Document ID: EPA-HQ-OPP-2003-0248-0008
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2003-11-26T05:00Z

1
CREOSOTE
­
TOXICOLOGY
1.0
EXECUTIVE
SUMMARY
Creosote
is
a
fungicide,
insecticide,
and
sporicide
used
as
a
wood
preservatives
for
above
and
below
ground
wood
protection
treatments
as
well
as
treating
wood
in
marine
environments.
All
21
Creosote
products
currently
registered
are
Restricted
Use
Pesticides;
20
are
End­
Use
Products
and
1
is
a
Manufacturing­
Use
Product
for
formulating
industrial
end­
use
wood
preservative
products.
Creosote
wood
preservatives
are
used
primarily
to
pressure
treat
railroad
ties/
crossties
(
represents
close
to
70%
of
all
Creosote
use)
and
utility
poles/
crossarms
(
represents
15
­
20%
of
all
Creosote
use).
The
industry
refers
to
different
blends
of
creosote
[
based
on
the
wood
treatment
standards
set
by
the
American
Wood­
Preservers'
Association
(
AWPA)],
as
P1/
P13,
P2,
and
P3.
Typically,
railroad
ties/
crossties
are
treated
with
a
P2
blend,
which
is
more
viscous
than
the
P1/
P13
blend
used
for
treating
utility
poles.
The
AWPA
cites
P3
as
"
Creosote­
petroleum".

The
toxicological
database
for
creosote
shows
that
for
acute
exposures,
creosote
is
moderately
toxic
by
the
oral,
dermal,
and
inhalation
route,
while
exposure
to
the
eye
produces
significant
irritation.
There
does
not
appear
to
be
any
differences
in
acute
toxic
response
to
either
the
P2
or
P1/
P13
blend
of
creosote.
Treatment­
related
effects
of
toxicological
concern
from
exposure
to
creosote
are
mutagenicity
and
carcinogenicity,
which
formed
the
basis
for
the
restricted
use
classification
for
creosote.
Other
toxicological
effects
of
concern
are
cardiomyopathy
resulting
from
inhalation
exposure,
and
discoloration
of
the
lungs
from
the
presence
of
black
pigment
granules
within
alveolar
macrophages.

Although
there
are
no
current
Agency
guideline
neurotoxicity
studies
available
for
creosote,
the
existing
studies
on
creosote
indicate
no
evidence
of
neurotoxicity
for
either
the
P1/
P13
or
P2
blends
of
creosote
(
ATSDR,
2002).
Based
on
the
above,
and
realizing
that
creosote
is
currently
registered
only
for
non
­
food
use
and
is
a
restricted
use
pesticide,
no
additional
neurotoxicity
testing
will
be
required
at
this
time.

2.0
PHYSICAL/
CHEMICAL
PROPERTIES
CHARACTERIZATION
Creosote
,
as
defined
by
the
American
Wood
Preservers
Association,
is
a
distillate
derived
from
coal
tar,
derived
by
the
high
temperature
carbonization
of
bituminous
coal.
Creosote
consists
primarily
of
liquid
and
solid
polyaromatic
hydrocarbons
(
PAH's)
and
contains
some
tar
acids
and
tar
bases.
The
two
major
types
of
creosote
in
use
are
P1/
P13
creosote
(
a
straight
creosote
distillate
used
for
ground
contact,
land,
and
fresh
and
marine
water
applications)
and
P2
creosote,
used
in
treatment
of
railroad
crossties.

3.0
Hazard
Assessment
2
3.1
Acute
Toxicity
Results
of
acute
toxicity
studies,
primary
eye
and
dermal
irritation
studies
and
dermal
sensitization
study
with
Creosote
P1/
P13
and
Creosote
P2
are
summarized
in
Table
1a
and
1b.

Table
1a.
Acute
Toxicity
of
Creosote
P1/
P13
Study
Type
Animal
Results
Tox
Cat
MRID
No
81­
1:
Acute
Oral
Rat
LD
50
Male
2451
mg/
kg
Female
1893
mg/
kg
III
43032101
81­
2:
Acute
Dermal
Rabbit
LD
50
Male
>
2000
mg/
kg
Female
>
2000
mg/
kg
III
43032102
81­
3:
Acute
Inhalation
Rat
LC
50
>
5
mg/
L
IV
43032103
81­
4:
Primary
Eye
Irritation
Rabbit
Irritation
clearing
in
8­
21
days
II
43032104
81­
5:
Primary
Dermal
Irritation
Rabbit
erythema
to
day
14
III
43032105
81­
6:
Dermal
Sensitization
Guinea
Pig
study
unacceptable
N/
A
43032106
3
Table
1b.
Acute
Toxicity
of
Creosote
P2
Study
Type
Animal
Results
Tox
Cat
MRID
No
81­
1:
Acute
Oral
Rat
LD
50
Male
2524
mg/
kg
Female
1993
mg/
kg
III
43032301
81­
2:
Acute
Dermal
Rabbit
LD
50
Male
>
2000
mg/
kg
Female
>
2000
mg/
kg
III
43032302
81­
3:
Acute
Inhalation
Rat
LC
50
>
5.3
mg/
L
IV
43032303
81­
4:
Primary
Eye
Irritation
Rabbit
Irritation
clearing
within
7
days
III
43032304
81­
5:
Primary
Dermal
Irritation
Rabbit
no
irritation
after
7
days
III
43032305
81­
6:
Dermal
Sensitization
Guinea
Pig
study
unacceptable
N/
A
43032306
3.2.
Subchronic
Toxicity
Reference:
R.
A.
Hilaski;
April
13,
1995;
North
American
P1/
P13
Creosote
CTM:
90­
Day
Subchronic
Dermal
Toxicity
Study
In
Rats.
IRDC,
Mattawan,
MI.;
Report
No.
671­
013.
Sponsored
by
The
Creosote
Council
II.
MRID
#
43616101
Unpublished.
Study
I.
D.
:
IRDC
671­
013
Executive
Summary:
In
a
90­
day
dermal
toxicity
study
(
MRID
#
43616101),
10
Charles
River
Crl:
CD
BR
rats
(
10/
sex/
dose)
were
given
dermal
applications
of
P1/
P13
creosote
in
corn
oil
mixture
at
dosage
levels
of
0,
4,
40
or
400
mg/
kg
bw/
day.
There
were
no
treatment­
related
effects
from
dermal
application
of
P1/
P13
creosote
on
body
weight,
food
consumption,
ophthalmology,
hematology,
clinical
chemistry,
or
organ
weights
at
any
dose
level
tested.
Mortality
(
death
of
one
male
rat
at
400
mg/
kg/
day)
was
observed
on
day
79
of
the
study.
No
testarticle
related
microscpoic
lesions
were
noted
at
the
application
site
on
the
skin
at
any
dose
level.
Based
on
the
results
of
this
study,
the
systemic
LOAEL
was
determined
to
be
400
mg/
kg
bw/
day
for
both
male
and
female
rats,
based
on
mortality.
The
systemic
NOAEL
was
determined
to
be
40
mg/
kg/
day.

