Poly(
hexamethylenebiguanide)
hydrochloride
(
PHMB)
Case
3122
PC
Code:
111801
Toxicology
Disciplinary
Chapter
for
the
Reregistration
Eligibility
Decision
Document
January
18,
2005
Jonathan
Chen,
Ph.
D.
Tim
McMahon,
Ph.
D.
Antimicrobials
Division
Office
of
Pesticide
Programs
U.
S.
Environmental
Protection
Agency
1200
Pennsylvania
Avenue,
NW
Washington,
DC
20460
TABLE
OF
CONTENTS
1.0
HAZARD
CHARACTERIZATION
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1
2.0
REQUIREMENTS
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2
3.0
DATA
GAPS
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3
4.0
HAZARD
ASSESSMENT
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3
4.1
Acute
Toxicity
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3
4.2
Subchronic
Toxicity
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4
4.3
Prenatal
Developmental
Toxicity
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7
4.4
Reproductive
Toxicity
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8
4.5
Chronic
Toxicity
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9
4.6
Carcinogenicity
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11
4.7
Mutagenicity
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14
4.8
Neurotoxicity
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15
4.9
Metabolism.
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16
5.0
TOXICITY
ENDPOINT
SELECTION
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17
5.1
See
Section
8.2
for
Endpoint
Selection
Table.
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17
5.2
Dermal
Absorption
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17
5.3
Classification
of
Carcinogenic
Potential
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17
6.0
FQPA
CONSIDERATIONS
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17
6.1
Special
Sensitivity
to
Infants
and
Children
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17
6.2
Recommendation
for
a
Developmental
Neurotoxicity
Study
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18
7.0
REFERENCES
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19
8.0
APPENDICES
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22
8.1
Toxicity
Profile
Summary
Tables
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23
8.1.1
Acute
Toxicity
Table
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23
8.1.2
Subchronic,
Chronic
and
Other
Toxicity
Tables
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23
8.2
Summary
of
Toxicological
Dose
and
Endpoints
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26
1
1.0
HAZARD
CHARACTERIZATION
Poly(
hexamethylenebiguanide)
hydrochloride
(
PHMB)
is
used
as
a
swimming
pool
sanitizer
and
algicide.
PHMB
is
the
active
ingredient
in
Vantocil
Ib
®
.
PHMB
is
also
used
in
several
other
types
of
applications,
including
as
a
preservative
for
cut
flowers,
materials
preservative,
and
all­
purpose
cleaner.

PHMB
technical
(
20%
aqueous
solution)
has
low
acute
toxicity
by
the
oral
(
Category
III)
and
dermal
routes
(
Category
III­
IV).
PHMB
has
severe
to
moderate
acute
eye
irritation
(
Category
I­
II)
and
slight
to
moderate
acute
dermal
irritation
(
Category
II
&
IV).
It
causes
mild
to
moderate
skin
sensitization
in
guinea
pigs.

The
21­
day
dermal
study
showed
no
systemic
toxicity,
but
it
did
show
severe
dermal
irritation
in
the
acute
assay.
The
21­
day
dermal
study
did
not
test
to
the
limit
dose
because
a
severe
dermal
irritation
was
found
at
a
dose
level
of
300
mg/
kg
in
a
preliminary
study.

Dermal
studies
demonstrate
that
the
target
organ
is
the
liver.
Reduced
body
weight
is
the
primary
effect
of
concern
in
all
animal
studies.

No
quantitative
or
qualitative
susceptibility
was
shown
in
the
prenatal
studies
or
the
reproductive
study.
The
rat
prenatal
study
showed
increased
incidence
of
extra
ribs
in
the
fetus
but
with
no
increased
susceptibility.
The
rabbit
prenatal
study
showed
possible
toxicity
in
the
form
of
reduced
numbers
of
litters
and
skeletal
abnormalities,
but
no
increased
susceptibility.
The
reproductive
study
showed
no
adverse
effects
on
reproduction.

Chronic
toxicity
studies
showed
multiple
effects
on
the
liver
in
both
sexes
of
rats
as
well
as
body
weight
decrement.
The
dog
study
showed
testes
and
liver
changes
in
males
and
clinical
signs
of
toxicity
and
clinical
effects
and
alterations
in
clinical
chemistry
in
1
out
of
4
females.

There
were
no
neurotoxic
effects
seen
in
any
subchronic
or
chronic
toxicity
studies.
Due
to
the
lack
of
neurotoxic
affects
no
neurotoxicity
tests
were
required.

The
carcinogenicity
studies
showed
an
apparent
increase
in
hemangiosarcomas
in
the
liver
of
female
rats,
increased
hemangiosarcomas
in
mice,
and
increased
squamous
cell
carcinomas
of
the
rectal­
anal
junction
in
mice.
The
potential
cancer
causing
effects
are
referred
to
the
Cancer
Assessment
Review
Committee
(
CARC).

There
is
no
evidence
of
a
mutagenic
response
in
a
battery
of
mutagenicity
studies,
including
a
lack
of
clastogenic
responses
in
peripheral
human
lymphocytes.

Rat
metabolism
studies
showed
that
PHMB
is
metabolized
in
a
similar
fashion
by
male
and
female
rats.
PHMB
was
excreted
mainly
through
feces.
Pooled
urine
showed
the
presence
of
more
than
one
metabolite.
2
2.0
TOXICOLOGY
DATA
REQUIREMENTS
The
toxicology
data
requirements
for
PHMB
are
shown
in
Table
1.
Use
of
the
new
guideline
numbers
does
not
imply
that
the
new
(
1998)
guideline
protocols
were
used.

Table
1.
Toxicity
Data
Requirements
for
PHMB
Test
Technical
Required
Satisfied
870.1100
Acute
Oral
Toxicity
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870.1200
Acute
Dermal
Toxicity
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870.1300
Acute
Inhalation
Toxicity
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870.2400
Primary
Eye
Irritation
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870.2500
Primary
Dermal
Irritation
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870.2600
Dermal
Sensitization
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yes
yes
no
yes
yes
yes
yes
yes
­
yes
yes
yes
870.3100
Oral
Subchronic
(
rodent)
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870.3150
Oral
Subchronic
(
nonrodent)
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870.3200
21­
Day
Dermal
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870.3250
90­
Day
Dermal
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870.3465
90­
Day
Inhalation
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.
yes
yes
yes
yes
no
yes
yes
yes
yes*
­

870.3700a
Developmental
Toxicity
(
rodent)
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870.3700b
Developmental
Toxicity
(
nonrodent)
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870.3800
Reproduction
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yes
yes
yes
yes
yes
yes
870.4100a
Chronic
Toxicity
(
rodent)
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870.4100b
Chronic
Toxicity
(
nonrodent)
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.
870.4200a
Oncogenicity
(
rat)
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870.4200b
Oncogenicity
(
mouse)
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870.4300
Chronic/
Oncogenicity
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yes
yes
yes
yes
no
yes*
yes
yes*
yes
yes
870.5100
Mutagenicity 
Gene
Mutation
­
bacterial
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.
870.5395/
Mutagenicity 
Structural
Chromosomal
Aberrations
870.5345
870.5550
Mutagenicity 
Other
Genotoxic
Effects
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.
yes
yes
yes
yes
yes
yes
870.7485
General
Metabolism
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yes
yes
*
Satisfied
by
the
90­
day
oral
study
and
the
dermal
absorption
value,
which
will
be
used
for
dermal
risk
assessments
*
Satisfied
by
Chronic/
Oncogenicity
test
3
3.0
DATA
GAPS
None
4.0
HAZARD
ASSESSMENT
4.1
Acute
Toxicity
Adequacy
of
database
for
acute
toxicity:
The
database
for
acute
toxicity
is
considered
complete.
No
additional
studies
are
required
at
this
time.

The
acute
toxicity
data
on
PHMB
(
20%
a.
i.;
technical
grade)
is
summarized
below
in
Table
2.
4
Table
2.
Acute
Toxicity
of
PHMB
Product
A.
I.
/
EPA
Reg.
No.
Baquacil
20%
PHMB
/
72674­
19
Baquacil
Ultra
20%
PHMB
/
72674­
22
A­
Breeze
96%
PHMB
/
72674­
32
870.1100
Acute
oral
toxicity
MRID
Tox
Category
LD50
=
2747
mg/
kg
00030330
III
LD50
=
1831mg/
kg
(
M)
LD50
=
1617mg/
kg
(
F)
44940701
III
LD50
=
1049mg/
kg
(
F)

45916505
III
870.1200
Acute
dermal
toxicity
MRID
Tox
Category
LD50
>
2.0
ml/
kg
00065124
III
LD50
>
2000mg/
kg
44940702
III
LD50
>
5000mg/
kg
45916506
IV
870.1300
Acute
inhalation
toxicity
MRID
Tox
Category
waived
LC50
=
1.76mg/
L
44970403
III
waived
870.2400
Acute
eye
irritation
MRIDs
Tox
Category
moderate
irritant
00046789;
00065120
II
moderate
irritant
44963902
II
corrosive
45916508
I
870.2500
Acute
dermal
irritation
MRIDs
Tox
Category
moderate
irritant
00046789;
00065120
II
slight
irritant
44949704
IV
slight
irritant
45916509
IV
870.2600
Skin
sensitization
MRID
moderate
sensitizer
42674201
Moderate
Sensitization
mild
sensitizer
44940705
4.2
Subchronic
Toxicity
Adequacy
of
database
for
subchronic
toxicity:
The
database
for
subchronic
toxicity
is
considered
complete.
No
additional
studies
are
required
at
this
time.

