
frequency
of
8­
azaguanine
resistant
colonies
with
increasing
concentrations
of
phenol.
The
results
were
the
same
as
the
sum
of
the
separate
effects
of
phenol
and
benzo[
a]
pyrene;
indicating
that
phenol
did
not
block
or
activate
the
mutagenicity
of
benzo[
a]
pyrene.
Evidence
of
mutagenicity
was
exhibited
by
the
statistically
significant
increase
in
the
frequency
of
8­
azaguanine
resistant
mutants
over
the
spontaneous
level
at
phenol
concentrations
of
250
and
500
µ
g/
mL.
Additive
results
were
observed
in
the
combination
experiment
with
12
µ
g/
mL
benzo[
a]
pyrene
at
the
250
and
500
µ
g/
mL
doses
of
phenol.

In
Vitro
Mammalian
Chromosome
Aberration
Test
in
HL60
Cell
Cultures;
OPPTS
870.5375
[
§
84­
2].
In
an
in
vitro
mammalian
chromosome
aberration
assay
(
Kolachana,
et
al
1993)
the
formation
of
active
oxygen
in
complex
biological
systems
was
measured
in
preincubated
HL60
Page
20
of
42
cell
cultures
exposed
to
phenol
(
distilled
high
purity)
at
a
concentration
of
100
µ
M
for
30
minutes.
DNA
was
extracted
to
measure
the
levels
of
8­
hydroxy­
2'­
deoxyguanosine
(
8OHdGua),
which
is
a
product
of
oxidative
damage.
8OHdGua
has
been
shown
to
be
mutagenic
and
was
used
as
a
marker
for
oxidative
DNA
damage.
A
statistically
significant,
3.5
fold
increase
of
8OHdGua
levels
in
DNA
was
observed
in
HL60
cells;
from
the
control
level
of
0.080
to
0.270
pmol
8OHdGua/
µ
g
after
30
minutes
of
incubation.
There
was
little
or
no
cytotoxicity
(
not
reported)
in
the
cells
for
at
least
6
hours
of
exposure
to
phenol;
indicating
the
8OHdGua
formation
in
these
cells
does
not
occur
after
cell
death.
Therefore,
phenol
induced
rapid
8OHdGua
formation
in
HL60
cells
(
increasing
the
steady
state
level
of
8­
hydroxy­
2'­
deoxyguanosine
in
DNA)
that
returned
to
normal
levels
following
further
incubation,
presumably
due
to
the
rapid
repair
of
DNA
damage.
However,
the
increase
in
this
oxidative
damage
product
indicated
the
genotoxic
effects
resulting
from
active
oxygen.

Mammalian
Spermatogonial
Chromosomal
Aberration
Test
in
Rats;
OPPTS
870.5380
[
§
84­
2].
In
a
mammalian
spermatogonial
chromosomal
aberration
assay
(
Bulsiewicz,
1977)
male
and
female
mice
of
the
Porton
strain
were
exposed
to
phenol
(
purity
not
reported)
in
drinking
water
at
concentrations
of
0.08,
0.8,
or
8.0
mg/
L/
day
for
30
days.
The
parent
(
P)
generation
was
initiated
when
6
males/
dose
were
mated
with
6
females/
dose.
After
the
30­
day
treatment,
the
males
were
anesthetized
and
testes
were
prepared
for
analysis.
Females
continued
to
receive
phenol
throughout
pregnancy
and
bringing
up
of
newborns.
Two
mice,
1
male
and
1
female,
from
each
of
six
families
were
mated
for
F2
generation
and
this
process
was
repeated
for
a
total
of
5
generations.
The
testes
of
6
males
from
each
generation
were
prepared
and
stained
to
observe
20
metaphases
from
spermatogonia
and
120­
150
from
primary
spermatocytes
for
chromosomal
anomalies.
Treatment­
related
effects
on
mortality
were
observed
at
the
high
dose
in
which
8
of
F3,
16
of
F4,
and
22
mice
of
F5
generations
died
with
exposure
to
8
mg/
L
phenol
per
day.
Numerous
associations
and
pulverization
of
the
chromosomes
made
their
analysis
impossible
in
many
cases.
Pulverization
was
observed
at
the
8
mg/
L
dose.
Chromosomal
aberrations
were
more
frequent
in
this
group
with
aberrations
observed
in
537
of
the
660
plates
analyzed.

There
was
evidence
of
chromosomal
aberrations
in
spermatogonia
and
primary
spermatocytes
in
all
generations
for
the
three
doses
of
phenol,
and
included
breaks
and
fractures
of
chromatids
and
chromosomes,
small
chromosomes,
ring
chromosomes,
centric
fusions,
acentric
fragments,
aneuploidy,
and
polyploidy
for
spermatogonia
and
chromatid
breaks,
univalents,
multivalents,
aneuploidy,
and
polyploidy
for
primary
spermatocytes.
The
induction
of
these
aberrations
were
dose­
dependent
and
more
apparent
in
later
generations.
Phenol
produced
dose­
dependent
changes
in
the
reproductive
cells
of
mice
that
increased
in
intensity
in
successive
generations.
Aberrations
were
observed
in
each
dose
group;
0.08
mg/
L/
day
(
27%
spermatogonia,
5%
primary
spermatocytes),
0.8
mg/
L/
day
(
52%
spermatogonia,
22%
diakinetic­
metaphasal
plates
of
spermatozoa),
and
8
mg/
L/
day
(
81%
spermatogonia,
24%
primary
spermatocytes).
Phenol
in
low
concentrations
produced
only
minor
changes
in
chromosomes
that
are
probably
eliminated
by
regulative
processes
in
the
body.
Higher
doses
of
phenol
produced
qualitative
and
quantitative
changes
such
as
large
numbers
of
spermatogonial
metaphases
and
total
absence
of
spermatocytes,
spermatids,
and
spermatozoa
in
testes
preparation
of
treated
mice.
These
effects
and
the
excessive
number
of
proliferating
spermatogonia
indicate
potential
carcinogenicity
of
phenol
at
higher
concentrations.
Phenol
was
mutagenic
in
the
Porton
strain
mice
due
to
the
evidence
of
a
concentration­
related
(
0.08­
8.0
mg/
L/
day)
positive
response
of
spermatogonial
chromosome
aberrations
following
30
days
of
exposure
to
phenol
in
water.

Mammalian
Bone
Marrow
Chromosome
Aberration
Test
in
Mice;
OPPTS
870.5385
[
§
84­
2].
In
a
mammalian
bone
marrow
chromosome
aberration
assay
(
Kolachana,
et
al.
1993)
the
formation
of
active
oxygen
in
complex
biological
systems
was
measured
in
B6C3F
1
male
mice
exposed
to
phenol
(
distilled
high
purity),
3
animals/
dose,
administered
via
intraperitoneal
injection
at
a
concentration
of
75
mg/
kg/
day
individually
and
combined
in
separate
experiments
with
75
mg/
kg/
day
of
hydroquinone
or
75
mg/
kg/
day
of
catechol.
Animals
were
sacrificed
1
hour
after
treatment
and
bone
marrow
cells
were
isolated
and
harvested
from
mice
femurs.
DNA
was
Page
21
of
42
extracted
from
bone
marrow
cells
to
measure
levels
of
8­
hydroxy­
2'­
deoxyguanosine
(
8OHdGua);
a
product
of
oxidative
damage
that
has
been
shown
to
be
mutagenic.
8OHdGua
was
used
as
a
marker
for
oxidative
damage
resulting
from
phenol
exposure.
Phenol,
hydroquinone,
and
catechol
administered
individually
did
not
have
significant
effects
on
the
steady­
state
level
of
8OHdGua.
With
a
range
of
0.045­
0.053
pmol
8OHdGua/
µ
g
DNA,
the
phenol
(
11%
increase),
hydroquinone
(
7%
increase),
and
catechol
(
26%
increase)
treated
cells
were
not
statistically
different
from
the
control.
The
combined
experiments
with
either
hydroquinone
or
catechol
induced
a
2­
fold
increase
in
8OHdGua
levels
over
control
values.
The
phenol
and
hydroquinone
experiment
increased
the
indicator
level
to
0.104
pmol
8OHdGua/
µ
g
DNA;
a
226%
increase
over
control
and
49
and
47%
increases
over
individual
phenol
and
hydroquinone
levels,
respectively.
Combined
administrations
of
phenol
and
catechol
induced
a
172%
increase
over
control
for
the
8OHdGua
level
and
was
65
and
73%
greater
than
individual
phenol
and
catechol
levels,
respectively.
The
levels
in
combined
experiments
were
significantly
greater
than
their
individual
counterparts.
Individual
treatment
with
phenol,
hydroquinone,
or
catechol
did
not
significantly
increase
8­
hydroxy­
2'­
deoxyguanosine
levels
in
mouse
bone
marrow
cells
compared
to
the
control.
The
phenol
and
hydroquinone
mixture
was
the
most
effective
combination
although
administration
of
all
combinations
of
the
test
articles
significantly
increased
the
8OHdGua
levels
via
oxidative
DNA
damage.
The
phenolic
metabolites
of
benzene
used
in
this
study,
(
phenol,
hydroquinone,
and
catechol),
increased
the
steady­
state
levels
of
8OHdGua
in
the
bone
marrow
of
B6C3F
1
mice
in
vivo;
indicating
that
activation
of
these
compounds
produces
active
oxygen
capable
of
causing
oxidative
DNA
damage.