This
study
is
classified
as
acceptable
and
satisfies
the
guideline
requirement
(
OPPTS
870.3250;
OPP
82­
3)
for
a
subchronic
dermal
toxicity
study
in
rats
for
P1/
P13
creosote
4
Reference:
R.
A.
Hilaski;
April
13,
1993;
North
American
P2
Creosote
CTM:
90­
Day
Subchronic
Dermal
Toxicity
Study
in
Rats.
IRDC,
Mattawan,
MI.;
Report
No.
671­
014.
Sponsored
by
The
Creosote
Council
II.
MRID
#
43616201.

Executive
Summary:
In
a
90­
day
dermal
toxicity
study
(
MRID
#
43616201),
Charles
River
rats
(
10/
sex/
dose)
were
given
dermal
applications
of
P2
creosote
in
corn
oil
at
dosage
levels
of
0,
4,
40
or
400
mg/
kg
bw/
day.
There
was
no
mortality
observed
in
this
study
at
any
dose
level.
Body
weight
in
high
dose
males
was
decreased
7­
8%
during
weeks
9­
12
of
the
study,
and
bodyweight
gain
decreased
15%
in
high
dose
males
for
the
treatment
period.
Food
consumption
in
high
dose
males
was
decreased
during
weeks
2­
4
and
week
6
by
4­
10%
vs
control.
Only
slight
dermal
irritation
was
observed
in
high
dose
males.
No
effects
were
observed
on
hematology
or
clinical
chemistry.
Treated
skin
in
the
400
mg/
kg/
day
dose
groups
(
male
and
female)
was
observed
with
increased
incidence
of
dermal
inflamation.
Based
on
the
results
of
this
study,
the
systemic
LOAEL
is
400
mg/
kg/
day,
based
on
decreased
body
weight
gain
in
male
rats.
The
systemic
NOAEL
is
40
mg/
kg/
day.
For
females,
the
NOAEL
is
set
at
400
mg/
kg
bw/
day
since
no
systemic
toxic
effects
were
noted
in
any
of
the
treated
groups.

Reference:
R.
I.
Hilaski,
March
28,
1995:
Thirteen
week
subchronic
inhalation
toxicity
study
on
North
American
P1/
P13
Creosote
CTM
in
rats.;
International
Research
and
Development
Corp.,
Mattawan,
MI
49071;
Project
No.
671­
016;
Creosote
Council
II;
MRID
#
43601001;
Unpublished
Executive
Summary:
In
a
subchronic
inhalation
toxicity
study
with
P1/
P13
creosote
(
MRID
#
43601001),
20
Sprague­
Dawley
rats/
sex/
group
were
treated
for
thirteen
weeks,
five
days
a
week,
six
hours
per
day
with
P1/
P13
Creosote
CTM
via
whole
body
exposure
at
doses
of
0,
5.4,
49
and
106
mg/
m3
(
0.005,
0.049
and
0.106
mg/
L
in
air,
respectively)
measured
gravimetrically.
The
aerosol
MMAD
was
between
2.2
and
3.0
microns
with
a
geometric
standard
deviation
between
1.91
and
1.99.
Subsequent
to
the
exposure
period
10
animals/
sex/
group
were
allowed
to
recover
for
6
weeks.

During
the
study
one
male
rat
of
the
mid
dose
group
(
49
mg/
m3)
died
from
myocardial
degeneration
that
resulted
in
heart
failure.
One
male
and
one
female
rat
in
the
highest
dose
group
had
similar
lesions
observed
at
terminal
necropsy.
Cardiac
pathology
(
ie:
hemorrhage,
lymphocytic
infiltration
and
cardiomyopathy)
was
noted
in
all
animals
of
all
groups
(
including
controls)
and
this
condition
may
have
been
exacerbated
by
treatment
with
creosote
in
the
mid
and
high
dose
animals.
Significant
treatment­
related
findings
in
the
mid
and
high
dose
animals
after
the
exposure
period
included
decreased
body
weight
gains
of
both
sexes
(
resolved
by
the
end
of
recovery
period),
altered
hematological
parameters
(
decreased
hemoglobin,
hematocrit,
numbers
of
erythrocytes,
increased
numbers
of
reticulocytes,
polychromasia,
poikilocytosis,
anisocytosis
­
both
sexes)
and
biochemical
parameters
(
increased
serum
cholesterol
levels
­
both
sexes,
phosphorous
levels
­
males
only).
Macroscopic
discolouration
of
the
lungs,
which
persisted
5
throughout
the
recovery
period,
was
correlated
with
the
presence
of
black
pigment
granules
within
alveolar
macrophages
of
animals
of
all
treatment
groups.
An
increase
in
liver/
brain
weights
(
statistically
significant
only
in
the
females),
increased
lung/
trachea/
body
weight
ratios
and
the
presence
of
small
cystic
spaces
containing
basophilic
mucoid
material
in
the
nasal
cavity
epithelium
was
still
evident
after
the
recovery
period
in
both
sexes.