There
were
no
systemic
effects
observed,
however
dermal
irritation
was
caused
by
PHMB.
5
870.3100
90­
Day
Oral
Toxicity
­
Rat
Executive
Summary:
In
a
90­
day
subchronic
toxicity
study
(
MRID
00053460),
young
adult
specific
pathogen
free
(
S.
P.
F.)
rats
(
25
M
+
25
F)
received
0,
2500,
and
5000
ppm
of
PHMB
in
the
diet
for
90
days.
Food
consumption,
general
clinical
observations,
body
weight,
and
hematological
parameters
were
examined.
At
the
end
of
the
90­
day
test
period
all
animals
were
sacrificed
with
chloroform,
and
an
immediate
postmortem
examination
was
made.
Organ
weights
were
recorded
and
organ/
body
weight
ratios
calculated
from
a
randomly
selected
five
males
and
five
females
from
each
group.
The
following
organs
were
included:
liver,
heart,
lung,
adrenals,
kidneys,
and
spleen.
Tissues
from
the
remaining
animals
were
fixed
in
Fenker's
fluid,
except
brains
and
spinal
cords,
which
were
fixed
in
10%
formal
saline
and
examined
microscopically.
The
following
were
examined:
liver,
kidney,
spleen,
heart,
lung,
adrenals,
gonads,
thymus,
thyroid,
pancreas,
stomach,
duodenum,
jejunum,
ileum,
cecum,
colon,
salivary
gland,
messenteric
lymph
nodes,
spinal
cord
and
brain
(
cerebrum,
cerebellum,
and
pons).

All
animals
survived
the
90­
day
test
period.
There
were
no
specific
adverse
effects
of
the
compound.
Food
consumption
was
comparable
for
the
test
groups
and
controls.
Body
weight
was
moderately
reduced
in
males
(
13.2%
less
than
controls),
and
females
(
16.6%
less
than
controls)
fed
the
compounds
at
the
highest
dietary
level
(
5000
ppm).
No
abnormalities
in
hematological
parameters
were
observed.
No
gross
abnormalities
were
observed.
No
remarkable
change
in
organ/
body
weight
ratios
was
detected.
Microscopic
evaluation
revealed
that
the
liver
of
some
females
given
the
compound
at
a
level
of
5000
ppm
showed
an
unusual
degree
of
iron
pigment
both
within
the
liver
cells
and
kupffer
cells.
Although
the
report
states
that
no
iron
pigments
was
seen
in
animals
fed
2500
ppm
test
material
in
the
diet,
the
study
does
not
include
detailed
histopathological
results
of
the
2500
ppm
animals.
Therefore,
the
NOAEL
cannot
be
determined
in
this
study.

870.3150
90­
Day
Oral
Toxicity
­
Dog
Executive
Summary:
In
a
90­
day
subchronic
toxicity
study
in
the
dog
(
MRID
00053461),
three
groups
of
Beagle
Dogs
(
4M
+
4F
per
group),
12.4
­
14.6
kg
initial
BW,
received
dietary
levels
of
0,
5500,
and
11000
ppm
of
PHMB
ad
libitum
for
90
days.
General
observation,
food
consumption,
body
weight
and
the
following
clinical
chemistry
measurements
were
performed:
hemoglobin,
packed
cell
volume
(
hematocrit),
leucocyte
count
(
total
and
differential),
blood
urea,
serum
alkaline
phosphatase,
BSP
(
liver
function
test)
and
urine
analyses
(
pH,
specific
gravity,
glucose,
protein,
bilirubin,
and
microscopy
of
centrifuge
deposit).
At
the
end
of
the
test
period
the
animals
were
sacrificed
with
an
overdose
of
pentobarbitone
administered
intravenously.
A
full
post­
mortem
examination
was
performed
at
the
time
of
necropsy:
heart,
liver,
kidneys,
adrenals,
spleen,
thyroid,
epididymis,
brain
and
pituitary.
Representative
pieces
of
tissues
for
microscopic
examination
were
taken
from
the
following:
brain
(
cerebrum,
cerebellum
and
pons),
spinal
cord,
pituitary,
submaxillory
gland,
thyroid,
thymus,
heart,
lung,
aorta,
stomach,
duodenum,
jejunum,
ileum,
colon,
liver,
spleen,
kidney,
bladder,
adrenal,
ovary
and
uterus
or
testis
and
epididymides,
and
sciatic
nerves.
6
Both
treated
and
control
animals
maintained
an
excellent
condition
throughout
and
no
adverse
effects
were
noted.
No
food
consumption
data
was
submitted.
Mean
body
weights
were
comparable
between
control
and
treated
animals
except
for
the
11,000
ppm
female
dogs
which
gained
significantly
less
total
weight
than
the
female
dogs.
Results
of
the
hematological
parameters
were
unremarkable.
The
clinical
function
test
showed
no
difference
in
retention
of
BSP
attributable
to
test
material.
Urine
analyses
do
not
appear
to
be
influenced
by
treatment.
Organ/
body
weight
ratios
showed
no
significant
variation
from
the
normal
as
a
result
of
treatment.
No
gross
pathology
attributable
to
test
material
was
detected.
Microscopic
examination
revealed
slight
hemosiderons
in
2
out
of
4
males
at
11,000
ppm.
No
other
microscopic
abnormalities
attributable
to
treatment
were
present
at
either
dose
level.

The
NOAEL
for
this
90­
day
dog
feeding
study
appears
to
be
5500
ppm
(
low
dose).
The
high
dose
treatment
caused
a
lower
total
weight
gain
in
female
dogs
and
slight
hemosiderons
in
2
out
of
4
male
dogs.

870.3200
21/
28­
Day
Dermal
Toxicity
 
Rat
Executive
Summary:
In
a
21­
day
dermal
toxicity
study
(
MRID
43047701),
PHMB
was
applied
at
dose
levels
of
0,
20,
60,
and
200
mg/
kg
to
the
shorn
backs
of
5
male
and
female
Alpk:
APfSD
(
Wistar­
derived)
rats
over
the
course
of
30
days
for
a
total
of
21
applications
of
6
hours
duration
each.

There
was
no
evidence
of
systemic
toxicity
at
any
dose
level
in
this
study.
Dermal
toxicity
was
evident
at
the
60
mg/
kg
and
200
mg/
kg
dose
levels
in
the
form
of
erythema,
edema,
scabbing,
acanthosis,
and
inflammatory
cell
infiltration
in
both
sexes.
Based
on
the
data
in
this
study,
the
Systemic
Toxicity
NOAEL
is
greater
than
or
equal
to
200
mg/
kg/
day
for
both
sexes,
and
the
Systemic
Toxicity
LOAEL
is
greater
than
200
mg/
kg/
day
for
both
sexes.
The
Dermal
Toxicity
NOAEL
is
20
mg/
kg/
day
for
both
sexes,
and
the
Dermal
Toxicity
LOAEL
is
60
mg/
kg/
day
for
both
sexes,
based
on
the
increased
incidence
of
erythema,
edema,
and
scabbing
observed
at
this
dose.

Although
there
was
no
evidence
for
systemic
toxicity
at
any
dose
level
tested
in
this
study,
higher
dose
levels
were
not
tested
due
to
the
presence
of
severe
dermal
irritation
at
a
dose
level
of
300
mg/
kg
in
a
preliminary
study.
Therefore,
this
study
is
classified
as
core
minimum
data
and
satisfies
the
guideline
requirement
(
870.3200
§
82­
2)
for
a
repeated
dermal
toxicity
study
in
rats.

870.3250
90­
Day
Dermal
This
requirement
is
satisfied
by
the
80­
week
dermal
carcinogenicity
study
in
mice,
which
will
be
used
for
dermal
risk
assessments.
7
870.3465
90­
Day
Inhalation
 
Rat
A
90­
day
inhalation
toxicity
study
with
PHMB
was
not
available.
The
inhalation
risk
assessment
was
performed
using
the
NOAEL
value
of
20
mg/
kg/
day
from
the
developmental
toxicity
study
in
rabbits
(
MRID
42865901).

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

There
was
no
quantitative/
qualitative
evidence
of
increased
susceptibility
of
developmental
effects
following
in
utero
exposure
in
the
rat
or
rabbit.
Maternal
toxicity
was
reported
at
lower
dose
levels
than
the
developmental
toxicity
in
rats.
In
rabbits,
developmental
effects
were
observed
at
the
same
dose
level
as
the
maternal
effects.

870.3700a
Prenatal
Developmental
Toxicity
Study
­
Rat
Executive
Summary:
In
the
rat
developmental
toxicity
study
(
Report
#
CTL/
P/
1262,
1976
cited
in
Report
#
003810,
1978.
Section
C­
11),
groups
of
at
least
20
pregnant
Alderley
Park
female
rats
were
fed
diets
containing
0,
200,
1000,
or
2000
ppm
(
0,
17.2,
86.2,
and
172.4
mg/
kg/
day)
PHMB
throughout
gestation.
On
gestation
day
20,
animals
were
killed
by
cervical
dislocation
until
at
least
20
pregnancies
in
each
group
were
established.
Mean
maternal
body
weight
and
food
consumption
were
reduced
significantly
in
animals
receiving
86.2
or
172.4
mg/
kg
PHMB
(
20%
a.
i.).
Maternal
microscopic
findings
revealed
an
enlarged
and
hemorrhagic
thymus
in
one
female
that
had
received
100
mg/
kg/
day
20%
PHMB.
Based
on
the
reduced
body
weight
and
reduced
food
consumption,
the
Maternal
Toxicity
LOAEL
is
86.2
mg/
kg/
day.
The
Maternal
Toxicity
NOAEL
is
17.2
mg/
kg/
day.

There
was
no
increase
in
late
resorptions
in
any
group.
The
fetal
weight
and
litter
weight
were
not
reduced
in
the
PHMB
treated
groups.
No
adverse
effects
in
ossification
were
seen
in
the
fetuses
from
the
PHMB
treated
animals.
The
fetus
from
the
100
mg/
kg/
day
group
showed
a
significant
increase
in
extra
ribs.
Based
on
the
increased
incidence
of
ribs
in
the
fetus,
the
Developmental
Toxicity
LOAEL
is
172.4
mg/
kg/
day.
The
Developmental
Toxicity
NOAEL
is
86.2
mg/
kg/
day.

