1
Date:
December
8,
1997
MEMORANDUM
SUBJECT:
PENTACHLOROPHENOL:
­
Report
of
the
Hazard
Identification
Assessment
Review
Committee.

FROM:
Jess
Rowland
Branch
Senior
Scientist,
Science
Analysis
Branch,
Health
Effects
Division
(
7509C)

THROUGH:
K.
Clark
Swentzel,
Chairman,
Hazard
Identification
Assessment
Review
Committee
Toxicology
Branch
II,
Health
Effects
Division
(
7509C)

TO:
Norm
Cook,
Chief
Risk
Assessment
and
Science
Support
Branch
Antimicorbial
Division
(
7505W)

PC
Code:
063001
On
November
25,
1997,
the
Health
Effects
Division's
Hazard
Identification
Review
committee
evaluated
the
toxicology
data
base
of
Pentachlorophenol,
selected
doses
and
endpoints
for
acute
dietary,
chronic
dietary
(
RfD)
as
well
as
occupational
and
residential
exposure
risk
assessments,
assessed
the
carcinogenic
potential
and
addressed
the
sensitivity
of
infants
and
children
from
exposure
to
Pentachlorophenol
as
required
by
the
Food
Quality
Protection
Act
(
FQPA).
2
Committee
Members
in
Attendance
Members
in
attendance
were
Karl
Baetcke,
William
Burnam,
George
Ghali,
Karen
Hamernik,
Susan
Makris,
Melba
Morrow,
Nancy
McCarroll,
Kathy
Raffale,
John
Redden,
Jess
Rowland
and
Clark
Swentzel.
Data
was
presented
by
Tim
McMahon
of
the
Antimicrobial
Division.

Report
Preparation:
Jess
Rowland,
M.
S
3
I.
INTRODUCTION
On
November
25,
1997,
the
Health
Effects
Division's
Hazard
Identification
Review
committee
evaluated
the
toxicology
data
base
of
Pentachlorophenol,
selected
doses
and
endpoints
for
acute
dietary,
chronic
dietary
(
RfD)
as
well
as
occupational
and
residential
exposure
risk
assessments,
assessed
the
carcinogenic
potential
and
addressed
the
sensitivity
of
infants
and
children
from
exposure
to
Pentachlorophenol
as
required
by
the
Food
Quality
Protection
Act
(
FQPA).

II.
HAZARD
IDENTIFICATION
A.
Acute
Dietary
(
one­
day)

Study
Selected:
Developmental
Toxicity
­
Rat
§
83­
3a
MRID
No.
43091702
Executive
Summary:
In
a
developmental
toxicity
study,
pregnant
Crl:
CD
BR
VAF/
plus
rats
(
25/
dose)
received
oral
administration
of
Pentachlorophenol
(
88.9%)
at
doses
of
0,
10,
30
or
80
mg/
kg/
day
during
gestation
days
6
through
15.
For
maternal
toxicity,
the
NOEL
was
30
mg/
kg/
day
and
the
LOEL
was
80
mg/
kg/
day
based
on
reduced
body
weight
gain
during
the
dosing
period
(
79%
of
control)
and
for
the
entire
gestation
period
(
88%
of
controls).
Developmental
toxicity
observed
at
80
mg/
kg/
day
included:
significant
increase
in
the
number
of
resorptions
(
mainly
early)
with
a
corroborative
decrease
in
litter
size;
.
reduced
mean
fetal
weights;
significant
increase
in
the
number
of
fetuses
with
external,
visceral
and/
or
skeletal
malformation/
variations
(
hydrocephaly,
diaphragmatic
hernia,
and
dilation
of
the
renal
pelvis);
and
significant
increase
in
the
number
of
litters
(
22
of
23)
that
contained
fetuses
(
6
of
22)
with
skeletal
anomalies.
The
most
common
were
vertebral
structural
variations
and
incomplete
ossification.
For
developmental
toxicity,
the
NOEL
was
30
mg/
kg
and
the
LOEL
was
80
mg/
kg/
day
based
on
increased
resorptions,
reduced
fetal
weight
and
skeletal
malformations/
variations.

Dose
and
Endpoint
for
Risk
Assessment:
Developmental
NOEL=
30
mg/
kg/
day
based
on
increased
resorptions,
reduced
fetal
weight
and
skeletal
malformations/
variations
at
80
mg/
kg/
day
(
LOEL).

Comments
about
Study
and
Endpoint:
The
skeletal
malformations/
variations
are
presumed
to
occur
after
a
single
exposure
(
dose)
and
thus
were
considered
to
be
appropriate
for
this
risk
assessment.

