Agency
Response
to
Avecia's
Comments
Regarding
PHMB
HIARC
Reports
September
24,
2004
Case
3122
PC
Code
111801
Jonathan
Chen,
Ph.
D.
Toxicologist
Office
of
Pesticide
Programs
Antimicrobials
Division
U.
S.
Environmental
Protection
Agency
1200
Pennsylvania
Avenue,
NW
Washington,
DC
20460
Page
2
of
6
On
12/
18/
2000
and
01/
25/
2001,
the
Health
Effects
Division's
Hazard
Identification
Assessment
Review
Committee
evaluated
the
toxicology
data
base
of
Poly(
hexamethylenebiguanide)
(
PHMB),
established
the
Reference
Doses
(
RfDs)
and
selected
the
toxicological
endpoints
for
dietary
as
well
as
occupational
exposure
risk
assessments.
On
March
21,
2002
Avecia
made
comments
on
the
first
PHMB
HIARC
report.
To
addressed
concerns,
HIARC
meet
again
After
receiving
the
comments
from
Avecia;
on
01/
30/
2003
and
02/
06/
2003,
to
discussed
the
comments
from
Avecia.
A
second
PHMB
HIARC
report
was
prepared
afterward.
On
March
18,
2004
Avecia
made
comments
on
the
second
HIARC
report.
RASSB
prepared
this
memorandum
to
respond
to
all
the
comments
from
Avecia.

The
Comments
and
Responses
to
the
comments
are
listed
below:

ISSUE
1
­
Dermal
Absorption
Factor
October
21,
2002
Avecia's
Comments:
The
dermal
absorption
factor
for
PHMB
is
estimated
to
be
less
than
1%
(
MRID
45710806)

March
18,
2004
Avecia's
Comments:
The
dermal
absorption
for
PHMB
was
reviewed
in
the
report
titled
"
Dermal
Absorption
Factor
for
PHMB",
MRID
45710806.
This
report
reviews
the
polymeric
nature
of
PHMB,
the
PHMB
absorption,
distribution,
metabolism
and
excretion
data,
and
several
PHMB
in
vitro
dermal
absorption
studies
(
conducted
to
be
OECD
draft
Guidelines).
Taking
the
results
of
these
studies
and
other
studies
referred
to
in
MRID
45710806,
a
factor
of
less
than
1%
dermal
absorption
for
humans
is
considered
to
be
highly
conservative
for
risk
assessment
purposes.

EPA
Response:

The
dermal
absorption
factor
cited
in
HIARC
Report
is
used
in
the
situation
when
route
to
route
extrapolation
is
necessary
for
the
risk
assessment.
It
is
a
relative
factor
when
compare
the
dermal
absorption
vs.
the
absorption
through
oral
routes.
For
PHMB,
there
is
no
acceptable
dermal
absorption
study.

The
studies
submitted
to
the
agency
are
in
vitro
dermal
absorption
studies.
These
studies
are
not
accepted
by
the
agency
because
the
in
vitro
study
protocol
does
not
account
for
the
influence
of
systemic
distribution
and
excretion
kinetics
upon
dermal
absorption.
Although
through
these
studies,
Avecia
is
trying
to
demonstrate
the
absorption
through
dermal
routes
is
low,
the
absorption
of
PHMB
through
oral
route
is
also
low.
Therefore,
in
the
HIARC
report,
it
specifically
emphasized
the
dermal
absorption
factor
of
100%
is
an
oral
equivalent
factor.