870.3700b
Prenatal
Developmental
Toxicity
Study
­
Rabbit
Executive
Summary:
In
the
rabbit
developmental
study
(
MRID
42865901),
administration
of
PHMB
to
20
pregnant
female
New
Zealand
White
rabbits
per
group
at
levels
of
0,
10,
20,
and
40
mg/
kg/
day
on
gestation
days
8
through
20
resulted
in
maternal
toxicity
at
40
mg/
kg/
day
in
the
form
of
increased
mortality
and
clinical
toxicity.
Mortality
occurred
in
6
rabbits
at
this
dose.
One
rabbit
died
probably
as
a
result
of
mis­
dosing;
one
rabbit
was
killed
in
extremis
on
day
22
due
to
8
inappetance
and
weight
loss
starting
on
day
11;
and
the
remaining
4
rabbits
were
killed
due
to
abortion
of
fetuses
and
thus
a
lack
of
data
for
analysis.
There
are
6
rabbits
that
died
in
the
40
mg/
kg/
day
dose
group;
clinical
signs
included
coldness
(
6/
20
vs.
0/
20
in
control),
few
feces
(
16/
20
vs.
7/
20
in
control),
no
feces
(
6/
20
vs.
0/
20
in
control),
thin
appearance
(
6/
20
vs.
0/
20
in
control)
and
subdued
behavior
(
3/
20
vs.
1/
20
in
control).
Based
on
the
increased
mortality,
reduced
food
consumption,
and
clinical
toxicity,
the
Maternal
Toxicity
LOAEL
is
40
mg/
kg/
day.
The
Maternal
Toxicity
NOAEL
is
20
mg/
kg/
day.

There
was
evidence
of
possible
developmental
toxicity
of
PHMB
at
40
mg/
kg/
day,
in
the
form
of
reduced
numbers
of
litters
and
skeletal
abnormalities
(
non­
ossified
5th
sternebrae
and
fused
3rd,
4th,
and
5th
sternebrae).
The
incidence
of
non­
ossified
5th
sternebrae
was
found
in
12
(
10.1%)
of
fetuses
from
the
40
mg/
kg/
day
dose
group
vs.
6
(
3.3%)
in
control,
and
a
fused
4th
and
5th
sternebrae,
found
in
7
(
5.9%)
of
fetuses
and
6
(
46.2%)
of
litters
at
the
40
mg/
kg/
day
dose
level,
compared
to
1
(
0.6%)
fetus
and
1
(
5.3%)
litter
in
controls.
The
incidence
of
fetuses
and
litters
with
fused
3rd
and
4th
sterebrae
at
the
40
mg/
kg/
day
dose
is
5
(
4.2%)
of
fetuses
and
3
(
23.1%)
of
litters
vs.
1
fetus
(
0.6%)
and
1
litter
(
5.3%)
in
controls.
The
developmental
toxicity
NOAEL
is
20
mg/
kg/
day,
based
on
reduced
number
of
litters
and
skeletal
abnormalities;
the
developmental
toxicity
LOAEL
is
40
mg/
kg/
day.
Developmental
effects
occurred
at
doses
that
also
caused
maternal
toxicity.
Therefore,
the
data
indicate
that
developmental
toxicity
at
the
high
dose
was
related
to
maternal
toxicity
(
6
out
of
20
animals
died
in
the
group,
no
quantitative/
qualitative
evidence
of
increased
susceptibility
of
developmental
effects
in
this
study).
(
Note:
dosing
started
at
gestation
day
(
gd)
8
which
is
different
from
the
guideline
specifying
that
the
study
should
start
at
gd
6)

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.

There
was
no
evidence
of
quantitative
or
qualitative
susceptibility
in
the
multi­
generation
reproduction
study.

870.3800
Reproduction
and
Fertility
Effects
­
Rat
Executive
Summary:
In
a
multi­
generation
reproduction
study
(
MRID
43617401),
male
and
female
Alpk:
APfSD
rats
(
26
males/
dose;
26
females/
dose),
obtained
from
the
Barriered
Animal
Breeding
Unit
at
Zeneca
Pharmaceuticals,
Alderley
Park,
UK,
received
PHMB
(
20.2%
a.
i.)
in
the
diet
at
nominal
doses
of
0,
200,
600,
and
2000
ppm
(
23.0,
69.6,
and
238.9
mg/
kg/
day
for
F0
males;
25.3,
77.0
and
258.2
mg/
kg/
day
for
F0
females;
23.9,
71.3,
and
249.3
mg/
kg/
day
for
F1
males;
and
26.1,
79.2,
270.5
mg/
kg/
day
for
F0
[
note:
we
believe
this
to
be
a
typo
and
should
be
the
data
for
F1]
females).
The
rats
in
each
generation
received
test
diets
continuously
until
termination.
Systemic
toxicity
was
observed
at
the
2000
ppm
dose
level
in
the
F0
generation
as
indicated
by
a
decrease
in
group
body
weight
(
9­
10%)
and
food
efficiency
(
7%)
for
the
10­
week
pre­
mating
period.
The
weight
of
the
epididymides
and
kidneys
were
also
significantly
decreased
in
F0
generation
males.
There
were
no
corresponding
effects
in
the
F1
parental
generation
except
9
for
decreased
food
efficiency
(
15%)
in
females
for
weeks
5­
7
pre­
mating.
There
were
no
detrimental
effects
of
treatment
with
PHMB
on
reproduction
in
this
study,
but
it
is
noted
that
there
was
a
dose­
related
decrease
in
number
of
pup
deaths
on
days
1­
5
post­
partum
for
both
generations.

The
Parental
Systemic
Toxicity
NOAEL
is
600
ppm
(
69.6
mg/
kg/
day
[
F0
males];
77.0
mg/
kg/
day
[
F0
females];
71.3
mg/
kg/
day
[
F1
males];
79.2
mg/
kg/
day
[
F1
females]);
The
Parental
Systemic
Toxicity
LOAEL
is
2000
ppm
(
238.9
mg/
kg/
day
[
F0
males];
258.2
mg/
kg/
day
[
F0
females];
249.3
mg/
kg/
day
[
F1
males];
270.5
[
F1
females])
based
on
decreased
body
weight
and
food
efficiency
in
F0
males
and
females,
and
decreased
epididymis
and
kidney
weight
in
F0
males.

Reproductive/
Systemic
Toxicity
NOAEL
is
2000
ppm;
Reproductive/
Systemic
Toxicity
LOAEL
is
greater
than
2000
ppm.

This
study
is
classified
as
acceptable
and
satisfies
the
guideline
requirement
(
OPPTS
870.3800;
§
83­
4)
for
a
2­
generation
reproduction
study
in
rats.

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

There
were
multiple
effects
on
the
liver
of
both
sexes
in
the
rat
study.
Body
weight
decrement
was
also
noted
in
the
rat
study.
The
dog
study
showed
a
change
in
the
testes
and
liver
of
male
dogs
and
clinical
signs
of
toxicity
and
clinical
chemistry
alterations
in
a
female
dog.

870.4100a
(
870.4300)
Chronic
Toxicity/
Carcinogenicity
Study
 
Rat
Executive
Summary:
In
a
rat
chronic/
oncogenicity
study
(
MRID
44059301)
male
and
female
Alpk:
APfSD
Wistar
rats
(
64/
sex/
dose)
were
fed
diets
containing
PHMB
at
0,
200,
600,
or
2000
ppm
(
equivalent
to
0,
12.1,
36.3,
and
126.1
mg/
kg/
day
in
males
and
14.9,
45.3,
and
162.3
mg/
kg/
day
in
females)
for
2
years.
An
interim
sacrifice
of
12
rats/
sex/
dose
was
conducted
at
52
weeks.

At
the
high
dose
(
2000
ppm),
survival
was
decreased
in
females
by
25%
vs.
controls.
Body
weights
were
significantly
(
p<
0.01
or
0.05)
reduced
by
5­
8%
in
high­
dose
females
throughout
the
study.
In
high­
dose
males,
body
weights
were
significantly
(
p<
0.01
or
0.05)
reduced
vs.
controls
through
week
79.
Food
utilization
(
g
growth/
100
g
feed)
for
the
first
12
weeks
decreased
significantly
(
p<
0.01)
vs.
controls,
97­
8%
in
both
sexes
at
2000
ppm.

The
liver
was
the
target
organ
in
males
and
females.
Plasma
alkaline
phosphatase
activity
was
elevated
significantly
(
p<
0.01)
over
controls
843­
74%
in
females
from
the
main
study
dosed
at
2000
ppm;
in
2000
ppm
males,
the
enzyme
was
significantly
increased
by
36
and
27%
at
weeks
14
and
27.
In
females
at
2000
ppm
absolute
liver
weight
was
reduced
significantly
(
p<
0.05)
by
10
11%.
In
2000
ppm
males,
microscopic
observations
of
liver
hepatocyte
fat
and
spongiosis
were
844
and
22%
over
controls;
corresponding
increase
in
these
lesions
were
not
seen
in
females.
There
were
no
corroborating
gross
pathology
findings
of
the
liver
abnormalities.

For
chronic
toxicity,
the
LOAEL
for
PHMB
is
2000
ppm
(
126.1
and
162.3
mg/
kg/
day
for
males
and
females
respectively)
and
the
NOAEL
is
600
ppm
(
36.3
and
45.3
mg/
kg/
day).

Under
the
conditions
of
this
study,
PHMB
appears
to
have
the
potential
to
induce
vascular
neoplasms
in
female
rats
of
this
strain.
The
study
pathologist
and
study
peer
reviewer
observed
hemangiosarcomas
of
the
liver
in
3/
64
2000
ppm
females;
benign
hemangioma
was
not
observed.
The
increased
incidence
of
hemangiosarcoma
in
females
gave
positive
results
in
trend
analyses
(
p<
0.05).
A
single
observation
of
benign
hemangioma
was
made
in
each
of
the
control
and
high
dose
male
groups;
no
hemangiosarcoma
was
observed
in
males.
A
Pathology
Working
Group
(
PWG)
was
convened
to
confirm
the
diagnoses
of
the
vascular
neoplasms
(
MRID
44042801).
The
PWG
observed
hemangioma
(
2/
64)
and
hemangiosarcoma
(
1/
64)
in
2000
ppm
females
and
2/
64
hemangiomas
in
2000
ppm
males.
The
PWG
concluded
that
the
findings
of
vascular
neoplasms
in
high
dose
females
were
incidental.
However,
the
report
of
the
PWG
consensus
indicated
that
no
hemangiosarcoma
or
hemangioma
had
been
observed
in
female
controls
in
18
studies
with
the
same
strain
of
rat.
Furthermore,
there
was
a
significant
increase
(
p<
0.01
or
0.05)
in
hemangiosarcomas
in
both
sexes
in
a
mouse
oncogenicity
study
with
PHMB.
Therefore
it
is
concluded
that
PHMB
appears
to
induce
hemangiosarcomas
of
the
liver
in
female
Alpk:
APfSD
rats.
Liver
hemangiosarcomas
are
rare
in
this
strain
of
rat.