This
risk
assessment
is
required.
4
Acute
Dietary
Risk
Assessment:
The
Committee
determined
that
the
10
x
factor
to
account
for
enhanced
sensitivity
of
infants
and
children
(
as
required
by
FQPA)
should
be
reduced
to
3
x.
For
acute
dietary
risk
assessment,
a
Margin
of
Exposure
(
MOE)
of
300
is
required
for
the
protection
of
the
general
U.
S.
population
including
infants
and
children
from
exposure
to
Pentachlorophenol.

Although
developmental
toxicity
studies
showed
no
increased
sensitivity
in
fetuses
as
compared
to
maternal
animals
following
in
utero
exposures
in
rats
and
rabbits
a
MOE
of
300
is
required
because
of
the
lack
of
an
acceptable
two
generation
reproductive
toxicity
study
in
rats
which
would
have
enabled
an
evaluation
of
sensitivity
between
adults
and
pups.

B.
Chronic
Dietary
[
Reference
Dose
(
RfD)]

Study
Selected:
Chronic
Toxicity
­
Dog
Guideline
§
82­
1b
MRID
No.
43982701
Executive
Summary:
In
a
chronic
toxicity
study,
Pentachlorophenol
(
90.9%)
was
administered
to
beagle
dogs
(
4/
sex/
dose)
in
gelatin
capsules
at
dose
levels
of
0,
1.5,
3.5,
or
6.5
mg/
kg/
day
for
52
weeks.
Treatment
related
effects
observed
at
the
lowest
dose
level
(
1.5
mg/
kg/
day)
were
increases
in
liver
weights
(
females)
and
alkaline
phosphatase
activity
(
males)
as
well
as
increases
in
the
incidences
of
granular
cytoplasmic
pigment
accumulation
of
the
liver
(
both
sexes)
and
lymphocytic
mucosal
inflammation
of
the
stomach.
For
systemic
toxicity,
the
LOEL
was
1.5
mg/
kg/
day
based
on
the
hepatotoxicity
discussed
above;
a
NOEL
was
not
established.

Dose
and
Endpoint
for
establishing
the
RfD:
LOEL=
1.5
mg/
kg/
day
based
on
hepatotoxicity
characterized
as
increases
in
liver
weights
and
alkaline
phosphatase
activity,
increased
incidences
of
granular
cytoplasmic
pigment
accumulation
in
the
liver
as
well
as
increased
incidence
of
lymphocytic
mucosal
inflammation
in
the
stomach.

Comments
about
Study
and
Endpoint:
Pigment
accumulation
seen
in
dogs
has
also
been
seen
in
rats.

For
chronic
risk
assessment,
an
UF
of
1000
was
applied
to
derive
the
RfD.
The
UF
of
1000
includes:
10
x
for
inter­
species
variation;
10
x
for
intra­
species
variation;
3
x
for
the
use
of
a
LOEL
(
under
FIFRA);
and
an
additional
3
x
for
the
data
gap
of
a
2­
generation
reproductive
toxicity
study
(
under
FQPA).

RfD
=
1.5
mg/
kg/
day
(
LOEL)=
0.0015
mg/
kg/
day
1000
(
UF)
5
C.
Occupational
Exposure
There
are
no
registered
residential
use
for
Pentachlorophenol
at
the
present
time
and
therefore
residential
risk
assessments
are
not
required..

1.
Dermal
Absorption
MRID
No
00259257
Executive
Summary:
In
a
dermal
absorption
study
14­
C
Pentachlorophenol
(
5%
solution
in
P­
9
oil)
was
applied
to
the
skin
of
yound
adult
Sprague­
Dawley
rats
for
0.25,
1,
4,
8
and
24
hours.
The
calculated
absorption
was
40%
at
8
hours
and
60%
at
24
hours.

Dermal
Absorption
Factor:
A
dermal
absorption
factor
of
40%
should
be
used
for
correcting
oral
dosing
to
dermal
dosing.

2.
Short­
Term
Dermal
­
(
1­
7
days)

Study
Selected:
Developmental
Toxicity
­
Rat
§
83­
3a
MRID
No.
43091702
Executive
Summary:
See
Acute
Dietary
Dose
and
Endpoint
for
Risk
Assessment:
Developmental
NOEL=
30
mg/
kg/
day
based
on
increased
resorptions,
reduced
fetal
weight
and
skeletal
malformations/
variations
at
80
mg/
kg/
day
(
LOEL).
Comments
about
Study
and
Endpoint:
Since
an
oral
NOEL
was
selected,
a
dermal
absorption
rate
of
40%
should
be
used
for
correcting
the
oral
dose
to
a
dermal
dose
for
risk
assessmeents.