Mammalian
Erythrocyte
Micronucleus
Test
in
Mice;
OPPTS
870.5395
[
§
84­
2].
In
a
bone
marrow
erythrocyte
micronucleus
assay
(
Barale,
et
al.
1990)
Swiss
CD­
1
male
mice
bone
marrow
cells
were
exposed
to
individual
and
combined
administrations
of
phenol
and
hydroquinone.
Groups
of
3
mice/
dose
received
an
intraperitoneal
injection
of
phenol
at
a
concentration
of
40,
80,
or
160
mg/
kg
body
weight
(
bw)
or
hydroquinone
at
40,
60,
or
80
mg/
kg
bw.
The
mixture
experiments
involved
all
possible
combinations
of
phenol
and
hydroquinone.
Phenol
at
a
concentration
of
40
mg/
kg
was
co­
administered
with
each
of
the
3
hydroquinone
concentrations
in
3
separate
experiments
and
this
process
was
repeated
for
the
60
and
80
mg/
kg
doses
of
phenol.
Animals
were
sacrificed
18
hours
after
treatment
and
bone
marrow
cells
were
harvested
to
score
PCEs
(
at
least
3000
per
animal)
and
normochromatic
erythrocytes
(
NCEs)
for
each
animal.
There
were
no
clinical
signs
of
toxicity
observed
following
treatment
with
phenol
or
hydroquinone
individually.
In
the
combination
experiment
the
myelotoxicity
(
expressed
as
the
increase
of
NCE/
PCE
ratio
and
compared
to
control
ratio)
increased
as
the
concentration
of
hydroquinone
increased.
This
ratio
exhibited
very
little
change
with
increasing
concentrations
of
phenol
at
each
hydroquinone
dose
level.
At
40
mg/
kg
hydroquinone
the
ratio
range
for
40­
160
mg/
kg
of
phenol
was
1.03­
1.04­
fold
greater
than
the
control.
The
60
and
80
mg/
kg
of
hydroquinone
exhibited
NCE/
PCE
ratios
for
the
phenol
range
that
were
1.23­
1.25­
fold
and
1.23­
1.45­
fold
greater,
respectively,
than
the
control
ratio.
Only
at
the
high
dose
of
hydroquinone
(
80
mg/
kg)
was
a
dose­
related
effect
observed
with
increasing
concentrations
of
phenol.

The
administration
of
phenol
at
concentrations
40­
160
mg/
kg
bw
did
not
result
in
micronuclei
induction
in
the
mouse
bone
marrow
cells;
therefore,
phenol
was
not
genotoxic
in
this
assay.
A
statistically
significant
increase
in
MNPCEs
was
observed
for
hydroquinone
although
it
was
considered
weakly
toxic.
The
increase
in
MNPCEs
was
observed
as
a
function
of
dose
for
hydroquinone
with
1.6­,
2.1­,
and
4.9­
fold
increases
over
control
for
the
40,
60,
and
80
mg/
kg
doses,
respectively.
Combined
treatment
of
the
test
articles
increased
the
number
of
MNPCEs
compared
to
the
control.
Co­
administration
of
phenol
and
hydroquinone
resulted
in
greater
than
a
2­
fold
increase
in
the
amount
of
MNPCEs
observed
with
hydroquinone
alone.
Greater
than
additive
effects
were
apparent
with
a
3.4­
fold
increase
at
the
lowest
concentration
(
phenol
40
mg/
kg,
hydroquinone
40
mg/
kg)
increasing
as
the
doses
were
raised.
There
was
an
11­
fold
increase
over
control
MNPCEs
at
the
maximum
concentration
(
phenol
160
mg/
kg,
hydroquinone
80
mg/
kg).
Phenol
was
not
toxic
and
hydroquinone
was
weakly
toxic
to
mouse
bone
marrow
cells;
however,
a
mixture
of
the
two
induced
a
dramatic
and
significant
decrease
in
bone
marrow
Page
22
of
42
cellularity.
A
powerful
synergism
between
phenol
and
hydroquinone
was
observed
in
the
induction
of
genotoxicity
and
somewhat
in
the
myelotoxicity
of
the
mouse
bone
marrow
cells.

Mammalian
Erythrocyte
Micronucleus
Test
in
Mice;
OPPTS
870.5395
[
§
84­
2].
In
a
mammalian
erythrocyte
micronucleus
assay
(
Chen
and
Eastmond,
1995)
CD­
1
male
mice,
in
groups
of
5/
dose
were
exposed
to
intraperitoneal
injections
of
phenol
(
99%
purity)
at
concentrations
of
0,
50,
75,
100,
or
160
mg/
kg/
day
or
combination
injections
of
hydroquinone
(
60
mg/
kg)
and
0,
50,
75,
100,
or
160
mg/
kg/
day
for
3
consecutive
days
at
24
hour
intervals.
Twenty­
four
hours
following
the
final
dose,
the
femoral
bone
marrow
cells
were
harvested
from
male
mice
and
slides
were
prepared
for
scoring
of
MNPCEs
per
2000
PCEs.
The
ratio
of
PCEs
to
normochromatic
erythrocytes
(
NCEs)
was
determined
for
each
animal
on
basis
of
the
number
of
mature
cells
(
NCEs)
encountered
while
accumulating
200
PCEs
and
was
an
indirect
measure
of
myelotoxicity
in
mouse
bone
marrow
cells.
There
was
no
depression
in
the
PCE/
NCE
ratio
with
the
individual
administrations
of
phenol
and
hydroquinone
(
with
0
mg/
kg
phenol),
while
the
mixture
exhibited
significant
decreases
(
42­
87%
reduction)
in
the
ratio
for
all
concentrations
of
phenol.
The
depression
in
bone
marrow
erythropoiesis
from
the
control
ratio
was
dose­
related
in
the
hydroquinone
(
constant
60
mg/
kg)
and
phenol
(
increasing
concentration
50­
160
mg/
kg/
day)
mixture
and
exhibited
a
decrease
in
PCE:
NCE
ratios
from
1.17
for
control
to
0.68
(
50
mg/
kg/
day),
0.36
(
75
mg/
kg/
day),
0.26
(
100
mg/
kg/
day),
and
0.15
(
160
mg/
kg/
day)
for
the
doses
of
phenol.
Individually,
phenol
was
weakly
and
hydroquinone
was
moderately
toxic
to
mouse
bone
marrow
cells.
The
frequencies
of
MN
ranged
from
2­
16
MN/
2000
PCE
following
treatment
with
the
individual
chemicals.
Concentrations
of
phenol
up
to
100
mg/
kg/
day
increased
MN
only
5
MNPCEs/
2000
PCEs;
slightly
above
controls
(
approximately
1
MNPCEs/
2000
PCEs).
The
maximum
dose
of
phenol
(
160
mg/
kg/
day)
increased
MN
to
10
per
2000
PCEs.
The
hydroquinone
experiment
increased
frequencies
of
MN
more
so
than
phenol.
A
hydroquinone
concentration
of
60
mg/
kg/
day
bw
increased
MNPCEs
to
approximately
16
MN/
2000
PCEs.

When
mice
were
administered
a
mixture
of
various
doses
of
phenol
(
50,
75,
100,
or
160
mg/
kg/
day)
and
a
constant
hydroquinone
(
60
mg/
kg/
day)
concentration
a
pronounced
increase
in
frequency
of
MN
was
observed.
Dose­
related
increases
in
MN
frequencies
from
18­
80
MN
were
noted
with
increasing
phenol
concentrations
(
when
combined
with
hydroquinone).
Statistically
significant
increases
in
MN
were
observed
at
the
two
highest
doses
of
phenol
(
100
and
160
mg/
kg/
day).
The
high­
dose
of
the
mixture
(
Phenol
160
mg/
kg/
day,
Hydroquinone
60
mg/
kg/
day)
was
approximately
4­
fold
greater
than
the
expected
additive
MN
frequencies
of
individual
doses
of
phenol
and
hydroquinone.
There
was
no
myelotoxicity
observed
in
individual
treatments
of
phenol
and
hydroquinone
as
measured
by
the
ratio
of
PCEs
to
NCEs.
Significant
decreases
in
the
PCE/
NCE
ratio
with
the
mixture
indicated
myelotoxic
effects
associated
with
treatment.
There
were
no
signs
of
genotoxicity
with
phenol
(
50­
160
mg/
kg/
day)
alone
and
minimal
increases
in
MN
with
hydroquinone
alone
during
the
study.
However,
the
combined
administration
of
phenol
and
hydroquinone
to
CD­
1
male
mice
resulted
in
a
statistically
significant
increase
in
the
frequency
of
MN.
There
was
a
synergism
in
myelotoxicity
and
genotoxicity
for
combined
administrations
of
phenol
and
hydroquinone
to
male
mice
bone
marrow
erythroblast
chromosomes.
Phenol
was
genotoxic
when
combined
with
hydroquinone.

Mammalian
Erythrocyte
Micronucleus
Test
in
Mice;
OPPTS
870.5395
[
§
84­
2].
In
a
mammalian
erythrocyte
micronucleus
assay
(
Gocke,
et
al.
1981)
NMRI
mice
in
groups
of
four/
dose
(
2
males,
2
females)
were
exposed
to
intraperitoneal
phenol
(
purity
not
reported)
at
concentrations
of
47,
94,
or
188
mg/
kg.
Doses
were
administered
twice,
once
at
0
hours
and
again
at
24
hours.
Animals
were
sacrificed
and
bone
marrow
cell
smears
were
prepared
6
hours
after
last
treatment.
For
each
animal,
1000
polychromatic
erythrocytes
were
scored.
There
were
no
treatment­
related
effects
on
mortality
(
100%
survival)
in
mice
receiving
treatment.
Variations
in
micronuclei
polychromatic
erythrocytes
(
MNPCEs)
were
observed
with
increasing
doses
of
phenol.
A
30%
decrease
from
control
levels
of
MNPCEs
was
observed
with
the
low
dose
(
47
mg/
kg);
however
there
were
increases
with
the
higher
doses
of
phenol.
The
94
and
188
mg/
kg
concentrations
of
phenol
resulted
in
2.4­
and
1.6­
fold
increases,
respectively,
in
the
number
of
MNPCEs
observed
in
Page
23
of
42
controls.
There
were
no
significant
increases
in
the
frequency
of
micronucleated
polychromatic
erythrocytes
in
mouse
bone
marrow
cells
at
the
concentrations
of
phenol
used
in
this
study.
Phenol
was
not
mutagenic
in
NMRI
mouse
bone
marrow
cells.

4.8
Neurotoxicity
Adequacy
of
database
for
Neurotoxicity:
Upon
review
of
the
toxicity
profile,
the
ADTC
committee
noted
neurotoxic
signs
in
acute
dermal
toxicity
studies
(
convulsions,
Brown,
et
al.;
tremors,
OTS
0515567;
stimulation
of
motor
nerve
endings
or
spinal
motor
centers,
Conning)
and
a
15­
day
inhalation
study
(
impaired
balance,
involuntary
muscle
twitches,
jerkiness,
and
increased
sluggishness).
The
IRIS
Toxicological
profile
reports
numerous
nervous
system
effects
have
been
observed
following
phenol
dosing
in
animals.
Studies
performed
by
ClinTrials
BioResearch
presented
one
animal
with
tremors
that
later
died
(
apparently
of
dehydration)
following
dosing
in
drinking
water
(
1998).
Additionally,
several
gavage
studies
have
shown
rats
and
mice
with
phenol­
related
tremors
(
43735402;
Dow
Chemical
Co.,
1994;
Moser
et
al.,
1995).
However,
in
a
specialized
13­
week
neurotoxicity
study
in
male
and
female
rats
that
included
a
Functional
Observational
Battery
(
FOB)
and
a
detailed
neurohistopathology
evaluation
(
ClinTrials
BioResearch,
1998),
nervous
system
effects
were
observed
as
tremors
in
one
animal
and
decreased
motor
activity
in
females.
A
short­
term
gavage
screening
study
(
Moser
et
al.,
1995)
found
that
the
only
effect
in
an
FOB
was
a
marginal
decrease
in
motor
activity
and
increased
rearing
post­
exposure.
Part
of
this
could
be
attributed
to
the
dehydration
observed
in
the
study,
but
it
was
also
concluded
that
phenol
contributed
to
the
decreased
motor
activity.