This
study
is
classified
as
acceptable
(
guideline
870.4300
§
83­
5)
and
satisfies
the
guideline
requirements
for
a
chronic/
oncogenicity
study
in
rats.

870.4100b
Chronic
Toxicity
­
Dog
Executive
Summary:
In
a
chronic
toxicity
study
(
MRID
43620501),
PHMB
was
administered
to
groups
of
4
male
and
female
Beagle
dogs
in
the
diet
initially
at
dose
levels
of
0,
300,
1500,
and
4500
ppm.
Following
an
unexpectedly
severe
reaction
in
3
of
4
males
at
4500
ppm
(
scrotal
skin
lesions),
3
of
4
males
were
killed
for
humane
reasons.
The
high
dose
was
discontinued
on
week
9
or
10,
and
then
recommenced
at
a
dose
of
3000
ppm
on
week
11
or
12.
Doses
received
in
the
study
were
0,
9,
46,
and
91
mg/
kg/
day
for
males
and
9,
45,
and
91
mg/
kg/
day
for
females
for
the
3000,
150
and
3000
ppm
dose
groups,
respectively.
Up
to
and
including
the
3000
ppm
dose,
there
were
no
consistent
effects
of
PHMB
on
body
weight,
weight
gain,
food
consumption,
or
hematological
parameters.
Plasma
alanine
aminotransferase
(
ALT)
activity
was
significantly
increased
in
male
and
female
dogs
at
the
3000
ppm
dose
level
beginning
at
week
8,
but
there
was
variability
in
the
response,
and
only
one
male
dog
was
available
for
measurement
after
week
10.
Testes
weight
was
decreased
29%
and
32%
for
the
left
and
right
testis
of
high
dose
male
dogs,
and
testicular
tubular
degeneration
was
observed
in
the
surviving
male
dog
as
well
as
in
one
dog
sacrificed
intercurrently.
Liver
weight
in
high
dose
male
dog
was
decreased
14%
at
the
high
dose,
and
microscopic
changes
of
the
liver
were
also
observed
in
male
dogs
at
the
high
dose.
In
one
female
dog
at
the
high
dose,
significant
clinical
signs
(
decreased
activity,
stiff/
splayed
gait,
slight
11
tremors)
were
observed
which
were
not
reversible.
In
addition,
plasma
alanine
aminotransferase
was
increased
almost
10­
fold
over
the
pre­
treatment
level
by
week
35
of
treatment.
Plasma
aspartate
aminotransferase
in
this
dog
was
almost
doubled
by
week
35
of
treatment.
Marked
dermatitis
of
the
limbs
was
also
observed
in
this
dog.
The
Systemic
Toxicity
LOAEL
is
3000
ppm
(
91
mg/
kg/
day)
for
male
and
female
dogs,
based
on
changes
in
testis
and
liver
weight
and
microscopic
observations
in
male
dogs
and
based
on
clinical
signs
of
toxicity
and
clinical
chemistry
alterations
in
the
female
dog.
The
Systemic
Toxicity
NOAEL
is
1500
ppm
(
46/
45
mg/
kg/
day,
male/
female)
for
male
and
female
dogs.

This
study
is
acceptable
and
satisfies
the
guideline
requirement
[
OPPTS
870.4100;
OPP
§
83­
1]
for
chronic
oral
toxicity
in
dogs.

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

The
combined
chronic/
carcinogenicity
study
in
rats
showed
an
apparent
increase
in
hemangiosarcomas
in
the
liver
of
female
rats.
The
mouse
study
showed
increased
hemangiosarcomas
and
squamous
cell
carcinomas
of
the
rectal­
anal
junction
in
both
sexes.

870.4200a
Carcinogenicity
Study
­
Rat
See
above
Chronic
toxicity/
Oncogenicity
study
rat
(
MRID
44059301)

870.4200b
Carcinogenicity
(
feeding)
­
Mouse
Executive
Summary:
In
a
mouse
oncogenicity
study
(
MRID
44074201),
PHMB
was
administered
to
C57B1/
10J
f
CD­
1/
Alpk
mice
(
55/
sex/
group)
at
0,
400,
1,200,
or
4,000
ppm
(
equivalent
to
55,
167,
or
715
mg/
kg/
day
for
males
and
69,
217,
or
856
mg/
kg/
day
for
females)
for
2
years.

At
the
1,200
ppm
level,
mice
were
observed
with
decreased
overall
body
weight
gains
(
males,
97%;
females
92%);
increases
in
hematology
parameters
(
p<
0.05)
including
hemoglobin
in
females
(
86%),
hematocrit
in
females
(
86%),
and
RBCs
in
females
(
85%);
decreased
absolute
weight
of
the
liver
in
males
(
915%)
and
in
females
(
921%);
increased
incidences
of
gross
pathological
changes
including
distended
caeca
in
females
(
4%
treated
vs.
0%
in
controls);
traumatized
pinnae
of
ears
in
males
(
36%
treated
vs.
4%
controls)
and
females
(
44%
treated
vs.
4%
controls);
and
increased
incidences
of
non­
neoplastic
lesions
including
luminal
dilatation
of
the
gall
bladder
in
females
(
9%
treated
vs.
2%
controls),
hepatocyte
hypertrophy
of
the
liver
in
males
(
13%
treated
vs.
0%
controls)
and
females
(
35%
treated
vs.
0%
controls),
ploidy
of
the
liver
in
males
(
13%
treated
vs.
0%
controls)
and
females
(
36%
treated
vs.
0%
controls),
pigmentation
of
the
liver
in
females
(
11%
treated
vs.
0%
controls),
and
inflammation
of
the
rectalanal
junction
in
males
(
44%
treated
vs.
2%
controls)
and
females
(
47%
treated
vs.
21%
controls).

At
the
4,000
ppm
dose
level,
decreased
overall
body
weight
gain
was
observed
in
males
12
(
950%)
and
females
(
932%);
increased
food
consumption
(
p<
0.05
or
0.01)
from
approximately
week
12
through
termination
in
males
(
87­
29%)
and
females
(
87­
26%);
decreased
food
utilization
(
p<
0.01)
during
weeks
1­
12
in
males
(
940%)
and
females
(
920%);
increased
hemoglobin
in
males
(
87%)
and
females
(
817%),
hematocrit
in
males
(
85%)
and
females
(
816%),
and
RBCs
in
males
(
810%)
and
females
(
817%);
decreased
weight
of
the
liver
in
males
(
20%)
and
females
(
30%);
decreased
weight
of
the
testes
of
males
(
915%)
and
in
adrenals
of
females
(
922%);
increased
incidences
of
gross
pathological
changes
including
swollen
anuses
in
males
(
18%
treated
vs.
0%
controls)
and
females
(
7%
treated
vs.
0%
controls),
distended
caeca
in
males
(
9%
treated
vs.
0%
controls)
and
females
(
13%
treated
vs.
0%
controls),
pinnae
of
ears
traumatized
in
males
(
27%
treated
vs.
4%
controls)
and
females
(
22%
treated
vs.
4%
controls),
distention
of
the
gall
bladder
in
males
(
49%
treated
vs.
11%
controls)
and
females
(
47%
treated
vs.
9%
controls);
liver
mass
in
males
(
48%
treated
vs.
20%
controls)
and
females
(
39%
treated
vs.
2%
controls);
epithelial
hyperplasia
of
the
gall
bladder
in
males
(
25%
treated
vs.
0%
controls)
and
females
(
13%
treated
vs.
0%
controls);
hepatocyte
hypertrophy
of
the
liver
in
males
(
53%
treated
vs.
0%
controls)
and
females
(
49%
treated
vs.
0%
controls);
increased
ploidy
of
the
liver
in
males
(
53%
treated
vs.
0%
controls)
and
females
(
38%
treated
vs.
0%
controls);
pigmentation
of
the
liver
in
males
(
36%
treated
vs.
0%
controls)
and
females
(
42%
treated
vs.
0%
controls);
and
inflammation
of
the
rectal­
anal
junction
in
males
(
82%
treated
vs.
2%
controls)
and
females
(
74%
treated
vs.
21%
controls).

Toxicity
observed
common
to
both
sexes
of
the
1,200
and
4,000
ppm
treatment
groups
included
decreased
overall
weight
gains,
pinnae
of
ears
traumatized,
hepatocyte
hypertrophy
of
the
liver,
increased
ploidy
of
the
liver,
and
inflammation
of
the
rectal­
anal
junction.
There
was
also
epithelial
hyperplasia
of
the
gall
bladder
common
to
females
of
both
treatment
groups
but
occurring
in
males
only
at
4,000
ppm.

No
treatment
related
effects
were
seen
in
mice
in
the
400
ppm
dose
group.

Based
on
decreased
body
weight
gains
and
non­
neoplastic
histopathological
changes
in
the
gall
bladder,
liver,
and
rectal­
anal
junction
of
mice
in
the
1,200
ppm
and
4,000
ppm
treatment
groups,
the
Systemic
Toxicity
LOAEL
in
male
and
female
mice
is
1,200
ppm
(
equivalent
to
55
mg/
kg/
day
in
males
and
69
mg/
kg/
day
in
females).
The
Systemic
Toxicity
NOAEL
is
400
ppm.

