Document ID: EPA-HQ-OPP-2004-0305-0036
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2006-03-22T05:00Z

1
PHMB
­
2nd
Report
of
the
Hazard
Identification
Assessment
Review
Committee
TXR
NO.
0051756
April
9,
2003
Case
3122
PC
Code
111801
Office
of
Pesticide
Programs
Health
Effects
Division
U.
S.
Environmental
Protection
Agency
1200
Pennsylvania
Avenue,
NW
Washington,
DC
20460
2
Committee
Members
in
Attendance
01/
30/
2003
Members
present
were:
J.
Rowland,
E.
Doyle,
B.
Tarplee,
A.
Asaad,
W.
Burnam,
D.
Nixon,
,
J.
Chen,
J.
Liccione,
S.
Markris,
E.
Mendez,
P.
V.
Shah,
and
W.
Dystra.
02/
04/
2003
Members
present
were:
J.
Rowland,
E.
Doyle,
B.
Tarplee,
A.
Asaad,
W.
Burnam,
P.
Hurley,
,
J.
Chen,
J.
Liccione,
S.
Markris,
E.
Mendez,
P.
V.
Shah,
and
W.
Dystra.

Also
in
attendance
were:
Tim
McMahon
of
the
Antimicrobial
Division.

Data
Evaluation
/
Report
Presentation
Jonathan
Chen
Toxicologist
Antimicrobial
Division...
3
INTRODUCTION
In
the
two
meetings
held
on
December
18,
2000
and
January
25,
2001,
the
Health
Effects
Division
(
HED)
Hazard
Identification
Assessment
Review
Committee
(
HIARC)
reviewed
the
recommendations
of
the
toxicology
reviewer
for
PHMB
with
regard
to
the
acute
and
chronic
Reference
Doses
(
RfDs)
and
the
toxicological
endpoint
selection
for
occupational/
residential
exposure
risk
assessments.
The
potential
for
increased
susceptibility
of
infants
and
children
from
exposure
to
PHMB
was
also
evaluated
as
required
by
the
Food
Quality
Protection
Act
(
FQPA)
of
1996.
On
01/
30/
2003
and
02/
06/
2003,
HIARC
reassessed
toxicological
endpoints
for
RfDs,
the
intermediate­
incidental
oral
exposure
and
long­
term
dermal
exposure
scenarios.
In
addition,
the
relative
dermal
absorption
factor
of
PHMB
when
compare
with
oral
exposure
was
also
discussed.

In
this
report,
the
NOAEL/
LOAEL
values
are
denoted
as
the
weight
of
the
technical
grade
of
the
PHMB
actually
used
in
the
study
in
mg/
kg/
day.
However,
for
comparison
purpose,
the
molar
equivalents
of
pure
PHMB
in
mg/
kg/
day
is
also
included
and
is
denoted
in
brackets
"[
]".

I.
FQPA
HAZARD
CONSIDERATIONS
1.
Adequacy
of
the
Data
Base
The
HIARC
concluded
that
the
toxicology
database
for
PHMB
is
complete
for
FQPA
consideration.

2.
Neurotoxicity
No
neurotoxic
effects
were
seen
in
any
of
the
submitted
studies.
The
decreased
activity,
stiff/
splayed
gait
and
slight
tremors
seen
in
one
female
dog
in
the
chronic
dog
toxicity
study
(
MRID
#
43620501)
can
be
attributed,
not
to
neurotoxicity,
but
rather
to
the
general
health
conditions
of
the
animals:
decreased
body
weight,
peeling
of
the
skin
on
the
pads
of
the
paws,
staining
of
paws
and
hocks,
forelimb,
hindlimb
and
forepaw
abrasions,
scarbs,
and
sores,
and
elevated
plasma
alanine
transminase
and
aspartate
transferase
activities
were
also
evident
in
this
dog.
The
HIARC
concluded
that
there
is
not
a
concern
for
neurotoxicity
resulting
from
exposure
to
PHMB.

3.
Developmental
Toxicity
Study
Conclusions
There
are
three
developmental
toxicity
studies.
These
three
studies
are
summarized
below.

MRID
#:
42865901
In
the
rabbit
developmental
study
(
MRID
#:
42865901),
administration
of
PHMB
technical
(
20.2%
a.
i.)
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.
There
are
6
rabbits
died
in
the
40
mg/
kg/
day
group.
The
incidence
of
several
clinical
signs
appeared
in
increased
in
the
40
mg/
kg/
day
dose
group,
and
included
coldness
(
6/
20
vs.
0/
20
in
control),
few
feces
(
16/
20
vs.
7/
20
in
controls),
no
feces
(
6/
20
vs.
0/
20
in
controls),
thin
appearance
(
6/
20
vs.
0/
20
in
controls)
and
4
subdued
behavior
(
3/
20
vs.
1/
20
in
control).
Based
on
the
increased
mortality;
reduced
food
consumption;
clinical
toxicity,
the
Maternal
LOAEL=
40
mg/
kg/
day.
The
maternal
toxicity
NOAEL
=
20
mg/
kg/
day.