Male
and
female
rats
of
the
low
dose
group
were
observed
to
have
mild
poikilocytosis
and
anisocytosis
while
the
females
only
showed
the
occasional
cyst
of
the
epithelium
in
the
nasal
cavity.
All
hematological
findings
in
low
dose
animals
showed
recovery.

Based
on
the
results
of
this
study,
the
systemic
LOAEL
is
49
mg/
m
3
for
both
sexes,
based
on
cardiac
pathology,
decreased
body
weight
gain,
altered
hematology
and
clinical
chemistry,
and
gross
pathological
findings
in
the
lungs.
The
systemic
NOAEL
is
5.4
mg/
m3
(
0.005
mg/
L)
for
P1/
P13.

This
study
is
classified
as
acceptable
(
guideline)
ans
satisfies
the
guideline
requirement
(
OPPTS
870.3465;
OPP
82­
4)
for
a
subchronic
inhalation
toxicity
study
in
rats.

Reference:
R.
J.
Hilaski;
March
27,
1995;
Thirteen
week
subchronic
inhalation
toxicity
study
on
North
American
P2
Creosote
CTM
in
rats.;
International
Research
and
Development
Corp.,
Mattawan,
MI
49071;
Project
No.
671­
018;
Creosote
Council
II;
MRID
#
43600901.
Unpublished.

Executive
Summary:
In
a
13­
week
inhalation
toxicity
study
(
MRID
#
43600901),
20
Sprague­
Dawley
rats/
sex/
group
were
treated
for
5
days/
week,
6
hours/
day
with
P2
Creosote
CTM
via
whole
body
exposure
at
doses
of
0,
4.7,
48
or
102
mg/
m3
(
0,
0.005,
0.048
or
0.102
mg/
L
)
in
air
measured
gravimetrically.
The
aerosol
size
MMAD
was
between
2.4
and
2.9
microns
with
a
geometric
standard
deviation
between
1.85
and
1.91.
Subsequent
to
the
exposure
period
10
rats/
sex/
group
were
allowed
to
recover
from
treatment
for
6
weeks.

During
the
exposure
period,
two
animals
(
low
dose
female;
mid
dose
male)
were
sacrificed
in
extremis
and
the
cause
of
morbidity
was
not
related
to
treatment.
Significant
treatment­
related
findings
in
mid
and
high
dose
animals
included
decreased
terminal
body
weight
and
body
weight
gain
(
m/
f),
altered
hematological
parameters
(
decreased
hemoglobin
content,
hematocrit,
erythrocyte
and
platelet
counts;
increased
reticulocyte
counts
and
mild
poikilocytosis,
m/
f)
and
biochemical
parameters
(
increased
serum
cholesterol
levels,
m/
f).
In
both
sexes
macroscopic
discolouration
of
the
lungs
persisted
through
the
recovery
period
and
correlated
with
the
presence
of
black
pigment
granules
within
alveolar
macrophages.
Both
sexes
showed
increased
absolute
and
relative
liver
and
thyroid
weights
and
increased
lung/
trachea/
body
weight
ratios.
Absolute
and
relative
thyroid
weights
of
high
dose
animals
actually
increased
after
the
recovery
period.
An
increased
incidence
of
lesions
of
the
nasal
cavity
epithelium
(
chronic
inflammation)
was
noted
following
treatment
(
all
treatment
groups,
m/
f)
but
appeared
to
lessen
in
incidence
and
severity
6
during
the
recovery
period
(
mainly
the
high
dose
group,
m/
f).
During
exposure
an
increased
incidence
of
thyroid
follicular
epithelial
cell
hypertrophy
occurred
in
all
male
groups
including
control
and
in
the
high
dose
female
group.
At
recovery
the
male
incidence
remained
similar
to
that
observed
at
exposure
while
the
incidence
in
females
of
the
high
dose
group
had
declined.
The
incidence
of
thyroid
follicular
cell
hypertrophy
was
slightly
increased
in
low
and
mid
dose
females
after
the
recovery
period.
Slightly
increased
incidence
of
mild
poikilocytosis
was
observed
in
all
treatment
groups
(
m/
f)
including
the
low
dose
group
and
control,
which
persisted
through
the
recovery
period.
Low
dose
animals
exhibited
lesions
of
the
nasal
cavity
epithelium
which
had
resolved
after
the
recovery
period.
Based
on
the
results
of
this
study,
the
systemic
LOAEL
is
48
mg/
m3
,
based
on
decreased
body
weight
and
weight
gain,
altered
hematology
ad
clinical
chemistry,
increased
absolute
and
relative
weight
of
the
liver
ad
thyroid,
and
increased
incidence
of
lesions
of
the
nasal
cavity.
The
systemic
NOAEL
is
set
at
4.7
mg/
m3
(
0.0047
mg/
L
)
for
P2
Creosote
CTM
in
rats.