Carcinogenic
potential
was
evidenced
by
increased
incidence
of
hemangiosarcomas
and
hemangiomas
in
both
sexes
of
mice
in
the
4,000
ppm
treatment
group.
In
males
at
this
treatment
level
a
statistically
significant
(
p
<
0.01)
increase
was
observed
in
combined
incidence
of
hemangiosarcoma
and
hemangioma
combined
(
20/
53
animals
[
38%])
vs.
6/
55
in
control
(
11%).
In
females,
a
significant
increase
(
p
<
0.05)
in
combined
incidence
of
hemangioma
and
hemangiosarcoma
was
also
observed
at
this
dose
(
15/
49
vs.
8/
54
in
control).
Historical
control
incidence
of
angiosarcoma
in
all
tissues
within
this
strain
of
mouse
ranged
from
2­
15%
in
males
and
0­
9%
in
females.
Concurrent
control
incidences
of
hemangiosarcomas
were
within
the
historical
control
range.
The
earliest
hemangiosarcomas
occurred
at
39
and
42
weeks
in
males
and
females,
respectively.
Hemangiosarcoma
of
the
liver
was
a
statistically
significant
factor
contributing
to
the
death
of
male
and
female
mice
at
4,000
ppm
PHMB.
Treatment­
related
13
squamous
cell
carcinomas
of
the
rectal­
anal
junction
were
found
in
5/
49
(
10%)
males
and
8/
39
(
21%)
females
of
the
4,000
ppm
treatment
group.
Two
males
in
the
4,000
treatment
group
had
papillomas
in
the
gall
bladder,
with
none
in
controls
or
at
other
treatment
levels.
No
treatmentrelated
carcinogenic
effects
were
observed
at
400
or
1,200
ppm.
Based
on
the
study
results,
carcinogenic
effects
(
vascular
system
and
anus)
were
observed
for
male
and
female
mice
at
dietary
levels
of
4,000
ppm
PHMB
(
equivalent
to
715
mg/
kg/
day
in
males
and
856
mg/
kg/
day
in
females).

Dosing
was
considered
to
be
excessive
at
the
high
dose
of
4000
ppm
based
on
decreased
overall
body
weight
gains
of
50%
in
males
and
32%
in
females
at
termination.
In
addition,
decreased
body
weight
gains
of
33%
in
males
and
19%
in
females
at
13
weeks.
The
study
indicated
that
the
animals
at
the
4000
ppm
dose
group
had
increased
food
consumption
(
p<
0.05
or
0.01)
from
approximately
week
12
through
termination
in
males
(
87­
29%)
and
females
(
87­
26%).

Dosing
was
considered
to
be
adequate,
but
not
excessive,
in
both
males
and
females
at
the
mid­
dose
of
1200
ppm
based
on
decreased
overall
body
weight
gains
(
males,
7%;
females,
2%),
and
increases
in
hematology
parameters,
and
non­
neoplastic
histopathological
changes
in
the
gall
bladder,
liver,
and
rectal­
anal
junction.

This
study
is
classified
as
acceptable
and
satisfies
the
guideline
requirements
for
a
carcinogenicity
study
[
OPPTS
870.4200
(
§
83­
2b)]
in
the
mouse.

870.4200b
Carcinogenicity
(
dermal)
­
Mouse
Executive
Summary:
In
an
80­
week
skin
painting
study
(
MRIDs
00066475,
00104796),
four
groups
of
specific
pathogen
free
(
50/
dose/
sex)
Alderley
Park
mice
received
dermal
applications
of
0.3
mL
of
the
test
material
at
doses
of
0
(
solvent
in
ethanol),
0.6
mg
(
0.2%
PHMB
in
ethanol),
6.0
mg
(
2%
PHMB
in
ethanol)
and
30.0
mg
(
10%
PHMB
in
ethanol)
per
day,
five
days
a
week
for
a
period
of
80
weeks.
The
treatment
dosages
are
equivalent
to
0,
15,
150,
and
750
mg/
kg­
day
of
20%
PHMB
solutions.

Mice
that
received
the
highest
dose
level
of
PHMB
(
750
mg/
kg­
day)
showed
a
poorer
health
status,
appearing
very
thin
throughout
the
experiment.
Mortality
in
both
male
and
female
mice
in
the
highest
dose
group
was
slightly
higher
than
in
other
groups
during
the
first
year.
This
pattern
continued
throughout
the
remainder
of
the
study
resulting
in
a
high
mortality
rate
(
75%
in
males
and
females)
in
the
highest
dose
animals
at
termination,
compared
with
approximately
30%
in
the
other
groups.
The
highest
dose
level
of
PHMB
resulted
in
noticeable
irritation
to
the
skin
of
both
males
and
females
immediately
after
application.
Erythema
and
some
clumping
of
the
growing
fur
were
noticed
during
the
first
few
weeks
and
after
the
4th
week,
hyperkeratosis
became
evident
especially
in
males.
No
differences
were
apparent
between
the
controls
and
those
mice
receiving
0.6
or
6.0
mg
PHMB
per
mouse
per
application.
A
significant
reduction
in
mean
body
weight
was
observed
for
both
male
and
female
animals
that
received
the
highest
dose
level.
There
were
no
overall
differences
in
food
consumption
between
the
control
and
treatment
groups.
14
Therefore,
the
systemic
toxicity
NOAEL
was
150
mg/
kg­
day
and
the
LOAEL
was
750
mg/
kg­
day
based
on
increased
mortality
and
decreased
body
weight
in
male
and
female
mice
receiving
PHMB
(
20%
a.
i.).

There
were
no
compound­
related
tumors
observed
in
male
mice.
Female
mice
had
significant
increasing
trends
in
liver
angiosarcomas
(
p<
0.01)
and
vascular
tumors
from
all
sites
combined
(
p<
0.05).
There
was
a
significant
difference
in
the
pair­
wise
comparison
of
the
30
mg
dose
group
with
the
controls
for
liver
angiosarcomas
at
p<
0.05.
The
statistical
analyses
of
the
female
mice
were
based
on
Peto's
prevalence
test.

The
HED
Cancer
Assessment
Review
Committee
considered
the
tumor
increase
at
the
high
dose
to
be
equivocal
since
tumors
were
observed
at
an
excessive
dose.
Vascular
tumors
were
not
seen
at
lower
doses.
Dosing
was
considered
to
be
excessive
at
the
high
dose
(
750
mg/
kg/
day
of
20%
PHMB
equivalent)
in
both
sexes
due
to
increased
mortality
(
78%,
high
dose,
versus
33%
and
28%
in
the
male
and
female
controls,
respectively)
and
decreased
body
weight
gain.
Overall
body
weight
gain
decreases
of
45%
and
17%
were
seen
in
males
and
females,
respectively.
No
treatment­
related
effects
were
noted
at
the
mid­
dose
level
of
150
mg/
kg/
day
of
20%
PHMB
equivalent.

This
carcinogenicity
study
is
classified
as
acceptable­
non­
guideline.
Although
this
nonguideline
(
dermal
painting)
study
does
not
fulfill
any
toxicity
guideline
requirement,
it
does
provide
useful
information
for
assessing
the
carcinogenic
potential
of
PHMB
and
should
be
evaluated
in
conjunction
with
the
1996
and
2002
guideline
PHMB
carcinogenicity
studies
(
MRID
44059301,
44042801,
44074201,
and
45710802).

4.7
Mutagenicity
Adequacy
of
database
for
mutagenicity:
The
following
assays
used
PHMB
at
19.6%
(
a.
i.).
The
database
for
mutagenicity
is
considered
adequate
based
on
1991
mutagenicity
guidelines
(
note:
assays
were
conducted
before
1991,
but
appear
to
meet
1991
guidelines).

There
is
no
evidence
that
Vantocil
IB
induced
any
genotoxicity.

Gene
Mutation
Guideline
OPPTS
870.5100
[
§
84­
2],
Microbial
gene
mutation
assy
MRID
41687004
This
study
is
classified
as
acceptable
and
satisfies
the
guideline
requirement
for
a
microbial
gene
mutation
assay
(
§
84­
2).
In
two
independently
performed
assays,
Salmonella
typhimurium
strains
TA1535,
TA1537,
TA1538,
TA98,
and
TA100
were
exposed
to
0.32­
500
µ
g/
plate
Vantocil
IB
(
19.6%
a.
i.)
in
the
absence
or
presence
of
S9
activation.
Additional
testing
was
carried
out
using
comparable
doses
with
and
without
S9
in
TA1537
and
TA98.
The
S9
fraction
was
derived
from
Aroclor
1254­
induced
rat
livers
and
the
test
material
was
delivered
to
the
nonactivated
and
S9­
activated
positive
controls.
There
was,
however,
no
evidence
that
Vantocil
IB
induced
a
mutagenic
response
in
any
strain
at
any
nonactivated
or
S9­
activated
dose.
15
Cytogenetics
Guideline
OPPTS
870.5395
[
§
84­
2],
Mouse
micronucleus
assay
MRID
#
41096901/
41404503
Study
is
classified
as
acceptable
and
satisfies
the
requirements
for
FIFRA
Test
Guideline
84­
2
for
a
micronucleus
assay.

Guideline
OPPTS
870.5375
[
§
84­
2],
In
vitro
cytogenetic
assay
with
human
lymphocytes
MRID
#
41404501/
42149905
This
study
is
classified
as
acceptable
and
satisfies
the
guideline
requirement
for
an
in
vitro
cytogenetic
study.
In
a
mouse
micronucleus
assay
(
MRID
#
41096901/
41404503),
groups
of
five
male
and
five
female
C57BL/
6JfCD­
1/
Alpk
mice
received
single
oral
gavage
administrations
of
250
or
400
mg/
kg
Vantocil
IB
(
19.6%
a.
i.)
prepared
in
deionized
water.
Mice
in
the
high­
dose
group
were
sacrificed
at
24,
48,
and
72
hours
post­
administration
and
harvested
bone
marrow
cells
were
examined
for
the
incidence
of
micronucleated
polychromatic
erythrocytes
(
MPEs).
Low­
dose
animals
were
sacrificed
at
24
hours.
Two
animals
receiving
400
mg/
kg
died
prior
to
the
scheduled
sacrifice.
There
was
also
clear
evidence
of
target
cell
cytotoxicity
in
the
high­
dose
males
and
females
at
all
sacrifice
intervals.
The
positive
control
induced
the
expected
high
yield
of
MPEs
in
males
and
females.
Vantocil
IB
did
not,
however,
induce
a
clastogenic
or
aneugenic
effect
in
either
sex
at
any
dose
or
sacrifice
time.