Although
a
90­
dermal
toxicity
study
in
rats
(
MRID
No.
43182301)
was
available
in
the
data
base,
it
was
not
considered
to
be
appropriate
for
this
risk
assessment
because
of
the
concern
for
the
developmental
effects
that
were
seen
in
rats
which
were
not
evaluated
in
the
dermal
study.
Also,
the
oral
NOEL
of
30
mg/
kg/
day
is
supported
by
the
NOEL
of
100
mg/
kg/
day
established
in
the
90­
day
dermal
study
when
the
dermal
absorption
rate
is
used
for
correcting
the
oral
dose
to
a
dermal
dose.
A
comparable
dermal
dose
of
75
mg/
kg/
day
is
obtained
when
used
in
conjunction
with
a
dermal
absorption
factor
of
40%
(
i.
e.,
oral
NOEL
30
mg/
kg/
day
÷
40%
DA
=
75
mg/
kg/
day).

This
risk
assessment
is
required.
6
3.
Intermediate­
Term
Dermal
(
7
Days
to
Several
Months)

Study
Selected:
Developmental
Toxicity
­
Rat
§
83­
3a
MRID
No.
43091702
Executive
Summary:
See
Acute
Dietary
Dose
and
Endpoint
for
Risk
Assessment:
Developmental
NOEL=
30
mg/
kg/
day
based
on
increased
resorptions,
reduced
fetal
weight
and
skeletal
malformations/
variations
at
80
mg/
kg/
day
(
LOEL).

Comments
about
Study
and
Endpoint:
Since
an
oral
LOEL
was
selected,
a
dermal
absorption
rate
of
40%
should
be
used
for
correcting
the
oral
dose
to
a
dermal
dose
for
risk
assessmeents.

Although
a
90­
dermal
toxicity
study
in
rats
(
MRID
No.
43182301)
was
available
in
the
data
base,
it
was
not
considered
to
be
appropriate
for
this
risk
assessment
because
of
the
concern
for
the
developmental
effects
that
were
seen
in
rats
which
are
not
evaluated
in
the
dermal
study.
Also,
the
oral
NOEL
of
30
mg/
kg/
day
is
supported
by
the
NOEL
of
100
mg/
kg/
day
established
in
the
90­
day
dermal
study
when
the
dermal
absorption
rate
is
used
for
correcting
the
oral
dose
to
a
dermal
dose.
A
comparable
dermal
dose
of
75
mg/
kg/
day
is
obtained
when
used
in
conjunction
with
a
dermal
absorption
factor
of
40%
(
i.
e.,
oral
NOEL
30
mg/
kg/
day
÷
40%
DA
=
75
mg/
kg/
day).

This
risk
assessment
is
required.

4.
Long­
Term
Dermal
(
Several
Months
to
Life­
Time)

Study
Selected:
Chronic
Toxicity
Dog
Guideline
§
83­
1b
MRID
No
43982701
Executive
Summary:
See
Chronic
Dietary
Dose
and
Endpoint
for
Risk
Assessment:
LOEL=
1.5
mg/
kg/
day
based
on
hepatoxicity
characterized
as
increases
in
liver
weights
and
alkaline
phosphatase
activity,
increased
incidences
of
granular
cytoplasmic
pigment
accumulation
in
the
liver
as
well
as
increased
incidence
of
lymphocytic
mucosal
inflammation
in
the
stomach.
7
Comments
about
Study
and
Endpoint:
Since
an
oral
LOEL
was
selected,
a
dermal
absorption
rate
of
40%
should
be
used
for
correcting
the
oral
dose
to
a
dermal
dose
for
risk
assessmeents.
This
dose
was
used
in
establishing
the
RfD.

This
risk
assessment
is
required.

5.
Inhalation
Exposure
(
Any­
Time
period)

Inhalation
toxicity
studies
with
the
technical
material
were
available
in
the
toxicology
data
base
and
the
available
studies
with
the
formuation
products
are
all
classified
as
Supplementary.
Therefore,
the
Committee
determined
that
Pentachlorophenol
should
be
placed
in
Toxicity
Category
I,
a
respirator
must
be
worn
during
use
and
a
Data
Call­
In
notice
should
be
issued
for
an
acute
inhalation
toxicity
study
with
the
technical
material.