There
was
evidence
of
possible
developmental
toxicity
of
PHMB
at
40
mg/
kg/
day,
in
the
form
of
reduced
number
of
litters
and
skeletal
abnormalities
(
non­
ossified
5th
sternebrae,
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
litter
with
fused
3rd
and
4th
sternebrae
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
=
20
mg/
kg/
day,
based
on
reduced
number
of
litters,
and
skeletal
abnormalities,
the
Developmental
toxicity
LOAEL
=
40
mg/
kg/
day.
The
developmental
effects
happened
at
a
dose
causing
severe
maternal
toxic
effects,
six
out
of
20
animal
died
in
the
group
indicating
no
quantitative
/
qualitative
evidence
of
increased
susceptibility
of
developmental
effects
in
this
study.
(
Note:
This
study
start
the
dosing
at
GD
8
which
is
different
from
the
guideline
specification
study
should
start
at
GD
6).

Report
No.
CTL/
P/
335,
1977
(
cited
in
Report
No.
003810,
1978.
Section
C­
9)

In
the
mice
developmental
study,
groups
of
at
least
21
pregnant
Alderley
strain
pregnant
mice
were
dose
orally
by
gavage
with
0,
10,
20
or
40
mg/
kg
of
20%
PHMB
at
gestation
days
(
GD)
6
through
15.
On
GD
18,
the
animals
were
killed
by
cervical
dislocation.
The
mean
maternal
body
weight
was
similar
in
the
control,
10
mg/
kg
and
20
mg/
kg
groups.
Slight
but
not
significant
reduced
body
weight
gain
was
noticed
in
the
40
mg/
kg
group.
Food
consumption
was
similar
for
all
groups.
Marginal
reduction
of
ossification
appears
to
occur
at
each
of
the
treatment
level
(
10,20
and
40
mg/
kg).
There
are
no
clear
teratogenic
effects
in
the
treatment
groups.

Report
No.
CTL/
P/
1262,
1976
(
cited
in
Report
No.
003810,
1978.
Section
C­
11)

In
the
rat
developmental
toxicity
study,
groups
of
at
least
20
pregnant
Alderley
Park
female
rats
were
fed
diets
containing
0,
200,
1000
or
2000
ppm
(
0,
10,
50
or
100
mg/
kg/
day)
of
20%
aqueous
solution
of
PHMB
throughout
gestation.
On
gestation
day
20,
animals
were
killed
by
cervical
dislocation.
Mean
maternal
body
weight
and
food
consumption
were
reduced
significantly
in
animals
receiving
50
or
100
mg/
kg
PHMB
(
20%
a.
i.).
Maternal
microscopic
findings
revealed
an
enlarged
and
hemorrhagic
thymus
in
one
female
which
had
received
100
mg/
kg/
day
20%
PHMB.
Based
on
the
reduced
body
weight
and
reduced
food
consumption,
the
Maternal
LOAEL=
50
mg/
kg/
day.
The
maternal
toxicity
NOAEL
=
10
mg/
kg/
day.
5
There
was
no
increase
in
late
resorptions
in
any
group.
The
fetal
weight
and
litter
weight
was
not
reduced
in
the
PHMB
treated
groups.
No
adverse
effects
in
ossification
were
seen
in
the
fetuses
from
the
PHMB
treated
animals.
The
fetuses
from
the
100
mg/
kg/
day
group
showed
a
significant
increase
in
extra
ribs.
Based
on
the
increased
increased
incidence
of
extra
ribs
in
fetuses,
the
developmental
toxicity
LOAEL
=
100
mg/
kg/
day.
The
developmental
toxicity
NOAEL
=
50
mg/
kg/
day.

4.
Reproductive
Toxicity
Study
Conclusions
In
a
rat
multigeneration
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
technical
(
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
F
0
males;
25.3,
77.0,
and
258.2
mg/
kg/
day
for
F
0
females;
23.9,
71.3,
and
249.3
mg/
kg/
day
for
F
1
males;
and
26.1,
79.2,
270.5
mg/
kg/
day
for
F
0
females).
The
rats
in
each
generation
received
test
diets
continuously
until
termination.
Systemic
toxicity
was
observed
at
the
2000
ppm
dose
level
in
the
F
0
generation
as
indicated
by
a
decrease
in
group
mean
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
F
0
generation
males.
There
were
no
corresponding
effects
in
the
F
1
parental
generation
except
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
=
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
=
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
mg/
kg/
day
[
F1
females]
)
based
on
decreased
body
weight
and
food
efficiency
in
F0
males
and
females,
and
decreased
epididymis
and
kidney
weight
in
F0
males.
The
reproductive
toxicity
NOAEL
=
2000
ppm;
and
the
reproductive
Toxicity
LOAEL
>
2000
ppm.

5.
Additional
Information
from
Literature
Sources
None.

6.
Pre­
and/
or
Postnatal
Toxicity
A.
Determination
of
Susceptibility
There
is
no
quantitative
/
qualitative
evidence
of
increased
susceptibility
of
rabbit,
mice
or
rat
fetuses
to
in
utero
exposure
in
developmental
studies.
There
is
no
quantitative
/
qualitative
evidence
of
increased
susceptibility
in
multi­
generation
reproduction
study
in
rats.