4.9
Metabolism
and
Pharmacokinetics
Adequacy
of
database
for
Metabolism
and
Pharmacokinetics:
The
database
for
metabolism
is
considered
to
be
complete.
No
additional
studies
are
required
at
this
time.
Phenol
is
essentially
completely
metabolized
in
24
hours.
The
portal­
of­
entry
metabolism
for
the
inhalation
and
oral
routes
appears
to
be
extensive
and
involves
sulfate
and
glucuronide
conjugation
and,
to
a
lesser
extent,
oxidation.
Phenol
was
predominantly
conjugated
with
sulfate
and
lower
amounts
of
glucuronic
acid
and
the
metabolites
were
rapidly
excreted
in
the
urine.
The
major
metabolites
found
include
phenyl
sulfate,
quinol
sulfate,
phenyl
glucuronide,
and
quinol
glucuronide.

870.7485
Metabolism
and
Pharmacokinetics
­
Rat
In
a
metabolism
and
pharmacokinetics
study
(
Capel,
et
al.
1971)
3
female
Wistar
Albino
rats
were
exposed
to
phenol
(
purity
not
reported)
by
stomach
syringe
or
tube
at
a
concentration
of
25
mg/
kg
(
5
14C
µ
Ci/
animal).
Animals
were
housed
in
metabolism
cages
that
collected
urine
in
receptacles
containing
a
few
mL
of
saturated
aqueous
HgCl
2
solution
to
prevent
bacterial
breakdown
of
conjugates.
After
24
hours,
radiochromatogram
scans
were
performed
on
urine
of
treated
animals.
An
average
of
95%
of
14C
phenol
(
25
mg/
kg)
was
excreted
in
the
urine
in
24
hours.
Four
metabolites,
the
sulfates
and
glucuronides
of
phenol
and
quinol,
were
found
in
the
urine
of
rats
after
an
oral
dose
of
phenol.
The
phenyl
sulfate
and
quinol
sulfate
metabolites
represented
54
and
1%,
respectively
of
the
metabolites
recovered
in
the
urine.
The
remaining
phenol
metabolites
recovered
from
the
urine
were
phenyl
glucuronide
(
42%)
and
quinol
glucuronide
(
2%).

In
a
metabolism
and
pharmacokinetics
study
(
Hughes
and
Hall
1995)
female
Fischer
344
rats
were
exposed
to
[
U­
14C]
phenol
(>
98%
radiochemical
purity,
specific
activity
100
µ
Ci/
µ
mol)
via
oral,
dermal,
intratracheal,
and
intravenous
administrations
at
a
concentration
of
63.5
nmol
(
3
µ
Ci/
animal,
approximately
350
nmol/
kg).
Animals
were
housed
in
metabolism
cages.
Urine
was
collected
at
4,
8,
12,
24,
48,
and
72
hours
and
feces
at
24,
48,
and
72
hours.
Excretion
samples
Page
24
of
42
were
analyzed
for
radioactivity.
Animals
from
the
oral,
iv,
and
it
experiments
were
sacrificed
72
hours
after
treatment;
organs,
muscle
tissue,
epididymal
fats,
and
contents
of
gastrointestinal
organs
were
examined.
Treated
skin
was
removed
from
animals
of
dermal
exposure
experiments
then
sacrificed
and
handled
in
a
similar
manner
as
previously
described
for
other
animals.

The
sum
of
radioactivity
detected
in
excreta
and
tissues
is
reported
as
disposition
results
expressed
as
a
percentage
of
the
recovered
dose.
The
total
mean
recovered
radioactivity
by
all
four
routes
was
90.5%
(+/­
10.2).
Phenol
was
absorbed
well
and
eliminated
primarily
in
urine
after
oral,
dermal,
iv,
and
it
administration.
Urine
provided
75­
95%
of
recovered
dose
within
72
hours
after
treatment
via
all
routes.
Similar
excretion
profiles
(
90%
of
recovered
dose)
of
radioactivity
were
observed
among
iv,
oral,
and
it
routes.
Dermal
administration
exhibited
the
lowest
total
amount
of
radioactivity
(
75%
of
recovered
dose).
Excretion
was
extensive
within
4
hours
for
oral,
it,
and
iv
administrations
with

70­
85%
of
recovered
dose
found
in
urine.
Essentially
complete
recovery
was
established
after
12
hours.
Since
iv
is
considered
a
standard
for
100%
absorption,
it
was
concluded
that
oral
and
it
routes
resulted
in
phenol
absorption
that
is
nearly
complete.
At
4
hours,
dermal
exposure
resulted
in
only
40%
of
recovered
phenol
in
urine.
This
elimination
was
70%
by
12
hours
and
essentially
complete
at
24
hours.
Skin
absorption
was
15­
20%
lower
than
other
routes
and
may
have
been
due
to
anatomical
difference
between
the
skin
and
gastrointestinal
tract
and/
or
lung.
The
stratum
corneum
acts
as
a
barrier
and
may
have
slowed
the
absorption
of
phenol
through
the
skin;
however,
once
phenol
was
absorbed
it
was
rapidly
eliminated
in
the
urine,
similar
to
the
other
experiments.

The
recovered
phenol
found
in
the
urine
of
treated
rats
8
hours
after
exposure
was
chiefly
in
the
form
of
two
metabolites.
Phenyl
sulfate
was
recovered
in
the
oral
(
63.4%),
dermal
(
48.4%),
it
(
68.7%),
and
iv
(
72.6%)
routes
of
administration.
The
second
metabolite,
phenyl
glucuronide,
was
also
present
after
oral
(
26.8%),
dermal
(
16.2%),
it
(
19.4%),
and
iv
(
14.3)
administrations
of
treated
animals.
Tissue
examination
of
rats
following
phenol
treatment
indicated
distribution
throughout
the
bodies
of
the
animals,
and
was
found
in
every
tissue
sampled.
The
greatest
concentration
of
radioactivity
was
found
in
the
contents
of
the
large
intestine
72
hours
after
exposure,
regardless
of
administration
route.
Absorption
of
phenol
was
extensive
following
iv,
oral,
and
it
administration
while
dermal
absorption
was
slightly
lower
by
comparison.
Phenol
was
predominantly
conjugated
with
sulfate
and
lower
amounts
of
glucuronic
acid.
These
metabolites
were
rapidly
excreted
in
the
urine.
Phenol
was
distributed
throughout
the
body
in
low
amounts
and
appeared
to
concentrate
in
liver,
lung,
and
kidney.
Overall,
the
exposure
of
phenol
to
rats
by
oral,
dermal,
intratracheal,
and
intravenous
routes
resulted
in
rapid
absorption,
conjugation,
and
elimination
in
urine.

870.7485
Metabolism
and
Pharmacokinetics
­
Mouse
In
a
metabolism
and
pharmacokinetics
study
(
Capel,
et
al.
1971)
3
groups
of
10
female
ICI
mice
were
exposed
to
phenol
(
purity
not
reported)
by
stomach
syringe
or
tube
at
a
concentration
of
25
mg/
kg
(
2.5
14C
µ
Ci/
animal).
Animals
were
housed
in
metabolism
cages
that
collected
urine
in
receptacles
containing
a
few
mL
of
saturated
aqueous
HgCl
2
solution
to
prevent
bacterial
breakdown
of
conjugates.
The
urine
of
the
10
mice
were
pooled
for
each
group.
After
24
hours,
radiochromatogram
scans
were
performed
on
urine
of
treated
animals.
An
average
of
66%
of
14C
phenol
(
25
mg/
kg)
was
excreted
in
the
urine
in
24
hours.
Four
metabolites,
the
sulfates
and
glucuronides
of
phenol
and
quinol,
were
found
in
the
urine
of
mice
after
an
oral
dose
of
phenol.
The
phenyl
sulfate
and
quinol
sulfate
metabolites
represented
46
and
5%,
respectively,
of
the
metabolites
recovered
in
the
urine.
The
remaining
phenol
metabolites
recovered
from
the
urine
were
phenyl
glucuronide
(
35%)
and
quinol
glucuronide
(
15%).

4.10
Dermal
Penetration
Page
25
of
42
Adequacy
of
database
for
Dermal
Penetration:
Dermal
penetration
studies
were
available
from
the
open
literature
and
IRIS
Toxicological
profile
for
phenol.
Phenol
is
readily
absorbed
by
the
inhalation,
oral,
and
dermal
routes.
Once
absorbed,
phenol
is
widely
distributed
in
the
body,
although
the
levels
in
the
lung,
liver,
and
kidney
are
often
reported
as
being
higher
than
in
other
tissues
(
on
a
per­
gram­
tissue
basis).
Elimination
from
the
body
is
rapid,
primarily
as
sulfate
and
glucuronide
conjugates
in
the
urine,
regardless
of
the
route
of
administration.
Phenol
does
not
appear
to
accumulate
significantly
in
the
body.

870.7600
Dermal
Penetration
­
Mouse
In
a
dermal
penetration
study
(
Behl
and
Linn,
1983)
skin
of
the
hairless
male
Skh­
hr

1
strain
of
mice
was
exposed
to
phenol
(>
98%
purity)
in
several
experiments.
1)
Abdominal
and
dorsal
skin
patches
were
excised
from
mice
aged
36,
92,
124,
340,
381,
and
441
days
to
measure
the
permeability
coefficient
of
phenol
in
various
aged
mice.
2)
Skin
was
immersed
in
saline
for
50
hours
to
determine
hydration
influences
which
were
measured
by
carrying
out
four
permeation
experiments
in
succession
on
the
same
piece
of
skin,
with
saline
rinsing
between
experiments.
3)
Mice
were
sacrificed
(
cervical
dislocation)
and
the
abdominal
and
dorsal
skin
surfaces
were
stripped
5,
10,
or
25
times
with
cellophane
tape.
The
epidermis
was
removed
from
the
dermal
sections
to
begin
permeation
process.
4)
Permeation
of
phenol
was
examined
in
pieces
of
skin
from
5
different
dorsal
locations
of
6
mice
at
concentrations
of
0.5,
1.0,
2.0,
4.0,
or
6.0%
(
w/
v).
These
phenol
concentrations
were
rotated
and
varied
between
mice.
The
permeation
experiment
was
initiated
within
30
minutes
of
skin
exposure
to
phenol
solution
and
completed
within
an
additional
2
hours.