In
an
in
vitro
mammalian
cell
cytogenetic
assay
(
MRID
#
41404501/
42149905),
human
lymphocytes
derived
from
male
and
female
donors
were
exposed
to
Vantocil
IB
(
19.6%
a.
i.
in
water)
doses
of
5,
25,
or
50
µ
g/
mL
without
S9
activation
(
both
donors)
and
levels
of
25,
100,
or
187.5
µ
g/
mL
(
male
donor)
or
25,
100,
250
µ
g/
mL
(
female
donor)
with
S9
activation
for
approximately
2.5­
3.5
hours.
The
S9
liver
homogenate
was
derived
from
Aroclor
1254
induced
Sprague­
Dawley
rat
livers,
and
the
test
material
was
delivered
to
the
test
system
in
physiological
saline.
A
50%
reduction
in
the
mitotic
index
occurred
at
50
µ
g/
mL
­
S9
(
both
donors)
and
at
100
µ
g/
mL
+
S9
(
male
donors)
or
at
250
µ
g/
mL
(
female
donors).
The
positive
controls
induced
the
expected
high
yield
of
chromosome
aberrations
in
the
lymphocytes
derived
from
the
male
and
female
donors.
There
was,
however,
no
evidence
that
Vantocil
IB
induced
a
clastogenic
effect.

Other
Mechanisms
of
Genotoxicity
Guideline
OPPTS
870.5550
[
§
84­
2],
In
vivo/
In
vitro
unscheduled
DNA
synthesis
assay
in
primary
rat
hepatocytes
MRID
#
41404502/
42149903
This
study
is
classified
as
acceptable
and
satisfies
the
guideline
requirement
for
a
UDS
assay
(
§
84­
4).
In
two
independently
performed
in
vivo/
in
vitro
unscheduled
DNA
synthesis
(
UDS)
assays
(
MRID
#
41404502/
42149903),
groups
of
two
to
three
male
rats
were
administered
single
oral
gavage
doses
of
750
or
1500
mg/
kg
Vantocil
IB
(
19.6%)
prepared
in
deionized
water.
Animals
were
sacrificed
at
4
and
12
hours
post­
treatment
and
recovered
hepatocytes
were
scored
for
UDS.
Clinical
toxicity
(
i.
e.,
excessive
salivation
and
subdued
nature)
was
observed
at
1500
mg/
kg;
higher
levels
were
lethal.
No
cytotoxicity
for
the
target
organ
was
seen
at
either
level.
The
positive
control
induced
the
expected
high
yield
of
hepatocytes
with
net
nuclear
grains.
There
was,
however,
no
evidence
that
the
Vantocil
IB
induced
a
genotoxic
response
at
either
dose
or
sacrifice
time.

4.8
Neurotoxicity
Adequacy
of
database
for
neurotoxicity:
No
indication
of
neurotoxicity,
neuropathology,
or
histopathology
of
the
nervous
system
has
been
reported
in
the
available
studies.
No
neurotoxicity
data
are
required.
16
870.6100
Delayed
Neurotoxicity
Study
­
Hen
Not
required
since
PHMB
is
not
an
organophosphate.

870.6300
Developmental
Neurotoxicity
Study
This
study
is
not
required
because
there
is
no
evidence
PHMB
will
induce
neurotoxic
effects.
In
addition,
there
is
no
quantitative
or
qualitative
evidence
of
increased
susceptibility
of
the
fetus
following
in
utero
exposure
in
the
prenatal
developmental
toxicity
studies
or
in
the
offspring
when
exposed
to
adults
in
the
two
generation­
reproduction
study.
Therefore,
PHMB
will
not
cause
an
FQPA
concern.

4.9
Metabolism
Adequacy
of
database
for
metabolism:
The
database
for
metabolism
is
considered
to
be
complete.
No
additional
studies
are
required
at
this
time.

870.7485
Metabolism
­
Rat
Executive
Summary:
Bioavailability
of
PHMB
was
investigated
in
male
and
female
Sprague­
Dawley
rats
fed
diets
of
200
ppm
or
2000
ppm
(
10
and
100
mg/
kg
nominal
dose)
for
fourteen
days
followed
by
a
single
radiolabelled
dose
of
either
0.08
mg/
kg
(
MRID
43567001
and
43599901),
or
after
a
single
100
mg/
kg
dose
(
MRID
00077926
and
00086363).
In
both
studies,
feces
represented
the
major
route
of
excretion
at
all
dose
levels,
comprising
greater
than
90%
of
the
administered
dose.
A
similar
excretion
in
feces
was
observed
in
bile­
cannulated
rats
after
a
single
radiolabelled
dose
of
20
mg/
kg
(
MRID
43567001).
Thus,
fecal
excretion
of
PHMBderived
radioactivity
represents
unabsorbed
test
material.
The
excretion
pattern
of
low,
mid,
and
high
molecular
weight
fractions
of
PHMB
was
similar.
Bioavailability
was
4.7%
and
3.9%
for
males
and
females,
respectively,
at
the
10
mg/
kg
dose,
and
3.9%
and
2.6%
for
males
and
females,
respectively,
at
the
100
mg/
kg
dose.
Tissue
distribution
in
rats
given
10
mg/
kg
PHMB
showed
concentrations
in
the
liver
and
kidney
of
male
rats
to
be
0.568
µ
g/
g
and
0.499
µ
g/
g,
respectively.
As
a
percentage
of
the
dose,
liver
of
male
and
female
rats
contained
0.18%
and
0.19%
of
the
dose,
respectively,
while
kidneys
contained
0.03%
and
0.04%
of
the
dose,
respectively.
Metabolite
analysis
of
pooled
urine
from
rats
administered
a
low
molecular
weight
fraction
of
PHMB
at
20
mg/
kg
(
the
fraction
showing
the
greatest
absorption)
revealed
the
presence
of
more
than
one
metabolite
but
identification
was
not
performed
due
to
the
small
amount
sample
available
for
analysis.

The
studies
when
taken
together
are
acceptable,
and
satisfy
the
§
85­
1
guideline
[
OPPTS
870.7485]
requirement.
17
5.0
TOXICITY
ENDPOINT
SELECTION
5.1
See
Section
8.2
for
Endpoint
Selection
Table.

5.2
Dermal
Absorption
A
value
for
dermal
absorption
was
not
needed
for
PHMB
based
on
the
selection
of
dermal
endpoints
from
a
route­
specific
(
dermal)
toxicity
study.

5.3
Classification
of
Carcinogenic
Potential
5.3.1
In
accordance
with
the
EPA
Draft
Guidelines
for
Carcinogen
Risk
Assessment
(
July
1999),
the
CARC
classified
PHMB
into
the
category
"
Suggestive
Evidence
of
Carcinogenicity,
but
Not
Sufficient
to
Assess
Human
Carcinogenic
Potential"
by
the
oral
and
dermal
routes.
The
weight­
of­
the­
evidence
considerations
for
this
classification
are
as
follows:

(
i)
A
treatment­
related
statistically
significant
increase
(
trend
and
pair­
wise)
in
vascular
tumors
(
mainly
benign)
was
seen
in
female
rats
at
an
oral
dose
that
was
considered
to
be
adequate,
but
not
excessive.
This
was
considered
as
the
strongest
evidence
in
the
CARC's
evaluation
of
PHMB.

(
ii)
Oral
exposure
to
male
and
female
mice
also
resulted
in
treatment­
related
vascular
tumors
seen
at
an
excessive
dose.
However,
at
the
next
highest
dose
level,
which
was
considered
adequate
but
not
excessive,
there
was
a
slight,
but
not
statistically
significant,
increase
in
this
same
tumor,
which
added
to
the
CARC's
concern
for
this
tumor
type.

(
iii)
It
is
noted
that
dermal
exposure
to
female
mice
resulted
in
an
equivocal
increase
in
vascular
tumors
seen
at
only
an
excessive
dose.

(
iv)
No
treatment­
related
increase
in
any
tumors
was
seen
in
male
rats
via
the
oral
route
or
in
male
mice
via
the
dermal
route
of
exposure.

Based
on
the
above,
the
Agency
has
determined
that
the
quantification
of
human
cancer
risk
is
not
required.

6.0
FQPA
CONSIDERATIONS
6.1
Special
Sensitivity
to
Infants
and
Children
There
is
no
qualitative
or
quantitative
evidence
of
increased
susceptibility
of
rabbit,
mice
or
rat
fetuses
in
utero
exposure
in
developmental
studies.

There
is
no
qualitative
or
quantitative
evidence
of
increased
susceptibility
in
multigeneration
reproduction
study
in
rats.
18
6.2
Recommendation
for
a
Developmental
Neurotoxicity
Study
PHMB
does
not
raise
an
FQPA
concern,
because
there
is
no
evidence
PHMB
will
induce
neurotoxic
effects.
There
is
no
quantitative
or
qualitative
evidence
of
increased
susceptibility
to
fetus
following
in
utero
exposure
in
the
prenatal
developmental
toxicity
studies
or
in
the
offspring
when
adults
are
exposed
in
the
two­
generation
reproductive
study.
19
7.0
REFERENCES
(
in
MRID
order)

MRID
00030330
Central
Toxicology
Laboratory.
Report
No.
CTL/
T/
1361.
January
1,
1979.
acute
oral
MRID
00046789/
00065120
Imperial
Chemical
Industries.
Report
No.
TR/
558.
October
26,
1966.
acute
eye
and
dermal
irritant
MRID
00053460
Griffiths,
D.,
M.
J.
Hayes,
and
T.
F.
McElligott
(
1966).
Ninety­
Day
Oral
Toxicity
of
Antibacterial
9073 
Albino
Rats.
Industrial
Hygiene
Research
Labs.
Report
No.
IHR/
199.
August
1,
1966.
Unpublished
MRID
00053461
Griffiths,
D.,
M.
J.
Hayes,
and
T.
F.
McElligott
(
1966).
Ninety­
Day
Oral
Toxicity
of
Antibacterial
9073 
Beagle
Dogs.
Industrial
Hygiene
Research
Labs.
Report
No.
IHR/
202.
September
1,
1966.
Unpublished.