B.
Degree
of
Concern
Analysis
and
Residual
Uncertainties
The
HIARC
concluded
that
there
are
no
concerns
or
residual
uncertainty
for
pre
6
and/
or
post­
natal
toxicity.

C.
Special
FQPA
Safety
Factor(
s):
The
HIARC
concluded
that
no
special
FQPA
safety
factor
is
required
(
1X)
for
PHMB.

The
Special
FQPA
Safety
Factor
recommended
by
the
HIARC
assumes
that
the
exposure
databases
(
dietary
food,
drinking
water,
and
residential)
are
complete
and
that
the
risk
assessment
for
each
potential
exposure
scenario
includes
all
metabolites
and/
or
degradates
of
concern
and
does
not
underestimate
the
potential
risk
for
infants
and
children.

7.
Recommendation
for
a
Developmental
Neurotoxicity
Study
The
HIARC
concluded
that
there
is
no
concern
for
developmental
neurotoxicity
resulting
from
exposure
to
PHMB.
Because
there
is
no
evidence
PHMB
will
induce
neurotoxic
effects.
In
addition,
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
exposed
to
adults
in
the
two­
generation
reproductive
study.
Based
on
the
weight
of
evidence
presented,
the
HIARC
concluded
that
a
developmental
neurotoxicity
study
is
not
required
for
PHMB.

II.
HAZARD
IDENTIFICATION
1.
Acute
Reference
Dose
(
aRfD)
Subpopulation
Females
13
­
50
Study
Selected:
Developmental
Toxicity
­
Rabbit
§
83­
3
MRID
No.:
42865901
Executive
Summary:
Administration
of
PHMB
technical
to
pregnant
female
New
Zealand
White
rabbits
resulted
in
maternal
toxicity
at
40
mg/
kg/
day
in
the
form
of
increased
mortality
and
clinical
toxicity.
There
was
evidence
of
possible
developmental
toxicity
of
PHMB
at
40
mg/
kg/
day,
in
the
form
of
reduced
number
of
litters
and
skeletal
abnormalities
(
non­
ossified
5th
sternebrae,
fused
3rd,
4th,
and
5th
sternebrae).
The
Maternal
NOAEL
=
20
mg/
kg/
day
and
the
Maternal
LOAEL=
40
mg/
kg/
day
(
increased
mortality;
reduced
food
consumption;
and
clinical
toxicity).
The
Developmental
toxicity
NOAEL
=
20
mg/
kg/
day
and
the
Developmental
toxicity
LOAEL
=
40
mg/
kg/
day(
reduced
number
of
litters
and
skeletal
abnormalities).

Dose
and
Endpoint
for
Establishing
RfD:
The
Developmental
toxicity
NOAEL
=
20
[
4]
mg/
kg/
day
based
on
reduced
number
of
litters
and
skeletal
abnormalities
at
40
[
8]
mg/
kg/
day
(
LOAEL).

Uncertainty
Factor
(
UF):
100X
(
10X
for
intraspecies
extrapolation;
and
10X
for
interspecies
extrapolation)
7
Acute
RfD
=
20
mg
/
kg
/
day
(
NOAEL)

100
(
UF)
0.2
mg
/
kg
/
day
=

Comments
about
Study/
Endpoint/
Uncertainty
Factor:
The
developmental
endpoint
is
presumed
to
occur
after
a
single
exposure.
Since
the
effect
resulted
from
in
utero
exposure,
it
is
applicable
for
risk
assessment
for
female
13­
50
subpopulation
group
only.

2.
Acute
Reference
Dose
(
aRfD)
General
Population
Including
Infants
and
Children
No
appropriate
endpoint
attributable
to
a
single
dose
was
identified
for
general
population
subgroup.
The
maternal
toxicity
observed
in
the
rabbit
study
is
not
appropriate
since
the
effects
are
not
attributable
to
a
single
exposure
(
dose).
Other
oral
studies
did
not
indicate
an
endpoint
attributable
to
a
single
dose.

3.
Chronic
Reference
Dose
(
cRfD)

Study
Selected:
Three
studies
are
considered
co­
critical
in
selecting
the
chronic
reference
dose
(
RfD):

(
1).
Rabbit
Developmental
Study
(
MRID
#:
42865901);
(
2).
Mouse
Developmental
Study
(
Report
No.
CTL/
P/
335,
1977
(
cited
in
Report
No.
003810,
1978.
Section
C­
9));
and
(
3).
Rat
Developmental
Study
(
Report
No.
CTL/
P/
1262,
1976
(
cited
in
Report
No.
003810,
1978.
Section
C­
11)).