The
phenol
permeability
coefficient
through
hairless
mouse
skin
underwent
no
appreciable
change
with
age
and
the
overall
average
range
from
18.3
to
25.4
P
X
103
cm/
hr
for
mice
aged
36
to
381
days.
The
441
day
old
mice
exhibited
a
slightly
smaller
permeability
coefficient
of
12.5
P
X
103
cm/
hr;
however,
it
was
concluded
that
this
decline
was
due
more
to
animal
variability
than
age.
Additionally,
the
permeability
coefficients
for
phenol
were
normalized
to
animal
mass
(
perm
coefficient/
body
weight)
and
age
patterns
were
reexamined.
Normalized
permeability
coefficients
were
approximately
105,
79,
58,
50,
56,
and
32
normalized
P
X
103
cm/
hr/
g
for
mice
aged
36,
92,
124,
340,
381,
and
441
days,
respectively.
The
mass­
weighted
values
decreased
appreciably
over
the
initial
year
of
age,
in
each
case
the
fall
in
magnitude
was
twofold.
Permeability
coefficients
through
abdominal
and
dorsal
skin
of
various
aged
mice
showed
no
significant
difference
in
values
of
the
two
sites.
Within
the
confines
of
this
study
there
was
no
factorable
site
dependency
to
the
permeation
of
phenol.
This
was
further
supported
by
the
hydration
study
in
which
permeability
coefficients
of
both
dorsal
and
abdominal
skin
remained
unchanged,
within
the
range
of
21­
24
P
X
103
cm/
hr
during
the
full
50
hours
of
hydration.
Phenol
permeability
coefficients
for
fresh
and
extensively
hydrated
skins
appeared
to
be
essentially
the
same.
Stripping
increased
permeability
of
abdominal
and
dorsal
skins
to
phenol.
Abdominal
permeability
coefficients
increased
with
28.4,
210,
354,
and
318
P
X
103
cm/
hr
for
0,
5,
10,
and
25
strippings,
respectively.
Similar
results
were
observed
in
the
0,
5,
10,
and
25
strippings
of
dorsal
skin
with
22.4,
120,
277,
and
275
P
X
103
cm/
hr,
respectively.
The
permeability
coefficients
obtained
tended
to
level
off
at
10
strippings.
Abdominal
permeability
for
partially
and
fully
stripped
skins
invariably
exceed
those
of
dorsal
surfaces
even
though
there
is
no
apparent
difference
for
the
intact
skins.
Abdominal
stratum
corneum
may
be
more
easily
removed
and
the
permeability
of
remaining
abdominal
strata
may
be
intrinsically
greater
than
that
of
the
dorsal
skin.
Phenol
exhibited
dose­
related
increases
in
skin
permeability
for
all
6
mice
of
permeation
study.
Regardless
of
location
of
excised
dorsal
skin,
the
permeability
increased
as
concentration
of
phenol
increased.
The
overall
mean
permeability
coefficients
were
20.3,
22.7,
30.7,
46.6,
165.4,
and
202.7
P
X
103
cm/
hr
for
0,
0.5,
1.0,
2.0,
4.0,
and
6.0
%
(
w/
v).

Phenol
chemically
alters
the
mouse
skin
stratum
corneum,
leading
to
increased
mass­
transfer
rates;
a
phenomenon
also
observed
in
isolated
human
epidermis
with
the
threshold
concentration
Page
26
of
42
of
1.5%
being
virtually
the
same
for
both
mouse
and
human
tissue.
Altering
the
stratum
corneum
decreased
the
partitioning
dependency
of
the
skin
permeation
process.
Significant
effects
on
the
lipid
medium
were
exhibited
by
a
6%
(
w/
v)
concentration
of
phenol.
Phenol
administered
at
a
concentration

5%
is
doubly
dangerous
because
the
permeability
coefficient
is
10­
fold
enhanced.
Therefore,
an
absorption
rate
of
5%
compared
with
a
1%
solution
is
not
just
5
times
but
50
times
greater.
It
was
observed
that
age
and
hydration
have
little
effect
on
the
permeability
of
phenol
through
human
and
mouse
skin
and
the
effects
on
the
skin
were
a
result
of
destroyed
barrier
integrity.
Permeation
and
chemical
denaturation
of
skin
by
phenol
were
found
to
be
similar
between
mouse
and
human
skin
tissue;
indicating
that
the
hairless
mouse
is
an
adequate
model
for
chemical
permeability
in
humans.
The
results
suggest
that
the
stratum
corneum
is
proportionally
impaired
as
the
phenol
concentration
is
increased.

5.0
Toxicity
Endpoint
Selection
5.1
See
Section
7.1,
Summary
of
Toxicological
Doses
and
Endpoint
Selection,
Table
3.

5.2
Dermal
Absorption
Dermal
Absorption
Factor:
50%

From
the
available
data,
dermal
absorption
percentages
of
20­
50%
have
been
observed
from
in
vivo
and
in
vitro
studies.
The
ADTC
selected
the
50%
dermal
absorption
value
for
phenol
for
use
as
a
conservative
value
in
risk
assessments.
This
value
also
takes
into
account
the
irritant
properties
of
phenol
which
may
increase
its
dermal
absorption.
Phenol
is
not
expected
to
result
in
chronic
dermal
exposure
due
to
its
volatile
nature
and
short
half­
life.
Therefore,
the
ADTC
did
not
select
a
long­
term
dermal
endpoint
for
phenol,
and
this
risk
assessment
is
not
required.

5.3
Classification
of
Carcinogenic
Potential
Phenol
is
characterized
as
a
Group
D,
not
classifiable
as
to
human
carcinogenicity
(
This
group
is
used
for
agents
with
inadequate
human
and
animal
evidence
of
carcinogenicity
or
for
which
no
data
are
available).
The
updated
toxicological
review
in
the
EPA
IRIS
database
(
USEPA,
2002)
provides
a
summary
of
the
weight
of
the
evidence
with
respect
to
the
carcinogenic
potential
of
phenol,
and
this
is
reproduced
in
part
below.

Chronic
drinking
water
bioassays
of
phenol
have
been
conducted
in
rats
and
mice
(
NIH
PB#
80­
1759).
In
these
studies,
NCI
concluded
that
phenol
was
not
carcinogenic
in
male
or
female
F344rats
or
B6C3F1
mice.
However,
the
report
also
noted
that
leukemia
and
lymphoma
were
significantly
increased
in
low­
dose
male
rats,
although
there
was
no
significant
increase
at
the
high­
dose.
The
increases
in
leukemia
are
of
particular
interest
in
light
of
the
leukemogenic
effects
of
benzene
(
for
which
phenol
is
a
metabolite)
in
humans.
(
In
experimental
animals,
benzene
has
not
been
shown
to
induce
leukemia,
although
increases
in
lymphoma
have
been
observed
[
e.
g.,
NTP,
1986].).

In
contrast
with
the
negative
results
for
oral
carcinogenicity,
dermally
administered
phenol
has
been
consistently
observed
to
be
a
promoter.
Several
authors
(
Salaman
and
Glendenning,
1957;
Boutwell
and
Bosch,
1959;
Wynder
and
Hoffmann,
1961)
observed
that
dermally
applied
phenol
promoted
DMBA­
initiated
skin
tumors.
These
studies
have
generally
reported
significant
skin
ulceration
at
all
phenol
doses
tested.
The
exception
is
Wynder
and
Hoffman
(
1961),
who
reported
that
5%
phenol
promoted
DMBA­
initiated
tumors
in
mice
in
the
absence
of
any
toxic
reactions.
When
the
same
phenol
dose
was
administered
in
different
volumes,
higher
promotion
activity
was
exhibited
by
the
more
concentrated
solution,
which
also
produced
severe
skin
Page
27
of
42
ulceration,
suggesting
that
some
of
the
promotion
activity
may
have
been
related
to
the
rapid
cell
division
of
repair
of
skin
damage
(
Salaman
and
Glendenning,
1957).

A
more
recent
study
of
the
tumor
promoting
ability
of
phenol
was
conducted
by
Spalding
et
al.
(
1993)
in
which
a
transgenic
mouse
line
possessing
the
properties
of
genetically
initiated
skin
and
sensitive
to
TPA
(
a
well
described
promotor
of
skin
papillomas
in
two­
stage
models)
was
treated
topically
2
times/
week
for
up
to
20
weeks
with
several
chemicals
including
phenol.
Papillomas
were
induced
with
the
chemicals
benzoyl
peroxide,
TPA,
and
2­
butanol
peroxide.
Three
mg
of
phenol
administered
for
20
weeks
resulted
in
a
single
papilloma
in
one
of
five
male
mice
at
7
weeks
and
persisted
over
the
20
week
treatment
period.
This
response
was
not
statistically
significant
compared
to
controls.

A
mechanistic
study
conducted
by
Stenius
et
al.
(
1989)
was
designed
to
assess
the
toxicity
and
carcinogenicity
of
phenol
when
administered
to
partially
hepatectomized
male
SD­
rats.
Phenol
was
administered
by
gavage
5
days/
week
for
7
weeks
at
a
concentration
of
100
mg/
kg/
day.
Animals
were
sacrificed,
by
decapitation,
1
week
after
last
treatment.
Sections
of
the
rat
liver
were
prepared
and
stained
to
measure
for
induction
of
 ­
glutamyltranspeptidase
(
GGT)
positive
enzyme­
altered
foci
as
an
indicator
of
tumor
initiation.
Additional
studies
involved
single
oral
administrations
of
phenol
to
measure
inductions
of
hepatic
ornithine
decarboxylase
(
ODC),
glutathione
(
GSH)
depletion,
and
in
vivo
lipid
peroxidation.