ISSUE
2
­
Intermediate
Term
and
Chronic
Reference
Dose
October
21,
2002
Avecia's
Comments:
In
its
4/
18/
01
HIARC
Report,
the
Agency
indicated
that
the
intermediate
term
reference
dose
was
based
on
effects
seen
in
a
26­
week
dog
study
(
MRID
86362).
Because
that
study
was
found
to
have
been
deficient
and
unacceptable
during
the
reregistration
process
under
FIFRA
88
(
reference
Phase
4
response
of
May
29,
1992)
it
is
not
an
acceptable
basis
for
establishment
of
a
reference
dose.
The
Agency's
final
decision
under
Page
3
of
6
Reregistration
Phase
4
was
that
this
study
was
unacceptable
and
that
a
new
study
was
required.
Avecia
accepted
this
decision
and
conducted
a
new
study
to
fulfill
this
data
requirement.
The
new
1­
year
dog
study
(
MRID
43620501)
was
determined
to
be
acceptable
and
to
fulfill
the
data
requirement.
The
NOAEL
in
the
1­
year
dog
study
is
37.5
mg/
kg
bw/
day.
Further
background
on
the
unacceptable
26­
week
dog
study
is
presented
in
the
Toxicological
End
Point
report.
There
are
a
number
of
other
acceptable
studies
which
should
be
considered
for
the
determination
of
an
intermediate
or
chronic
oral
reference
dose
for
PHMB,
based
on
EPA
Guidance,
which
identifies
that
chronic
reference
doses
are
to
be
set
on
the
basis
of
chronic
studies,
if
such
studies
are
available,
and
that
chronic
studies
can
be
used
for
intermediate
term
reference
dose.
The
lowest
NOAEL
is
36
mg/
kg
bw/
day
for
the
dietary
chronic
toxicity
study
in
rats
(
MRID
44059301
&
44042801)
and
should
be
the
basis
for
establishing
an
intermediate
and
chronic
oral
reference
dose
for
PHMB.

March
18,
2004
Avecia's
Comments:
Avecia's
letter
of
October
21,
2003
and
the
report
titled
"
Selection
of
Toxicological
End
Points
for
Determination
of
Reference
Dose
Values
for
PHMB",
MRID
45789601,
state
that
EPA
Guidance
indicated
that
chronic
reference
doses
are
to
be
set
on
the
basis
of
chronic
studies,
if
available,
and
the
chronic
studies
can
be
used
for
an
intermediate
term
reference
dose.
As
pointed
out
in
these
two
documents
(
Avecia's
10/
21/
03
letter
and
MRID
45789601),
there
are
four
separate
PHMB
chronic
studies
(
MRID
43617401,
MRID
44059301,
MRID
44074201,
MRID
43620501).
The
lowest
NOAEL
is
36
mg/
kg/
day
for
the
dietary
chronic
study
in
rats
(
MRID
44059301)
and
Avecia
believes
that
this
should
be
the
basis
for
establishing
an
intermediate
term
or
chronic
oral
reference
dose
for
PHMB.

EPA's
Response:

Because
reduce
body
weight,
reduce
body
weight
gain
are
the
concerns
for
all
the
PHMB
related
studies.
These
effects
begin
at
the
early
stage
of
each
study
and
do
not
get
worse
with
longer
period
time
of
exposure.
Therefore,
the
decision
is
based
not
only
the
duration
of
the
study,
but
also
the
types
of
effects
seen
in
all
studies.

ISSUE
3
­
PHMB
Dermal
Sensitization
October
21,
2002
Avecia's
Comments:
The
4/
18/
01
HIARC
report
raised
the
issue
of
dermal
sensitization
and
Avecia
believes
it
is
important
to
review
the
dermal
sensitization
potential
of
PHMB
at
this
time.
There
have
been
dermal
irritation
and
dermal
sensitization
studies
in
animals
and
humans
and
these
are
on
file
at
EPA.
These
studies
are
reviewed
in
the
report
titled
"
Dermal
Sensitization
Potential
of
PHMB",
being
submitted
herewith.
Additionally,
a
report
titled
"
Polyhexamethylene
biguanide
Cosmocil
CQ:
Skin
Irritation
Study
in
Humans"
is
also
being
submitted
at
this
time.
The
sensitization
studies
are
reviewed
in
the
former
report.
PHMB
has
been
shown
to
be
a
dermal
irritant
in
studies
with
humans
and
animals.
In
addition,
the
dermal
sensitization
potential
of
PHMB
has
been
evaluated
in
guinea
pigs
and
humans.
The
overall
assessment
of
the
sensitization
potential
of
PHMB
is
confounded
since
PHMB
is
a
dermal
irritant
and,
in
many
cases,
it
is
difficult
to
separate
dermal
sensitization
from
dermal
irritation
responses.
The
dermal
sensitization
review
report
presents
the
results
for
dermal
irritation
and
sensitization
studies
with
human
subjects
to
facilitate
the
evaluation
of
the
dermal
sensitization
potential
of
PHMB
in
humans.
This
Page
4
of
6
review
concluded
that
the
threshold
for
dermal
irritation
in
human
subjects
is
at
least
1.0%
PHMB.
Overall
results
of
relevant
dermal
sensitization
studies
with
humans
show
that
PHMB
is
not
a
dermal
sensitizer
and
that
PHMB
should
not
be
considered
a
human
sensitizer
under
actual
or
proposed
conditions
for
use.