Executive
Summary:

(
1).
Rabbit
developmental
study
(
MRID
#:
42865901)

In
the
rabbit
developmental
study
(
MRID
#:
42865901),
administration
of
PHMB
technical
(
20.2%
a.
i.)
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.
There
are
6
rabbits
died
in
the
40
mg/
kg/
day
group.
The
incidence
of
several
clinical
signs
appeared
in
increased
in
the
40mg/
kg/
day
dose
group,
and
included
coldness
(
6/
20
vs.
0/
20
in
control),
few
feces
(
16/
20
vs.
7/
20
in
controls),
no
feces
(
6/
20
vs.
0/
20
in
controls),
thin
appearance
(
6/
20
vs.
0/
20
in
controls)
and
subdued
behavior
(
3/
20
vs.
1/
20
in
control).
Based
on
the
increased
mortality;
reduced
food
consumption;
clinical
toxicity,
the
Maternal
LOAEL=
40
mg/
kg/
day.
The
maternal
toxicity
NOAEL
=
20
mg/
kg/
day.
8
There
was
evidence
of
possible
developmental
toxicity
of
PHMB
at
40
mg/
kg/
day,
in
the
form
of
reduced
number
of
litters
and
skeletal
abnormalities.
The
developmental
toxicity
NOAEL
=
20
mg/
kg/
day,
based
on
reduced
number
of
litters,
and
skeletal
abnormalities,
the
Developmental
toxicity
LOAEL
=
40
mg/
kg/
day.

(
2)
.
Mouse
Developmental
Study
(
Report
No.
CTL/
P/
335,
1977
(
cited
in
Report
No.
003810,
1978.
Section
C­
9))

In
the
mice
developmental
study,
groups
of
at
least
21
pregnant
Alderley
strain
pregnant
mice
were
doses
orally
by
gabage
with
0,
10,
20
or
40
mg/
kg
of
20%
PHMB
at
gestation
days
(
GD)
6
through
15.
On
GD
18,
the
animals
were
killed
by
cervical
dislocation.
The
mean
maternal
body
weight
was
similar
in
the
control,
10
mg/
kg
and
20
mg/
kg
groups.
Slight
but
not
significant
reduced
body
weight
gain
was
noticed
in
the
40
mg/
kg
groups.
Food
consumption
was
similar
for
all
groups.
Based
on
the
slight
reduced
body
weight
gain,
the
Maternal
LOAEL=
40
mg/
kg/
day.
The
maternal
toxicity
NOAEL
=
20
mg/
kg/
day.

(
3).
Rat
Developmental
Study
(
Report
No.
CTL/
P/
1262,
1976
(
cited
in
Report
No.
003810,
1978.
Section
C­
11))

In
the
rat
developmental
toxicity
study,
groups
of
at
least
20
pregnant
Aderley
Park
female
rats
were
fed
diets
containing
0,
200,
1000
or
2000
ppm
(
0,
10,
50
or
100
mg/
kg/
day)
of
20%
aqueous
solution
of
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
50
or
100
mg/
kg
PHMB
(
20%
a.
i.).
Maternal
microscopic
findings
revealed
an
enlarged
and
hemorrhagic
thymus
in
one
female
which
had
received
100
mg/
kg/
day
20%
PHMB.
Based
on
the
reduced
body
weight
and
reduced
food
consumption,
the
Maternal
LOAEL=
50
mg/
kg/
day.
The
maternal
toxicity
NOAEL
=
10
mg/
kg/
day.

Dose
and
Endpoint
for
Establishing
RfD:
The
Maternal
toxicity
NOAEL
=
20
[
4]
mg/
kg/
day
(
based
on
th
increased
mortality;
reduced
food
consumption;
clinical
toxicity
in
the
rabbit
developmental
toxicity;
reduced
body
weight
gain
in
the
mouse
developmental
toxicity,
and
the
reduced
body
weight
and
reduced
food
consumption
in
the
rat
developmental
toxicity.

Uncertainty
Factor(
s):
100X
(
10X
for
intraspecies
extrapolation;
and
10X
for
interspecies
extrapolation)
9
Chronic
RfD
=
20
mg
/
kg
/
day
(
NOAEL)

100
(
UF)
0.2
mg
/
kg
/
day
=

Comments
about
Study/
Endpoint/
UF:
The
HIARC
determined
that
an
additional
uncertainty
factor
is
not
required
for
the
used
of
a
short­
term
study
for
deriving
the
RfD
based
on
the
following
factors:
(
i).
A
clear
NOAEL
was
demonstrated
in
each
of
these
studies;
(
ii).
although
reduced
number
of
litters
were
noticed
in
the
rabbit
developmental
study,
similar
effects
and/
or
abortions
were
not
observed
in
the
rat
and
mouse
developmental
studies;
(
iii)
similar
effects
(
reduced
body
weight
and
decreased
body
weight
gain)
were
also
noticed
in
2­
year
mouse
oncogenicity
study
(
MRID
44074201)
and
2­
year
rat
oncogenicity
(
MRID
44059301);
and
(
iv)
there
is
no
evidence
in
the
available
data
to
indicate
that
the
effects
will
increase
in
severity
over
time.

The
HIARC
determine
that
the
26
week
study
in
dogs
is
not
appropriate
for
establishing
regulatory
endpoints
because
the
study
is
unacceptable
and
does
not
meet
the
guideline
requirement.