MRID
00065124
Trueman,
R.
W.
and
D.
Eaton
(
1977).
Baquacil
SB:
Acute
Dermal
Toxicity
and
Skin
Irritation
Effects.
Central
Toxicology
Laboratory.
Imperial
Chemical
Industries
Ltd.,
England.
Report
No.
CTL/
T/
1057.
October
6,
1977.
Unpublished.

MRID00065131
Hodge,
M.
C.
E.
and
S.
Palmer
(
1976).
Baquacil
SB:
A
tertology
Study
in
the
Rat
by
Dietary
Administration.
ICI
Central
Toxicology
Laboratory.
Report
No.
CTL/
P/
262.
July
1,
1976.
Unpublished
MRID
00066475/
00104796
Ishmael,
J.
and
T.
M.
Weight.
Polyhexamethylene
Biguanide
(
PHMB)
80
Week
Mouse
Skin
Painting
Study:
Incidence
of
Tumors
in
the
Liver.
Imperial
Chemical
Industries
Limited,
Central
Toxicology
Laboratory.

MRID
00077926
Bratt,
H.
(
1977).
Vantocil
IB:
Absorption
and
Excretion
Studies
in
the
Rat.
ICI
Americas,
Inc.
Wilmington,
DE.
Report
No.
CTL/
P/
163B.
Unpublished.

MRID
00086362
Trutter,
J.
A.
and
D.
R.
Patterson
(
1977).
26­
week
Toxicity
study
in
Dogs:
20%
PHMB.
Final
report.
Hazelton
Laboratories
America
Inc.
Report
No.
458­
123.
June
30,
1977.
Unpublished
MRID
00086363
Bratt,
H.
(
1975).
Vantocil
IB:
Absorption
and
Excretion
Studies
in
the
Rat.
ICI
Americas,
Inc.
Wilmington,
DE.
Report
No.
CTL/
P/
163B.
March
10,
1975.
Unpublished.
20
MRID
41096901/
41404503
Randall,
V.
and
S.
L.
Beck
(
1989).
"
Vantocil"
IB:
An
Evaluation
in
the
Mouse
Micronucleus
Test
(
Original
Report)
MRID
#
41096901;
"
Vantocil"
IB:
An
Evaluation
in
the
Mouse
Micronucleus
Test
(
Addendum)
MRID
#
41404503.
ICI
Central
Toxicology
Laboratory.
Alderely
Park,
Nr.
Macclesfield,
Cheshire,
UK.
Study
No.
CTL/
P/
2436.
April
14,
1989.
Unpublished.

MRID
41404501/
42149905
Howard,
C.
A.
(
1989).
Vantocil
IB:
An
Evaluation
in
the
In
vivo
Cytogenetic
Assay
in
Human
Lymphocytes.
ICI
Central
Toxicology
Laboratory.
Alderely
Park,
Nr.
Macclesfield,
Cheshire,
UK.
Report
No.
CTL/
P/
2582.
July
26,
1989.
Unpublished.

MRID
41404502/
42149903
Trueman,
R.
W.
(
1989).
Vantocil
IB:
An
Assessment
for
the
Induction
of
Unscheduled
DNA
Synthesis
in
Rat
Hepatocytes
In
vivo;
ICI
Central
Toxicology
Laboratory.
Alderely
Park,
Macclesfield,
Cheshire,
UK.
Study
No.
CTL/
P/
2603.
August
29,
1989.
Unpublished.

MRID
41687004
Callander,
R.
D.
(
1989).
Vantocil
IB:
An
Evaluation
in
the
Salmonella
Mutation
Assay.
ICI
Central
Toxicology
Laboratory.
Alderely
Park,
Macclesfield,
Cheshire,
UK.
Report
No.
CTL/
P/
2406.
June
7,
1989.
Unpublished.

MRID
42674201
Duerden,
L.
(
1993).
Polyhexamethlyene
Biguanide:
Skin
Sensitization
to
the
Guinea
Pig
of
a
20%
Aqueous
Solution.
Zeneca
Inc.
Wilmington,
DE.
Study
Nos.
GG5741/
GG5694.
February
10,
1993.

MRID
42865901
Brammer,
A.
(
1993).
Polyhexamethylene
Biguanide:
Developmental
Toxicity
Study
in
the
Rabbit.
Zeneca
Central
Toxicology
Lab.
Lab
Project
No.
CTL/
P/
3997.
Study
No.
RB0614.
July
14,
1993.
Unpublished
MRID
430477­
01
Lees,
D.
and
A.
M.
Leah
(
1993).
PHMB:
21­
Day
Dermal
Toxicity
Study
in
the
Rat.
Study
performed
by
Zeneca
Central
Toxicology
Laboratory.
Alderley
Park,
Macclesfield,
Cheshire,
UK.
Study
number
LR0559.
Completed
on
November
25,
1993.

MRID
43567001
Lythgoe,
R.
E,
E.
F.
Howard,
and
E.
Prescott
(
1995).
PHMB:
Absorption,
Distribution,
Metabolism,
and
Excretion
Following
Single
Oral
Dosing.
Zeneca
Central
Toxicology
Laboratory.
Alderley
Park,
Macclesfield,
Cheshire,
UK.
Lab
Project
No.
URO
360.
February
22,
1995.
Unpublished.

MRID
43599901
Lythgoe,
R.
E
and
E.
F.
Howard
(
1995).
PHMB:
Bioavailability
Following
21
Dietary
Administration
in
the
Rat.
Zeneca
Central
Toxicology
Laboratory.
Alderley
Park,
Macclesfield,
Chesire,
UK.
Lab
Project
No.
URO
468.
March
22,
1995.
Unpublished.

MRID
43617401
Milburn,
G.
M.
(
1995).
Polyhexamethylene
Biguanide:
Multi­
generation
Study
in
the
Rat.
Study
performed
by
Zeneca
Central
Toxicology
Laboratory.
Alderley
Park,
Macclesfield,
Cheshire,
UK.
Study
Nos.
RR0621/
F0;
RR0621/
F1.
Study
completed
on
March
8,
1995.
Unpublished.

MRID
43620501
Horner,
S.
A.
(
1995).
Polyhexamethylene
Biguanide:
1
Year
Dietary
Toxicity
Study
in
Dogs.
Study
performed
by
Zeneca
Central
Toxicology
Laboratory.
Alderley
Park,
Macclesfield,
Cheshire,
UK.
Report
number
CTL/
P/
4488;
Study
number
PD0947.

MRID
44042801
Busey,
W.
M.
(
1996)
Polyhexamethylene
Biguanide
(
PHMB):
Two
Year
Feeding
Study
in
Rats.
Pathology
Working
Group
Peer
Review
of
Proliferative
Vascular
Lesions
in
Male
and
Female
rats.
Zeneca
CTL,
Alderley
Park,
Macclesfield,
Cheshire,
UK.
Study
No.
PR0936,
Report
No.
CTL/
C/
3172.
May
13,
1996.
Unpublished.

MRID
44059301
Horner,
S.
A.
(
1996).
Polyhexamethylene
Biguanide:
Two
Year
Feeding
Study
in
rats.
Study
performed
by
Zeneca
Central
Toxicology
Laboratory.
Alderley
Park,
Macclesfield,
Cheshire,
UK.
Laboratory
Report
No.
CTL/
P/
4663,
Study
No.
PR0936.
June
5,
1996.
Unpublished.

MRID
44074201
Milburn,
G.
M.
(
1996).
Polyhexamethylene
Biguanide:
Two
Year
Oncogenicity
Study
in
Mice.
Zeneca
Central
Toxicology
Laboratory.
Alderley
Park,
Macclesfield,
Cheshire,
UK.
SK10
4TJ.
Laboratory
Study
No.
PM0937.
June
21,
1996.
Unpublished.
22
8.0
APPENDICES
Tables
for
Use
in
Risk
Assessment
23
8.1
Toxicity
Profile
Summary
Tables
8.1.1
Acute
Toxicity
Table
­
See
Section
4.1
8.1.2
Subchronic,
Chronic,
and
Other
Toxicity
Tables
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification/
Doses
Results
870.3100
90­
Day
oral
toxicity
rodents
00053460
(
1966)
Supplementary
0,
2500,
5000
ppm
NOAEL
and
LOAEL
were
not
established
due
to
inadequate
data.

870.3150
90­
Day
oral
toxicity
in
nonrodents
00053461
(
1966)
Minimum
0,
5500,
11000
ppm
NOAL
=
5500
ppm
LOAEL
=
11,000
ppm
based
on
slight
hemosiderosis
in
males,
decrease
total
body
weight
gain
in
females.

870.3200
21/
28­
Day
dermal
toxicity
430477­
01
(
1993)
Core
minimum/
guideline
0,
20,
60,
and
200
mg/
kg/
d
NOAL
=
20
mg/
kg/
day
LOAEL
=
60
mg/
kg/
day
based
on
the
increased
incidence
erythema,
edema,
and
scabbing.

870.3250
90­
Day
dermal
toxicity
This
study
is
satisfied
by
the
80­
week
dermal
carcinogenicity
study
in
mice,
which
will
be
used
for
dermal
non­
cancer
risk
assessment
870.3465
90­
Day
inhalation
toxicity
No
appropriate
route­
specific
study
was
available.
An
older
study
conducted
with
Vantocil
B
contained
many
deficiencies.

870.3700a
Prenatal
developmental
in
rodents
00065131
(
1979)
minimum/
guideline
0,
200.
1000,
2000
ppm
0,
17.2,
86.2,
172.4
mg/
kg/
d
Maternal
NOAEL
=
17.2
mg/
kg/
day
LOAEL
=
86.2
mg/
kg/
day
based
on
reduced
body
weight
and
reduced
food
consumption.
Developmental
NOAEL
=
86.2
mg/
kg/
day
LOAEL
=
172.4
mg/
kg/
day
based
on
increased
incidence
of
extra
ribs
in
the
fetuses.