March
18,
2004
Avecia's
Comments:
The
April
9,
2003
HIARC
report
states
that
"
PHMB
is
a
moderate
skin
sensitization
agent
in
guinea
pig
study
(
MRID#
00160084)'.
This
citation
is
incorrect.
MRID
#
00160084
is
not
a
PHMB
study,
but
a
study
titled
"
Dermal
Sensitization
(
with
HS­
Sanitizing
Carpet
Shampoo).
The
subject
active
ingredient
in
this
study
was
alkyl
benzyl
ammonium
chloride,
not
PHMB.

Avecia's
letter
of
October
21,2003,
in
response
to
the
first
PHMB
HIARC
report,
reviewed
PHMB's
potential
for
human
sensitization,
and
referred
to
the
report,
"
Dermal
Sensitization
Potential
of
Polyhexamethylene
Biguanide
(
PHMB)"
MRID45789602.
These
two
documents
point
out
that
1981
PHMB
dermal
sensitization
study
in
humans
(
MRID127871)
was
confounded
by
the
fact
that
induction
does
was
significantly
irritating
to
test
subjects.
Guideline
for
human
testing
(
OECD,
1997)
indicate
that
any
skin
irritation
is
sufficient
grounds
to
terminate
treatment
for
exposed
individuals
(
MRID45789602).
Therefore,
MRID
127871
should
be
disregarded
when
evaluating
the
human
skin
sensitization
potential
for
PHMB.
MRID
45789602
points
to
other
human
skin
sensitization
studies
that
are
in
EPA's
files
and
concluded
that
"
overall
results
of
relevant
dermal
sensitization
studies
with
humans
show
that
PHMB
is
not
a
dermal
sensitizer".

EPA's
Response:

The
correct
MRID
for
the
guinea
dermal
sensitization
studies
is
42674201.
In
the
study
moderate
dermal
sensitization
was
observed
in
response
to
dermal
application
of
20.2%
PHMB
to
female
guinea
pigs.

There
are
two
PHMB
human
skin
sensitization
studies
been
submitted
to
the
agency:

1.
Smith,
I.
1981.
Human
Sensitiztion
Testing
of
Vantocil
IB.
Prepared
by
Ian
Smith
Consultancy,
Longniddry,
Edinburgh,
EM32
OLH.
ISC
Project
No.
0018.
[
MRID
00127871].
Unpublished
Report.

2.
Kaidbey,
K.
1995.
An
Assessment
of
the
Contact
Sensitizating
Potential
of
Cosmocil
CQ
(#
S2082001)
by
means
of
the
maximization
assay
in
Humans.
Ivy
Laboratories
(
KGL,
Inc.)
3401
Market
Street,
Suite
226
&
232.
Philadelphia,
PA
19104­
3355.
Project
ID:#
KS950101.
[
MRID45187705].
Unpublished
Report.