4.
Short­
Term
Incidental
Oral
Ingestion
Exposure
(
1­
30
days)

Study
Selected:
Three
studies
are
considered
co­
critical:

(
1).
Rabbit
Developmental
Study
(
MRID
#:
42865901);

(
2).
Mouse
Developmental
Study
(
Report
No.
CTL/
P/
335,
1977
(
cited
in
Report
No.
003810,
1978.
Section
C­
9));
and
(
3).
Rat
Developmental
Study
(
Report
No.
CTL/
P/
1262,
1976
(
cited
in
Report
No.
003810,
1978.
Section
C­
11)).

Executive
Summary:
See
chronic
RfD
above.

Dose/
Endpoint
Selected
for
Risk
Assessment:
The
Maternal
toxicity
NOAEL
=
20
mg/
kg/
day
(
based
on
the
increased
mortality;
reduced
food
consumption;
clinical
toxicity
in
the
rabbit
developmental
toxicity;
reduced
body
weight
gain
in
the
mouse
developmental
toxicity,
and
the
reduced
body
weight
and
reduced
food
consumption
in
the
rat
developmental
toxicity)

Comments
about
Study/
Endpoint:
This
endpoint
is
appropriate
for
the
population
(
infant
and
children)
and
duration
of
10
concern.

5.
Intermediate
Term
Incidental
Oral
Ingestion
Exposure
(
1
­
6
months)

Study
Selected:
Three
studies
are
considered
co­
critical:

(
1).
Rabbit
Developmental
Study
(
MRID
#:
42865901);

(
2).
Mouse
Developmental
Study
(
Report
No.
CTL/
P/
335,
1977
(
cited
in
Report
No.
003810,
1978.
Section
C­
9));
and
(
3).
Rat
Developmental
Study
(
Report
No.
CTL/
P/
1262,
1976
(
cited
in
Report
No.
003810,
1978.
Section
C­
11)).

Executive
Summary:
See
chronic
RfD
above.

Dose/
Endpoint
Selected
for
Risk
Assessment:
The
Maternal
toxicity
NOAEL
=
20
mg/
kg/
day
(
based
on
the
increased
mortality;
reduced
food
consumption;
clinical
toxicity
in
the
rabbit
developmental
toxicity;
reduced
body
weight
gain
in
the
mouse
developmental
toxicity,
and
the
reduced
body
weight
and
reduced
food
consumption
in
the
rat
developmental
toxicity)

Comments
about
Study/
Endpoint:
This
does
endpoint
is
appropriate
for
the
population
(
infant
and
children)
and
duration
of
concern.

6.
Dermal
Absorption
Dermal
Absorption
Factor:
There
is
no
acceptable
dermal
absorption
study
for
PHMB
available.
A
dermal
absorption
factor
is
not
required
for
non­
cancer
risk
assessments
since
a
dermal
toxicity
study
was
used
for
dermal
exposure
risk
assessments.
Although
some
evidence
indicates
the
absolute
dermal
absorption
factor
may
be
low
(
MRID
44046301),
the
absorption
of
PHMB
through
oral
route
is
also
low
(
Makromol
Chem.
177,
2591­
2605
cited
in
Report
No.
003810,
1978.
Section
C­
9).
Therefore,
for
potential
cancer
dermal
risk
assessments,
dermal
absorption
factor
of
100%
should
be
applied
(
oral
equivalent)
based
on
the
comparable
results
in
the
oral
and
dermal
toxicity
study
in
mice
and
rats.

7.
Dermal
Exposure:
Short­
Term
(
1­
30
days)
Exposure
Study
Selected:
80­
Weeks
Skin
Painting
Study
11
MRID
No.:
00066475
and
00104796
Executive
Summary:
Four
groups
of
specific
pathogen
free
(
50M
+
50F)
Alderley
Park
Mice
received
dermally
0.3ml
at
doses
of
0
(
solvent
in
ethanol),
0.6mg
(
0.2%
PHMB
in
ethanol),
6.0mg
(
20%
PHMB
in
ethanol)
and
30.0mg
(
10%
PHMB
in
ethanol)
per
day
for
five
days
a
week
for
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
showed
a
poorer
condition,
being
very
thin
throughout
the
experiment.
Death
in
both
males
and
females
in
the
highest
dose
group
were
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
was
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,
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.
There
was
a
significant
increase
in
the
incidence
of
liver
tumors
in
the
highest
treated
group.
Therefore
for
20%
PHMB
solution,
the
NOAEL
=
150
mg/
kg/
day
and
the
LOAEL
=
750
mg/
kg/
day
based
on
increased
mortality,
decreased
body
weight
and
the
liver
tumors.

Dose/
Endpoint
for
Risk
Assessment:
The
NOAEL
of
150
mg/
kg/
day
of
the
20%
PHMB
based
on
increased
mortality,
and
decreased
body
weight
at
750
mg/
kg/
day
(
LOAEL).

Comments
about
Study/
Endpoint:
The
HIARC
selected
this
dose
and
endpoint
because
it
represents
the
appropriate
route
of
concern.
In
addition,
there
is
no
significant
dermal
irritation
at
the
selected
dose.
Although
it
is
a
long
term
study,
the
selected
dose
should
be
protective
for
both
short­
and
intermediate­
term
exposure.