870.3700b
Prenatal
developmental
in
nonrodents
42865901
(
1993)
minimum
0,
10,
20,
40
mg/
kg/
day
Maternal
NOAEL
=
20
mg/
kg/
day
LOAEL
=
40
mg/
kg/
day
based
on
increased
mortality,
reduced
food
consumption,
and
clinical
toxicity.
Developmental
NOAEL
=
20
mg/
kg/
day
LOAEL
=
40
mg/
kg/
day
based
on
reduced
number
of
litters
and
skeletal
abnormalities.
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification/
Doses
Results
24
870.3800
Reproduction
and
fertility
effects
43617401(
1995)
acceptable/
guideline
1,
200,
600,
2000
ppm
F0
males
23.0,
69.6,
238.9
mg/
kg/
d
F0
females
25.3,
77.0,
258.2
mg/
kg/
d
F1
male
23.9,
71.3,
249.3
mg/
kg/
d
F1
female
26.1,
79.2,
270.5
mg/
kg/
day
Parental/
Systemic
NOAEL
=
600
ppm
LOAEL
=
2000
ppm
based
on
decreased
body
weight
and
food
efficiency
in
F0
males
and
females
and
decreased
epididymis
and
kidney
weight
in
F0
males.
Reproductive
NOAEL
=
2000
ppm
LOAEL
not
observed.
Offspring
NOAEL
=
2000
mg/
kg/
day
870.4100a
Chronic
toxicity
rodents
44059301/
44042801
(
1996)
acceptable/
guideline
0,
200,
600,
2000
ppm
male
0,
12.1,
36.3,
126.1
mg/
kg/
day
female
14.9,
45.3,
162.3
mg/
kg/
day
NOAEL
=
600
ppm
LOAEL
=
2000
ppm
based
on
decreased
survival,
reduced
body
weight,
and
decreased
food
utilization
in
females
and
decreased
body
weight
and
decreased
food
utilization
in
males.

870.4100b
Chronic
toxicity
dogs
43620501
(
1995)
acceptable/
guideline
0,
300,
1500,
4500
ppm
0,
9,
46,
91
mg/
kg/
day
for
males,
,
45
and
91
mg/
kg/
day
for
females.
4500
ppm
reduced
to
3000
ppm
(
91mg/
kg/
day)
on
week
11­
12.
NOAEL
=
46/
45
mg/
kg/
day
for
males/
females
LOAEL
=
91
mg/
kg/
day
based
on
changes
in
testis,
liver
weight,
and
microscopic
observations
in
males
and
clinical
signs
of
toxicity
and
clinical
chemistry
alterations
in
females.

870.4200
Carcinogenicity
rats
44059301/
44042801
(
1996)
acceptable/
guideline
0,
200,
600,
2000
ppm
male
0,
12.1,
36.3,
126.1
mg/
kg/
day
female
14.9,
45.3,
162.3
mg/
kg/
day
NOAEL
=
600
ppm
LOAEL
=
2000
ppm
based
on
decreased
survival,
reduced
body
weight,
and
decreased
food
utilization
in
females
and
decreased
body
weight
and
decreased
food
utilization
in
males.
Vascular
tumors
at
126/
162
mg/
kg/
day
870.4300
Carcinogenicity
mice
(
oral)
44074201(
1996)
acceptable/
guideline
0,
400,
1,200,
4000
ppm
male
55,
167,
715
mg/
kg/
d
female
69,
217,
856
mg/
kg/
d
NOAEL
=
400
ppm
LOAEL
=
1,200
ppm
based
on
decreased
body
weight,
nonneoplastic
histopathological
changes
in
gall
bladder,
liver,
and
rectal­
anal
junction.
Vascular
tumors
and
rectal­
anal
tumors
at
715/
856
mg/
kg/
day
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification/
Doses
Results
25
870.4300
Carcinogenicity
mice
(
dermal)
93191028,
00066475,
00104796
(
1990)
acceptable/
non­
guideline
0,
15,
150,
and
750
mg/
kg/
day
PHMB
NOAEL
=
150
mg/
kg/
day
LOAEL
=
750
mg/
kg/
day
based
on
increased
mortality
and
decreased
body
weight
in
male
and
female
mice
receiving
PHMB.
Vascular
tumors
at
750
mg/
kg/
day
Gene
Mutation
870.5265
Microbial
gene
mutation
assay
41687004
(
1996)
acceptable
3.3,
10,
33.3,
100,
333.3
µ
g/
plate
No
evidence
of
mutagenic
response
Cytogenetics
870.5395
Micronucleus
Assay
870.5375
Cytogenetic
assay
with
human
lymphocytes
41096901/
41404503
(
1989)
acceptable/
guideline
250,
400
mg/
kg
41404501/
42149905
(
1989)
acceptable/
guideline
5,
25,
50
µ
g/
mL
­
S9
male
25,
100,
187.5
µ
g/
mL
+
S9
female
25,
100,
250
µ
g/
mL
+
S9
No
evidence
of
clastogenic
or
aneugenic
effects
No
evidence
of
clastogenic
effects
Other
Effects
870.5550
Unscheduled
DNA
synthesis
assay
in
rat
hepatocytes
41404502/
42149903
(
1989)
acceptable/
guideline
750,
1500
mg/
kg
No
evidence
of
a
genotoxic
response
870.6300
Developmental
neurotoxicity
Not
required;
no
evidence
of
neurotoxicity,
no
evidence
of
selective
developmental
or
reproductive
toxicity
to
offspring
870.7485
Metabolism
and
pharmaco­
kinetics
435999­
01,
435670­
01,
00077926,
and
00086363
(
1975&
1995)
together
they
are
acceptable/
guideline
200,
2000
ppm
10,
100
mg/
kg
Metabolite
analysis
of
pooled
urine
from
rats
administered
a
low
molecular
weight
fraction
of
PHMB
at
20
mg/
kg
(
the
fraction
showing
the
greatest
absorption)
revealed
the
presence
of
more
than
one
metabolite
but
identification
was
not
performed
due
to
the
small
amount
of
sample
available
for
analysis.
26
8.2
Summary
of
Toxicological
Dose
and
Endpoints
for
PHMB
for
Use
in
Human
Risk
Assessment1
Exposure
Scenario
Dose
Used
in
Risk
Assessment,
UF
Special
FQPA
SF*
and
Level
of
Concern
for
Risk
Assessment
Study
and
Toxicological
Effects
Acute
Dietary
(
Females
13­
50
years
of
age)
NOAEL
=
20
mg/
kg/
day
UF
=
100
Acute
RfD
=
0.2
mg/
kg/
day
FQPA
SF
=
1
aPAD
=
acute
RfD
FQPA
SF
=
0.2
mg/
kg/
day
Rabbit
Developmental
Study
(
MRID
42865901)

LOAEL
=
40
mg/
kg/
day
based
on
reduced
number
of
litters
and
skeletal
abnormalities.

Acute
Dietary
(
General
population
including
infants
and
children)
No
appropriate
single
dose
effects
were
identified
for
general
population
Chronic
Dietary
(
All
populations)
NOAEL=
20
mg/
kg/
day
UF
=
100
Chronic
RfD
=
0.2
mg/
kg/
day
FQPA
SF
=
1
cPAD
=
chronic
RfD
FQPA
SF
=
0.2
mg/
kg/
day
Rabbit
Developmental
Study
(
MRID
#:
42865901)
LOAEL
=
40
mg/
kg/
day
Based
on
the
increased
mortality,
reduced
food
consumption,
and
clinical
toxicity;

Mouse
Developmental
Study
(
Report
No.
CTL/
P/
335,
1977
(
cited
in
Report
No.
003810,
1978.
Section
C­
9))
LOAEL
=
40
mg/
kg/
day;
Based
on
reduced
body
weight
gain;
and
Rat
Developmental
Study
(
Report
No.
CTL/
P/
1262,
1976
(
cited
in
Report
No.
003810,
1978.
Section
C­
11))
LOAEL
=
50
mg/
kg/
day
Based
on
reduced
food
consumption.

Short­
Term
Incidental
Oral
(
1­
30
days)
NOAEL=
20
mg/
kg/
day
Residential
LOC
for
MOE
=
100
Occupational
=
NA
See
Chronic
RfD
Intermediate­
Term
Incidental
Oral
(
1­
6
months)
NOAEL=
20
mg/
kg/
day
Residential
LOC
for
MOE
=
100
Occupational
=
NA
See
Chronic
RfD
Exposure
Scenario
Dose
Used
in
Risk
Assessment,
UF
Special
FQPA
SF*
and
Level
of
Concern
for
Risk
Assessment
Study
and
Toxicological
Effects
27
Short­
Term,
Intermediate­
Term,
and
Long
Term
Dermal
Exposure
Dermal
(
or
oral)
study
NOAEL=
150
mg/
kg/
day
(
Relative
dermal
absorption
rate
=
100%)
Residential
LOC
for
MOE
=
100
Occupational
LOC
for
MOE
=
100
80­
Week
Dermal
Painting
Study
(
MRIDs
00066475
and
00104796)
LOAEL
=
750
mg/
kg/
day
based
on
decreased
body
weight
and
liver
tumors.

Short­
Term
and
Intermediate­

Term
Inhalation
Exposure
No
appropriate
route­
specific
study
was
available.
The
oral
endpoint
of
20
mg/
kg
with
a
Margin
of
Exposure
of
100
(
10x
inter­
species
extrapolation,
10x
intra­
species
variation)
is
used.
An
additional
10x
route­
to­
route
extrapolation
is
used
to
determine
if
a
confirmatory
inhalation
toxicity
study
is
warranted.

Cancer
(
oral,

dermal)
The
HED
Cancer
Assessment
Review
Committee
(
CARC)
classified
PHMB
as
"
Suggestive
Evidence
of
Carcinogenicity,
but
not
sufficient
to
Assess
Human
Carcinogenic
Potential"
by
the
oral
and
dermal
routes.
Quantification
of
human
cancer
risk
is
not
required.

1
UF
=
uncertainty
factor,
FQPA
SF
=
FQPA
safety
factor,
NOAEL
=
no
observed
adverse
effect
level,
LOAEL
=
lowest
observed
adverse
effect
level,
PAD
=
population
adjusted
dose
(
a
=
acute,
c
=
chronic)
RfD
=
reference
dose,
LOC
=
level
of
concern,
MOE
=
margin
of
exposure