This
study
is
classified
as
acceptable
(
guideline)
and
satisfies
the
guideline
requirement
(
OPPTS
870.3465;
OPP
82­
4)
for
a
subchronic
inhalation
toxicity
study
in
rats
for
P2
creosote.

3.3
Developmental
Toxicity
Reference:
Raymond
York,
(
March
10,
1995).
Developmental
Toxicity
Study
In
Rats:
North
American
P1/
P13
Creosote.
IRDC,
500
North
main
Street,
Mattawan,
MI,
Report
number
671­
020,
The
Creosote
Council
II,
Mellon
Hall,
Duquesne
University,
Pittsburgh,
U.
S.
A.
MRID
#
43584201.
Unpublished.

In
a
developmental
toxicity
study
using
P1/
P13
creosote
(
MRID
#
43584201),
pregnant
female
Sprague­
Dawley
rats
(
30/
dose)
were
administered
P1/
P13
creosote
at
dose
levels
of
0,
25,
50,
and
175
mg/
kg/
day
on
gestation
days
6
through
15
inclusive.
Decreased
body
weight
and
food
consumption
were
observed
in
dams
at
the
175
mg/
kg/
day
dose
level.
Decreased
uterine
weight
was
observed
in
dams
at
the
high
dose,
which
is
reflected
partly
by
the
decreased
live
fetuses
per
litter
at
the
high
dose
(
although
mean
fetal
weight
was
not
affected).
Cesarean
section
observations
showed
significantly
increased
resorptions
and
post­
implantation
loss
as
well
as
decreased
number
of
live
fetuses
per
litter
at
the
175
mg/
kg/
day
dose.
Based
on
the
results
of
this
study,
the
maternal
NOAEL
is
50
mg/
kg/
day,
and
the
maternal
LOAEL
is
175
mg/
kg/
day,
based
on
decreased
body
weight
gain
and
food
consumption
during
the
study.

No
treatment­
related
malformations
(
external,
visceral
or
skeletal)
were
observed
in
any
of
the
fetuses
at
25
mg/
kg
bw/
day.
At
50
mg/
kg
bw/
day,
the
overall
incidence
of
malformations
on
a
fetal
and
litter
basis
were
statistically
elevated
compared
to
controls.
However,
these
individual
malformations
were
not
seen
at
higher
dose
levels
and/
or
fell
within
the
range
of
historical
control
data.
At
175
mg/
kg/
day
there
was
(
i)
an
overall
significant
increased
incidence
of
developmental
malformations,
(
ii)
increased
incidence
of
cardiovascular,
vertebral
and
digital
malformations,
compared
to
lower
dose
levels,
concurrent
controls
or
historical
controls
(
2429
and
2898
fetuses
7
examined
viscerally
and
skeletally
respectively)
and
(
iii)
an
increased
incidence
of
malformations
at
this
dose
level
in
spite
of
increased
fetal
loss
(
resorptions)
(
Beck
and
Lloyd,
1963)
thus
resulting
in
fewer
fetuses
available
for
teratogenic
examination.
Although
the
incidence
of
fetal
malformations
observed
at
175
mg/
kg/
day
dose
level
in
rats
was
low
and
could
be
related
to
maternal
stress
(
decreased
body
weight
gain
and
food
consumption),
the
teratogenic
potential
of
P1/
P13
Creosote
cannot
be
ruled
out.
Based
on
these
data,
the
developmental
toxicity
NOAEL
is
50
mg/
kg/
day,
and
the
developmental
toxicity
LOAEL
is
175
mg/
kg/
day,
based
on
increased
post­
implantation
loss,
increased
mean
resorptions,
decreased
live
fetuses
per
litter,
and
increased
developmental
malformations.

This
study
is
classified
as
acceptable
and
satisfies
the
guideline
requirement
(
83­
3)
for
a
developmental
toxicity
study
in
rats
with
P1/
P13
creosote.

Reference:
Developmental
Toxicity
Study
In
Rats:
North
American
P2
Creosote.
Raymond
G.
York
(
March
10,
1995),
IRDC,
500
North
Main
Street,
Mattawan,
MI,
Report
number
671­
022,
The
Creosote
Council
II,
Mellon
Hall,
Duquesne
University,
Pittsburgh,
U.
S.
A.
MRID
#
43584202.
Unpublished.

Executive
Summary:
In
a
developmental
toxicity
study
(
MRID
#
43584202),
pregnant
female
Sprague­
Dawley
rats
(
30/
dose)
were
administered
P2
creosote
by
gavage
on
gestation
days
6
through
15
inclusive
at
dose
levels
of
0,
25,
75,
and
225
mg/
kg/
day.
Although
decreases
in
body
weight
and
food
consumption
were
observed
at
all
dose
levels,
food
efficiency
appeared
affected
only
at
the
high
dose
of
225
mg/
kg/
day.
Thus,
the
cesarean
section
effects
observed
at
this
dose
(
decreased
implantations/
dam,
increased
pre­
and
post­
implantation
loss,
increased
resorptions,
decreased
uterine
weight)
could
be
secondary
to
the
decreased
food
efficiency
observed
at
this
dose.
This
distinction
is
a
fine
one,
however,
based
on
results
with
P1/
P13
creosote
in
which
no
decrease
in
food
efficiency
was
observed
at
a
dose
of
175
mg/
kg,
but
increased
resorptions,
increased
post­
implantation
loss,
and
decreased
live
fetuses
per
litter
were
observed
at
175
mg/
kg.
The
Maternal
NOAEL
in
this
study
is
determined
to
be
75
mg/
kg/
day,
and
the
LOAEL
225
mg/
kg/
day,
based
on
decreased
food
efficiency
observed
in
maternal
rats
at
225
mg/
kg/
day.