In
addition
the
HIARC
also
recommended
that
concerns
for
dermal
sensitization
should
be
addressed
on
the
label
of
the
final
product
if
dermal
contact
is
the
primary
exposure
concern
for
this
product
or
if
there
is
a
possibility
of
dermal
contact
with
the
final
product.
This
recommendation
is
based
on
the
following
factors:

(
1)
PHMB
is
a
moderate
skin
sensitization
agent
in
guinea
pig
study
(
MRID
#
00160084)
and
(
2)
PHMB
is
demonstrated
to
be
a
human
skin
sensitizer
in
the
1981
dermal
sensitization
study
(
MRID
#
00127871).
12
8.
Dermal
Exposure:
Intermediate­
Term
(
1
­
6
Months)

Study
Selected:
80­
Weeks
Skin
Painting
Study
MRID
No.:
00066475
and
00104796
Executive
Summary:
See
short
term
dermal
above.

Dose/
Endpoint
for
Risk
Assessment:
The
NOAEL
of
150
mg/
kg/
day
of
the
20%
PHMB
based
on
increased
mortality,
decreased
body
weight
and
liver
tumors
at
750
mg/
kg/
day
(
LOAEL).

Comments
about
Study/
Endpoint:
The
HIARC
selected
this
dose
and
endpoint
because
it
is
of
the
appropriate
route
of
concern.
In
addition,
there
is
no
significant
dermal
irritation
at
the
selected
dose.
Although
it
is
a
long
term
study,
the
selected
dose
should
be
protective
for
both
short­
and
intermediate­
term
exposure.

9.
Dermal
Exposure
Long­
Term
(>
6
Months)

Study
Selected:
80­
Weeks
Skin
Painting
Study
MRID
No.:
00066475
and
00104796
Executive
Summary:
See
short
term
dermal
above.

Dose/
Endpoint
for
Risk
Assessment:
The
NOAEL
of
150
mg/
kg/
day
of
the
20%
PHMB
based
on
increased
mortality,
decreased
body
weight
and
liver
tumors
at
750
mg/
kg/
day
(
LOAEL).

Comments
about
Study/
Endpoint:
This
dose,
end
point
and
study
represent
the
appropriate
route
and
duration
for
this
exposure
scenario.

10.
Inhalation
Exposure
(
All
Durations)
No
appropriate
endpoint
was
identified
for
inhalation
exposures.
In
addition,
due
to
low
vapor
pressure,
no
respirable
particles
are
generated
during
manufacture,
handling,
or
storage
of
the
product.
The
end
uses
do
not
involve
spray
applications.
Therefore,
inhalation
exposure
risk
assessment
is
not
required.

11.
Margins
of
Exposure
Summary
of
target
Margins
of
Exposure
(
MOEs)
for
risk
assessment.
13
Route
Duration
Short­
Term
(
1­
30
Days)
Intermediate­
Term
(
1
­
6
Months)
Long­
Term
(>
6
Months)

Occupational
(
Worker)
Exposure
Dermal
100
100
100
Inhalation
N/
A
N/
A
N/
A
Residential
(
Non­
Dietary)
Exposure
Oral
100
100
N/
A
Dermal
100
100
100
Inhalation
N/
A
N/
A
N/
A
Note:
For
Occupational
exposure:
This
is
based
on
the
conventional
uncertainty
factor
of
100X
(
10X
for
intraspecies
extrapolation
and
10X
for
interspecies
variation)

For
Residential
exposure:
This
is
based
on
the
conventional
uncertainty
factor
of
100X
(
10X
for
intraspecies
extrapolation
and
10X
for
interspecies
variation).

12.
Recommendation
for
Aggregate
Exposure
Risk
Assessments
For
short,
intermediate
and
long
terms
risk
assessment,
the
oral
and
dermal
exposure
can
be
aggregate
due
to
the
common
endpoints
(
decrease
body
weight)
were
selected.

III.
CLASSIFICATION
OF
CARCINOGENIC
POTENTIAL
1.
Combined
Chronic
Toxicity/
Carcinogenicity
Study
in
Rats
MRID
No.
44059301
and
44042801
Discussion
of
Tumor
Data
In
a
rat
chronic/
oncogenicity
study
(
MRID
44059301)
male
and
female
Alpk:
APfSD
Wistar
rats
(
64/
sex/
dose)
were
fed
diets
containing
poly(
hexamethylenebiguanide)
hydrochloride
(
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
over
controls
(
p<
0.01)
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
14
significantly
(
p<
0.05)
by
11%.
In
2000
ppm
males,
microscopic
observations
of
liver
hepatocyte
fat
and
spongiosis
were
844
and
22%
over
controls;
corresponding
increases
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
determined
that
there
were
3/
64
incidences
of
hemangiosarcoma
of
the
liver
in
2000
females;
the
benign
hemangioma
was
not
observed.
The
increased
incidence
of
the
hemangiosarcoma
in
females
gave
positive
results
in
trend
analyses
(
p<
0.05).
A
single
observation
of
benign
hemangioma
was
made
in
each
the
control
and
high
dose
males;
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
determined
that
there
were
2/
64
incidences
of
the
hemangioma
and
1/
64
of
the
hemangiosarcoma
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
(
§
83­
5)
and
satisfies
the
guideline
requirements
for
a
chronic/
oncogenicity
study
in
rats.