A
total
of
209
volunteers
commenced
the
1981
study,
a
total
of
191
subjects
completed
the
human
repeated
insult
patch
study,
according
to
the
study
protocol,
which
involved
induction
of
PHMB
testing
material
at
2%
(
v/
v)
with
challenge
applications
of
six­
week
applications
at
both
this
and
lower
concentrations.
The
conclusion
of
the
study
is
that
PHMB
when
applied
under
patch
conditions
on
human
volunteers
at
level
of
2%
v/
v
can
induce
skin
sensitization.
In
the
elicitation
phase,
at
concentration
as
0.1%
v/
v
can
elicitate
the
skin
sensitization.
The
researcher
discussed
the
irritation
issue
in
the
report.
Page
5
of
6
It
was
mentioned
that
low
level
of
irritation
was
observed
in
the
subjects
applied
at
2%
showed
that
it
is
not
capable
of
causing
primary
irritation
reaction.
The
Agency
considers
PHMB
is
a
dermal
sensitization
agent
is
based
on
the
response
of
subjects
at
0.1­
0.2%
v/
v
at
the
elicitation
phase
of
the
study.

There
are
27
healthy
normal
adult
volunteers
are
involved
in
the
1995
study.
None
of
the
subjects
had
a
medical
or
dermatological
illness
and
none
were
sensitive
to
sunlight
or
to
topical
preparations
and/
or
cosmetics.
One
subject
was
dropped
from
the
study
during
the
induction
phase
for
lack
of
compliance,
while
another
withdraws
voluntarily
for
personal
reasons.
The
study
was
composed
of
two
phases:
(
1)
an
induction
phase,
and
(
2)
a
challenge
phase.
In
the
induction
phase,
the
site
of
application
was
pretreated
with
0.25%
aqueous
sodium
sulfate
(
SLS)
for
a
period
of
24
hours.
After
pretreatment,
a
1.0%
(
v/
v)
PHMB
in
water
was
applied
to
the
upper
outer
arm,
volar
part
of
forearm
or
the
back
of
each
subject
for
either
48
hours
(
or
72
hours
when
placed
over
a
weekend).
A
total
of
5
induction
exposure
sequences
(
24
hour
SLS
pretreatment
followed
by
48
hours
of
test
material)
was
applied
to
each
subject.
There
are
no
adverse
effects
happened
at
any
of
subjects.
Therefore,
the
induction
phase
indicate
that
these
individuals
are
not
been
induced
with
the
1.0
%
v/
v
of
PHMB
solution.
After
10
day
resting
period,
in
the
induction
phase,
the
researcher
continue
to
challenge
these
not
been
induced
subjects
to
1.0%
and
0.2%
to
new
skin
on
the
opposite
arm
for
48
hours.
There
is
no
adverse
effects
or
unanticipated
reactions
were
encountered
in
any
of
the
panelists.
It
is
agreed
that
any
skin
irritation
is
sufficient
grounds
to
terminate
treatment
for
exposed
individuals.
However,
in
the
study,
none
of
the
subjects
reached
a
state
of
any
signs
of
irritation
in
the
induction
phase
of
the
study.
Therefore,
with
limited
number
of
individual
involved
in
the
study
and
inadequate
dosing
in
the
induction
phase,
the
agency
consider
the
Kaidbey
(
1995)
study
is
inadequate
to
assess
the
dermal
sensitization
potential
of
PHMB.

ISSUE
4
­
PHMB
Acute
Toxicity
Avecia's
Comments:
Avecia
believes
that
there
are
inaccuracies
in
the
PHMB
acute
toxicity
data
table
listed
in
the
4/
18/
01
HIARC
report.
Some
of
the
studies
listed
were
repeated
and
replaced
by
other
studies.
The
studies
that
should
be
listed
are
those
that
were
submitted/
cited
for
reregistration
and
have
been
found
to
be
at
least
tentatively
acceptable,
or
determined
to
be
accepted
for
other
regulatory
actions.
Also,
the
MRID
listed
in
the
table
as
MRID
150084
is
for
an
efficacy
study
on
a
quaternary
ammonium
end­
use
product
submitted
by
Lonza.
A
table
outlining
PHMB
acute
toxicity
data
on
20%
active
ingredient
products
is
attached.
This
table
lists
MRID
numbers
of
acute
toxicity
studies
submitted
or
cited
at
reregistration
or
submitted
to
EPA
and
found
to
be
acceptable
under
other
regulatory
actions.
Page
6
of
6
EPA's
Response:

Following
table
will
be
used
for
PHMB
related
risk
assessment.

Table:
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