With
regards
to
assessing
the
teratogenic
potential
of
P2
Creosote
in
rats,
no
treatment­
related
malformations
(
external,
visceral
or
skeletal)
were
observed
at
the
25
mg/
kg
bw/
day
dose
level.
The
single
incidences
of
malformations
[
craniorachischisis,
hydrocephaly
and
malpositioned
eye
(
same
pup)]
observed
at
the
75
mg/
kg
bw/
day
dose
level,
and
hydrocephaly
at
the
225
mg/
kg
bw/
day
dose
level
compared
to
none
observed
in
lower
dose
levels,
concurrent
controls
or
historical
controls
(
2429
and
2898
fetuses
examined
viscerally
and
skeletally
respectively)
were
considered
treatment­
related.
It
should
be
noted
that
at
225
mg/
kg
bw/
day
one
whole
litter
was
resorbed
and
the
number
of
fetuses
examined
at
this
level
for
visceral
and
skeletal
malformations
was
approximately
50%
of
those
examined
at
the
mid­
dose
level.
The
developmental
toxicity
NOAEL
is
determined
to
be
25
mg/
kg/
day
in
this
study,
based
on
the
incidences
of
malformations
observed
at
75
mg/
kg/
day
which
exceeded
both
concurrent
and
historical
control
incidence.
8
Reference:
York,
R.
(
1994):
Developmental
Toxicity
Study
in
New
Zealand
White
Rabbits:
Creosote
P1/
P13.
Laboratory
Project
number
672­
002.
Study
conducted
by
IRDC.
Unpublished.

In
a
developmental
toxicity
study
in
rabbits
(
MRID
44839802),
artificially
inseminated
New
Zealand
White
Rabbits
(
20/
dose)
were
administered
creosote
P1/
P13
in
corn
oil
by
gavage
on
gestation
days
6
through
18.
Doses
were
0,
1,
9,
and
75
mg/
kg/
day.
At
the
75
mg/
kg/
day
dose
level,
increased
abortions
(
3
rabbits
vs.
0
control),
reduced
live
fetuses
(
28
vs.
50
in
control),
and
decreased
implantation
sites
were
noted
in
maternal
rabbits.
There
was
no
significant
effect
of
creosote
P1/
P13
treatment
on
offspring
in
this
study.
The
Maternal
NOAEL
in
this
study
is
determined
to
be
9
mg/
kg/
day
based
on
effects
noted
at
75
mg/
kg/
day.
The
Developmental
NOAEL
is
determined
to
be
75
mg/
kg/
day,
and
the
LOAEL
>
75
mg/
kg/
day.

3.4
Reproductive
Toxicity
Reference:
Marcinowski,
J.
(
1993).
Two­
Generation
Reproduction/
Fertility
Study
in
Rats:
Lab
Project
Number:
672­
006.
Unpublished
study
prepared
by
International
Research
&
Development
Corp.

In
a
two­
generation
reproduction
toxicity
study
(
MRID
42893201),
Charles
River
Crl:
CD
rats,
26/
sex/
group,
were
dosed
by
gavage
with
P1/
P13
creosote
in
corn
oil
at
doses
of
0,
25,
75,
and
150
mg/
kg/
day.
Pre­
mating
treatment
phase
lasted
approximately
17
weeks,
which
may
have
contributed
to
the
decreased
fertility
observed
in
this
study.
Systemic
effects
observed
in
this
study
for
parental
animals
included
a
dose­
related
decrease
in
body
weight
during
the
pre­
mating
period
at
all
dose
levels.
Salivation
was
observed
at
75
mg/
kg/
day
and
above
in
the
F1
generation.
Effects
in
offspring
included
a
dose­
related
decrease
in
growth
of
the
F0
generation
starting
at
25
mg/
kg/
day
(
as
shown
by
decreased
pup
weight).
For
the
F0
pups,
mean
number
of
live
pups
per
litter
was
decreased
at
75
and
150
mg/
kg/
day,
and
percent
live
pups
at
175
mg/
kg/
day
was
also
decreased.
In
the
F1
pups,
the
percent
live
pups
was
decreased
at
75
and
150
mg/
kg/
day,
but
pup
growth
was
affected
only
at
150
mg/
kg/
day
as
shown
by
decreased
mean
pup
weight.
Decreased
fertility
and
pregnancy
indices
were
observed
in
the
F1
female
parental
rats
at
all
dose
levels,
but
this
was
not
interpreted
as
a
treatment­
related
effect,
as
it
was
more
likely
related
to
the
fact
that
the
critical
weight
for
fertility
was
exceeded
by
the
17­
week
pre­
mating
interval.
Based
on
the
results
of
this
study,
the
Parental
Systemic
NOAEL
is
<
25
mg/
kg/
day,
and
the
parental
systemic
LOAEL
is
25
mg/
kg/
day,
based
on
decreased
pre­
mating
body
weight.
The
developmental
NOAEL
in
this
study
is
<
25
mg/
kg/
day,
and
the
developmental
LOAEL
is
25
mg/
kg/
day,
based
on
a
dose­
related
decrease
in
pup
body
weight
for
the
F0
pups
from
days
14­
21.
The
reproductive
NOAEL
is
<
25
mg/
kg/
day,
and
the
reproductive
LOAEL
is
25
mg/
kg/
day,
based
on
reduced
pregnancy
and
fertility
indices
in
F1
female
parental
rats.
9
3.5
Chronic
Toxicity/
Carcinogenicity
The
chronic
toxicity/
carcinogenicity
data
base
submitted
to
the
Agency
for
creosote
consists
of
a
six­
month
initiation/
promotion
study
of
creosote
conducted
in
mice.
This
study
was
not
designed
for
purposes
of
deriving
a
quantitative
risk
estimate
of
carcinogenic
potency.
However,
a
recently
conducted
study
by
Culp
et
al.
(
Carcinogenesis
vol.
19,
no.
1,
pp.
117­
124)
did
examine
tumors
induced
by
coal
tar
mixtures
and
is
also
summarized
in
this
section.