Adequacy
of
the
Dose
Levels
Tested:
The
dose
levels
tested
were
judged
to
be
adequate
since
there
was
evidence
of
carcinogenicity
at
the
highest
dose
tested.

2.
Carcinogenicity
Study
in
Mice
MRID
No.
44074201
Discussion
of
Tumor
Data
In
a
mouse
oncogenicity
study
(
MRID
44074201),
poly(
hexamethylenebiguanide)
hydrochloride
(
PHMB,
20.2%
a.
i.)
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
15
hemoglobin
in
females
(
86%),
hematocrit
in
females
(
86%),
and
RBCs
in
females
(
85%);
decreased
absolute
weight
of
the
liver
in
males
(
915%)
and
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);
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),
increased
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
rectal­
anal
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
(
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
1
in
males
(
23%
treated
vs.
9%
controls)
and
females
(
15%
treated
vs.
8%
controls);
and
increased
incidences
of
non­
neoplastic
microscopic
lesions
including
luminal
dilatation
of
the
gall
bladder
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
rectalanal
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
gallbladder
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.
16
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
and
4,000
ppm
treatment
groups,
the
chronic
LOAEL
in
male
and
female
mice
is
1,200
ppm
(
equivalent
to
167
mg/
kg/
day
and
217
mg/
kg/
day,
respectively).
The
chronic
NOAEL
is
400
ppm
(
equivalent
to
55
mg/
kg/
day
in
males
and
69
mg/
kg/
day
in
females).

Carcinogenic
potential
was
evidenced
by
statistically
significant
(
p<
0.01)
increased
incidence
of
hemangiosarcomas
in
both
sexes
of
mice
in
the
4,000
ppm
treatment
group.
In
males
at
this
treatment
level
20/
55
animals
(
36%)
exhibited
hemangiosarcomas
and
17/
55
(
31%)
females
exhibited
hemangiosarcomas
at
all
sites
vs
6/
55
(
11%)
and
7/
55
(
13%)
at
all
sites
for
respective
controls.
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
death
of
male
and
female
mice
at
4,000
ppm
PHMB.
Treatment­
related
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
treatment­
related
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
at
4,000
ppm
was
considered
adequate
but
not
excessive
in
this
study.
Although
body
weight
gain
was
decreased
up
to
47%
in
males
and
32%
in
females,
mortality
was
not
excessive
at
this
dose.

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

Adequacy
of
the
Dose
Levels
Tested:
The
dose
levels
tested
were
judged
to
be
adequate
since
there
was
evidence
of
carcinogenicity
at
the
highest
dose
tested.

3.
Dermal
Carcinogenicity
Study
in
Mice
MRID
No.
00066475
and
00104796
Discussion
of
Tumor
Data
Four
groups
of
specific
pathogen
free
(
50M
+
50F)
Alderley
Park
Mice
received
dermally
17
0.3ml
at
doses
of
0
(
solvent
in
ethanol),
0.6mg
(
0.2%
PHMB
in
ethanol),
6.0mg
(
20%
PHMB
in
ethanol)
and
30.0mg
(
10%
PHMB
in
ethanol)
per
day
for
five
days
a
week
for
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
showed
a
poorer
condition,
being
very
thin
throughout
the
experiment.
Death
in
both
males
and
females
in
the
highest
dose
group
were
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
was
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,
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.
There
was
a
significant
increase
in
the
incidence
of
liver
tumors
in
the
highest
treated
group.
Therefore
for
20%
PHMB
solution,
the
NOAEL
=
150
mg/
kg/
day
and
the
LOAEL
=
750
mg/
kg/
day
based
on
increased
mortality,
decreased
body
weight
and
the
liver
tumors.

Adequacy
of
the
Dose
Levels
Tested:
The
dose
levels
tested
were
judged
to
be
adequate
since
there
was
evidence
of
carcinogenicity
at
the
highest
dose
tested
following
repeated
dermal
exposure
to
mice.

4.
Classification
of
Carcinogenic
Potential
The
HIARC
recommend
that
the
carcinogenic
potential
of
PHMB
should
be
evaluated
by
the
CARC
due
to
the
evidence
of
carcinogenicity
in
mice
and
rats.

IV.
MUTAGENICITY
In
two
independently
performed
microbial
gene
mutation
assays
(
MRID
No.
41687004),
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
an
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
test
system
in
dimethyl
sulfoxide.
All
strains
responded
in
the
expected
manner
to
the
nonactivated
and
S9­
activated
positive
controls.
There
was,
however,
no
evidence
that
Ventocil
IB
induced
a
mutagenic
response
in
any
strain
at
any
nonactivated
or
S9­
activated
dose.

In
a
mouse
micronucleus
assay
(
MRID
No.
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.
bone
marrow
cells
from
mice
in
the
high­
dose
group
were
examined
for
the
incidence
of
micronucleated
polychromatic
erythrocytes
(
MPEs).
Low­
dose
animals
were
sacrificed
at
24
hours.
Two
18
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.
The
study
is
classified
as
Acceptable
and
satisfies
the
requirements
for
FIFRA
Test
Guideline
84­
2
for
a
micronucleus
assay.