Due
to
the
lack
of
an
appropriate
inhalation
toxicity
study,
doses
and
endpoints
were
not
selected
for
inhalation
risk
assessments.

D
Margin
of
Exposure
for
Occupational
Exposures:

For
Short­
and
Intemediate­
Term
dermal
risk
assessment,
a
MOE
of
100
is
adequate
because
a
NOEL
was
used
for
these
risk
assessments.
For
Long­
Term
dermal
risk
assessment,
however,
a
MOE
of
300
is
required
because
of
the
use
of
a
LOEL
for
this
risk
assessment.
The
additional
UF
of
3
is
applied
under
FIFRA
(
i.
e.,
lack
of
a
NOEL
in
the
critical
study)
and
NOT
under
FQPA.
The
latter
(
FQPA)
does
not
apply
for
these
risk
assessments,
since
there
are
no
registered
residential
uses
at
the
present
time
and
thus
infants
and
childern
are
not
expected
to
be
exposed
to
Pentachlorophenol.

III.
CARCINOGENICITY
CLASSIFICATION
The
National
Toxicology
Program
(
NTP)
conducted
a
toxicity/
carcinogenicity
study
with
two
composition
of
Pentachlorophenol:
TG­
Penta
and
Dowicide
EC­
7.
Both
preparations
contained
90%
penta,
but
differed
in
the
level
and
nature
of
impurities.
Male
and
female
B6C3F1
mice
were
fed
diets
containing
TG­
Penta
at
100
or
200
ppm
and
EC­
7
at
100,
200
or
600
ppm
for
2
years.
Statistically
significant
increases
in
the
incidences
of
multiple
biologically
significant
tumor
types
(
hepatocellular
adenomas
and
carcinomas,
adrenal
medulla
pheochrocytomas
and
malignant
pheochrocytomas,
and/
or
hemangiosarcomas
and
hemangiomas)
were
observed
in
one
or
both
sexes.

The
NTP
has
also
just
completed
a
toxicology/
carcinogenesis
study
in
rats.
The
Agency
is
awaiting
the
receipt
of
a
draft
copy
of
the
Technical
Report.
8
Based
on
the
observance
of
increased
tumors
in
the
mouse
study
and
the
pending
results
of
the
rat
study,
the
Committee
recommended
that
the
carcinogenic
potential
of
Pentachlorophenol
should
be
evaluated
by
the
Cancer
Assessment
Review
Committee.

IV.
FQPA
CONSIDERATIONS
1.
Determination
of
Sensitivity
The
oral
perinatal
and
prenatal
data
demonstrated
no
indication
of
increased
sensitivity
of
rats
or
rabbits
to
in
utero
exposure
to
Pentachlorophenol.

In
a
prenatal
developmental
toxicity
study,
Sprague­
Dawley
rats
(
at
least
22/
group)
received
oral
administrations
of
Pentachlorophenol
(
88.9%)
in
corn
oil
at
doses
of
0,
10,
30,
or
80
mg/
kg/
day
during
gestation
days
6
through
15.
Cesarean
sections
were
performed
on
gestation
day
20.
For
maternal
toxicity,
the
NOEL
was
30
mg/
kg/
day
and
the
LOEL
was
80
mg/
kg/
day,
based
on
reduced
bodyweight
gains.
For
developmental
toxicity,
the
NOEL
was
30
mg/
kg/
day
and
the
LOEL
was
80
mg/
kg/
day
based
on
increased
resorptions
(
mainly
early)
with
corollary
reductions
in
litter
size,
reduced
fetal
weight,
and
increased
litter
incidences
of
external,
visceral,
and/
or
skeletal
malformations
and
variations.
These
findings
included
hydrocephaly,
diaphragmatic
hernia,
dilatation
of
the
renal
pelvis,
vertebral
structural
variations,
and
incomplete
ossification
of
the
sternebrae.
(
MRID
No.
43091702)

Apparently
in
other
older
developmental
toxicity
studies
in
rodents
found
in
the
literature,
maternal
and
developmental
effects
were
observed
at
30
mg/
kg/
day,
with
a
NOEL
of
3
mg/
kg/
day.
Although
the
NOELs
for
these
studies
may
have
been
lower
than
the
1994
study,
no
special
sensitivity
was
noted
for
the
offspring.

The
IRIS
Data
Base
referenced
a
study
by
Larsen
et
al.
(
1975)
which
demonstrated
that
Pentachlorophenol
does
not
cross
the
placenta.
No
data
were
provided
in
the
package
to
allow
adequate
review
of
this
hypothesis
at
the
time
of
this
review.