Phenol
did
not
increase
the
number
or
volume
of
foci
and
was
found
to
have
no
tumor­
initiating
properties
within
the
confines
of
this
study.
Lipid
peroxidation
was
not
induced
following
administration
of
phenol
as
measured
by
malondialdehyde
(
MDA)
in
the
urine.
There
were
small
and
inconsistent
effects
observed
in
hepatic
ornithine
decarboxylase
(
ODC)
in
which
there
was
an
increase
at
the
mid­
dose,
but
a
decrease
at
the
high­
dose.
Observed
measurements
of
hepatic
ODC
were
18.8,
32.3,
and
11.4
pmol/
mg/
h
for
the
phenol
doses
of
0,
50,
and
100
mg/
kg/
day,
respectively.
Phenol
did
not
induce
GSH
depletion
in
hepatocytes.

6.0
FQPA
Considerations
The
ADTC
concluded
that
the
available
toxicity
database
for
phenol
was
adequate
for
hazard
characterization
for
the
registered
uses.
In
addition
to
several
reports
from
the
scientific
literature,
there
is
a
recent
(
2002)
updated
Toxicological
Profile
in
the
IRIS
database
for
phenol.

6.3
Developmental
Toxicity
Study
Conclusions
The
toxicity
profile
for
phenol
presented
several
developmental
and
reproductive
toxicity
studies
found
in
the
open
literature.
These
studies
are
also
referred
to
in
the
IRIS
update.
In
addition,
the
National
Toxicology
Program
conducted
developmental
toxicity
studies
in
both
rats
and
mice.
The
ADTC
considered
the
NTP
studies
as
well
as
the
published
report
by
Ryan
et
al.
(
2001)
to
be
acceptable
for
regulatory
purposes.
Published
reports
by
Kavlock
(
1990)
and
Bishop
(
1997)
were
considered
unacceptable
for
purposes
of
determining
the
developmental
toxicity
of
phenol,
based
on
study
design.

In
the
NTP
rat
developmental
toxicity
study
(
MRID
#
43735402),
phenol,
in
distilled
water,
was
administered
to
groups
of
23
rats/
dose
via
gavage
at
dose
levels
of
0,
30,
60,
or
120
mg/
kg/
day
from
gestation
days
(
GD)
6
to
15.
No
significant
maternal
toxicity
was
observed
up
to
the
highdose
of
120
mg/
kg/
day
tested
in
this
study.
In
offspring,
the
only
effect
noted
was
a
significant
decrease
in
mean
fetal
body
weight,
but
no
teratogenic
effects
were
observed.
Therefore,
the
maternal
toxicity
LOAEL
is
greater
than
120
mg/
kg/
day
and
the
Developmental
toxicity
LOAEL
is
120
mg/
kg/
day.
Page
28
of
42
In
the
NTP
mouse
developmental
toxicity
study
(
MRID
#
43735401),
phenol
was
administered
in
distilled
water
to
groups
of
31­
36
mice/
dose
by
gavage
at
dose
levels
of
0,
70,
140,
or
280
mg/
kg/
day
from
gestation
days
(
GD)
6
to
15.
Clinical
signs
of
toxicity
were
observed
in
maternal
animals
at
a
dose
of
280
mg/
kg/
day,
which
included
signs
of
neurotoxicity
(
tremors,
ataxia,
lethargy).
In
addition,
maternal
body
weight
was
decreased
during
the
treatment
period
(
31%
decrease)
and
entire
gestation
period
(
28%
decrease).
Offspring
in
the
280
mg/
kg/
day
dose
group
experienced
an
increase
in
cleft
palate
in
8
of
214
fetuses
(
3
litters)
but,
this
increase
was
not
statistically
significant.
The
fetuses,
male
and
female
combined,
exhibited
reduced
mean
fetal
weights.
The
high­
dose
(
280
mg/
kg/
day)
was
fetotoxic
due
to
significant
reductions
(
18%)
from
controls
in
mean
fetal
weight
in
treated
animals.
The
Maternal
and
Developmental
toxicity
NOAEL
was
140
mg/
kg/
day,
and
the
Maternal
and
Developmental
toxicity
LOAEL
was
280
mg/
kg/
day
in
this
study.

6.4
Reproductive
Toxicity
Study
Conclusions
In
a
two­
generation
reproduction
toxicity
study
conducted
by
Ryan
et
al
(
2001),
phenol
(
100%
purity)
was
administered
to
groups
of
30
Sprague­
Dawley
rats/
sex/
dose
in
drinking
water
at
concentrations
of
200,
1000,
or
5000
ppm
(
14,
70,
and
310
mg/
kg/
day
for
males
and
20,
93,
and
350
mg/
kg/
day
for
females,
respectively)
for
both
generations.
There
were
treatment­
related
decreases
from
control
in
body
weight
and
body
weight
gain
in
P1
generation
rats
treated
with
phenol.
These
reductions
were
concomitant
with
decreases
in
food
and
water
consumption
and
observed
in
the
high­
dose
rats.
There
were
also
treatment­
related
decreases
from
controls
in
F1
body
weight
in
the
5000
ppm
phenol­
treated
rats.
The
lower
maternal
body
weight
may
have
contributed
to
the
lower
birth
weight
of
F1
generation
as
a
result
of
the
decreased
food
and
water
consumption
during
lactation
and
decreased
palatability.
The
Maternal
Toxicity
NOAEL
is
1000
ppm
in
the
P1
and
F1
generations.
The
Maternal
Toxicity
LOAEL
is
5000
ppm
based
on
decreases
in
water
and
food
consumption,
body
weight
(
average
11%
decrease
during
pre­
mating
weeks
1
and
10,
gestation,
and
lactation)
and
body
weight
gain
(
average
18%
decrease
during
pre­
mating
weeks
1
through
10)
in
the
P1
and
F1
generations.
These
effects
are
associated
with
flavor
aversion
to
phenol
in
the
drinking
water.

There
were
no
treatment­
related
effects
on
reproductive
performance
in
either
the
P1
or
F1
generation.
The
estrus
cycle,
epididymal
sperm
count,
motility,
sperm
morphology,
testicular
sperm
count,
and
production
rate
were
unaffected
by
phenol
treatment
in
the
P1
and
F1
generations.
However,
the
percent
of
offspring
alive
after
PND
0
was
significantly
decreased
in
the
5000
ppm
groups
with
a
10%
decrease
on
PND
4
for
the
P1
generation
and
decreases
of
28
and
24%
on
PND
4
and
7­
21,
respectively,
for
the
F1
generation.
The
Reproductive
Toxicity
NOAEL
is
greater
than
or
equal
to
5,000
ppm
in
the
P1
and
F1
generations
(
highest
dose
tested).
The
Reproductive
Toxicity
LOAEL
is
greater
than
5,000
ppm
in
the
P1
and
F1
generations
(
not
established).

There
were
treatment­
related
effects
for
both
F1
and
F2
generations
with
increases
in
litter
mortality
(
more
so
in
the
F2
generation)
and
reduced
offspring
body
weights
in
the
high­
dose
group.
This
occurred
concurrently
with
maternal
toxicity
(
decreased
maternal
body
weight);
believed
to
be
secondary
to
the
animals'
aversion
to
the
flavor
of
the
phenol­
treated
water
and
resulted
in
decreased
maternal
as
well
as
offspring
body
weight.
There
were
delays
in
vaginal
patency
of
F1
females
(
38.3
days
for
treated
females
vs.
34.6
days
for
control
females)
and
preputial
separation
of
F1
males
(
47.8
days
for
treated
males
vs.
44
days
for
control
males)
observed
with
decreases
in
pre­
and
post­
weaning
body
weights
in
the
high­
dose
group.
Therefore,
the
onset
of
puberty
was
delayed
and
attributed
to
decreased
food
and
water
consumption
and
reduced
body
weight.
The
Offspring
Toxicity
NOAEL
is
1000
ppm.
The
Offspring
Toxicity
LOAEL
is
5000
ppm
based
on
decreases
in
body
weight
of
F1
and
F2
offspring
(
5­
7%
on
PND
0;
15­
30%
on
PND
4­
21),
decreases
in
litter
survival
of
P1
and
F1
offspring
(
P1
generation:
90%
treated
vs.
99%
control
on
PND
4;
96%
treated
vs.
100%
control
Page
29
of
42
animals
on
PND
7­
21
and
F1
generation:
67%
treated
vs.
93%
control
on
PND
4;
74%
treated
vs.
98%
control
on
PND
7­
21),
delays
in
preputial
separation
in
F1
males
(
47.8
days
for
treated
males
vs.
44
days
for
control
males),
and
delays
in
vaginal
patency
in
F1
females
(
38.3
days
for
treated
females
vs.
34.6
days
for
control
females).

6.5
Information
from
Literature
Sources
Information
describing
hazards
of
phenol
were
obtained
mainly
from
published
scientific
literature
on
the
toxicity
of
this
compound,
including
technical
reports
from
the
National
Toxicology
Program
(
ntp­
server.
niehs.
nih.
gov)
and
the
USEPA's
IRIS
website
(
epa.
gov/
iris)
.
Product
chemistry
data
were
obtained
from
the
Handbook
of
Physics
and
Chemistry,
64th
edition
(
CRC
Press),
1983.

6.6
Pre­
and/
or
Postnatal
Toxicity
A.
Determination
of
Susceptibility
The
ADTC
concluded
that
there
is
no
evidence
for
susceptibility
of
phenol
from
the
available
data
on
developmental
and
reproductive
toxicity.

B.
Degree
of
Concern
Analysis
and
Residual
Uncertainties
The
ADTC
concluded
that
there
are
low
concerns
and
no
residual
uncertainties
for
pre
and/
or
postnatal
toxicity
with
phenol
for
any
of
the
available
studies.
Conservative
NOAELs
were
established
for
all
developmental
and
offspring
effects.
The
developmental
and
reproductive
toxicity
studies
conducted
with
phenol
provide
adequate
information
on
the
dose­
response
relationships
for
developmental
and
reproductive
toxicity
and
are
considered
adequate
studies
for
regulatory
purposes.

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

The
hazard
based
default
special
FQPA
safety
factor
(
1X)
can
be
removed
when
assessing
dietary
risks
resulting
from
the
uses
of
phenol.

6.7
Recommendation
for
a
Developmental
Neurotoxicity
Study
The
ADTC
did
not
recommend
a
developmental
neurotoxicity
study.