Reference:
Naas,
D.
J.
(
1996)
A
6­
month
dermal
oncogenicity
study
of
creosote
in
mice.
WIL
Research
Laboratories,
Inc.,
1407
George
Road,
Ashland,
OH
44805­
9281,
Project
No.
WIL­
100005,
January
11,
1996.
MRID
44844401.
Unpublished.

EXECUTIVE
SUMMARY:
In
a
dermal
oncogenicity
study
(
MRID
44844401),
North
American
P1/
P13
creosote
composite
(
100.0%,
lot
no.
P1/
13­
009­
A)
was
administered
to
groups
of
30
male
Crl:
CD­
1
®
mice
by
applying
50

L
aliquots
of
1%,
50%
or
100%
corresponding
to
10

g/

L,
500

g/

L,
or
undiluted
creosote
to
the
shaved
backs
of
the
mice.
Acetone
was
utilized
as
a
solvent
throughout
the
study
and
was
used
as
the
solvent
control.
9,10­
Dimethyl­
1,2­
benzanthracene
(
DMBA)
was
utilized
as
a
positive
tumor
initiator,
and
12­
0­
tetradecanoylphorbol
13­
acetate
(
TPA)
was
used
as
a
positive
tumor
promoter
in
the
study.
Creosote
was
tested
as
a
tumor
initiator
with
TPA
as
promotor,
as
a
promotor
with
DMBA
as
initiator,
and
as
both
initiator
and
promotor
(
complete
carcinogen).
A
positive
control
group
with
DMBA
and
TPA,
and
acetone
controls
groups
with
DMBA
and
TPA
were
included.
The
initiation
phase
consisted
of
5
applications/
week
for
2
weeks
followed
by
a
two
week
rest
period,
and
then
promotion
(
2
applications/
week
for
26
weeks).

Creosote
treatment
at
50%
and
100%
especially
during
the
promotion
phase
caused
skin
irritation
and
clinical
signs
including
severe
erythema,
slight
edema,
eschar,
and
exfoliation.
Increased
incidences
of
thickened
skin
(
7­
11/
30,
p
<
0.01),
scabbing
(
16­
20/
30,
p
<
0.01),
acute
inflammation
(
12­
18/
30,
p
<
0.01),
ulceration
(
6­
10/
30,
p
<
0.05­
0.01),
and
epithelial
hyperplasia
(
13­
23/
30,
p
<
0.01)
were
seen
at
the
application
site
during
necropsy
compared
to
the
DMBA/
acetone
controls
(
0/
30).
Dermal
treatment
with
Creosote
did
not
result
in
a
significant
decrease
in
survival,
although
6
mice
died
during
treatment
in
the
DMBA/
100%
creosote
group
compared
to
none
in
the
acetone
control
groups.
Group
mean
body
weights
of
males
treated
with
100%
creosote
during
the
initiation
phase
were
decreased
by
6­
8%
by
the
end
of
the
2­
week
treatment
regimen;
however,
they
gained
weight
rapidly
over
the
next
week
and
no
further
decreases
in
weight
or
weight
gain
were
seen
with
creosote
treatment
compared
to
the
acetone
controls.
Food
consumption
in
the
experimental
groups
was
generally
greater
than
in
the
solvent
control
groups.

Increased
incidences
of
enlarged
lymph
nodes
were
seen
with
50%
(
6/
30,
p
<
0.05),
and
100%
creosote
(
5­
9/
30,
p
<
0.05­
0.01)
during
the
promotion
phase
with
DMBA
as
initiator
and
with
100%
creosote
as
both
initiator
and
promotor
(
6­
9/
30,
p
<
0.05­
0.01)
compared
to
0/
30
in
the
10
solvent
controls.
Incidences
of
enlarged
spleen
were
also
increased
(
15­
19/
30,
p
<
0.01)
with
50%
and
100%
creosote
in
the
promotion
phase
compared
to
the
controls
(
1/
30).

The
LOAEL
is
50

L
of
50%
or
25,000

g/
day
twice/
week
applied
to
the
skin
for
26
weeks,
based
on
skin
toxicity,
enlarged
lymph
nodes
and
enlarged
spleen.
The
NOAEL
was
50

L
of
1%
or
500

g/
day
applied
to
the
skin
twice/
week
for
26
weeks.

Topical
treatment
of
male
Crl:
CD­
1
®
mice
for
2
weeks
in
the
initiation
phase
of
the
study
with
all
concentrations
of
creosote
followed
by
treatment
with
TPA
resulted
in
increased
incidences
of
neoplasms,
chiefly
skin
papillomas
(
acetone/
TPA
control,
0%;
creosote/
TPA
treated,
80­
90%,
p
<
0.01).
Treatment
twice
a
week
for
26
weeks
during
the
promotion
phase
with
50

L
of
500

g/

L
or
undiluted
creosote
following
the
DMBA
initiation
phase
resulted
in
tumor
incidences
of
100%
compared
to
3%
in
the
DMBA/
acetone
control.
Topical
treatment
with
undiluted
creosote
in
both
the
initiation
and
promotion
phases
resulted
in
a
100%
tumor
incidence
compared
to
0%
in
the
acetone
control
group.
Creosote
acted
as
an
initiator,
promoter,
and
complete
carcinogen
under
the
conditions
of
this
study.