In
two
independently
performed
in
vivo/
in
vitro
unscheduled
DNA
synthesis
(
UDS)
assays
(
MRID
No.
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.
This
study
is
classified
as
Acceptable
and
satisfies
the
guideline
requirement
for
a
UDS
assay
(
84­
4).

In
an
in
vitro
mammalian
cell
cytogenetic
assays
(
MRID
No.
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
+
S9
(
male
donor)
or
at
25,
100
or
250
µ
g/
mL
(
female
donor)
with
S9
activation
for
approximately
2.5
­
3.5
hours.
The
S9
liver
homogenate
was
derived
from
Aroclor
12254
induced
Sprague­
Dawley
rat.
Livers
and
the
test
material
was
delivered
tp
the
test
system
in
physiological
saline.
A
50%
reduction
in
mitotic
index
occurred
at
50
µ
g/
mL
­
S9
(
both
donors)
and
at
100
µ
g/
mL
+
S0
(
male
donor)
or
at
250
µ
g/
mL
+
S9
(
female
donor).
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.
This
study
is
classified
as
Acceptable
and
satisfies
the
guideline
requirement
for
an
in
vitro
cytogenetic
assay.

V.
HAZARD
CHARACTERIZATION
PHMB
technical
(
20%
aqueous
solution)
is
Toxicity
Category
III
for
acute
oral
and
acute
dermal
studies.
There
is
no
acute
inhalation
study.
PHMB
technical
is
a
primary
skin
and
eye
irritant
(
Toxicity
Catagory
I).
PHMB
is
a
dermal
sensitizer.
PHMB
technical
is
negative
for
mutagenic
potential
in
a
battery
of
required
mutagenicity
studies.
The
chronic
rat
and
dog
oral
and
chronic
mouse
dermal
studies
demonstrate
that
the
target
organs
are
the
liver.
Reduced
body
weight
is
the
primary
effects
of
concern
in
all
the
animal
studies.
The
developmental
studies
in
rats
and
rabbits
did
not
demonstrate
any
prenatal
extrasensitivity
There
were
no
developmental
effects
below
the
level
of
maternal
toxicity.
The
determination
of
the
potential
of
carcinogenic
effects
of
PHMB
technical
is
referred
to
Cancer
Assessment
Review
Committee.
(
CARC).

VI.
DATA
GAPS
19
None
VII.
ACUTE
TOXICITY
Acute
Toxicity
of
20%
PHMB
Guideline
No.
Study
Type
MRID
#(
S).
Results
Toxicity
Category
81­
1
Acute
Oral
00030330
LD
50
=
2747mg/
kg
III
81­
2
Acute
Dermal
00065124
LD
50
>
5.0
mg/
kg
III
81­
3
Acute
Inhalation
None
LC
50
=
m/
L
81­
4
Primary
Eye
Irritation
00046789
00065120
Severe
Eye
Irritant
I
81­
5
Primary
Skin
Irritation
00046789
00065120
Severe
dermal
irritant
I
81­
6
Dermal
Sensitization
00150084
Moderate
Sensitization
20
VIII.
SUMMARY
OF
TOXICOLOGY
ENDPOINT
SELECTION
Summary
of
Toxicological
Dose
and
Endpoints
for
20%
PHMB
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
(
MRID42865901)

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
can
be
selected
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
th
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
21
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
decrease
body
weight
and
liver
tumors
Short­
Term,
Intermediate­

Term,
and
Long
Term
Inhalation
Exposure
No
appropriate
endpoint
was
identified
for
inhalation
exposures.
In
addition,
due
to
low
vapor
pressure,
no
respirable
particles
are
generated
during
manufacture,
handling,
or
storage
of
the
product.
The
end
uses
do
not
involve
spray
applications.
Therefore,
inhalation
exposure
risk
assessment
is
not
required.

Cancer
(
oral,

dermal,

inhalation)
The
determination
of
the
potential
of
carcinogenic
effects
of
PHMB
technical
is
referred
to
Cancer
Assessment
Review
Committee.
(
CARC).

UF
=
uncertainty
factor,
FQPA
SF
=
Special
FQPA
safety
factor,
NOAEL
=
no
observed
adverse
effect
level,
LOAEL
=
lowest
observed
adverse
effect
level,
PAD
=
population
adjusted
dose
(
a
=
acute,
c
=
chronic)
RfD
=
reference
dose,
MOE
=
margin
of
exposure,
LOC
=
level
of
concern,
NA
=
Not
Applicable
NOTE:
The
Special
FQPA
Safety
Factor
recommended
by
the
HIARC
assumes
that
the
exposure
databases
(
dietary
food,
drinking
water,
and
residential)
are
complete
and
that
the
risk
assessment
for
each
potential
exposure
scenario
includes
all
metabolites
and/
or
degradates
of
concern
and
does
not
underestimate
the
potential
risk
for
infants
and
children.