7.0
Summary
of
Toxicological
Doses
and
Endpoints
for
Phenol
for
Use
in
Human
Risk
Assessment1
7.1
Summary
Table
of
Toxicological
Dose
and
Endpoint
Selection
(
Table
3)
Page
30
of
42
Exposure
Scenario
Dose
(
mg/
kg/
day)
used
in
risk
assessment
UF
Special
FQPA
SF
and
Level
of
Concern
for
Risk
Assessment
Study
and
Toxicological
Effects
Acute
Dietary
(
gen
population)
This
risk
assessment
is
not
required.

Acute
Dietary
(
females
13­
49)
This
risk
assessment
is
not
required.

Chronic
Dietary
(
all
populations)
NOAEL=
60
UF
=
100
Chronic
RfD
=
0.6
mg/
kg/
day
100X
Developmental
toxicity
study
in
rats
(
NTP,
1983)
Based
on
significant
reductions
from
the
control
in
mean
fetal
body
weight/
litter
at
120
mg/
kg/
day.

Incidental
Oral
Short­
Term
(
1
­
30
Days)

Residential
Only
NOAEL=
60
mg/
kg/
day
MOE
=
100
Developmental
toxicity
study
in
rats
(
NTP,
1983)
Based
on
significant
reductions
from
the
control
in
mean
fetal
body
weight/
litter
at
120
mg/
kg/
day.

Incidental
Oral
Intermediate­
Term
(
1
­
6
Months)

Residential
Only
NOAEL=
60
mg/
kg/
day
MOE
=
100
Developmental
toxicity
study
in
rats
(
NTP,
1983)
Based
on
significant
reductions
from
the
control
in
mean
fetal
body
weight/
litter
at
120
mg/
kg/
day.

Dermal1
Short
and
intermediateterm
NOAEL
=
60
mg/
kg/
day
MOE
=
100
Developmental
toxicity
study
in
rats
(
NTP,
1983).
Based
on
significant
reductions
from
the
control
in
mean
fetal
body
weight/
litter
at
120
mg/
kg/
day.

Inhalation2
(
All
durations)
LOAEL
=
0.1
mg/
L
MOE
=
300
(
ST,
IT)

MOE
=
1000
(
LT)
Dalin
and
Kristofferson:
Physiological
Effects
of
a
Sub­
lethal
Concentration
of
Inhaled
Phenol
on
the
Rat.
Ann.
Zool.
Fennici
11:
193­
199,
1974
LOAEL
of
0.1
mg/
L,
based
on
alterations
in
sliding
angle
from
tilting
plane
test,
and
significant
increases
in
liver
enzymes
Cancer
Data
inadequate
for
assessment
of
human
carcinogenic
potential
(
USEPA,
2002)

1a
dermal
absorption
factor
of
50%
should
be
used
since
an
oral
endpoint
was
selected.

7.2
Rationale
for
Toxicological
Dose
and
Endpoint
Selection
8.0
Toxicity
Profile
Tables
Page
31
of
42
8.1
Acute
Toxicity
Profile
Table
­
(
See
Section
4.1,
Acute
Toxicity,
Table
2).

8.2
Subchronic,
Chronic
and
Other
Toxicity
Profiles
Table
(
Table
4)

Guideline
Number/
Study
Type/
Test
Substance
(%
a.
i.)
MRID
Number
(
Year)/
Citation/
Classification/
Doses
Results
Non­
guideline
­
Subchronic
(
Oral)
Range
Finding
Study
(
Rat)
Phenol
purity
not
reported
NIH
PB#
­
80­
1759
Acceptable
­
Non­
guideline
0,
100,
300,
1000,
3000,
and
10000
ppm
NOAEL
=
3000
ppm
LOAEL
=
10,000
ppm,
based
on
significant
decreases
in
mean
body
weight
gain.

Considering
the
test
article
was
administered
in
the
drinking
water,
palatability
at
the
high
dose
may
have
affected
water
consumption..

Non­
guideline
­
Subchronic
(
Oral)
Range
Finding
Study
(
Mouse)
Phenol
purity
not
reported
NIH
PB#
­
80­
1759
Acceptable
­
Non­
guideline
0,
100,
300,
1000,
3000,
and
10000
ppm
NOAEL
=
3000
ppm
LOAEL
=
10,000
ppm,
based
on
significant
decreases
in
mean
body
weight
gain.

Considering
the
test
article
was
administered
in
the
drinking
water,
palatability
at
the
high
dose
may
have
affected
water
consumption..

Special
Study
­
Nonguideline
Two
Week
Inhalation
Study
(
Rat)
Phenol
purity
not
reported
Dalin
and
Kristoffersson.
1984
Acceptable
­
Non­
guideline
600
+/­
10
L/
hr
in
an
inhalation
chamber
with
a
phenol
concentration
of
100
mg/
m3
CNS
effects
measured
by
the
"
tilting­
plane"
method
showed
significant
decreases
in
the
value
of
the
sliding
angle
after
exposure
to
phenol.
The
mean
sliding
angle
was
71.2
±
2.4
degrees
prior
to
phenol
administration
and
following
treatment
there
was
a
significant
decrease
(
6%)
to
66.8
±
1.7
degrees.
Rats
had
elevated
plasma
Mg2+
levels
(
Hypermagnesaemia)
and
exhibited
toxic
effects
in
the
central
nervous
system
(
CNS).

870.3700a
(
§
83­
3)
Developmental­
Rat
Phenol
purity
99.9%
43735402
Acceptable
­
Non­
guideline
0,
30,
60
or
120
mg/
kg/
day
Maternal
Toxicity
NOAEL

120
mg/
kg/
day
(
highest
dose
tested)
LOAEL
>
120
mg/
kg/
day
(
not
established)
Reproductive
Toxicity
NOAEL

120
mg/
kg/
day
(
highest
dose
tested)
LOAEL
>
120
mg/
kg/
day
(
not
established)
Developmental
Toxicity
NOAEL
=
60
mg/
kg/
day
LOAEL
=
120
mg/
kg/
day,
based
on
reduced
fetal
weight
Guideline
Number/
Study
Type/
Test
Substance
(%
a.
i.)
MRID
Number
(
Year)/
Citation/
Classification/
Doses
Results
Page
32
of
42
870.3700a
(
§
83­
3)
Developmental­
Rat
Phenol
purity
90%
Argus,
1997
Acceptable
­
Guideline
3
time
daily
with
0,
20,
40,
or
120
mg/
kg/
dose
(
0,
60,
120,
or
360
mg/
kg/
day)
Maternal
Toxicity
NOAEL
=
60
mg/
kg/
day
LOAEL
=
120
mg/
kg/
day,
based
on
small
decreases
in
maternal
body
weight
Developmental
Toxicity
NOAEL
=
120
mg/
kg/
day
LOAEL
=
360
mg/
kg/
day,
based
on
decreased
fetal
body
weight
and
delayed
ossification
870.3700a
(
§
83­
3)
Developmental­
Mouse
Phenol
purity
99.9%
34735401
Unacceptable
(
Upgradable)
0,
70,
140,
or
280
mg/
kg/
day
Maternal
Toxicity
NOAEL
=
140
mg/
kg/
day
LOAEL
=
280
mg/
kg/
day,
based
on
increased
mortality,
significant
reductions
in
body
weight,
and
clinical
signs
of
CNS
toxicity
(
tremors,
lethargy,
and
ataxia)
Reproductive
Toxicity
NOAEL

280
mg/
kg/
day
(
highest
dose
tested)
LOAEL
>
280
mg/
kg/
day
(
not
established)
Developmental
Toxicity
NOAEL
=
140
mg/
kg/
day
LOAEL
=
280
mg/
kg/
day,
based
on
reduced
fetal
weight
and
an
apparent
increase
in
te
incidence
of
cleft
palate
Non­
guideline
­
Developmental
Toxicity
­
Rat
Phenol
purity
>
99%
Narotsky
and
Kavlock.
1995
Acceptable
­
Non­
guideline
40,
and
53.3
mg/
kg/
day
Maternal
Toxicity
NOAEL
>
40
mg/
kg/
day
(
lowest
dose
tested)
LOAEL
=
40
mg/
kg/
day,
based
on
reduced
body
weight
gains
and
severe
respiratory
signs
Reproductive
Toxicity
NOAEL
=
40
mg/
kg/
day
LOAEL
=
53.3
mg/
kg/
day,
based
on
significantly
reduced
litter
sizes,
full
resorption,
and
prenatal
loss
Developmental
Toxicity
NOAEL

53.3
mg/
kg/
day
(
highest
dose
tested)
LOAEL
>
53.3
mg/
kg/
day
(
not
established)
Guideline
Number/
Study
Type/
Test
Substance
(%
a.
i.)
MRID
Number
(
Year)/
Citation/
Classification/
Doses
Results
Page
33
of
42
870.3800
(
§
83­
4)
Reproduction
­
Rat
Phenol
purity
100%
Ryan,
et
al.
2001
Acceptable­
Guideline
0,
200,
1000,
and
5000
ppm
Males:
0,
14,
70,
and
310
mg/
kg/
day
Females:
0,
20,
93,
and
350
mg/
kg/
day
Maternal
Toxicity
NOAEL
=
1,000
ppm
in
the
P1
and
F1
generations
LOAEL
=
5,000
ppm
based
on
decreases
in
water
and
food
consumption,
body
weight
(
average
11%
decrease
during
premating
weeks
1
and
10,
gestation
and
lactation)
and
body
weight
gain
(
average
18%
decrease
during
pre­
mating
weeks
1
through
10)
in
the
P1
and
F1
generations.
These
effects
are
associated
with
flavor
aversion
to
phenol
in
the
drinking
water
Reproductive
Toxicity
NOAEL

5,000
ppm
in
the
P1
and
F1
generations
(
highest
dose
tested)
LOAEL
>
5,000
ppm
in
the
P1
and
F1
generations
(
not
established)
Offspring
Toxicity
NOAEL
=
1,000
ppm
LOAEL
=
5,000
ppm
based
on
decreases
in
body
weight
of
F1
and
F2
offspring
(
5­
7%
on
PND
0;
15­
30%
on
PND
4­
21),
decreases
in
litter
survival
of
P1
and
F1
offspring
(
P1
generation:
90%
in
treated
animals
vs.
99%
in
control
animals
on
PND
4;
96%
in
treated
animals
vs.
100%
in
control
animals
on
PND
7­
21.
F1
generation:
67%
in
treated
animals
vs.
93%
in
control
animals
on
PND
4;
74%
in
treated
animals
vs.
98%
in
control
animals
on
PND
7­
21)
and
delays
in
preputial
separation
in
F1
males
(
47.8
days
for
treated
males
vs.
44
days
for
control
males)
and
vaginal
patency
in
F1
females
(
38.3
days
for
treated
females
vs.
34.6
days
for
control
females)
Guideline
Number/
Study
Type/
Test
Substance
(%
a.
i.)
MRID
Number
(
Year)/
Citation/
Classification/
Doses
Results
Page
34
of
42
870.4200a
(
§
83­
2)
Carcinogenicity
­
Rat
Phenol
purity
98.47%
NIH
PB#
80­
1759
Acceptable
­
Non­
guideline
0,
2500,
or
5000
ppm
Male:
0,
322,
or
645
mg/
kg/
day
Female:
0,
360,
or
721
mg/
kg/
day
NOAEL