This
oncogenicity
study
in
the
mouse
is
Acceptable/
Nonguideline.
The
study
had
numerous
deficiencies
that
limited
the
information
obtainable
on
possible
systemic
toxic
effects,
but
the
data
demonstrated
unequivocally
the
oncogenic
nature
of
creosote
when
applied
to
the
skin
of
Crl
CD­
1
®
mice.
The
deficiencies
did
not
affect
this
outcome
of
the
study,
which
was
designed
to
assess
the
skin
tumor
initiating,
promoting,
and
complete
carcinogenicity
of
creasote.

Reference:
Culp,
S.
J.,
Gaylor,
D.
W.,
Sheldon,
W.
G.,
Goldstein,
L.
S.,
and
Beland,
F.
A.
(
1998):
A
comparison
of
the
tumors
induced
by
coal
tar
and
benzo(
a)
pyrene
in
a
2­
year
bioassay.
Carcinogenesis
19:
1,
pp.
117­
124
Summary:
In
a
study
by
Culp
et
al.
(
1998)
female
B6C3F1
mice
(
48
mice/
group)
were
given
coal
tar
samples
in
the
diet,
derived
from
manufactured
gas
plant
waste
sites
at
0,
12,
33,
117,
333,
739,
and
1300
mg/
kg/
day
(
coal
tar
sample
1)
or
40,
120,
and
346
mg/
kg/
day
(
coal
tar
sample
2)
for
2
years.
Coal
tar
sample
1
was
a
mixture
of
samples
from
seven
waste
sites
and
coal
tar
sample
2
was
a
mixture
from
two
of
the
waste
sites
plus
a
third
waste
site
with
a
high
benzo(
a)
pyrene
content.
Significant
concentration­
related
increases
in
incidence
of
tumors
of
the
liver,
lung,
forestomach,
and
increased
incidence
of
hemangiosarcoma,
histiocytic
sarcoma,
and
sarcoma
were
observed
for
both
coal
tar
sample
1
and
2.
Tumors
of
the
small
intestine
were
also
observed
in
addition
in
those
mice
receiving
coal
tar
sample1,
similar
to
an
earlier
study
by
Culp
(
Polycyclic
Aromatic
Compounds
11:
161­
168;
1996).
11
4.0
Dose­
Response
Assessment
On
April
1,
1999,
the
Health
Effects
Division's
Hazard
Identification
Assessment
Review
Committee
(
HIARC)
evaluated
the
toxicological
endpoints
selected
for
occupational
and
residential
(
dermal
and
inhalation)
exposure
risk
assessments
for
Creosote.
On
September
3,
2003,
the
Antimicrobials
Division
Toxicity
Endpoint
Selection
Committee
(
ADTC)
met
to
verify
the
selected
endpoints
for
long­
term
dermal
risk
assessments
for
creosote
and
inhalation
risk
assessment,
and
also
discussed
whether
dermal
and
inhalation
Margins
of
Exposure
should
be
combined
for
creosote
risk
assessment.

As
there
are
no
existing
tolerances
or
other
clearances
for
residues
of
creosote
in
food,
an
FQPA
assessment
is
not
necessary.
Potential
post­
application
exposures
to
residents,
including
children
(
e.
g.,
from
use
of
railroad
ties
by
homeowners),
could
not
be
assessed
due
to
lack
of
exposure
data.
The
available
evidence
on
developmental
and
reproductive
effects
of
creosote
was
assessed
by
the
Health
Effects
Division
(
HED)
Hazard
Identification
Assessment
Review
Committee
on
April
1,
1999
The
committee
expressed
concern
for
potential
infants
and
children's
susceptibility
of
creosote,
based
on
the
severity
of
offspring
vs.
maternal
effects
observed
with
testing
of
creosote
in
the
P1/
P13
blend
developmental
toxicity
study
in
rats
at
the
175
mg/
kg/
day
dose
level
as
well
as
deficiencies
observed
in
the
2­
generation
reproduction
toxicity
study
in
rats.

The
toxicological
endpoints
selected
for
various
exposure
scenarios
are
summarized
in
Table
2
below.
12
Table
2.
Summary
of
Doses
and
Endpoints
Selected
for
Creosote
Risk
Assessments.

EXPOSURE
SCENARIO
DOSE
(
mg/
kg/
day)
ENDPOINT
STUDY
Acute
and
Chronic
Dietary
Acute
and
Chronic
Dietary
risk
assessment
not
required
Carcinogenicity
(
Dietary)
Creosote
has
been
shown
to
exert
positive
mutagenic
effects
in
vitro,
and
has
been
shown
to
be
positive
for
carcinogenicity
in
an
initiation/
promotion
study.
Creosote
has
been
classified
as
a
B1
carcinogen
in
IRIS.
Oral
cancer
slope
factor
for
benzo(
a)
pyrene,
a
component
of
creosote,
used
as
indicator
for
carcinogenic
potential
of
creosote:
7.3
(
mg/
kg/
day)­
1
+
50%
dermal
absorption.