There
was
discussion
of
the
possibility
that
developmental
effects
noted
in
rodents
following
in
utero
exposure
to
Pentachlorophenol
were
related
to
impurities
in
the
test
substance
(
including
hexadioxin).
Apparently,
there
were
some
studies
conducted
to
pursue
these
effects,
and
one
by
Schwetz
and
Gehring
(
1973)
was
discussed
in
the
1990
RfD
report.
Additionally,
elevation
of
maternal
body
temperature
was
cited
as
a
cause
of
developmental
toxicity.
This
is
feasible
since
pentachlorophenol
uncouples
oxidative
phosphorylation
and
increases
body
temperature,
and
maternal
heat
stress
is
known
to
result
in
developmental
toxicity.
9
In
a
prenatal
developmental
toxicity
study,
New
Zealand
White
rabbits
(
20/
group)
received
oral
administrations
of
Pentachlorophenol
(
88.9%)
in
corn
oil
at
doses
of
0,
7.5,
15,
or
30
mg/
kg/
day
in
corn
oil
(
1
ml/
kg)
on
gestation
days
6­
18.
For
maternal
toxicity,
the
NOEL
was
15
mg/
kg/
day,
and
the
LOEL
was
30
mg/
kg/
day
based
on
minimally
reduced
body
weight
gain
and
consistent
reductions
in
food
consumption
during
the
treatment
period.
No
unequivocal
treatment­
related
developmental
effects
were
noted;
therefore,
the
developmental
NOEL
was
>
30
mg/
kg/
day
(
HDT)
(
MRID
No.
43091701)

A
one­
generation
reproduction
study
in
rats
was
described
in
the
literature.
No
data
or
adequate
DER
were
provided
for
review.
Various
accounts
of
this
study
in
the
data
package
do
not
provide
a
clear
description
of
the
study
design,
although
it
was
apparently
conducted
as
part
of
a
two­
year
chronic
study.
Dietary
levels
for
the
chronic
study
are
described
as
0,
8,
23,
77,
or
231
ppm
(
equivalent
to
0,
1,
3,
10,
or
30
mg/
kg/
day,
respectively).
According
to
the
1990
RfD
report,
a
significant
decrease
in
percent
pups
born
alive,
and
significant
decreases
in
survival
throughout
lactation
were
observed
at
30
mg/
kg/
day.
Apparently,
there
was
also
a
developmental
segment
to
the
study
since
increased
variations
in
lumbar
spurs
and
vertebrae
with
unfused
centra
were
described
for
the
same
dose
level.
Based
on
these
findings,
it
is
assumed
that
the
NOEL
for
effects
on
the
offspring
was
10
mg/
kg/
day,
and
the
LOEL
was
30
mg/
kg/
day.
For
the
adults,
the
NOEL
for
chronic
systemic
toxicity
was
3
mg/
kg/
day,
with
a
LOEL
of
10
mg/
kg/
day,
based
on
liver
and
kidney
pathology.
It
appears
that
the
major
flaw
of
this
study
is
the
lack
of
a
second
generation.
(
Schwetz,
et
al.,
1978)

2.
Recommendation
for
a
developmental
neurotoxicity
study
Based
on
the
following
weight­
of­
the­
evidence
review
of
the
available
data,
the
Committee
determined
that
a
developmental
neurotoxicity
study
is
not
required.

#
There
was
no
evidence
of
frank,
unequivocal
neurotoxicity
in
the
database,
including
changes
in
brain
weight
or
incidence
of
neuropathology
in
the
central
or
peripheral
nervous
system
tissues
(
nonperfused).
The
nervous
system
has
not
been
generally
considered
a
target
tissue
(
NTP
Technical
Report,
1989).

#
No
evidence
of
abnormalities
in
the
development
of
the
fetal
nervous
system
were
observed
in
the
prenatal
developmental
toxicity
studies
in
either
rats
or
rabbits,
at
maternally
toxic
oral
doses
up
to
30
mg/
kg/
day.
Incidences
of
hydrocephaly
in
the
prenatal
rat
study
were
seen
in
only
2
fetuses
of
2
litters
and
were
within
published
historical
control
ranges.

#
There
was
minimal
clinical
evidence
of
nonspecific
neurobehavioral
effects
such
as
salivation,
ataxia,
or
convulsions.

VII.
DATA
GAPS
Two­
Generation
Reproductive
Toxicity
­
Rat
(
§
83­
4)
10