5000
ppm
(
highest
dose
tested)
for
both
male
and
female
rats
LOAEL
>
5000
ppm
(
not
established)

Various
neoplasms
were
observed
in
both
control
and
treated
rats.
The
low
dose
male
rats
exhibited
increased
tumor
occurrence
over
controls.
Pheochromocytomas
of
the
adrenal
medulla
were
found
in
44%
of
low
dose
males;
significantly
higher
(
p=
0.046)
than
the
26%
in
controls
and
18%
in
high
dose
males.
The
incidence
of
either
leukemia
or
lymphomas
in
high
dose
and
low
dose
males
were
higher
than
controls,
but
were
only
significantly
higher
(
p=
0.008)
in
low
dose
treated.
The
incidence
of
interstitial­
cell
tumors
in
the
testis
of
males
is
also
significantly
higher
(
p=
0.05)
in
low
dose
males
than
control;
found
in
49
of
the
50
animals.
Results
of
histopathologic
examinations
suggest
phenol
may
have
increased
the
incidence
of
pheochromocytoma,
leukemia
or
lymphoma
in
low
dose
male
rats.
Females
did
not
exhibit
increased
incidences
of
tumors
at
any
time
in
this
study.

870.4200b
(
§
83­
2)
Carcinogenicity
­
Mouse
Phenol
purity
98.47%
NIH
PB#
80­
1759
Acceptable
­
Non­
guideline
0,
2500,
or
5000
ppm
Male:
0,
590,
or
1180
mg/
kg/
day
Female:
0,
602,
or
1204
mg/
kg/
day
NOAEL

5000
ppm
(
highest
dose
tested)
for
male
and
female
mice
LOAEL
>
5000
ppm
(
not
established)

Neoplasms
observed
in
treated
animals
were
of
the
usual
number
and
type
found
in
mice.
Uterine
endometrial
stromal
polyps
were
increased
in
5
of
48
high­
dose
female
mice,
although
this
was
not
significantly
different
from
similar
historical
control
mice.
Any
other
neoplasms
noted
were
occurrences
normally
associated
with
aged
B6C3F1
mice
and
were
not
treatment
related.

Results
of
the
histopathologic
examinations
suggest
phenol
was
not
toxic
or
carcinogenic
to
B6C3F1
mice
under
the
conditions
of
this
2
year
drinking
water
carcinogenic
bioassay;
no
tumor
at
any
site
in
the
mice
could
be
clearly
associated
with
the
administration
of
phenol
in
this
study.
Guideline
Number/
Study
Type/
Test
Substance
(%
a.
i.)
MRID
Number
(
Year)/
Citation/
Classification/
Doses
Results
Page
35
of
42
Non­
guideline
­
Mechanistic
Study
Phenol
purity
99.5%
Stenius,
et
al.
1989
Acceptable
­
Non­
guideline
0
or
100
mg/
kg/
day
5
days/
week
for
7
weeks
NOAEL

100
mg/
kg
(
highest
dose
tested)
LOAEL
>
100
mg/
kg
(
not
established)

Phenol
is
not
a
potent
stimulator
of
foci
development
and
can
be
regarded
at
a
negative
control
in
this
study
because
it
should
not
be
susceptible
to
oxidation­
reduction
reactions.

870.5100
(
§
84­
2)
Bacterial
reverse
mutation
test
Phenol
purity
not
reported
Florin,
et
al.
1980
Acceptable
­
Non­
guideline
2.3
­
2343

g/
plate
3

mol/
plate
Negative
There
was
no
evidence
of
induced
mutant
colonies
over
background.
Positive
controls
produced
the
appropriate
responses
in
the
corresponding
strains
of
the
bacterial
reverse
mutagenesis
test.
S.
typhimurium
did
not
show
mutagenic
activity
in
the
presence
or
absence
of
metabolic
activation
when
phenol
was
administered
at
3

mol/
plate.

870.5100
(
§
84­
2)
Bacterial
reverse
mutation
test
Phenol
purity
99.9%
Haworth,
et
al.
1983
Acceptable
­
Non­
guideline
0,
33,
100,
333,
1000,
2500,
and
3333

g/
plate
Negative
There
was
no
evidence
of
induced
mutant
colonies
over
background.
Positive
controls
produced
appropriate
responses
in
corresponding
strains
of
the
bacterial
reverse
mutagenesis
test.
S.
typhimurium
did
not
show
mutagenic
activity
in
the
presence
or
absence
of
metabolic
activation
following
administration
of
phenol.

870.5100
(
§
84­
2)
Bacterial
reverse
mutation
test
Phenol
purity
98%
Pool
and
Lin.
1982
Acceptable
­
Non­
guideline
0.5,
5,
50,
500,
and
5000

g/
plate
Negative
The
most
abundant
phenolic
compounds
found
in
smokehouse
smoke
condensates
were
not
mutagenic
in
the
Salmonella
Typhimurium
assay.
There
was
no
evidence
of
mutagenic
activity
following
administration
of
phenol
to
5
bacterial
strains
of
S.
typhimurium
in
the
presence
or
absence
of
metabolic
activation.

870.5100
(
§
84­
2)
Bacterial
reverse
mutation
test
Phenol
purity
not
reported
Gocke,
et
al.
1981
Acceptable
­
Non­
guideline
0
­
3000

g/
plate
Negative
Phenol
was
not
mutagenic
in
the
bacterial
strains
in
the
absence
of
metabolic
activation.
Phenol
showed
mutagenic
effects,
in
the
presence
of
metabolic
activation,
predominantly
in
the
Ames
tester
strains
of
S.
typhimurium
that
are
sensitive
for
frameshift
mutagens
(
ie.,
TA
98).
Guideline
Number/
Study
Type/
Test
Substance
(%
a.
i.)
MRID
Number
(
Year)/
Citation/
Classification/
Doses
Results
Page
36
of
42
870.5275
(
§
82­
4)
Sex­
linked
recessive
lethal
test
in
Drosophila
melanogaster
Phenol
purity
not
reported
Gocke,
et
al.
1981
Acceptable
­
Non­
guideline
50
mM
Negative
Phenol
was
administered
to
D.
melanogaster
and
3543,
3458,
and
2139
chromosomes
were
tested
for
sex­
linked
recessive
lethals
in
Broods
1,
2,
and
3,
respectively.
There
were
no
significant
increases
in
recessive
lethals
observed
following
administration
of
phenol
to
Broods
1,
2,
and
3
and
only
17
(
0.48%),
6
(
0.17%),
and
7
(
0.33%)
sex­
linked
recessive
lethals,
respectively,
were
measured
in
the
chromosomes
tested.

After
feeding
phenol
to
adult
flies,
the
frequency
of
recessive
lethals
was
increased,
but
not
to
significant
levels.
Phenol
was
not
mutagenic
within
the
confines
of
this
study.

870.5275
(
§
82­
4)
Sex­
linked
recessive
lethal
test
in
Drosophila
melanogaster
Phenol
purity
99.9%
Woodruff,
et
al.
1985
Acceptable
­
Non­
guideline
Feeding:
0
and
2000
ppm
Injection:
0
and
5250
ppm
Negative
Phenol
was
tested
up
to
cytotoxic
concentrations
2000
and
5250
ppm
in
feeding
and
injection
studies,
respectively.
The
number
of
sex­
linked
recessive
lethal
mutations
in
the
feeding
study
were
7
and
11
at
the
0
and
2000
ppm
doses,
respectively.
The
injection
assay
resulted
in
5
(
0
ppm)
and
6
(
5250
ppm)
sex­
linked
recessive
lethal
mutations,
while
the
feeding
study
exhibited
0.12
(
0
ppm)
and
0.17
(
2000
ppm)
lethals.
These
sex­
linked
recessive
lethal
mutations
were
not
significantly
different
from
those
found
in
controls.
One
cluster
of
32
lethals
and
one
cluster
of
86
lethals
were
observed
in
the
treated
feeding
experiment.
Phenol
was
negative
in
inducing
sex­
linked
recessive
lethal
mutation
in
D.
melanogaster.
Guideline
Number/
Study
Type/
Test
Substance
(%
a.
i.)
MRID
Number
(
Year)/
Citation/
Classification/
Doses
Results
Page
37
of
42
870.5300
(
§
84­
2)
In
Vitro
mammalian
call
gene
mutation
test
Phenol
purity
not
reported
Pashin
and
Bahitova.
1982
Acceptable
­
Non­
guideline
Phenol:
0,
25,
50,
100,
250,
and
500

g/
mL
Benzo[
a]
pyrene
and
Phenol
mix:
100,
250,
500

g/
mL.
The
mixture
includes
the
addition
of
sodium
Phenobarbital
metabolic
activation.
Positive
At
doses
of
25,
50,
100,
250,
and
500

g/
mL
phenol,
there
was
a
dose­
dependent
increase
in
the
number
of
revertant
colonies
(
1.2­,
1.2­,
1.7­,
2.5­,
and
4.3­
fold
increases,
respectively).
Statistically
significant
increases
were
observed
in
the
frequency
of
AGr
(
selective
agent,
8­
azaguanine
added
to
determine
resistant
mutants)
mutants
over
spontaneous
levels
with
52
and
72%
increases
at
250
and
500

g/
mL,
respectively.
The
combination
of
phenol
with
benzo[
a]
pyrene
at
a
concentration
of
12

g/
mL,
exhibited
an
increase
in
frequency
of
8­
azaguanine
resistant
colonies
with
increasing
concentrations
of
phenol.
The
results
were
the
same
as
the
sum
of
the
separate
effects
of
phenol
and
benzo[
a]
pyrene
and
the
researchers
concluded
that
phenol
did
not
block
or
activate
the
mutagenicity
of
benzo[
a]
pyrene.