Short­
Term
(
Dermal)
Oral
NOAEL=
50
decreased
body
weight
gain
at
175
mg/
kg/
day
Developmental
Toxicity
­
Rat
MOE
=
100
(
50%
dermal
absorption
used
to
correct
for
use
of
oral
endpoint)

Intermediate­
term
(
Dermal)
Dermal
NOAEL
=
40
Decreased
body
weight
gain
at
400
mg/
kg/
day
90­
Day
Dermal
Toxicity
Study
in
the
Rat
MOE
=
100
Long­
Term
(
Dermal)
a
Oral
LOAEL
=
25
mg/
kg/
day
decreased
pre­
mating
body
weight
2­
generation
reproduction
study
­
Rat
MOE
=
300
(
10x
interspecies,
10x
intraspecies,
3x
for
use
of
a
LOAEL)

Inhalation
(
any
time
period)
b
NOAEL
=
0.0047mg/
m3
MOE
=
100
decreased
body
weight,
body
weight
gain,
altered
hematology
90­
day
Inhalation
Study
in
the
Rat
Dermal
absorption
c
50%,
estimated
from
ratio
of
oral/
dermal
LOAELs
13
aafter
re­
examination
of
the
toxicology
data,
the
ADTC
concluded
that
the
2­
generation
reproduction
toxicity
study
was
appropriate
for
long­
term
dermal
risk
assessment
for
the
following
reasons:
the
duration
of
the
2­
generation
reproduction
study
is
more
representative
of
the
time
frame
(
i.
e.
long­
term)
than
the
90­
day
dermal
study,
and
is
consistent
with
OPP
policy
regarding
duration
of
the
study
vs.
route
of
exposure;
body
weight
gain
decreases
in
the
2­
generation
reproduction
toxicity
study
were
observed
in
the
F2
generation,
supporting
the
time
frame
for
the
long­
term
endpoint
(
i.
e.
>
6
months).
The
90­
day
dermal
study
effects
are
not
as
representative
of
the
time
frame
for
the
long­
term
dermal
risk
assessment.
However,
the
two
studies
can
be
considered
co­
critical
studies
for
this
endpoint.
Correction
of
the
LOAEL
from
the
2­
generation
reproduction
toxicity
study
for
dermal
absorption
(
50%)
and
use
of
a
LOAEL
(
3x
extra
UF)
yields
a
MOE
and
endpoint
(
300
and
50
mg/
kg/
day)
similar
to
the
90­
day
dermal
toxicity
study
(
40
mg/
kg/
day
and
MOE
of
300
[
extra
3x
to
extrapolate
to
long­
term
endpoint]).

bthe
ADTC
re­
examined
the
use
of
the
inhalation
toxicity
study
selected
for
inhalation
risk
assessment
for
creosote
and
concluded
that
a
developmental
toxicity
study,
as
used
for
the
oral
and
dermal
risk
assessments
of
creosote,
is
not
appropriate
for
inhalation
risk
assessment
because:
(
1)
the
inhalation
toxicity
study
showed
significant
effects
on
body
weight
gain
early
in
the
study
(
one
week)
and
is
therefore
relevant
for
short­
term
assessment
(
2)
it
is
also
a
route­
specific
study;
and
(
3)
the
inhalation
NOAEL
is
more
sensitive
than
the
developmental
NOAEL.
Therefore,
the
inhalation
study
will
remain
as
the
study
for
the
short­
term
inhalation
endpoint.

CNo
dermal
absorption
studies
for
creosote
are
available.
The
HIARC
estimated
a
dermal
absorption
of
50%
based
on
the
results
of
an
oral
developmental
toxicity
in
rats
and
a
90­
day
dermal
toxicity
studies
in
the
same
species
(
rats)
with
similar
endpoints
(
e.
g.,
decrease
in
body
weight
gains).
Benzo(
a)
pyrene
has
also
shown
a
similar
extent
of
dermal
absorption
(
Ng
et
al.,
Toxicol.
Appl.
Pharamcol.
115:
216­
223,
1992)
and
supports
the
HIARC's
decision
for
creosote.

5.0
Cumulative
Exposure
Section
408(
b)(
2)(
D)(
v)
of
FFDCA
requires
that,
when
considering
whether
to
establish,
modify,
or
revoke
a
tolerance,
the
Agency
consider
available
information
concerning
the
cumulative
effects
of
a
particular
pesticide's
residues
and
other
substances
that
have
a
common
mechanism
of
toxicity.
As
there
are
no
tolerances
for
creosote,
the
Agency
is
not
considering
whether
creosote
has
a
common
mechanism
of
toxicity
with
any
other
chemicals.
However,
based
on
the
complex
nature
of
the
creosote
mixture,
components
of
this
mixture
may
act
in
similar
ways
to
produce
the
adverse
effects
noted
for
creosote.

6.0
Endocrine
Disruption
EPA
is
required
under
FFDCA,
as
amended
by
FQPA,
to
develop
a
screening
program
to
determine
whether
certain
substances
(
including
all
active
pesticides
or
other
ingredients)
"
may
have
an
effect
in
humans
that
is
similar
to
an
effect
produced
by
a
naturally
occurring
estrogen,
or
other
such
endocrine
effects
as
the
Administrator
may
designate."
Following
the
recommendations
of
its
Endocrine
Disruptor
Screening
and
Testing
Advisory
Committee
(
EDSTAC),
the
EPA
has
determined
that
there
was
scientific
bases
for
including,
as
part
of
the
program,
the
androgen
and
thyroid
hormone
systems,
in
addition
to
the
estrogen
hormone
system.
EPA
also
adopted
EDSTAC
recommendation,
that
program
include
evaluations
of
potential
effects
in
wildlife
may.
For
pesticide
chemicals,
EPA
will
use
FIFRA
and,
to
some
extent
that
effects
in
wildlife
may
help
determine
whether
a
substance
may
have
an
effect
on
humans,
FFDCA
authority
to
require
the
wildlife
evaluations.
As
the
science
develops
and
resources
allow,
screening
additional
hormone
systems
may
be
added
to
the
Endocrine
Disruptor
Screening
Program.

When
the
appropriate
screening
and/
or
testing
protocols
being
considered
under
the
Agency's
EDSP
have
been
developed,
creosote
may
be
subjected
to
additional
screening
and/
or
testing
to
14
better
characterize
effects
related
to
endocrine
disruption.