870.5375
(
§
84­
2)
In
Vitro
mammalian
chromosome
aberration
test
Phenol
purity
not
reported
(
high
commercial
grade)
Kolachana,
et
al.
1993
Acceptable
­
Non­
guideline
HL60
cells
exposed
for
30
minutes
to
100

M
phenol
Positive
Phenol
increased
the
steady
state
level
of
8­
hydroxy­
2'­
deoxyguanosine
in
DNA
of
human
leukemia
HL60
cells.
The
increase
in
this
oxidative
damage
product
was
3.5­
fold
and
indicates
genotoxic
effects
resulting
from
active
oxygen
following
exposure
to
phenol.

870.5380
(
§
84­
2)
Mammalian
spermatogonial
chromosomal
aberration
test
­
Rat
Phenol
purity
not
reported
Bulsiewicz.
1977
Acceptable
­
Non­
guideline
0.08,
0.8,
or
8.0
mg/
L/
day
for
30
days
for
5
generations
Positive
There
was
evidence
of
a
concentration­
related
(
0.08­
8.0
mg/
L)
positive
response
of
spermatogonial
chromosome
aberrations
in
Porton
strain
male
mice
following
30
days
of
exposure
to
phenol
in
water.

870.5385
(
§
84­
2)
Mammalian
bone
marrow
chromosome
aberration
test
­
Mouse
Phenol
purity
not
reported
(
high
commercial
grade)
Kolachana,
et
al.
1993
Acceptable
­
Non­
guideline
75
mg/
kg/
day
Negative
Individual
treatment
with
phenol,
hydroquinone,
or
catechol
did
not
significantly
increase
8­
hydroxy­
2'­
deoxyguanosine
levels
in
mouse
bone
marrow
cells
compared
to
the
control
with
only
11,
7,
and
26%
increases,
respectively,
in
treated
cells
over
control)
Guideline
Number/
Study
Type/
Test
Substance
(%
a.
i.)
MRID
Number
(
Year)/
Citation/
Classification/
Doses
Results
Page
38
of
42
870.5395
(
§
84­
2)
Mammalian
erythrocyte
­
Mouse
Phenol
purity
not
reported
Barale,
et
al.
1990
Acceptable
­
Non­
guideline
40,
80,
and
160
mg/
kg/
day
Negative
There
was
no
significant
increase
in
the
frequency
of
micronucleated
polychromatic
erythrocytes
in
bone
marrow
of
Swiss
CD­
1
male
mice
after
treatment
with
phenol
(
40­
160
mg/
kg).
However,
when
phenol
is
combined
with
hydroquinone
(
40­
80
mg/
kg)
a
significant
dose­
related
increase
was
observed.

870.5395
(
§
84­
2)
Mammalian
erythrocyte
­
Mouse
Phenol
purity
99%
Chen
and
Eastmond.
1995
Acceptable
­
Non­
guideline
50,
75,
100,
or
160
mg/
kg/
day
Negative
There
was
no
significant
increase
in
the
frequency
of
micronucleated
polychromatic
erythrocytes
in
bone
marrow
of
CD­
1
male
mice
following
treatment
with
phenol
(
50­
160
mg/
kg)
alone.
However,
when
phenol
is
combined
with
hydroquinone
(
60
mg/
kg),
a
significant
increase
in
MNPCEs
was
observed.
The
data
suggest
that
phenol
genotoxic
when
combined
with
hydroquinone.

870.5395
(
§
84­
2)
Mammalian
erythrocyte
­
Mouse
Phenol
purity
not
reported
Gocke,
et
al.
1981
Acceptable
­
Non­
guideline
47,
98,
and
188
mg/
kg/
day
Negative
There
were
no
significant
increases
in
the
frequency
of
micronucleated
polychromatic
erythrocytes
in
mouse
bone
marrow
cells
at
the
concentrations
of
phenol
used
in
this
study.
Phenol
was
not
mutagenic
in
NMRI
mouse
bone
marrow
cells.

870.7485
(
§
85­
1)
Metabolism
and
pharmacokinetics
­
Rat
Phenol
purity
not
reported
Capel,
et
al.
1972
Acceptable
­
Non­
guideline
25
mg/
kg/
day
An
average
of
95%
of
14C
dose
of
phenol
(
25
mg/
kg)
was
excreted
in
the
urine
in
24
hours.
Four
metabolites,
the
sulfates
and
glucuronides
of
phenol
and
quinol,
were
found
in
the
urine
of
rats
after
an
oral
dose
of
phenol.
The
phenyl
sulfate
and
quinol
sulfate
metabolites
represented
54
and
1%,
respectively
of
the
metabolites
recovered
in
the
urine.
The
remaining
phenol
metabolites
recovered
from
the
urine
were
phenyl
glucuronide
(
42%)
and
quinol
glucuronide
(
2%).
Guideline
Number/
Study
Type/
Test
Substance
(%
a.
i.)
MRID
Number
(
Year)/
Citation/
Classification/
Doses
Results
Page
39
of
42
870.7485
(
§
85­
1)
Metabolism
and
pharmacokinetics
­
Rat
Phenol
purity
not
reported
Hughes
and
Hall.
1995
Acceptable
­
Non­
guideline
350
nmol/
kg
Absorption
of
phenol
was
extensive
following
iv,
oral,
and
it
administration
while
dermal
absorption
was
slightly
lower
by
comparison.
Phenol
was
predominantly
conjugated
with
sulfate
and
lower
amounts
of
glucuronic
acid.
These
metabolites
were
rapidly
excreted
in
the
urine.
Phenol
was
distributed
throughout
the
body
in
low
amounts
and
appeared
to
concentrate
in
liver,
lung,
and
kidney.
The
data
suggest
that
the
exposure
of
phenol
to
rats
by
oral,
dermal,
intratracheal,
and
intravenous
routes
resulted
in
rapid
absorption,
conjugation,
and
elimination
in
urine.

870.7485
(
§
85­
1)
Metabolism
and
pharmacokinetics
­
Mouse
Phenol
purity
not
reported
Capel,
et
al.
1971
Acceptable
­
Non­
guideline
25
mg/
kg/
day
Intestinal
conjugation
of
phenol
prior
to
absorption
was
significant
only
at
low
dose,
the
first­
pass
intestinal
conjugation
alone
does
not
explain
lack
of
carcinogenicity
of
phenol
at
much
higher
doses.
The
data
suggest
that
a
combination
of
first
pass
conjugation
and
zonal
segregation
of
hepatic
enzymes
may
contribute
to
the
greater
production
of
hydroquinone
after
oral
administration
of
benzene
than
phenol.
Hydroquinone
and
other
metabolites
may
be
the
metabolic
basis
for
carcinogenic
and
genotoxic
effects
observed
with
benzene
but
not
phenol.

870.7600
(
§
85­
3)
Dermal
Penetration
Phenol
purity
not
reported
Behl
and
Linn.
1983
Acceptable
­
Non­
guideline
0.5,
1.0,
2.0,
4.0,
and
6.0%
(
w/
v)
in
saline
solution
Age
and
hydration
have
little
effect
on
the
permeability
of
phenol
through
human
and
mouse
skin
and
the
effects
on
the
skin
were
a
result
of
destroyed
barrier
integrity.
Permeation
of
and
chemical
denaturation
by
phenol
were
found
to
be
similar
between
mouse
and
human
skin
tissue;
indicating
that
the
hairless
mouse
is
an
adequate
model
for
chemical
permeability
in
humans.
The
results
suggest
that
the
stratum
corneum
is
proportionally
impaired
as
the
phenol
concentration
is
increased.
Page
40
of
42
9.0
References
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MRID
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Price,
C
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95­
2)
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MRID
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Price,
C
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(
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Berman
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Brown
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Chen
H
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"
Synergistic
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the
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metabolites
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hydroquinone
in
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8):
1963­
1969.

ClinTrials
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1998.
A
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week
neurotoxicity
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the
drinking
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the
rat.
Volumes
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and
2.
Senneville,
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Project
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P.
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Conning
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the
most
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aid
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Med
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155­
159
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Kristoffersson.
"
Physiological
effects
of
a
sub­
lethal
concentration
of
inhaled
phenol
on
the
rat."
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Ann
Zool
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193­
199.
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41
of
42
Dow
Chemical
Co.
1994.
Pharmacokinetics,
metabolism,
and
distribution
of
C
14
phenol
in
Fischer
344
rats
after
gavage,
drinking
water,
and
inhalation
exposure,
with
cover
letter
dated
07/
13/
1994.
U.
S.
EPA/
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M.
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and
J.
S.
Bus,
authors.

Flickinger
CW.
1976.
"
The
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Catechol,
resorcinol
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hydroquinone
­
A
review
of
the
industrial
toxicology
and
current
industrial
exposure
limits."
Am
Ind
Hyg
Assoc
J
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596­
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al.
"
Screening
of
tobacco
smoke
constituents
for
mutagenicity
using
the
Ames'
test."
1980
Toxicology
15(
3):
219­
232
Gocke
et
al.
"
Mutagenicity
of
cosmetics
ingredients
licensed
by
the
European
Communities."
1981
Mutation
Research
90(
2)
91­
109
Haworth,
Lawlor,
Mortelmans,
Speck,
and
Zeiger.
"
Salmonella
Mutagenicity
Test
Results
for
250
Chemicals."
Env.
Mutagenesis
Supplement
1:
3­
142,
1983.

Hughes
and
Hall.
"
Disposition
of
Phenol
in
Rat
after
Oral,
Dermal,
Intravenous,
and
Intratracheal
Administration."
1995.

Kolachana
P,
Subrahmanyam
V,
Meyer
K,
Zhang
L,
Smith
M.
"
Benzene
and
its
phenolic
metabolites
produces
oxidative
DNA
damage
in
HL60
cells
in
vitro
and
in
the
bone
marrow
in
vivo."
1993
Cancer
Research
53:
1023­
1026.

Moser,
V.
C.,
B.
M.
Cheek
and
R.
C.
MacPhail.
1995.
A
multidisciplinary
approach
to
toxicological
screening:
III.
Neurobehavioral
toxicity.
J
Toxicol
Environ
Health.
45(
2):
173­
210.
Nagel
et
al.
"
Induction
of
filamentation
by
mutagens
and
carcinogens
in
a
ion
mutant
of
Esherichia
coli."
1982
Mutation
Research
105(
5):
309­
312.

Narotsky
M,
Kavlock
R.
"
A
multidisciplinary
approach
to
toxicological
screening:
II.
Developmental
Toxicity."
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